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The flavonoid quercetin inhibits thyroid-restricted genes expression and thyroid function
... It is the most abundant flavonoid present in fruits and vegetables, and it is an active ingredient of several herbal remedies such as Ginkgo biloba, Hypericum perforatum (St. John's wort), and Annona squamosa [3,4]. Quercetin has been extensively studied for its antiproliferative, antiviral, anti-inflammatory and antioxidants activities and for its potential effect in cancer and in cardiovascular, inflammatory and infective diseases [5][6][7][8][9][10]. ...
... Based on this, our group performed a series of experiments to evaluate the effects of quercetin on thyroid cell growth and function [4,19]. For this purpose, we used FRTL-5 cells, a non-transformed rat thyroid cell line in continuous culture that represents a reliable model for the study of thyroid cell physiology [19][20][21][22][23][24][25]. ...
... Besides the effect on thyroid growth, quercetin also decreased the expression of the following thyroid-specific genes: sodium/iodide symporter (NIS), thyroglobulin (TG), TPO and TSH receptor (TSHR) [4,19]. The effect was dose-and time-dependent, with a maximal decrease observed with 10 µM after 48 h of treatment ( Figure 3). ...
Quercetin is the most abundant flavonoid present in fruits and vegetables. For its antiproliferative, antiviral, anti-inflammatory and antioxidants activities, it is an active ingredient of several herbal remedies and is available as a nutraceutical. Experimental studies performed in vitro have demonstrated that quercetin inhibits growth and function in normal thyroid cells and may act as a thyroid disruptor. These effects have also been confirmed in vivo using rodent models. Some studies have reported the ability of quercetin to interfere with the metabolism of thyroid hormones, since it inhibits the 5′-deiodinase type 1 (D1) activity in the thyroid, as well as in the liver. Besides the effects on normal thyroid cells, several experiments performed in vitro have shown a potential therapeutic role of quercetin in thyroid cancer. Indeed, quercetin inhibits the growth, the adhesion and the migration of thyroid cancer cells, and it also has redifferentiation properties in some thyroid cancer cell lines. In conclusion, these data suggest that, although its effects can be of benefit in hyperthyroidism and thyroid cancer, caution is required in the use of high doses of quercetin due to its anti-thyroid properties. Further in vivo studies are certainly needed to confirm these hypotheses.
... QT can inhibit thyroid hormones in hyperthyroidisminduced mouse by boosting antioxidant [16]. QT can inhibit thyroid functions; therefore, the repressive influences of QT on thyroid functions should be taken into consideration when applied in therapy [17]. In addition, the low solubility of QT, quercetin nanoparticles (QT-NPs) largely immersed to increase the bioavailability [15,18]. ...
... Group (4) (Hyper): hyperthyroid group. Group (5) (Hyper+QT): hyperthyroid treated with 10 mg/ kg of quercetin for further 2 weeks [17,22]. Group (6) (Hyper+QT-NPs): hyperthyroid treated with 10 mg/kg of quercetin nanoparticles for further 2 weeks [23] as depicted in Fig. 1. ...
... Such a relationship between thyroid hormones and the enzymes of the polyol pathway has been reported in a few studies [2,14]. Further, given the reported limitations of quercetin on thyroid gland function during therapy [17], the present study was assembled to study the possible interaction between polyol enzyme, aldose reductase, and LT4-hyperthyrodism in rat mode. Moreover, study the therapeutic effect of nano-quercetin on hyperthyroidism via inhibition of aldose reductase. ...
The polyol pathway is a primary mechanism for the formation of sorbitol, and its accumulation is a major factor in many diseases’ complications. Importantly, there have previously been some indications that there is a relationship between polyol intermediates and thyroid hormones in hyperthyroidism state. Hence, this study aimed to shed light on the therapeutic impact of nano-quercetin (QT-NPs) on hyperthyroidism via inhibiting the polyol pathway. Besides control groups, hyperthyroidism was triggered in the rats by 100 μg/kg of l-thyroxin and further treated with quercetin (QT) and nano-quercetin (10 mg/kg body weight). Additionally, levels of thyroid hormones (T3 and T4), oxidative markers, and the antioxidant system were monitored. Besides histological investigation of thyroid gland, the level of aldose reductase was estimated by qPCR. The obtained findings indicated an elevation of T3 and T4 which indicated hyperthyroidism. This hyperthyroid state was accompanied by an elevation in oxidative stress and a decline in antioxidant status. Importantly, the expression level of aldose reductase was elevated, as was the level of sorbitol. The treatment with QT and QT-NPs potentially reduced the expression level of aldose reductase and the concentration of sorbitol, indicating the inhibition capability of QT and QT-NPs on the polyol pathway key enzyme. Furthermore, rat groups treated with QT and QT-NPs showed an elevation in the antioxidant system (GSH, GPx) with a notable decline in the oxidative stress marker MDA. Furthermore, histopathological examination of the thyroid tissue of hyperthyroidism group treated with QT-NPs confirms the potential effect of QT-NPs on the thyroid tissue. In conclusion, QT-NPs showed therapeutic superiority over QT in hyperthyroidism treatment through inhibition of aldose reductase, which is the key enzyme in the polyol pathway.
... Indeed, quercetin decreases NIS mRNA expression in thyroid cells at 1 μM (Giuliani et al., 2008) and inhibits TPO activity with a IC 50 of 2.4 μM (Divi and Doerge, 1996). The inhibition of the thyroid iodide uptake as well as that of the expression of the thyroid-specific genes TG, TPO, TSHR is observed at 5 μM with a maximum effect at 10 μM (Giuliani et al., 2008(Giuliani et al., , 2014b. Of relevance is the observation that the anti-thyroid effects of quercetin were also confirmed in vivo. ...
... Of relevance is the observation that the anti-thyroid effects of quercetin were also confirmed in vivo. Indeed, treatment of Sprague-Dawley rat with 50 mg/kg of quercetin by intraperitoneal (i.p.) injection for 14 days resulted in a significant decrease of the radioiodide uptake (Giuliani et al., 2014b). This treatment was chosen since a previous study demonstrated that it is able to give a quercetin plasma concentration in Sprague-Dawley rats that can peak 2.6 μM (Piantelli et al., 2006). ...
... In fact, some studies have reported a discrepancy between the effects caused by quercetin and those caused by rutin, a glycoside of quercetin where the latter is linked to the disaccharide rutinose (Dihal et al., 2006;Gonçalves et al., 2013;Hsieh et al., 2013). Regarding the effects on thyroid, the treatment of Wistar rats with rutin 20 mg/kg of body weight (B.W.) s.c. for 5 days caused an increase of iodide uptake and NIS expression contrary to what was observed in Sprague-Dawley rats treated with quercetin 50 mg/kg/day i.p. for 14 days (Giuliani et al., 2014b). This discrepancy may be related to the different route of administration that can affect the metabolism of the compounds. ...
In the past few decades, there has been a lot of interest in plant constituents for their antioxidant, anti-inflammatory, anti-microbial and anti-proliferative properties. However, concerns have been raised on their potential toxic effects particularly when consumed at high dose. The anti-thyroid effects of some plant constituents have been known for some time. Indeed, epidemiological observations have shown the causal association between staple food based on brassicaceae or soybeans and the development of goiter and/or hypothyroidism. Herein, we review the main plant constituents that interfere with normal thyroid function such as cyanogenic glucosides, polyphenols, phenolic acids, and alkaloids. In detail, we summarize the in vitro and in vivo studies present in the literature, focusing on the compounds that are more abundant in foods or that are available as dietary supplements. We highlight the mechanism of action of these compounds on thyroid cells by giving a particular emphasis to the experimental studies that can be significant for human health. Furthermore, we reveal that the anti-thyroid effects of these plant constituents are clinically evident only when they are consumed in very large amounts or when their ingestion is associated with other conditions that impair thyroid function.
... Quercetin, a flavonoid found in several foods (vegetables, fruit, tea, etc.), may activate the mechanisms involved in the protection against osteoporosis, some cancer types, cardiovascular or respiratory diseases (Boots et al., 2008) through its antioxidant, antitumor, antimicrobial, antifungal, anti-parasite, anti-inflammatory effects (Yang et al., 2020). However, precaution in quercetin administration must be taken in consideration since few studies present its antithyroid effects (goiter development and thyroid hormones altered synthesis) (Dos Santos et al., 2011;Giuliani et al., 2014). ...
... Several authors reported the inhibitory effect of higher doses of quercetin (50 mg/kg/day) after intraperitoneal administration (Giuliani et al., 2014), results that we did not record, perhaps because of the administration route that realized a different bio-distribution of the investigated polyphenol metabolites (Dos Santos et al., 2011). ...
... In recent studies, quercetin seems to reduce the expression of the thyrotropin receptor, TPO and thyroglobulin (Tg) genes [30]. The antithyroid impact of quercetin was further evaluated in vivo: Quercetin was administered (50 mg/kg) to a Sprague-Dawley rat and after 14 days of treatment, radioiodine uptake decreased significantly demonstrating that quercetin may act as a thyroid disruptor [30]. ...
... In recent studies, quercetin seems to reduce the expression of the thyrotropin receptor, TPO and thyroglobulin (Tg) genes [30]. The antithyroid impact of quercetin was further evaluated in vivo: Quercetin was administered (50 mg/kg) to a Sprague-Dawley rat and after 14 days of treatment, radioiodine uptake decreased significantly demonstrating that quercetin may act as a thyroid disruptor [30]. ...
Nutraceuticals are defined as a food, or parts of a food, that provide medical or health benefits, including the prevention of different pathological conditions, and thyroid diseases, or the treatment of them. Nutraceuticals have a place in complementary medicines, being positioned in an area among food, food supplements, and pharmaceuticals. The market of certain nutraceuticals such as thyroid supplements has been growing in the last years. In addition, iodine is a fundamental micronutrient for thyroid function, but also other dietary components can have a key role in clinical thyroidology. Here, we have summarized the in vitro, and in vivo animal studies present in literature, focusing on the commonest nutraceuticals generally encountered in the clinical practice (such as carnitine, flavonoids, melatonin, omega-3, resveratrol, selenium, vitamins, zinc, and inositol), highlighting conflicting results. These experimental studies are expected to improve clinicians’ knowledge about the main supplements being used, in order to clarify the potential risks or side effects and support patients in their use.
... In another study aimed at investigating the effect of aqueous solution of 20% Aloe vera gel on thyroid hormones, it was found that aqueous solution of 20% Aloe vera has a role in reducing thyroid activity [2]. It has also been shown that quercine reduces the expression of the receptor of thyrotropin, thyroid peroxidase, and thyroglobulin genes, and in vivo conditions impair thyroid function [9]. ...
Background: Thyroid gland is one of the important glands of the body that regulates the body's energy metabolism. This gland is shaped like a butterfly and is located in front of the trachea. Considering the increasing prevalence of thyroid gland diseases and the lack of proper treatment of this disease, the present study was conducted to investigate the effect of new healthy and live food supplement from wheat on changes in T3, T4, and TSH hormones in rats. Methods: In this research, a new and green route synthesized healthy and live food supplement. This organic biomaterial was named NBS. The NBS healthy and live food supplement had various. For induction of disease, the lead acetate was used in diet of rats. The mice received the new food supplement for nutrition at therapeutic concentrations of 125, 250 and 500 mg/ kg body weight. Results: According to the results, it can be concluded that food supplement (healthy and live) causes the relative return of T3, T4 and TSH levels to normal. It was determined that the concentration of 500 mg/ kg has the most effective therapeutic effect on the condition of hypothyroidism. Conclusions: The new food supplement (healthy and alive) has suitable therapeutic effect for treating abnormalities of thyroid parameters.
... It is important to take necessary precautions under the guidance of a doctor [45]. On the other hand, potential side effects of que overdose should also be considered, such as nausea, abdominal discomfort, or interference with thyroid function [46]. ...
Objective
This review summarizes the molecular properties, anticancer effects, and bioavailability of quercetin (Que). We discussed its role in preventing and treating gynecologic cancers, assisting in the treatment of drug-resistant cases, and synergizing with other treatments. This review includes an analysis of Que’s impact on breast, ovarian, and cervical cancer.
Mechanism
Gynecologic cancers are a significant cause of cancer-related deaths, leading to low survival rates and a high burden on patients and healthcare systems. They are regarded as a major health problem in women. The use of complementary therapies, such as Que, can contribute to improving patient outcomes and the quality of life. The utilization of medicinal plants as complementary and alternative medicine (CAM) is on the rise worldwide, offering new approaches to cancer treatment. This approach may provide potential treatments for various cancers, including female cancers such as breast, ovarian, and cervical cancer, either alone or in combination with other medications.
Findings in Brief
Among various natural compounds, Que is commonly used as an anti-cancer supplement due to its antioxidant and anti-inflammatory properties. Que is effective in preventing and treating female cancers in a dose- and time-dependent manner, as demonstrated by numerous in vitro and in vivo studies and experiments. However, more clinical studies are required to establish this flavonoid as a therapeutic agent or as part of a drug combination in humans.
Conclusions
Que helps prevent and treat gynecological cancers, reduce drug resistance, and increase the effectiveness of chemical drugs and radiotherapy. It achieves this through its anti-inflammatory, pro-oxidative, anti-proliferative, induction of apoptosis, and cell cycle arrest mechanisms. However, more human studies are needed to accurately determine of the mechanisms of action and the extent of its effectiveness.
... Previous research indicates that, as a thyroid disruptor with anti-thyroid effects, Quercetin downregulates NIS in an in vitro condition and reduces thyroid radioiodide uptake in vivo. The suppression of phospholipase A2 and lipoxygenase pathways was hypothesized to be the molecular pathway by which Quercetin reduced iodide uptake and NIS expression [13,14]. On the other hand, it was discovered that Quercetin increased NIS mRNA levels in a human FTC cells, indicating that Quercetin regulates NIS expression differentially among species. ...
The alternative manner of iodide and glucose uptake found in different types of thyroid cancer, referred to flip-flop. ATC cells indicate low iodide uptake and high glucose uptake, which lack the morphology and genetic characteristics of well-differentiated tumors and become increasingly invasive. Importance placed on the discovery of innovative multi-targeted medicines to suppress the dysregulated signaling in cancer. In this research, we aimed to clarify molecular mechanism of Rutin as a phytomedicine on anaplastic thyroid cancer cell line based on iodide and glucose uptake.
The MTT test was employed to test cell viability. Iodide uptake assay was performed using a spectrophotometric assay to determine iodide uptake in SW1736 cells based on Sandell–Kolthoff reaction. For glucose uptake detection, ‘‘GOD-PAP’’ enzymatic colorimetric assay was applied to measure the direct glucose levels inside of the cells. Determination of NIS, GLUT1 and 3 mRNA expression in SW1736 cells was performed by qRT-PCR. Determination of NIS, GLUT1 and 3 protein levels in SW1736 cells was performed by western blotting.
According to our results, Rutin inhibited the viability of SW1736 cells in a time- and dose-dependent manner. Quantitative Real-time RT-PCR analysis exposed that NIS mRNA levels were increased in Rutin treated group compared to the control group. Accordingly, western blot showed high expression of NIS protein and low expression of GLUT 1 and 3 in Rutin treated SW1736 cell line. Rutin increased iodide uptake and decreased glucose uptake in thyroid cancer cell line SW1736 compared to control group.
Multiple mechanisms point to Rutin’s role as a major stimulator of iodide uptake and inhibitor of glucose uptake, including effects at the mRNA and protein levels for both NIS and GLUTs, respectively. Here in, we described the flip-flop phenomenon as a possible therapeutic target for ATC. Moreover, Rutin is first documented here as a NIS expression inducer capable of restoring cell differentiation in SW1736 cell line. It also be concluded that GLUTs as metabolic targets can be blocked specifically by Rutin for thyroid cancer prevention and treatment.
... In experimental models of hyperthyroidism, it was demonstrated that the administration of quercetin can protect liver functions from oxidative stress [97], and that this effect is mediated by Nrf2 activation and subsequent increases in HO-1 and NQO-1 production [98,99]. Recently, it was observed that quercetin may downregulate the gene expression of thyroid-restricted genes (sodium/iodide symporter, thyroid peroxidase, Tg, and the thyrotropin receptor), indicating that this compound has important inhibitory effects on TH metabolism [100]. However, quercetin might carry a potential toxicity risk if it is administered in excess, since it can inhibit thyroid-cell growth and iodide uptake, thereby negatively interfering with thyroid function. ...
Thyroid hormones (TH) perform a plethora of actions in numerous tissues and induce an overall increase in metabolism, with an augmentation in energy demand and oxygen expenditure. Oxidants are required for normal thyroid-cell proliferation, as well as for the synthesis of the main hormones secreted by the thyroid gland, triiodothyronine (T3) and thyroxine (T4). However, an uncontrolled excess of oxidants can cause oxidative stress, a major trigger in the pathogenesis of a broad spectrum of diseases, including inflammation and cancer. In particular, oxidative stress is implicated in both hypo- and hyper-thyroid diseases. Furthermore, it is important for the TH system to rely on efficient antioxidant defense, to maintain balance, despite sustained tissue exposure to oxidants. One of the main endogenous antioxidant responses is the pathway centered on the nuclear factor erythroid 2-related factor (Nrf2). The aim of the present review is to explore the multiple links between Nrf2-related pathways and various TH-associated conditions. The main aspect of TH signaling is described and the role of Nrf2 in oxidant-antioxidant homeostasis in the TH system is evaluated. Next, the antioxidant function of Nrf2 associated with oxidative stress induced by TH pathological excess is discussed and, subsequently, particular attention is given to the cardioprotective role of TH, which also acts through the mediation of Nrf2. In conclusion, the interaction between Nrf2 and most common natural antioxidant agents in altered states of TH is briefly evaluated.
... A similar study reported that quercetin inhibited tumor growth via induction of apoptosis and activation of DRS, CHOP, and caspase-3 in the human SKOV-3 xenograft model [113]. Other studies have reported quercetin to improve the expression of an endogenous antioxidant enzyme, reduce intracellular ROS levels, suppress ROS-induced injury, and show a proapoptotic effect in human ovarian cancer SKOV-3 and C13 cells [96][97][98][99]. Quercetin arrested the cell cycle, upregulated P-21, and induced down-regulation of DNA-PK, cyclin D1, and phospho-histone H3 via the deactivation of MAPK-ERK pathways, as shown in Fig. (7) [51, 176, 178]. ...
Quercetin is a plant pigment found in many fruits, vegetables, beverages, and other parts of plants, such as leaves, flowers, bark, stems, and roots. The rich sources of quercetin are the dock, watercress, sweet potato, onion, grapes, berries, cherries, and broccoli. Quercetin exhibits various pharmacological activities, such as anticancer, antiviral, anti-inflammatory, and antioxidant. Several studies have reported quercetin as a potential anticancer compound. This review article provides information on the role of quercetin in many types of cancer, such as breast cancer, colon cancer, liver cancer, lung cancer, prostate cancer, bladder cancer, gastric cancer, bone cancer, blood cancer, brain cancer, cervical cancer, head and neck cancer, skin cancer, eye cancer, thyroid cancer, ovarian cancer, kidney cancer, and mesothelioma cancer. The present review emphasizes the anticancer activity of quercetin via different mechanisms, such as induced apoptosis, inhibition of tumor progression, cancer cell cycle arrest via different pathways, decreased proliferation, modification of the tumor microenvironment, etc.
... In addition to their potential to cause ''cabbage'' goiter, GLSs are also known for their antinutritive properties, especially indole glucosinolates [12]. Besides, studies revealed that polyphenols such as chlorogenic acid, quercetin, and rutin are found to be thyroid peroxidase (TPO) inhibitors and are considered as etiological factors for hypothyroidism [13,14]. These chemicals are also reported to be present in M. stenopetala leaves [5,6,15,16]. ...
Moringa stenopetala (M. stenopetala) leaf powder is extensively used as food, for preparation of nutraceuticals and herbal medicines in many developing countries. Glucosinolates and phenolics are known to be important bioactive constituents of these preparations. In this study, a selective and fast RP-HPLC method was developed and validated for simultaneous determination of intact glucosinolates and phenolics in M. stenopetala leaf powders. The developed method was linear with a coefficient of determination (r²) ≥ 0.998, precision ≤ 1.5%, and recovery values close to 100%. The method was also sensitive with detection and quantification limits below 1.5 µg/mL and 5 µg/mL, respectively. Besides the use of external standards, quantitative analysis of multicomponents by a single marker (QAMS) was developed and applied to commercial Moringa samples. The correlation coefficient (r ≥ 0.9993) between the QAMS and the external standard method proved the consistency and the strength of the relationship between the two methods. Rutin was used as single marker for the determination of five bioactive components in M. stenopetala leaf samples. Furthermore, a radar plot was used to differentiate samples collected from different geographical origin. Analysis results of the commercial samples revealed that rutin was found to be the constituent with the highest concentration (varying from 6.6 mg/g to 18.8 mg/g) among the phenolics while glucomoringin (0.2–4.2 mg/g) was the most common glucosinolate.
... The antithyroid effect of quercetin was further assessed in vivo. It was administered (50 mg/kg) to a Sprague-Dawley rat, and after 14 days of treatment, the radioiodine uptake decreased significantly, indicating that quercetin may act as a thyroid disruptor (129,135). Soybean extracts inhibit iodine uptake and increase the protein Restoring the normal secretion of thyroid hormones is important in idiopathic male infertility content of a known autoimmune Tg fragment in rat Fischer thyroid cells. These effects may be responsible for the link between more frequent soy consumption and thyroid disorders such as hypothyroidism, goiter, and autoimmune thyroid disease (135, 137). ...
It is estimated that more and more couples suffer from fertility and pregnancy maintenance disorders. It is associated with impaired androgen secretion, which is influenced by many factors, ranging from genetic to environmental. It is also important to remember that fertility disorders can also result from abnormal anatomy of the reproductive male and female organ (congenital uterine anomalies – septate, unicornuate, bicornuate uterus; acquired defects of the uterus structure – fibroids, polyps, hypertrophy), disturbed hormonal cycle and obstruction of the fallopian tubes resulting from the presence of adhesions due to inflammation, endometriosis, and surgery, abnormal rhythm of menstrual bleeding, the abnormal concentration of hormones. There are many relationships between the endocrine organs, leading to a chain reaction when one of them fails to function properly. Conditions in which the immune system is involved, including infections and autoimmune diseases, also affect fertility. The form of treatment depends on infertility duration and the patient’s age. It includes ovulation stimulation with clomiphene citrate or gonadotropins, metformin use, and weight loss interventions. Since so many different factors affect fertility, it is important to correctly diagnose what is causing the problem and to modify the treatment regimen if necessary. This review describes disturbances in the hormone secretion of individual endocrine organs in the context of fertility and the maintenance of pregnancy.
... Oncological patients with various comorbidities who are being treated with antibiotics, anticoagulants, corticosteroids, cyclosporine, digoxin or those on chemotherapy should not take natural supplements with quercetin unless their doctor agrees [200]. Excessive intake of quercetin can lead to side effects, such as digestive effects: nausea, abdominal discomfort or interfering with thyroid function [201]. ...
Over the past few years, the cancer-related disease has had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment. The drugs used for cancer therapy, have high side effects in addition to the high cost. Subsequently, to reduce these side effects, many studies have suggested the use of natural bioactive compounds. Among these, which have recently attracted the attention of many researchers, quercetin has such properties. Quercetin, a plant flavonoid found in fresh fruits, vegetables and citrus fruits, has anti-cancer properties by inhibiting tumor proliferation, invasion, and tumor metastasis. Several studies have demonstrated the anti-cancer mechanism of quercetin, and these mechanisms are controlled through several signalling pathways within the cancer cell. Pathways involved in this process include apoptotic, p53, NF-κB, MAPK, JAK/STAT, PI3K/AKT, and Wnt/β-catenin pathways. In addition to regulating these pathways, quercetin controls the activity of oncogenic and tumor suppressor ncRNAs. Therefore, in this comprehensive review, we summarized the regulation of these signalling pathways by quercetin. The modulatory role of quercetin in the expression of various miRNAs has also been discussed. Understanding the basic anti-cancer mechanisms of these herbal compounds can help prevent and manage many types of cancer.
... This suggests that the slight activity observed for 4b on inhibition of VEGFR2 phosphorylation manifested itself on the migration of HUVECs while the high decline in tube formation is a contribution from another target. This phenomenon termed polypharmacology [5] has been reported for flavonoids as they can interfere with one or more targets to achieve a certain effect [50][51][52]. As mentioned earlier, flavonoids can interact with numerous angiogenic targets such as EGFR [27,28], VEGFR2 [12,[24][25][26] and MMPs [29][30][31][32], as well as the MAPK/ERK [27], HIF1-α/Akt [34,35] and IL-6/STAT3 [27] pathways. ...
Antiangiogenic agents attenuate tumours’ growth and metastases and are therefore beneficial as an adjuvant or standalone cancer regimen. Drugs with dual antiproliferative and antiangiogenic activities can achieve anticancer efficacy and overcome acquired resistance. In this study, synthetic flavones (5a,b) with reported anticancer activity, and derivatives (4b and 6a), exhibited significant inhibition of endothelial cell tube formation (40–55%, 12 h) at 1 µM, which is comparable to sunitinib (50% inhibition at 1 µM, 48 h). Flavones (4b, 5a,b and 6a) also showed 25–37% reduction in HUVECs migration at 10 µM. In a Western blotting assay, 5a and 5b subdued VEGFR2 phosphorylation by 37% and 57%, respectively, suggesting that VEGFR2 may be their main antiangiogenic target. 5b displayed the best docking fit with VEGFR2 in an in silico study, followed by 5a, emphasizing the importance of the 7-hydroxyl group accompanied by a 4−C=S for activity. Conversely, derivatives with a 4-carbonyl moiety fitted poorly into the target’s binding pocket, suggesting that their antiangiogenic activity depends on a different target. This study provides valuable insight into the Structure Activity Relationships (SAR) and modes of action of halogenated flavones with VEGFR2 and highlights their therapeutic potential as antiangiogenic/anticancer lead compounds.
... In their studies, Verma et al. (2013) demonstrated that high concentrations of flavonoids caused cell necrosis and even the death of mice. Giuliani et al. (2014) showed that excessive and prolonged doses of quercetin inhibited thyroid function. Several studies report the use of Allium cepa to test the toxicity of plant extracts (ANCIA et al., 2016;BEZERRA et al., 2016;ANJOS et al., 2018). ...
Virola sebifera (Aubl.), belonging to the Myristicaceae family, popularly known as mucuíba, and ucuúba, is among the various species with medicinal use found in the Cerrado, has several ethnobotanical uses and medicinal benefits, being applied in folk medicine for the treatment of various illnesses. Based on this, the present study aimed to investigate the chemical composition of Virola sebifera using high performance liquid chromatography and analyze the cytotoxic activity of its leaf extracts. The leaf extracts were prepared using different methodologies: i) 70% ethanol in an ultrasonic bath, originating the crude ultrasonic extract (CEU); ii) 70% ethanol, in a soxhlet apparatus, originating the crude soxhlet extract (CES); and iii) sequential extraction in a soxhlet apparatus, starting with the hexane solvent, followed by methanol and 70% ethanol, originating, respectively, the hexane extract (HE), methanol extract (ME) and ethanol extract (EE). HPLC analyzes showed that extracts from V. sebifera leaves have a diverse matrix of phenolic compounds, including phenolic acids (syringic acid, p-coumaric acid, rosmarinic acid and chlorogenic acid) and flavonoids (morina, quercetin, catechin, hesperidin, naringin and rutin). The in vitro toxic activities were analyzed in CEU, CES, and EE and observed a great inhibition of Allium strain, this suggest an anticarcinogenic activity. The results obtained indicate that V. sebifera has potential antioxidant activity, due to the presence of a diversity of phenolic compounds, thus evidencing its medicinal potential, requiring further studies with the species in order to confirm the results obtained and direct its use safe.
... [35] It should be noted that in vitro studies have demonstrated that quercetin and other flavonoids interfere with thyroid hormone synthesis at multiple steps in the synthetic pathway. [36][37][38][39] The use of quercetin has rarely been associated with hypothyroidism. The clinical impact of this association may be limited to those individuals with pre-existent thyroid disease or those with sub-clinical thyroidism. ...
This brief note introduces the reproduction of medical content, authored by Doctor Paul E. Marik. Dr. Marik is Professor of Medicine and Chief of Pulmonary Medicine and Critical Care at Eastern Virginia Medical School in Norfolk, Virginia (USA). Dr. Marik is an extremely qualified and experienced professional. The reprinting of the material was authorized by Dr. Marik himself on 12/02/2020. This material is relevant in the Brazilian scenario due to standardized procedures for patients infected with the coronavirus. Only 1 of the 5 files kindly provided by the author, in PDF format, was selected and reproduced as received, without any editing. Due to the pandemic's long duration, the Journal editors (who are not medical doctors) have already had the opportunity to monitor the development of the disease in more than one infected person. The type of treatment offered to patients seems to influence the course, duration, and severity of the disease. The treatments described in the materials below appear to be effective and have good results. The editors will refrain from making additional comments on the proposed methods not to influence anyone, restricting themselves to suggesting that they be discussed with the reader's trusted doctor in case of need or doubts. Complete, updated information and also translated into Portuguese are available at . We are grateful to Dr. Marik for his kindness in giving us his time in this troubled period.
... Rutin treatment has been showing to inhibit AMPK phosphorylation and increase iodide uptake in PCCL3 cells, an effect reversed by AMPK activator AICAR (Gonçalves et al., 2018), therefore, AMPK inhibition could possibly be the mechanism by which quercetin increased iodide uptake. Previous studies demonstrate that quercetin acts as a thyroid disruptor with anti-thyroid properties, downregulating NIS in a non-tumoral rat thyroid cell line FRTL-5 and reducing thyroid radioiodide uptake in rats (Giuliani et al., 2008(Giuliani et al., , 2014. On the other hand, quercetin was shown to increase NIS mRNA levels in a human follicular thyroid cancer cell line (FTC-133), thus suggesting a species-specific regulation of NIS expression by quercetin (Kang et al., 2011). ...
Thyroid cancer is the most frequent cancer of the endocrine system. Most patients are treated with thyroidectomy followed by radioiodine therapy. However, in part of the patients, a reduction of the sodium-iodide symporter (NIS) occurs, rendering radioiodine therapy ineffective. Moreover, epithelial–mesenchymal transition (EMT) may occur, leading to more aggressive and invasive features. Herein, we evaluated the effect of the flavonoid quercetin on EMT and NIS expression in BCPAP, a papillary thyroid carcinoma cell line. BCPAP was treated with 100 μM quercetin for 24h and cell viability, apoptosis, EMT markers and NIS were evaluated. Quercetin decreased cell viability by enhancing apoptosis. The flavonoid also reduced matrix metalloproteinase 9 and increased E-cadherin mRNA levels, inhibiting BCPAP adhesion and migration. Additionally, quercetin increased NIS expression and function. Thus, our results suggest that quercetin could be useful as adjuvant in thyroid cancer therapy, inducing apoptosis, reducing invasion and increasing the efficacy of radioiodine therapy.
... administration of various treatments (drugs, supplements) has been shown to lead to significant changes in thyroid structure, which is reflected in parenchymal alterations (Giuliani et al., 2014(Giuliani et al., , 2017Šošić-Jurjević et al., 2014;Miler et al., 2017). Thus, it is of great importance to define and list all the changes in old thyroids, thus far lacking in the literature, to set a clear ground for different experimental designs which would use OA thyroids in their studies. ...
The aim of the present study was to determine and elaborate on all changes in old-aged (OA) versus young-aged (YA) rat thyroids by using
stereological, ultrastructural, hormonal, and gene expression analyses. We used 4- and 24-month-old male Wistar rats in our evaluation,
presenting all changes in comparison with YA rats. Results showed that the thyroid parenchyma was characterized by higher absolute
volumes of the gland, colloid, epithelium, and interstitium by 135, 135, 140, and 142% (p < 0.05) respectively, while the relative volumes
of colloid and glands were unchanged. Ultrastructural analysis revealed less active glands, with smaller amounts of lysosomes, thyroglobulin
(Tg) granules, and microvilli in the luminal colloid. Optical density values for thyroid peroxidase (TPO), Tg, and vascular-endothelial
growth factor immunostaining remained unchanged; however, TPO and Tg exhibited visually stronger expression in small active follicles.
Thyroxine (T4)-Tg, the relative intensity of fluorescence (RIF), serum T4, and the sodium-iodide symporter immunohistochemical and gene
expressions decreased by 20, 40, 29, and 31% (p < 0.05), respectively, in OA thyroids. Pituitary thyroid-stimulating hormone (TSH) RIF
increased by 44% (p < 0.05), but the TSH serum concentration remained unchanged. In conclusion, the obtained results indicate depression
of the thyroid gland synthetic and secretory capacity with advanced age.
... Kabbash and Shoeib (2012) have isolated two new flavonol glycosides from the aerial parts of A. halimus while Clauser et al. (2013) have isolated other four new glycosylated flavonoids along with other known phenolic compounds. Almost all of these molecules, mainly flavonoids glycosides, are known by their anti-hyperthyroid activity since they are able to inhibit the synthesis of thyroid hormones by acting as alternative substrates for the key enzyme in thyroid hormones biosynthesis thyroperoxidase (TPO), and therefore to a rise in TSH levels in male Sprague-Dawley rat treated by 50 mg/ kg quercetin during 14 days (Giuliani et al., 2014;Gonçalves et al., 2017). ...
Traditional medicine is gaining an increasing importance in diseases management. Besides, thyroid disease is one of the common endocrine disorders spreading at high frequency worldwide. The present work is an ethnopharmacological study aiming to identify, document and analyze aromatic and medicinal plants used in Algerian traditional medicines for thyroid disorders management. Semi-structured interviews with 120 herbalists and traditional practitioners and rural dwellers were realized in eleven locations in Algeria throughout field studies achieved from June 2017 to July 2019. Results reveal the use of 63 medicinal plants belonging to 59 genera and 34 families. The most represented botanical families were Lamiaceae, Fabaceae, Apiaceae, Amaranthaceae and Asteraceae. However, the most cited plant species were Atriplex halimus L., Bunium incrassatum (Boiss.) Amo, Nigella sativa L., Aquilaria malaccensis Lam. and Saussurea costus (Falc.) Lipsch. These species are taken alone or in mixtures of two or more ingredients from different origins such as honey, olive oil, and goat milk. Our findings revealed new therapeutic uses of 60 medicinal plants that have not been previously reported for the treatment of thyroid in Algeria. This is the first study documenting the traditional uses based on herbal medicine for thyroid management in Algeria. Our findings are relevant in the search for novel drug discovery. Obviously, it is the time to increase effective scientific studies on mechanisms of action of these medicinal plants in order to validate their popular usages.
... Furthermore, flavonoids show antithyroid and goitrogenic effects, mainly mediated through the inhibition of thyroperoxidase activity, which is critical for the biosynthesis of thyroid hormones (Divi and Doerge 1996;Ferreira et al. 2006;Santos et al. 2011;Giuliani et al. 2014Giuliani et al. , 2017. Additionally, it has been shown that flavonoids decrease thyroid type 1 deiodinase activity and inhibit thyroid hormone metabolism (Ferreira et al. 2002). ...
Schinus terebinthifolia Raddi, Anacardiaceae, is a Brazilian plant species, with anti-inflammatory and healing properties. This plant is popularly used for the treatment of several disorders, including thyroid dysfunctions. However, its influence on thyroid physiology is not fully understood. This study investigated the effects of a S. terebinthifolia leaf methanolic extract on the proliferation, viability, and reactive oxygen species (ROS) level of rat thyroid follicular cells. For this, PCCL3 cells were treated with different concentrations of the extract (1–100 μg/ml) and times of exposure (24, 48, and 72 h). The 30 μg/ml concentration significantly reduced cell viability. Thyrocytes treated with the extract presented altered cell morphologies and evidence of oxidative stress. The 50 μg/ml concentration of the extract elicited a pronounced increase in ROS level. The results demonstrated that S. terebinthifolia leaf is harmful to thyroid cells after exposure to high concentrations for prolonged periods. These potentially harmful effects should be considered when this medicinal plant is used in humans. This observation is particularly relevant to individuals with an increased risk of thyroid dysfunctions.
... Flavonoids are important dietary supplements found abundantly in green tea, red wine, and vegetables and fruits like onions, tomatoes, and apples (Giuliani et al. 2014;Rakers et al. 2014;Wang et al. 2011Wang et al. , 2018. Bioavailability of flavonoids is generally poor as flavonoids exist as glycosides. ...
Food nutrients play a vital role in the existence, sustenance, and evolution of all forms of life including human, and their adequacy largely depends on their chemical type, intake, and bioavailability. While knowledge on the bioavailability of ingested components is essential to estimate the quantity of nutrient that must be supplied to meet the minimum daily requirements, safety and bio–efficacy is critical for nutrient acceptability. Safety limits are imposed by regulatory agencies to restrict and regulate intake of nutrients to avoid possible adverse effects. With increased enforcement of regulations, the food industry is subjected to stringent scrutiny to ensure food quality and safety. Worldwide, viz. FAO/WHO, FDA, CFDA, EFSA and other regulatory agencies, and FSSAI in India aims at protecting the health of the public through strengthening the measures for assurance of food safety. Aspects relating to essential nutrients and their health effects, bioavailability, safety and regulations are discussed in this chapter.
... Giuliani et al. investigated the inhibitory effects of quercetin on thyroid function in vivo through evaluation of radioiodine uptake in the Sprague-Dawley rat, which was significantly decreased after 14 days of quercetin treatment. These data confirm that quercetin can act as a thyroid disruptor, and they suggest that caution is needed in its supplemental and therapeutic use [51]. Amraz-e-Balghami, Deedan-e-Ama, Tahabbuj, Obesity, Hypothyroidism. ...
Hypothyroidism is the most common thyroid disorder, affects women more frequently, and incidence increases with age. The prevalence of hypothyroidism in developed countries is around 4-5%, whereas, in India, it is about 11%. The common symptoms of hypothyroidism in adults are weight gain, fatigue, lethargy, cold intolerance, constipation, change in voice, and dry skin. It can affect all systems of the body. Diagnosis is mainly based on clinical history and laboratory investigations. Untreated hypothyroidism increases morbidity and mortality. In conventional medicine, the treatment of choice is Levothyroxine, whereas in Unani System of Medicine, pharmacotherapy consists of single and compound drugs. Single drugs are selected as per the constitution (Mizaj) of drugs as opposed to the abnormal constitution (Su-e-Mizaj) of disease and its pathology. Some drugs increase the basal metabolic rate whereas some evacuate the morbid material from the body by the action of purgation. The drugs are used either in a single form or as a prescription of more than one drug in the form of decoction (Joshandah), infusion (Kheshandah), or powder (Safoof). This review aims at providing comprehensive information regarding various drugs used in Unani system of medicine that is used in the management of thyroid dysfunction.
... This may be especially important in elderly subjects, as they are high risk individuals who more susceptible to these concerns. Notably, it has been reported that high flavonoids composition can lead to thyroid toxicity and carcinogenesis [267,268]. Moreover, out of the flavonoids studied, resveratrol and kaempferol are inhibitors of human cytochrome P450 1A1 (CYP1A1) [269]. ...
Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.
... As a major member of polyphenols family, flavonoids are the most abundant polyphenolic compounds in human diet [2]. The shared feature of these natural substances is their benzo-γpyrone structure that corresponds to their biological properties [3,4]. Several researches have indicated that these substances exhibit various beneficial effects in several human diseases, such as osteoarthritis (OA), cancer, Alzheimer's diseases (AD) and atherosclerosis [2,[5][6][7]. ...
Background
Based on the anti-inflammatory and anti-oxidant properties of kaempferol and apigenin, we hypothesized that co-injection of these phytochemicals would increase the effectiveness of cell therapy in knee osteoarthritic rats.
Methods
Anterior cruciate ligament transection (ACLT) was used to induce osteoarthritis (OA). Animals were treated by weekly intra-articular injections of kaempferol (10 or 20 μM) and/or isolated MSCs from synovial membrane (SMMSCs) (3 × 106 cells), a mixture of apigenin (0.1 μM) and kaempferol alone or SMMSCs, hyaluronic acid or PBS (group size n = 6), for three weeks. After three months, the levels of IL-1β, tumor necrosis factor alpha (TNF-α), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured in the cartilage homogenate. Furthermore, relative expressions of collagen II2a1, aggrecan, IL-1β, TNF-α, inducible nitric oxide synthase (iNOS), SOX-9, MMP-3 and MMP-13 were assessed using real-time PCR. Radiological evaluation, before/after treatments, and histopathological assessments were carried out to evaluate the knees.
Results
Non-toxic concentrations of kaempferol and apigenin determined to be 10, 20 μM and 0.1, 0.3 μM, respectively. In comparison with the OA group, the levels of TNF-α, IL-1β and MDA significantly decreased in OA + MSCs + kaempferol + apigenin group and a significant increase in SOD level was observed. The levels of MMP-13, MMP-3, TNF-α, IL-1β, iNOS were significantly decreased in the groups of OA + MSCs + A0.1 μM + K10 μM and OA + MSCs + K20 μM. Co-treatment of kaempferol and apigenin increased the gene expression levels of collagen IIa1, aggrecan and SOX-9 genes.
Conclusion
We showed that kaempferol and apigenin potentially increase the efficiency of OA cell therapy in the rat model of ACLT-induced OA.
... Some studies showed that 1.25∼20 μM of quercetin inhibited normal thyroid cell growth in association with the inhibition of the insulininduced PI3K/AKT pathway. Moreover, quercetin decreases the expression of thyroid-stimulating-hormone-modulated thyroid-restricted gene sodium/iodide symporter (NIS) [96,97]. By contrast, treatment with 50∼75 μM quercetin shows an excellent anticancer activity by inducing S phase arrest and apoptosis via Hsp90 and Caspase-3/PARP pathways in BCPAP cells [41,42]. ...
Papillary thyroid carcinoma (PTC) is the most common subtype of differentiated thyroid cancers in Asian coastal cities, where the patients have increased risk of potentially high or excessive iodine intake. Given the high metastasis and recurrence of patients with BRAFV600E mutation, the mortality rate of thyroid cancer has recently shown an upward trend. A variety of therapies, including surgery, radiotherapy, and chemotherapy, have been used to treat thyroid cancer, but these therapies still have limitations, including postoperative complications, drug resistance, poor efficacy, or serious side effects. Recent studies have shown the potential of active ingredients derived from herbal medicine in inhibiting PTC via various cell signaling pathways. Some plant-derived compounds, such as apigenin, genistein, and curcumin, are also known to prevent and treat PTC. This article summarizes the recent advances in the structure-functional impact of anti-PTC active ingredients and their effects on PTC cells and tumor microenvironments with an emphasis on their challenges from basic research to clinical practice.
Ancient humans used dietary plants and herbs to treat disease and to pursue eternal life. Today, phytochemicals in dietary plants and herbs have been shown to be the active ingredients, some of which have antiaging and longevity-promoting effects. Here, we summarize 210 antiaging phytochemicals in dietary plants and herbs, systematically classify them into 8 groups. We found that all groups of phytochemicals can be categorized into six areas that regulate organism longevity: ROS levels, nutrient sensing network, mitochondria, autophagy, gut microbiota, and lipid metabolism. We review the role of these processes in aging and the molecular mechanism of the health benefits through phytochemical-mediated regulation. Among these, how phytochemicals promote longevity through the gut microbiota and lipid metabolism is rarely highlighted in the field. Our understanding of the mechanisms of phytochemicals based on the above six aspects may provide a theoretical basis for the further development of antiaging drugs and new insights into the promotion of human longevity.
Consuming vegetables from the Brassica genus is not just a dietary choice but a health-conscious decision. The vegetables, rich in over 100 diverse β-thioglucoside-N-hydroxysulfates, known as glucosinolates, have been linked to myriad health benefits. When the glucosinolates interact with the enzyme myrosinase, typically after chewing, they form isothiocyanates, some immediately broken down to release a permanently charged thiocyanate ion. Glucosinolates’ enzymatic and non-enzymatic breakdown produces major isothiocyanates, thiocyanates, nitriles, indole-3-carbinol, and diindolylmethane dimers.
A diet rich in polyphenols and other types of phytonutrients can reduce the occurrence of chronic diseases. However, a well-established cause—and—effect association has not been clearly demonstrated and several other issues will need to be fully understood before general recommendations will be carried out In the present review, some of the future challenges that the research on phenolic compounds will have to face in the next years are discussed: toxicological aspects of polyphenols and safety risk assessment; synergistic effects between different polyphenols; metabotype-based nutritional advice based on a differential gut microbial metabolism of polyphenols (precision nutrition); combination of polyphenols with other bioactive compounds; innovative formulations to improve the bioavailability of phenolic compounds; and polyphenols in sports nutrition and recovery.Other aspects related to polyphenol research that will have a boost in the next years are: polyphenol and gut microbiota crosstalk, including prebiotic effects and biotransformation of phenolic compounds into bioactive metabolites by gut microorganisms; molecular docking, molecular dynamics simulation, and quantum and molecular mechanics studies on the protein–polyphenol complexes; and polyphenol-based coating films, nanoparticles, and hydrogels to facilitate the delivery of drugs, nucleic acids and proteins.In summary, this article provides some constructive inspirations for advancing in the research of the applications, risk assessment and metabolic effects of dietary polyphenols in humans.
Sweet cherry intake affects oxidative stress and hepatic lipid metabolism, depending on composition, mainly (poly)phenol profile and daylight length. Thyroid hormones (TH) respond to daylight changes and regulate the hepatic glucose metabolism. This study investigated whether cherries with different phenolic hallmarks exhibit seasonal responses to TH and hepatic glucose metabolism. Fischer 344 rats fed a standard diet were chronically exposed to L6 (6 h light), L12 (12 h light), and L18 (18 h light) photoperiods and were supplemented with two sweet cherries (Ch1 and Ch2). Serum TH levels and glucose metabolism-related metabolites were affected by both the cherry composition and photoperiod. Thus, Ch1 and Ch2 reduced serum T3 levels in L6, whereas Ch2 increased it in L18, nullifying the photoperiod effect. Moreover, although photoperiod was the main factor affecting the hepatic expression of gluconeogenesis-related genes, Ch1 exerted effects mainly on L6 photoperiod and Ch2 on L18, tending to cancel out the photoperiod effects.
Lifestyle is an important factor in health, and researchers are trying to see the adverse effect on human health of a change in lifestyle. Many people follow unhealthy lifestyles, which affect human physical and mental health. Millions of people suffer from various problems like cardiovascular disease, overweight, malnutrition, hypertension, stress, violence, etc. There are many medicines that can cure these diseases, but they have side effects. When a man consumes green leaves and vegetables in his diet, his chances of reducing the risk of any disease increase. Every plant has primary and secondary metabolites. Flavonoid is a secondary metabolite found in various plants that plays an important role in the survival of the plant by performing physiological activities and being able to withstand adverse effects from the environment. Quercetin is one such bioflavonoid found in many plants, like onions, citrus fruits, parsley, etc. It comes under the category of flavone, with five hydroxy groups and a chromen-4-one skeletal structure. It has various applications, which include anti-cancer, anti-bacterial, anti-viral, anti-inflammatory, anti-diabetic, etc. However, the use of quercetin is limited due to its poor bioavailability, poor aqueous solubility, lower stability in the gastrointestinal tract, and first-pass effect. To enhance the application of quercetin, various derivatives of quercetin and its metal complex are required that are water soluble, which helps them reach the target site without any first-pass effect and provides them with stability. This review is divided into three main sections: The first section explains about flavonoids and their types; the second section explains about quercetin, its various methods of synthesis, its derivatives, and its metal complex; and the last section represents the complete applications of quercetin, with the drawbacks and how to overcome or deal with the drawbacks.
Environmental Endocrine Toxicants: Biology, Effects, and Management presents important knowledge of human exposure to endocrine toxicants and the related harmful effects. The book highlights the cutting-edge research currently being conducted on the subject and focuses on the challenges of dealing with increasing pollution levels, increased use of synthetic chemicals, and environmental endocrine disruptors that endanger the human endocrine system and its respective hormones.
Found in various man-made and natural substances and materials, endocrine toxicants include pesticides, herbicides, industrial chemicals, solvents and by-products, phytoestrogens, nanomaterials, and chemicals used in personal care products. These endocrine disruptors may mimic or interfere with the body’s hormones and are linked with developmental, reproductive, brain, immune, and other problems.
The volume discusses the many potential endocrine toxicants and the pathways through which they disrupt the endocrine system.
Key features:
Provides an overview of the chemical nature and mechanisms of endocrine disruptors
Discusses the sources of endocrine toxicants
Assesses the impact of endocrine toxicants on a sustainable environment
Looks at endocrine toxicants and their effect on human health, such as on thyroid glands, on human reproduction, etc.
The aim of this study was to evaluate the quality of African moringa (Moringa stenopetala) leaf preparations using easily applicable analytical methods. For this purpose, a novel simple and fast LC‐UV method was developed and validated to determine the most common phenolic compounds. The method showed good linearity with determination coefficients (r2) ≥ 0.999. Detection limits were below 0.4 μg/mL and quantification limits below 1.2 μg/mL. Relative standard deviation (RSD) values for intra‐ and inter‐day precision were less than 2% and recoveries were close to 100%. Robustness of the method was evaluated using an experimental design. The developed method was applied to analyse some commercial moringa leaf samples obtained from Ethiopia. Unknown compounds were tentatively identified as neochlorogenic acid and kaempferol 3‐O‐rhamnosylglucoside (KRG) by means of mass spectrometry (MS). Rutin was found to be the most common compound. Its content in samples varied from 2 to 18 mg/g. The amounts of (neo)chlorogenic acid and KRG were less than 2 mg/g, while quercetin and caffeic acid were not detected. The method allowed to observe differences in phenolic composition between regions. Results for loss on drying and ash content revealed that 40% and 50%, respectively, of the samples were not compliant.
Background
Given the challenges on diabetic nephropathy (DN) treatment, research has been carried out progressively focusing on dietary nutrition and natural products as a novel option with the objective of enhancing curative effect and avoiding adverse reactions. As a representative, Quercetin (Qu) has proved to be of great value in current data.
Purpose
We aimed to synthetize the evidence regarding the therapeutic effect and specific mechanism of quercetin on DN via systematically reviewing and performing meta-analysis.
Methods
Preclinical literature published prior to August 2021, was systematical retrieval and manually filtrated across four major databases including PubMed, Web of Science, EMBASE and Cochrane library. Pooled overall effect sizes of results were generated by STATA 16.0, and underlying mechanisms were summarized. Three-dimensional dose/time-effect analyses and radar maps were conducted to examine the dosage/time-response relations between Qu and DN.
Results
This paper pools all current available evidence in a comprehensive way, and shows the therapeutic benefits as well as potential action mechanisms of Qu in protecting the kidney against damage. A total of 304 potentially relevant citations were identified, of which 18 studies were enrolled into analysis. Methodological quality was calculated, resulting in an average score of 7.06/10. This paper provided the preliminary evidence that consumption of Qu could induce a statistical reduction in mesangial index, Scr, BUN, 24-h urinary protein, serum urea, BG, kidney index, TC, TG, LDL-C, AST, MDA, AGE, TNF-α, TGF-β1, TGF-β1 mRNA, CTGF and IL-1β, whereas HDL-C, SOD, GSH, GSH-Px, CAT and smad-7 were significantly increased. Furthermore, Qu could remarkably improve the renal pathology. In terms of the mechanisms underlying therapy of DN, Qu exerts anti-diabetic nephropathy properties possibly through PI3K/PKB, AMPK-P38 MAPK, SCAP/SREBP2/LDLr, mtROS-TRX/TXNIP/NLRP3/IL-1β, TGF-β1/Smad, Nrf2/HO-1, Hippo, mTORC1/p70S6K and SHH pathways. Dose/time-response images predicted a modest association between Qu dosage consumption/administration length and therapeutic efficacy, with the optimal dosage at 90-150 mg/kg/d and administration length ranging from 8 weeks to 12 weeks.
Conclusions
Quercetin exhibit highly pleiotropic actions, which simultaneously contributes to prevent fundamental progression of DN, such as hyperglycemia, dyslipidemia, inflammation, fibrotic lesions and oxidative stress. The therapeutic effect becomes stronger when Qu administration at higher dosages lasts for longer durations. Taken together, quercetin could be used in patients with DN as a promising agent, which has well-established safety profiles and nontoxicity according to existing literature.
Flavonoids -a class of low molecular weight secondary metabolites- are ubiquitous and cornucopia throughout the plant kingdom. Structurally, the main structure consists of C6-C3-C6 rings with different substitution patterns so that many sub-classes are obtained, for example: flavonols, flavonolignans, flavonoid glycosides, flavans, anthocyanidins, aurones, anthocyanidins, flavones, neoflavonoids, chalcones, isoflavones, flavones and flavanones. Flavonoids are evaluated to have drug like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others. However, information on the relationship between their structure and biological activity is scarce. Therefore, the present review tries to summarize all the therapeutic activities of flavonoids, their mechanisms of action and the structure activity relationship.
Nutraceuticals’ properties render them a good source of potential drug leads in pharmaceutical research, but the elucidation of their mechanism of action (MoA) is challenging, partly because natural compounds can bind multiple targets with unrelated structures. In this work, we present a pipeline that integrates complementary systems biology and chemoinformatics-based approaches with the goal of identifying potential targets and generating MoA hypotheses that can be tested in a new cycle of experiments. We focus on how we can integrate knowledge from multiple sources into an ensemble score and translate our results into biological insights, providing use cases on three extensively studied nutraceuticals, epigallocatechin-3-gallate, quercetin, and resveratrol as well as on a prototypical proinflammatory stimulus, TNF-α. Fifty-seven of our top 60 predicted targets were already identified in the literature as experimentally perturbed by the corresponding compounds, interestingly observing anticancer, antiviral, and antibacterial MoA to be shared among the tested nutraceuticals.
Quercetin, a naturally occurring dietary flavonoid, is well known to ameliorate chronic diseases and aging processes in humans, and its antiviral properties have been investigated in numerous studies. In silico and in vitro studies demonstrated that quercetin can interfere with various stages of the coronavirus entry and replication cycle such as PLpro, 3CLpro, and NTPase/helicase. Due to its pleiotropic activities and lack of systemic toxicity, quercetin and its derivatives may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections. There is evidence that quercetin in combination with, for example, vitamins C and D, may exert a synergistic antiviral action that may provide either an alternative or additional therapeutic/preventive option due to overlapping antiviral and immunomodulatory properties. This review summarizes the antiviral significance of quercetin and proposes a possible strategy for the effective utilization of natural polyphenols in our daily diet for the prevention of viral infection.
Present study was focused on the isolation and characterization of the anti-inflammatory compound(s) from the methanolic extracts of Arisaema tortuosum tuber by column chromatography, TLC, FT-IR, 1H, 13C NMR and HR-MS. Among all the fractions obtained A. tortuosum fraction 3 (PC-1) and fraction 5 (PC-2) showed significant in vivo anti-inflammatory activity. This study endorsed that the isolated bioactive compound PC-2 showed better anti-inflammatory activity at a dose of 25 mg/Kg BW. The results indicate that PC-2 and PC-1 methanolic extract of A. tortuosum tuber may be competing for the tent in the therapy of inflammatory ailments.
Hypothyroidism is the most common thyroid disorder, affects women more frequently, and incidence increases with age. The prevalence of hypothyroidism in developed countries is around 4-5%, whereas, in India, it is about 11%. The common symptoms of hypothyroidism in adults are weight gain, fatigue, lethargy, cold intolerance, constipation, change in voice, and dry skin. It can affect all systems of the body. Diagnosis is mainly based on clinical history and laboratory investigations. Untreated hypothyroidism increases morbidity and mortality. In conventional medicine, the treatment of choice is Levothyroxine, whereas in Unani System of Medicine, pharmacotherapy consists of single and compound drugs. Single drugs are selected as per the constitution (Mizaj) of drugs as opposed to the abnormal constitution (Su-e-Mizaj) of disease and its pathology. Some drugs increase the basal metabolic rate whereas some evacuate the morbid material from the body by the action of purgation. The drugs are used either in a single form or as a prescription of more than one drug in the form of decoction (Joshandah), infusion (Kheshandah), or powder (Safoof). This review aims at providing comprehensive information regarding various drugs used in Unani system of medicine that is used in the management of thyroid dysfunction.
There is an increasing trend of using of natural compounds, such as plant phenolics, for their preservative effect in food due to food safety, nutritive and possible therapeutic effects. Flavonoids, small molecular weight, short carbon chain and ubiquitous compounds formed as secondary metabolites exert preservative effect due to antioxidant and antimicrobial activity. These can be added into foods as powder, gel, liquid, raw or in extract form, with latter form being more suitable to get desired antioxidant and antimicrobial effect in lower concentrations to avoid deterioration in sensory attributes of food products. There is a need to standardize efficient processing protocols for extraction of phenolics from plant material in high concentrations and active form.
Quercetin, a potential fish food supplement, has been reported to process many beneficial properties. However, some negative effects of quercetin have been observed, which pointed out necessity for additional studies to evaluate its safety. Therefore, the present study investigated effects of quercetin (0.01, 0.1, 1, 10, 100 and 1000 μg/L) on shoaling and anxiety behaviors through novel tank tests in zebrafish (Danio rerio). Furthermore, oxidative stress, neuroinflammation and apoptosis in the brains were examined to learn more about mechanisms of action related to quercetin. The results showed that quercetin at the lower concentrations exerted beneficial effects on shoaling and anxiety behaviors. On the contrary, when quercetin was up to 1000 μg/L, it exerted detrimental effects shown as decreases of movement and increases of anxiety behaviors. Generally, U-shaped responses of antioxidant enzyme activities (superoxide dismutase and catalase), and inversed U-shaped responses of inflammatory mediators (cyclooxygenase-2) and cytokines (interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor α) to quercetin treatment were found in the brains. In addition, quercetin at the lower concentrations attenuated cell apoptosis, while even more apoptosis was found at the 1000 μg/L quercetin group. In conclusion, quercetin could exert beneficial or detrimental effects on the shoaling and anxiety behaviors depending on the treatment concentrations, and the underlying mechanisms are potentially associated with neuroinflammation and neuron apoptosis.
Fennel seeds consumption decreased the weights of body, liver, kidneys
and testes but increased thyroid gland weight of male rats.
Long-term exposure to fennel with high doses has reduced thyroid
hormones (T3 and T4) serum levels, while low doses and short-term
exposure showed non-significant effects.
Fennel consumption illustrated non-significant change in TSH serum
levels in different doses and periods of time.
Long-term exposure to fennel with high doses increased liver enzymes
(GOT, GPT, ALP) serum levels, while low doses and short-term
exposure showed non-significant effects.
Long-term exposure to fennel with high doses increased renal function
tests (Urea, Total protein, Creatinine) serum levels, while low doses and
short-term exposure showed non-significant effects.
Long-term exposure to fennel with high doses decreased testes hormone
(Testosterone) serum levels, while low doses and short-term exposure
showed non-significant effects.
Fennel seeds consumption for short and long periods of time and
in all concentrations caused empty follicles from colloid,
and damage of thyroid gland. Liver sections showed sinusoidal . .
..dilatation degeneration effect in the renal epithelial cells of both distal
. and proximal convoluted tubules. Testis showed seminiferous tubules
..with No sperms appear inside the lumen certain. Wide areas of necrosis
. of spermatogonia cells in addition to necrosis in all the organs above.
Quercetin is a plant flavonoid and has antioxidative properties. In this study, we evaluated the therapeutic effect of quercetin on thyroid dysfunction in L-thyroxin (LT4)-induced hyperthyroidism rats. LT4 was used to prepare the experimental hyperthyroidism model via the intraperitoneal injection. Quercetin was injected at a series doses (5, 50, and 100 mg/kg) to LT4-induced hypothyroidism rats once a day for 14 days. The body weight and food intake were measured once a week. The levels of thyroid hormones, liver function, oxidative stress markers, and antioxidant markers were measured using commercial enzyme-linked immunosorbent assay kits. Hematoxylin-eosin staining was used to observe the thyroid tissue histological changes. The levels of nuclear and total nuclear factor erythroid 2-related factor 2 (Nrf2) were determined by western blot. The liver oxidative stress markers in LT4-induced hyperthyroidism Nrf2 knockout rats were determined to evaluate the role of Nrf2 on quercetin induced protective effects. LT4 administration increased the levels of serum triiodothyronine and thyroxine, activity of oxidative stress markers with a parallel decrease in antioxidant markers and Nrf2. However, the simultaneous administration of quercetin, reversed all these effects indicating its potential in the regulation of hyperthyroidism. Furthermore, the loss function of Nrf2 diminished these effects resulting from the quercetin application, indicating the inhibitory effects caused by the quercetin may be involved in Nrf2 signaling pathway. These results indicate that quercetin could be used to protect against experimental hyperthyroidism-induced liver damage via Nrf2 signaling pathway.
Aims:
The present study was designed to compare the effects of a low-fat diet (LF), calorie restriction (CR), quercetin (Que) and exercise (Ex) on hepatic steatosis in a high-fat (HF) diet-induced obesity prone (OP) model in the perspective of microRNA (miR)-dependent thyroid hormone (TH) synthesis and action.
Main methods:
Male C57BL/6J mice were administered a HF diet for 10 weeks to induce OP phenotype and then divided into 5 groups, HF diet (OP-HF), LF diet (OP-LF), 70% CR (OP-CR), 0.05% Que (OP-Que) and a treadmill exercise regimen (OP-Ex); one additional group fed LF diet served as control (LF). 7 weeks later, serum indexes, metabolic alterations, redox status and histological appearance in the thyroid and liver, and TH related miRs with their targets expressions were determined.
Key findings:
No significance on T3 levels was observed among the six groups. LF, CR, Que and Ex significantly ameliorated HF-induced hepatic steatosis to varying degrees, inhibited T4 production via differentially elevating miR-339, miR-383 and miR-146b to decrease NIS expression and regulating miR-200a/Nrf2 to maintain redox status in the thyroid. Furthermore, these four interventions differentially and significantly decreased miR-383 and miR-146b to elevate TRb and DIO1 expression, and subsequent TH responsive lipid metabolism genes regulation. Among them, the effects of CR on hepatic steatosis were the most prominent.
Significance:
Our data indicated that amelioration of hepatic steatosis by LF, CR, Que and Ex resulted in many shared, but also many differential changes in the miR-dependent TH production and action.
For some classes of dietary polyphenols, there are now sufficient intervention studies to indicate the type and magnitude of effects among humans in vivo, on the basis of short-term changes in biomarkers. Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.
Thyroid iodide uptake through the sodium-iodide symporter (NIS) is not only an essential step for thyroid hormones biosynthesis, but also fundamental for the diagnosis and treatment of different thyroid diseases. However, part of patients with thyroid cancer is refractory to radioiodine therapy, due to reduced ability to uptake iodide, which greatly reduces the chances of survival. Therefore, compounds able to increase thyroid iodide uptake are of great interest. It has been shown that some flavonoids are able to increase iodide uptake and NIS expression in vitro, however, data in vivo are lacking. Flavonoids are polyhydroxyphenolic compounds, found in vegetables present in human diet, and have been shown not only to modulate NIS, but also thyroperoxidase (TPO), the key enzyme in thyroid hormones biosynthesis, besides having antiproliferative effect in thyroid cancer cell lines. Therefore, we aimed to evaluate the effect of some flavonoids on thyroid iodide uptake in Wistar rats in vivo. Among the flavonoids tested, rutin was the only one able to increase thyroid iodide uptake, so we decided to evaluate the effect of this flavonoid on some aspects of thyroid hormones synthesis and metabolism. Rutin led to a slight reduction of serum T4 and T3 without changes in serum thyrotropin (TSH), and significantly increased hypothalamic, pituitary and brown adipose tissue type 2 deiodinase and decreased liver type 1 deiodinase activities. Moreover, rutin treatment increased thyroid iodide uptake probably due to the increment of NIS expression, which might be secondary to increased response to TSH, since TSH receptor expression was increased. Thus, rutin might be useful as an adjuvant in radioiodine therapy, since this flavonoid increased thyroid iodide uptake without greatly affecting thyroid function.
This thesis focuses on the possible health-beneficial effects of the
flavonoid quercetin. Especially the relation between the in vitro and in vivo
behavior of quercetin is explored. Furthermore, the possible use of this
flavonoid in sarcoidosis, an inflammatory disease, is examined.
Firstly, the behavior of quercetin during oxidative stress was evaluated
in vitro. Chapter 2 describes the protection against lipid peroxidation
offered by catechol-containing antioxidants such as quercetin. The effects of
its oxidation products, formed during this protection, are discussed. In
chapter 3 the reaction of the main oxidation product of quercetin, i.e. QQ,
with thiols is further examined. Especially the reactions of QQ with GSH or
with vitamin C are evaluated and compared. To investigate the reaction of
QQ with DT-diaphorase (NQO-1), the experiments described in chapter 4 are
performed. The possible role of this enzyme in the protection against QQinduced toxicity is examined. Since the QQ-toxicity appears to be focused on
its reaction with thiols, chapter 5 focuses on the fate of the adducts formed
between QQ and various thiols, including GSH, the most abundant
endogenous thiol. The in vitro work was concluded by investigating the
protective effect of quercetin in relation to the potential toxic effects of its
oxidation products in a more integrated cell system, using rat lung epithelial
cells (RLEs) as described in chapter 6.
Secondly, the in vitro and ex vivo anti-inflammatory as well as the in
vivo anti-oxidative effects of quercetin have been examined. Chapter 7
presents the effects of a four-weeks comprising quercetin intervention on the
antioxidant status as well as on the basal and ex vivo-induced inflammation
in healthy volunteers. The potential toxicity of QQ is also discussed. The ex
vivo anti-inflammatory effect of quercetin has further been examined in both
sarcoidosis patients and healthy controls in chapter 8. Moreover, the
antioxidant status of both the patients and their matched controls has been
quantified.
Thirdly, the in vivo anti-oxidative and anti-inflammatory effects of
quercetin supplementation in sarcoidosis patients are reported in chapter 9.
Implications for the use of antioxidant supplementation, with for example
quercetin, in the treatment of this disease are given.
Finally, the results and impacts of our findings are summarized in
chapter 10. Implications for further research are also given.
Apart from its well-known deleterious dental and skeletal effects, fluoride excess can have toxic effects on many other tissues. Fluoride, when in excess, is known to interfere with thyroid gland function. Fluoride-induced thyroid disturbances similar to those observed in iodine deficiency state in spite of adequate iodine intake have been documented. Similar thyroid disturbances in individuals with dental fluorosis have not been well studied in populations with endemic fluorosis. This work was undertaken to study the effects of fluoride-induced thyroid disturbances in individuals with dental fluorosis.
The study group included 65 subjects with dental fluorosis from endemic fluorosis populations. An additional control group was comprised of 10 subjects without dental fluorosis. The drinking water fluoride levels of the study populations were analyzed. Serum free FT3, FT4, and TSH levels of both groups were assessed.
All subjects with dental fluorosis had serum levels of thyroid hormones (FT3, FT4, and TSH) within the normal range, with the exception of 1 individual, who had elevated levels of TSH. Statistical significance was found when FT3 and TSH values were compared with different Dean's index groups by a 1-way ANOVA test: FT3 (F = 3.4572; P=.0377) and TSH (F = 3.2649 and P=.0449).
Findings of this study did not show any significant alterations in the levels of the thyroid hormones FT3, FT4, and TSH in subjects with dental fluorosis. Our observations suggest that thyroid hormone levels were not altered in subjects with dental fluorosis. Hence, future studies of this kind, along with more detailed investigations are needed.
There is increasing interest in the potential health benefits of dietary flavonoids. Fruits and vegetables, tea, and cocoa are rich natural sources of flavonoids. Epidemiological studies have indicated that consumption of these foods is likely to be associated with a reduced risk of cardiovascular disease, but the etiology of this benefit is not yet clearly defined. Furthermore, in some acute interventions, a positive effect of tea and cocoa on vascular function has been reported. An alternative source of flavonoids is dietary supplements, which have become increasingly popular in the recent past. In this context, it needs to be critically evaluated whether vascular health-promoting and other positive properties of flavonoid-rich diets can be replaced by purified flavonoids as dietary supplements. Plant sources of flavonoids contain a complex mixture of secondary plant metabolites and not only flavonoids per se. This complex mixture of secondary plant metabolites cannot be simply exchanged by single purified compounds as dietary supplements. If flavonoids are given as dietary supplements, toxicity issues as well as nutrient drug interactions need to be taken into account. Purified flavonoids given in high doses as dietary supplements may affect trace element, folate, and vitamin C status. Furthermore, they may exhibit antithyroid and goitrogenic activities. In this review article, the available literature on the safety issues surrounding high dose supplemental flavonoid consumption has been summarized.
Polyphenols in dietary and botanical matrices are usually present as simple and complex O-glycosides. In fermented dietary materials, the glycosidic moiety is removed and accompanied in some cases by more complex changes to the polyphenol. As for most xenobiotics, polyphenols undergo phase II conjugation in the intestinal wall during their absorption from the gut. In contrast, a few polyphenols, such as puerarin in the kudzu vine, are C-glycosides and are stable in the gut and during absorption, distribution and excretion. Large bowel bacteria reduce polyphenol aglycones, causing opening of the heterocyclic B-ring and ring cleavage. The products are mostly absorbed and enter the bloodstream. Phase I and II metabolism events occur in the intestine and the liver - most polyphenols predominantly circulate as β-glucuronides and sulfate esters with very little as the aglycones, the presumed active forms. In addition, metabolism can occur in non-hepatic tissues and cells including breast tumor cells that have variable amounts of cytochrome P450s, sulfatase and sulfotransferase activities. Inflammatory cells produce chemical oxidants (HOCl, HOBr, ONO(2)(-)) that will react with polyphenols. The isoflavones daidzein and genistein and the flavonol quercetin form mono- and dichlorinated products in reaction with HOCl. Genistein is converted to 3'-nitrogenistein in the lung tissue of lipopolysaccharide-treated rats. Whereas polyphenols that can be converted to quinones or epoxides react with glutathione (GSH) to form adducts, chlorinated isoflavones do not react with GSH; instead, they are converted to β-glucuronides and are excreted in bile. Analysis of polyphenols and their metabolites is routinely carried out with great sensitivity, specificity and quantification by LC-tandem mass spectrometry. Critical questions about the absorption and tissue uptake of complex polyphenols such as the proanthocyanins can be answered by labeling these polyphenols with (14)C-sucrose in plant cell culture and then purifying them for use in animal experiments. The (14)C signature is quantified using accelerator mass spectrometry, a technique capable of detecting one (14)C atom in 10(15) carbon atoms. This permits the study of the penetration of the polyphenols into the interstitial fluid, the fluid that is actually in contact with non-vascular cells.
High-fluoride (100 and 200 ppm) water was administered to rats orally to study the fluoride-induced changes on the thyroid hormone status, the histopathology of discrete brain regions, the acetylcholine esterase activity, and the learning and memory abilities in multigeneration rats. Significant decrease in the serum-free thyroxine (FT4) and free triiodothyronine (FT3) levels and decrease in acetylcholine esterase activity in fluoride-treated group were observed. Presence of eosinophilic Purkinje cells, degenerating neurons, decreased granular cells, and vacuolations were noted in discrete brain regions of the fluoride-treated group. In the T-maze experiments, the fluoride-treated group showed poor acquisition and retention and higher latency when compared with the control. The alterations were more profound in the third generation when compared with the first- and second-generation fluoride-treated group. Changes in the thyroid hormone levels in the present study might have imbalanced the oxidant/antioxidant system, which further led to a reduction in learning memory ability. Hence, presence of generational or cumulative effects of fluoride on the development of the offspring when it is ingested continuously through multiple generations is evident from the present study.
Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed "Let food be thy medicine and medicine be thy food." Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, gamma-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.
Recombinant human thyrotropin (rhTSH; Thyrogen®) is approved for use in a 0.9 mg dose/day for 2 consecutive days for diagnosis and treatment of differentiated thyroid cancer. It is recommended that it be injected immediately after reconstitution in the distilled water diluent supplied by the manufacturer. However, Thyrogen has been used off-label in doses less than the standard 0.9 mg dose for stimulation of radioiodine uptake in the treatment of multinodular goiter. To determine whether the biologic activity of Thyrogen can be preserved after dilution, we designed experiments to assess the biologic stability of Thyrogen under different durations and temperatures of storage.
rhTSH was diluted in 1% bovine serum albumin in phosphate-buffered saline to a concentration of 0.9 mg /mL and further diluted to 0.1 mg/mL. Aliquots of 0.5 mL were stored at room temperature, 4°C, -11°C, and -60°C for various lengths of time. In addition, rhTSH aliquots were also subjected to incubation for 1 hour at 50°C and to 10 cycles of freezing in dry ice alternating with thawing at 37°C. Bioassays were performed in FRTL-5 cells. rhTSH was added to the media at a final concentration of either 5 ng/mL or 20 ng/mL, and the cells were then incubated for 48 hours. Potency was assessed by measurement of ¹²⁵I-iodide uptake in comparison to cells treated with perchlorate to block iodide uptake. Samples were immunoassayed at day 185 of storage.
Samples stored at 4°C, -11°C, -60°C, and room temperature retained activity after storage periods of up to 204 days. Samples subjected to 10 freeze-thaw cycles or heated to 50°C for 1 hour retained full biologic activity. Immunoassay at day 185 showed no difference in immunoactivity in relation to the storage condition.
rhTSH kept at 4°C, -11°C, -60°C, and room temperature maintained good biologic potency for more than 6 months of storage when tested in vitro, indicating that the biologic activity is very stable. However, altered sialylation occurring during storage could have altered the half-life of rhTSH. Nevertheless, the data provide reassurance that storage in the cold for a few months does not result in significant loss of biologic activity.
Phosphoinositide-3-kinase (PI3K) inhibition increases functional sodium iodide symporter (NIS) expression in both FRTL-5 rat thyroid cell line and papillary thyroid cancer lineages. In several cell types, the stimulation of PI3K results in downstream activation of the mechanistic target of rapamycin (MTOR), a serine-threonine protein kinase that is a critical regulator of cellular metabolism, growth, and proliferation. MTOR activation is involved in the regulation of thyrocyte proliferation by TSH. Here, we show that MTOR inhibition by rapamycin increases iodide uptake in TSH-stimulated PCCL3 thyroid cell line, although the effect of rapamycin was less pronounced than PI3K inhibition. Thus, NIS inhibitory pathways stimulated by PI3K might also involve the activation of proteins other than MTOR. Insulin downregulates iodide uptake and NIS protein expression even in the presence of TSH, and both effects are counterbalanced by MTOR inhibition. NIS protein expression levels were correlated with iodide uptake ability, except in cells treated with TSH in the absence of insulin, in which rapamycin significantly increased iodide uptake, while NIS protein levels remained unchanged. Rapamycin avoids the activation of both p70 S6 and AKT kinases by TSH, suggesting the involvement of MTORC1 and MTORC2 in TSH effect. A synthetic analog of rapamycin (everolimus), which is clinically used as an anticancer agent, was able to increase rat thyroid iodide uptake in vivo. In conclusion, we show that MTOR kinase participates in the control of thyroid iodide uptake, demonstrating that MTOR not only regulates cell survival, but also normal thyroid cell function both in vitro and in vivo.
Plant polyphenols, a large group of natural antioxidants, are serious candidates in explanations of the protective effects of vegetables and fruits against cancer and cardiovascular diseases. Epidemiologic studies are useful for evaluation of the human health effects of long-term exposure to physiologic concentrations of polyphenols, but reliable data on polyphenol contents of foods are still scarce. The aim of this review is to summarize available epidemiologic data on the health effects of polyphenols, focusing on the flavonoid sub-classes of flavonols, flavones, and catechins and on lignans. Data obtained to date suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases but not on cancer, with the possible exception of lung cancer. There is a need for more research on stroke and lung diseases such as asthma and chronic obstructive pulmonary disease. Most studies to date have included only fla-vonols and flavones. With data becoming available for other poly-phenols, these compounds should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiologic studies, including residual confounding (by smoking and other dietary factors) and exposure assessment. Am J Clin Nutr 2005;81(suppl):317S–25S.
In FRTL-5 thyroid cells depleted of thyrotropin, insulin, and serum for 3 days, growth and synthesis of thyroglobulin are inhibited. Readdition of insulin or IGF-I in the absence of thyrotropin stimulates thyroglobulin synthesis or thyroglobulin mRNA level by 2-4-fold but has no effect on cell growth. The half-maximal effects of insulin and IGF-I are at 100 and 10 ng/ml, respectively. In both cases, the increased mRNA levels are accompanied by an increase in transcription rate. Maximally effective concentrations of insulin or IGF-I are additive with thyrotropin in increasing thyroglobulin mRNA levels and in increasing transcription; in contrast, the effect of insulin is not additive with IGF-I.
We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases such as cancer and cardiovascular diseases is emerging. The health effects of polyphenols depend on the amount consumed and on their bioavailability. In this article, the nature and contents of the various polyphenols present in food sources and the influence of agricultural practices and industrial processes are reviewed. Estimates of dietary intakes are given for each class of polyphenols. The bioavailability of polyphenols is also reviewed, with particular focus on intestinal absorption and the influence of chemical structure (eg, glycosylation, esterification, and polymerization), food matrix, and excretion back into the intestinal lumen. Information on the role of microflora in the catabolism of polyphenols and the production of some active metabolites is presented. Mechanisms of intestinal and hepatic conjugation (methylation, glucuronidation, sulfation), plasma transport, and elimination in bile and urine are also described. Pharmacokinetic data for the various polyphenols are compared. Studies on the identification of circulating metabolites, cellular uptake, intracellular metabolism with possible deconjugation, biological properties of the conjugated metabolites, and specific accumulation in some target tissues are discussed. Finally, bioavailability appears to differ greatly between the various polyphenols, and the most abundant polyphenols in our diet are not necessarily those that have the best bioavailability profile. A thorough knowledge of the bioavailability of the hundreds of dietary polyphenols will help us to identify those that are most likely to exert protective health effects.
For some classes of dietary polyphenols, there are now sufficient intervention studies to indicate the type and magnitude of effects among humans in vivo, on the basis of short-term changes in biomarkers. Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.
This article gives an overview of the potential hazards of polyphenol consumption, as reported during the round-table discussion at the 1st International Conference on Polyphenols and Health, held in Vichy, France, November 2003. Adverse effects of polyphenols have been evaluated primarily in experimental studies. It is known, for example, that certain polyphenols may have carcinogenic/genotoxic effects or may interfere with thyroid hormone biosynthesis. Isoflavones are of particular interest because of their estrogenic activity, for which beneficial as well as detrimental effects have been observed. Furthermore, consumption of polyphenols inhibits nonheme iron absorption and may lead to iron depletion in populations with marginal iron stores. Finally, polyphenols may interact with certain pharmaceutical agents and enhance their biologic effects. It is important to consider the doses at which these effects occur, in relation to the concentrations that naturally occur in the human body. Future studies evaluating either beneficial or adverse effects should therefore include relevant forms and doses of polyphenols and, before the development of fortified foods or supplements with pharmacologic doses, safety assessments of the applied doses should be performed.
Plant polyphenols, a large group of natural antioxidants, are serious candidates in explanations of the protective effects of vegetables and fruits against cancer and cardiovascular diseases. Epidemiologic studies are useful for evaluation of the human health effects of long-term exposure to physiologic concentrations of polyphenols, but reliable data on polyphenol contents of foods are still scarce. The aim of this review is to summarize available epidemiologic data on the health effects of polyphenols, focusing on the flavonoid subclasses of flavonols, flavones, and catechins and on lignans. Data obtained to date suggest beneficial effects of both flavonoids and lignans on cardiovascular diseases but not on cancer, with the possible exception of lung cancer. There is a need for more research on stroke and lung diseases such as asthma and chronic obstructive pulmonary disease. Most studies to date have included only flavonols and flavones. With data becoming available for other polyphenols, these compounds should be included in future studies. Careful design of prospective studies is important to offset some of the major drawbacks of epidemiologic studies, including residual confounding (by smoking and other dietary factors) and exposure assessment.
Flavonoids comprise a class of low molecular weight compounds displaying a variety of biological activities including inhibition of tumor growth and metastasis. To gain insight into the mechanisms underlying metastasis inhibition, we have employed the B16-BL6 murine melanoma metastasis model. B57BL/6N mice were injected i.v. with tumor cells and Apigenin, Quercetin, or Tamoxifen, each at 50 mg/kg given i.p., and lung tumor cell colonies counted 14-6 days thereafter. Three different injection schedules were used for each drug: (a) daily injection, starting 24 h before injection of the tumor cells; (b) single dose, 24 h preceding tumor challenge; (c) daily injection, starting 24 h after the injection of the tumor cells. All three compounds significantly reduced tumor lung deposits (Apigenin = Quercetin > Tamoxifen). However, when treatment was delayed by 24 h after tumor cells (schedule c), multiple daily doses of Apigenin or Quercetin were less effective that a single dose of the same compound given 24 h before tumor challenge (schedule b). Apigenin and Quercetin, but not Tamoxifen, were found to inhibit VCAM-1 expression in a dose-dependent manner in HUVEC and in murine pulmonary endothelial cells. In ex vivo experiments, the number of tumor cells adhering to lung vessels was significantly diminished in animals treated with a single dose of Apigenin and Quercetin. These findings indicate that the inhibition of tumor cell metastasis by Apigenin or Quercetin may significantly depend on the ability of these compounds to alter the host's microenvironment, further substantiating the role of the intravascular processes in the metastatic cascade.
Increased major histocompatibility complex (MHC) class I gene expression in nonimmune cell 'target tissues' involved in organ-specific diseases may be important in the pathogenesis of autoimmune diseases. This possibility in part evolves from studies of cultured thyrocytes where properties appear relevant to the development of thyroid autoimmune disease. In FRTL-5 rat thyroid cells in continuous culture, hormones and growth factors that regulate cell growth and function specifically decrease MHC class I gene expression. We hypothesized that this could reflect a mechanism to preserve self-tolerance and prevent autoimmune disease. The mechanisms of action of some of these hormones, namely TSH and hydrocortisone, have been already characterized. In this report, we show that IGF-I transcriptionally downregulates MHC class I gene expression and that its action is similar to that of insulin. The two hormones have a complex effect on the promoter of the MHC class I gene, PD1. In fact, they decrease the full promoter activity, but upregulate the activity of deleted mutants that have lost an upstream, tissue-specific regulatory region but still retain the enhancer A region. We show that insulin/IGF-I promotes the interactions of the p50/p65 subunits of NF-kappaB and AP-1 family members with these two regions, and that the tissue-specific region acts as a dominant silencer element on insulin/IGF-I regulation of promoter activity. These observations may be important to understand how MHC class I gene transcription is regulated in the cells.
The effect of the flavonoid quercetin and its conjugate rutin was investigated on (biomarkers of) colorectal cancer (CRC). Male F344 rats (n = 42/group) were fed 0, 0.1, 1, or 10 g quercetin/kg diet or 40 g rutin/kg diet. Two wk after initial administration of experimental diets, rats were given 2 weekly subcutaneous injections with 15 mg/kg body wt azoxymethane (AOM). At wk 38 post-AOM, quercetin dose dependently (P < 0.05) decreased the tumor incidence, multiplicity, and size, whereas tumor incidences were comparable in control (50%) and rutin (45%) groups. The number of aberrant crypt foci (ACF) in unsectioned colons at wk 8 did not correlate with the tumor incidence at wk 38. Moreover, at wk 8 post-AOM, the number and multiplicity of ACF with or without accumulation of beta-catenin were not affected by the 10 g quercetin/kg diet. In contrast, another class of CRC-biomarkers, beta-catenin accumulated crypts, contained less beta-catenin than in controls (P < 0.05). After enzymatic deconjugation, the plasma concentration of 3'-O-methyl-quercetin and quercetin at wk 8 was inversely correlated with the tumor incidence at wk 38 (r = -0.95, P </= 0.05). Rats supplemented with 40 g rutin/kg diet had only 30% of the (3'-O-methyl-) quercetin concentration of 10 g quercetin/kg diet-fed rats (P < 0.001). In conclusion, quercetin, but not rutin, at a high dose reduced colorectal carcinogenesis in AOM-treated rats, which was not reflected by changes in ACF-parameters. The lack of protection by rutin is probably due to its low bioavailability.
TSH receptor mRNA levels in FRTL-5 thyroid cells are autoregulated at a transcriptional level by the same hormones required for the growth and function of the cells: TSH, insulin, and insulin-like growth factor-I (IGF-I). Thus, the ability of TSH, via its cAMP signal, to down-regulate steady state receptor mRNA levels is preceded by the action of TSH to decrease pre-mRNA levels in nuclear run-on assays to the same quantitative level as evident in Northern analyses. In contrast, the receptor mRNA half-life is shown not to change when down-regulation is reversed by withdrawing TSH in the presence or absence of actinomycin-D. Evidence is additionally provided that TSH receptor mRNA levels are increased by insulin, IGF-I, or calf serum in both Northern and run-on assays. This action cannot be duplicated by hydrocortisone and is evident at more than 20-fold lower concentrations of IGF-I than insulin. Moreover, insulin, IGF-I, and/or calf serum are required for the autoregulatory negative transcriptional regula...
Autoimmune thyroid disease is associated with enhanced expression of major histocompatibility complex class I antigens on thyrocytes. To better understand this phenomenon, we have studied the normal expression of class I genes in FRTL-5 rat thyroid cells. A variety of hormones and growth factors that regulate the growth and function of these thyroid cells were found to decrease class I RNA levels: serum, insulin or insulin-like growth factor-I (IGF-I), and hydrocortisone. Antibody preparations from Graves' patients (thyroid-stimulating antibodies), which increase cAMP levels and stimulate the thyroid, also decrease class I RNA levels. This is consistent with the fact that TSH, via its cAMP signal, reduces class I transcripts. The class I response to TSH, serum, insulin, IGF-I, or hydrocortisone is specific, in that the same agents do not similarly affect TSH receptor, thyroglobulin, thyroid peroxidase, malic enzyme, or beta-actin RNA levels. Both gamma- and alpha-interferon increase class I RNA levels in ...
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less than those of the vehicle control group. The Markov transition matrix analyses indicate female mice in the 2,000 mg/kg group had a significantly higher probability of extended estrus than did the vehicle control females. The incidences of hepatocytic hypertrophy were significantly increased in males and females in the 250 mg/kg or greater groups. Significantly increased incidences of focal hepatocytic necrosis occurred in 1,000 and 2,000 mg/kg males. The incidences of hyaline droplet accumulation in the respiratory epithelium of the nose were significantly increased in 500 mg/kg males and 1,000 and 2,000 mg/kg females. In the olfactory epithelium of the nose, the incidences of hyaline droplet accumulation were significantly increased in the 125 (female only), 500, and 1,000 mg/kg groups. Incidences of atrophy of the olfactory epithelium were significantly increased in the 1,000 mg/kg groups. The incidences of pigment accumulation in macrophages in the olfactory epithelium were significantly increased in males in the 500 mg/kg or greater groups and in 1,000 and 2,000 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 100, 300, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 (females) weeks. Additional groups of 10 male and 10 female rats (special study) were administered the same doses, 5 days per week for 14 weeks. Survival of 1,000 mg/kg males was significantly less than that of the vehicle controls. At week 14, all dosed groups of males and 1,000 mg/kg females had increased levels of thyroid stimulating hormone compared to those of the vehicle control groups. There were no significant decreases in the levels of triiodothyronine or total thyroxine. Mean body weights of 300 mg/kg males and females were less (10% or more) than those of the vehicle controls after week 93, and those of 1,000 mg/kg males and females were less after week 89. Clinical findings included ruffled fur in seven, eight, and 10 males in the 100, 300, and 1,000 mg/kg groups, respectively, beginning at week 89; four vehicle control males also had ruffled fur. Liver weights were significantly increased in all dosed groups of special study rats at 14 weeks. In the liver at 2 years, incidences of hepatocellular adenoma were slightly increased in 100 and 300 mg/kg males. Significantly increased incidences of nonneoplastic lesions at 2 years included hepatocyte hypertrophy and bile duct hyperplasia in all dosed groups of males and females, focal fatty change in all dosed groups of females, cystic degeneration in 100 and 1,000 mg/kg males, and oval cell hyperplasia and necrosis in 1,000 mg/kg males. In the thyroid gland, incidences of follicular cell adenoma were slightly increased in 300 and 1,000 mg/kg males and 300 mg/kg females. Single incidences of follicular cell carcinoma occurred in the 300 and 1,000 mg/kg female groups. There were significantly increased incidences of follicular cell hypertrophy in all dosed groups of males and females and follicle hyperplasia in all dosed groups of males. In the nose, adenoma of the respiratory epithelium occurred in two females receiving 300 mg/kg. Except for respiratory epithelium hyperplasia in 100 mg/kg females, the incidences of transitional epithelium and respiratory epithelium hyperplasia were significantly increased in all dosed groups of males and females. Except for olfactory epithelium respiratory metaplasia in 100 mg/kg females, the incidences of atrophy, respiratory metaplasia, nerve atrophy, and pigmentation were significantly increased in the olfactory epithelium of all dosed groups of males and females. Incidences of goblet cell hyperplasia in the respiratory epithelium were significantly increased in 300 and 1,000 mg/kg males and females, and incidences of chronic active inflammation were significantly increased in 1,000 mg/kg males and females. The incidence of submucosa fibrosis was significantly increased in 1,000 mg/kg males. The incidences of mononuclear cell leukemia in 300 and 1,000 mg/kg males were significantly greater than that in the vehicle controls. Dose-related increased severity of kidney nephropathy was noted in all dosed groups of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 200, 600, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 weeks. Survival of 600 and 2,000 mg/kg males was significantly less than that of the vehicle controls; survival of 600 mg/kg females was significantly greater than that of the vehicle controls. Mean body weights of 600 and 2,000 mg/kg males were less (10% or more) than those of the vehicle controls after weeks 85 and 77, respectively; mean body weights of 2,000 mg/kg females were generally less than those of the vehicle controls between weeks 17 and 69 and after week 93. In the liver, there were significantly increased incidences of hepatocellular adenoma in all dosed groups of females, hepatocellular carcinoma in all dosed groups of males and 2,000 mg/kg females, and hepatoblastoma in all dosed groups of males and 600 and 2,000 mg/kg females. The increased incidences of these neoplasms were primarily due to increased incidences of multiple adenoma, carcinoma, and hepatoblastoma. Except for the incidences of hepatocellular carcinoma or hepatoblastoma (combined) in 200 and 600 mg/kg females, the incidences of hepatocellular adenoma or carcinoma (combined), hepatocellular carcinoma or hepatoblastoma (combined), and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) were significantly increased in all dosed groups of males and females. Significantly increased incidences of nonneoplastic liver lesions included hypertrophy in all dosed groups of males and females, erythrophagocytosis in all dosed groups of males and in 600 and 2,000 mg/kg females, hematopoietic cell proliferation, inflammation, and necrosis in 600 and 2,000 mg/kg males, and cytoplasmic vacuolization, eosinophilic focus, and mixed cell focus in all dosed groups of females. In the thyroid gland, two incidences each of follicular cell adenoma occurred in the 600 and 2,000 mg/kg male groups. The incidence of follicle hyperplasia was significantly increased in 2,000 mg/kg males, and the incidences of follicular cell hypertrophy were significantly increased in 2,000 mg/kg males and 600 and 2,000 mg/kg females. In the forestomach, the incidences of inflammation, epithelium hyperplasia, and epithelium hyperkeratosis were significantly increased in all dosed groups of males and in 2,000 mg/kg females; the incidences of epithelium ulcer were significantly increased in 2,000 mg/kg males and females. GENETIC TOXICOLOGY Ginkgo biloba extract was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101, with and without exogenous metabolic activation. (ABSTRACT TRUNCATED)
Nutraceutically, much of the literature has indicated that an aglycon and its related glycoside would act similarly. However, controversial reports are accumulating. We hypothesize that rutin (RT) and quercetin (QT) pharmacodynamically could act differently. To confirm this, doxorubicin (DR) (8.5 mg/kg) was used to induce rat chronic kidney disease (CKD) and then treated with QT and RT (each 70 mg/kg body weight per day) for 13 weeks. QT exhibited better body weight gaining effect (420 ± 45) vs RT, 350 ± 57 g/rat (p < 0.001). DR raised the ratio kidney-to-body weight (%) to 0.82 (p < 0.001) vs RT, 0.62 (p < 0.01), and QT, 0.35 (p < 0.01). DR reduced the glomerular filtration rate to 25.2 vs RT, 48 ± 11.3; QT, 124.7 ± 12.8 (p < 0.001) and the control, 191.5 ± 15.7 mL/h (p < 0.001). DRCKD reduced hematocrit to 29 ± 5; RT, to 28 ± 5 (p < 0.05); QT, to 36 ± 6 vs the control 37.5 ± 4%, (p < 0.01). DRCKD reduced the serum albumin (s-Ab) to 2.1 ± 0.2 (p < 0.001); QT, to 2.7 ± 0.2 (p < 0.05) vs the normal 4.3 ± 0.5 g/dL, yet RT was totally ineffective. DRCKD raised serum cholesterol level to 340 ± 30; vs RT, 260 ± 12; QT, 220 ± 25; and the normal value, 70 ± 25 mg/dL. DRCKD increased serum triglyceride to 260 ± 15 (p < 0.001), RT and QT restored it to 170 ± 25 and 200 ± 15 (p < 0.05) vs the normal 26-145 mg/dL. DRCKD elevated blood urea nitrogen to 38 ± 3 vs RT, to 98 ± 6 mg/dL (p < 0.001), implicating "protein-energy malnutrition". RT stimulated serum creatinine (sCr) production to reach 6.0 ± 0.9 mg/dL (p < 0.001). QT did not alter the sCr level. RT but not QT induced uremia and hypercreatininemia. DR significantly downregulated Bcl-2, but highly upregulated Bax, Bad, and cleaved caspase-3, implicating the intrinsic mitochondrial pathway. DR damaged DNA, but QT completely rescued such an effect and recovered renal amyloidosis and collagen deposition. Conclusively, RT and QT act differently, and RT is inferior to QT with respect to treating CKD.
Quercetin, which is considered as a health-promoting antioxidant, belongs to the broad flavonoids group. Numerous experimental studies have proved that quercetin and vitamin C provide anti-inflammatory and antioxidant properties. The aim of this study is to assess the effects of both quercetin and vitamin C on lipid profile and muscle damage in human subjects.
A randomized, placebo-controlled, double-blind clinical trial was carried out on 60 males for eight weeks. The subjects were randomly assigned to one of the four groups: 1) quercetin + vitamin C (500 mg/day quercetin + 200 mg/day vitamin C) 2) quercetin (500 mg/day quercetin + 200 mg/day placebo) 3) vitamin C (500 mg/day vitamin C + 200 mg/day placebo) and 4) placebo (500 mg/day placebo + 200 mg/day placebo). Blood samples, body weight and percent of body fat were measured before and after intervention. In addition, dietary intake was estimated using 24-h recall.
No significant changes occurred in high-density lipoprotein levels between groups and in the four groups before and after supplementation. Low density lipoprotein values decreased significantly (P = 0.048) in the "Quercetin + Vit C" group but decrease was not considerable in other groups before and after intervention and among groups. Fat-soluble vitamins' intake was significantly high among 4 groups.
Quercetin and vitamin C supplementation may not be beneficial in lipid profile improvement, although it may reduce induce muscle damage and body fat percent.
Scope:
Epidemiologic evidence supports that dietary quercetin reduces cardiovascular disease (CVD) risk, but its oral bioavailability is paradoxically low. The aim of this study was to determine whether dietary fat would improve quercetin bioavailability in adults at high risk for CVD and to assess lipid-mediated micellarization of quercetin in vitro.
Methods and results:
In a randomized, cross-over study, overweight/obese men and postmenopausal women (n = 4 M/5 F; 55.9 ± 2.1 years; 30.8 ± 1.4 kg/m(2) ) ingested 1095 mg of quercetin aglycone with a standardized breakfast that was fat-free (<0.5 g), low-fat (4.0 g), or high-fat (15.4 g). Plasma was obtained at timed intervals for 24 h to measure quercetin and its methylated metabolites isorhamnetin and tamarixetin. Compared to the fat-free trial, plasma quercetin maximum concentration (Cmax ), and area under curve (AUC0-24 h ) increased (p < 0.05) by 45 and 32%, respectively, during the high-fat trial. During the high-fat trial, isorhamnetin Cmax and AUC0-24 h also increased by 40 and 19%, respectively, whereas Cmax and AUC0-24 h of tamarixetin increased by 46 and 43%, respectively. Dietary fat dose-dependently increased micellarization efficiency of quercetin aglycone in vitro.
Conclusion:
Dietary fat improves quercetin bioavailability by increasing its absorption, likely by enhancing its micellarization at the small intestine.
Catechins, the flavonoids found in abundance in green tea, have many beneficial health effects such as antioxidative, anticarcinogenic, anti-inflammatory, antiallergic, and hypotensive properties. However, flavonoids have antithyroid/goitrogenic effect, although less information is available about the effect of pure catechin on thyroid physiology. The present investigation has been undertaken to explore the effect of catechin administration on thyroid physiology in rat model. For the in vivo experiment catechin was injected intraperitoneally (i.p.) at doses of 10, 20 and 30 mg/kg body to male albino rats for 15 and 30 days, respectively, and thyroid activities were evaluated with respect to determination of serum levels of thyroid hormones, thyroid peroxidase, 5'-deiodinase I (5'-DI), and Na(+), K(+)-ATPase activities that are involved in the synthesis of thyroid hormone. Catechin decreased the activities of thyroid peroxidase and thyroidal 5'-deiodinase I, while Na(+), K(+)-ATPase activity significantly increased in dose-dependent manner; substantial decrease in serum T3 and T4 levels coupled with significant elevation of serum TSH were also noted. Histological examinations of the thyroid gland revealed marked hypertrophy and/or hyperplasia of the thyroid follicles with depleted colloid content. In in vitro study, short-term exposure of rat thyroid tissue to catechin at the concentrations of 0.10, 0.20, and 0.30 mg/ml leads to decrease in the activities of thyroid peroxidase and 5'-deiodinase I, while the activity of thyroidal Na(+), K(+)-ATPase remains unaltered even at high concentration of catechin treatment. The present study reinforces the concept that catechin, tea flavonoids possess potent antithyroid activity as evidenced from in vivo and in vitro studies.
Thyroid peroxidase (TPO), a tissue-specific enzyme expressed in differentiated thyroid follicular cells, is a major antigen that has been linked to autoimmune thyroid disease. We have previously reported the functional expression of the lipopolysaccharide (LPS) receptor Toll-like receptor 4 on thyroid follicular cells. Here we investigated the effect of LPS in TPO expression and analyzed the mechanisms involved. We found a dose-dependent enhancement of TSH-induced TPO expression in response to LPS stimulation. EMSAs demonstrated that LPS treatment increased thyroid transcription factor-1 and -2 binding to the B and Z regions of TPO promoter, respectively. Moreover, LPS increased TSH-stimulated TPO promoter activity. Using bioinformatic analysis, we identified a conserved binding site for transcription nuclear factor-κB (NF-κB) in the TPO promoter. Chemical inhibition of NF-κB signaling and site-directed mutagenesis of the identified κB-cis-acting element abolished LPS stimulation. Furthermore, chromatin immunoprecipitation assays confirmed that TPO constitutes a novel NF-κB p65 subunit target gene in response to LPS. Additionally, our results indicate that p65 phosphorylation of serine 536 constitutes an essential step in the p65-dependent, LPS-induced transcriptional expression of TPO. In conclusion, here we demonstrated that LPS increases TPO expression, suggesting a novel mechanism involved in the regulation of a major thyroid autoantigen. Our results provide new insights into the potential effects of infectious processes on thyroid homeostasis.
The aim of this study was to investigate the effects of quercetin on nitric oxide synthase (NOS), nuclear factor-κB (NF-κB) and apoptosis in renal ischemia/reperfusion (I/R) injury in rats. A total of 42 Sprague-Dawley rats were divided into three groups. The control, I/R and I/R+quercetin (I/R+Q) groups were treated with quercetin (50 mg/kg intraperitoneal) 1 h prior to the induction of ischemia. Tissue malondialdehyde (MDA) and glutathione (GSH) levels were determined by high-performance liquid chromatography (HPLC). p53, endothelial NOS (eNOS) and NF-κB expression were assessed immunohistochemically, and apoptosis assesment was performed using terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) assay. The mRNA levels of inducible NOS (iNOS) in renal tissue were determined by real-time polymerase chain reaction (RT-PCR). MDA levels were significantly decreased in the quercetin group compared to the I/R group. However, GSH levels were significantly increased with quercetin treatment in the I/R group. Histological results, the number of apoptotic and p53-positive cells, NF-κB and eNOS expression levels were significantly decreased in the quercetin treatment group compared to the I/R group. iNOS gene expression increased in the I/R group, but no significant difference was found between the I/R and quercetin treatment groups. Therefore, quercetin not only has antioxidant and anti-apoptotic activities, but also has an inhibitory effect on eNOS and NF-κB for renal tissue protection during I/R injury in rats. Therefore, quercetin may be a promising renoprotective therapeutic agent.
Increased consumption of fruit and vegetables can represent an easy strategy to significantly reduce the incidence of cancer. We recently demonstrated that the flavonoid quercetin, naturally present in the diet and belonging to the class of phytochemicals, is able to sensitize several leukemia cell lines and B cells isolated from patients affected by chronic lymphocytic leukemia (B-CLL), in addition to apoptotic inducers (anti-CD95 and rTRAIL). Further, it potentiates the effect of fludarabine, a first-line chemotherapeutic drug used against CLL. The proapoptotic activity of quercetin in cell lines and B-CLL is related to the expression and activity of Mcl-1-antiapoptotic proteins belonging to the Bcl-2 family. Quercetin downregulates Mcl-1 mRNA and protein levels acting on mRNA stability and protein degradation. Considering the low toxicity of the flavonoids toward normal peripheral blood cells, our experimental results are in favor of a potential use of quercetin in adjuvant chemotherapy in CLL or other types of cancer.
Oxidative stress in the central nervous system is one of the key players for neurodegeneration. Thus, antioxidants could play important roles in treating several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and aging-related brain disorders. This review is focused on the new developments in oxidative stress-induced neurodegeneration. Further, based on our own investigations, new roles of quercetin, an antioxidant compound in hypoxia and ischemia induced neuroprotection in relation to suppression of oxidative stress, improvement in behavioral function, reduction in infarct volume, brain swelling, and cellular injury in both in vivo and in vitro models are discussed. Our new findings clearly suggest that antioxidant compounds have potential role in therapeutic strategies to treat neurodegenerative diseases in clinical settings.
Endemic fluorosis is a serious problem in public health. Previous studies have indicated that patients with thyroid goiters usually live in fluoride-affected areas. However, the mechanism of goitrogenesis caused independently by fluoride is still unclear. The principle objective of this study was to investigate the possible roles of nitric oxide (NO) and vascular endothelial growth factor (VEGF) in the genesis of fluoride-induced nodular goiters. Eighty SD rats (40 males and 40 females) at the age of 4 weeks were used to establish animal models via fluoride-supplemented drinking water. These rats were randomly divided into four groups of 20. Group 1 was used as the control and were given deionized water. Group 2 (LF), group 3 (MF), and group 4 (HF) were given deionized water containing 50mg/L, 100mg/L, and 200mg/L of sodium fluoride (NaF), respectively. Thyroid samples were collected on day 150. Pathological observation was performed to evaluate structural changes in the thyroid gland. The expression of VEGF mRNA in the thyroid glands was assessed by reverse transcriptional PCR. The serum NO level was analyzed by spectrometric methods. In addition, immunohistochemistry was conducted to evaluate expression and deposition of VEGF in the thyroid gland. The results showed that the average relative weight of the thyroid glands of rats in the fluoride-treated groups was significantly higher than that in control rats (p<0.05). The proliferation and dilatation of capillary blood vessels, enlarged follicles with excessive colloid, and obvious nodules were found in the thyroid glands of fluoride-treated rats. Compared to the control group, the expression of VEGF mRNA in the thyroid gland and the serum NO levels in the fluoride-treated groups were significantly increased (p<0.05). Furthermore, the deposition of VEGF in epithelial and follicular cells of the thyroid gland was significantly higher in fluoride-treated groups than in the control group. These results suggested that abnormal expression of VEGF induced by fluoride can lead to the proliferation of vascular endothelial cells in the thyroid gland. Accordingly, VEGF oversecreted locally by vascular endothelial cells might contribute to the proliferation of epithelial and follicular cells, resulting in the formation of hyperplastic nodules and enlargement of the thyroid gland. Furthermore, we proposed that there might be a positive feedback mechanism between NO and VEGF expression in fluoride-induced goiter formation. It was concluded that angiogenic and vasodilative factors such as VEGF and NO must be involved in fluoride-induced thyroid goitrogenesis.
Oral glucosamine and chondroitin sulfate, alone and in combination, have been used worldwide for the treatment of osteoarthritis (OA), but their efficacy is controversial. This clinical study was aimed at investigating the potential of a dietary supplement containing glucosamine and chondroitin sulfate in combination with derivatives of quercetin, a naturally occurring flavonoid, (GCQ supplement) for knee OA care.
A randomized, double-blind, placebo-controlled study was conducted in 40 Japanese subjects with symptomatic knee OA. Subjects were randomly assigned to GCQ supplement (1200 mg glucosamine hydrochloride, 60 mg chondroitin sulfate and 45 mg quercetin glycosides per day) or placebo and the treatment and follow-up were continued for 16 weeks. The results of symptomatic efficacy assessment based on Japanese Orthopaedic Association criteria showed that scores for two of the four symptom/function subscales, as well as the aggregate scores, were significantly improved at week 16 or earlier in the GCQ group compared to the placebo group. Moreover, analyses of cartilage metabolism biomarkers showed a trend of improvement in type II collagen synthesis/degradation balance in the GCQ group during follow-up.
GCQ supplement was thought to be more effective than placebo in decreasing the intensity of knee OA-associated clinical symptoms.
Biochemical and genetic studies on cellular and animal models on the mechanism(s) of action of phytochemicals provide a functional explanation of how and why a diet rich in fruits and vegetables is considered healthy. It is not unusual to find molecules that protect against diseases, which greatly differ from a physiopathological point of view, such as cancer and cardiovascular disorders. Quercetin falls into this category and possesses a broad range of biological properties. Uptake, metabolism and circulating concentrations of quercetin and its metabolites suggest that a regular diet provides amounts of quercetin (<1 μM) not compatible with its chemopreventive and/or cardioprotective effects. However, it appears relatively easy to increase total quercetin concentrations in plasma (>10 μM) by supplementation with quercetin-enriched foods or supplements. Multiple lines of experimental evidence suggest a positive association between quercetin intake and improved outcomes of inflammatory cardiovascular risk. The ameliorating effect of quercetin administration can be extended to other chronic inflammatory disorders but only if supplementation occurs in patients. Quercetin can be considered the prototype of a naturally-occurring chemopreventive agent because of its key roles in triggering the "hallmarks of cancer". However, several critical points must be taken into account when considering the potential therapeutic use of this molecule: (1) pharmacological versus nutraceutical doses applied, (2) specificity of its mechanism of action compared to other phytochemicals, and (3) identification of "direct" cellular targets. The design of specific clinical trials is extremely warranted to depict possible applications of quercetin in adjuvant cancer therapy.
Quercetin is a typical anti-oxidative flavonoid ubiquitously distributed in vegetables. It is likely to act as a bioactive compound by exerting reactive oxygen species (ROS)-scavenging activity and/or binding to specific proteins such as oxidative enzymes and transcriptional factors in signal transduction pathways. Its absorption and metabolism (as well as its molecular targets) have been extensively explored from the viewpoint of its potential for disease prevention. It is known that glucuronide and/or sulfate conjugates with or without O-methylation exclusively circulate in the human bloodstream after intake of a quercetin-containing diet. We propose that glucuronide conjugates of quercetin function not only as detoxified metabolites but hydrophilic bioactive agents to various ROS-generating systems and precursors of hydrophobic aglycone. Quercetin aglycone is assumed to emerge in the target site by the action of β-glucuronidase activity under oxidative stress such as inflammation. The cardiovascular system and central nervous system seem to be the major targets of conjugated quercetin glucuronides circulating in the human bloodstream.
Greater understanding about the pathogenesis of metabolic syndrome and potential causes suggests that plant polyphenols might be useful as a treatment. Dietary excess energy can be stored in adipocytes, leading to the release of proinflammatory cytokines and adipose-related hormones that cause vascular injury. Plant polyphenols, organic compounds found in numerous plant species and their fruits, are being actively studied as potential treatments for components of the metabolic syndrome. Individual polyphenols that have been examined include resveratrol, quercetin, epigallocathechin-3-gallate, and curcumin. Resveratrol lowers weight, blood pressure, glucose, and insulin resistance in rodents, and a human trial is currently underway. Quercetin decreases lipid and glucose levels in obese rats, and in a human investigation of subjects with the metabolic syndrome has lowered blood pressure without significant alteration of lipids. Epigallocathechin-3-gallate-induced weight loss has attenuated glucose levels and insulin resistance in rodents and improved hemoglobin A(1c) and lipid in human studies. Plant extracts also can be used. Grape seed and chokeberry extracts have decreased blood pressure and lipid levels in small human trials. Other human investigations have shown the beneficial effects of cocoa, coffee, carob, and Momordica charantia. Thus far, most studies have involved a small number of subjects and have been of short duration. Future studies should be designed to account for a disease process in which the pathogenic factors may take place for years before disease manifestations take place, the possibly limited bioavailability of polyphenols, and the potential need to provide combinations or modifications of polyphenols.
Paraquat (PQ) is known to induce pulmonary injury via a redox cyclic reaction. The present study was aimed to determine the protective effects of quercetin against PQ-induced pulmonary injury in association with its antioxidant activity.
Male rats were challenged acutely by PQ (50 mg/kg, i.p.) with or without quercetin post-treatment. Pulmonary heme oxygenase-1 (HO-1) expression, malondialdehyde (MDA) level, and the total oxyradical scavenging capacity (TOSC) toward hydroxyl, peroxyl radicals and peroxynitrite were measured 24 h after PQ treatment. Different groups of rats were instilled with PQ (0.5 mg/kg) directly into the right lung. Quercetin was administered to the rats daily for 14 days after PQ instillation. Serum NO, pulmonary glutathione (GSH) and 4-hydroxyproline (4-HP) concentrations were quantified in conjunction with histopathological examination to determine the fibrotic changes in lung.
Pulmonary MDA level and HO-1 expression were elevated and the TOSC was reduced rapidly by an intraperitoneal dose of PQ. These changes were inhibited by quercetin post-treatment. In rat lungs instilled with PQ 14 days before, NO, MDA and 4-HP were elevated, and GSH was reduced, which were all inhibited significantly by daily quercetin treatment. Histopathological examination also revealed that quercetin ameliorated the increase in fibroblast distribution and collagen deposition in the lungs instilled with PQ.
The present results demonstrate that quercetin administration to rats effectively inhibits the development of PQ-induced pulmonary injury most probably via its antioxidant activity.
Molecular mechanisms underlying the links between dietary intake of flavonoids and reduced cardiovascular disease risk are only partially understood. Key events in the pathogenesis of cardiovascular disease, particularly thrombosis, are inhibited by these polyphenolic compounds via mechanisms such as inhibition of platelet activation and associated signal transduction, attenuation of generation of reactive oxygen species, enhancement of nitric oxide production and binding to thromboxane A(2) receptors. In vivo, effects of flavonoids are mediated by their metabolites, but the effects and modes of action of these compounds are not well-characterized. A good understanding of flavonoid structure-activity relationships with regard to platelet function is also lacking.
Inhibitory potencies of structurally distinct flavonoids (quercetin, apigenin and catechin) and plasma metabolites (tamarixetin, quercetin-3'-sulphate and quercetin-3-glucuronide) for collagen-stimulated platelet aggregation and 5-hydroxytryptamine secretion were measured in human platelets. Tyrosine phosphorylation of total protein, Syk and PLCgamma2 (immunoprecipitation and Western blot analyses), and Fyn kinase activity were also measured in platelets. Internalization of flavonoids and metabolites in a megakaryocytic cell line (MEG-01 cells) was studied by fluorescence confocal microscopy. Key results: The inhibitory mechanisms of these compounds included blocking Fyn kinase activity and the tyrosine phosphorylation of Syk and PLCgamma2 following internalization. Principal functional groups attributed to potent inhibition were a planar, C-4 carbonyl substituted and C-3 hydroxylated C ring in addition to a B ring catechol moiety.
The structure-activity relationship for flavonoids on platelet function presented here may be exploited to design selective inhibitors of cell signalling.
TSH receptor mRNA levels in FRTL-5 thyroid cells are autoregulated at a transcriptional level by the same hormones required for the growth and function of the cells: TSH, insulin, and insulin-like growth factor-I (IGF-I). Thus, the ability of TSH, via its cAMP signal, to down-regulate steady state receptor mRNA levels is preceded by the action of TSH to decrease pre-mRNA levels in nuclear run-on assays to the same quantitative level as evident in Northern analyses. In contrast, the receptor mRNA half-life is shown not to change when down-regulation is reversed by withdrawing TSH in the presence or absence of actinomycin-D. Evidence is additionally provided that TSH receptor mRNA levels are increased by insulin, IGF-I, or calf serum in both Northern and run-on assays. This action cannot be duplicated by hydrocortisone and is evident at more than 20-fold lower concentrations of IGF-I than insulin. Moreover, insulin, IGF-I, and/or calf serum are required for the autoregulatory negative transcriptional regulation of the TSH receptor by TSH/cAMP, as is the case for thyroglobulin. This occurs despite the opposite actions of TSH/cAMP on the two genes, positive in the case of thyroglobulin and negative with TSH receptor. The positive and negative regulatory actions, respectively, of insulin/IGF-I and TSH on receptor gene expression are associated with coincident increases or decreases in cell surface receptors measured by [125I]TSH binding. The autoregulation additionally involves the interplay of a second cAMP-modulated regulatory factor, one which up-regulates TSH receptor mRNA levels rather than causing down-regulation. Thus, cycloheximide inhibits the transcriptional action of both TSH/cAMP and insulin/IGF-I/serum within 4 h, i.e. a rapidly synthesized protein is an intermediate in both cases. The presence of cycloheximide for as little as 1 h, however, uncovers the ability of TSH/cAMP to increase TSH receptor mRNA levels. This activity is the result of the action of a stable cAMP-induced activator which can be detected physiologically, i.e. in the absence of cycloheximide. For example, low levels of a cAMP analog (0.2 mM), as opposed to high levels (greater than 1 mM), can increase TSH receptor RNA levels. Low levels also accelerate the insulin/IGF-I-dependent return of receptor mRNA to normal levels after TSH withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)
Autoimmune thyroid disease is associated with enhanced expression of major histocompatibility complex class I antigens on thyrocytes. To better understand this phenomenon, we have studied the normal expression of class I genes in FRTL-5 rat thyroid cells. A variety of hormones and growth factors that regulate the growth and function of these thyroid cells were found to decrease class I RNA levels: serum, insulin or insulin-like growth factor-I (IGF-I), and hydrocortisone. Antibody preparations from Graves' patients (thyroid-stimulating antibodies), which increase cAMP levels and stimulate the thyroid, also decrease class I RNA levels. This is consistent with the fact that TSH, via its cAMP signal, reduces class I transcripts. The class I response to TSH, serum, insulin, IGF-I, or hydrocortisone is specific, in that the same agents do not similarly affect TSH receptor, thyroglobulin, thyroid peroxidase, malic enzyme, or beta-actin RNA levels. Both gamma- and alpha-interferon increase class I RNA levels in FRTL-5 cells, even in the presence of the serum, IGF-I, or hormones noted above, i.e. they overcome hormonal negative regulation in normal thyrocytes. In contrast, methimazole treatment of rat FRTL-5 thyroid cells, but not rat fibroblasts or rat FRT thyroid cells, which have no TSH receptor and no TSH-regulated function, results in reduced class I RNA levels. The action of methimazole can inhibit interferon action, is transcriptional, is duplicated by iodide, and is additive with the negative regulatory action of hormones and serum factors, including TSH.
A rat thyroid peroxidase cDNA has been isolated from a FRTL-5 thyroid cell library and sequenced. The cDNA is 2776 base pairs long with an open reading frame of 770 amino acids. By comparison to full-length human thyroid peroxidase cDNA and based on its identification of a 3.2 kilobase mRNA in rat thyroid FRTL-5 cell Northern blots, the rat peroxidase cDNA appears to lack 400-500 base pairs at the 5'-end of the mRNA. It exhibits only a 74% nucleotide and 77% amino acid sequence similarity to human thyroid peroxidase cDNA within the total aligned sequences, although the predicted active site regions are highly conserved (greater than 90-100%). The cDNA has been used to map the thyroid peroxidase gene in mice to chromosome 12 and to compare thyroid peroxidase and thyroglobulin gene expression in FRTL-5 rat thyroid cells. Despite the fact TSH action in both cases is duplicated, and presumably mediated, by cAMP, TSH-induced increases in thyroid peroxidase and thyroglobulin mRNA levels differ. Differences exist with respect to hormone concentration and time. The ability of TSH to increase thyroglobulin, but not thyroid peroxidase mRNA levels, requires insulin, 5% serum, or insulin-like growth factor-I. Insulin or insulin-like growth factor-I alone can increase thyroglobulin mRNA levels as well as or better than TSH but have only a small effect on thyroid peroxidase mRNA levels by comparison to TSH. The ability of TSH to increase thyroglobulin gene expression is readily detected in nuclear run-on assays but not the ability of TSH to increase thyroid peroxidase gene expression. Cycloheximide inhibits TSH-increased thyroglobulin but not peroxidase mRNA levels. Finally, methimazole and phorbol 12-myristate 13-acetate show different effects on TSH-induced increases in thyroglobulin and thyroid peroxidase mRNA levels.
The major histocompatibility complex (MHC) is composed of a set of linked genes encoding proteins involved in the host's immune response1. A subset of these proteins are the classical transplantation antigens, which are responsible for rapid allograft rejection and are involved in the associative recognition of foreign antigens by cytotoxic T cells1,2. Three different genetic loci coding for the transplantation antigens in humans (HLA-A, -B and -C) and in mice (H-2K, D and L) have been identified3,4; they are highly polymorphic1. The recent molecular cloning of HLA5,6 and H-27,8 cDNA sequences provide the basis for detailed characterization of the genetic organization and expression of the MHC. We report here the identification, by analysis of cDNA clones, of at least three distinct classes of H-2 messenger RNAs that can be differentiated on the basis of their disparate 3'-non-translated regions, and describe an unusual sequence arrangement in one class of H-2-like molecule.
This chapter discusses the current perceptions of the role of the thyrotropin receptors (TSHR) in disease states. It describes the epitopes of autoantibodies against the TSHR (TSHRAbs)-stimulating TSHRAbs and blocking TSHRAbs, which cause hyper- (Graves' disease) or hypothyroidism idiopathic myxedemal-and will examine the basis for their development. Mutations of the TSHR associated with hyperfunctioning adenomas and will relate these to mutations in the lutropin/choriogonadotropin receptor (LH/CGR) associated with precocious puberty are also described. The complex processes required for thyroid growth and function are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGFI, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH, as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction are being rapidly unraveled in several laboratories, since the recent cloning of the receptor.
Flavonoids are widely distributed in plant-derived foods and possess a variety of biological activities including antithyroid effects in experimental animals and humans. A structure-activity study of 13 commonly consumed flavonoids was conducted to evaluate inhibition of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis. Most flavonoids tested were potent inhibitors of TPO, with IC50 values ranging from 0.6 to 41 microM. Inhibition by the more potent compounds, fisetin, kaempferol, naringenin, and quercetin, which contain a resorcinol moiety, was consistent with mechanism-based inactivation of TPO as previously observed for resorcinol and derivatives. Other flavonoids inhibited TPO by different mechanisms, such as myricetin and naringin, showed noncompetitive inhibition of tyrosine iodination with respect to iodine ion and linear mixed-type inhibition with respect to hydrogen peroxide. In contrast, biochanin A was found to be an alternate substrate for iodination. The major product, 6,8-diiodo-biochanin A, was characterized by electrospray mass spectrometry and 1H-NMR. These inhibitory mechanisms for flavonoids are consistent with the antithyroid effects observed in experimental animals and, further, predict differences in hazards for antithyroid effects in humans consuming dietary flavonoids. In vivo, suicide substrate inhibition, which could be reversed only by de novo protein synthesis, would be long-lasting. However, the effects of reversible binding inhibitors and alternate substrates would be temporary due to attenuation by metabolism and excretion. The central role of hormonal regulation in growth and proliferation of thyroid tissue suggests that chronic consumption of flavonoids, especially suicide substrates, could play a role in the etiology of thyroid cancer.
Bioflavonoids have been regarded as therapeutic agents for a wide range of disease including inflammation. In this report, we investigated effects of bioflavonoid quercetin on mitosis and apoptosis of glomerular cells in vitro and in vivo. Serum-stimulated rat mesangial cells were treated with or without quercetin, and total cell number, percentages of mitotic cells, and incorporation of [(3)H]-thymidine were evaluated. All three assays showed that mitogenic activity of mesangial cells was markedly attenuated by quercetin. To examine the effect of quercetin on apoptosis, mesangial cells were pretreated with or without quercetin and stimulated by hydrogen peroxide or tumor necrosis factor-alpha. Hoechst staining and DNA ladder assay showed that both apoptotic responses were dramatically inhibited by quercetin. We further investigated effects of quercetin on in vivo mitosis and apoptosis of glomerular cells. Rats were administered with or without quercetin intraperitoneally, and nephrotoxic serum nephritis was induced. Immunohistochemical analyses showed that treatment with quercetin significantly reduced the number of proliferating cell nuclear antigen (+) cells and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (+) cells in the glomerulus. These data suggested that quercetin has the potential for inhibiting mitosis and apoptosis of glomerular cells both in vitro and in vivo.
Some dietary flavonoids inhibit thyroperoxidase and hepatic deiodinase activity, indicating that these compounds could be classified as anti-thyroid agents. In this study, we evaluated the in vitro effect of various flavonoids on thyroid type 1 iodothyronine deiodinase activity (D1). D1 activity was measured in murine thyroid microsome fractions by the release of 125I from 125I-reverse T3. D1 activity was significantly inhibited by all the flavonoids tested; however, the inhibitory potencies on thyroid D1 activity differed greatly among them. A 50% inhibition of D1 activity (IC(50)) was obtained at 11 microM baicalein, 13 microM quercetin, 17 microM catechin, 55 microM morin, 68 microM rutin, 70 microM fisetin, 72 microM kaempferol and 77 microM biochanin A. Our data reinforce the concept that dietary flavonoids might behave as antithyroid agents, and possibly their chronic consumption could alter thyroid function.
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.