Article

Luteolin enhances insulin sensitivity via activation of PPARΓ transcriptional activity in adipocytes

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Abstract

Obesity and insulin resistance have been linked to a low-grade chronic inflammatory response characterized by increased macrophage infiltration, altered cytokine production and activation of inflammatory signaling pathway in adipose tissue. Pharmacological agents and natural products that are capable of reducing inflammatory activity possess anti-diabetic properties. Luteolin, a naturally occurring flavonoid, has been demonstrated to inhibit lipopolysaccharide-induced tumor necrosis factor-α (TNFα) release and activation of NF-κB pathway in macrophages. However, little is known about the mechanism and effect of luteolin on inflammation-related insulin resistance in adipocytes. In this study, we investigated the effect of luteolin on insulin action in 3T3-L1 adipocytes and primary adipose cells. Here we showed that luteolin treatment for 24 h increased the response of glucose uptake to insulin stimulation in 3T3-L1 adipocytes. Our results also demonstrated that luteolin enhanced Akt2 phosphorylation in an insulin-stimulated state. Furthermore, luteolin treatment decreased mRNA levels of TNFα, interleukin-6 and MCP-1, while it increased the gene expression of adiponectin and leptin in 3T3-L1 adipocytes and primary mouse adipose cells. Most interestingly, we found that treatment of luteolin markedly enhanced peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity in 3T3-L1 adipocytes, and luteolin-increased expression of adiponectin and leptin was blocked by GW9662, a PPARγ antagonist. Thus, our data suggest that luteolin influences insulin action and production of adipokines/cytokines in adipocytes by activating the PPARγ pathway.

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... Akin to our results, the HOMA-IR index was also significantly decreased by luteolin in KK-Ay diabetic [25] and HFD mice [26,28]. Moreover, previous research involving adipocytes [29] and HFD mice [27] had established that luteolin increased glucose uptake through enhanced insulin-signalling and glucose transporter type 4 (GLUT4) gene expression. Luteolin also potentiated insulin effect in endothelium via an IKKβ/ IRS-1/Akt/eNOS-dependent pathway [30]. ...
... Reaffirming this, luteolin had downregulated TNF-α expression in mast cells in mice [27] and decreased NF-κB levels in ulcerative colitis rats [32] through the modulation of PPAR-γ. In accordance with the results of this study, in vitro research in 3T3-L1 and primary mouse adipocytes confirmed that luteolin enhanced the gene expression and transcriptional activation of PPAR-γ [29]. Luteolin was reported to bind to PPAR-γ in a different mode from thiazolidinediones but it activated GLUT4 to a comparative degree as rosiglitazone in murine 3T3-L1 cells [33]. ...
... TNF-α mediated activation of the IKKβ/NF-κB pathway, with overexpression of suppressor of cytokine signalling 3 (SOCS3) by IL-6, resulted in attenuation of insulin receptor signal transduction, down-regulation of GLUT4 and Insulin Receptor Substrate-1 (IRS-1), attenuation of insulin-mediated glucose uptake, β-cell malfunction, and eventually insulin resistance [3]. Luteolin modulated these inflammatory mediators and reduced TNF-α and IL-6 levels in in vitro studies [7,9,27,29,30]. Consistent with studies in KK-Ay mice [25], HFD mice [26,27], STZ-diabetic mice [9,34] and STZ-diabetic rats [35], a significant reduction in TNF-α and IL-6 was observed in our results, which suggests that luteolin may have an ameliorating effect on insulin resistance via its antiinflammatory activity. ...
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Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10 days. Subsequently, a single dose of 40 mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200 mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10 mg/kg) or luteolin (50 mg/kg or 100 mg/kg) once daily for 28 days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic β-cells and kidneys to near normalcy. Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, β-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.
... 41 In this regard, an in vitro study 42 has shown an up-regulating role of chamomile extract on PPAR and glucose transporter (GLUT)-4 gene expression, which raises insulin sensitivity as well as decreases peripheral glucose levels, respectively. 42 Additionally, αglucosidase is an important carbohydrate digestive enzyme in the enterocyte brush border 39 which might be suppressed by quercetin and esculetin, two main components of chamomile, and thus reduce circulating glucose levels dramatically. 43 Additionally, prolonged exposure to hyperglycemia is accompanied by high levels of reducing sugars which react with lipids and proteins and has a deteriorative effects on endogenous antioxidant capacity. ...
... 51 Studies have shown that luteolin, one of the active components of chamomile, leads to an increase in the expression of the adiponectin gene. 42 Besides, the chamazulene carboxylic acid constituent of chamomile structurally shows similarities to profens and acts as a selective inhibitor of cyclooxygenase-2 and thereby may help to improve inflammatory responses. 46,52 Due to high amounts of chamomile antioxidants, it has been assumed that this herbal medicine extract can ameliorate oxidative stress and chronic inflammation in people suffering from DM. 25 The biological activities of chamomile on dyslipidemia have attracted a great deal of attention. ...
... 60 Therefore, due to the antioxidant properties of chamomile, it is recommended to investigate the effects of chamomile on the factors involved in the AMPK signaling pathway. Studies have shown that adiponectin, by binding to its receptor, leads to activating the AMPK pathway, 51 and considering the effect of luteolin, one of the active components of chamomile on increasing the expression of adiponectin gene, 42 it is recommended that future studies evaluate the effect of chamomile on the levels and expression of adiponectin gene expression. ...
Article
Chamomile, as a rich source of phenolic compounds and terpenoids, seems to be an effective approach in the management of chronic conditions such as diabetes mellitus. The aim of this systematic review was to evaluate evidence from animal and human studies of the effects of chamomile on metabolic risk markers and complications of diabetes mellitus. The literature search was conducted in PubMed, SCOPUS, Embase, ProQuest and Google Scholar electronic and were considered the articles published on April 2019. Original studies that investigated the effect of chamomile in diabetes mellitus which met the inclusion criteria were eligible. After screening 208 citations, 15 studies were included. The results of these studies demonstrated a significant effect of chamomile administration on metabolic profiles. All 12 studies that examined the impact of chamomile sup-plementation on glycemic control indicated this feature. Four of the five studies appraising the impact of cha-momile on lipid profiles showed that it improved dyslipidemia. Six studies showed that chamomile markedly decreased oxidative stress particularly malondialdehyde. Altogether, four chamomile studies evaluating diabetes complications, including renal and hepatic profiles, found significant decreases compared to controls. These findings extend the novel functions of chamomile in the improvement of glycemic and lipid profiles and oxi-dative stress indicators in diabetes mellitus and related complications. In-depth studies focusing on underlying mechanisms are warranted to make useful conclusions.
... Luteolin did not change the adipocyte formation or cellular lipid content in differentiated 3T3-L1 cells. In previous studies, luteolin resulted in contradictory results in intracellular lipid accumulation (Ding, Jin and Chen, 2010;Mosqueda-Solís et al., 2017;Park et al., 2009). Luteolin (from 10 μM) showed a lipid accumulation inhibiting effect on differentiated 3T3-L1 cells treated with IBMX, dexamethasone, and insulin at the early stage of differentiation (Park et al., 2009). ...
... Multiple dietary polyphenols such as apigenin, esculetin, and cyclocarioside have shown anti-adipogenic effects via AMPK inhibition (Guru et al., 2020). Luteolin showed AMPK activation effects that may attenuate the expression of PPARγ and C/EBPs to inhibit adipogenesis, but also can induce PPARγ activation (Ding et al., 2010;Zhang et al., 2016). The AMPK activating and the PPARγ partial agonism effects of luteolin may result in different adipogenic and lipogenic profiles when combined with ROSI and the POP mixture. ...
... Besides impacts on PPARγ, luteolin and luteolin-7-O-glucoside have shown inhibitory effects on glucose uptake via the glucose transporter (GLUT) 4 (Nagai et al., 2016;Nishina et al., 2015). In differentiated 3T3-L1 cells, luteolin promoted PPARγ expression and PPARγ DNA binding activity, and enhanced glucose uptake via glucose transporter (GLUT) 4 (Ding et al., 2010). Recently, the adipogenic and lipogenic effects of selected plastic extracts were elucidated, and showed chemicals extracted from plastic products increased adipocyte formation and lipid accumulation without the activation of PPARγ or glucocorticoid receptor pathways (Völker et al., 2022). ...
Article
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Human exposure to persistent organic pollutants (POPs) may contribute to obesogenic effects. We have previously shown that POP mixtures modelled on blood levels relevant to the Scandinavian population induces adipogenic effects in the mouse 3T3-L1 cell line. Luteolin is a flavone that has shown anti-lipogenic and anti-adipogenic effects on adipogenesis in in vitro models. In this study, luteolin has been applied to inhibit adipocyte formation and intracellular lipid content increase induced by a human relevant mixture of POPs. 3T3-L1 cells were exposed to a POP mixture consisting of 29 chemicals, including amongst others polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), it perfluoroalkylated acids (PFAAs), and polybrominated diphenyl ethers (PBDEs). Rosiglitazone was applied as a positive lipogenic control. Luteolin was tested between 0.5 and 10 μM. High content analysis was used to assess changes in adipocyte formation and intracellular lipid content in the 3T3-L1 cell line. Luteolin significantly reduced POP-induced adipocyte formation at 2, 5 and 10 μM, and lipid accumulation at 10 μM. Interestingly, luteolin did not affect rosiglitazone induced adipo- and lipogenic effects, suggesting differences in mechanisms of action. In conclusion, this in vitro study shows that dietary polyphenols such as luteolin may protect against POP induced adipo- and lipogenic effects.
... Moreover, rutin has been confirmed to regulate Glut-4 translocation in adipocytes and skeletal muscle cells by stimulating Akt synthesis and phosphorylation [40]. Ding et al., (2010) reported that the levels of Glut-4 gene expression were significantly increased in adipose cells that were treated with luteolin (20 µmol/L) for 24h [41]. ...
... Moreover, rutin has been confirmed to regulate Glut-4 translocation in adipocytes and skeletal muscle cells by stimulating Akt synthesis and phosphorylation [40]. Ding et al., (2010) reported that the levels of Glut-4 gene expression were significantly increased in adipose cells that were treated with luteolin (20 µmol/L) for 24h [41]. ...
... Moreover, rutin has been confirmed to regulate Glut-4 translocation in adipocytes and skeletal muscle cells by stimulating Akt synthesis and phosphorylation [40]. Ding et al., (2010) reported that the levels of Glut-4 gene expression were significantly increased in adipose cells that were treated with luteolin (20 µmol/L) for 24h [41]. ...
... Moreover, rutin has been confirmed to regulate Glut-4 translocation in adipocytes and skeletal muscle cells by stimulating Akt synthesis and phosphorylation [40]. Ding et al., (2010) reported that the levels of Glut-4 gene expression were significantly increased in adipose cells that were treated with luteolin (20 µmol/L) for 24h [41]. ...
Article
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How to cite this article: Almterin M, Aboalhaıja N, Zıhlıf M, Afıfı F. Effects of Ononis natrix on glucose and lipid metabolism: An in vivo study. J Res Pharm. 2024; 28(1): 278-288. ABSTRACT: Several medicinal plants have been used historically and are claimed to be effective in either preventing or treating diabetes. This study aimed to evaluate the effect and the mechanism of O. natrix extract (ONE) as an antihyperglycemic and antihyperlipidemic agents in in vivo experiments. Lipid profile was analyzed using fully automated chemistry analyzer. Blood serum samples were used to measure high-density lipoprotein (HDL), triglycerides (TG), total cholesterol (TC) and Low-density lipoprotein (LDL). The expression levels of AMPK alpha-2 and Glut-4 receptors in diabetic rats were investigated using Western blotting. Oral starch tolerance test (OSTT) and oral glucose tolerance test (OGTT) were determined for the plant extracts at three concentrations on Wistar rats. Acarbose or metformin and glipizide were used as positive controls. Blood glucose levels were measured at −30, 0, 45, 90 and 135 min.ONE (250mg/kg and 125 mg/kg), administered before or after induction of diabetes using streptozotocin (STZ), significantly (p<0.05) reduced the blood glucose level by applying preventive and treatment protocols. The expression levels of Glut-4 receptors were significantly increased in rats given ONE (250 mg and 125 mg/kg) compared to the diabetic rats after 8 days of treatment. ONE (250 mg/kg) enhanced significantly (p<0.05) starch tolerance area under the curve (AUC) and glucose tolerance AUC. O. natrix extracts can activate the Glut-4 receptor, and enhance the glucose and starch tolerance in experimental rats. Hence, this widely distributed species in Jordan can be considered as a potential candidate for management of diabetes.
... In human adipocytes cells, administration of chamomile extract resulted in expression of PPARγ target genes [49]. Luteolin, another ingredient of chamomile [50], increases insulin sensitivity and activates PPARγ transcription in adipocyte cells [51]. In addition, luteolin modulates GLUT-4 receptors in vitro, which can decrease insulin resistance. ...
... In addition, luteolin modulates GLUT-4 receptors in vitro, which can decrease insulin resistance. Luteolin also increased adiponectin gene expression [51], which can increase peripheral glucose utilization by activation of the AMPK enzyme and expression of the PPARγ gene in muscle and adipose tissue. Moreover, adiponectin suppresses gluconeogenesis [52,53]. ...
Article
The use of natural and herbal products as alternative therapies, in conjunction with blood glucose-lowering medications, is on the rise for patients with diabetes. Our objective was to conduct a systematic review and comprehensive meta-analysis of both human and animal models to investigate the impact of chamomile consumption on glycemic control. A systematic search was conducted on all published papers from January 1990 up to January 2022 via Scopus, PubMed/Medline, Google Scholar, and ISI Web of Science. Human and animal articles evaluating the effect of chamomile on serum glycemic markers were included. We used the random-effects model to establish the pooled effect size. The dose-dependent effect was also assessed. Overall, 4 clinical trials on human and 8 studies on animals met the inclusion criteria. With regard to RCTs, a favorable effect of chamomile consumption on serum fasting blood glucose (Standardized Mean Differences (SMD): -0.65, 95% CI: -1.00, -0.29, P < 0.001; I2 = 0%) and hemoglobin A1C (HbA1C) levels (SMD: -0.90, 95% CI: -1.39, -0.40, P < 0.001; I2 = 45.4%) was observed. Considering animal studies, consumption of chamomile extracts significantly reduced serum blood glucose (SMD: -4.37, 95% CI: -5.76, -2.98, P < 0.001; I2 = 61.2%). Moreover, each 100 mg/d increase in chamomile extract intervention resulted in a significantly declined blood glucose concentrations (MD: -54.35; 95% CI: -79.77, -28.93, P < 0.001; I2 = 94.8). The current meta-analysis revealed that chamomile consumption could exert favorable effects on serum blood glucose and HbA1C. However, additional randomized controlled trials are needed to further confirm these findings.
... Luteolin is believed to enhance the function of insulin and boost transcriptional activation of PPARγ [90]. Luteolin also lowers inflammatory monocyte chemotactic protein-1 (MCP-1), molecular circulation levels and resists augmentation of adiponectin in obese mice [91]. ...
... [ [90][91][92][93] ( 2. Increased the adiponectin and PPAR-γ expression in adipose tissues, improved insulin signaling and enhanced GLUT 4. ...
Article
Background & purpose Diabetes is a disease that has affected many people worldwide. According to the World Health Organization, approximately 80% of humans still rely on conventional or folk medicament in developed countries. The effectiveness of herbal medicines was credited to the phytochemical components. Objective This review aims to highlight the pathological pathways of diabetes and the antidiabetic mechanism of phytochemicals. Materials and methods This organized search was compiled from the databases such as PubMed, Scopus, Embase, ScienceDirect, Web of Science, and Google Scholar till February 2023. Results Inflammatory and oxidative stress are mainly two examples of pathological pathways of diabetes that are explored. The reported antidiabetic phytochemicals work by increasing insulin secretion, lowering hepatic glucose output, controlling specific enzymes, and utilizing other mechanisms. For instance, studies on α-glucosidase inhibitors, modulation peroxisome proliferator-activated receptor-α, hypolipidaemic activity, antioxidants, inhibition of glycolytic enzymes like phosphoenolpyruvate carboxykinase, improvement of glycosylated haemoglobin and increased expression of glucose transporters have been conducted. Conclusion Many natural secondary metabolites (phytochemicals) have significant potential for the manufacture of marketable, new, and efficient anti-diabetic medicines which can be used for clinical purposes.
... It has been shown to improve glucose metabolism in mice fed a high-fat diet (HFD). It has also been reported to significantly improve insulin resistance in mice fed a high-fat diet (HFD) and to significantly increase peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity in 3T3-L1 adipocytes [29][30][31][32][33]. Various studies in Italy have documented the impact of luteolin on depression-like behavior across multiple paradigms, including open field, novelty suppressed feeding, forced swim test, and elevated plus maze. ...
Article
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Phenolic molecules are secondary metabolites that facilitate several biological processes. Secondary metabolites are non-nutritive substances that hold significant medicinal value. Our study combined the biological activities, general features, daily usage conditions, and biosynthesis of luteolin as reported in the literature. The literature review revealed that luteolin exhibits biological activities including antioxidant, antibacterial, anticancer, and anti-inflammatory properties. It was observed that it exerts effects on illnesses including cardioprotection, cholesterol regulation, neuroprotection, autistic spectrum disorders, gastrointestinal issues, obesity, insulin sensitivity, anxiety/depression, and arthritis. In this regard, luteolin was identified as a significant molecule for pharmacological applications. Article is published under the CC BY license.
... Based on the strong association between lipid metabolism and diabetes [48], luteolin has also been reported to exert therapeutic effects on type 2 diabetes mellitus (T2DM) and its complications by improving insulin sensitivity, reducing blood glucose levels, and alleviating oxidative stress and inflammation in diabetic models [49,50]. Luteolin exerts antidiabetic effects by modulating various signaling pathways, including PPARγ, GLUT, and cyclin-CDK [51,52], and protects against diabetic complications such as nephropathy [53] and cardiomyopathy [54]. ...
Article
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Purpose of Review Luteolin, a natural polyphenolic flavone, is a bioactive compound with high thermal stability. Owing to its prominent antioxidant activity, luteolin has been reported to exert therapeutic effects on inflammation-associated diseases. This review discusses the therapeutic potential of luteolin for treating dental diseases. Recent Findings Luteolin has multifaceted pharmacological activities, including anti-inflammatory, neuroprotective, anticancer, and cardioprotective effects. Furthermore, the antibacterial effects of luteolin are accompanied by an anti-biofilm effect. More recently, luteolin has been identified as an inhibitor of protein kinase R (PKR), which plays an essential role in inflammasome activation. In this regard, we demonstrated the potential of luteolin as a pulp sedation compound for pulpitis that acts by suppressing PKR-mediated inflammation in dental pulp cells. Summary Although conventional dental treatments for dental caries or periodontitis largely depend on cause-related therapy, disruption of biofilms and regulation of inflammation are prerequisites for a favorable prognosis. Together with its superior anti-inflammatory and antibacterial effects, the biocompatible features of luteolin make it a promising candidate for treating dental diseases with fewer side effects.
... Its tendency to reduce diabetic conditions in Type I/II diabetes models and diabetes-related cognitive loss and nephropathy in rats is well established [66,67]. Besides, it was also noted that luteolin inhibits DPP-IV [68], LPS-induced TNFα release, and activation of the NF-κB pathway [69]. One of the important factors controlling insulin secretion is the MAFA protein, whose expression is negatively impacted by uric acid [70]. ...
Article
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Type 2 diabetes mellitus (T2DM), or “insulin-independent diabetes mellitus,” is a worldwide health concern. Diabetes affects roughly 415 million individuals worldwide, with 193 million undiagnosed cases. The number of people afflicted in the following decades is predicted to double. Although various synthetic medications are currently available to treat/manage T2DM, their side effects compel researchers to seek novel treatment options. Because of their affinity for biological receptors and broad bioactivity, nature has long been a source of innovative medication. V. amygdalina is one of the numerous natural productswith antidiabetic properties. Several studies have shown that the extracts have antidiabetic effects in vitro and in vivo. This review examined the antidiabetic and pharmacokinetic characteristics of phytoconstituents found in V. amygdalina.
... Normalization of the lipids and adiponectin together with alteration of the activities of glucose metaboloizing enzymes decrease in the level of thiobarbitutic acid reactive substance. Saponin maybe reduce the oxidative stress and inhibit the production of ROS due to this the level of superoxidase dismutase level increases [24,25]. Tannin having antioxidant properties so it may increase the level of superoxidase dismutase, catalase and glutathione peroxidase. ...
Article
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Objective: The present study was carried out to evaluate the pharmacological screening of Chrozophora tinctoria leaves extract as antidiabetic effect in rat. Method: The method is used to evaluate pharmacological potential of aqueous leaves extract as antidiabetic effect in rat. In this model, streptozotocin(60mg/kg b.w.) induced rats for one day through intraperitoneal administration, the effect of Chrozophoratinctoria at different dose level that is higher dose (100mg/kg b.w. p.o.) and lower dose (50mg/kg b.w. p.o.). From the study observed that Chrozophoratinctoria significantly protect the destruction of β-cells of pancreas from streptozotocin induced diabetes in rats. Streptozotocin induced ruputered and destruction of islet of langerhens and acini, destruction of intralobular duct and interlobular duct, and necrosis in parts of pancreas was found to be reduced in the groups receiving Chrozophoratinctoria along with streptozotoc in. Chrozphoratinctoria also normalized the streptozotocin induced diabetes decrease the blood glucose serum insulin, protein and uric acid levels. This is also evidenced by the histopathological studies. Result and discussion: The ant diabetic activity of Chrozophora tinctoria was determined by having comparsion between diseased group and treatment group with reference to standard group on the basis of improvement in elevated levels of biomarkers such as blood glucose (97.8±5.7**), serum insulin(1.48±0.36**), protein(6.4±0.36**), uric acid(2.04±0.27**), triglyceride(135.2±3.20**), total cholesterol(02.5±2.6**), SGOT(88.81±6.90**), SGPT(67.8±10.28**), HDL(51.76±7.92**) and LDL(80.68±10.62**) decrease the level of TBARS(258.93±7.85**) and increase the level of SOD (73.82±10.60**), Catalase(16.47±0.42**) and GSH (0.47±0.21ns). At the last it was observed that high dose(100mg/kg) of Chrozophora tinctoria was more significantly effective as compared to the low dose (50mg/kg) on the basis of evaluation of overall biological parameter and histopathological activities.
... Luteolin: Among the foods containing luteolin are celery, parsley, onion leaves, carrots, peppers, broccoli cabbage and chrysanthemum flowers [89,90]. Adiponectin, leptin and GLUT 4 are genes that luteolin is shown to activate and enrich in 3T3-L1 adipocytes, as well as in primary mouse adipose cells and this induction is inhibited by PPARγ antagonists [91]. A combination of luteolin and luteolin-7-O-glucoside has been shown to have antioxidant properties, which may be useful for treating diabetes, improving insulin levels, blood glucose levels, reducing HbA1c values, decreasing HOMA-IR values and inhibiting lipid synthesis [92]. ...
Article
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The impact of diabetes mellitus on the health care system is significant due to its global prevalence affecting millions of individuals. This condition is commonly related with factors such as obesity, urbanization, and genetic alterations. Those with diabetes mellitus have elevated blood glucose levels because an inability to produce, secrete or bind to insulin causes a lowering of insulin levels. Flavonoids are phenolic compounds found in fruits, vegetables and fungi. Carbon atoms are comprised of 15 chains of three carbon atoms in a skeleton. The anthocyanidin family includes flavonoids, flavones, flavanones, isoflavones, flavanols and flavonoids. In addition to their antidiabetic properties, flavonoids also have antioxidant properties. Molecular mechanisms underlying the antidiabetic properties of dietary flavonoids are summarized in this review. Other natural compounds with antidiabetic properties include cosmosiin, didymin, diosmin, naringin, isosiennsetin, nobiletin, poncirin, quercetin, rhoifolin, sinensetin, naringenin, sudachitin, rutin, hesperidin and tangeretin, which also improve lipid and phospholipid metabolism. The progression of diabetes is influenced by diabetes biomarkers. Citrus flavonoids are therefore promising candidates for antidiabetic action, even though further research is necessary to prove their effectiveness.
... And evidence from experimental studies suggests that phytochemicals down regulate the generation of free radicals and the release of pro-inflammatory cytokines and therefore increased the gene expression of adiponectin in adipose tissues. Some phytochemicals have also been found to be potent transcriptional activators of PPAR (peroxisome proliferator-associated receptor) target genes in animal [36][37][38] adipose tissues. PPAR-γ regulates adiponectin gene 39,40 expression and secretion. ...
Article
Background: Regular consumption of dietary phytochemicals as part of dietary pattern has been suggested as a possible effective dietary strategy of modulating circulating adiponectin level in patients with type 2 diabetes mellitus. However, findings from previous studies across different ethnic groups are inconsistent. Objective: The aim of this study was to determine the relationship between intake of dietary phytochemicals and circulating level of adiponectin among a group of patients with type 2 diabetes mellitus in a specialist hospital in north eastern Nigeria. Methods: Dietary intake assessment was done using a semi quantitative food frequency questionnaire and intake of dietary phytochemicals was calculated as dietary phytochemical index. The study subjects were categorized in to four quartiles according to their median intake of dietary phytochemicals. Fasting plasma glucose and adiponectin were measured among the study subjects. Analysis of variance and partial correlation analyses were used to determine the relationships between the study variables. Results: Higher circulating adiponectin level was observed among subjects with higher intake of dietary phytochemicals in the fourth quartile compared to the subjects with lower intake of dietary phytochemicals in the first quartile (9.8 ± 2.5µg/mL vs 8.2 ± 2.3µg/mL, p-value for trend < 0.05).There was a statistically significant positive correlation between intake of dietary phytochemicals and plasma level of adiponectin, among the study subjects, regardless of gender and independent of age and BMI and duration of diabetes mellitus (r = 0.20, p < 0.05). Conclusion: We conclude that among subjects with type 2 diabetes mellitus in this study, consumption of a diet rich in phytochemicals has the potential to improve circulating adiponectin level. We recommend further interventional studies to establish the role of dietary phytochemicals in the optimization of the management of type 2 diabetes
... Luteolin activates insulin action and facilitates transcriptional activation of PPARγ [99]. Moreover, it reduces inflammatory molecules, monocyte Chemotactic Protein-1 (MCP-1), resistin and upregulates adiponectin levels in obese mice [100]. ...
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The rising burden of Diabetes mellitus (DM) globally and particularly in sub-Sahara Africa calls for alternative treatment solutions. This is because the currently available drugs for its management are limited due to undesirable adverse effects and high cost. Thus, this review explores diabetes and summarizes its treatment options, focusing mainly on medicinal plants therapy. Information on twenty-five selected medicinal plants from sub-Sahara Africa having hypoglycemic and anti-diabetic potentials was obtained via electronic search of major databases, such as Pubmed/Medline, Scopus, Google Scholar and web of science. Predominant bioactive compounds found in these plants include tannins, carpaine, terpenoids, hexadecenoic acid, luteolin, saponins, glycosides, rutin, quercetin, vindoline and kaempferol. Robust evidence indicates that these medicinal plants and their bioactive components exert their antidiabetic potentials via different mechanisms, including: regeneration of pancreatic β-cell and insulin secretion; inhibition of α-amylase, inhibition of intestinal glucose absorption and liver glucose production; antioxidative stress; limitation of glycogen degradation and gluconeogenesis; anti-inflammatory, immunoregulatory. DM imposes a tremendous burden in the region, and its prevalence is not abating; thus the rich flora of the region with known hypoglycemic and antidiabetic efficacy could be explored as a complementary therapy in its management.
... Luteolin [87] was reported to intercalate and disrupt bacterial cytosolic membranes [88] and significantly increase the expression of adiponectin, leptin and PPARγ in murine adipocytes in vitro [89]. Luteolin reduced obesity-associated IR in mice by activating AMPKα1 signaling in adipose tissue macrophages [90], and was suggested to modulate IR in humans [91]. ...
Article
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Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4. Certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR, yet their mode of action remains obscured. We hypothesized that these products belong to a novel class of bioactive molecules that we have named membrane-active immunomodulators (MAIMs). A representative MAIM, the naturally occurring medium chain fatty acid ester diethyl azelate (DEA), has been shown to increase the fluidity of cell plasma membranes with subsequent downstream effects on cellular signaling. DEA has also been shown to improve markers of IR, including blood glucose, insulin and lipid levels, in humans. The literature supports the notion that DEA and other natural MAIMs share similar mechanisms of action in improving IR. These findings shed a new light on the mechanism of IR mitigation using natural products, and may facilitate the discovery of other compounds with similar activities.
... Among the putative compounds, luteolin, and apigenin, both under the flavone class of flavonoids, were previously identified as compounds present in A. sessilis varieties of other countries. Several studies have already presented the antidiabetic activity of luteolin through inhibition of α-amylase and α-glucosidase activities (Zhang et al., 2017;Kim, Kwon, Son, 2000), including improvement of insulin sensitivity in adipocytes by increasing glucose uptake and reducing mRNA levels of cytokines linked to insulin resistance, such as TNF-α, interleukin-6, and MCP-1 (Zang, Igarashi, Li, 2016;Ding, Jin, Chen, 2010). Continuous oral feeding of 200 mg/kg dose of luteolin in streptozotocin-induced diabetic rats for 8 weeks demonstrated a significant fall in blood glucose levels compared to baseline values. ...
... 36 compounds belonged to the active group with their values of EC50≤30 μM. The nonactive group included 18 inactive compounds (the EC50 values>30 μM) 20 and 288 decoys obtained from ZINC15 database through using Decoy Finder 2.0. ...
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Peroxisome proliferative activating receptors (PPARs) are a subfamily of three ligand-inducible transcription factors which are important targets in drug discovery for the treatment of metabolic syndrome (MetS). This study aimed to discover flavonoids as potential PPAR agonists. The results showed that the generated 3D-pharmacophore model for PPAR activators included four pharmacophoric features, namely one hydrophobic, two hydrogen acceptors and one hydrogen donor point, respectively. This pharmacophore model had the specificity, accuracy and sensitivity were 74%, 74% and 75%, respectively. 648 out of 3,848 flavonoid compounds satisfied all the features of the chosen pharmacophore model. Molecular docking results demonstrated that these compounds bound well in the binding site of PPARs. Among them, F85 was the most potential compound with the binding affinities of PPARα (-9.6 kcal/mol), PPARγ (-10.5 kcal/mol), PPARδ (-9.5 kcal/mol). Through forming hydrogen bonds and hydrophobic interactions with the key residues, F85 could reach deeper into the binding pocket of the receptors. Moreover, F85 was stable in the binding site of PPARs during the molecular dynamics simulations. Therefore, this compound was deemed to be potent as PPAR agonist.
... Likewise, luteolin was able to prevent hepatic and adipocyte fibrosis and IR via the toll-like receptor (TLR) signaling pathway (Kwon & Choi, 2018). By directly stimulating the PPARγ pathway or regulating the insulin signaling cascades, luteolin may also improve the function of insulin in adipocytes (Ding, Jin & Chen, 2010). ...
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Insulin resistance (IR) is a main etiology of various metabolic diseases such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia and coronary heart disease. IR is a multi-factorial etiology disease regulated by various mechanisms. Obesity, a significant public health problem worldwide, is considered as a high-risk factor to induce IR and T2DM. Thus, inhibiting obesity-induced IR is one of the key therapeutic strategies to improve T2DM. Natural products from herbs and nutraceuticals have shown promising efficacy on obesity-induced IR and T2DM owing to its multi-component and multi-target characteristics. However, the active constituents and the action mechanisms are still not yet well elucidated. In this review, the natural constituents with protective capacities against IR were summarized. The active constituents include crude extracts such as polyphenols, saponins, alkaloids, terpenoids, phenylpropanoids, as well as monomeric compounds such as curcumin, berberine, capsaicin, naringenin, quercetin, betaine and isoliquiritigenin. The action mechanisms of these active constituents could be mainly divided into 4 categories: ameliorating metabolic abnormality, inhibiting inflammation, reversing gut microbiota dysbiosis, regulating micro RNAs (miRNAs). Their precise roles in regulating PI3K/AKT, AMPK, PPARs, SIRT1 and NF-κB pathways, brown adipose tissue activity and white adipose tissue browning, NLRP3 inflammasome activity, gut microbiota structure and composition and miRNA expression were discussed. The sources, chemical structures, experimental models, pharmacological effects and action targets of these active constituents were also summarized. This review provides new active constituents, therapeutic targets and reasoning for the clinical application of herbs and nutraceuticals in the treatment of IR and T2DM.
... However,GLUT-4 expression was markedly low in the diabetic group [43]. GLUT-4, which is specifically distributed on the cell membrane of adipose cells, is majorly responsible for basal glucose transport and regulates the transport of insulin and glucose through translocation and activation, facilitated by the PI3K/phosphorylated protein kinase B (p-Akt) pathway [44]. GLUT-4 knockout in mouse models confirmed that the extensive metabolic and tissue-specific regulation of the GLUT-4 gene has a significant effect on insulin-induced glucose clearance. ...
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Unlabelled: Reduced activity of glucose transporter type 4 isoform (GLUT-4), an insulin-sensitive glucose transporter distributed on the adipocytes, is associated with impaired insulin signaling. Insulin resistance resulting from alteration in glucose transport is responsible for exacerbating the emergence of metabolic abnormalities. The present study aimed to investigate the effects of the antidote gallic acid (GA) on expression-related changes in GLUT-4 and insulin receptor substrate-1 (IRS-1) in the visceral adipose tissue and on the subsequent development of insulin resistance in a high-fat diet (HFD)-induced obesity animal model. Methods: Twenty-four female Swiss albino mice were used and separated into the following four groups (six animals in each group): control group (standard pellet diet), HFD group, (60% HFD), HFD + GA group (60% HFD and GA 50 mg/kg body weight for 60 days), and GA group (GA 50 mg/kg body weight for 60 days). The effect of HFD on serum glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL), low-density lipoprotein (LDL) cholesterol, and insulin was evaluated. Additionally, homeostasis model assessment for insulin resistance (HOMA-IR) and glucose tolerance test (GTT) was performed. The serum antioxidative profile, which comprises oxidative parameters (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GPx]) was measured. The effectiveness of GA against HFD-induced alteration in GLUT-4 and IRS-1 expression was also evaluated. Results: The experimental group that fed on GA + HFD had improved levels of serum triglycerides (p˂0.001), cholesterol (p˂0.05), and LDL cholesterol. GA administration also significantly improved hyperinsulinemia and HOMA-IR index (p˂0.001) in HFD mice. GA improved GTT results (p˂0.05); activity of SOD, CAT, and GPx (p˂0.05); and upregulated mRNA expression of GLUT-4 and IRS-1(p˂0.05) in the visceral adipose tissue in the HFD + GA experimental group. Conclusion: A link exists between insulin resistance, GLUT-4, and IRS-1 expression in the adipose tissue, and the initiation of metabolic syndrome, a condition characterized by obesity. GA may promote insulin signaling, glucose uptake, and lipid metabolism in the adipose tissues by mitigating oxidative stress. GA can also be used to manage obesity-related comorbidities including type 2 diabetes and dyslipidemia. Supplementary information: The online version contains supplementary material available at 10.1007/s40200-023-01194-5.
... It was reported that some flavonoid compounds, such as hispidulin and luteolin, which both exhibit similar structures to pectolinarigenin, targeted peroxisome proliferators-activated receptor γ (PPARγ) and induced PPARγ activation [23,24]. PPARγ is a key transcription factor involved in lipid metabolism, PPARγ activation induces decreased lipid biosynthesis and increased lipid metabolism [25]. ...
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A comparative study was conducted to determine whether hesperetin and pectolinarigenin could lower total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) in a high-fat diet (HFD)-induced high lipid model in Golden Syrian hamsters. 48 Golden Syrian hamsters (8 weeks old) were fed with a HFD for 15 days. HFD induced significant increases in plasma TC, TG, LDL, and HDL. Then, these high lipid hamsters were divided into four groups and were administered with 0.5% sodium carboxymethyl cellulose (CMC-Na), hesperetin (100 mg/kg/day), pectolinarigenin (100 mg/kg/day) or atorvastatin (1.0 mg/kg/day), for 7 weeks. It was found that pectolinarigenin treatment resulted in significant reductions in body weight, adiposity index, serum levels of TC, TG and hepatic TC, TG and free fatty acid compared to those in control hamsters with hyperlipidemia (P<0.05). However, hesperetin treatment only caused reductions in plasma TC and hepatic TG levels. Besides, the hamsters treated with pectolinarigenin showed a relatively normal hepatic architecture compared to the hepatic steatosis shown in the control group. Moreover, the expressions of fatty-acid synthase (Fasn) and solute carrier family 27 member 1 (Slc27a1) involved in lipid biosynthesis, were suppressed in the pectolinarigenin-treated groups, and the expression of carnitine palmitoyltransferase 1A (Cpt1a) involved in fatty acid oxidation was increased in the pectolinarigenin-treated group. Taken together, these results suggest pectolinarigenin exerts stronger protective effects against hyperlipidemia and hepatic steatosis than hesperetin, which may involve the inhibition of lipid uptake and biosynthesis.
... To study GLUT1 and GLUT4 gene expression, luteolin was added to primary adipose cells for six hours. GLUT1 gene expression was not substantially elevated relative to the control, but GLUT4 protein and gene expression were significantly increased [114]. According to Puhl et al., luteolin is a partial agonist of PPAR-γ with affinity EC 50 = 15.6 μM [115]. ...
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Immunologists have long considered inflammation to be a two-edged sword. Short term inflammation can be beneficial but long term chronic inflammation is damaging. Obesity, type 2 diabetes (T2D), and cancer have recently been added to the never-ending list of inflammatory diseases. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) is involved in inflammation and obesity. Clinicians employed PPAR-γ agonists, both synthetic and natural, to treat disorders such as obesity and T2D without fully understanding the biochemical features and potential adverse effects. This is one of the reasons for the controversy surrounding the thiazolidinedione class of medicines, including rosiglitazone and pioglitazone.
... GLUT-4, which is speci cally found on the cell membrane of adipose cells, is responsible for the majority of basal glucose transport. GLUT-4 predominantly regulates the transport of insulin and glucose through translocation and activation facilitated by the PI3K/phosphorylated protein kinase (p-Akt) pathway [40]. Transgenic mice which is over expressing or lacking GLUT4 have been shown to have reduced or enhanced entire body insulin sensitivity [41] highlighting its importance in glucose homeostasis. ...
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Objective - A primary loophole exacerbating the emergence of metabolic abnormalities is insulin resistance results due to impaired glucose transport. Glucose transporter type 4 isoform (GLUT-4) is a insulin-sensitive receptor associated with glucose uptake over the surface of adipocytes for glucose metabolism. Impaired insulin signalling is linked with reduced GLUT-4 activity. The aim of present study was to examine the expression of GLUT-4 and insulin receptor substrate-1 (IRS-1) in visceral adipose tissue of high fat diet induced (HFD) obesity animal model with respect to antidote gallic acid (GA). Methods - Experimental animal, female swiss albino mice were fed a standard and high-fat diet (HFD) in order to study the therapeutic effects of gallic acid (GA) against metabolic changes obesity induced HFD, animal model. Results - Experimental group fed HFD along with GA displayed improved triglyceride and serum cholesterol levels. Alongwith this hyperinsulinemia and an increase in homeostasis model assessment for insulin resistance (HOMA IR) were observed in HFD group, which were alleviated by GA. Apart from this, GA, had improved glucose tolerance test (GTT), and upregulation in mRNA expression of GLUT-4 and IRS-1 in visceral adipose tissues in HFD + GA experimental group. Conclusion - The current study found a link between insulin resistance, GLUT-4 and IRS-1 expression in adipose tissue and the beginning of the metabolic syndrome, a condition characterised by obesity. Gallic acid may enhance insulin signalling, glucose, and lipid metabolism in adipose tissues, and it may even be used to manage comorbidities related to obesity, such as diabetes type 2 and dyslipidemia.
... Indeed, in mouse 3T3-L1 adipocytes exposed to glucose, luteolin reduced the levels of inflammatory cytokines TNF-α, IL-6 and MCP-1 (Ding, Jin, and Chen 2010); the reduction is associated with increased expression and activation of PPARγ, leading to upregulation of the adipokines, leptin and adiponectin. Moreover, luteolin enhanced the response of mouse 3T3-L1 adipocytes to insulin, resulting in enhanced glucose uptake and increased activation of Akt2 phosphorylation (Ding, Jin, and Chen 2010). A lowering of insulin resistance by luteolin was also observed in spontaneous type-2 diabetic KK-A y mice (which develop obesity and hyperglycemia at 7 or 8 weeks old), coupled with reduced fasting blood glucose level, serum HbA 1C level and insulin level when compared with KK-A y mice not treated with luteolin (Zang, Igarashi, and Li 2016). ...
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Diabetes, being the most widespread illness, poses a serious threat to global public health. It seems that inflammation plays a critical role in the pathophysiology of diabetes. This review aims to demonstrate a probable link between type 2 diabetes mellitus (T2DM) and chronic inflammation during its development. Additionally, the current review examined the bioactivity of natural flavones and the possible molecular mechanisms by which they influence diabetes and inflammation. While natural flavones possess remarkable anti-diabetic and anti-inflammatory bioactivities, their therapeutic use is limited by the low oral bioavailability. Several factors contribute to the low bioavailability, including poor water solubility, food interaction, and unsatisfied metabolic behaviors, while the diseases (diabetes, inflammation, etc.) causing even less bioavailability. Throughout the years, different strategies have been developed to boost flavones' bioavailability, including structural alteration, biological transformation, and innovative drug delivery system design. This review addresses current advancements in improving the bioavailability of flavonoids in general, and flavones in particular. Clinical trials were also analyzed to provide insight into the potential application of flavonoids in diabetes and inflammatory therapies.
... Lutein (Figure 4) is abundant in celery, parsley, broccoli, onion leaves, and chrysanthemum blooms, among other vegetables and fruits [87]. In 3T3-L1 adipocytes and primary mouse adipose cells, luteolin potentiates insulin action and enhances peroxisome proliferator-activated receptor (PPAR) expression and transcriptional activity, and the expression of PPAR target genes such as adiponectin, leptin, and GLUT4, and a PPAR antagonist inhibits this induction [88]. e decrease in circulation levels of inflammatory mediators such as monocyte chemoattractant protein 1 (MCP-1) and resistin, as well as the increase in adiponectin levels in obese mice, is likely to be managed by luteolin's beneficial effects on metabolic pathways implicated in insulin resistance and DM pathogenesis [89]. ...
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Diabetes mellitus (DM) is a fatal metabolic disorder, and its prevalence has escalated in recent decades to a greater extent. Since the incidence and severity of the disease are constantly increasing, plenty of therapeutic approaches are being considered as a promising solution. Many dietary polyphenols have been reported to be effective against diabetes along with its accompanying vascular consequences by targeting multiple therapeutic targets. Additionally, the biocompatibility of these polyphenols raises questions about their use as pharmacological mediators. Nevertheless, the pharmacokinetic and biopharmaceutical properties of these polyphenols limit their clinical bene t as therapeutics. Pharmaceutical industries have attempted to improve compliance and therapeutic effects. However, nanotechnological approaches to overcome the pharmacokinetic and biopharmaceutical barriers associated with polyphenols as antidiabetic medications have been shown to be effective to improve clinical compliance and efficacy. Therefore, this review highlighted a comprehensive and up-to-date assessment of polyphenol nanoformulations in the treatment of diabetes and vascular consequences.
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Luteolin is widely distributed phytochemical, a flavonoid, in kingdom plantae. Luteolin with potential antioxidant activity prevent ROS‐induced damages and reduce oxidative stress which is mainly responsible in pathogenesis of many diseases. Several chemo preventive activities and therapeutic benefits are associated with luteolin. Luteolin prevents cancer via modulation of numerous pathways, that is, by inactivating proteins; such as procaspase‐9, CDC2 and cyclin B or upregulation of caspase‐9 and caspase‐3, cytochrome C, cyclin A, CDK2, and APAF‐1, in turn inducing cell cycle arrest as well as apoptosis. It also enhances phosphorylation of p53 and expression level of p53‐targeted downstream gene. By Increasing BAX protein expression; decreasing VEGF and Bcl‐2 expression it can initiate cell cycle arrest and apoptosis. Luteolin can stimulate mitochondrial‐modulated functions to cause cellular death. It can also reduce expression levels of p‐Akt, p‐EGFR, p‐Erk1/2, and p‐STAT3. Luteolin plays positive role against cardiovascular disorders by improving cardiac function, decreasing the release of inflammatory cytokines and cardiac enzymes, prevention of cardiac fibrosis and hypertrophy; enhances level of CTGF, TGFβ1, ANP, Nox2, Nox4 gene expressions. Meanwhile suppresses TGFβ1 expression and phosphorylation of JNK. Luteolin helps fight diabetes via inhibition of alpha‐glucosidase and ChE activity. It can reduce activity levels of catalase, superoxide dismutase, and GS4. It can improve blood glucose, insulin, HOMA‐IR, and HbA1c levels. This review is an attempt to elaborate molecular targets of luteolin and its role in modulating irregularities in cellular pathways to overcome severe outcomes during diseases including cancer, cardiovascular disorders, diabetes, obesity, inflammation, Alzheimer's disease, Parkinson's disease, hepatic disorders, renal disorders, brain injury, and asthma. As luteolin has enormous therapeutic benefits, it could be a potential candidate in future drug development strategies.
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The global prevalence of diabetes mellitus (DM) and its complications has been showing an upward trend in the past few decades, posing an increased economic burden to society and a serious threat to human life and health. Therefore, it is urgent to investigate the effectiveness of complementary and alternative therapies for DM and its complications. Luteolin is a kind of polyphenol flavonoid with widely existence in some natural resources, as a safe dietary supplement, it has been widely studied and reported in the treatment of DM and its complications. This review demonstrates the therapeutic potential of luteolin in DM and its complications, and elucidates the action mode of luteolin at the molecular level. It is characterized by anti-inflammatory, antioxidant, and neuroprotective effects. In detail, luteolin can not only improve endothelial function, insulin resistance and β-cell dysfunction, but also inhibit the activities of dipeptidyl peptidase-4 and α-glucosidase. However, due to the low water solubility and oral bioavailability of luteolin, its application in the medical field is limited. Therefore, great importance should be attached to the joint application of luteolin with current advanced science and technology. And more high-quality human clinical studies are needed to clarify the effects of luteolin on DM patients.
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Mesmo não havendo um consenso na literatura sobre a influência deste flavonoide no tecido adiposo, ficou latente a importância da luteolina na diferenciação da adipogênese, seus efeitos regulatórios no metabolismo e acúmulo de lipídios em protocolo in vitro e em modelos animais. Desta forma, o objetivo desta revisão é relatar, identificar e compreender as ações e efeitos da luteolina na inflamação do tecido adiposo.
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Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been shown to play an important role in the regulation of expression of a subclass of adipocyte genes and to serve as the molecular target of the thiazolidinedione (TZD) and certain non-TZD antidiabetic agents. Hypercorticosteroidism leads to insulin resistance, a variety of metabolic dysfunctions typically seen in diabetes, and hypertrophy of visceral adipose tissue. In adipocytes, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive cortisone into the active glucocorticoid cortisol and thereby plays an important role in regulating the actions of corticosteroids in adipose tissue. Here, we show that both TZD and non-TZD PPARgamma agonists markedly reduced 11beta-HSD-1 gene expression in 3T3-L1 adipocytes. This diminution correlated with a significant decrease in the ability of the adipocytes to convert cortisone to cortisol. The half-maximal inhibition of 11beta-HSD-1 mRNA expression by the TZD, rosiglitazone, occurred at a concentration that was similar to its K(d) for binding PPARgamma and EC(50) for inducing adipocyte differentiation thereby indicating that this action was PPARgamma-dependent. The time required for the inhibitory action of the TZD was markedly greater for 11beta-HSD-1 gene expression than for leptin, suggesting that these genes may be down-regulated by different molecular mechanisms. Furthermore, whereas regulation of PPARgamma-inducible genes such as phosphoenolpyruvate carboxykinase was maintained when cellular protein synthesis was abrogated, PPARgamma agonist inhibition of 11beta-HSD-1 and leptin gene expression was ablated, thereby supporting the conclusion that PPARgamma affects the down-regulation of 11beta-HSD-1 indirectly. Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11beta-HSD-1 in adipose tissue. This decrease in enzyme expression correlated with a significant decline in plasma corticosterone levels. In sum, these data indicate that some of the beneficial effects of PPARgamma antidiabetic agents may result, at least in part, from the down-regulation of 11beta-HSD-1 expression in adipose tissue.
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Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.
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Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARgamma to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARgamma agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARgamma-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARgamma, supporting the direct transcriptional regulation of ATGL by PPARgamma. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARgamma positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARgamma's effects on lipid metabolism.
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The adipocyte-derived secretory protein adiponectin functions as an insulin-sensitizing agent. In plasma, adiponectin exists as low, medium, and high molecular weight oligomers. Treatment with trans-10, cis-12 conjugated linoleic acid (t-10, c-12 CLA) reduces levels of adiponectin as well as triglyceride (TG) in mice and adipocyte cell culture models. The aim of this study was to determine whether the effects of t-10, c-12 CLA on adiponectin and TG are mediated through modulation of the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma). 3T3-L1 cells were treated either during or after differentiation into adipocytes with 100 microM t-10, c-12 CLA with or without 10 microM troglitazone, a PPARgamma agonist, or 1 microM GW9662, a PPARgamma antagonist, and adiponectin and TG levels were analyzed. Treatment with t-10, c-12 CLA reduced TG as well as cellular and secreted adiponectin levels and impaired the assembly of adiponectin oligomers. These changes were accompanied by decreases in PPARgamma mass. Troglitazone was able to reverse the t-10, c-12 CLA-mediated decrease in TG levels and restore the assembly of adiponectin oligomers but was unable to restore adiponectin synthesis. Conversely, treatment with GW9662 decreased TG mass and impaired adiponectin oligomer assembly but did not decrease total adiponectin mass. In a reporter assay, t-10, c-12 CLA appeared to be a partial PPARgamma agonist and prevented the stimulation of reporter activity by troglitazone. Therefore, the t-10, c-12 CLA isomer appears to alter adipocyte adiponectin metabolism through PPARgamma-dependent and PPARgamma-independent mechanisms.
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily PPARα is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARγ is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARα and PPARγ respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARα controls intra- and extracellular lipid metabolisms whereas PPARγ triggers adipocyte differentiation and promotes lipid storage. In addition. PPARs also modulate the inflammatory response. PPAR activators have been shown to exert antiinflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-KB (NF-κB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.
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Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARγ but also PPARα as determined using the chimera assay system. These compounds also activated full-length human PPARγ and PPARα in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARγ and PPARα in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARγ and PPARα can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
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Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPARgamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-alpha, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.
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Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3'-kinase (PI3K)/Akt, nuclear factor kappa B (NF-kappaB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin.
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In light of the pivotal role that PPARgamma2 plays in the expression of fat specific genes (e.g., A-FABP), we have examined the hypothesis that a rise in PPARgamma2 protein is required for the expression of A-FABP, and that the acceleration of fat cell differentiation by the thiazolidinedione agent, pioglitazone (PIOG), reflects an increase in the abundance of PPARgamma2 mRNA and protein. Western analyses surprisingly revealed that undifferentiated 3T3-L1 fibroblasts contained significant levels of PPARgamma2 protein; that the amount of total cellular PPARgamma2 only increased 2-fold during differentiation; and that the levels of PPARgamma2 protein and mRNA were not increased by PIOG even though fat cell differentiation was accelerated by PIOG as revealed by a 20-fold increase in A-FABP expression. Cell fractionation studies revealed that PPARgamma2 was evenly distributed between the cytosolic and nuclear compartments in both undifferentiated and differentiating 3T3-L1 cells. Immunocytochemical studies with a PPARgamma2-specific antibody indicated that PPARgamma2 was diffusely distributed throughout the cytosol of undifferentiated 3T3-L1 cells, but as the differentiation progressed, the PPARgamma2 became focused around the developing lipid droplets. In contrast to PPARgamma2, undifferentiated 3T3-L1 cells contained no measurable quantities of RXRalpha, but once fat cell differentiation was initiated by treatment with IBMX and dexamethasone, the cellular content of RXRalpha increased several fold. The rise in RXRalpha content paralleled the induction of A-FABP, but the expression of RXRalpha was not enhanced by PIOG. Although the amount of PPARgamma2 and RXRalpha was unaffected by PIOG, gel shift assays revealed that PIOG stimulated PPARgamma2/RXRalpha binding to the adipose response element of A-FABP by 5-fold in less than 12 h. Apparently, RXRalpha rather than PPARgamma2 is the pivotal trans-factor essential for the initiation of terminal fat cell differentiation. However, the high cytsolic content of PPARgamma2 and its association with the lipid droplet of differentiating 3T3-L1 cells suggests PPARgamma2 may possess a cytosolic function in the developing fat cell.
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Flavonoids are a group of polyphenolic compounds ubiquitously found in plants including fruits, and vegetables. Broad ranges of the biological activities of flavonoids have been reported using in vitro studies. I report that several natural flavonoids blocked glucose uptake in myelocytic U937 cells. Although there were some variations in the blocking activity of individual flavonoids, approximately half of the glucose uptake was blocked by flavonoids at the concentrations of 8-50 microM. The decreasing order of the blocking activity was fisetin >/= myricetin >/= quercetin >/= apigenin > genistein > cyanidin > daidzein >/= hesperetin > naringenin > catechin. Fisetin showed approximately 50% inhibition of glucose uptake at a concentration of 8 microM. Similar patterns of the inhibition were observed in lymphocytic Jurkat cells. Fisetin and quercetin inhibited glucose transport in a competitive manner. K(i) values for fisetin and quercetin were proximately 9 and 12 microM, respectively. This study showed that some types of natural flavonoids block glucose uptake in U937 cells and that natural flavonoids could be used as alternative blockers of glucose uptake in vitro.
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The facilitative hexose transporter GLUT1 is a multifunctional protein that transports hexoses and dehydroascorbic acid, the oxidized form of vitamin C, and interacts with several molecules structurally unrelated to the transported substrates. Here we analyzed in detail the interaction of GLUT1 with a group of tyrosine kinase inhibitors that include natural products of the family of flavones and isoflavones and synthetic compounds such as the tyrphostins. These compounds inhibited, in a dose-dependent manner, the transport of hexoses and dehydroascorbic acid in human myeloid HL-60 cells, in transfected Chinese hamster ovary cells overexpressing GLUT1, and in normal human erythrocytes, and blocked the glucose-displaceable binding of cytochalasin B to GLUT1 in erythrocyte ghosts. Kinetic analysis of transport data indicated that only tyrosine kinase inhibitors with specificity for ATP binding sites inhibited the transport activity of GLUT1 in a competitive manner. In contrast, those inhibitors that are competitive with tyrosine but not with ATP failed to inhibit hexose uptake or did so in a noncompetitive manner. These results, together with recent evidence demonstrating that GLUT1 is a nucleotide binding protein, support the concept that the inhibitory effect on transport is related to the direct interaction of the inhibitors with GLUT1. We conclude that predicted nucleotide-binding motifs present in GLUT1 are important for the interaction of the tyrosine kinase inhibitors with the transporter and may participate directly in the binding transport of substrates by GLUT1.
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARalpha is highly expressed in liver, skeletal muscle, kidney, heart and the vascular wall. PPARgamma is predominantly detected in adipose tissue, intestine and macrophages. PPARs are activated by fatty-acid derivatives and pharmacological agents such as fibrates and glitazones which are specific for PPARalpha and PPARgamma respectively. PPARs regulate lipid and lipoprotein metabolism, glucose homeostasis, cell proliferation and differentiation, and apoptosis. PPARalpha controls intra- and extracellular lipid metabolisms whereas PPARgamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs also modulate the inflammatory response. PPAR activators have been shown to exert anti-inflammatory activities in various cell types by inhibiting the expression of proinflammatory genes such as cytokines, metalloproteases and acute-phase proteins. PPARs negatively regulate the transcription of inflammatory response genes by antagonizing the AP-1, nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription and nuclear factor of activated T-cells signalling pathways and by stimulating the catabolism of proinflammatory eicosanoids. These recent findings indicate a modulatory role for PPARs in inflammation with potential therapeutical applications in chronic inflammatory diseases.
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Several herbal medicines improve hyperlipidemia, diabetes and cardiovascular diseases. However, the molecular mechanism underlying this improvement has not yet been clarified. In this study, we found that several isoprenols, common components of herbal plants, activate human peroxisome proliferator-activated receptors (PPARs) as determined using the novel GAL4 ligand-binding domain chimera assay system with coactivator coexpression. Farnesol and geranylgeraniol that are typical isoprenols in herbs and fruits activated not only PPARgamma but also PPARalpha as determined using the chimera assay system. These compounds also activated full-length human PPARgamma and PPARalpha in CV1 cells. Moreover, these isoprenols upregulated the expression of some lipid metabolic target genes of PPARgamma and PPARalpha in 3T3-L1 adipocytes and HepG2 hepatocytes, respectively. These results suggest that herbal medicines containing isoprenols with dual action on both PPARgamma and PPARalpha can be of interest for the amelioration of lipid metabolic disorders associated with diabetes.
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In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-gamma (PPARgamma), we identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC(50) versus PPARgamma and was 10- and 600-fold less potent in binding experiments using PPARalpha and PPARdelta, respectively. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric analysis of the PPARgamma ligand binding domain treated with GW9662 established Cys(285) as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARgamma. The functional activity of GW9662 as an antagonist of PPARgamma was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARdelta and PPARalpha. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects observed in the reporter gene assays. Control activators increased PPAR:RXR heterodimer formation and coactivator binding to both PPARgamma and PPARdelta. Corepressor binding was decreased. In the case of PPARalpha, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The experimental data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes.
Article
We have previously shown that the flavonoid luteolin inhibits the expression of pro-inflammatory molecules induced by LPS. In the present study we tested the ability of luteolin to block signalling pathways implicated in LPS-induced inflammatory gene expression in macrophages. Exposure of the murine macrophage cell line RAW 264.7 to LPS increased phosphorylation of the mitogen-activated protein kinase family members ERK1/2, p38 and JNK1/2 in a time-dependent manner. Pretreatment of RAW 264.7 with luteolin inhibited the LPS-induced ERK1/2 and p38, but not JNK1/2, phosphorylation, and blocked the LPS-induced TNF-α release. To investigate which of these pathways contribute to the inhibitory effects of luteolin on TNF-α release, cells were pretreated with pharmacological inhibitors of these pathways; PD98059 and SB203580 when used alone failed to inhibit TNF-α release, whereas pretreatment with both agents attenuated TNF-α release. We have previously shown that luteolin blocks Akt phosphorylation in response to LPS in RAW 264.7 macrophages. To determine the role of Akt in TNF-α release, cells were transiently transfected with a dominant negative form of Akt (K179M). Overexpression of K179M Akt did not alter LPS-induced TNF-α release, suggesting that inhibition of this kinase does not mediate the inhibitory action of luteolin. In addition, DRB (a pharmacological inhibitor of CK2) blocked TNF-α release in a concentration-dependent manner, whereas co-treatment of cells with luteolin and DRB did not have an additive effect. We conclude that luteolin interferes with LPS signalling by reducing the activation of several MAPK family members and that its inhibitory action on TNF-α release correlates with inhibition of ERK, p38 and CK2 activation. British Journal of Pharmacology (2002) 136, 1058–1064. doi:10.1038/sj.bjp.0704803
Article
The thiazolidinedione (TZD) class of antidiabetic drugs has been shown to inhibit the formation of bone-resorbing osteoclasts in vitro and to decrease bone resorption markers in vivo. These drugs also inhibit the expression of leptin in adipocytes. Less leptin can be associated with higher bone mass, based on analyses of mice deficient in leptin action. Effects of 1-year treatment with troglitazone, a member of the TZDs, on bone mineral density (BMD) and bone metabolism were examined in 25 Japanese type 2 diabetic patients. Glucose metabolism was improved, whereas body mass index and percent body fat did not change throughout the study. The percent change of BMD was negatively correlated with that of serum leptin, whereas it was not associated with changes of bone metabolic markers, type I collagen N-telopeptide (NTx), bone alkaline phosphatase (ALP), body mass index, or HbA1c. Serum leptin decreased in 68% of subjects (responders) after 1-month treatment and was consistently lower than the basal level throughout the treatment. Percent changes of BMD were significantly higher in the responders than in the nonresponders and in nondiabetic subjects at 6 and 12 months. NTx and bone ALP decreased at 1 month but increased thereafter in either group of patients. Thus, it is suggested that the decrease in serum leptin with no reduction in body fat mass by troglitazone is associated with preventing bone loss in type 2 diabetic patients. Hence, TZDs may have an advantage for diabetic patients who have risk factors for osteoporosis.
Article
Abietic acid is one of the terpenoids, which are multifunctional natural compounds. It has been reported that abietic acid suppresses effects on inflammation. However, the mechanism underlying the anti-inflammatory effects remains unclear. The present work indicates that abietic acid suppresses the protein expression of tumor necrosis factor-alpha and cyclooxygenase 2, which are involved in inflammation, in lipopolysaccharide-stimulated macrophages. Moreover, this effect resembles that of thiazolidinedione, a synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand. Indeed, abietic acid activates PPARgamma in luciferase reporter assays. The activity of abietic acid induces PPARgamma target gene expression in RAW264.7 macrophages and 3T3-L1 adipocytes. These data indicate that abietic acid is a PPARgamma ligand and that its anti-inflammatory effect is partly due to the activation of PPARgamma in stimulated macrophages. The present work suggests a novel possibility that abietic acid, a naturally occurring compound, can be used not only for anti-inflammation but also for regulating lipid metabolism and atherosclerosis.
Article
Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.
Article
Tumor necrosis factor-alpha (TNFalpha) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with luteolin, a plant flavonoid, greatly sensitized TNFalpha-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of luteolin, we discovered that luteolin inhibited TNFalpha-induced activation of nuclear transcription factor-kappa B (NF-kappaB), the main survival factor in TNFalpha signaling. As a result, luteolin suppressed the expression of NF-kappaB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by luteolin followed by TNFalpha. In addition, inhibition of NF-kappaB by luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFalpha. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by luteolin and TNFalpha, suggesting that NF-kappaB and JNK are closely associated with the sensitization effect of luteolin. Data from this study reveal a novel function of luteolin and enhance the value of luteolin as an anticancer agent.
Article
Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily, is activated by several compounds, including the thiazolidinediones. In addition to being a therapeutic target for obesity, hypolipidaemia and diabetes, perturbation of PPARγ signalling is now believed to be a strategy for treatment of several cancers, including breast. Although differential expression of PPARγ is observed in tumours compared to normal tissues and PPARγ agonists have been shown to inhibit tumour cell growth and survival, the interdependence of these observations is unclear. This study demonstrated that the potent, irreversible and selective PPARγ antagonist GW9662 prevented activation of PPARγ and inhibited growth of human mammary tumour cell lines. Controversially, GW9662 prevented rosiglitazone-mediated PPARγ activation, but enhanced rather than reversed rosiglitazone-induced growth inhibition. As such, these data support the existence of PPARγ-independent pathways and question the central belief that PPARγ ligands mediate their anticancer effects via activation of PPARγ. British Journal of Pharmacology (2004) 143, 933–937. doi:10.1038/sj.bjp.0705973
Article
Interleukin (IL)-8 plays a central role in the initiation and maintenance of inflammatory responses in the inflammatory bowel disease. The proinflammatory cytokine-mediated production of IL-8 requires activation of various kinases, which leads to the IkappaB degradation and NF-kappaB activation. In this study, we investigated the role of luteolin, a major flavonoid of Lonicera japonica, on TNF-alpha-induced IL-8 production in human colonic epithelial cells. HT29 cells were stimulated with TNF-alpha in the presence or absence of luteolin. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, and the mitogen-activated protein kinases (MAPKs) activation and IkappaB degradation were determined by Western blot analysis. NF-kappaB activation was assessed by the electrophoretic motility shift assay (EMSA). Luteolin suppressed TNF-alpha-induced IL-8 production in dose-dependent manner. In addition, luteolin inhibited TNF-alpha-induced phosphorylation of p38 MAPK and extracellular-regulated kinases (ERK), IkappaB degradation, and NF-kappaB activation. These results suggest that luteolin has the inhibitory effects on TNF-alpha-induced IL-8 production in the intestinal epithelial cells through blockade in the phosphorylation of MAPKs, following IkappaB degradation and NF-kappaB activation.
Article
We have developed two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) and 18O proteolytic labeling strategies to identify and compare levels of secretory proteins with low abundance in the conditioned medium of rat adipose cells without or with insulin stimulation. Culture medium was concentrated and secreted proteins were separated on a RP-HPLC followed by LC-MS/MS analysis. For 18O proteolytic labeling, 16O- to 18O-exchange in the digested peptides from eight individual fractions was carried out in parallel in H2(16)O and H(2)18O with immobilized trypsin, and the ratios of isotopically distinct peptides were measured by mass spectrometry. A total of 84 proteins was identified as secreted adipokines. This large number of secretory proteins comprise multiple functional categories. Comparative proteomics of 18O proteolytic labeling allows the detection of different levels of many secreted proteins as exemplified here by the difference between basal and insulin treatment of adipose cells. Taken together, our proteomic approach is able to identify and quantify the comprehensive secretory proteome of adipose cells. Thus, our data support the endocrine role of adipose cells in pathophysiological states through the secretion of signaling molecules.
Article
The nuclear factor (NF)-kappaB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IkappaB phosphorylation/degradation, NF-kappaB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IkappaB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10(-/-) mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kappaB cis-elements (cis-NF-kappaB(EGFP)), we found that luteolin blocks LPS-induced IkappaB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-alpha gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-kappaB(EGFP) mice. These results indicate that luteolin blocks LPS-induced NF-kappaB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses.
Article
The peroxisome proliferator-activated receptor (PPAR) is one of the indispensable transcription factors for regulating lipid metabolism in various tissues. In our screening for natural compounds that activate PPAR using luciferase a