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Anthocyanins from Aronia melanocarpa Elliot induce apoptosis in Caco‐2 cells through Wnt/β‐catenin signaling pathway
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. In this study, the Caco‐2 in vitro cell model was used to study the effect and mechanism of Aronia melanocarpa Elliot anthocyanins (AMA) on colon cancer. The experimental results showed that the binding energy of anthocyanins on β‐Catenin was in the range of ‐5.92 to 4.95 kcal/mol, with good low energy parameters and binding positions. AMA can inhibit cell proliferation and cause cell cycle arrest. RT‐PCR and Western blot results showed that AMA can reduce cytolpasmic β‐Catenin and inhibit the expression of related proteins in Wnt/β‐catenin signaling pathway. This study revealed the AMA inhibitory effect and mechanism of malignant biological behavior of Caco‐2 cells, in order to provide theoretical basis for the prevention and treatment of colon cancer by Aronia melanocarpa Elliot.
... Moreover, such effects have been assayed in diverse types of CC cell lines, such as Caco-2, DLD1-1, HT-29, HCT-116, SW480, or SW620, therefore covering a wide range of types of cells associated with CC development and progression (Table 3). Beyond the protective effects reported against PC [142], ACNs from Aronia melanocarpa (black chokeberry) extracts were also reported to be effective against CC cells lines, inducing apoptosis in Caco-2 cells through the Wnt/beta-catenin signalling pathway [146]. A similar effect was observed by Gill et al. [147], which assayed three different species of chokeberries (purple, red and black, the last one being the Aronia melanocarpa). ...
... Retarded carcinogenesis and castration-resistant PC growth (suppression of androgen receptor-mediated cell proliferation and metabolism) [143] Chokeberry extracts (ACNs) Caco-2 cells (CC) ↓ cell growth; G1/G0 and G2/M phases arrest; ↑ p21WAF1 and p27KIP1 expression; ↓ cyclin A and cyclin B expression [146] Chokeberry extracts (ACNs and phenolics) HT-29 (CC) ↓ cell proliferation [147] Coloured fruits and vegetables ...
Anthocyanins are widespread and biologically active water-soluble phenolic pigments responsible for a wide range of vivid colours, from red (acidic conditions) to purplish blue (basic conditions), present in fruits, vegetables, and coloured grains. The pigments’ stability and colours are influenced mainly by pH but also by structure, temperature, and light. The colour-stabilizing mechanisms of plants are determined by inter- and intramolecular co-pigmentation and metal complexation, driven by van der Waals, π–π stacking, hydrogen bonding, and metal-ligand interactions. This group of flavonoids is well-known to have potent anti-inflammatory and antioxidant effects, which explains the biological effects associated with them. Therefore, this review provides an overview of the role of anthocyanins as natural colorants, showing they are less harmful than conventional colorants, with several technological potential applications in different industrial fields, namely in the textile and food industries, as well as in the development of photosensitizers for dye-sensitized solar cells, as new photosensitizers in photodynamic therapy, pharmaceuticals, and in the cosmetic industry, mainly on the formulation of skin care formulations, sunscreen filters, nail colorants, skin & hair cleansing products, amongst others. In addition, we will unveil some of the latest studies about the health benefits of anthocyanins, mainly focusing on the protection against the most prevalent human diseases mediated by oxidative stress, namely cardiovascular and neurodegenerative diseases, cancer, and diabetes. The contribution of anthocyanins to visual health is also very relevant and will be briefly explored.
... g/l) (Skupień et al., 2008). The Aronia anthocyanin-rich methanolic extract (0.05, 0.1, and 0.2 mg/ml of medium for 48 h) inhibited cell proliferation and caused cell cycle arrest in human colon cancer cell line Caco-2 (Wei, Yu, Hao, Fan, & Gao, 2020). The effect was associated with the reduction of cytoplasmic β-catenin and inhibition of the expression of proteins related to the Wnt/β-catenin signaling pathway . ...
... In a recent review, Dharmawansa, Hoskin, and Rupasinghe (2020) summarized the differences between anthocyanin-induced effects in normal and cancer cells. While in normal cells anthocyanins mediate processes, that contribute to cancer prevention, including antioxidant defence (via ROS scavenging, activation of glutathione antioxidant system and Nrf2 pathway) and reduction in the formation of oxidative DNA adducts (Amararathna, Hoskin, & Rupasinghe, 2020;Ferrari et al., 2016;Shih, Yeh, & Yen, 2007), suppression of inflammatory responses via downregulation of NF-κB and AP-1 signaling pathways (Ferrari et al., 2016;Jang, Lee, Choi, & Yim, 2020;Limtrakul, Yodkeeree, Pitchakarn, & Punfa, 2015), in cancer cells anthocyanins can induce DNA damages (via modulation the activity of DNA topoisomerases I and II) (Habermeyer et al., 2005), inhibit cell growth and proliferation (via modulation of MAPK, NF-κB, AMPK, insulin/IGF-1, and Wnt/β-catenin pathways) (Kim, Shin, & Park, 2005;Klein & Fischer, 2002;Vendrame & Klimis-Zacas, 2015;Wang, DeGroff, & Clinton, 2003;Wei et al., 2020;Yun-Kyoung, Park, Kim, Lee, & Park, 2010) and induce apoptosis (via mitochondrial pathway and activation of caspase-9) (Yun, Afaq, Khan, & Mukhtar, 2009). ...
Background
Black chokeberry (Aronia melanocarpa (Micht.) Elliot) is a great dietary source of a wide range of biologically active compounds, such as anthocyanins, flavonoids, other phenolic compounds, vitamins, and minerals that have a wide range of health benefits.
Scope and approach
Here we provide an overview of the in vitro and in vivo effects of A. melanocarpa extracts to reveal its potential anti-aging properties in terms of meeting the criteria for a geroprotector. The possible mechanisms of the anti-aging action of black chokeberry extracts are highlighted.
Key findings and conclusions
A. melanocarpa extract exhibit geroprotective activity like lifespan extension, anti-proliferative activity, improvement of glucose and lipid metabolism, amelioration of neurodegenerative disorders, antiviral and antibacterial activity, protection of the gastrointestinal system. The mechanisms of A. melanocarpa anti-aging action may be associated with the hormesis effect, activation of antioxidant-defense, modulation of insulin/IGF-1 signaling, and anti-inflammatory activity.
... Aronia melanocorpa exerts anti-proliferative effects on human colon cancer cells by suppressing cell growth, inducing apoptosis and cell cycle arrest, and upregulating the expression of numerous cell cycle-related genes [10,[26][27][28]. Normal colon and human HT-29 colon cancer cell lines were exposed to Aronia melanocarpa extract for 24 hours. ...
... A study by Anwar et al. demonstrated that a berry anthocyanin-rich extract was capable of decreasing CRC cell viability by suppressing cyclin-dependent kinase inhibitor 1 (p21Waf/Cif1), activating caspase-3, and enhancing ROS production [58]. Aronia melanocarpa Elliot anthocyanins inhibited Wnt/β-catenin activity in Caco-2 cells, resulting in inhibited cell growth and enhanced apoptosis induction [105]. Anthocyanins derived from purple-fleshed potatoes inhibited cell growth and sphere formation of colonic CSCs, which were also regulated by the Wnt/β-catenin pathway [106]. ...
Colorectal cancer (CRC) is a prevalent and serious gastrointestinal malignancy with high mortality and morbidity. Chemoprevention refers to a newly emerged strategy that uses drugs with chemopreventive properties to promote antioxidation, regulate cancer cell cycle, suppress proliferation, and induce cellular apoptosis, so as to improve cancer treatment outcomes. Natural polyphenols are currently recognized as a class of chemopreventive agents that have shown remarkable anticarcinogenic properties. Numerous in vitro and in vivo studies have elucidated the anti-CRC mechanisms of natural polyphenols, such as regulation of various molecular and signaling pathways. Natural polyphenols are also reportedly capable of modulating the gut microbiota and cancer stem cells (CSCs) to suppress tumor formation and progression. Combined use of different natural polyphenols is recommended due to their low bioavailability and instability, and combination treatment can exert synergistical effects, reduce side effects, and avoid drug resistance in CRC treatment. In summary, the application of polyphenols in the chemoprevention and treatment of CRC is promising. Further clinical evaluation of their effectiveness is warranted and anticipated.
... Hence, inhibition of this protein by an extract of Aronia berries implies some promise for the discovery of novel anticancer agents from these berries by targeting SLC1A5 [22]. In addition, anthocyanins of Aronia berries were found to inhibit Caco-2 cell growth through the Wnt/β-catenin signaling pathway [23]. ...
Aronia berry (black chokeberry) is a shrub native to North America, of which the fresh fruits are used in the food industry to produce different types of dietary products. The fruits of Aronia melanocarpa (Aronia berries) have been found to show multiple bioactivities potentially beneficial to human health, including antidiabetic, anti-infective, antineoplastic, antiobesity, and antioxidant activities, as well as heart-, liver-, and neuroprotective effects. Thus far, phenolic compounds, such as anthocyanins, cyanidins, phenolic acids, proanthocyanidins, triterpenoids, and their analogues have been identified as the major active components of Aronia berries. These natural products possess potent antioxidant activity, which contributes to the majority of the other bioactivities observed for Aronia berries. The chemical components and the potential pharmaceutical or health-promoting effects of Aronia berries have been summarized previously. The present review article focuses on the molecular targets of extracts of Aronia berries and the examples of promising lead compounds isolated from these berries, including cyanidin-3-O-galactoside, chlorogenic acid, quercetin, and ursolic acid. In addition, presented herein are clinical trial investigations for Aronia berries and their major components, including cancer clinical trials for chlorogenic acid and COVID-19 trial studies for quercetin. Additionally, the possible development of Aronia berries and their secondary metabolites as potential therapeutic agents is discussed. It is hoped that this contribution will help stimulate future investigations on Aronia berries for the continual improvement of human health.
... In addition, Aornia mealnocarpa also contains catechol, chlorogenic acid, caffeic acid and other functional components [11]. Based on previous studies in our laboratory, we found that AMA can effectively delay the aging of mice and has significant therapeutic effect on colon cancer mice [12]. So our research group are devoted to studying the preventive effect and mechanism of AMA on liver fibrosis. ...
In order to explore the effect and mechanism of Aornia mealnocarpa Elliot anthocyanins (AMA) at the cellular level on hepatic fibrosis (HF), molecular docking, RT-PCR and Western Blotting were used to explore the molecular mechanism and the effects of different doses AMA on HSC-T6 cells by TGF-β1 induction. The results showed that the binding energy of anthocyanins on TGF-β1 (PDB ID: 3KFD) was in the range of −9.5 to 8.6 kcal/mol, with good low energy parameters and binding positions. AMA could effectively inhibit the expressions of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total serum bilirubin (TSB), and improved the expressions of total protein (TP) and albumin (ALB). RT-PCR and Western bloting results showed that AMA could inhibited the secretion of inflammatory cytokines IL-1, IL-6, TNF-α and COX-2, and inhibit the expression of TGF-β1, P-Smad2, α-SMA and Collagen I in TGF-β /Smad signaling pathway. This study revealed the AMA’s inhibition effects and mechanism of malignant biological behavior of HSC-T6 cells, in order to provide theoretical basis for the prevention and treatment of HF by Aronia melanocarpa Elliot.
... The chokeberry anthocyanin extract inhibited the growth of HT-29 cells [38,40], and reduced the total number of ACF and colonic cellular proliferation in the AOM rat model [44]. A special black chokeberry (Aronia meloncarpa E) exhibited antioxidative effects, inhibited cell growth, promoted cell phase arrest, and upregulated several cell cycle-related genes [46][47][48][49]. ...
Colorectal cancer (CRC) is still a big health burden worldwide. Nutrition and dietary factors are known to affect colorectal cancer development and prognosis. The protective roles of diets rich in fruits and vegetables have been previously reported to contain high levels of cancer-fighting phytochemicals. Anthocyanins are the most abundant flavonoid compounds that are responsible for the bright colors of most blue, purple, and red fruits and vegetables, and have been shown to contribute to the protective effects of fruits and vegetables against cancer and other chronic diseases. Berries and grapes are the most common anthocyanin-rich fruits with antitumor effects. The antitumor effects of anthocyanins are determined by their structures and bioavailability as well as how they are metabolized. In this review, we aimed to discuss the preventive as well as therapeutic potentials of anthocyanins in CRC. We summarized the antitumor effects of anthocyanins and the mechanisms of action. We also discussed the potential pharmaceutical application of anthocyanins in practice.
... Colorectal cancer (CRC) accounts for the third highest cancerrelated mortalities worldwide [1]. Currently, conventional treatment that involves using chemotherapeutic drugs as oxaliplatin, Xeloda and 5-flurouracil (5-FU) exerts strong side effects, such as neurotoxicity, diarrhea and skin rash in addition to drug resistance [2,3]. Additionally, surgical treatment for CRC is always associated with post-operative tumour metastasis due to the migration of cancer cells to neighbouring tissues [4]. ...
Background
Drawbacks and side effects of currently available therapies to colorectal cancer (CRC) devoted the researchers to search for new therapeutic strategies.
Objective
This study was designed to investigate the effects of zinc nanoparticles biosynthesized with berberine (ZnNPs-BER) on Caco-2 cells compared to 5-Fluorouracil (5-FU) and explore the possible underlying pathways.
Methods
Caco-2 and Vero cells were treated with 5-FU, BER, or ZnNPs-BER for 24 h. Cell viability was measured by MTT assay. Oxidative stress and apoptotic markers and cell cycle were determined. Additionally, Cox-2 and NF-kB levels were also measured.
Results
The IC50 of 5-FU, BER, and ZnNPs-BER on Caco-2 cells were 34.65 µM, 19.86 µg/ml and 10.49 µg/ml, respectively by MTT assay. The IC50 value for 5-FU in Vero cells was 21.7 μg/ml, however, BER and BER-ZnNPs treatment showed non-toxic effects to the Vero cells. Further, ZnNPs-BER exerted significant induction of ROS besides exhaustion of the antioxidant capacity of tumor cells indicated by declined GSH and elevated NO and MDA contents. Marked increments in levels of Bax and caspase-3 were detected together with declines in Bcl-2 levels in Caco-2 cells submitted to BER-ZnNPs therapy. On the molecular basis, upregulation in mRNA levels of pro-apoptotic genes (Bax, caspase-3, and tumor suppressor gene p53) with downregulation in the antiapoptotic gene (Bcl-2) were observed in ZnNPs-BER treated Caco-2 cells. Furthermore, ZnNPs-BER showed more pronounced effects on apoptosis increased cell percentage in the S and subG1 phases. In addition, green synthesis of ZnNPs with BER showed notable induction of Cox2 and NF-kB in Caco-2 cells.
Conclusion
Therefore, the antitumor potential of ZnNPs-BER in colon cancer cells may be endorsed for induction of oxidative stress, inflammation, and apoptotic changes in tumor cells. Our study documents the new therapeutic potential of Zn nanoparticles conjugated with BER, as a new option for combined chemotherapy.
... Also, emodin increased the sensitivity of HCC cells to sorafenib via Akt signaling [53]. Also, in line with the results of the present work, previous studies have reported that some nature-derived compounds can modulate the Wnt/β-catenin signaling in cancer cells and the liver of HCC animals [54][55][56]. One of the limitations of the present study is that we did not investigate the effect of R. turkestanicum on protein expression of PI3K, Akt, PTEN, Wnt4, and β-catenin. ...
Aim of the study Hepatocellular carcinoma (HCC) is common cancer that causes many deaths worldwide. Recent studies have reported anti-cancer effects of R. turkestanicum against various cell lines including leukemia cervical tumor, and breast cancer. In this study, we aimed to identify the effect of R. turkestanicum against diethylnitrosamine (DEN)-induced HCC.
Methods Wistar rats were divided into four groups of control, DEN, DEN + 100 mg/kg or 400 mg/kg of hydroethanolic extract of the plant roots.
Results After four months, the animals in the DEN group showed HCC foci in the liver, an increase of hepatic lipid peroxidation, attenuation of hepatic antioxidant capacity, an increase of blood liver enzymes (ALT, AST, and ALP), bilirubin, albumin, creatinine, glucose, and reduction of the body weight. The plant extract could decrease the levels of liver enzymes, total bilirubin, direct bilirubin, albumin, urea, and creatinine in the blood. Also, the extract attenuated oxidative stress and improved pathological changes in the liver. Quantitative real-time PCR revealed a decrease in gene expression of Wnt/β-catenin and Akt and an increase in PTEN as the tumor suppressor gene.
Conclusion The extract of R. turkestanicum reduced DEN-induced liver changes through inhibiting oxidative stress and attenuating the expression of Wnt/β-catenin and Akt and elevating PTEN expression.
Coffee (Coffea arabica L.) is one of the most popular and widely consumed products throughout the world, mainly due to its taste, aroma, caffeine content, and natural antioxidants. Among those antioxidants, anthocyanins are one of the most important natural pigments, which can be found in coffee husks. It is widely known that anthocyanins have multiple health benefits partially linked to their antioxidant properties. However, anthocyanins have low stability and are sensitive to all types of changes. In order to prevent its degradation, anthocyanins can be stabilized with nanoparticles. Thus, the main objective of this study was to evaluate the stability of the anthocyanins extracted from coffee husks, using three different extracting agents (ethanol, methanol, and water) and stabilizing them through conjugation with zinc oxide nanoparticles. The anthocyanins extracts were mainly composed of cyanidin-3-rutinoside (97%) and the total phenolic compounds of the fresh extracts were 458.97 ± 11.32 (methanol), 373.53 ± 12.74 (ethanol), and 369.85 ± 15.93 (water) mg GAE/g. On the other hand, the total phenolic compounds of the nanoparticle-anthocyanin conjugates underwent no significant changes after stabilization as the major loss was less than 3%. Furthermore, the percentage of anthocyanins' degradation was less than 5% after 12 weeks of storage. On top of that, fresh anthocyanin extracts and anthocyanin-nanoparticle conjugates exhibited a strong protective effect against oxidative stress and increased the survival rate of Caenorhabditis elegans.
Anthocyanins have been reported to have potential as dietary or pharmaceutical supplements in the application of cancer prevention and adjunctive treatment. However, there are few studies on the effect of anthocyanins on melanoma, which have only been performed in cell lines. The objective of this work was to investigate the anticancer effects and mechanisms of bilberry anthocyanin extract (BAE) on melanoma In Vitro and In Vivo. Moreover, a primary study was done to investigate how BAE influenced C57BL/6 mice bearing subcutaneous B16-F10 tumors treated with dacarbazine (DTIC). BAE-induced apoptosis in B16-F10 cells was associated with activation of the mitochondrial pathway induced by increased reactive oxygen species. More, In Vivo anticancer activity studies indicated that BAE attenuated melanoma growth, as identified by hematoxylin-eosin staining, Ki-67, and TUNEL assays. Further western blot results revealed higher phospho-Akt expression with the combination of BAE and DTIC, indicating no suppression of the PI3K/AKT signaling pathway. In summary, this study demonstrated the anti-melanoma activity of BAE and investigated its mechanism. Notably, it should be careful to use products enriching BAE for those melanoma patients treated with DTIC.
Anthocyanins have been associated with beneficial effects on human health. Cancer has been one of the main public health issues due to its aggressiveness and high mortality rate. This systematic review aimed to address recent research (from January 2000 to September 2021) on the anticancer activity of anthocyanins assessed by in vitro assays. The selected studies revealed that anthocyanins have anticancer potential by inhibiting cancer cell viability and proliferation, controlling cell cycle, and promoting apoptosis.
Morus nigra is a rich source of anthocyanins, phytochemicals that have anticancer effects. This study aimed to investigate the effects of M. nigra extract (MNE) on diethylnitrosamine (DEN)‐induced hepatocellular carcinoma (HCC). Male Sprague–Dawley rats were assigned into four groups (n = 10): control, DEN, and DEN +100 or 400 mg/kg of MNE. After 4 months, the DEN group showed a significant mortality rate, hepatic lipid peroxidation, dysplastic nodules in the cirrhotic liver, and an increase of blood bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). Also, the body weight gain, blood albumin and glucose, liver antioxidant capacity (thiol groups), and some hematological parameters (RBC, hematocrit, hemoglobin, and platelet) were significantly decreased in the DEN group. MNE significantly increased survival, reduced the size of HCC nodules, improved liver oxidant/antioxidant status, and prevented the above‐mentioned changes in the blood (except ALP, glucose, and platelet). Quantitative real‐time PCR showed that MNE decreased the expression of Wnt4 and β‐catenin, while had no significant effect on PI3K, Akt, and PTEN expression. The MNE did not exhibit antiproliferative activity against HepG2 liver cancer cells. In conclusion, MNE exhibits a hepatoprotective effect through inhibiting oxidative stress and Wnt4/β‐catenin pathway and therefore prolongs the survival of rats with HCC.
Background: Current treatment of osteosarcoma is limited in part by side effects and low tolerability, problems generally avoided with traditional Chinese medicine. Ganoderma lucidum, a traditional Chinese medicine with antitumor effects, offers a potential alternative, but little is known about its molecular mechanisms in osteosarcoma cells. Objective: To investigate the effect of G lucidum on osteosarcoma cells and its mechanism. Methods: Osteosarcoma MG63 and U2-OS cells were treated with G lucidum, followed by assays for cell proliferation (Cell Counting Kit-8), colony formation, and apoptosis (Alexa Fluor 647-Annexin V/propidium iodide, flow cytometry). Migration and invasion of cells were assessed by wound healing and Transwell invasion assays, and the effect of G lucidum on Wnt/β-catenin signal transduction was studied by real-time quantitative polymerase chain reaction, western blot, and dual-luciferase assay. Results: G lucidum inhibited the proliferation, migration, and invasion, and induced apoptosis of human osteosarcoma MG63 and U2-OS cells. Dual-luciferase assay showed that G lucidum suppressed the transcriptional activity of T-cell factor/lymphocyte enhancer factor in the Wnt/β-catenin signaling pathway. Moreover, G lucidum blocked Wnt/β-catenin signaling by inhibiting the Wnt co-receptor LRP5 and Wnt-related target genes, such as β-catenin, cyclin D1, C-Myc, MMP-2, and MMP-9. At the same time, when Wnt/β-catenin was inhibited, the expression of E-cadherin was upregulated. Conclusions: Our results suggest that G lucidum broadly suppresses osteosarcoma cell growth by inhibiting Wnt/β-catenin signaling.
The primary objective of the study was to determine the effect of process conditions on extraction efficiency and the total amount of released polyphenols and antioxidant activity (AA) in black chokeberry juice. The study samples were fruits of black chokeberry (Aronia melanocarpa (Michx.) Elliott) cv. Galicjanka. In the study, two kinds of presses-piston press and twin gear juice extractor-were used, and two raw material pretreatment methods-freezing and thawing and enzymatic liquefaction-were applied. The study showed that pressing efficiency depends on the design of press and the nature of pretreatment. The highest pressing efficiency was obtained using the twin gear juice extractor. Enzymatic liquefaction of shredded fruits significantly increased the efficiency of pressing by the piston press. The type of press and the pretreatment method used had an effect on the quality traits of the extracted juices. The highest content of soluble solids was obtained for fruits not subjected to any pretreatment and pressed using the twin gear press. The highest total phenolic content was obtained in juice extracted using the piston press from shredded fruits subjected to enzymatic treatment at 45°C. A higher total phenolic content was also a characteristic of juice obtained from fruits not subjected to any pretreatment and extracted using the twin gear press. The capacity of the black chokeberry juices for free radical quenching oscillated around the level of approximately 90%. The study showed that the application of suitable processing methods is necessary for the acquisition of products with desirable quality traits.
Acute lung injury (ALI) is associated with deterioration of alveolar-capillary lining and transmigration and activation of inflammatory cells. Sildenafil, phosphodiesterase 5 (PDE5) inhibitor, inhibits degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. Positive effects of sildenafil treatment result from influencing proliferation of regulatory T cells and production of proinflammatory cytokines and autoantibodies as well as from modulation of platelet activation, angiogenesis, and pulmonary vasoreactivity. This study evaluated if intravenous sildenafil can influence inflammation, edema formation, apoptosis, and respiratory parameters in rabbits with a model of ALI induced by repetitive lung lavage by saline (30 ml/kg). animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with sildenafil intravenously (1 mg/kg; ALI + Sil), and healthy ventilated controls (Control) which were oxygen-ventilated for 4 hours following treatment administration. during this period, respiratory parameters (ventilator pressures, lung compliance, blood gases, oxygenation indexes etc.) were regularly measured. at the end of experiment, animals were overdosed by anesthetics. The left lung was saline-lavaged and total and differential cell counts and protein content in the bronchoalveolar lavage fluid (BAL) were estimated. The right lung was used for determination of lung edema formation expressed as wet/dry lung weight ratio, for detection of inflammation and oxidative stress markers by ELISA methods, and for detection of lung epithelial cells apoptosis by TUNEL methods and level of caspase-3. Sildenafil treatment reduced leak of cells (P < 0.05), particularly of neutrophils (P < 0.001) into the lung, release of pro-inflammatory mediators (TNF-α, P < 0.001; IL-8 and IL-6, P < 0.01), level of nitrite/nitrate (P < 0.001), markers of oxidative damage (3-nitrotyrosine and malondialdehyde, both P < 0.01), lung edema formation (P < 0.01), protein content in BAL (P < 0.001), and apoptosis of epithelial cells (P < 0.01), and improved respiratory parameters. Concluding, the results indicate a future potential of PDE5 inhibitors also for the therapy of ALI.
Long noncoding RNAs (lncRNAs), with length of more than 200 nucleotides, are not translated into proteins but involved in multiple diverse diseases, especially tumorigenesis. The dysregulation of lncRNAs greatly contributes to the progression of various tumors through specific signaling pathways, including Wnt/β-catenin signaling pathway, which is associated with malignant features of tumors. The interactions between lncRNAs, which have specific expression characteristics in diverse cancer tissues, and Wnt/β-catenin signaling pathway, exhibit potential as novel biomarkers and therapeutic targets. In this review, we aim to present research findings on the roles of Wnt pathway-related lncRNAs and their effects on Wnt/β-catenin signaling to regulate tumorigenesis in different cancer types. Results may be used as basis to develop or improve strategies for treatment of different carcinomas.
Ischaemic brain injury continues to be devastating, causing social, medical and relationship disruption. Oxidativedamage has been reported to be one of the mechanisms for brain damage following ischaemic stroke. The antioxidant activityof Hibiscus sabdariffa L. was investigated for a possible protective effect against ischaemia-induced brain damage in rats.Adult male Wistar rats (n=35) were divided into five groups of 7 rats per group. Group 1 served as control was given tapwater; Group 2: 500 mg/kg daily of Hibiscus sabdariffa L. extract (HSE); Group 3: bilateral common carotid artery occlusion(BCCAO) for 30 minutes followed by reperfusion for 24 hours; Group 4: 500 mg/kg (HSE) before BCCAO; Group 5: 500mg/kg vitamin E before BCCAO. All administrations were oral and lasted 3 weeks. Behavioural studies namely: transitions,rearings, groomings and forelimb grip strength were carried out. Rats were thereafter euthanized and biochemical[malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)], histological andmorphological investigations were carried out on rat whole brain. Animals pretreated with HSE showed a significant (p<0.05)reduction in their body weight compared to the control group. BCCAO produced a significant (p<0.05) reduction in GSH,SOD and CAT while elevating MDA non-significantly. The HSE and Vitamin E pretreatment ameliorated these biochemicalalterations and also attenuated reactive changes in cortical neurons. BCCAO treatment increased grooming and forelimbstrength which both HSE and vitamin E pretreatment reversed. The results suggest that H. sabdariffa L and vitamin E were protective in acute cerebral ischaemia induced by bilateral common carotid artery occlusion in adult male rats.
Liver ageing is a significant risk factor for chronic liver diseases. Anthocyanin is a food additive that has previously shown efficacy in increasing longevity. Here, we tested whether anthocyanins could protect young mice from accelerated ageing of the liver. Kunming mice were injected with D-galactose to accelerate ageing and were given 20 or 40 mg/kg anthocyanins as an intervention. After eight weeks, whole liver function and structure were evaluated, and the expression levels of genes involved in the DNA damage signalling pathway were assessed by Western blot analysis. Anthocyanins delayed the reduction of the liver index (p < 0.05), hepatic tissue injury and fibrosis. Anthocyanins also maintained the stability of the redox system (GSH-PX, T-SOD and MDA) in plasma and liver structures (p < 0.001) and reduced the levels of inflammatory factors (IL-1, IL-6 and TNF-α) in the liver (p < 0.05). Moreover, the expression levels of sensors (ATM and ATR), mediators (H2AX and γ-H2AX) and effectors (Chk1, Chk2, p53 and p-p53) in the DNA damage signalling pathway were all reduced. Anthocyanins could be widely used in the field of health products to slow ageing-related deterioration of liver function and structure by inhibiting DNA damage.
Periodontitis is associated with reduced antioxidant capacity and increased oxidative damage. Oxidative stress induces inflammation and bone loss contributing to the pathological progression of periodontal disease. Calendula officinalis (CLO) has demonstrated anti-inflammatory and anti-oxidant activities. Therefore, the aim of this study was to evaluate the effect of CLO on oxidative stress and bone loss in rats subjected to experimental periodontitis (EP). For this, 72 male Wistar rats were divided into groups: Naïve, Saline (SAL) and CLO. Rats received SAL or CLO (90 mg/kg) 30 min before ligature and daily until the 11th day. Naïve group experienced no manipulation. After 11 days, the animals were euthanized and left maxillae collected for macroscopic analysis of alveolar bone loss (ABL). Periodontium was analyzed by macroscopy, scanning electron microscopy; confocal and light polarized microscopy. Immunohistochemical examination of DKK1, WNT 10b and β-catenin was performed. The gingival tissue was collected to reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) analyses. The 11 days of ligature induced bone loss, breakdown of collagen fibers, increased the immunostaining DKK-1 while reduced WNT 10b and β-catenin expressions. Periodontitis reduced GSH, SOD, CAT and increase MDA. All findings were reversed by 90 mg/kg of CLO. In summary our findings demonstrated that CLO reduced oxidative stress and bone loss and preserved collagen fibers in rats with EP, with participation of WNT signaling pathway.
Background:
Canonical Wnt signaling plays a key role in tumor cell proliferation, which correlates with the accumulation of β-catenin in cell due to inactivation of glycogen synthetase kinase-3 β. However, uncontrolled expression of β-catenin leads to fibromatosis, sarcoma and mesenchymal tumor formation. Recently, a number of polyphenolic compounds of naturally occurring flavonoid family have been screened for the inhibition of Wnt signaling.
Objective:
Elucidation of the binding mode of inhibitors to β-catenin, reporting more potent inhibitors for the disease-causing protein and designing a pharmacophore model based on naturally occurring compounds, flavonoids.
Materials and methods:
In this study, a comparative molecular docking analysis was performed to elucidate the binding mode of experimentally reported and unknown inhibitors. Based on the knowledge of geometry, binding affinity and drug score, we described a subset of novel inhibitors.
Results:
The binding energy of known inhibitors (isorhamnetin, fisetin, genistein and silibinin) was observed in a range of -5.68 to -4.98 kcal/mol, while novel inhibitors (catechin, luteolin, coumestrol and β-naphthoflavone) exhibited -6.50 to -5.22 kcal/mol. We observed good placement and strong interactions of selected compounds inside the binding pocket of β-catenin. Moreover, flavonoid family members and T cell factors 4 (TCF4) compete for β-catenin binding by sharing common binding residues.
Conclusion:
This study will largely help in understanding the molecular basis of β-catenin/TCF4 inhibition through flavonoids by exploring their structural details. Finally, the novel inhibitors proposed in this study need further attention to uncover cancer treatment and with the generated pharmacophore model, more and potent β-catenin inhibitors can be easily screened.
The purpose of the present study was to evaluate small and high molecular phenolics (tannins) and antioxidant activity of
Aronia melanocarpa berries, juice and pomace in order to find new potential sources of natural antioxidants. The fruits of Aronia melanocarpa Elliot were collected in the middle of October at a plantation near Wroclaw, Poland. The pomace has a much higher content
of phenolics in comparision to juice and fruits. Results showed that polymeric proanthocyanins, predominantly of (−)epicatechin,
are the major class of polyphenolic compounds in chokeberry, represent 66% of fruits polyphenols. The average concentration
ranged from 1578.79mg/100g of DW for chokeberry juice up to 8191.58mg/100g in pomace. The concentration of phenolic acids
(chlorogenic and neochlorogenic acids) in juice was higher than in pomace. Anthocyanins in Aronia melanocarpa are second phenolic compound group and represent about 25% of total polyphenols, mixture of four different cyanidin glycosides:
3-galactoside, 3-glucoside, 3-arabinoside and 3-xyloside. The higher antioxidant activity expressed as TEAC was measured in
pomace >fruit >juice.
The present study was conducted to evaluate the efficacy of fenofibrate and pioglitazone in a mouse model of amyloidogenesis induced by amyloidβ (βA) peptide. Mice were injected intracerebroventricularly with βA1-40 (400 pmol/mouse) once, followed by treatment with fenofibrate (300 mg/kg), pioglitazone (30 mg/kg),or both. After 21 days of daily treatment, memory impairment and cognitive function were evaluated by Morris water maze (MWM), Y-maze and object recognition tests. On the 22nd day, mice were sacrificed, and their hippocampi were dissected to determine the levels of α- and β-secretase, peroxisome proliferator-activated receptor (PPARα and β), Wnt and β-catenin. Significant memory impairment and cognitive dysfunction were observed in the mouse model group. This finding was associated with a significant increase in α- and β-secretase levels and a significant decrease in Wnt, β-catenin, and PPARα and β levels. Neuronal damage was also evident after histopathological examination. Treatment with fenofibrate, pioglitazone and their combination resulted in a significant improvement in the behavioural and neurochemical changes induced by βA injection. The present findings indicate that the combined administration of fenofibrate and pioglitazone was more effective than monotherapy in ameliorating the behavioural, neurochemical and histopathological changes in amyloidogenesis model mice and provide a promising therapeutic approach in the management of Alzheimer's disease complicated by diabetes and hypercholesterolemia.
Negative elongation factor E (NELFE) has been demonstrated to promote cancer progression as an RNA‑binding protein (RBP). However, the expression patterns, biological role and molecular mechanism of NELFE in pancreatic cancer (PC) remain largely unknown. The expression levels of NELFE in 120 pairs of PC tissues and adjacent non‑tumor clinical samples collected from patients with PC were examined via reverse transcription‑quantitative (RT‑q) PCR and immunohistochemistry. The mRNA expression levels of NELFE, N‑Myc downstream‑regulated gene 2 (NDRG2), c‑Myc, survivin and cyclin D1 were detected via RT‑qPCR. The protein expression levels of NELFE, NDRG2, total β‑catenin, nuclear β‑catenin, cytosolic β‑catenin, E‑cadherin, N‑cadherin and Vimentin were measured by western blotting. NELFE and NDRG2 were then knocked‑down by short hairpin (sh)RNA. PC cell proliferation was detected by MTT and colony formation assays. Invasion and migration were detected by transwell assays. The interaction between NELFE and NDRG2 was detected by luciferase reporter assays, mRNA decay assays and RNA immunoprecipitation. NELFE expression was increased in PC tissues compared with the paired non‑cancerous tissues. NELFE expression was upregulated in PC cells when compared with normal pancreatic cells (HPDE6‑C7). The present study revealed that knockdown of NELFE inhibited the proliferation, invasion and migration of PC cells. In addition, transfection of the sh‑NELFE vector inhibited the epithelial‑to‑mesenchymal transition in PC cells by suppressing the expression and nuclear accumulation of β‑catenin. Further mechanistic studies revealed that NELFE activates the Wnt/β‑catenin signaling pathway by decreasing the stabilization of NDRG2 mRNA in PC. To the best of our knowledge, these results revealed the promotional function of NELFE on PC tumorigenesis and metastasis for the first time, helping to provide a promising strategy for the treatment of patients with PC.
Molecular docking is a theoretical simulation method based on bioinformatics, which studies the interaction between molecules (such as ligands and receptors), and predicts their binding modes and affinity via a computer platform. This technology acts as a promising mean in medicinal chemistry such as structure‐based rational drug design, which is accepted by researchers in the scientific community. During recent years, various fundamental studies involving biomolecular interaction in the food matrix have gradually emerged. The remarkable advantages of molecular docking such as predicting experiments are attracting increasing attention for its application potential in various fields. This review presents the theory and software development of molecular docking, and emphasizes its application in the field of food science, including nutritional components and food safety. Moreover, the operational mechanisms of molecular docking are further summarized in this review. This article is protected by copyright. All rights reserved.
Introduction:
Several regimens for treating hematologic malignancies are given inpatient due to multiple factors. Many clinicians are evaluating methods to deliver traditionally inpatient regimens in the outpatient setting to increase patient satisfaction, improve access to therapy, and reduce costs. A regimen traditionally administered inpatient, dexamethasone, cytarabine, and cisplatin (DHAP) is a common and effective salvage regimen for relapsed/refractory non-Hodgkin's lymphoma. DHAX, which substitutes oxaliplatin for cisplatin, has been identified as a reasonable alternative to DHAP and offers the potential for tolerable administration in the outpatient setting as well.
Case description:
A 74-year-old patient with double hit relapsed/refractory diffuse large B cell lymphoma was given rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAX) in our outpatient clinic; however, this regimen is traditionally administered in the inpatient setting. Our main obstacle being cytarabine doses traditionally given 12 h apart. The outpatient regimen given to our patient was rituximab and oxaliplatin on day 1, cytarabine dose one late afternoon on day 2, cytarabine dose two early morning on day 3, and dexamethasone on days 1-4. Doses of oxaliplatin and cytarabine were reduced due to thrombocytopenia experienced with Cycle 1. He did not experience any increased toxicities or complications associated with the regimen moving forward.
Discussion:
This illustrates a unique administration of R-DHAX in an infusion center that operates during typical outpatient clinic hours. Both DHAP and DHAX, with or without rituximab, administered in the outpatient setting may be options to consider in relapsed/refractory non-Hodgkin's lymphoma.
Aim: Aging is the greatest risk factor for most neurodegenerative diseases. Cardiovascular circulatory system is an important part of maintaining normal human life activities. The core of the aging process is DNA damage, a food additive called Anthocyanin which has shown high efficacy in preventing aging, We examine whether anthocyanins could keep young mice from accelerated ageing of the heart. Materials and Methods: In order to accelerate ageing, Mice of Kunming were injected with D-galactose and they were given anthocyanins of 20 and 40 mg/kg as an intervention. Results: The whole function and structure of heart were evaluated after eight weeks and the expression levels of genes involved in the DNA damage signalling pathway were evaluated through Western blot analysis. Reduction of the heart index and the heart tissue damage was delayed by Anthocyanins. it maintained the stability of the redox system in serum such as GSH-PX, T-SOD and MDA and heart tissue. In the DNA damage signalling pathway, the expression levels of sensors such as ATM and ATR and effectors such as Chk1 and Chk2 were reduced. Conclusion: Anthocyanins can be diffusely used to slow ageing-related deterioration of heart structure and function by inhibiting DNA damage in the field of health products. © 2019, Association of Pharmaceutical Teachers of India. All right reserved.
The effects of essential oil from Carpesium abrotanoides L. (CAEO) on the proliferation and apoptosis of human hepatic cancer cells were investigated in this study. MTT assays indicated that CAEO inhibited the proliferation of HCC cells with the IC50 values ranging from 41.28±3.06 to 130.36±20.79 μg/mL. Moreover, many obviously nuclear morphological changes of apoptotic cells in CAEO-treated HepG2 cells were detected by Hoechst 33258 staining and fluorescence microscopy. Flow cytometry was used to detect cell apoptosis and cell cycle, and noticeable findings showed that CAEO arrested cell-cycle at S and G2/M phases. The decreased Bcl-2/Bax protein ratio and the activation of caspase-3, caspase-9 were also detected by Western blotting. All results suggested that CAEO is a potential agent to fight against liver cancer, and the mitochondria-mediated intrinsic apoptotic pathway could be involved in CAEO-mediated apoptosis of human liver carcinoma cells.
Aims Extending work with brain tumours, the hypothesis that micronutrients may usefully augment anticancer regimens, chokeberry (Aronia melanocarpa) extract was tested to establish whether it has pro-apoptotic effects in AsPC-1, an established human pancreatic cell line, and whether it potentiates cytotoxicity in combination with gemcitabine. Pancreatic cancer was chosen as a target, as its prognosis remains dismal despite advances in therapy.
Methods An MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to assess the growth of the single pancreatic cancer cell line AsPC-1, alone and in comparison or combination with gemcitabine. This was backed up by flow cytometric DRAQ7 cell viability analysis. TUNEL assays were also carried out to investigate pro-apoptotic properties as responsible for the effects of chokeberry extract.
Results Chokeberry extract alone and its IC75 value (1 µg/mL) in combination with gemcitabine were used to assess the growth of the AsPC-1 cell line. Gemcitabine in combination with chokeberry extract was more effective than gemcitabine alone. TUNEL assays showed apoptosis to be a mechanism occurring at 1 µg/mL concentration of chokeberry, with apoptotic bodies detected by both colourimetric and fluorometric methods.
Conclusions The implication of this study, using single cancer cell line, is that chemotherapy (at least with gemcitabine) might be usefully augmented with the use of micronutrients such as chokeberry extract.
Sulphide-2-chloroethyl-3-chloropropyl is an alkylating agent. It posssesses mutagenic and carcino- genic properties, participates in oxidative processes and can induce lipid peroxidation.The aim of our investigation was to define antioxidative activity of natural anthocyanins after single experimental intoxi- cation with sulphide-2-chloroethyl-3-chloropropyl in mice. Catalase activity in hemolysate, thiobarbituric acid reacting substances (TBARS) concentration in hemolysate and selected organs were determined. The study confirms increased lipid peroxidation as a result of sulphide-2-chloroethyl-3-chloropropyl intoxica- tion, but natural anthocyanines derived from Aronia Melanocarpa also seem to play a protective role as an antioxidative agent.
The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.
Palliative chemotherapy significantly reduces mortality in patients with stage IV colon cancer, but is less prescribed with rising age. In this paper, we highlight the pattern of palliative treatment and possible effects on survival among elderly patients.
From January to December 2004, 78 files on the management of stage IV colorectal cancer (CRC) patients over 70 years, collected from 10 Italian Centres, were retrospectively examined. Determinants of receipt of palliative chemotherapy and their relation to toxicity and survival were considered.
The proportion of elderly patients receiving first-line palliative chemotherapy was 98.7% and it was evaluated according to age, gender, educational level and comorbidities; patients receiving second-line therapy comprised 47.4%, those receiving third-line therapy 14.1% and those treated with a fourth-line therapy totalled 2.6%. Forty-one percent of patients received best supportive care (BSC) alone.
In Italy, a proportion of elderly patients with metastatic chemonaive CRC are usually treated with a tolerability and overall survival similar to those for the younger population. Among progressive patients after second-line therapy, 45.8% usually undergo third line therapy; the remaining 54.2% undergo BSC.
Anthocyanins are one of the most important water-soluble plant pigments. They belong to flavonoids and are derivatives of 2-phenylo-benzo-gamma pyren. They have antioxidant and anti-inflammatory properties and, therefore, may be potentially used to combat oxidative stress, frequently present in cardiovascular diseases.
To assess the effects of anthocyanins from chokeberry (Aronia Melanocarpa) on some parameters of oxidation-reduction balance in an animal model.
Of 20 male Wistar rats, 10 received for 3 months pure water, and the other rats 10-100 mg/l of anthocyanins from Aronia melanocarpa. Afterwards, blood samples were collected for assessment of the (1) content of substances reacting with thiobarbitural--TBARS, (2) antioxidant status and glutathione peroxidase activity, (3) concentration of sulphydryl groups, and (4) nitrite concentration.
Anthocyanins significantly reduced the content of TBARS and thiol protein groups and non-significantly increased glutathione peroxidase activity, total content of antioxidants and nitrite concentration.
Anthocyanins from chokeberry decrease lipid peroxidation which may be potentially used to combat oxidative stress.
Reactive oxygen species (ROS) play a critical role in the impairment of nitric oxide-mediated vascular functions and overall pathogenesis associated with cardiovascular disease. Plant pigment anthocyanins are exceptionally potent oxygen radical scavengers that produce beneficial effects in diseases outside the cardiovascular system. We examined for the first time the potential coronary vasoactive and vasoprotective properties of three anthocyanin enhanced extracts prepared from chokeberry (Ck), bilberry (B), or elderberry (E). Coronary arterial rings were isolated from 64 pigs and incubated in sterile tissue culture media overnight for use in one of four separate in vitro isometric force recording studies. Ck and B, but not E, produced dose- and endothelium-dependent vasorelaxation. (%maximal relaxation at 5 mg total anthocyanins per liter: Ck = 68 +/- 11, B = 59 +/- 10). Coronary vascular tone, endothelium-dependent vasorelaxation to A23187, and vasorelaxation to DEA NONOate were not affected by exposure of rings to any extract at 0.05 mg total anthocyanins per liter for 5 or 30 min. Ck extract at 0.05 mg total anthocyanins per liter showed the greatest protection against loss of A23187 relaxation following exposure to ROS from pyrogallol (Ck, % maximal relaxation and -logED50 to A23187, respectively, means +/- SE: Ck alone, 93 +/- 5%, 7.91 +/- 0.1; pyrogallol alone, 76 +/- 7%, 7.46 +/- 0.06; pyrogallol + Ck, 98 +/- 1%, 7.82 +/- 0.06; control: 99 +/- 1%, 7.86 +/- 0.07; P < 0.05 control vs. pyrogallol alone). Neither the extracts nor pyrogallol affected responses to DEA NONOate. Thus anthocyanin-enhanced extracts produce endothelium-dependent relaxation in porcine coronary arteries. Extract concentrations too low to directly alter coronary vascular tone protect coronary arteries from ROS without altering vasorelaxation to endogenous or exogenous NO. These results suggest that such extracts could have significant beneficial effects in vascular disease.