PMID: 

Daru. 2019 Dec ;27(2):721-733. Epub 2019 Nov 18. PMID: 31736017

Abstract Title: 

Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats.

Abstract: 

BACKGROUND: The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties.OBJECTIVES: The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity.METHODS: Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p).RESULTS: After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factorerythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats.CONCLUSIONS: EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.

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PMID: 

Inflammation. 2019 Nov 26. Epub 2019 Nov 26. PMID: 31768706

Abstract Title: 

Ellagic Acid Ameliorates Renal Ischemic-Reperfusion Injury Through NOX4/JAK/STAT Signaling Pathway.

Abstract: 

Ellagic acid (EA), a natural polyphenolic compound, has been proved to possess multiple biological activities including alleviating ischemic-reperfusion (I/R) injury. The aim of this current study was to investigate whether EA alleviates I/R injury via regulating inflammatory signaling pathway. Rats were subjected to ischemic-reperfusion (I/R) injury and given orally with different doses of EA before surgery. H&E staining, ELISA assay, and biochemical index analysis were performed to evaluate renal injury and inflammatory factors. Oxidative stress level was detected by DCFH-DA staining and corresponding assay kits. In addition, TUNEL assay and flow cytometric assay were applied for exploring the apoptosis of tissue and cells, respectively. Western blot assay was used to assess protein expressions in tissue and cells. The results showed that EA attenuated the renal I/R injury and reserved renal cell function in vivo. The levels of TNF-a, IL-1β, IL-6, and MCP-1, oxidative stress level, and apoptosis were suppressed in EA-treated rats. Mechanistic studies showed that EA suppressed the phosphorylation of JAK1, JAK2, and STAT1 and reduced the NOX4 level. EA reduced apoptosis, hypoxia-induced inflammatory response, and ROS levels. Moreover,overexpression of NOX4 reversed the protective function with NOX4 inhibition, indicating that the effect of EA against renal IRI or cell hypoxia/reoxygenation might mainly depend on NOX4. The results suggest that EA exerts the renoprotective effect via suppressing NOX4/JAK/STAT signaling pathway, which may be a novel potential therapy for the treatment of acute kidney injury in clinic.

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PMID: 

Nutrients. 2019 Dec 10 ;11(12). Epub 2019 Dec 10. PMID: 31835645

Abstract Title: 

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells.

Abstract: 

Extracellular acidity has been implicated in enhanced malignancy and metastatic features in various cancer cells. Gastric cancer cell lines (AGS and SNU601) maintained in an acidic medium have increased motility and invasiveness. In this study, we investigated the effect of ellagic acid, a plant-derived phenolic compound, on the acidity-promoted migration and invasion of gastric cancer cells. Treating cells maintained in acidic medium with ellagic acid inhibited acidity-mediated migration and invasion, and reduced the expression of MMP7 and MMP9. Examining regulatory factors contributing to the acidity-mediated invasiveness, we found that an acidic pH increased the expression of COX1 and COX2; importantly, expression decreased under the ellagic acid treatment. The general COX inhibitor, sulindac, also decreased acidity-mediated invasion and expression of MMP7 and MMP9. In addition, acidity increased the mRNA protein expression of transcription factors snail, twist1, and c-myc; these were also reduced by ellagic acid. Together, these results suggest that ellagic acid suppresses acidity-enhanced migration and invasion of gastric cancer cells via inhibition of the expression of multiple factors (COX1, COX2, snail, twist1, and c-myc); for this reason, it may be an effective agent for cancer treatment under acidosis.

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PMID: 

Nutrients. 2019 May 15 ;11(5). Epub 2019 May 15. PMID: 31096648

Abstract Title: 

Seed Extract Affects Weight and Body Composition of Healthy Obese Adults during 12 Weeks of Consumption: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

Abstract: 

The aim of this pilot study was to evaluate the effects of a sunflower () seed extract, standardized for 40% chlorogenic acids on weight and body composition of obese adults. Fifty subjects were randomly assigned to sunflower extract or isocaloric placebo groups, receiving respectively 500 mg/day of treatment for 12 weeks. At the end of the intervention, a significant decrease in body weight, Body Mass Index (BMI), and waist circumference was observed, especially for obese female subjects above 30 years. Those changes were associated with modified body composition related to fat mass loss. A decrease in blood cholesterol was also observed, supporting the potential action of sunflower extract on lipid metabolism. It was concluded that consumption of sunflower extract has a beneficial effect on body weight, fat mass, and lipid profile, providing evidence for its use as a natural anti-obesity herbal extract.

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PMID: 

Crit Care. 2019 12 12 ;23(1):407. Epub 2019 Dec 12. PMID: 31831039

Abstract Title: 

Effect of high-dose vitamin C therapy on severe burn patients: a nationwide cohort study.

Abstract: 

BACKGROUND: Vitamin C is a well-documented antioxidant that reduces oxidative stress and fluid infusion in high doses; however, the association between high-dose vitamin C and reduced mortality remains unclear. This study evaluates the effect of high-dose vitamin C in severe burn patients under two varying thresholds.METHODS: We enrolled adult patients with severe burns (burn index≥ 15) who were registered in the Japanese Diagnosis Procedure Combination national inpatient database from 2010 to 2016. Propensity score matching was performed between patients who received high-dose vitamin C within 1 day of admission (vitamin C group) and those who did not (control group).High-dose vitamin C was defined as a dosage in excess of 10 g or 24 g within 2 days of admission. The primary outcome was in-hospital mortality.RESULTS: Eligible patients (n = 2713) were categorized into the vitamin C group (n = 157) or control group (n = 2556). After 1:4 propensity score matching, we compared 157 and 628 patients who were administered high-dose vitamin C (> 10-g threshold) and controls, respectively. Under this particular threshold, high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio, 0.79; 95% confidence interval, 0.66-0.95; p = 0.006). In contrast, in-hospital mortality did not differ between the control and high-dose vitamin C group under the> 24-g threshold (risk ratio, 0.83; 95% confidence interval, 0.68-1.02; p = 0.068).CONCLUSIONS: High-dose vitamin C therapy was associated with reduced mortality in patients with severe burns when used under a minimum threshold of 10 g within the first 2 days of admission. While"high-dose"vitamin C therapy lacks a universal definition, the present study reveals that different"high-dose"regimens may yield improved outcomes.

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PMID: 

Mar Drugs. 2019 Oct 17 ;17(10). Epub 2019 Oct 17. PMID: 31627432

Abstract Title: 

Fucoidan-Rich Substances fromImprove Trimethyltin-Induced Cognitive Dysfunction via Down-Regulation of Amyloidβ Production/Tau Hyperphosphorylation.

Abstract: 

() was investigated to compare the effect of polyphenol and fucoidan extract and mixture (polyphenol:fucoidan = 4:6) on cognitive function. The ameliorating effect ofwas evaluated using the Y-maze, passive avoidance and Morris water maze tests with a trimethyltin (TMT)-induced cognitive dysfunction model, and the results showed that the fucoidan extract and mixture (4:6) had relatively higher learning and memory function effects than the polyphenol extract. After a behavioral test, the inhibitory effect of lipid peroxidation and cholinergic system activity were examined in mouse brain tissue, and the fucoidan extract and mixture (4:6) also showed greater improvements than the polyphenol extract. Mitochondrial activity was evaluated using mitochondrial reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP,ΔΨm), adenosine triphosphate (ATP) content, and mitochondria-mediated protein (BAX, cytochrome C) analysis, and these results were similar to the results of the behavioral tests. Finally, to confirm the cognitive function-related mechanism of, the amyloid-β production and tau hyperphosphorylation-medicated proteins were analyzed. Based on these results, the improvement effect ofwas more influenced by fucoidan than polyphenol. Therefore, our study suggests that the fucoidan-rich substances incould be a potential material for improving cognitive function by down-regulating amyloid-β production and tau hyperphosphorylation.

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PMID: 

Glycobiology. 2019 Nov 19. Epub 2019 Nov 19. PMID: 31742327

Abstract Title: 

Fucoidan suppresses the gastric cancer cell malignant phenotype and production of TGF-β1 via CLEC-2.

Abstract: 

The sulfated polysaccharide fucoidan displays excellent anticancer properties with low toxicity in many kinds of cancers. However, its detailed pharmacological effect and mechanism of action in gastric carcinoma remains unclear. In this study, we found that fucoidan could suppress gastric cancer (GC) cell growth, as well as cell migration and invasion. A cytokine expression screen demonstrated that TGF-β1 secretion was decreased in fucoidan-treated cells. Fucoidan has been reported to be a platelet agonist for the C-type lectin-like receptor 2 (CLEC-2), and our previous research found that upregulation of CLEC-2 inhibited GC progression. Here, we confirmed that fucoidan, combined with CLEC-2, significantly increased CLEC-2 expression in GC cells via the transcription factor CDX2, an important regulator of gut homeostasis. In addition, the inhibitory effect of fucoidan on the gastric cancer cell malignant phenotype and TGF-β1 secretion could be restored by knocking down CLEC-2. Thus, our data suggest that fucoidan targets CLEC-2 to exert anti-tumorigenesis and anti-metastatic activity, suggesting that fucoidan is a promising treatment for gastric carcinoma.

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PMID: 

Animals (Basel). 2019 Dec 10 ;9(12). Epub 2019 Dec 10. PMID: 31835456

Abstract Title: 

Protective Effects of Fucoidan against Hydrogen Peroxide-Induced Oxidative Damage in Porcine Intestinal Epithelial Cells.

Abstract: 

This study was conducted to evaluate the effectiveness of fucoidan in ameliorating hydrogen peroxide (HO)-induced oxidative stress to porcine intestinal epithelial cell line (IPEC-1). The cell viability test was initially performed to screen out appropriate concentrations of HOand fucoidan. After that, cells were exposed to HOin the presence or absence of pre-incubation with fucoidan. Hydrogen peroxide increased the apoptotic and necrotic rate, boosted reactive oxygen species (ROS) generation, and disturbed the transcriptional expression of genes associated with antioxidant defense and apoptosis in IPEC-1 cells. Pre-incubation with fucoidan inhibited the increases in necrosis and ROS accumulation induced by HO. Consistently, in the HO-treated IPEC-1 cells, fucoidan normalized the content of reduced glutathione as well as the mRNA abundance of NAD(P)H quinone dehydrogenase 1 and superoxide dismutase 1 while it prevented the overproduction of malondialdehyde. Moreover, HOstimulated the translocation of nuclear factor-erythroid 2-related factor-2 to the nucleus of IPEC-1 cells, but this increase was further promoted by fucoidan pre-treatment. The results suggest that fucoidan is effective in protecting IPEC-1 cells against oxidative damage induced by HO, which may help in developing appropriate strategies for maintaining the intestinal health of young piglets.

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PMID: 

Korean J Fam Med. 2019 Nov ;40(6):362-367. Epub 2019 May 9. PMID: 31067851

Abstract Title: 

Comparison of Vitex agnus-castus Extracts with Placebo in Reducing Menopausal Symptoms: A Randomized Double-Blind Study.

Abstract: 

BACKGROUND: Menopausal symptoms have remarkable negative effects on women's quality of life, justifying the need to assess various therapeutic options. This research aimed to determine the effectiveness of Vitex agnus-castus extracts in alleviating menopausal symptoms in comparison with that of placebo.METHODS: This study was a randomized controlled double-blind clinical trial with a study group of 52 women referred to a clinic in Kermanshah in 2017. The participants were randomly divided into two groups: Vitex group (26 subjects) and placebo group (26 subjects). Menopausal symptoms were assessed using the Greene Scale before and 8 weeks after the intervention.RESULTS: After the intervention, the mean scores for total menopausal disorder, anxiety, and vasomotor dysfunction were significantly lower in the Vitex group than in the placebo group (P0.05).CONCLUSION: Administration of Vitex agnus-castus extracts as a phytoestrogenic medicine can alleviate menopausal symptoms in women.

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PMID: 

J Food Biochem. 2019 Mar ;43(3):e12750. Epub 2018 Dec 13. PMID: 31353538

Abstract Title: 

Vitex agnus-castus safeguards the lung against lipopolysaccharide-induced toxicity in mice.

Abstract: 

Vitex agnus-castus (VAC, Verbenaceae) is widely used in Chinese traditional medicine as an antiinflammatory agent. This study aimed to explore the efficacy of the VAC extract to protect against lipopolysaccharide (LPS)-induced acute lung injury. The results have shown that VAC had a potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as there was a significant decrease in lung wet/dry ratio and in protein content. VAC also decreased the lactate dehydrogenase's activity in the bronchoalveolar fluid. VAC ameliorated LPS-induced inflammatory cells infiltration into the lung tissue and reversed the histopathological lesions of the lung. Furthermore, VAC counteracted LPS-induced oxidative stress as it attenuated the lipid peroxidation marker, malondialdehyde, in the lung. VAC increased the antioxidant activity as evident by elevated superoxide dismutase activity and increased reduced glutathione content in the lung tissue. Collectively, VAC has a protective activity against LPS-induced acute lung damage through its antioxidant potential. PRACTICAL APPLICATIONS: Vitex agnus-castus has been used in various traditional medicines for treating various ailments as digestive complains, acne, rheumatic pains, menstrual irregularities, premenstrual syndrome, infertility, and hyperprolactinemia. Its leaves are used as a spice and the fruits are used as a substitute for pepper. VAC food supplements are used by women against psychic and somatic premenstrual symptoms. The findings of this study can demonstrate the potent protective activity of the VAC extract against LPS-induced acute lung damage due to its antioxidative effects. Therefore, VAC could be developed as a health functional food to improve acute lung damage and many diseases caused by oxidative damage.

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