PMID: 

PPAR Res. 2019 ;2019:2601408. Epub 2019 Dec 17. PMID: 31933619

Abstract Title: 

Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-in Mice.

Abstract: 

Background: Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice.Methods: To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection.Results: Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-(PPAR-), and the protective effects of piperine were abolished by the treatment of the PPAR-antagonist in vivo and in vitro.Conclusions: Piperine could suppress DOX-related cardiac injury via activation of PPAR-in mice.

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PMID: 

J BUON. 2019 Nov-Dec;24(6):2316-2321. PMID: 31983100

Abstract Title: 

Piperine alkaloid induces anticancer and apoptotic effects in cisplatin resistant ovarian carcinoma by inducing G2/M phase cell cycle arrest, caspase activation and inhibition of cell migration and PI3K/Akt/GSK3β signalling pathway.

Abstract: 

PURPOSE: Ovarian cancer is one the prevalent cancers in women and is responsible for 5% of all the cancer-related mortality. Owing to late diagnosis, frequent relapses, side effects of chemotherapy, development of drug resistance, there is pressing need to screen out novel and effective treatment options. Herein, we examined the anticancer effects of a secoiridoid glycoside Piperine against ovarian cancer cells.METHODS: CCK8 assay was used to examine the anti-proliferative effects. DAPI and annexin V/propidium iodide (PI) staining assays were used to examine apoptotic cell death. Cell cycle analysis was performed by flow cytometry. The protein expressions were examined by western blotting.RESULTS: Piperine inhibited the growth of the ovarian cancer OVACAR-3 cell with IC50 of 28µM. In contrast, Piperine had low cytotoxic effects on the normal astrocytes (SV40) cells with an IC50 of 200 µM. Also, Piperine exerted antiproliferative effects on the OVACAR-3 ovarian cancer cells by apoptotic cell death. This was concomitant with upregulation of apoptotic proteins such as caspase 3 and 9 and Bax expressions. Piperine also induced arrest of the OVACAR-3 cells at the G2/M phase of the cell cycle. Finally, Piperine also blocked the PI3K/Akt/GSK3β signal transduction pathway in OVACAR-3 ovarian cancer cells.CONCLUSIONS: These results suggest that Piperine exerts potent anticancer effects on ovarian cancer cells and may prove beneficial in the management of ovarian cancer.

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PMID: 

Front Pharmacol. 2019 ;10:289. Epub 2019 Apr 26. PMID: 31105555

Abstract Title: 

ARoot Extract Exerts Anti-inflammatory Properties by Affecting Two Distinct Steps of NF-κB Signaling.

Abstract: 

, commonly known as comfrey, constitutes a traditional medicinal plant with a long-standing therapeutic history, and preparations thereof have been widely used for the treatment of painful muscle and joint complaints, wound and bone healing, and inflammation. Today, its topical use is based on its analgesic and anti-inflammatory effects, which have been substantiated by modern clinical trials. However, the molecular basis of its action remained elusive. Here, we show that a hydroalcoholic extract of comfrey root impairs the development of a pro-inflammatory scenario in primary human endothelial cells in a dose-dependent manner. The extract, and especially its mucilage-depleted fraction, impair the interleukin-1 (IL-1) induced expression of pro-inflammatory markers including E-selectin, VCAM1, ICAM1, and COX-2. Both preparations inhibit the activation of NF-κB, a transcription factor of central importance for the expression of these and other pro-inflammatory genes. Furthermore, our biochemical studies provide evidence that comfrey inhibits NF-κB signaling at two stages: it dampens not only the activation of IKK1/2 and the subsequent IκBα degradation, but also interferes with NF-κB p65 nucleo-cytoplasmatic shuttling and transactivation. These results provide a first mechanistic insight into the mode of action of a century-old popular herbal medicine.

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PMID: 

Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Jan 21:158635. Epub 2020 Jan 21. PMID: 31978554

Abstract Title: 

The role ofβ-carotene and vitamin A in atherogenesis: Evidences from pre-clinical and clinical studies.

Abstract: 

Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate thatβ-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linkingthese nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

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PMID: 

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019 Jul ;35(7):625-630. PMID: 31537248

Abstract Title: 

[Folic acid relieves rat cardiomyocyte injury induced by homocystein through DNA methylation].

Abstract: 

Objective To investigate the effect of homocysteine (Hcy) on the cardiomyocytes cultured in vitro, and to analyze the role of folic acid in DNA methylation to explore the protective effect and mechanism of folic acid during Hcy exposure of H9C2 cardiomyocytes. Methods H9C2 cells were treated with Hcy at different concentrations (0, 0.5, 1, 2) mmol/L for 24 hours. Cell viability was tested by CCK-8 assay. The apoptosis was detected by flow cytometry. H9C2 cells were divided into 2 mmol/L Hcy group, 0.1 mmol/L folic acid combined with 2 mmol/L Hcy group, 0.1 mmol/L folic acid group and DMSO control group. The above corresponding treatment lasted 24 hours. Then we detected the cell viability and apoptosis. The total DNA methylation level was determined by MethylFlash ELISA kit. DNMT1, DNMT3a, DNMT3b mRNA and protein expression were detected by real-time quantitative PCR and Western blot analysis. Results The number of H9C2 cells treated with different concentrations of Hcy for 24 hours decreased with the increase of Hcy concentration. Compared with the control group, the activity and apoptosis of the cells in the 2 mmol/L Hcy treatment group were reduced, and the number of cells in the folic acid combined with Hcy treatment group was significantly higher than that in the Hcy treatment group. Compared with the other groups, the total apoptosis rate of Hcy treatment group increased, methylation level decreased significantly, and the level of DNA methylation increased in the folic acid combined with Hcy treatment group. The level of DNMT1 mRNA significantly increased only in the folic acid treatment group, and the levels of DNMT1, DNMT3a and DNMT3b were not significantly changed. Conclusion Folic acid can relieve the damage of Hcy to myocardial cells by DNA methylation.

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PMID: 

Environ Pollut. 2019 Dec ;255(Pt 3):113331. Epub 2019 Oct 8. PMID: 31614245

Abstract Title: 

PM2.5-induced extensive DNA methylation changes in the heart of zebrafish embryos and the protective effect of folic acid.

Abstract: 

We previously found that folic acid (FA) attenuated cardiac defects in zebrafish embryos exposed to extractable organic matter (EOM) from PM2.5, but the underlining mechanisms remain to be elucidated. Since DNA methylation is crucial to cardiac development, we hypothesized that EOM-induced aberrant DNA methylation changes could be diminished by FA supplementation. In this study, zebrafish embryos were exposed to EOM in the absence or presence of FA. Genomic-wide DNA methylation analysis identified both DNA hypo- and hyper-methylation changes in CCGG sites in zebrafish embryos exposed to EOM, which were attenuated by FA supplementation. We identified a total of 316 genes with extensive DNA methylation changes in EOM samples but little or no DNA methylation changes in EOM plus FA samples. The genes were involved in critical cellular processes and signaling pathways important for embryo development. In addition, the EOM-decreased SAM/SAH ratio was counteracted by FA supplementation. Furthermore, FA attenuated the EOM-induced changes in the expression of genes involved in the regulation of DNA methylation and in folate biosynthesis. In conclusion, our data suggest that FA supplementation protected zebrafish embryos from the cardiac developmental toxicity of PM2.5 by alleviating EOM-induced DNA methylation changes.

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PMID: 

Neurotox Res. 2019 Nov 13. Epub 2019 Nov 13. PMID: 31721048

Abstract Title: 

Folic Acid Protects Rat Cerebellum Against Oxidative Damage Caused by Homocysteine: the Expression of Bcl-2, Bax, and Caspase-3 Apoptotic Genes.

Abstract: 

There is evidence that oxidative stress involves in homocysteine-induced pathogenesis. Considering the antioxidative properties of folic acid and its involvement as a cofactor for methionine synthase (MS) in the homocysteine-methionine cycle, the aim of this study was to evaluate the mechanism associated with homocysteine-induced toxicity and its prevention with folic acid supplementation. Male rat pups were divided into four groups including control, homocysteine (Hcy), Hcy + folic acid and folic acid groups. The Hcy group received Hcy 0.3-0.6μmol/g body weight, while Hcy + folic acid group received folic acid orally as 0.011 μmol/g body weight along with Hcy on a postnatal day (PD) 4 until 25. The reduced and oxidized glutathione (GSH and GSSG) levels, GSH/GSSG ratio, protein carbonyl content, cystathionine β synthase (CBS), and MS activities in the cerebellum were measured 25 days after birth. Levels of malondialdehyde (MDA), marker of lipid peroxidation were measured. Also, Bcl2, Bax, and caspase-3 expression levels were measured by real-time quantitative PCR. Furthermore, caspase-3 protein level assay was performed by the ELISA test. Results indicated that Hcy administration could promote both lipid and protein oxidation, which was associated with increased amounts of caspase-3 mRNA and protein levels and Bax mRNA expression level in this group. Cerebellar MS, CBS enzyme activity, GSH, GSSG, and GSH/GSH ratio did not change following Hcy administration. Folic acid significantly reduced MDA level, protein carbonyl content, Bax, the caspase-3 mRNA, and protein expression levels in the cerebellum of Hcy-treated group. Moreover, cerebellar MS, CBS enzyme activity, GSH, and GSH/GSH ratio increased following folic acidtreatment. We conclude that Hcy might cause apoptosis in the cerebellum. We suggest that folic acid, in addition of having antioxidant properties, can protect cerebellum against homocysteine-mediated neurotoxicity via modulating the expression of proteins that are contributed in regulation of apoptosis in the rat's cerebellum.

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PMID: 

Biosci Rep. 2019 Nov 29 ;39(11). PMID: 31670376

Abstract Title: 

Homocysteine and psoriasis.

Abstract: 

Psoriasis is caused by a complex interplay among the immune system, genetic background, autoantigens, and environmental factors. Recent studies have demonstrated that patients with psoriasis have a significantly higher serum homocysteine (Hcy) level and a higher prevalence of hyperhomocysteinaemia (HHcy). Insufficiency of folic acid and vitamin B12 can be a cause of HHcy in psoriasis. Hcy may promote the immuno-inflammatory process in the pathogenesis of psoriasis by activating Th1 and Th17 cells and neutrophils, while suppressing regulatory T cells. Moreover, Hcy can drive the immuno-inflammatory process by enhancing the production of the pro-inflammatory cytokines in related to psoriasis. Hcy can induce nuclear factor kappa B activation, which is critical in the immunopathogenesis of psoriasis. There may be a link between the oxidative stress state in psoriasis and the effect of HHcy. Hydrogen sulfide (H2S) may play a protective role in the pathogenesis of psoriasis and the deficiency of H2S in psoriasis may be caused by HHcy. As the role of Hcy in the pathogenesis of psoriasis is most likely established, Hcy can be a potential therapeutic target for the treatment of psoriasis. Systemic folinate calcium, a folic acid derivative, and topical vitamin B12 have found to be effective in treating psoriasis.

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PMID: 

Aging (Albany NY). 2019 Nov 22 ;11(22):10356-10373. Epub 2019 Nov 22. PMID: 31757935

Abstract Title: 

Folic acid delays age-related cognitive decline in senescence-accelerated mouse prone 8: alleviating telomere attrition as a potential mechanism.

Abstract: 

The occurrence of telomere attrition in brain may cause senescence and death of neurons, leading to cognitive decline. Folic acid (FA) has been reported to improve cognitive performance in mild cognitive impairment; however, its association with telomere remains unclear. The study aimed to investigate if alleviation of telomere attrition by FA supplementation could act as a potential mechanism to delay age-related cognitive decline in senescence-accelerated mouse prone 8 (SAMP8). Aged SAMP8 mice were assigned to four treatment groups: FAdeficient diet (FA-D) group, FA-normal diet (FA-N) group, low FA-supplemented diet (FA-L) group and high FAsupplemented diet (FA-H) group. There was also an age-matched senescence-accelerated mouse resistant 1 (SAMR1) control group (Con-R), and a young SAMP8 control group (Con-Y). The results demonstrated that FA supplementation delayed age-related cognitive decline and neurodegeneration in SAMP8 mice. Importantly, this effect could be attributed to the alleviated telomere attrition, which might be interpreted by the decreased levels of reactive oxygen species. Additionally, improved telomere integrity stimulated mitochondrial function via telomere-p53-mithondria pathway, consequently delayed neuronal degeneration. In conclusion, we demonstrate that FA supplementation delays age-related neurodegeneration and cognitive decline in SAMP8 mice, in which alleviated telomere attrition could serve as one influential factor in the process.

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PMID: 

BMC Neurosci. 2020 Jan 15 ;21(1):1. Epub 2020 Jan 15. PMID: 31941442

Abstract Title: 

Folic acid ameliorates depression-like behaviour in a rat model of chronic unpredictable mild stress.

Abstract: 

BACKGROUND: Depression is characterized by significant and low mood. Classical antidepressants are still not adequate in treating depression because of undesirable side effects. Folic acid, a member of the vitamin B complex, in considered to be strongly associated with the function and development of the central nervous system. Thus, in this study, we established a model of depression through chronic unpredictable mild stress (CUMS) in rats and assessed the antidepressant effects and mechanisms of folic acid.METHODS: Sprague-Dawley rats were randomly divided into four groups: control, chronic unpredictable mild stress (CUMS), CUMS treated with folic acid, and CUMS treated with citalopram. Rats were assessed in terms of weight change, open-field test and sucrose preference. Homocysteine, monoamine neurotransmitters, interleukin-6, brain-derived neurotrophic factor (BDNF),β-endorphin levels in the serum and brains of rats were analysed.RESULTS: Folic acid exhibited antidepressant-like effects in open-field and sucrose preference tests. Folic acid treatment effectively increased the levels of monoamine neurotransmitters, BDNF andβ-endorphin, interleukin-6 and homocysteine levels were also significantly suppressed by folic acid administration.CONCLUSIONS: These findings serve as preclinical evidence that folic acid plays an antidepressant-like role in several pathways involving monoamine neurotransmitters. Thus, folic acid may be used as a potential antidepressant.

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