PMID: 

Exp Mol Pathol. 2020 Jan 7 ;113:104374. Epub 2020 Jan 7. PMID: 31917966

Abstract Title: 

Perinatal exposure to bisphenol A impacts in the mammary gland morphology of adult Mongolian gerbils.

Abstract: 

The endocrine disruptive effects caused by bisphenol A (BPA) are well known. Despite this, to date, evaluation of its long term effects is limited, meaning that there is still much to be unveiled in terms of alterations caused by perinatal exposure to BPA. Our aim was to determine if perinatal exposure to two different doses of BPA causes long term morphological and molecular alteration effects in the mammary gland (MG). We evaluated MG from Mongolian gerbil offspring exposed perinatally (during gestation and lactation) to 50 or 5000μg/kg/day BPA. At 90 days of age the animals were subjected to a single dose of N-nitroso-N-methylurea in order to mimic a carcinogenic environment. At 6 months of age, animals in estrous were euthanized for morphological evaluation of the MGs. The MG architecture presented considerable changes interms of detached epithelial cells, inflammation, glandular hyperplasia, and collagen fiber deposition. Furthermore, a higher index of epithelial cell proliferation was detected in comparison to the intact control group. In addition, we verified a higher molecular expression of EZH2 in the vehicle treated group, indicating that corn oil applied alone can alter the expression of this epigenetic biomarker. In conclusion, BPA perinatal exposure promotes significant changes in glandular cytoarchitecture and increases glandular epithelium proliferation rate, leading to the retention of stem-like properties. This event could compromise the fate and differentiation potential of mammary epithelium.

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PMID: 

Food Chem Toxicol. 2020 Jan 14 ;137:111128. Epub 2020 Jan 14. PMID: 31952986

Abstract Title: 

Bisphenol A exposure is involved in the development of Parkinson like disease in Drosophila melanogaster.

Abstract: 

The pathogenesis of Parkinson's disease has not been fully clarified yet but its cause is known to be multifactorial. One of these factors is oxidative stress induced by exposure to environmental toxifiers. We studied the effect of Bisphenol A (BPA) at concentrations of 0.5 mM and 1 mM, the concentration of 1 mM corresponding to Lowest Observed Adverse Effect Level (LOAEL) for humans in adult Drosophila melanogaster. The BPA induced oxidative stress was established by increased levels of malondialdehyde, reactive species, and decreased activity of the antioxidant enzymes superoxide dismutase and catalase, and detoxificant enzyme glutathione-S-transferase. Associated with oxidative stress, there was a reduction of acetylcholinesterase activity and a reduction of dopamine levels, which are related to the decreased locomotion activity as observed in negative geotaxis, open field and equilibrium behaviors in group exposed to 1 mM of BPA. Oxidative stress also impaired mitochondrial and cellular metabolic activity in the head causing an increase in the mortality of flies exposed to both BPA concentrations. Therefore, BPA induced Parkinsonian-like changes inflies and it is possible that the oxidative stress is closely related to this effect, providing new insights for future studies.

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PMID: 

Mol Neurobiol. 2019 Dec 14. Epub 2019 Dec 14. PMID: 31838720

Abstract Title: 

Epigallocatechin-3-Gallate (EGCG) Improves Cognitive Deficits Aggravated by an Obesogenic Diet Through Modulation of Unfolded Protein Response in APPswe/PS1dE9 Mice.

Abstract: 

Epigallocatechin-3-gallate (EGCG), a catechin found in green tea, has been previously investigated for its neuroprotective effects in vitro and in vivo. In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD). C57BL/6 wild-type (WT) and APP/PS1 mice were used in this study. APP/PS1 mice were fed with a palmitic acid-enriched HFD (APP/PS1 HFD) containing 45% of fat mainly from hydrogenated coconut oil. Intraperitoneal glucose tolerance tests (IP-GTT) and insulin tolerance tests (IP-ITT) were performed. Western blot analyses were performed to analyse protein expression, and water maze and novel object recognition test were done to evaluate the cognitive process. EGCG treatment improves peripheral parameters such as insulin sensitivity or liver insulin pathway signalling, as well as central memory deficits. It also markedly increased synaptic markers and cAMP response element binding (CREB) phosphorylation rates, as a consequence of a decrease in the unfolded protein response (UPR) activation through the reduction in the activation factor 4 (ATF4) levels and posterior downregulation of protein tyrosine phosphatase 1B (PTP1B). Moreover, EGCG significantly decreased brain amyloidβ (Aβ) production and plaque burden by increasing the levels of α-secretase (ADAM10). Also, it led to a reduction in neuroinflammation, as suggested by the decrease in astrocyte reactivity and toll-like receptor 4 (TLR4) levels. Collectively, evidence suggests that chronic EGCG prevents distinctneuropathological AD-related hallmarks. This study also provides novel insights into the metabolic and neurobiological mechanisms of EGCG against cognitive loss through its effects on UPR function, suggesting that this compound may be a promising disease-modifying treatment for neurodegenerative diseases.

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PMID: 

J Agric Food Chem. 2020 Jan 18. Epub 2020 Jan 18. PMID: 31957426

Abstract Title: 

Neuroprotective and anti-inflammatory effects of pterostilbene metabolites in human neuroblastoma SH-SY5Y and RAW 264.7 macrophage cells.

Abstract: 

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted yielding very low phenolic bioavailability what makes difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against LPS-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4´-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of ROS levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.

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PMID: 

BMC Complement Altern Med. 2019 Nov 21 ;19(1):326. Epub 2019 Nov 21. PMID: 31752797

Abstract Title: 

Mulberry leaf reduces inflammation and insulin resistance in type 2 diabetic mice by TLRs and insulin Signalling pathway.

Abstract: 

BACKGROUND: It has been testified that Diabetes mellitus (DM) has a close association with chronic inflammation and Toll-like Receptors (TLRs), and DM could be prevented by mulberry leaf. Therefore, a hypothesis came into being that mulberry leaf could ameliorate proinflammation and insulin resistance (IR) through TLRs and insulin signalling pathways.METHODS: Water extracts of mulberry leaf (WEM) was given to diabetic mice by gavage for 10 weeks, and the diabetic mice was injected with low-dose streptozocin, fed with high-fat and high-sugar diet. Oral glucose tolerance tests (OGTTs) were conducted. At the same time, homeostasis model assessment of insulin (HOMA-IR) and the level of the inflammatory factor, tumour necrosis factor-α(TNF-α) was measured. The expressions of critical nodes of TLRs and insulin signalling pathway were also examined.RESULTS: WEM contributed to a significant decrease in fasting blood glucose, AUC from the investigation of OGTTs and HOMA-IR. The levels of the inflammatory factor, tumour necrosis factor-α (TNF-α) also declined. Moreover, WEM suppressed the expression of TLR2, myeloid differentiation primary-response protein 88 (MyD88), tumour-necrosis-factor receptor-associated factor 6 (TRAF6), nuclear factor kappa B (NF-κB) in the skeletal muscle. WEM could up-regulate the expression of insulin receptor (InsR) and insulin receptor substrate 1 (IRS1), and down-regulate the phosphorylation of IRS1 in adipose tissue.CONCLUSION: Through this study, a conclusion could be made that WEM mitigates hyperglycemia, IR, and inflammation through the interactions among TLR2 signalling pathway, insulin signalling pathway and TNF-α.

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PMID: 

Rev Int Androl. 2019 Dec 30. Epub 2019 Dec 30. PMID: 31899187

Abstract Title: 

Protective effect of black mulberry (Morus nigra L.) fruit hydroalcoholic extract against testosterone-induced benign prostatic hyperplasia in rats.

Abstract: 

BACKGROUND: Finding new agents for prevention and/or treatment of benign prostatic hyperplasia (BPH) especially from natural sources is a demanding field.OBJECTIVES: This study aimed to evaluate the effect of black mulberry (BM) (Morus nigra) fruit hydroalcoholic extract on the establishment of BPH in rats.MATERIALS AND METHODS: Forty-nine adult male rats were randomly assigned into 7 equal groups: I: Sham control (SC), a sham surgery was performed. II: positive control (PC), rats were castrated and received testosterone propionate, at 10mg/kg/day S.C. for BPH induction. III: comparative control (CC), BPH was induced and the rats received finasteride at 5mg/kg/day P.O. IV-VII: (T1-T4): BPH was induced and the rats received BM extract at 25, 50, 100 and 200mg/kg/day P.O. for 4 consecutive weeks.RESULTS: Finasteride and/or BM extract especially at the two higher dosages, significantly affected prostate weight, prostatic index, percent of inhibition, serum and prostatic levels of dihydrotestosterone (DHT), serum prostate-specific antigen (PSA), antioxidant parameters of prostatic tissue as well as histopathological and histomorphometric parameters (epithelial thickness and acinar area) of prostate.CONCLUSIONS: BM extract has protective effects against experimentally-induced BPH in rats with regard to histopathological and biochemical parameters which may be related to its antioxidant as well as DHT reducing properties in prostatic tissue.

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PMID: 

J Food Drug Anal. 2020 Jan ;28(1):84-93. Epub 2019 Jun 27. PMID: 31883611

Abstract Title: 

Mulberry fruits extracts induce apoptosis and autophagy of liver cancer cell and prevent hepatocarcinogenesis in vivo.

Abstract: 

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Taiwan. Many risks factors induce liver chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mulberry fruits containing polyphenols to remove free radicals and mitigate inflammation has been reported to not only against gastric cancer, melanoma and leukemia but also prevent liver injury induced by alcohol or CClin previous researches. The aim of this study is to examine whether Mulberry could inhibit hepatocarcinogenesis. In animal experiment, diethylnitrosamine (DEN) was used to induce hepatic tumorgenesis. After injecting DEN, the rats treated with mulberry water extracts (MWE) had less and smaller tumor than others without MWE. Moreover, MWE reduced the serum ALT and AST, HCC marker, cleavage caspases, Ser-15-p53 and Ser46-p53 induced by DEN. Further, we observed that mulberry polyphenol extracts (MPE) inhibited the cell growth of HepG2 cell and Hep3B cell. By using flow cytometry and western blotting methods, MPE induced HepG2 cell apoptosis by increase subG1 cells and the elevated expression of caspase-3/8/9. Instead of apoptosis, MPE caused Hep3B cells autophagy by inhibiting Akt and mTOR phosphorylation. Comprehensively, mulberry extracts has a potential to be a health supplement to prevent hepatocarcinogenesis in the future.

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PMID: 

Nutrients. 2020 Jan 9 ;12(1). Epub 2020 Jan 9. PMID: 31936461

Abstract Title: 

Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart.

Abstract: 

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (, six homeobox 1 () and mads box transcription enhancer factor 2, polypeptide C (, involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

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PMID: 

Ann Palliat Med. 2019 Nov ;8(5):565-575. PMID: 31865720

Abstract Title: 

Resveratrol increase myocardial Nrf2 expression in type 2 diabetic rats and alleviate myocardial ischemia/reperfusion injury (MIRI).

Abstract: 

BACKGROUND: Oxidative stress is one of the main factors that increases reperfusion injury in the diabetic heart. Resveratrol could decrease oxidation and promote antioxidant factor expression. Nrf2 is an important endogenous antioxidant. making the heart more resistant to ischemic injury. As Nrf2 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of Nrf2 in the diabetic heart may overcome its increased susceptibility to ischemic injury.METHODS: A total of 50 diabetic rats were randomly divided into five groups: the sham operation group (DM + sham), the MIRI group (DM + MI/R), the resveratrol treatment group (DM + MI/R + RSV), the resveratrol + ex527 (SIRT1 inhibitor) group (DM + MI/R + RSV + ex527), and the resveratrol + LY294002 (Akt inhibitor) group (MD + MI/R + RSV + LY294002). Another 20 normal rats were randomly divided into two groups: the sham-operated group (CON + sham) and the myocardial ischemia-reperfusion group (CON + MI/R). A type 2 diabetes model was induced by a high-fat diet-fed and intraperitoneal injection of streptozotocin (STZ). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasma were collected to measure the creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), malondialdehyde (MDA) level, glutathione (GSH) level, and superoxide dismutase (SOD) activity. Pathologic changes in myocardial tissues were observed by Hematoxylin and eosin (HE) straining. SIRT1, p-GSK3β, Nrf2, HO-1 protein expressions were measured by western blot.RESULTS: Compared with the control (CON) group, the diabetic (DM) group had more severe myocardial injury, higher oxidative stress index increase, and a more reduced expression of Nrf2 in the myocardium. After supplementing with resveratrol, the myocardial damage was reduced and the oxidative stress index decreased in the DM group, while the Nrf2 in the myocardium was increased. It also was found that inhibition of SIRT1 also partially inhibited the expression of Nrf2 and the corresponding antioxidant factor HO-1. Decreased expression of p-GSK3β by Akt inhibitors also partially inhibited Nrf2 and HO-1 expression.CONCLUSIONS: Resveratrol can enhance the expression of Nrf2 in a diabetic heart by stimulating SIRT1 or inhibiting GSK3β, alleviating myocardial oxidative stress, and improving ischemia-reperfusion injury.

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PMID: 

Biochem Biophys Res Commun. 2020 Jan 13. Epub 2020 Jan 13. PMID: 31948760

Abstract Title: 

Hearing loss through apoptosis of the spiral ganglion neurons in apolipoprotein E knockout mice fed with a western diet.

Abstract: 

Age-related hearing loss (ARHL) is a neurodegenerative disease associated with an aged population. ARHL is influenced by biological factors such as aging, sex difference, and atherosclerosis. The mechanisms of ARHL caused by atherosclerosis have not been previously determined in apolipoprotein E knockout (ApoE KO) male mice. To investigate the onset and cause of the hearing loss, ApoE KO male mice were treated with a western diet (ApoE KO-WD) for 16 weeks. The lipid profile, atherosclerotic plaques throughout the aorta, and auditory brainstem response (ABR) thresholds were measured in the ApoE KO-WD male mice. The expression of S100 calcium-binding protein B (S100B), a neuronal damage biomarker, was also observed. Reactive oxygen species (ROS) and apoptosis rates were detected in the cochlea of the ApoE KO male mice. Atherosclerotic plaques on the aorta and ABR thresholds were significantly increased in the ApoE KO-WD male mice at 24 weeks of age. ABR thresholds had a statistically significant positive correlation with the area of atherosclerotic plaques (r = 0.783, p = 0.013) in male mice at 24 weeks of age. S100B protein expression and the dihydroethidium (DHE) reaction to ROS in the cochlear spiral ganglion neurons (SGNs) were significantly increased in the ApoE KO and ApoE KO-WD male mice. Cells positive for active caspase-3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in the SGNs were significantly increased in ApoE KO-WD male mice indicating an increased rate of cellular apoptosis. In conclusion, ROS in the SGNs were activated by increased S100B expression in ApoE KO-WD male mice, and this resulted inan increased apoptosis rate. Thus, hearing loss began at 16 weeks in ApoE KO-WD male mice. Our results suggest that the ApoE KO-WD male mice are a suitable animal model for studying ARHL associated with exacerbated atherosclerosis.

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