PMID: 

Biomed Pharmacother. 2019 Apr ;112:108675. Epub 2019 Feb 16. PMID: 30780108

Abstract Title: 

Mulberry leaf active components alleviate type 2 diabetes and its liver and kidney injury in db/db mice through insulin receptor and TGF-β/Smads signaling pathway.

Abstract: 

Mulberry leaf is one of the commonly used traditional Chinese medicines, has been shown to exert hypoglycemic effects against diabetes. The aim of this study is to investigate the effects and mechanism of mulberry leaf flavonoids (MF), polysaccharides (MP) and alkaloids (MA) on diabetic and its liver and kidney injury. The db/db mice was adopted and the results showed that the FBG (fasting blood glucose) of model group continued to increase and associated liver and kidney injury. After the intervention of MP and MA, the value of FBG exhibited the most obvious hypoglycemic effect. MF and MP have obvious improved effect on kidney injury, which reduced the content of mALB/Cre (microalbumin/creatinine) in urine and improved the tubular epithelial cells edematous and renal cystic epithelial thickening. While the MF and MA possessed a significant effect on liver damage, manifested in reducing the levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) and pathological changes of liver on db/db mice. Through metabolomics analysis, 13 endogenous potential biomarkers were identified in serum. The three effective components of mulberry can regulate the 13 potential biomarkers and the corresponding metabolic pathway. Collectively, the components of mulberry leaf have clear hypoglycemic effect and protective effect on liver and kidney injury and the effects are related to insulin receptor and TGF-β/Smads signaling pathway.

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PMID: 

Food Funct. 2019 Mar 20 ;10(3):1513-1528. PMID: 30785176

Abstract Title: 

Protective effect of mulberry (Morus atropurpurea) fruit against diphenoxylate-induced constipation in mice through the modulation of gut microbiota.

Abstract: 

Mulberry (Morus atropurpurea) has long been used to treat gastro-intestinal ailments; however, the functional basis of its therapeutic effects remains unclear. The aim of this study was to measure the effects of mulberry (administered by gavage) on diphenoxylate-induced constipation in mice and elucidate the mechanisms underlying these effects using constipation and physicochemical indexes, histological morphology and 16S rDNA amplicon analysis of fecal microbiota. Sixty Kunming mice were randomly divided into the following six groups (n = 10 per group): normal control, constipation model, positive control, and low-, mid- and high-dose mulberry groups. After 14 days of treatment, constipation was induced over 5 days and measurements were conducted. The results show that mulberry treatment prevented constipation by increasing the fecal water content, shortening the first red fecal defecation time, promoting gastric evacuation, and increasing the gastric-intestinal transit rate (P

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PMID: 

Nat Prod Res. 2019 Mar 1:1-8. Epub 2019 Mar 1. PMID: 30822142

Abstract Title: 

Antiproliferative activity of stilbene derivatives and other constituents from the stem bark of Morus nigra L.

Abstract: 

The antiproliferative activities of 2',3,4',5,5'-pentahydroxy-cis-stilbene 1, resveratrol 2, oxyresveratrol 3, norartocarpetin 4, kuwanon C 5, morusin 6, cudraflavone A7, kuwanon G 8, albafuran C 9, mulberrofuran G 10, 3-acetyl-O-α-amyrin 11, 3-acetyl-O-β-amyrin 12, ursolic acid-3-O-acetate 13 and uvaol 14, previously identified from the barks of Morus nigra L., were investigated against HepG2 and MCF-7 cell lines. In addition, a series of methylated stilbenes 15-19 were prepared using compounds 1-3 and their antiproliferative effects were similarly investigated. The structure of a new 2',3,4'-trimethoxy-5-hydroxy-trans-stilbene 19 was elucidated using spectroscopic techniques. It showed remarkable activity against MCF-7 cells with IC12.5 μM. However, kuwanon C (5) showed the highest antiproliferative activity with IC3.92 and 9.54 μM against MCF-7 and HepG2, respectively.

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PMID: 

Phytochemistry. 2019 Jul ;163:1-10. Epub 2019 Apr 8. PMID: 30974396

Abstract Title: 

Antimicrobial mechanism of reaction products of Morus notabilis (mulberry) polyphenol oxidases and chlorogenic acid.

Abstract: 

Herein, five polyphenol oxidases (PPOs) obtained from Morus notabilis (Mn) were characterized. Chlorogenic acid was the most readily oxidized substrate by these MnPPOs, and the products derived from the oxidation of chlorogenic acid by MnPPOs were tested for antimicrobial activity. The results showed that products of the five MnPPOs exhibited good inhibitory effects against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Sclerotinia sclerotiorum, and Botrytis cinerea. Because the products of MnPPO1 exhibited the strongest antimicrobial activity, the antimicrobial mechanism of these products was explored. The results showed that the products of MnPPO1 increased cell membrane permeability and chitinase andβ-1,3-glucanase activities.

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PMID: 

Molecules. 2019 Apr 11 ;24(7). Epub 2019 Apr 11. PMID: 30978947

Abstract Title: 

Anti-Inflammatory Effects of High Hydrostatic Pressure Extract of Mulberry () Fruit on LPS-Stimulated RAW264.7 Cells.

Abstract: 

Mulberry fruit (L.) contains abundant bioactive compounds, including anthocyanins and flavonols, and has been reported to possess potent beneficial properties including anticancer, antidiabetic, and anti-oxidant effects. High hydrostatic pressure (HHP) processing, a nonthermal food processing technology, is suitable for the extraction of bioactive compounds from plants. Nevertheless, the anti-inflammatory effects of HHP extract of mulberry fruit (HM) in RAW264.7 cells remain unclear. The present study aimed to investigate the anti-inflammatory effects of HM on lipopolysaccharide (LPS)-induced inflammation. RAW264.7 cells were treated with various concentrations (0.1-1μg/mL) of HM in the presence or absence of LPS. HM inhibited the inflammatory mediator, nitric oxide (NO) release, and mRNA expression of nitric oxide synthase 2 (NOS2) in LPS-induced RAW264.7 cells. In addition, HM suppressed both mRNA and protein expressions of prostaglandin-endoperoxide synthase2 (PTGS2). Moreover, it reduced the LPS-induced secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. These results revealed that HM exerts anti-inflammatory effects by inhibiting several mediators and cytokines involved in the inflammatory process.

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PMID: 

Int J Mol Sci. 2019 May 7 ;20(9). Epub 2019 May 7. PMID: 31067694

Abstract Title: 

The Root Bark ofL. Suppressed the Migration of Human Non-Small-Cell Lung Cancer Cells through Inhibition of Epithelial⁻Mesenchymal Transition Mediated by STAT3 and Src.

Abstract: 

The root bark ofL. (MA) has been traditionally used for the treatment of various lung diseases in Korea. Although recent research has demonstrated its anticancer effects in several cancer cells, it is still unclear whether MA inhibits the migratory ability of lung cancer cells. The present study investigated the effects of MA on the migration of lung cancer cells and explored the underlying mechanism. Results from a transwell assay and wound-healing assay demonstrated that methylene chloride extracts of MA (MEMA) suppressed the migration and invasion of H1299, H460, and A549 human non-small-cell lung cancer (NSCLC) cells in a concentration-dependent manner. Results from Western blot analyses showed that MEMA reduced the phosphorylation of STAT3 and Src. In addition, MEMA downregulated the expression of epithelial-mesenchymal transition (EMT) marker proteins including Slug, Snail, Vimentin, and N-cadherin, while upregulating the expression of Occludin-a tight-junction protein. The regulation of EMT markers and the decrease of migration by MEMA treatment were reversed once phospho-mimetic STAT3 (Y705D) or Src (Y527F) was transfected into H1299 cells. In conclusions, MEMA inhibited the migratory activity of human NSCLC cells through blocking Src/STAT3-mediated EMT.

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PMID: 

Pharmacol Res. 2019 Aug ;146:104341. Epub 2019 Jul 2. PMID: 31276774

Abstract Title: 

Morus alba (mulberry), a natural potent compound in management of obesity.

Abstract: 

Obesity is defined as body mass index, higher than 30 kg/m, which are associated with diverse diseases including type 2 diabetes, hypertension, coronary diseases, certain cancers, osteoarthritis and dyslipidemia. The subject of this review article was to evaluate the potency of Morus alba or"mulberry"as natural potent anti-obesity agent in management of obesity. For writing this manuscript, we searched in all accessible international databases, electronic resources (PubMed, Science Direct, Springer, Wiley and Google), unpublished data (R&D reports, thesis and dissertation). The inhibitory effects of mulberry on digestive enzymes and adipocyte differentiation, and its stimulatory effects on energy expenditures, and lipid metabolism are responsible mechanisms for management of obesity in obese patients. Furthermore, the results of these preclinical studies and its related mechanisms should be evaluated in large clinical trials.

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PMID: 

J Agric Food Chem. 2019 Sep 11 ;67(36):10222-10234. Epub 2019 Sep 3. PMID: 31385700

Abstract Title: 

Natural Flavones fromagainst Methicillin-Resistantvia Targeting the Proton Motive Force and Membrane Permeability.

Abstract: 

The emergence and rapid spread of methicillin-resistant(MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.

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PMID: 

Biochem Biophys Res Commun. 2019 Sep 11. Epub 2019 Sep 11. PMID: 31521245

Abstract Title: 

Melatonin alleviates cigarette smoke-induced endothelial cell pyroptosis through inhibiting ROS/NLRP3 axis.

Abstract: 

Endothelial dysfunction (ED) is a crucial and initial stage for the development of cardiovascular diseases. Accumulated evidence has demonstrated causative links between cigarette smoke (CS) and ED. However, the underlying mechanisms remain largely unknown. Pyroptosis is a unique form of inflammatory cell death. In this study, we found that cigarette smoke extract (CSE) increased pyroptosis in endothelial cells (ECs) as evidenced by increasing lactate dehydrogenase release and the number of propidium iodide (PI) positive cells. A specific NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inhibitor (MCC950) pretreatment dramatically reduced CSE-induced pyroptosis. Additionally, we also observed that N-Acetylcysteine (NAC, a ROS scavenger) pretreatment inhibited NLRP3 inflammasome activation as evidenced by suppressing the upregulation of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-1β and IL-18 protein levels in CSE-treated ECs. Meanwhile, NAC pretreatment also remarkably inhibited CSE-induced EC pyroptosis. Melatonin is a hormone synthesized and secreted by mammalian pineal gland and plays a protective role in various cardiovascular diseases through its powerful anti-inflammatory and antioxidant properties. In this study, melatonin was observed to inhibit ROS production, NLRP3 inflammasome activation and pyroptosis in CSE-treated ECs. Moreover, oxidative stress and NLRP3 inflammasome activation in carotid arteries of smoking rats was also inhibited by melatonin. In conclusion, our study generated two novel findings, (i) CS activates ROS/NLRP3 axis and induces EC pyroptosis; (ii) melatonin attenuates CS-induced EC pyroptosis by inhibiting ROS/NLRP3 axis.

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PMID: 

Int J Biol Sci. 2019 ;15(9):1905-1920. Epub 2019 Jul 21. PMID: 31523192

Abstract Title: 

Melatonin Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib through the PERK-ATF4-Beclin1 Pathway.

Abstract: 

The mechanisms of resistance to the targeted drug sorafenib in the treatment of hepatocellular carcinoma (HCC) are poorly understood. The purpose of this study was to investigate the mechanism of sorafenib resistance and to elucidate the role of melatonin in overcoming sorafenib resistance. We first observed that sorafenib induced endoplasmic reticulum (ER) stress and activated autophagy in HCC, and the inhibition of ER stress and autophagy by specific inhibitors (PBA, TUDC and 3-MA) increased sorafenib-induced apoptosis, indicating that cells resist apoptosis by inducing ER stress and autophagy in the presence of sorafenib. Furthermore, specimens from patients with HCC revealed a close relationship between ER stress and autophagy, as demonstrated by the high correlation between expression of the autophagy-associated protein Beclin1 and expression of unfolded protein response (UPR) pathway proteins, especially PKR-like ER stress kinase (PERK); moreover, patients with combined expression of PERK and Beclin1 had more advanced disease (higher clinical stage) and a shorter overall survival time. ER stress inhibitors significantly blocked sorafenib-induced autophagy, selective knockdown of PERK and activating transcription factor 4 (ATF4) expression reduced sorafenib-induced autophagy activity compared with knockdown of the other two UPR pathways, and silencing ATF4 inhibited the expression of Beclin1. These results suggest that autophagy is downstream of ER stress and that the PERK-ATF4-Beclin1 pathway plays a role in ER stress-related autophagy. Interestingly, a low concentration of melatonin increased the sensitivity of HCC to sorafenib by inhibiting autophagy through the PERK-ATF4-Beclin1 pathway. Taken together, our findings suggest that cotreatment with sorafenib and melatonin is a potential therapy for HCC. Furthermore, ER stress-related autophagy plays key roles in apoptosis resistance. Therefore, targeting the PERK-ATF4-Beclin1 pathway may prove instrumental in HCC therapy.

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