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[Display omitted] • 64 metabolites of chlorogenic acids were identified in rats' plasma and hearts. • The metabolic pathways of chlorogenic acids in rats' plasma and hearts were summarized. • The metabolites' types of chlorogenic acids under physiological and pathological conditions were similar. • Caffeic acid, methyl caffeate and dihydrocaffeic acid were active metabolites. Chlorogenic acid (CGA) has gained considerable attention as pervasive human dietary constituents with potential cardiovascular-preserving effects. CGA and its structural isomers neochlorogenic acid (NCGA), cryptochlorogenic acid (CCGA) possessed potential capacities on improving myocardial hypertrophy. This study aimed to clarify the active metabolites responsible for improving myocardial hypertrophy of CGA, NCGA and CCGA. As a result, similar to in heart, the different metabolites between pathological and myocardial hypertrophy plasma were basically inactive phase Ⅱ metabolites. Finally, 10 metabolites which were accurately identified in CGA, CCGA and NCGA were chosen to be candidates. And the isoproterenol induced H9c2 cells were used as the myocardial hypertrophy model to screen the active metabolites. In conclusion, based on the results of quantification of cardiomyocyte surface area and expression of ANP, BNP and HIF-1α mRNA, caffeic acid, methyl caffeate and dihydrocaffeic acid were identified as the active metabolites. [ABSTRACT FROM AUTHOR]

Abstract: The hypoglycemic and hypolipidemic effect of an α-glucan (designed here as MT-α-glucan) from fruit body of maitake (Grifola frondosa) on diabetic mouse model induced by streptozotocin and high-fat-diet were evaluated, and its effect on immune function of diabetic mice was investigated. Treatment with MT-α-glucan (300 or 100mgkg−1) could decrease the levels of fasting plasma glucose, triglycerides, cholesterol, free fatty acid, the proliferative response of macrophages and IL-1, NO production by macrophages significantly. Treatment with MT-α-glucan could increase the serum insulin, the proliferative response and IL-2 production of splenocytes induced by ConA significantly. Ultrastructural changes of pancreatic β-cells were ameliorated in the treatment group. These data suggest that MT-α-glucan has hypoglycemic and hypolipidemic effect on the diabetic mice model, which might be related to its benefit effect on immune reactions involved in pathogenesis of diabetes mellitus, leading to attenuate the degree of injured β-cells of the pancreatic islets. [Copyright &y& Elsevier]

Background: Radix Ginseng, one of the well-known medicinal herbs, has been used in the management of diabetes and its complications for more than 1000 years.Purpose: The aim of this review is devoted to summarize the phytochemistry and pharmacokinetics of Ginseng, and provide evidence for the antidiabetic effects of Ginseng and its ingredients as well as the underlying mechanisms involved.Methods: For the purpose of this review, the following databases were consulted: the PubMed Database (https://pubmed.ncbi.nlm.nih.gov), Chinese National Knowledge Infrastructure (http://www.cnki.net), National Science and Technology Library (http://www.nstl.gov.cn/), Wanfang Data (http://www.wanfangdata.com.cn/) and the Web of Science Database (http://apps.webofknowledge.com/).Results: Ginseng exhibits glucose-lowering effects in different diabetic animal models. In addition, Ginseng may prevent the development of diabetic complications, including liver, pancreas, adipose tissue, skeletal muscle, nephropathy, cardiomyopathy, retinopathy, atherosclerosis and others. The main ingredients of Ginseng include ginsenosides and polysaccharides. The underlying mechanisms whereby this herb exerts antidiabetic activities may be attributed to the regulation of multiple signaling pathways, including IRS1/PI3K/AKT, LKB1/AMPK/FoxO1, AGEs/RAGE, MAPK/ERK, NF-κB, PPARδ/STAT3, cAMP/PKA/CERB and HIF-1α/VEGF, etc. The pharmacokinetic profiles of ginsenosides provide valuable information on therapeutic efficacy of Ginseng in diabetes. Although Ginseng is well-tolerated, dietary consumption of this herb should follow the doctors' advice.Conclusion: Ginseng may offer an alternative strategy in protection against diabetes and its complications through the regulations of the multi-targets via various signaling pathways. Efforts to understand the underlying mechanisms with strictly-controlled animal models, combined with well-designed clinical trials and pharmacokinetic evaluation, will be important subjects of the further investigations and weigh in translational value of this herb in diabetes management. [ABSTRACT FROM AUTHOR]

The glutamate receptor was one of the most intensely investigated targets for neuroprotection. However, numerous clinical trials of glutamate receptor antagonists for the treatment of stroke were unsuccessful. These failures have led to pessimism in the field. But recent advances could provide hope for the future. This minireview looks beyond the traditional mechanism of glutamate-receptor-driven excitotoxicity to identify other mechanisms of ionic imbalance. These advances include findings implicating sodium–calcium exchangers, hemichannels, volume-regulated anion channels, acid-sensing channels, transient receptor potential channels, nonselective cation channels and signaling cascades that mediate crosstalk between redundant pathways of cell death. Further in vivo validation of these pathways could ultimately lead us to new therapeutic targets for stroke, trauma and neurodegeneration. [Copyright &y& Elsevier]

Abstract: Matrix metalloproteinase-9 (MMP-9) may play a role in the inflammatory glial response during Alzheimer''s disease (AD). Astrocytes can degrade beta-amyloid (Aβ) and extracellular proteolysis via MMP-9 may be involved. Because Apolipoprotein E (APOE) genotype is an important factor for AD, we ask whether various apoE isoforms can influence Aβ-induced MMP-9 responses in primary rat astrocytes. Our data show that apoE4 significantly dampens Aβ-induced MMP-9 levels, possibly by downregulating the Rho–Rho kinase (ROCK) pathway. Reduction of astrocytic MMP-9 by apoE4 may affect Aβ clearance and promote Aβ deposition in AD. [Copyright &y& Elsevier]

• Ang-II increases both para- and trans-cellular cerebral endothelial permeability. • Ang-II disrupts the membrane distributions of ZO-1 and VE-Cad. • Ang-II decreases protein levels of JAM-A and Mfsd2a but increases Cav1. • Ang-II-induced endothelial permeability is ameliorated by PPARalpha agonists. • PPARalpha pathways may offer potential therapeutic targets in cell-based therapy. Angiotensin-II (Ang-II) is a key factor in hypertension, diabetes and aging, which are all primary risk factors for CNS disease. Furthermore, Ang-II may play under-appreciated roles in neurogenesis, angiogenesis and CNS remodeling. Therefore, any contemplated attempts for neurorestorative therapies in the CNS should consider the context of Ang-II signaling. Here, we investigate how Ang-II may regulate cerebral endothelial permeability, a key functional feature of the neurovascular unit. Exposure of human brain endothelial cell cultures to Ang-II increased its permeability to BSA-Alexa488 tracer. Immunocytochemistry and pulse-chase experiments suggested that both para-cellular as well as trans-cellular pathways were involved. Candesartan but not PD123319 blocked Ang-II permeability effects, suggesting that Ang-II effects may be mediated via type 1 receptor. Immunocytochemistry and western blots showed that Ang-II disrupted the membrane distributions of ZO-1 and VE-Cad, decreased total levels of JAM-A and Mfsd2a, and increased Cav1. These effects of Ang-II were accompanied by dephosphorylation of PPARalpha. Finally, Ang-II-induced increases in endothelial permeability were ameliorated by PPARalpha agonists. Taken together, these studies suggest that Ang-II may disrupt both para- and trans-cellular permeability in cerebral endothelium, and PPARalpha-related pathways may offer potential therapeutic targets for ameliorating these effects in cell-based regenerative medicine. [ABSTRACT FROM AUTHOR]

Abstract: In gray matter, cerebral endothelium is known to provide trophic support for neighboring cells such as neurons. However, signaling from cerebral endothelium to white matter cells remains to be elucidated. Here, we show that vascular endothelial growth factor (VEGF-A) secreted from cerebral endothelial cells promotes the migration but not the proliferation of oligodendrocyte precursor cells (OPCs). Cultured OPCs were obtained from newborn rat cortex, and treatment with conditioned culture media of cerebral endothelial cells increased the OPC proliferation and migration. Importantly, co-treatment with anti-neutralizing antibody for Flk-1 (VEGF-receptor2) inhibited OPC movement but did not affect OPC propagation. Western blot and flow cytometry analyses confirmed that our cultured cerebral endothelial cells produced VEGF-A and our cultured OPCs expressed Flk-1. Taken together, our current data suggest that cerebral endothelium is supportive for oligodendrocyte lineage cells and VEGF-A may participate in the endothelium–OPC cell–cell signaling. This phenomenon may be important for white matter homeostasis. [Copyright &y& Elsevier]

• SMYA ameliorates glucose metabolism, insulin sensitivity, and hyperglucagonemia in diabetic mice. • SMYA attenuates left ventricular dysfunction and myocardial remodeling in diabetic mice. • SMYA inhibits myocardial apoptosis, inflammation, and lipid accumulation in diabetic mice. • SMYA modulates GLC/AMPK/NF-κB and GLC/PPARα/PGC-1α pathways in the hearts of diabetic mice. Diabetic cardiomyopathy (DCM) is a main cause of heart failure and death in diabetic patients. However, countermeasures to limit the development of this disease remain insufficient. Si-Miao-Yong-An decoction (SMYA), a Chinese herbal prescription, exhibits both lipid-lowering and cardiovascular preserving effects, and may have an effect on DCM management. The current study is aimed to investigate the effects of SMYA on the cardiac function in diabetic mice and the underlying mechanisms involved. Streptozotocin-induced diabetic mice were fed intragastrically with SMYA every day for 15 weeks. Cardiac function was assessed by echocardiograph. Histopathological alterations in the heart were determined by hematoxylin/eosin, wheat germ agglutinin, Masson's trichrome, Terminal dUTP nick end-labeling, Oil red O staining, and transmission electron microscopy. The potential involvements of GLC/AMPK/NF-κB and GLC/PPARα/PGC-1α signaling pathways were investigated by western blot and/or immunohistochemical staining. Treatment of diabetic mice with SMYA improved insulin sensitivity, and attenuated the increases of water consumption, food intake, blood glucose, and serum GLC. Furthermore, SMYA ameliorated cardiac systolic and diastolic functions, suppressed the myocardial hypertrophy, fibrosis, apoptosis, inflammation, and lipid accumulation as well as preserved the myofilaments arrangement and mitochondrial integrity. Finally, SMYA downregulated the expressions of GCGR, PGC-1α, PPARα and the phosphorylation of NF-κB, as well as upregulated the phosphorylation of AMPK in the hearts of diabetic mice. SMYA may ameliorate glucolipid metabolism and cardiac function through the regulation of GLC/AMPK/NF-κB and GLC/PPARα/PGC-1α signaling pathways in diabetic mice, suggesting that this prescription could provide a new source of drug candidates to protect against DCM. [ABSTRACT FROM AUTHOR]

SMYAD attenuated cardiac fibrosis via decreasing collagen synthesis by suppressing TGF-β1 pathway and increasing collagen degradation by interfering with MMP-TIMPs expression. • SMYAD reduced fibrosis level and improved TAC-induced heart failure in mice. • SMYAD attenuated cardiac fibrosis via decreasing collagen synthesis by suppressing TGFβ1/Smad pathway and increasing collagen degradation by interfering with MMP-TIMPs expression. • Our study suggests the potential of SMYAD for the treatment of heart failure. Myocardial fibrosis is an important pathological feature of pressure overload cardiac remodeling. Si-Miao-Yong-An decoction (SMYAD), a traditional Chinese formula, is now clinically used in the treatment of cardiovascular diseases in China. However, its mechanisms in the prevention of heart failure are not fully revealed. To determine whether treatment with SMYAD for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a mice model of heart failure. Mice were subjected to transverse aorta constriction to generate pressure overload induced cardiac remodeling and then were administered SMYAD (14.85 g/kg/day) or captopril (16.5 mg/kg/day) intragastrically for 4 weeks after surgery. Echocardiography and immunohistochemical examination were used to evaluate the effects of SMYAD. The mRNA of collagen metabolism biomarkers were detected. Protein expression of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway were assessed by Western blot. SMYAD significantly improved cardiac function, increased left ventricle ejection fraction, and decreased fibrosis area and αSMA expression. Moreover, SMYAD reduced proteins expression related to collagen metabolism, including Col1, Col3, TIMP2 and CTGF. The increased levels of TGF-β1, Smad2, and Smad3 phosphorylation were attenuated in SMYAD group. In addition, SMYAD reduced the levels of TGF-β1, p-TAK1 and p-p38 compared with TAC group. SMYAD improved cardiac fibrosis and heart failure by inhibition of TGF-β1/Smad and TGF-β1/TAK1/p38 pathway. SMYAD protected against cardiac fibrosis and maintained collagen metabolism balance by regulating MMP-TIMP expression. Taken together, these results indicate that SMYAD might be a promising therapeutic agent against cardiac fibrosis. [ABSTRACT FROM AUTHOR]