Endogenous hydrogen sulfide and ERK1/2-STAT3 signaling pathway may participate in the association between homocysteine and hypertension

Background Homocysteine(Hcy)is a risk factor for hypertension,although the mechanisms are poorly understood.Methods We first explored the relationship between Hcy levels and blood pressure(BP)by analyzing the clinical data of primary hypertensive patients admitted to our hospital.Secondly,we explored a rat model to study the effect of Hcy on blood pressure and the role of H2S.An hyperhomocysteinemia(HHcy)rat model was induced to explore the effect of Hcy on blood pressure and the possible mechanism.We carried out tissue histology,extraction and examination of RNA and protein.Finally,we conducted cell experiments to determine a likely mechanism through renin-angiotensin-aldosterone system(RAAS)and extracellular signal-regulated kinase 1/2(ERK1/2)signaling pathway.Results In primary hypertensive inpatients with HHcy,blood pressure was significantly higher as compared with inpatient counterparts lacking HHcy.In the rat model,blood pressure of the Wistar rats was significantly increased with increases in serum Hcy levels and decreased after folate treatment.Angiotensin converting enzyme 1(ACE1)expression in the Wistar Hcy group was enhanced comparing to controls,but was decreased in the Wistar folate group.Angiotensin II receptor type 1(AGTR1)levels in the kidney tissue increased in the Wistar folate group.Both serum H2S and kidney cystathionineγ-lyase decreased with elevated levels of serum Hcy.In vitro,increased concentrations and treatment times for Hcy were associated with increased expression of collagen type 1 and AGTR1.This dose and time dependent response was also observed for p-STAT3 and p-ERK1/2 expression.Conclusion Endogenous H2S might mediate the process of altered blood pressure in response to changes in serum Hcy levels,in a process that is partly dependent on activated RAAS and ERK1/2-STAT3 signaling pathway.

Geniposide, the component of the Chinese herbal formula Tongluojiunao, protects amyloid-β peptide(1–42)-mediated death of hippocampal neurons via the non-classical estrogen signaling pathway

Tongluojiunao （TLJN） is an herbal medicine consisting of two main components, geniposide and ginsenoside Rg1. TLJN has been shown to protect primary cultured hippocampal neurons. How-ever, its mechanism of action remains unclear. In the present study, primary cultured hippocampal neurons treated with Aβ1-42 （10 μmol/L） signiifcantly increased the release of lactate dehydroge-nase, which was markedly reduced by TLJN （2 μL/mL）, speciifcally by the component geniposide （26 μmol/L）, but not ginsenoside Rg1 （2.5 μmol/L）. hTe estrogen receptor inhibitor, ICI182780 （1 μmol/L）, did not block TLJN-or geniposide-mediated decrease of lactate dehydrogenase under Aβ1-42-exposed conditions. However, the phosphatidyl inositol 3-kinase or mitogen-activated protein kinase pathway inhibitor, LY294002 （50 μmol/L） or U0126 （10 μmol/L）, respectively blo cked the decrease of lactate dehydrogenase mediated by TLJN or geniposide. hTerefore, these results suggest that the non-classical estrogen pathway （i.e., phosphatidyl inositol 3-kinase or mitogen-activated protein kinase） is involved in the neuroprotective effect of TLJN, speciifcally its component, geniposide, against Aβ1-42-mediated cell death in primary cultured hippocampal neurons.

Protective effects of curcumin in APPswe transfected SH-SY5Y cells

The APPswe plasmid was transfected into the neuroblastoma cell line SH-SY5Y to establish a cell model of Alzheimer＇s disease. Graded concentration and time course experiments demonstrate that curcumin significantly upregulates phosphatidylinositol 3-kinase （PI3K）, Akt, nuclear factor E2-related factor-2 （Nrf2）, heme oxygenase 1 and ferritin expression, and that it significantly downregulates heme oxygenase 2, reactive oxygen species and amyloid-beta 40/42 expression. These effects of curcumin on PI3K, Akt and Nrf2 were blocked by LY294002 （PI3k inhibitor） and NF-E2-related factor-2 siRNA. The results indicate that the cytoprotection conferred by curcumin on APPswe transfected SH-SY5Y cells is mediated by its ability to regulate the balance between heme oxygenase 1 and 2 via the PI3K/Akt/Nrf2 intracellular signaling pathway.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

肺转移前微环境体外模型的建立与双参颗粒干预机制

目的:构建肺转移前微环境体外模型,观察S1pr1-stat3信号通路在模型成熟过程中的作用,同时验证双参颗粒对该模型的干预作用,探讨其可能的机制。方法:体外构建小鼠Lewis肺癌细胞和原代骨髓细胞共培养模型,并用S1pr1激活剂SEW2871干预髓系细胞分化的过程,观察相关蛋白MMP9、Lox、Version及Fibronectin的表达情况,并检测模型中骨髓来源的抑制性细胞(MDSCs)细胞的分化情况及双参颗粒对模型的干预效果。结果:S1pr1可以明显促进肺转移前微环境体外模型的成熟构建,S1pr1-stat3是该模型成熟的关键信号通路,双参颗粒不仅显著降低模型中该信号通路相关蛋白的表达,同时对微环境成熟的关键蛋白的表达也具有抑制作用,还可显著降低该信号通路相关的骨髓细胞向MDSCs细胞的分化(P<0.05),同时对转移前微环境中部分肿瘤源性细胞因子如粒细胞-巨噬细胞集落刺激因子(GM-CSF)及转化生长因子(TGF-β)有显著抑制作用(P<0.05)。结论:双参颗粒通过抑制S1pr1-stat3信号通路及部分肿瘤源性细胞因子的表达,抑制肺转移前微环境模型的成熟。