摘要：
Ginseng has been traditionally used to treat diabetes mellitus (DM) in China. Ginsenoside Rg1 is a major active ingredient in processed ginseng, which elicits proven biological and pharmacological effects. Although a correlation between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and predisposition to type 1 diabetes mellitus (T1DM) has been identified, the mechanism underlying the potential function and activation of NLRP3 inflammasome in DM have not been elucidated to date. The present study aimed to elucidate the effects and underlying mechanism of Rg1 on streptozotocin (STZ)-induced T1DM in mice through short or long-term observation. Concurrently, we intended to explore the relationships between inflammasome, pyroptosis and oxidative stress and the role of NLRP3 and Keap1/Nrf2/HO-1 pathways in the development and progression of DM. Using ELISA and Western blot analysis, we found that Rg1 attenuated abnormally elevated blood glucose, reduced inflammatory factors IL-1beta and IL-18 in the blood, decreased ALT and AST levels, promoted insulin secretion, and weakened the function of NLRP3 in mouse liver and pancreas. In addition, Rg1 protected against STZ-induced reactive oxygen species-mediated inflammation by upregulating Nrf2/ARE pathway, which further activated antioxidant enzymes. Interestingly, Rg1 also regulated H3K9 methylation in liver and pancreas, as detected by immunohistochemistry. In summary, these data provide new understanding about the mechanism of Rg1 action, suggesting that it is a potential drug applied for preventing the occurrence and development of T1DM.
期刊：
Evidence-Based Complementary and Alternative Medicine,2020年2020 ISSN：1741-427X
通讯作者：
Hu, Zhixi
作者机构：
[Hu, Zhixi; Li, Lin] Hunan Univ Chinese Med, Domest Class Discipline Construct Project Chinese, Changsha, Hunan, Peoples R China.;[Hu, Zhixi; Li, Lin] Hunan Univ Chinese Med, Inst Tradit Chinese Med Diagnost, Changsha, Hunan, Peoples R China.;[Cheng, Bin; Zhong, Senjie; Qiu, Hong] Hunan Univ Chinese Med, Postgrad Sch, Changsha, Hunan, Peoples R China.
通讯机构：
[Hu, Zhixi] H;Hunan Univ Chinese Med, Domest Class Discipline Construct Project Chinese, Changsha, Hunan, Peoples R China.;Hunan Univ Chinese Med, Inst Tradit Chinese Med Diagnost, Changsha, Hunan, Peoples R China.
摘要：
Myeloid differentiation factor 88 (MyD88) and Toll or interleukin-1 receptor-domain-containing adaptor-inducing interferon-beta (IFN-beta) (TRIF) are two pivotal downstream adaptors of Toll-like receptors. Activation of MyD88 or TRIF signaling in cardiac immune pathology of severe inflammation negatively influences heart function. In the present study, severe septic cardiac injury was induced in C57BL/6 mice by cecum ligation and puncture (CLP). A total of 64 mice were divided randomly into the following four groups (n=16/group; 8 for observation of survival rate, 8 for heart sample analysis): Sham, CLP, anti-MyD88-CLP and anti-TRIF-CLP. Anti-MyD88 and anti-TRIF antibodies were administered to the respective mice through the tail veins 2 h before CLP. Measurements of cardiac function, including M-modes, velocity vector imaging and cardiac troponin I, were performed. Myocardial inflammatory cytokines were examined by reverse transcription-polymerase chain reaction (RT-PCR), myocardial neutrophil infiltration was measured by a myeloperoxidase activity assay, intracellular adhesion molecule and vascular cell adhesion molecule mRNA expression levels were investigated, and histopathological characteristics were evaluated. Levels of mRNA transcripts encoding genes for apoptosis production and MyD88, TRIF, nuclear factor-kappaB and IFN regulatory factor 3 were investigated by RT-PCR. Mice challenged with CLP demonstrated deleterious cardiac function, increased levels of interleukin-1beta (IL-1beta), IL-6beta, and tumor necrosis factor-alpha mRNA, increased neutrophil infiltration, and increased apoptosis. In contrast, mice in the anti-MyD88 CLP and anti-TRIF CLP groups retained cardiac function with reduced cytokine release, decreased neutrophil infiltration, and reduced apoptosis. In addition, there was no significant difference between the anti-MyD88 CLP and anti-TRIF CLP groups. Thus, the present study indicated that MyD88 and TRIF blockades serve notable and equivalent roles in protecting cardiac deterioration from severe sepsis by attenuating cytokine release, reducing neutrophil infiltration and alleviating apoptosis.
摘要：
Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-beta deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGT(f/f)Cre+) mice using a Cre/LoxP system under the CAMKII alpha promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGT(f/f)Cre+ mice compared with GGT(f/f)Cre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGT(f/f)Cre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
