Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications.

Pyroptosis is an inflammatory form of programmed cell death that is dependent on inflammatory caspases, leading to the cleavage of gasdermin D (GSDMD) and increased secretion of interleukin (IL)-1ß and IL-18. Recent studies have reported that hyperglycemia-induced cellular stress stimulates pyroptosis, and different signaling pathways have been shown to play crucial roles in regulating pyroptosis. This review summarized and discussed the molecular mechanisms, regulation, and cellular effects of pyroptosis in diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. In addition, this review aimed to provide new insights into identifying better treatments for diabetic microvascular complications.

Yishen Huashi Granules Ameliorated the Development of Diabetic Nephropathy by Reducing the Damage of Glomerular Filtration Barrier.

Background: Diabetic nephropathy (DN) is one of the most common complications of diabetes and the primary cause of end-stage renal disease. At present, renin-angiotensin-aldosterone system (RAAS) blockers have been applied as first-class drugs to restrain development of DN; however, its long-term effect is limited. Recent evidence has shown definite effects of Chinese medicine on DN. Yishen Huashi (YSHS) granule is a traditional Chinese Medicine prescription that has been used in the clinic to treat DN, but its mechanism is not understood. Methods: In the present study, both in vitro and in vivo studies were carried out. The DN model was induced by STZ in Wistar rats, and GEnC and HPC cell lines were applied in the in vitro study. Quality of YSHS was evaluated by LC-MS/MS. A metabolomic study of urine was carried out by LC-MS; influence of YSHS on composition of DN was analyzed by network pharmacology. Mechanism of the YSHS on DN was analyzed by Q-PCR, Western Blot, and multi-immunological methods. Results: We found YSHS administration significantly reduced levels of HbA1c and mALB. Histopathological analysis found that YSHS preserved integrity of glomerular filtration barrier by preserving viability of glomerular endothelial cells and podocytes, inhibiting glomerular fibrosis, reducing oxidative stress damage, and enhancing cross-talk among glomerular endothelial cells and podocytes. Network pharmacology, differential metabolite analysis, as well as intracellular pathway experimental study demonstrated that the PI3K/AKT/mTOR signaling pathway played a pivotal role in it. Conclusion: Our present findings supplied new understanding toward the mechanism of YSHS on inhibiting DN.

Intake of flavonoids from Astragalus membranaceus ameliorated brain impairment in diabetic mice via modulating brain-gut axis.

BACKGROUND: Brain impairment is one of a major complication of diabetes. Dietary flavonoids have been recommended to prevent brain damage. Astragalus membranaceus is a herbal medicine commonly used to relieve the complications of diabetes. Flavonoids is one of the major ingredients of Astragalus membranaceus, but its function and mechanism on diabetic encepholopathy is still unknown. METHODS: Type 2 diabetes mellitus (T2DM) model was induced by high fat diet and STZ in C57BL/6J mice, and BEnd.3 and HT22 cell lines were applied in the in vitro study. Quality of flavonoids was evaluated by LC-MS/MS. Differential expressed proteins in the hippocampus were evaluated by proteomics; influence of the flavonoids on composition of gut microbiota was analyzed by metagenomics. Mechanism of the flavonoids on diabetic encepholopathy was analyzed by Q-PCR, Western Blot, and multi-immunological methods et al. RESULTS: We found that flavonoids from Astragalus membranaceus (TFA) significantly ameliorated brain damage by modulating gut-microbiota-brain axis: TFA oral administration decreased fasting blood glucose and food intake, repaired blood brain barrier, protected hippocampus synaptic function; improved hippocampus mitochondrial biosynthesis and energy metabolism; and enriched the intestinal microbiome in high fat diet/STZ-induced diabetic mice. In the in vitro study, we found TFA increased viability of HT22 cells and preserved gut barrier integrity in CaCO2 monocellular layer, and PGC1α/AMPK pathway participated in this process. CONCLUSION: Our findings demonstrated that flavonoids from Astragalus membranaceus ameliorated brain impairment, and its modulation on gut-brain axis plays a pivotal role. Our present study provided an alternative solution on preventing and treating diabetic cognition impairment.

Total flavonoids of Astragalus Ameliorated Bile Acid Metabolism Dysfunction in Diabetes Mellitus.

Astragalus Radix is one of the common traditional Chinese medicines used to treat diabetes. However, the underlying mechanism is not fully understood. Flavones are a class of active components that have been reported to exert various activities. Existing evidence suggests that flavones from Astragalus Radix may be pivotal in modulating progression of diabetes. In this study, total flavones from Astragalus Radix (TFA) were studied to observe its effects on metabolism of bile acids both in vivo and in vitro. C57BL/6J mice were treated with STZ and high-fat feeding to construct diabetic model, and HepG2 cell line was applied to investigate the influence of TFA on liver cells. We found a serious disturbance of bile acids and lipid metabolism in diabetic mice, and oral administration or cell incubation with TFA significantly reduced the production of total cholesterol (TCHO), total triglyceride, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and low-density lipoprotein (LDL-C), while it increased the level of high-density lipoprotein (HDL-C). The expression of glucose transporter 2 (GLUT2) and cholesterol 7α-hydroxylase (CYP7A1) was significantly upregulated on TFA treatment, and FXR and TGR5 play pivotal role in modulating bile acid and lipid metabolism. This study supplied a novel understanding towards the mechanism of Astragalus Radix on controlling diabetes.

WITHDRAWN: Effects of traditional Chinese medicine Fuzhisan on PP1 expression in the hippocampus of SAMP8 mice.

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Changes in cerebral glucose metabolism in patients with mild-to-moderate Alzheimer's disease: a pilot study with the Chinese herbal medicine fuzhisan.

The aim of this study was to investigate the effects of fuzhisan (FZS, 10mg/day), a Chinese herbal medicine, on cerebral glucose metabolism and neuropsychological metrics in patients with mild-to-moderate Alzheimer's disease (AD). This was a 12-week, randomized, double-blind, placebo-controlled pilot study. Twenty-two subjects were randomly assigned to groups that received FZS (n=12) or placebo (n=10). Positron emission tomography (PET) was used to study the regional cerebral metabolic rate of glucose consumption (rCMRglc) at baseline and week 12. We evaluated the clinical efficacy of FZS on cognition and behavioral functions using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Neuropsychiatric Index (NPI), respectively. Compared with placebo, FZS significantly improved ADAS-Cog scores and NPI scores at week 12. Moreover, FZS treatment favorably improved rCMRglc in the bilateral temporal and parietal cortices, hippocampus, and posterior cingulate gyrus. These results suggest that FZS treatment may have a positive effect on cognition, behavioral functions, and rCMRglc in mild-to-moderate AD patients.

Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice.

Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS (2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's disease.