Mangiferin activates Nrf2 to attenuate cardiac fibrosis via redistributing glutaminolysis-derived glutamate.

Cardiac injury is followed by fibrosis, characterized by myofibroblast activation. Excessive deposition of extracellular matrix (ECM) impairs the plasticity of myocardium and results in myocardial systolic and diastolic dysfunction. Mangiferin is a xanthonoid derivative rich in plants mangoes and iris unguicularis, exhibiting the ability to ameliorate metabolic disorders. This study aims to investigate whether mangiferin attenuates cardiac fibrosis via redox regulation. The transverse aortic constriction (TAC) in mice induced cardiac fibrosis with impaired heart function. Oral administration of mangiferin (50 mg/kg, 4 weeks) inhibited myofibroblast activation with reduced formation of ECM. The impaired left ventricular contractive function was also improved by mangiferin. TGF-ß1 stimulation increased glutaminolysis to fuel intracellular glutamate pool for the increased demands of nutrients to support cardiac myofibroblast activation. Mangiferin degraded Keap1 to promote Nrf2 protein accumulation by improving its stability, leading to Nrf2 activation. Nrf2 transcriptionally promotes the synthesis of antioxidant proteins. By activating Nrf2, mangiferin promoted the synthesis of glutathione (GSH) in cardiac fibroblasts, likely due to the consumption of glutaminolysis-derived glutamate as a source. Meanwhile, mangiferin promoted the exchange of intracellular glutamate for the import of extracellular cystine to support GSH generation. As a result of redistribution, the reduced glutamate availability failed to support myofibroblast activation. In support of this, the addition of extracellular glutamate or α-ketoglutarate diminished the inhibitory effects of mangiferin on cardiac myofibroblast proliferation and activation. Moreover, cardiac knockdown of Nrf2 attenuated the cardioprotective effects of mangiferin in mice subjected to TAC. In conclusion, we demonstrated that activated myofibroblasts were sensitive to glutamate availability. Mangiferin activated Nrf2 and redistributed intracellular glutamate for the synthesis of GSH, consequently impairing cardiac myofibroblast activation due to decreased glutamate availability. These results address that pharmacological activation of Nrf2 could restrain cardiac fibrosis via metabolic regulation.

Diagnostic Values of Advanced Glycation End Products and Homocysteine in Patients with Alzheimer's Disease and Sarcopenia.

This study is aimed at exploring the diagnostic value of advanced glycation end products (AGEs) and homocysteine (Hcy) in Alzheimer's disease (AD) complicated with sarcopenia (SP) and to analyze the risk factors related to AD complicated with SP. A total of 168 patients admitted to our hospital from November 2019 to December 2021 were enrolled. Patients were divided into the NC (no SP and AD) group with 29 cases, the AD group with 39 cases, the AD+SP group with 35 cases, and the SP group with 65 cases. The general information, Mini-Mental State Examination (MMSE) scores, and serum levels of AGEs and Hcy among the four groups were compared. Unordered logistic regression was used to analyze the influencing factors of SP patients complicated with dementia. The AGE level was higher in the AD or AD+SP group than the NC or SP group (P < 0.05). There was no significant difference between the SP group and the NC group or between the AD group and the AD+SP group (P > 0.05). The Hcy level was higher in the SP or AD group than the NC group (P < 0.05). There were no significant differences between the AD group and NC group or between the SP group and AD+SP group (P > 0.05). The ROC curve of serum AGEs and Hcy for the diagnosis of AD showed that the area under curve (AUC) was 0.887, P < 0.05 (95% CI: 0.821-0.954, sensitivity: 80.95%, specificity: 73.81%) and 0.7423, P < 0.05 (95% CI: 0.6382-0.8465, sensitivity: 60.42%, specificity: 57.59%), respectively. The ROC curve of serum AGEs and Hcy for the diagnosis of SP showed that the AUC was 0.5533, P > 0.05 (95% CI: 0.4294-0.6771) and 0.8744, P < 0.05 (95% CI: 0.8006-0.9483). Age (P < 0.001), depression (P = 0.001), malnutrition (P = 0.002), and BMI (P < 0.001) were independent influencing factors of SP complicated with AD in elderly inpatients. In conclusion, combined serum AGEs and Hcy had a good diagnostic value for AD combined with SP, which may be helpful for early detection of patient condition.

Analysis of Changes of Intestinal Flora in Elderly Patients with Alzheimer's Disease and Liver Cancer and Its Correlation with Abnormal Gastrointestinal Motility.

OBJECTIVE: To investigate the changes of intestinal flora in elderly patients with Alzheimer's disease and liver cancer and its correlation with abnormal gastrointestinal motility. METHODS: From January 2018 to December 2020, 102 elderly patients with Alzheimer's disease and liver cancer were selected as the observation group. Eighty-nine healthy patients during the same period were selected as the control group. The two groups of intestinal flora (intestinal microbial diversity) were detected by real-time fluorescent quantitative PCR (RT-qPCR) and high-throughput sequencing. The two groups of serum motilin (MTL) and gastrin (GAS) levels were measured by the Hitachi automatic biochemical analyzer 7600. Pearson correlation analysis software was used to analyze the relationship between changes in the intestinal flora and gastrointestinal motility in elderly patients with Alzheimer's disease and liver cancer. RESULTS: The contents of Bifidobacteria and Lactobacilli in the observation group were lower than those in the control group, and the contents of Escherichia coli, Helicobacter pylori, and Streptococcus were higher than those in the control group. The Chaol index and Shannon index in the observation group were higher than those in the control group. The gastrointestinal motility levels MTL and GAS of the observation group were higher than those of the control group. The results of Pearson correlation analysis showed that the Chaol index and Shannon index of elderly patients with Alzheimer's disease and liver cancer were positively correlated with MTL and GAS. CONCLUSION: Elderly patients with Alzheimer's disease and liver cancer often have changes in the intestinal flora, which are correlated with abnormal gastrointestinal motility. Strengthening the analysis of changes in patients' intestinal flora can enhance clinical medication knowledge and improve gastrointestinal motility in patients.

Neuroprotective effects of midazolam on focal cerebral ischemia in rats through anti­apoptotic mechanisms.

Stroke is a cerebrovascular circulatory disorder and its high mortality rate represents a prominent threat to human health. Subsequent apoptosis and cytotoxicity are the main causes underlying the poor prognosis. Midazolam (MDZ) is a benzodiazepine drug that is clinically used during surgical procedures and for the treatment of insomnia, with a potential ability to treat stroke. The protective effect of MDZ was investigated on glutamate­induced cortical neuronal injuries in vitro and transient middle cerebral artery occlusion (tMCAO) rat models in vivo. Western blot analysis and semi quantitative RT­PCR were used to evaluate the potential underlying mechanisms. In vitro studies revealed that MDZ regulated apoptosis­associated gene expression and inhibited lactate dehydrogenase (LDH) release, protecting against neuronal damage. In vivo studies revealed that MDZ reduced LDH­induced neuronal damage by reducing LDH release from the peripheral blood, and brain tissue staining revealed that MDZ protected neurons during tMCAO. MDZ protected neurons under an ischemic environment by inhibiting LDH release and regulating apoptosis­associated gene expression to reduce cytotoxicity and apoptosis. These results provide a reliable basis for further studies on the effect of MDZ, to improve the prognosis of cerebral infarction.

Propofol attenuates inflammatory damage on neurons following cerebral infarction by inhibiting excessive activation of microglia.

The overall incidence rate of stroke is increasing worldwide. Inflammatory damage following a stroke is a leading cause for the poor prognosis and high disability rate observed in stroke patients. Microglia are considered to be the main causative agents of inflammatory injury following cerebral infarction, as they secrete various inflammatory cytokines and cytotoxic factors. The aim of the present study was to identify novel methods for attenuating inflammatory injury and improving the prognosis of stroke patients. Lipopolysaccharide-stimulated microglia were treated using propofol in vitro and a transient middle cerebral artery occlusion/reperfusion model was constructed in rats. Expression of cytotoxic factors, microglia proliferation and the neuroprotective effects of propofol were measured in vitro and in vivo. The in vitro studies demonstrated that propofol inhibits the expression of multiple cytotoxic factors, prevents structural changes to cytoskeletal proteins, and suppresses microglial migration via the adenosineA2b receptors. The results of the in vivo experiments revealed that propofol inhibits the abnormal proliferation of microglia, as well as reduces the expression levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor α, and the cytotoxic factor nitric oxide through the A2b receptor. In conclusion, propofol inhibited the excessive activation of microglia through the A2b receptor and attenuated the inflammatory injury following cerebral infarction. The current study may provide a reliable basis for further clinical studies on propofol and its putative role in improving the prognosis of patients with cerebral infarction.