Exercise improves cognitive dysfunction and neuroinflammation in mice through Histone H3 lactylation in microglia.

BACKGROUND: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. RESULTS: Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. CONCLUSION: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.

Increased expression of SLC25A18 is associated with Alzheimer's disease and is involved in Aß42-induced mitochondrial dysfunction and apoptosis in neuronal cells.

Alzheimer's disease (AD) is currently one of the most serious public health concerns in the world. However, the best approach to treat AD has yet to be discovered, implying that we must continue to work hard to find new AD target genes. In this study, we further analysed Gene Expression Omnibus (GEO) data and discovered that the expression of the Mitochondria glutamate carrier SLC25A18 is associated with AD by screening the differentially expressed genes in different regions of the brains of Alzheimer's disease patients. To verify the expression of SLC25A18 during Alzheimer's disease development, we analysed animal models (5×FAD transgenic AD animal model, chemically induced AD animal model, natural ageing animal model), and the results showed that the expression of SLC25A18 was increased in animal models of AD. Further investigation of the different regions found that SLC25A18 expression was elevated in the EC, TeA, and CA3, and expressed in neurons. Next, We found that Aß42 treatment elevated SLC25A18 expression in Neuro 2A cells. Reducing SLC25A18 expression attenuated mitochondrial dysfunction and neuronal apoptosis caused by Aß42. Overexpression of SLC25A18 increased ATP and intracellular superoxide anions but decreased mitochondrial membrane potential. The results indicate that SLC25A18 affects mitochondrial function and neuronal apoptosis, and is related to AD, which makes it a potential target for treating brain dysfunction.

The relationship between Alzheimer's disease and intestinal microflora structure and inflammatory factors.

To analyze the structural characteristics of intestinal microflora and changes of serum inflammatory factors of the Alzheimer's disease, and to explore the relationship between them and dementia, we selected 30 patients in the AD group and 30 patients in the normal group, and collected stool samples to analyze the intestinal flora structure characteristics of the two groups of patients, and statistically analyzed the inflammatory cytokines TNF-α, IL-1ß, IL-6, and IL-8 by ELISA from the venous blood of the two groups. The results show that the dominant Bacteroides in the two groups are Bacteroides, Firmicutes, Proteobacteria, and Actinobacteria. The abundance of Bacteroides, Firmicutes, and Proteobacteria in the AD group shows a statistical difference. At the genus level, the abundance of anti-inflammatory bacteria such as Lactobacillus, Bifidobacterium, and Ruminococcus drops in AD group, while the abundance of pro-inflammatory bacteria such as Escherichia and Enterococcus raises. Statistical analysis of inflammatory cytokines in the two groups suggests that TNF-α and IL-6 levels significantly increase in the AD group, with statistical differences. Therefore, it is speculated that the increased abundance of pro-inflammatory bacteria in intestinal flora may lead to or aggravate neuroinflammation through the release of inflammatory factors, thus further leading to the occurrence and development of AD.

Study on the Effect of PDA-PLGA Scaffold Loaded With Islet Cells for Skeletal Muscle Transplantation in the Treatment of Diabetes.

At present, islet cells transplantation was limited by the way in which islet cells are implanted into the body, their ability to adapt to the microenvironment and the maintenance time for relieving diabetic symptoms. In order to solve this problem, we made PDA-PLGA scaffold loaded with islet cells and used it for skeletal muscle transplantation to investigate its therapeutic effect in the treatment of diabetes. The PLGA scaffold was prepared by the electrospinning method, and modified by polydopamine coating. A rat diabetic model was established to evaluate the efficacy of PDA-PLGA scaffold loaded with RINm5f islet cells through skeletal muscle transplantation. The results showed that the PDA-PLGA scaffold has good biosafety performance. At the same time, transplantation of the stent to the skeletal muscle site had little effect on the serum biochemical indicators of rats, which was conducive to angiogenesis. The PDA-PLGA scaffold had no effect on the secretory function of pancreatic islet cells. The PDA-PLGA scaffold carrying RINm5f cells was transplanted into the skeletal muscle of type I diabetic rats. 1 week after the transplantation of the PDA-PLGA cell scaffold complex, the blood glucose of the treatment group was significantly lower than that of the model group (p < 0.001) and lasted for approximately 3 weeks, which further indicated the skeletal muscle transplantation site was a new choice for islet cell transplantation in the future.

Echinocystic acid, a natural plant extract, alleviates cerebral ischemia/reperfusion injury via inhibiting the JNK signaling pathway.

Echinocystic acid (EA) was found to possess antiviral, anti-inflammatory and antioxidation activities. A recent study showed the antiapoptotic effects of EA on acute myocardial infarction. In this study, we demonstrated the potential neuroprotective effects of EA on cerebral ischemia/reperfusion (I/R) injury in mice. Intraperitoneal injection of EA 1 h before ischemia significantly reduced the cerebral infarct volume and neurological deficit after 60 min of ischemia and 24 h of reperfusion. The neuroprotective effects of EA occurred in a dose-dependent manner. Then, we explored the mechanisms of neuroprotection by EA. This compound exerted antiapoptotic activity by upregulating the level of Bcl-2 and simultaneously downregulating the levels of cleaved caspase-3 and Bax. Furthermore, EA also possessed anti-inflammatory activity and prevented the excessive phosphorylation of NF-κB (p-P65) and the increase in IL-1ß and IL-6 levels. Finally, our data indicated that EA treatment decreased the level of phosphorylated JNK in vivo, and the JNK activator anisomycin (AN) reversed the neuroprotective effects of EA, indicating that the JNK pathway is involved in the antiapoptotic and anti-inflammatory mechanisms of EA. In summary, our findings suggest that EA provides neuroprotective effects through its antiapoptotic and anti-inflammatory activities by inhibiting the JNK signaling pathway in cerebral I/R injury. Due to its safety and lack of toxicity, EA is a potential candidate for the treatment of ischemic stroke in future clinical trials.