Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.

Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases.

ABSTRACT: Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.

Roles and Molecular Mechanisms of Physical Exercise in Sepsis Treatment.

Physical exercise is a planned, purposeful action to keep a healthy lifestyle and improve physical fitness. Physical exercise has been widely used as a non-pharmacological approach to preventing and improving a wide range of diseases, including cardiovascular disease, cancer, metabolic disease, and neurodegenerative disease. However, the effects of physical exercise on sepsis have not been summarized until now. In this review, we discuss the effects of physical exercise on multiple organ functions and the short- and long-time outcomes of sepsis. Furthermore, the molecular mechanisms underlying the protective effects of physical exercise on sepsis are discussed. In conclusion, we consider that physical exercise may be a beneficial and non-pharmacological alternative for the treatment of sepsis.

The Herbal Medicine Scutellaria-Coptis Alleviates Intestinal Mucosal Barrier Damage in Diabetic Rats by Inhibiting Inflammation and Modulating the Gut Microbiota.

Recent studies have confirmed that increased intestinal permeability and gut-origin lipopolysaccharide (LPS) translocation are important causes of metabolic inflammation in type 2 diabetes (T2D), but there are no recognized therapies for targeting this pathological state. Scutellaria baicalensis and Coptis chinensis are a classic herbal pair often used to treat diabetes and various intestinal diseases, and repair of intestinal barrier damage may be at the core of their therapeutic mechanism. This study investigated the effects of oral administration of Scutellaria-Coptis (SC) on the intestinal mucosal barrier in diabetic rats and explored the underlying mechanism from the perspective of anti-inflammatory and gut microbiota-modulatory effects. The main results showed that, in addition to regulating glycolipid metabolism disorders and inhibiting serum inflammatory factors, SC could also upregulate the expression levels of the tight junction proteins claudin-1, occludin, and zonula occludens (ZO-1), significantly improve intestinal epithelial damage, and inhibit excessive LPS translocation into the blood circulation. Furthermore, it was found that SC could reduce the levels of the inflammatory factors interleukin-1ß (IL-1ß), IL-6, and tumour necrosis factor-α (TNF-α) in intestinal tissue and that the anti-inflammatory effects involved the TLR-4/TRIF and TNFR-1/NF-κB signalling pathways. Moreover, SC had a strong inhibitory effect on some potential enteropathogenic bacteria and LPS-producing bacteria, such as Proteobacteria, Enterobacteriaceae, Enterobacter, Escherichia-Shigella, and Enterococcus, and could also promote the proliferation of butyrate-producing bacteria, such as Lachnospiraceae and Prevotellaceae. Taken together, the hypoglycaemic effects of SC were related to the protection of the intestinal mucosal barrier, and the mechanisms might be related to the inhibition of intestinal inflammation and the regulation of the gut microbiota.

Gut Microbiota, a Potential New Target for Chinese Herbal Medicines in Treating Diabetes Mellitus.

The gut microbiota, as an important factor affecting host health, plays a significant role in the occurrence and development of diabetes mellitus (DM), and the mechanism may be related to excessive endotoxins, altered short-chain fatty acids (SCFAs), and disordered bile acid metabolism. Traditional Chinese medicine (TCM) has a long history of treating DM, but its mechanism is not very clear. Recent research has suggested that Chinese herbal medicine can improve glucose metabolism by remodeling the gut microbiota, which opens new avenues for further research on hypoglycemic mechanisms. This review presents the recent progress of Chinese herbs, herbal extracts, and herbal compound preparations in treating DM through regulating the gut microbiota and summarizes the main mechanisms involved, namely, anti-inflammatory and antioxidative effects, protecting the intestinal barrier and inhibiting lipotoxicity. In addition, some suggestions for improvement are also proposed.