Wenjing Xie’s research while affiliated with Hangzhou First People's Hospital and other places

Sepsis-induced cardiomyopathy (SIC) is one of the most common complications of infection-induced sepsis. An imbalance in inflammatory mediators is the main factor leading to SIC. N6-methyladenosine (m6A) is closely related to the occurrence and development of sepsis. m6A reader YTH Domain Containing 1 (YTHDC1) is an m6A N6-methyladenosine recognition protein. However, the role of YTHDC1 in SIC remains unclear. Herein, we demonstrated that YTHDC1-shRNA inhibits inflammation, reduces inflammatory mediators, and improves cardiac function in a lipopolysaccharide (LPS)-induced SIC mouse model. Based on the Gene Expression Omnibus (GEO) database analysis, serine protease inhibitor A3N (SERPINA3N) is a differential gene of SIC. Further, RNA immunoprecipitation (RIP) indicated that SERPINA3N mRNA can bind to YTHDC1, which regulates the expression of SERPINA3N. SERPINA3N-siRNA reduced LPS-induced inflammation of cardiac myocytes. In conclusion, the m6A reader YTHDC1 regulates SERPINA3N mRNA expression to mediate the levels of inflammation in SIC. Such findings add to the relationship between m6A reader YTHDC1 and SIC, providing a new research avenue for the therapeutic mechanism of SIC.

The treatment options for sepsis-associated encephalopathy caused by systemic inflammation are still not sufficient. Protein kinase C interaction protein 1 (PICK1) has attracted much attention because of its important physiological functions in many tissues. However, its role in sepsis-associated encephalopathy remains elusive. Our study results revealed that the expression levels of PICK1 protein in mice with lipopolysaccharide-induced sepsis-associated encephalopathy were not significantly changed, but PICK1 deficiency led to excessive activation of microglia and Toll-like receptor (TLR)4 pathways, which aggravated the sepsis- associated encephalopathy. We also observed that PICK1 and TLR4 form a complex in microglial cells, thereby providing brain protection. These findings contribute to our understanding of the important role of PICK1 in sepsis and may provide novel therapeutic targets to treat sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis caused by neuroinflammation. Electroacupuncture (EA) can be used to treat SAE, but the underlying mechanism is not clear. Lack of PICK1 further aggravates the inflammatory response in mice with sepsis. Therefore, we sought to investigate whether PICK1 is involved in the protective effects of electroacupuncture to SAE. In this study, mice were treated with EA after lipopolysaccharide (LPS) treatment. Behavioral tests; microglial activity of hippocampus; neuron survival and the inflammatory factors PICK1 and TLR4, as well as TLR4-related proteins, such as ERK, JNK, and P38, were assessed after EA treatment. PICK1, TLR4, and TLR4-related proteins, as well as PICK1-TLR4 complex levels were assessed in BV2 cells treated with LPS, PICK1 siRNA, or PICK1 polypeptide. The results indicated that EA could improve neurological assessment and reduce activation of microglial and TLR4 and expression of proinflammatory cytokines. EA also reduced the expression of TLR4 and phosphorylation of ERK/JNK/P38 while, increased the expression of PICK1 and TLR4 complexes. PICK1 knockdown further promoted the expression of TLR4 and phosphorylation of ERK/JNK/P38 in BV2 cells, but this effect was reversed by PICK1 polypeptides. These results suggest that EA may reduce neuroinflammation responses, decrease inflammatory factors, and finally, protect SAE by increasing the formation of PICK1-TLR4 complexes in microglia.