Recombinant CC16 inhibits NLRP3/caspase-1-induced pyroptosis through p38 MAPK and ERK signaling pathways in the brain of a neonatal rat model with sepsis

Abstract

BackgroundSepsis is a critical disease associated with extremely high mortality. Some severe forms of sepsis can induce brain injury, thus causing behavioral and cognitive dysfunction. Pyroptosis is a type of cell death that differs from apoptosis and plays an important role in the occurrence and development of infectious diseases, nervous system-related diseases. A recent study has found that there is pyroptosis in the hippocampus of sepsis-induced brain injury, but its mechanism and treatment scheme have not been evaluated.MethodsWe established immediately a septic rat model by cecal ligation and perforation (CLP) after administration with recombinant club cell protein (rCC16) and/or U46619 in different groups. The clinical performance, survival percentage, vital signs, and neurobehavioral scores were monitored at different time points. Cortical pathological changes were also examined. The expression of cortical nucleotide-binding domain leucine-rich repeat-containing pyrin domain-containing 3 (NLRP3), caspase-1, (p)-p38 mitogen-activated protein kinase (MAPK), and (p)-extracellular signal-related kinase (ERK) was detected by western blotting and immunofluorescence analysis. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha in the cortical supernatant were detected by enzyme-linked immunosorbent assay.ResultsCompared with the sham group, the clinical performance, survival percentage, vital signs, and severe cortical pathological changes in the CLP group were worse; NLRP3, caspase-1, and inflammatory factor levels were increased; and phosphorylation of p38 MAPK and ERK was also increased. Meanwhile, multiple indicators were deteriorated further after administration of U46619 in CLP rats. The clinical performance of CLP rats, however, was better after rCC16 administration; cortical pathological changes were attenuated; and NLRP3, caspase-1, and inflammatory factor levels and the phosphorylation of signaling pathway proteins (p38 MAPK and ERK) were reduced. Interestingly, the CLP rats showed the opposite changes in all indicators after administration with both rCC16 and U46619 when compared with those administered rCC16 alone.ConclusionsIn sepsis, rCC16 inhibits cortical pyroptosis through p38 MAPK and ERK signaling pathways. Meanwhile, rCC16 has a protective effect on newborn rats with sepsis, but it is not clear whether its mechanism is directly related to pyroptosis.

Renal dysfunction reduces the diagnostic and prognostic value of serum CC16 for acute respiratory distress syndrome in intensive care patients

“…Those studies suggested that exogenous supplementation of recombinant CC16 could ameliorate cigarette smoke-induced lung inflammation in a murine disease model of chronic obstructive pulmonary disease [ 28 ]. Zhou et al suggested that CC16 is an inhibitor of cell pyroptosis and inflammatory factors induced by LPS [ 29 ], demonstrating the potential value of CC16 in therapeutic efforts to repair acute lung injury induced by coronavirus disease 19 (COVID-19). Further investigations of the function of CC16 in critical care patients are needed in the future.…”

Pyroptotic cell death in the R6/2 mouse model of Huntington’s disease: new insight on the inflammasome

“…With this in mind, we have demonstrated that pyroptosis plays a role in the degeneration of striatal neurons in HD, and we infer that counteracting the process and the inflammasome with appropriate compounds could be beneficial in fighting Huntington’s disease 37 .…”

Qingxin Kaiqiao Fang Inhibits Aβ25-35‐Induced Apoptosis in Primary Cultured Rat Hippocampal Neuronal Cells via the p38 MAPK Pathway: An Experimental Validation and Network Pharmacology Study

“…Because p38 MAPK plays a role in the process of apoptosis, the p38 MAPK inhibitor SB203580 has been used to decrease p38 MAPK activation by many researchers [25,26]. In this study, to verify that the inhibition of p38 MAPK activity has an antiapoptotic effect, U46619, an agonist of p38 MAPK, was applied [27,28]. Our results demonstrated that the 25 mg mL −1 QKF + SB203580 group, but not the U46619-treated group, exhibited increased preservation of neuronal morphology, enhanced neuron viability, a decreased number of TUNEL-positive cells, upregulated expression of an antiapoptotic protein, and downregulated expression of proapoptotic proteins.…”

“…Horseradish peroxidase-(HRP-) conjugated IgG secondary antibody was purchased from Beijing Bioss Biotechnology Co., Ltd. (Beijing, China), and the BCA protein assay kit was obtained from Beyotime Biotechnological Technology Co., Ltd. (Shanghai, China). [25][26][27][28][29][30][31][32][33][34][35] . QKF is composed of 10 herbs: Radix Rehmanniae (Sheng Di Huang), Radix Paeoniae Alba (Bai Shao), Radix Ophiopogonis (Mai dong), Cortex Moutan Radicis (Mu dan pi), Poria cocos (Fu Ling), Herba Dendrobii Rhizoma (Shi Hu), Rhizoma Acori Tatarinowii (Shi Chang Pu), Rhizoma Anemarrhenae (Zhi mu), Sophorae Flavescentis (Ku Shen), and Pericarpium Citri Reticulatae (Chenpi), all of which are recorded in the Chinese Pharmacopoeia, as being present in QKF at a ratio of 2 : 2: 2 : 2: 2 : 2: 2 : 1.5 : 1.5 : 1 on a dry-weight basis, respectively.…”