Abstract. Stroke, characterized by a disruption of blood supply to the brain, is a major cause of morbidity and mortality worldwide. Although humanin, a 24-amino acid polypeptide, has been identified to have multiple neuroprotective functions, the level of humanin in plasma has been demonstrated to decrease with age, which likely limits the effects against stroke injury. A potent humanin analogue, S14G-humanin (HNG), generated by replacement of Ser14 with glycine, has been demonstrated to have 1,000-fold stronger biological activity than humanin. The present study established an in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model using SH-SY5Y neuroblastoma cells to mimic the in vivo ischemia/reperfusion injury in stroke. Adding HNG (0-10 µg/l) to SH-SY5Y cells to different extents blocked OGD/R-induced reduction of cell viability and antioxidative capacity, as well as decreased the elevated apoptosis rate induced by OGD/R, with the most evident effects at 1 µg/l HNG. Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) signaling was attenuated in OGD/R processes, yet reactivated with HNG treatment. FLLL32 (5 µM), a specific inhibitor of the signal, abolished effects of HNG on anti-apoptosis and antioxidation in OGD/R processes. Co-treatment with HNG and FLLL32 failed to interrupt upregulation of cytochrome c, B-cell lymphoma 2-associated X protein and cleaved caspase-3 provoked by OGD/R. Similar to FLLL32, Jak2/Stat3 signaling activated by HNG was also repressed by inhibitor of phosphoinositide 3-kinase (PI3K; 10 µM LY294002) or protein kinase B (AKT; 5 µM MK-2206 2HCl). These data collectively indicated that HNG has neuroprotective effects against OGD/R by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway, suggesting that HNG may be a promising agent in the management of stroke.

HNG might exert neuroprotective effects through alleviating apoptosis and activating of SOCS3 - STAT3 - MCL-1 signal transduction pathway. Highlights (1) Cerebral ischemia led to neuronal loss in hippocampal CA1 region of rats. (2) HNG had neuroprotective effects on ischemia/reperfusion rats. (3) The protective effect of HNG might be related to the SOCS3 - STAT3 - MCL-1 pathway.

Secukinumab is a specific neutralizing antibody for IL-17A. At present, numerous studies have confirmed the important role of IL-17A in sepsis, but the role of secukinumab in sepsis has not been studied. The present study explored the protective effect and underlying mechanism of secukinumab in severe sepsis model rats. We established a severe sepsis rat model using cecal ligation and puncture (CLP). The optimal dose of secukinumab was determined by observing the 7-day survival rate of severe sepsis model rats. The expression levels of TNF-α, IL-6, and IL-17A in plasma and lung tissue were determined by enzyme-linked immunosorbent assay. The degree of pathological damage to lung tissue was evaluated by hematoxylin–eosin (H–E) staining and pathological damage scale. The expressions of IKBα/NFκB pathway proteins and downstream-related inflammatory factors were detected by western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). Our results show that high-dose secukinumab can inhibit the activation of the IKBα/NFκB inflammatory pathway by neutralizing IL-17A and reducing the gene expression of pathway-related inflammatory cytokines, thereby reducing the levels of inflammatory cytokines in lung tissue and plasma, thereby reducing the damage of lung tissue in severe sepsis model rats and improving the systemic inflammatory response.