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Background: Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug., Methods: In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models., Results: TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fibrosis in lungs were alleviated by cangrelor treatment. Cangrelor significantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fluid (BALF) (p < 0.001). We also found that cangrelor decreased the inflammatory response in the CLP mouse model and inhibited the expression of inflammatory cytokines, IL-1β (p  < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangrelor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001)., Conclusion: Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the inflammatory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis.

Sepsis is a severe system inflammatory response syndrome in response to infection. The vascular endothelium cells play a key role in sepsis-induced organ dysfunction. The heat shock protein 70 (HSP70) has been reported to play an anti-inflammatory role and protect from sepsis. The present study is aimed at finding the function of HSP70 against sepsis in vascular endothelium cells. Lipopolysaccharide (LPS) and HSP70 agonist and inhibitor were used to treat HUVEC. Cell permeability was measured by transepithelial electrical resistance (TEER) assay and FITC-Dextrans. Cell junction protein levels were measured by western blot. Mice were subjected to cecal ligation and puncture (CLP) to establish a sepsis model and were observed for survival. After LPS incubation, HSP70 expression was decreased in HUVEC. LPS induced the inhibition of cell viability and the increases of IL-1 β , IL-6, and TNF- α . Furthermore, cell permeability was increased and cell junction proteins (E-cadherin, occludin, and ZO-1) were downregulated after treatment with LPS. However, HSP70 could reverse these effects induced by LPS in HUVEC. In addition, LPS-induced elevated phosphorylation of p38 can be blocked by HSP70. On the other hand, we found that inhibition of HSP70 had similar effects as LPS and these effects could be alleviated by the inhibitor of p38. Subsequently, HSP70 was also found to increase survival of sepsis mice in vivo . In conclusion, HSP70 plays a protective role in sepsis by maintenance of the endothelial permeability via regulating p38 signaling., Competing Interests: The authors declare no conflicts of interest in this work., (Copyright © 2020 Xiaoyan Yuan et al.)

Sepsis is a life-threatening condition. Polydatin (PD), a small natural compound from Polygonum cuspidatum, possesses antioxidant and anti-inflammatory properties. However, the protective mechanism of PD on sepsis-induced acute myocardial damage is still unclear. The aim of this study was to investigate the effect and mechanism of action of PD on lipopolysaccharide (LPS)-induced H9c2 cells and in a rat model of sepsis, and explored the role of PD-upregulated sirtuin (SIRT)6. LPS-induced H9c2 cells were used to simulate sepsis. Cecal ligation and puncture (CLP)-induced sepsis in rats were used to verify the protective effect of PD. ELISA, western blotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to study the protective mechanism of PD against septic myocardial injury. PD pretreatment suppressed LPS-induced H9c2 cell apoptosis by promotion of SIRT6-mediated autophagy. Downregulation of SIRT6 or inhibition of autophagy reversed the protective effect of PD on LPS-induced apoptosis. PD pretreatment also suppressed LPS-induced inflammatory factor expression. CLP-induced sepsis in rats showed that PD pretreatment decreased CLP-induced myocardial apoptosis and serum tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 expression. 3-Methyladenine (autophagy inhibitor) pretreatment prevented the protective effect of PD on septic cardiomyopathy. SIRT6 expression was increased with PD treatment, which confirmed that PD attenuates septic cardiomyopathy by promotion of SIRT6-mediated autophagy. All these results indicate that PD has potential therapeutic effects that alleviate septic myocardial injury by promotion of SIRT6-mediated autophagy.

The mechanism underlying sepsis‑induced cardiomyopathy (SICM) remains unclear. The aim of the present study was therefore to illuminate the mechanisms and effects of apelin on SICM, using both patient clinical features and a sepsis rat model. A total of 73 adult patients with or without sepsis were analyzed. Male rats were used to generate the sepsis model through cecal ligation and puncture (CLP). The clinical analysis results demonstrated that sepsis induced cardiac dysfunction, including a decrease of left ventricular end‑diastolic dimension, fractional shortening, ejection fraction, left ventricular end‑systolic dimension, and stroke volume, compared with healthy controls. In addition, the results demonstrated that white blood cell count and inflammatory cytokine expression increased in sepsis patients compared with healthy controls. ELISA analyses revealed that apelin was upregulated following sepsis. The animal model study demonstrated that rats treated with apelin had significantly reduced mortality and suppressed sepsis‑induced myocardial damage and inflammatory responses, through suppression of activation of the Toll‑like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) signaling pathways. Taken together, the present results suggested that apelin had a protective effect against sepsis‑induced cardiac impairment by attenuating TLR4 and NLRP3 signaling‑mediated inflammatory responses.