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Aims: Sepsis-induced acute kidney injury (SI-AKI) is the fifth most common cause of hospital-acquired acute kidney injury. Pannexin1 (Panx1) triggers inflammation and apoptosis which act as crucial factors in the pathogenesis of SI-AKI. We aimed to investigate the expression of Panx1 and its role on the inflammation and apoptosis in SI-AKI., Materials and Methods: SI-AKI model was established by lipopolysaccharide (LPS) injection in mice and LPS-treated HK-2 cells in vitro. Panx1 was inhibited by pretreating with carbenoxolone (CBX) or small interfering RNA in vivo and vitro, respectively. The expression of Panx1 was determined by qPCR, western blot and immunohistochemistry (IHC). Kidney damage was evaluated by kidney function, histopathological examination and AKI biomarkers. Inflammatory cytokines were detected by qPCR and ELISA. Apoptosis was detected by TUNEL staining and the expression of apoptosis-related proteins. The activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome was measured by western blot., Key Findings: Panx1 increased in LPS-induced SI-AKI mice and HK-2 cells, as well as in SI-AKI patients. CBX alleviated the renal function and pathological damage, as well as decreased the mRNA of kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Inhibiting Panx1 decreased the production of IL-1β, IL-6 and TNF-α, as well as tubular cell apoptosis in SI-AKI. Inhibiting Panx1 suppressed inflammatory cytokines and apoptosis via inhibiting NLRP3 inflammasome activation and regulating apoptotic protein Bax and Bcl2 expression, respectively., Significance: These observations suggest that pharmacological inhibition of Panx1 might be a potential approach in the clinical therapy of SI-AKI., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Skeletal muscles of patients with Duchenne muscular dystrophy (DMD) show numerous alterations including inflammation, apoptosis, and necrosis of myofibers. However, the molecular mechanism that explains these changes remains largely unknown. Here, the involvement of hemichannels formed by connexins (Cx HCs) was evaluated in skeletal muscle of mdx mouse model of DMD. Fast myofibers of mdx mice were found to express three connexins (39, 43 and 45) and high sarcolemma permeability, which was absent in myofibers of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice (deficient in skeletal muscle Cx43/Cx45 expression). These myofibers did not show elevated basal intracellular free Ca(2+) levels, immunoreactivity to phosphorylated p65 (active NF-κB), eNOS and annexin V/active Caspase 3 (marker of apoptosis) but presented dystrophin immunoreactivity. Moreover, muscles of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice exhibited partial decrease of necrotic features (big cells and high creatine kinase levels). Accordingly, these muscles showed similar macrophage infiltration as control mdx muscles. Nonetheless, the hanging test performance of mdx Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice was significantly better than that of control mdx Cx43(fl/fl)Cx45(fl/fl) mice. All three Cxs found in skeletal muscles of mdx mice were also detected in fast myofibers of biopsy specimens from patients with muscular dystrophy. Thus, reduction of Cx expression and/or function of Cx HCs may be potential therapeutic approaches to abrogate myofiber apoptosis in DMD.

Apoptotic cell death is a critical step in organism development and tissue homeostasis. Apoptotic cells affect immune cell activities in normal tissues. It is not clear whether similar cell death machinery causes tumor environments to evade anti-tumor immune responses. Here, using a mouse transplant model, we found a large number of tumor cells undergoing intrinsic apoptosis in tumors derived from the 4T1 breast cancer cell line, where neutrophils significantly accumulated. Interestingly, these apoptotic 4T1 tumor cells directly induced neutrophil extracellular traps (NETs) in a pannexin 1 (Panx1) channel-dependent manner, and knockdown of Panx1 in 4T1 cells led to a reduction in tumor size. Spermidine released through Panx1 from apoptotic 4T1 cells induced NETs in bone marrow-derived neutrophils in vitro. In addition, inhibition of spermidine synthesis suppressed tumor growth in the mouse transplant model. Collectively, our data suggested a new immune-escape mechanism for tumors by Panx1-mediated secretome from intrinsic apoptotic cells, which may provide a new therapeutic target for cancer. • 4T1 breast tumor cells undergo a high frequency of intrinsic apoptosis. • Secretome from apoptotic 4T1 cells induce neutrophils extracellular traps. • Pannexin1 is indispensable to architect the unique tumor immune microenvironments. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP) is the most commonly used drug in testicular cancer. However, drug resistance severely limits its clinical use and the underlying mechanisms need to be further clarified. The aim of present study was to investigate the role of ATP/IP 3 pathway mediated by pannexin1 (Panx-1) channels on DDP-induced apoptosis and to reveal the potential mechanisms of DDP-resistance in testicular cancer. We found that the expression of Panx-1 in I-10/DDP cells (DDP-resistance) was decreased compared with parental I-10 cells determined by western blotting and immunofluorescence assay. To further clarify the role of Panx-1 in DDP resistance, Panx-1 function was modulated by overexpression and knockdown of Panx-1 expression. Panx-1 overexpression increased DDP-induced apoptosis, ATP release and IP 3 levels. On the contrary, Panx-1 silencing decreased DDP-induced apoptosis, ATP release and IP 3 levels. Apyrase (hydrolyzing extracellular ATP) or xestospongin C (antagonizing IP 3 receptor) also decreased DDP-induced apoptosis. Our findings demonstrate that Panx-1 is involved in DDP-resistance and ATP/IP 3 pathway mediated by Panx-1 channels participates in DDP-induced apoptosis in testicular cancer. Panx-1 modulation may be interesting to amplify the clinical effect of DDP and reverse the resistance of testicular cancer cells to DDP. [ABSTRACT FROM AUTHOR]