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Necroptosis is a form of regulated necrosis mainly controlled by receptor-interacting protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Necroptosis has important roles in defensing against pathogenic infections, but it is also implicated in various inflammatory diseases including pancreatitis. Baicalin, a flavonoid from Scutellaria baicalensis Georgi, has been shown to possess anti-inflammatory and anti-pyroptosis properties, yet it is unclear whether baicalin can inhibit necroptosis and confer protection against necroptosis-related diseases. Here we reported that baicalin significantly inhibited necroptosis in macrophages induced by lipopolysaccharide plus pan-caspase inhibitor (IDN-6556), or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). Mechanistically, baicalin did not inhibit the phosphorylation of RIPK1, RIPK3 and MLKL, nor membrane translocation of p-MLKL, during necroptotic induction, but instead inhibited p-MLKL oligomerization that is required for executing necroptosis. As intracellular reactive oxygen species (ROS) has been reported to be involved in p-MLKL oligomerization, we assessed the effects of N-acetyl-L-cysteine (NAC), an ROS scavenger, on necroptosis and found that NAC significantly attenuated TSI-induced necroptosis and intracellular ROS production concomitantly with reduced levels of oligomerized p-MLKL, mirroring the effect of baicalin. Indeed, inhibitory effect of baicalin was associated with reduced TSI-induced superoxide (indicating mitochondrial ROS) production and increased mitochondrial membrane potential within cells during necroptosis. Besides, oral administration of baicalin significantly reduced the severity of caerulein-induced acute pancreatitis in mice, an animal model of necroptosis-related disease. Collectively, baicalin can inhibit necroptosis through attenuating p-MLKL oligomerization and confers protection against caerulein-induced pancreatitis in mice.

Background/Aims: Sonodynamic therapy (SDT), based on the synergistic effect of low-intensity ultrasound and sonosensitizer, is a potential approach for non-invasive treatment of cancers. In SDT, mitochondria played a crucial role in cell fate determination. However, mitochondrial activities and their response to SDT remain elusive. The purpose of this study was to examine the response of mitochondria to SDT in tumor cells. Methods: A human breast adenocarcinoma cell line - MCF-7 cells were subjected to 5-aminolevulinic acid (ALA)-SDT, with an average ultrasonic intensity of 0.25W/cm2. Mitochondrial dynamics and redox balance were examined by confocal immunofluorescence microscopy and western blot. The occurrence of mitophagy was determined by confocal immunofluorescence microscopy. Results: Our results showed that ALA-SDT could induce mitochondrial dysfunction through mitochondrial depolarization and fragmentation and lead to mitophagy. The Parkin-dependent signaling pathway was involved and promoted resistance to ALA-SDT induced cell death. Finally, excessive production of ROS was found to be necessary for the initiation of mitophagy. Conclusion: Taken together, we conclude that ROS produced by 5-ALA-SDT could initiate PINK1/Parkin-mediated mitophagy which may exert a protective effect against 5-ALA-SDT-induced cell death in MCF-7 cells.

As a common disorder, acute kidney injury (AKI) is characterized by high mortality and morbidity, and current therapeutic options for AKI remain limited. Irisin, a muscle factor, plays an important role in metabolic disorders. However, the role of irisin in AKI is still unclear. To assess the effect of irisin on the course of AKI, we used an ischemia/reperfusion (I/R) C57BL/6 mouse model. Supplementation with irisin attenuated kidney injury induced by I/R, as shown by decreases in the levels of serum creatinine and blood urea nitrogen. Animal model studies also showed that irisin pretreatment upregulates the expression of uncoupling protein 2 (UCP2) and protects against the renal cell apoptosis and oxidative stress caused by I/R.In vitro, hypoxia/recovery (H/R) treatment was applied to induce tubular cell apoptosis. Irisin pretreatment ameliorated the cell apoptosis induced by H/R, while transfection of UCP2 siRNA significantly reduced the protective effect of irisin in cells after H/R. In addition, AMPK signaling may be involved in irisin-mediated upregulation of UCP2 in a renal proximal tubular epithelial cell (PTEC) model. Thus, the renoprotective effect of irisin on AKI may be mediated through increasing the expression of UCP2 in kidneys after I/R.

Purpose: To investigate the specific molecular mechanisms and effects of curcumin derivative J147 on diabetic peripheral neuropathy (DPN). Methods: We constructed streptozotocin (STZ)-induced DPN rat models to detected mechanical withdrawal threshold (MWT) in vivo using Von Frey filaments. In vitro, we measured cell viability and apoptosis, adenosine 5‘-monophosphate-activated protein kinase (AMPK) and transient receptor potential A1 (TRPA1) expression using MTT, flow cytometry, qRT-PCR and western blot. Then, TRPA1 expression level and calcium reaction level were assessed in agonist AICAR treated RSC96cells. Results: The results showed that J147reduced MWT in vivo, increased the mRNA and protein level of AMPK, reduced TRPA1 expression and calcium reaction level in AITCR treated RSC96 cells, and had no obvious effect on cell viability and apoptosis. Besides, AMPK negative regulated TRPA1 expression in RSC96 cells. Conclusions: J147 could ameliorate DPN via negative regulation AMPK on TRPA1 in vivo and in vitro. A curcumin derivative J147might be a new therapeutic potential for the treatment of DPN.

PTEN-induced putative kinase 1 (PINK1) was identified initially as a gene upregulated in cancer cells which regulates cellular processes of significance in cancer cell biology, including cell survival, stress resistance and the cell cycle. However, the expression and function of PINK1 in non-small cell lung cancer (NSCLC) has not been determined yet. We demonstrated high PINK1 expression in NSCLC tumor tissues and cell lines as assessed by western blot and immunohistochemistry (IHC) assays. In addition, IHC analysis revealed that PINK1 expression was associated with a more invasive tumor phenotype and poor prognosis. Furthermore, in vitro studies using upregulation and knockdown of PINK1 confirmed that PINK1 promoted cell proliferation of NSCLC, which might be through as the NF-κB pathway. Moreover, we also demonstrated that downregulation of PINK1 enhanced cisplatin (CDDP)-induced NSCLC cell apoptosis. Together, our findings indicate that PINK1 plays a significant role in NSCLC progression and chemoresistance, and highlights its potential role as a target in future anticancer therapies.