Transient receptor potential channel 1 deficiency impairs host defense and proinflammatory responses to bacterial infection by regulating protein kinase Cα signaling

Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1-/- mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca2+ entry and triggered protein kinase Cα (PKC-α) activity to facilitate nuclear translocation of NF-kB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCγ signaling circuit.Fil: Zhou, Xikun. University Of North Dakota; Estados Unidos. West China Hospital Of Sichuan University; ChinaFil: Ye, Yan. University Of North Dakota; Estados UnidosFil: Sun, Yuyang. University Of North Dakota; Estados UnidosFil: Li, Xuefeng. West China Hospital Of Sichuan University; China. University Of North Dakota; Estados UnidosFil: Wang, Wenxue. University Of North Dakota; Estados UnidosFil: Privratsky, Breanna. University Of North Dakota; Estados UnidosFil: Tan, Shirui. University Of North Dakota; Estados UnidosFil: Zhou, Zongguang. West China Hospital Of Sichuan University; ChinaFil: Huang, Canhua. West China Hospital Of Sichuan University; ChinaFil: Wei, Yu-Quan. West China Hospital Of Sichuan University; ChinaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute Of Environmental Health Sciences; Estados UnidosFil: Singh, Brij B.. University Of North Dakota; Estados UnidosFil: Wu, Min. University Of North Dakota; Estados Unido

Vitamin E Inhibits Osteoclastogenesis in Protecting Osteoporosis

The most common orthopedic condition affecting senior adults is osteoporosis, which is defined by a decrease in bone mass and strength as well as microstructural degradation that leads to fragility fractures. Bone remodeling is a well-planned, ongoing process that replaces deteriorated, old bone with new, healthy bone. Bone resorption and bone creation work together during the cycle of bone remodeling to preserve the bone’s volume and microarchitecture. The only bone-resorbing cells in the human body, mononuclear preosteoclasts fuse to form osteoclasts, are multinucleated cells. In numerous animal models or epidemiological studies, vitamin E’s anti-osteoporotic characteristics have been extensively described. This review aims to summarize recent developments in vitamin E’s molecular features as a bone-protective agent. In RANKL/RANK/OPG signaling pathway, vitamin E inhibits synthesis of RANKL, stimulation of c-Fos, and increase level of OPG. Vitamin E also inhibits inflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-27, and MCP-1, negative regulating the JAK–STAT, NF-κB, MAPK signaling pathways. Additionally, vitamin E decreases malondialdehyde and increases superoxide dismutase, GPx and heme oxygenase-1, in suppressing osteoclasts. In this article, we aim to give readers the most recent information on the molecular pathways that vitamin E uses to enhance bone health

Preoperative Risk Factors for Short-Term Postoperative Mortality of Acute Mesenteric Ischemia after Laparotomy: A Systematic Review and Meta-Analysis

Objective. Our objective was to comprehensively present the evidence of preoperative risk factors for short-term postoperative mortality of acute mesenteric ischemia after laparotomy. Methods. PubMed, Embase, and Google Scholar were searched from January 2000 to January 2020. Studies evaluating the postoperative risk factors for short-term postoperative mortality of acute mesenteric ischemia after laparotomy were included. The outcome extracted were patients’ demographics, medical history, and preoperative laboratory tests. Results. Twenty studies (5011 patients) met the inclusion criteria. Studies were of high quality, with a median Newcastle-Ottawa Scale Score of 7. Summary short-term postoperative mortality was 44.38% (range, 18.80%–67.80%). Across included studies, 49 potential risk factors were examined, at least two studies. Meta-analysis of predictors based on more than three studies identified the following preoperative risk factors for higher short-term postoperative mortality risk: old age (odds ratio [OR], 1.90, 95% confidence interval [CI], 1.57–2.30), arterial occlusive mesenteric ischemia versus mesenteric venous thrombosis (OR, 2.45, 95% CI 1.12–5.33), heart failure (OR 1.33, 95% CI 1.03–1.72), renal disorders (OR 1.61, 95% CI 1.24–2.07), and peripheral vascular disease (OR 1.38, 95% CI 1.00–1.91). Nonsurvivors were older (standardized mean difference [SMD], 0.32, 95% CI 0.24–0.40), had higher creatinine levels (SMD 0.50, 95% CI 0.25–0.75), and had lower platelet counts (SMD −0.32, 95% CI −0.50 to −0.14). Conclusion. The short-term postoperative mortality of acute mesenteric ischemia who underwent laparotomy is still high. A better understanding of these risk factors may help in the early identification of high-risk patients, optimization of surgical procedure, and improvement of perioperative management

From Intestinal Epithelial Homeostasis to Colorectal Cancer: Autophagy Regulation in Cellular Stress

The intestinal epithelium is continuously exposed to abundant stress stimuli, which relies on an evolutionarily conserved process, autophagy, to maintain its homeostasis by degrading and recycling unwanted and damaged intracellular substances. Otherwise, disruption of this balance will result in the development of a wide range of disorders, including colorectal cancer (CRC). Dysregulated autophagy is implicated in the regulation of cellular responses to stress during the development, progression, and treatment of CRC. However, experimental investigations addressing the impact of autophagy in different phases of CRC have generated conflicting results, showing that autophagy is context-dependently related to CRC. Thus, both inhibition and activation of autophagy have been proposed as therapeutic strategies against CRC. Here, we will discuss the multifaceted role of autophagy in intestinal homeostasis and CRC, which may provide insights for future research directions