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

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

Temperature Regulation Model and Experimental Study of Compressed Air Energy Storage Cavern Heat Exchange System

The first hard rock shallow-lined underground CAES cavern in China has been excavated to conduct a thermodynamic process and heat exchange system for practice. The thermodynamic equations for the solid and air region are compiled into the fluent two-dimensional axisymmetric model through user-defined functions. The temperature regulation model and experimental study results show that the charging time determines the air temperature and fluctuates dramatically under different charging flow rates. The average air temperature increases with increasing charging flow and decreasing charging time, fluctuating between 62.5 °C and −40.4 °C during the charging and discharging processes. The temperature would reach above 40 °C within the first 40 min of the initial pressurization stage, and the humidity decreases rapidly within a short time. The use of the heat exchange system can effectively control the cavern temperature within a small range (20–40 °C). The temperature rises and regularly falls with the control system’s switch. An inverse relationship between the temperature and humidity and water vapor can be seen in the first hour of the initial discharging. The maximum noise is 92 and 87 decibels in the deflation process

Preoperative short-course radiotherapy followed by consolidation chemotherapy for treatment with locally advanced rectal cancer : a meta-analysis

Background The addition of consolidation chemotherapy to preoperative short-course radiotherapy during the prolonged interval between the completion of radiation and surgery in locally advanced rectal cancer (LARC) could enhance pathologic response and might act on potential micrometastasis. We performed this meta-analysis to evaluate whether short-course radiotherapy followed by consolidation chemotherapy (SCRT/CCT) could be a neoadjuvant treatment option compared with conventional long-course chemoradiotherapy (LCCRT). Methods We searched the PubMed, EMBASE, MEDLINE, and Cochrane Library databases. The primary endpoints were pathological outcomes, and the secondary endpoints included survival rate, sphincter preservation rate, R0 resection rate and toxicity. RevMan 5.3 was used to calculate pooled risk ratio (RRs) and 95% confidence intervals (CIs). Results A total of seven eligible studies and 1865 participants were included in this meta-analysis. Compared with the LCCRT, SCRT/CCT increased pathologic complete response (pCR) rate [RR = 1.74, 95% CI (1.41, 2.15), P < 0.01] and led to a lower proportion of patients with adjuvant pathologic tumor stage 3-4 (ypT3-4) disease [RR = 0.88, 95% CI (0.80, 0.97), P = 0.01] or lymph node positive (ypN +) disease [RR = 0.83, 95% CI (0.71, 0.98), P = 0.02]. In addition, the disease-free survival (DFS) was better in SCRT/CCT group [RR = 1.10, 95% CI (1.02, 1.18), P = 0.01], while overall survival rate and toxicity and surgical procedures were similar between two groups. Conclusion Based on better pathological outcomes and DFS in SCRT/CCT group, we recommended preoperative short-course radiotherapy followed by consolidation chemotherapy as the optional neoadjuvant treatment for LARC

Polymorphisms of Glucose-Regulated Protein 78 and Risk of Colorectal Cancer : A Case-Control Study in Southwest China

Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C&gt;T) and rs430397 (G&gt;A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction–restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.06–1.83 for CT genotype and OR = 2.10, 95% CI = 1.06–4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P = 0.030), but not with status of lymph nodes metastasis (P = 0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR = 1.63, 95% CI = 1.23–2.15 for GA genotype and OR = 2.92, 95% CI = 1.23–6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC.Funding Agencies|Outstanding Doctoral Dissertation Foundation of Ministry of Education of China|2007B66|</p