Acute liver injury (ALI), often caused by viruses, alcohol, drugs, etc., is one of the most common clinical liver diseases. Although pyroptosis plays an important role in ALI, there is still a lack of effective clinical drugs related to this mechanism. Here, we show that phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, can significantly alleviate concanavalin A (ConA)-induced inflammatory liver damage and carbon tetrachloride (CCl 4 )-induced chemical liver damage in a dose-dependent manner. PEITC dose-dependently reversed the ALI-induced increase in plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and reduced the protein levels of hepatocyte pyroptosis markers such as Nod-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and cleaved gasdermin D (GSDMD). In vitro experiments have also verified the inhibitory effect of PEITC on hepatocyte pyroptosis. Furthermore, PEITC inhibits pyroptosis by interacting with cysteine 191 of GSDMD. In summary, our findings establish a role for PEITC in rescuing hepatocyte pyroptosis via direct inhibition of GSDMD, which may provide a new potential therapeutic strategy for ALI.
Genetic studies of Tibetans, an ethnic group with a long-lasting presence on the Tibetan Plateau which is known as the highest plateau in the world, may offer a unique opportunity to understand the biological adaptations of human beings to high-altitude environments. We conducted a genome-wide study of 1,000,000 genetic variants in 46 Tibetans (TBN) and 92 Han Chinese (HAN) for identifying the signals of high-altitude adaptations (HAAs) in Tibetan genomes. We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most differentiated in the two regions, respectively. Strong positive correlations were also observed between the frequency of TBN-dominant haplotypes in the two gene regions and altitude in East Asian populations. Linkage disequilibrium and further haplotype network analyses of world-wide populations suggested the antiquity of the TBN-dominant haplotypes and long-term persistence of the natural selection. Finally, a "dominant haplotype carrier" hypothesis could describe the role of the two genes in HAA. All of our population genomic and statistical analyses indicate that EPAS1 and EGLN1 are most likely responsible for HAA of Tibetans. Interestingly, one each but not both of the two genes were also identified by three recent studies. We reanalyzed the available data and found the escaped top signal (EPAS1) could be recaptured with data quality control and our approaches. Based on this experience, we call for more attention to be paid to controlling data quality and batch effects introduced in public data integration. Our results also suggest limitations of extended haplotype homozygosity-based method due to its compromised power in case the natural selection initiated long time ago and particularly in genomic regions with recombination hotspots.
// Wen Liu 1, * , Wenjie Guo 1, * , Nan Hang 1 , Yuanyuan Yang 1 Xuefeng Wu 1 , Yan Shen 1 , Jingsong Cao 2 , Yang Sun 1 , Qiang Xu 1 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China 2 Eternity Bioscience Inc, Cranbury, NJ 08512, USA * Co-first authors, These authors contributed equally to this work Correspondence to: Qiang Xu, e-mail: molpharm@163.com Yang Sun, e-mail: yangsun@nju.edu.cn Keywords: colitis, MALT1, IL-1β, NF-κB, NLRP3 inflammasome Received: January 15, 2016 Accepted: March 31, 2016 Published: April 20, 2016 ABSTRACT Mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), a paracaspase and essential regulator for nuclear factor kB (NF-κB) activation, plays an important role in innate and adaptive immunity. Suppression of MALT1 protease activity with small molecule inhibitors showed promising efficacies in subtypes of B cell lymphoma and improvement in experimental autoimmune encephalomyelitis model. However, whether MALT1 inhibitors could ameliorate colitis remains unclear. In the present study, we examined the pharmacological effect of two specific MALT1 inhibitors MI-2 and mepazine on the dextran sulfate sodium (DSS)-induced experimental colitis in mice, followed by mechanistic analysis on NF-κB and NLRP3 inflammasome activation. Treatment with MI-2 and mepazine dose-dependently attenuated symptoms of colitis in mice, evidenced by reduction in the elevated disease activity index, the shortening of colon length as well as the histopathologic improvement. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF, IL-1β, IL-6, IL-18, IL-17A and IFN-γ, were markedly suppressed by MALT1 inhibitors. The underlying mechanisms for the protective effect of MALT1 inhibitors in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in macrophages. The in vitro study showed that MALT1 inhibitors decreased production of IL-1β/IL-18 in phorbol myristate acetate-differentiated THP-1 cells and bone marrow derived macrophage via suppressing the activation of NF-κB and NLRP3 inflammasome. Taken together, our results demonstrated that inhibition of the protease activity of MALT1 might be a viable strategy to treat inflammatory bowel disease and the NLRP3 inflammasome and NF-κB activation are critical components in MALT1 signaling cascades in this disease model.
Abstract Background Bexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of Bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer. Methods We utilized both TCGA data and a cohort of Chinese patients. In a meticulous analysis of 478 colon cancer cases, SEZ6L2 expression levels were examined in relation to clinical characteristics, staging parameters, and treatment outcomes. Additionally, we investigated the pharmacological impact of Bexarotene on SEZ6L2, demonstrating a significant downregulation of SEZ6L2 at both mRNA and protein levels in colon cancer patients following Bexarotene treatment. Results SEZ6L2 consistently overexpresses in colon cancer, serving as a potential universal biomarker with prognostic significance, validated in a diverse Chinese cohort. In vitro, SEZ6L2 promotes cell viability without affecting migration. Bexarotene treatment inhibits SEZ6L2 expression, correlating with reduced viability both in vitro and in vivo. SEZ6L2 overexpression accelerates declining survival rates in an in vivo context. Bexarotene’s efficacy is context-dependent, effective in parental cells but not with SEZ6L2 overexpression. Computational predictions suggest a direct SEZ6L2-Bexarotene interaction, warranting further experimental exploration. Conclusion The study provides valuable insights into SEZ6L2 as a prognostic biomarker in colon cancer, revealing its intricate relationship with clinical parameters, treatment outcomes, and Bexarotene effects. Context-dependent therapeutic responses emphasize the nuanced understanding required for SEZ6L2’s role in colon cancer, paving the way for targeted therapeutic strategies.
Abstract New immunosuppressants are needed to assist therapeutic efforts to manage immunological diseases. Along with known compounds 1 – 4 , new diterpenes myrocin E ( 5 ), libertellenone J ( 6 ) and libertellenone K ( 7 ) were isolated from the culture of Phomopsis sp. S12, from the apparently normal seed of Illigera rhodantha (Hernandiaceae). The structures were elucidated by a combination of spectroscopic and computational approaches, in conjunction with the low‐temperature (100 K) single‐crystal X‐ray diffraction with copper K α radiation. Libertellenone J ( 6 ) was shown to reduce significantly the production of NO, IL‐1β, IL‐6 and TNF‐α with an IC 50 range of 2.2–10.2 μ M , and to decrease the levels of iNOS, IL‐1β, IL‐6 and TNF‐α mRNA expression in lipopolysaccharide‐activated macrophages with IC 50 values of 3.5–15.2 μ M . These significant results may inspire the development of new immunosuppressive agents.
We describe an integrated java-based program that provides elaborate graphic and plain-text output of pairwise linkage disequilibrium (LD) analysis of single nucleotide polymorphisms genotypic data. It is most suitable for molecular geneticists, who are focusing on LD measures estimation, statistical significance test and extent prediction.The software is available at: http://www.chgb.org.cn/lda/lda.htm.Detailed tutorials, LDA help system and examples are distributed within LDA software. For Macintosh OS X user, the Jre version 1.4 can be downloaded from http://connect.apple.com.
Exosomes, a group of vesicles originating from the multivesicular bodies (MVBs), are released into the extracellular space when MVBs fuse with the plasma membrane. Numerous studies indicate that exosomes play important roles in cell‐to‐cell communication, and exosomes from specific cell types and conditions display multiple functions such as exerting positive effects on regeneration in many tissues. It is widely accepted that the therapeutic potential of stem cells may be mediated largely by the paracrine factors, so harnessing the paracrine effects of stem and progenitor cells without affecting these living, replicating, and potentially pluripotent cell populations is an advantage in terms of safety and complexity. Ascending evidence indicated that exosomes might be the main components of paracrine factors; thus, understanding the role of exosomes in each subtype of stem cells is far‐reaching. In this review, we discuss the functions of exosomes from different types of stem cells and emphasize the therapeutic potentials of exosomes, providing an alternative way of developing strategies to cure diseases.
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