The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing recently and has become one of the most common clinical liver diseases. Since the pathogenesis of NAFLD has not been completely elucidated, few effective therapeutic drugs are available. As the “second genome” of human body, gut microbiota plays an important role in the digestion, absorption and metabolism of food and drugs. Gut microbiota can act as an important driver to advance the occurrence and development of NAFLD, and to accelerate its progression to cirrhosis and hepatocellular carcinoma. Growing evidence has demonstrated that gut microbiota and its metabolites directly affect intestinal morphology and immune response, resulting in the abnormal activation of inflammation and intestinal endotoxemia; gut dysbiosis also causes dysfunction of gut-liver axis via alteration of bile acid metabolism pathway. Because of its composition diversity and disease-specific expression characteristics, gut microbiota holds strong promise as novel biomarkers and therapeutic targets for NAFLD. Intervening intestinal microbiota, such as antibiotic/probiotic treatment and fecal transplantation, has been a novel strategy for preventing and treating NAFLD. In this article, we have reviewed the emerging functions and association of gut bacterial components in different stages of NAFLD progression and discussed its potential implications in NAFLD diagnosis and therapy.

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1-/- fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate. 

/pdf/pear1-regulates-expansion-of-activated-fibroblasts-and-1n61w1im.pdf

PEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis

Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K-AKT-mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2-AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC.ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT-mTOR pathway. 

/pdf/zdhhc2-mediated-agk-palmitoylation-activates-akt-mtor-1f5ir7kc.pdf

ZDHHC2-mediated AGK palmitoylation activates AKT/mTOR signaling to reduce sunitinib sensitivity in renal cell carcinoma

Human microproteins encoded by long non‐coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493‐encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA‐binding protein PABPC4 and transferred to ribosomes for translation of a 95‐amino‐acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N‐terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK‐mediated AKT phosphorylation. Moreover, the formation of the SMIM26‐AGK‐SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493‐encoded microprotein SMIM26 and establishes its anti‐metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers.

LINC00493‐encoded microprotein SMIM26 exerts anti‐metastatic activity in renal cell carcinoma

Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose global prevalence is rapidly increasing. Acetyl CoA carboxylases 1 (ACACA) is the key enzyme that controls the rate of fatty acid synthesis. Hence, it is crucial to investigate the function of ACACA in regulating lipid metabolism during the progress of NAFLD.Firstly, a fatty liver mouse model was established by high-fat diet at 2nd, 12th, and 20th week, respectively. Then, transcriptome analysis was performed on liver samples to investigate the underlying mechanisms and identify the target gene of the occurrence and development of NAFLD. Afterwards, lipid accumulation cell model was induced by palmitic acid and oleic acid (PA ∶ OA molar ratio = 1∶2). Next, we silenced the target gene ACACA using small interfering RNAs (siRNAs) or the CMS-121 inhibitor. Subsequently, experiments were performed comprehensively the effects of inhibiting ACACA on mitochondrial function and lipid metabolism, as well as on AMPK- PPARα- CPT1A pathway.This data indicated that the pathways significantly affected by high-fat diet include lipid metabolism and mitochondrial function. Then, we focus on the target gene ACACA. In addition, the in vitro results suggested that inhibiting of ACACA in vitro reduces intracellular lipid accumulation, specifically the content of TG and TC. Furthermore, ACACA ameliorated mitochondrial dysfunction and alleviate oxidative stress, including MMP complete, ATP and ROS production, as well as the expression of mitochondria respiratory chain complex (MRC) and AMPK proteins. Meanwhile, ACACA inhibition enhances lipid metabolism through activation of PPARα/CPT1A, leading to a decrease in intracellular lipid accumulation.Targeting ACACA can reduce lipid accumulation by mediating the AMPK- PPARα- CPT1A pathway, which regulates lipid metabolism and alleviates mitochondrial dysfunction. 

ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARα- CPT1A axis

Sepsis is a dysregulated inflammatory consequence of systemic infection. As a result, excessive platelet activation leads to thrombosis and coagulopathy, but we currently lack sufficient understanding of these processes. Here, using the cecal ligation and puncture (CLP) model of sepsis, we observed septic thrombosis and neutrophil extracellular trap formation (NETosis) within the mouse vasculature by intravital microscopy. STING activation in platelets was a critical driver of sepsis-induced pathology. Platelet-specific STING deficiency suppressed platelet activation and granule secretion, which alleviated sepsis-induced intravascular thrombosis and NETosis in mice. Mechanistically, sepsis-derived cGAMP promoted the binding of STING to STXBP2, the assembly of SNARE complex, granule secretion, and subsequent septic thrombosis, which probably depended on the palmitoylation of STING. We generated a peptide, C-ST5, to block STING binding to STXBP2. Septic mice treated with C-ST5 showed reduced thrombosis. Overall, platelet activation via STING reveals a potential strategy for limiting life-threatening sepsis-mediated coagulopathy.

STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion.

Background: Impaired mitochondrial function contributes to non-alcoholic steatohepatitis (NASH). Acylglycerol kinase (AGK) is a subunit of the translocase of the mitochondrial inner membrane 22 (TIM22) protein import complex. AGK mutation is the leading cause of Sengers syndrome, characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, lactic acidosis, and liver dysfunction. The potential roles and mechanisms of AGK in NASH are not yet elucidated. Methods: Hepatic-specific AGK-deficient mice and AGK G126E mutation (AGK kinase activity arrest) mice were on a choline-deficient and high-fat diet (CDAHFD) and a methionine choline-deficient diet (MCD). The mitochondrial function and the molecular mechanisms underlying AGK were investigated in the pathogenesis of NASH. Results: The levels of AGK were significantly downregulated in human NASH liver samples. AGK deficiency led to severe liver damage and lipid accumulation in mice. Aged mice lacking hepatocyte AGK spontaneously developed NASH. AGK G126E mutation did not affect the structure and function of hepatocytes. AGK deficiency, but not AGK G126E mice, aggravated CDAHFD- and MCD-induced NASH symptoms. AGK deficiency-induced liver damage could be attributed to hepatic mitochondrial dysfunction. The mechanism revealed that AGK interacts with mitochondrial respiratory chain complex I subunits, NDUFS2 and NDUFA10, and regulates mitochondrial fatty acid metabolism. Moreover, the AGK DGK domain might directly interact with NDUFS2 and NDUFA10 to maintain the hepatic mitochondrial respiratory chain complex I function. Conclusions: The current study revealed the critical roles of AGK in NASH. AGK interacts with mitochondrial respiratory chain complex I to maintain mitochondrial integrity via the kinase-independent pathway.

AGK regulates the progression to NASH by affecting mitochondria complex I function

/pdf/inhibition-of-ldha-to-induce-eef2-release-enhances-5pig2wmh.pdf

Inhibition of LDHA to Induce EEF2 Release Enhances Thrombocytopoiesis.

Aquaporin 7 (AQP7) gene as a candidate Antifreeze gene was investigated and associated with fresh and frozen semen quality traits in 45 Simmental and Charolais bulls. PCR-SSCP, PCR-RFLP, and sequencing method were employed to detect the single nucleotide polymorphisms (SNPs) of the AQP7 gene. Two mutations, A264G and G371C, were identifi ed. Th e allele frequencies were A (0.97, 0.96) to B (0.03, 0.04) and C (0.97, 0.91) to D (0.03, 0.09) in Sim- mental and Charolais bulls, respectively. A264G substitution was signifi cantly associated with acrosome integrity ratio (P < 0.01) and motility (P < 0.05) in frozen semen. Meanwhile, G371C substitution was signifi cantly associated with acrosome integrity ratio (P < 0.05), percentages of viable sperm (P < 0.05), and motility (P < 0.01) in frozen semen. Th e results prove that AQP7 gene SNPs are useful for marker-assisted selection in early seed selection in the bull industry.

/pdf/association-analysis-of-aquaporin-7-aqp7-gene-variants-with-q243xggfa1.pdf

Association analysis of aquaporin 7 (AQP7) gene variants with semen quality and fertility in bulls

The invention belongs to the technical field of animal genetic engineering, and particularly relates to a growth hormone receptor gene taken as a Chinese grassland red bull excellent slaughter trait molecular marker and an application thereof. The length of a nucleotide sequence of an obtained GHR genetic segment is 489bp and the nucleotide sequence is a part of an exon. A base mutation exists at a 289-position basic group to cause the generation of restrictive fragment length polymorphism. The mutant site is taken as the molecular marker and detected by a PCR-RFLP (polymerase chain reaction-restrictive fragment length polymorphism) method using restriction enzyme BstACI, and detection results are associated with the Chinese grassland red bull slaughter traits so as to provide theoretical basis for selection breeding of Chinese grassland red bull. The invention is characterized in that partial segment of GHR gene associated with the Chinese grassland red bull excellent slaughter traits is obtained, and polymorphism analysis is conducted to the segment for providing the molecular marker for marker assisted selection of the Chinese grassland red bull.

Identification method taking growth hormone receptor gene as Chinese grassland red bull excellent slaughter trait molecular marker and application thereof

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