Browsing by Author "Zhang, Ting"

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    Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease
    (MDPI, 2020-03) Jiang, Yanchao; Zhang, Ting; Kusumanchi, Praveen; Han, Sen; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of Medicine
    Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury.
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    Caspase-8 and FADD prevent spontaneous ZBP1 expression and necroptosis
    (National Academy of Sciences, 2022) Rodriguez, Diego A.; Quarato, Giovanni; Liedmann, Swantje; Tummers, Bart; Zhang, Ting; Guy, Cliff; Crawford, Jeremy Chase; Palacios, Gustavo; Pelletier, Stephane; Kalkavan, Halime; Shaw, Jeremy J. P.; Fitzgerald, Patrick; Chen, Mark J.; Balachandran, Siddharth; Green, Douglas R.; Medical and Molecular Genetics, School of Medicine
    Caspase-8 and Fas-associated death domain (FADD) play key roles in the regulation of cell death by necroptosis. The absence of either protein results in early embryonic lethality due to the activation of the kinase receptor interacting protein kinase-3 (RIPK3) and its phosphorylation of the necroptosis executioner, mixed-lineage kinase-like (MLKL). We genetically engineered and characterized a mouse model to monitor MLKL phosphorylation in the absence of necroptosis in vivo. Ablation of caspase-8 or FADD resulted in the transcriptional upregulation in several tissues of Z-DNA binding protein-1 (ZBP1), a cytosolic nucleic acid sensor capable of activating RIPK3, and ZBP1 was required for spontaneous phosphorylation of MLKL. Our findings provide a mechanism by which the FADD/Caspase-8 complex prevents necroptosis.
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    Critical Role of microRNA-21 in the Pathogenesis of Liver Diseases
    (Frontiers Media, 2020-01-31) Zhang, Ting; Yang, Zhihong; Kusumanchi, Praveen; Han, Sen; Liangpunsakul, Suthat; Medicine, School of Medicine
    MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings.
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    Domain Adaptation Tracker With Global and Local Searching
    (IEEE, 2018) Zhao, Fei; Zhang, Ting; Wu, Yi; Wang, Jinqiao; Tang, Ming; Medicine, School of Medicine
    For the convolutional neural network (CNN)-based trackers, most of them locate the target only within a local area, which makes the trackers hard to recapture the target after drifting into the background. Besides, most state-of-the-art trackers spend a large amount of time on training the CNN-based classification networks online to adapt to the current domain. In this paper, to address the two problems, we propose a robust domain adaptation tracker based on the CNNs. The proposed tracker contains three CNNs: a local location network (LL-Net), a global location network (GL-Net), and a domain adaptation classification network (DA-Net). For the former problem, if we come to the conclusion that the tracker drifts into the background based on the output of the LL-Net, we will search for the target in a global area of the current frame based on the GL-Net. For the latter problem, we propose a CNN-based DA-Net with a domain adaptation (DA) layer. By pre-training the DA-Net offline, the DA-Net can adapt to the current domain by only updating the parameters of the DA layer in one training iteration when the online training is triggered, which makes the tracker run five times faster than MDNet with comparable tracking performance. The experimental results show that our tracker performs favorably against the state-of-the-art trackers on three popular benchmarks.
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    Epidemiology of Alcohol-associated Liver Disease
    (Elsevier, 2021) Han, Sen; Yang, Zhihong; Zhang, Ting; Ma, Jing; Chandler, Kristina; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) is a consequence of excessive alcohol use. It comprises a spectrum of histopathologic changes ranging from simple steatosis, steatohepatitis, and cirrhosis to hepatocellular carcinoma. The public health impact of ALD is growing because of an increase in the prevalence and incidence of ALD in parallel with liver transplant and mortalities. There are multiple factors involved in the pathogenesis and progression of ALD. Reducing alcohol consumption is the cornerstone of ALD management. The efforts to reduce excessive alcohol use at the individual and population levels are urgently needed to prevent adverse outcomes from ALD.
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    Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy
    (China Anti-Cancer Association, 2021-03-25) Zhang, Ting; Yang, Xinrui; Xu, Wanping; Wang, Jing; Wu, Dawei; Hong, Zhixian; Yuan, Shengxian; Zeng, Zhen; Jia, Xiaodong; Lu, Shanshan; Safadi, Rifaat; Han, Sen; Yang, Zhihong; Neckers, Leonard M.; Liangpunsakul, Suthat; Zhou, Weiping; Lu, Yinying; Medicine, School of Medicine
    Objective: Hepatocellular carcinoma (HCC), the main type of liver cancer, has a high morbidity and mortality, and a poor prognosis. RNA helicase DDX5, which acts as a transcriptional co-regulator, is overexpressed in most malignant tumors and promotes cancer cell growth. Heat shock protein 90 (HSP90) is an important molecular chaperone in the conformational maturation and stabilization of numerous proteins involved in cell growth or survival. Methods: DDX5 mRNA and protein expression in surgically resected HCC tissues from 24 Asian patients were detected by quantitative real-time PCR and Western blot, respectively. The interaction of DDX5-HSP90 was determined by molecular docking, immunoprecipitation, and laser scanning confocal microscopy. The autophagy signal was detected by Western blot. The cell functions and signaling pathways of DDX5 were determined in 2 HCC cell lines. Two different murine HCC xenograft models were used to determine the function of DDX5 and the therapeutic effect of an HSP90 inhibitor. Results: HSP90 interacted directly with DDX5 and inhibited DDX5 protein degradation in the AMPK/ULK1-regulated autophagy pathway. The subsequent accumulation of DDX5 protein induced the malignant phenotype of HCC by activating the β-catenin signaling pathway. The silencing of DDX5 or treatment with HSP90 inhibitor both blocked in vivo tumor growth in a murine HCC xenograft model. High levels of HSP90 and DDX5 protein were associated with poor prognoses. Conclusions: HSP90 interacted with DDX5 protein and subsequently protected DDX5 protein from AMPK/ULK1-regulated autophagic degradation. DDX5 and HSP90 are therefore potential therapeutic targets for HCC.
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    Long non-coding RNA H19 – a new player in the pathogenesis of liver diseases
    (Elsevier, 2021) Yang, Zhihong; Zhang, Ting; Han, Sen; Kusumanchi, Praveen; Huda, Nazmul; Jiang, Yanchao; Liangpunsakul, Suthat; Medicine, School of Medicine
    The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long noncoding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and diverse mechanisms. LncRNA H19, one of the first lncRNAs being identified, is highly expressed in fetal liver but not in adult normal liver. Its expression, however, is increased in liver diseases with various etiologies. In this review, we focused on the roles of H19 in the pathogenesis of liver diseases. This comprehensive review is aimed to provide useful perspectives and translational applications of H19 as a potential therapeutic target of liver diseases.
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    Long non-coding RNAs in liver diseases: Focusing on nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease
    (The Korean Association for the Study of the Liver, 2020-10) Han, Sen; Zhang, Ting; Kusumanchi, Praveen; Huda, Nazmul; Jiang, Yanchao; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of Medicine
    Long non-coding RNAs (lncRNAs), a class of transcribed RNA molecules with the lengths exceeding 200 nucleotides, are not translated into protein. They can modulate protein-coding genes by controlling transcriptional and posttranscriptional processes. The dysregulation of lncRNAs has been related to various pathological disorders. In this review, we summarized the current knowledge of lncRNAs and their implications in the pathogenesis of three common liver diseases: nonalcoholic fatty liver disease, alcohol-related liver disease, and cholestatic liver disease. Future studies to further define the role of lncRNAs and their mechanisms in various types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting specific lncRNAs for the treatment of liver diseases.
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    Role of microRNA-7 in liver diseases: a comprehensive review of the mechanisms and therapeutic applications
    (Sage, 2020) Han, Sen; Zhang, Ting; Kusumanchi, Praveen; Huda, Nazmul; Jiang, Yanchao; Liangpunsakul, Suthat; Yang, Zhihong; Medicine, School of Medicine
    MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.
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    The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease
    (The American Society for Clinical Investigation, 2021-08-23) Yang, Zhihong; Smalling, Rana V.; Huang, Yi; Jiang, Yanchao; Kusumanchi, Praveen; Bogaert, Will; Wang, Li; Delker, Don A.; Skill, Nicholas J.; Han, Sen; Zhang, Ting; Ma, Jing; Huda, Nazmul; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.