IU Indianapolis ScholarWorks :: Browsing by Author "Liu, Gang"

Browsing by Author "Liu, Gang"

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Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease
(Elsevier, 2018-09) Khambu, Bilon; Yan, Shengmin; Huda, Nazmul; Liu, Gang; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Autophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis. Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases. Impaired autophagy prevents the clearance of excessive lipid droplets (LDs), damaged mitochondria, and toxic protein aggregates, which can be generated during the progression of various liver diseases, thus contributing to the development of steatosis, injury, steatohepatitis, fibrosis, and tumors. In this review, we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases. We also examine the mechanisms of defects in autophagy, and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), focusing mainly on steatosis and liver injury. Finally, we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.
Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions
(MDPI, 2019-10-11) Yan, Shengmin; Khambu, Bilon; Hong, Honghai; Liu, Gang; Huda, Nazmul; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
Coagulopathy as a Prodrome of Cytokine Storm in COVID-19-Infected Patients
(Frontiers in Medicine, 2020-10) Guo, Hui; Sheng, Ying; Li, Wei; Li, Fei; Xie, Zongyu; Li, Jing; Zhu, Yuhe; Geng, Jian; Liu, Gang; Wang, LeJian; Li, Jing; Wang, Fengchao; School of Nursing
Background The rapid coronavirus disease 2019 (COVID-19) pandemic has hit hard on the world and causes panic since the virus causes serious respiratory infectious illness and easily leads to severe conditions such as immune system overactivation or cytokine storm. Due to the limited knowledge of this infectious course of this coronavirus and a lack of an effective treatment for this fatal disease, the mortality remains high. The emergence of cytokine storm in patients on severe condition has been reported as the top reason of the death of patients with COVID-19 infection. However, the causative mechanism of cytokine storm remains elusive. Thus, we aim to observe the association of coagulopathy (D-dimer) with cytokine (i.e. IL-6) and CT imaging in COVID-19 infected patients. Methods In this retrospective observational study, we systematically analyzed the comprehensive clinical laboratory data of COVID-19 positive patients in different illness groups of mild, moderate, severe conditions according to Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition). T tests and Chi-square tests were used for two-group comparisons. One-way ANOVA was used for three-group comparisons. Pearson and spearman correlation coefficients of the D-dimer level with IL-6 and CT imaging were computed at baseline. With regular liquid biopsy approach, D-dimer, IL-6, NLR was recorded repeatedly with time curve to investigate the disease progression, along with CT imaging, and other indicators. Results All the 64 patients were clinically evaluated and classified into three groups of mild (32 cases), moderate (23 cases), severe (9 cases). D-dimer level positively correlated with IL-6 (R=0.5) at the base line when COVID-19 infected patients were admitted. In addition, we observed that D-dimer rises early than cytokine storm represented by IL-6 surge, which suggests that coagulopathy might act as trigger to potentiate cytokines storm. Conclusion Integrated analysis revealed the positive correlation of coagulopathy with cytokine storm in COVID-19 infected patients, D-dimer rise early, which indicated coagulopathy act as a prodrome of cytokine storm. Coagulopathy can be used to monitor early cytokine storm in COVID-19 infected patients.
Hepatic senescence, the good and the bad
(Baishideng Publishing Group, 2019-09-14) Huda, Nazmul; Liu, Gang; Hong, Honghai; Yan, Shengmin; Khambu, Bilon; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Gradual alterations of cell's physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells. Once becoming senescent, the cell stops dividing permanently but remains metabolically active. Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers, such as, morphological changes, expression of cell cycle inhibitors, senescence associated β-galactosidase activity, and changes in nuclear membrane. When cells in an organ become senescent, the entire organism can be affected. This may occur through the senescence-associated secretory phenotype (SASP). SASP may exert beneficial or harmful effects on the microenvironment of tissues. Research on senescence has become a very exciting field in cell biology since the link between age-related diseases, including cancer, and senescence has been established. The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence. The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes. Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration. This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.
The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors
(Springer Nature, 2020-05) Khambu, Bilon; Hong, Honghai; Liu, Sheng; Liu, Gang; Chen, Xiaoyun; Dong, Zheng; Wan, Jun; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Autophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not unclear. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1), which was released from autophagy-deficient hepatocytes. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis. We found that in liver-specific autophagy-deficient (Atg7ΔHep) mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of Hmgb1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. However, RAGE expression was only found on ductual cells and Kupffer's cells but not on hepatoctyes, suggesting that HMGB1 might promote hepatic tumor growth through a paracrine mode, which altered the tumor microenvironment. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potentially important role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.
NRF2 transcriptionally regulates Caspase-11 expression to activate HMGB1 release by Autophagy-deficient hepatocytes
(Springer Nature, 2023-07-28) Khambu, Bilon; Cai, Genxiang; Liu, Gang; Bailey, Niani Tiaye; Mercer, Arissa A.; Baral, Kamal; Ma, Michelle; Chen, Xiaoyun; Li, Yu; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Injury or stress can induce intracellular translocation and release of nuclear HMGB1, a DAMP molecule known to participate in inflammation and other pathological processes. Active release of HMGB1 from stimulated macrophages can be mediated by inflammasomes, which cleave Gasdermin D to form pores on cytoplasmic membranes. We previously had shown that active release of HMGB1 from autophagy deficient hepatocytes also depended on the inflammasome but how the inflammasome was activated was not known. Here we report that persistent activation of transcription factor NRF2 under the autophagy deficient condition led to transcriptional upregulation of Caspase-11 expression, which could then activate the CASPASE-1inflammasome. Using chromatin immunoprecipitation (CHIP) and luciferase-based reporter assays, we show that NRF2 directly binds to the Caspase-11 promoter and transcriptionally increase the expression of Caspase-11. Genetic deletion of Caspase-11 in autophagy-deficient livers represses the release of HMGB1 and its pathological consequence, ductular cell proliferation. Consistently, deletion of NLRP3, which can activate CASPASE-1 mediated inflammasomes under other types of signals, did not prevent HMGB1 release and ductular cell proliferation in autophagy deficient livers. Surprisingly, while cleavage of GASDEMIN D occurred in autophagy-deficient livers its deletion did not prevent the HMGB1 release, suggesting that CASPASE-11-mediated inflammasome activation may also engage in a different mechanism for HMGB1 release by the autophagy deficient hepatocytes. Collectively, this work reveals the novel role of NRF2 in transcriptional upregulation of Caspase-11 and in inflammasome activation to promote active release of HMGB via a non-Gasdermin D mediated avenue.
Promotion of diet-induced obesity and metabolic syndromes by BID is associated with gut microbiota
(Wolters Kluwer, 2022) Yan, Shengmin; Zhou, Jun; Zhang, Hao; Lin, Zhen; Khambu, Bilon; Liu, Gang; Ma, Michelle; Chen, Xiaoyun; Chalasani, Naga; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
A growing body of evidence has indicated an expanding functional network of B-cell lymphoma 2 (BCL-2) family proteins beyond regulation of cell death and survival. Here, we examined the role and mechanisms of BH3 interacting-domain death agonist (BID), a pro-death BCL-2 family member, in the development of diet-induced metabolic dysfunction. Mice deficient in bid (bid-/- ) were resistant to high-fat diet (HFD)-induced obesity, hepatic steatosis, and dyslipidemia with an increased insulin sensitivity. Indirect calorimetry analysis indicated that bid deficiency increased metabolic rate and decreased respiratory exchange ratio, suggesting a larger contribution of lipids to overall energy expenditure. While expression of several genes related to lipid accumulation was only increased in wild-type livers, metabolomics analysis revealed a consistent reduction in fatty acids but an increase in certain sugars and Krebs cycle intermediates in bid-/- livers. Gut microbiota (GM) analysis indicated that HFD induced gut dysbiosis with differential patterns in wild-type and in bid-/- mice. Notably, abrogation of GM by antibiotics during HFD feeding eliminated the beneficial effects against obesity and hepatic steatosis conferred by the bid deficiency. Conclusion: These results indicate that the protective role of bid-deficiency against diet-induced metabolic dysfunction interacts with the function of GM.
Senescence Connects Autophagy Deficiency to Inflammation and Tumor Progression in the Liver
(Elsevier, 2022) Huda, Nazmul; Khambu, Bilon; Liu, Gang; Nakatsumi, Hirokazu; Yan, Shengmin; Chen, Xiaoyun; Ma, Michelle; Dong, Zheng; Nakayama, Keiichi I.; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
Background & aims: Cellular senescence frequently is present in injured livers. The induction mechanism and the pathologic role are not always clear. We aimed to understand the dynamics of senescence induction and progression, and the mechanism responsible for the pathology using a mouse model that disables the essential process of autophagy. Methods: Mice deficient in key autophagy genes Atg7 or Atg5 in the liver were used. Senescence was measured using established cellular and molecular signatures. The mechanistic roles of nuclear factor erythroid 2 (NRF2), forkhead box K1, and C-C motif chemokine receptor 2 (CCR2) were assessed using mouse genetic models. Liver functions, pathology, and tumor development were measured using biochemical and histologic approaches. Results: Inducible deletion of Atg7 rapidly up-regulated cyclin-dependent kinase inhibitors independently of injury and induced senescence-associated β-galactosidase activities and senescence-associated secretory phenotype (SASP). Sustained activation of NRF2 was the major factor causing senescence by mediating oxidative DNA damage and up-regulating C-C motif chemokine ligand 2, a key component of autophagy-related SASP, via the NRF2-forkhead box K1 axis. Senescence was responsible for hepatic inflammation through CCR2-mediated recruitment of CD11b+ monocytes and CD3+ T cells. The CCR2-mediated process in turn enhanced senescence and SASP by up-regulating cyclin-dependent kinase inhibitors and chemokines. Thus, senescence and inflammation can mutually augment each other, forming an amplification loop for both events. The CCR2-mediated process also modulated liver injury and tumor progression at the later stage of autophagy deficiency-related pathology. Conclusions: These results provide the insight that hepatic senescence can occur early in the disease process, triggers inflammation and is enhanced by inflammation, and has long-term effects on liver injury and tumor progression.
System modeling reveals the molecular mechanisms of HSC cell cycle alteration mediated by Maff and Egr3 under leukemia
(BMC, 2017-10-03) Li, Rudong; Wang, Yin; Cheng, Hui; Liu, Gang; Cheng, Tao; Liu, Yunlong; Liu, Lei; Medical and Molecular Genetics, School of Medicine
Background Molecular mechanisms of the functional alteration of hematopoietic stem cells (HSCs) in leukemic environment attract intensive research interests. As known in previous researches, Maff and Egr3 are two important genes having opposite functions on cell cycle; however, they are both highly expressed in HSCs under leukemia. Hence, exploring the molecular mechanisms of how the genes act on cell cycle will help revealing the functional alteration of HSCs. Results We herein utilize the bioinformatic resources to computationally model the acting mechanisms of Maff and Egr3 on cell cycle. Using the data of functional experiments as reference, molecular acting mechanisms are optimally enumerated through model selection. The results are consolidated by evidences from gene sequence analysis, thus having enhanced the confidence of our pilot findings, which suggest that HSCs possibly undergo a “adaptation - suppression” process in response to the malignant environment of leukemia. Conclusion As a pilot research, our results may provide valuable insights for further experimental studies. Meanwhile, our research method combining computational modeling and data from functional experiments can be worthwhile for knowledge discovery; and it can be generalized and extended to other biological/biomedical studies. Electronic supplementary material The online version of this article (doi:10.1186/s12918-017-0467-4) contains supplementary material, which is available to authorized users.

Browsing by Author "Liu, Gang"

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