Browsing by Author "Li, Yu"

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    Aging exaggerates acute-on-chronic alcohol-induced liver injury in mice and humans by inhibiting neutrophilic sirtuin 1-C/EBPα-miRNA-223 axis
    (Wolters Kluwer, 2022) Ren, Ruixue; He, Yong; Ding, Dong; Cui, Aoyuan; Bao, Huarui; Ma, Jing; Hou, Xin; Li, Yu; Feng, Dechun; Li, Xiaoling; Liangpunsakul, Suthat; Gao, Bin; Wang, Hua; Medicine, School of Medicine
    Background and aims: Aging exacerbates liver neutrophil infiltration and alcohol-associated liver disease (ALD) in mice and humans, but the underlying mechanisms remain obscure. This study aimed to examine the effect of aging and alcohol consumption on neutrophilic Sirtuin 1 (SIRT1) and microRNA-223 (miR-223), and their contribution to ALD pathogeneses. Approach and results: Young and aged myeloid-specific Sirt1 knockout mice were subjected to chronic-plus-binge ethanol feeding. Blood samples from healthy controls and patients with chronic alcohol drinking who presented with acute intoxication were analyzed. Neutrophilic Sirt1 and miR-223 expression were down-regulated in aged mice compared with young mice. Deletion of the Sirt1 gene in myeloid cells including neutrophils exacerbated chronic-plus-binge ethanol-induced liver injury and inflammation and down-regulated neutrophilic miR-223 expression. Immunoprecipitation experiments revealed that SIRT1 promoted C/EBPα deacetylation by directly interacting with C/EBPα, a key transcription factor that controls miR-223 biogenesis, and subsequently elevated miR-223 expression in neutrophils. Importantly, down-regulation of SIRT1 and miR-223 expression was also observed in circulating neutrophils from middle-aged and elderly subjects compared with those from young individuals. Chronic alcohol users with acute intoxication had a reduction in neutrophilic SIRT1 expression in young and middle-aged patients, with a greater reduction in the latter group. The neutrophilic SIRT1 expression correlated with neutrophilic miR-223 and serum alanine transaminase levels in those patients. Conclusions: Aging increases the susceptibility of alcohol-induced liver injury in mice and humans through the down-regulation of the neutrophilic SIRT1-C/EBPα-miR-223 axis, which could be a therapeutic target for the prevention and/or treatment of ALD.
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    Dynamic MTORC1-TFEB feedback signaling regulates hepatic autophagy, steatosis and liver injury in long-term nutrient oversupply
    (Taylor & Francis, 2018) Zhang, Hao; Yan, Shengmin; Khambu, Bilon; Ma, Fengguang; Li, Yong; Chen, Xiaoyun; Puertollano, Rosa; Li, Yu; Chalasani, Naga; Yin, Xiao-Ming; Martina, Jose A.; Pathology & Laboratory Medicine, IU School of Medicine
    Normal metabolism requires a controlled balance between anabolism and catabolism. It is not completely known how this balance can be retained when the level of nutrient supply changes in the long term. We found that in murine liver anabolism, as represented by the phosphorylation of RPS6KB (ribosomal protein S6 kinase), was soon elevated while catabolism, as represented by TFEB (transcription factor EB)-directed gene transcription and lysosomal activities, was downregulated after the administration of a high-fat diet (HFD). Surprisingly, neither the alteration in RPS6KB phosphorylation nor that in TFEB functions was static over the long course of HFD feeding. Instead, the 2 signals exhibited dynamic alterations in opposite directions, which could be explained by the dependence of MTORC1 (MTOR complex 1) activation on TFEB-supported lysosome function and the feedback suppression of TFEB by MTORC1. Disruption of the dynamics by enforced expression of TFEB in HFD-fed mice at the peaks of MTORC1 activation restored lysosome function. Consistently, interference of MTORC1 activation with rapamycin or with a constitutively activated RRAGA mutant at the peak or nadir of MTORC1 oscillation enhanced or reduced the lysosome function, respectively. These treatments also improved or exacerbated hepatic steatosis and liver injury, respectively. Finally, there was a significant inverse correlation between TFEB activation and steatosis severity in the livers of patients with non-alcohol fatty liver diseases, supporting the clinical relevance of TFEB-regulated events. Thus, maintaining catabolic function through feedback mechanisms during enhanced anabolism, which is caused by nutrient oversupply, is important for reducing liver pathology.
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    Effects of Granule Dendrobii on chronic atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats
    (Baishideng, 2022) Wu, Yue; Li, Yu; Jin, Xiao-Ming; Dai, Guan-Hai; Chen, Xuan; Tong, Ye-Ling; Ren, Ze-Ming; Chen, Yu; Xue, Xiao-Min; Wu, Ren-Zhao; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Dendrobium officinale is an herb of Traditional Chinese Medicine (TCM) commonly used for treating stomach diseases. One formula of Granule Dendrobii (GD) consists of Dendrobium officinale and American Ginseng (Radix Panacis quinquefolii), and is a potent TCM product in China. Whether treatment with GD can promote gastric acid secretion and alleviate gastric gland atrophy in chronic atrophic gastritis (CAG) requires verification. Aim: To determine the effect of GD treatment on CAG and its potential cellular mechanism. Methods: A CAG model was induced by feeding rats N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 wk. After oral administration of low, moderate, and high doses of GD in CAG rats for 8 wk, its effects on body weight, gastric mucosa histology, mucosal atrophy, intestinal metaplasia, immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2, and hemoglobin and red blood cells were examined. Results: The body weights of MNNG-induced CAG model rats before treatment (143.5 ± 14.26 g) were significantly lower than that of healthy rats (220.2 ± 31.20 g, P < 0.01). At the 8th week of treatment, the body weights of rats in the low-, moderate-, and high-dose groups of GD (220.1 ± 36.62 g) were significantly higher than those in the untreated group (173.3 ± 28.09 g, all P < 0.01). The level of inflammation in gastric tissue of the high-dose group (1.68 ± 0.54) was significantly reduced (P < 0.01) compared with that of the untreated group (3.00 ± 0.00, P < 0.05). The number and thickness of gastric glands in the high-dose group (31.50 ± 6.07/mm, 306.4 ± 49.32 µm) were significantly higher than those in the untreated group (26.86 ± 6.41/mm, 244.3 ± 51.82 µm, respectively, P < 0.01 and P < 0.05), indicating improved atrophy of gastric mucosa. The areas of intestinal metaplasia were significantly lower in the high-dose group (1.74% ± 1.13%), medium-dose group (1.81% ± 0.66%) and low-dose group (2.36% ± 1.08%) than in the untreated group (3.91% ± 0.96%, all P < 0.01). The expression of PCNA in high-dose group was significantly reduced compared with that in untreated group (P < 0.01). Hemoglobin level in the high-dose group (145.3 ± 5.90 g/L), medium-dose group (139.3 ± 5.71 g/L) and low-dose group (137.5 ± 7.56 g/L) was markedly increased compared with the untreated group (132.1 ± 7.76 g/L; P < 0.01 or P < 0.05). Conclusion: Treatment with GD for 8 wk demonstrate that GD is effective in the treatment of CAG in the MNNG model by improving the histopathology of gastric mucosa, reversing gastric atrophy and intestinal metaplasia, and alleviating gastric inflammation.
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    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.
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    Protein Kinase Cδ Suppresses Autophagy to Induce Kidney Cell Apoptosis in Cisplatin Nephrotoxicity
    (American Society of Nephrology, 2017-04) Zhang, Dongshan; Pan, Jian; Xiang, Xudong; Li, Yu; Dong, Guie; Livingston, Man J.; Chen, Jian-Kang; Yin, Xiao-Ming; Dong, Zheng; Pathology and Laboratory Medicine, School of Medicine
    Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and renoprotective approaches are unavailable. Recent work unveiled a critical role of protein kinase Cδ (PKCδ) in cisplatin nephrotoxicity and further demonstrated that inhibition of PKCδ not only protects kidneys but enhances the chemotherapeutic effect of cisplatin in tumors; however, the underlying mechanisms remain elusive. Here, we show that cisplatin induced rapid activation of autophagy in cultured kidney tubular cells and in the kidneys of injected mice. Cisplatin also induced the phosphorylation of mammalian target of rapamycin (mTOR), p70S6 kinase downstream of mTOR, and serine/threonine-protein kinase ULK1, a component of the autophagy initiating complex. In vitro, pharmacologic inhibition of mTOR, directly or through inhibition of AKT, enhanced autophagy after cisplatin treatment. Notably, in both cells and kidneys, blockade of PKCδ suppressed the cisplatin-induced phosphorylation of AKT, mTOR, p70S6 kinase, and ULK1 resulting in upregulation of autophagy. Furthermore, constitutively active and inactive forms of PKCδ respectively enhanced and suppressed cisplatin-induced apoptosis in cultured cells. In mechanistic studies, we showed coimmunoprecipitation of PKCδ and AKT from lysates of cisplatin-treated cells and direct phosphorylation of AKT at serine-473 by PKCδin vitro Finally, administration of the PKCδ inhibitor rottlerin with cisplatin protected against cisplatin nephrotoxicity in wild-type mice, but not in renal autophagy-deficient mice. Together, these results reveal a pathway consisting of PKCδ, AKT, mTOR, and ULK1 that inhibits autophagy in cisplatin nephrotoxicity. PKCδ mediates cisplatin nephrotoxicity at least in part by suppressing autophagy, and accordingly, PKCδ inhibition protects kidneys by upregulating autophagy.
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    Understanding Transcription Factor Regulation by Integrating Gene Expression and DNase I Hypersensitive Sites
    (Hindawi, 2015-09-03) Wang, Guohua; Wang, Fang; Huang, Qian; Li, Yu; Liu, Yunlong; Wang, Yadong; Medical and Molecular Genetics, School of Medicine
    Transcription factors are proteins that bind to DNA sequences to regulate gene transcription. The transcription factor binding sites are short DNA sequences (5-20 bp long) specifically bound by one or more transcription factors. The identification of transcription factor binding sites and prediction of their function continue to be challenging problems in computational biology. In this study, by integrating the DNase I hypersensitive sites with known position weight matrices in the TRANSFAC database, the transcription factor binding sites in gene regulatory region are identified. Based on the global gene expression patterns in cervical cancer HeLaS3 cell and HelaS3-ifnα4h cell (interferon treatment on HeLaS3 cell for 4 hours), we present a model-based computational approach to predict a set of transcription factors that potentially cause such differential gene expression. Significantly, 6 out 10 predicted functional factors, including IRF, IRF-2, IRF-9, IRF-1 and IRF-3, ICSBP, belong to interferon regulatory factor family and upregulate the gene expression levels responding to the interferon treatment. Another factor, ISGF-3, is also a transcriptional activator induced by interferon alpha. Using the different transcription factor binding sites selected criteria, the prediction result of our model is consistent. Our model demonstrated the potential to computationally identify the functional transcription factors in gene regulation.
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    Yiwei decoction promotes apoptosis of gastric cancer cells through spleen-derived exosomes
    (Frontiers Media, 2023-06-01) Chen, Yingzhi; Li, Yu; Wu, Yue; Chen, Shiyong; Jin, Xiaoming; Chen, Xuan; Fei, Baoying; Xue, Xiaomin; Wu, Renzhao; Chai, Kequn; Anatomy, Cell Biology and Physiology, School of Medicine
    Yiwei decoction (YWD) is a formula of traditional Chinese medicine (TCM) that is clinically effective for the prevention and treatment of gastric cancer recurrence and metastasis. According to the theory of TCM, YWD tonifies the body and strengthens the body’s resistance to gastric cancer recurrence and metastasis potentially via the immune regulation of the spleen. The aims of the present study were to investigate whether YWD-treated spleen-derived exosomes in rats inhibit the proliferation of tumor cells, to elucidate the anticancer effects of YWD, and to provide evidence supporting the use of YWD as a new clinical treatment for gastric cancer. Spleen-derived exosomes were obtained by ultracentrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot analysis. The location of the exosomes in tumor cells was then determined by immunofluorescence staining. After tumor cells were treated with different concentrations of exosomes, the effect of exosomes on cell proliferation was determined by cell counting kit 8 (CCK8) and colony formation assays. Tumor cell apoptosis was detected by flow cytometry. Particle analysis and western blot analysis identified the material extracted from spleen tissue supernatant as exosomes. Immunofluorescence staining showed that spleen-derived exosomes were taken up by HGC-27 cells, and the CCK8 assay confirmed that the relative tumor inhibition rate of YWD-treated spleen-derived exosomes in the 30 μg/mL reached 70.78% compared to control exosomes in the 30 μg/mL (p < 0.05). Compared to control exosomes in the 30 μg/mL, the colony formation assay indicated that YWD-treated spleen-derived exosomes in the 30 μg/mL colonies have decreased by 99.03% (p < 0.01). Moreover, flow cytometry analysis showed that treatment with YWD-treated exosomes in the 30 μg/mL increased the apoptosis rate to 43.27%, which was significantly higher than that of the control group in the 30 μg/mL (25.91%) (p < 0.05). In conclusion, spleen-derived exosomes from YWD-treated animals inhibit the proliferation of HGC-27 cells via inducing apoptosis, suggesting that spleen-derived exosomes are involved in mediating the antitumor effect of YWD. These results demonstrated a novel exosome-mediated anticancer effect of YWD as a TCM formula, thereby supporting the use of YWD-treated exosomes as a new approach for the clinical treatment of gastric cancer.