Browsing by Author "Wang, Li"
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Item Association between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease(Elsevier, 2018) Chang, Binxia; Hao, Shuli; Zhang, Longyu; Gao, Miaomiao; Sun, Ying; Huang, Ang; Teng, Guangju; Li, Baosen; Crabb, David W.; Kusumanchi, Praveen; Wang, Li; Liangpunsakul, Suthat; Zou, Zhengsheng; Medicine, School of MedicineBackground Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD); though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD. Methods ALDH2 genotype was performed in 535 healthy controls and 281 patients with ALD. Results The prevalence of the common form of the SNP rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, p<0.0001). Among controls, 23.7% had heterozygous (glu/lys) genotype when compared to 4.6% in those with ALD (OR 0.16, 95%CI 0.09–0.28). The allele frequency for 504lys allele in patients with ALD was 2.3%; compared to 14.5% in healthy controls (OR 0.13, 95%CI 0.07–0.24). Conclusions Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses.Item Circadian clock control of hepatic lipid metabolism: role of small heterodimer partner (Shp)(BMJ Journals, 2016-10) Wang, Li; Liangpunsakul, Suthat; Medicine, School of MedicineHepatic steatosis, the accumulation of triglyceride droplets in the hepatocytes, is a common hepatic pathology seen in subjects with obesity/metabolic syndrome and those with excessive alcohol use. The pathogenesis underlying hepatic steatosis is complex. Recent studies have shown the specific role played by the molecular clock mechanism in the control of lipid metabolism and that the disruption of these tissue clocks may lead to the disturbances in lipid homeostasis. This review reports a novel role of small heterodimer partner in maintaining triglyceride and lipoprotein homeostasis through neuronal PAS domain protein 2.Item Corrigendum to “Long non-coding RNA in liver metabolism and disease: Current status” [Liver Res. 1 (2017) 163–167](Elsevier, 2022-11-19) Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat; Wang, Li; Biochemistry and Molecular Biology, School of Medicine[This corrects the article DOI: 10.1016/j.livres.2017.09.001.].Item Ensuring sample quality for blood biomarker studies in clinical trials: a multicenter international study for plasma and serum sample preparation(2017-12) Kong, Feng-Ming (Spring); Zhao, Lujun; Wang, Luhua; Chen, Yuhchyau; Hu, Jie; Fu, Xiaolong; Bai, Chunxue; Wang, Li; Lawrence, Theodore S.; Anscher, Mitchell S.; Dicker, Adam; Okunieff, Paul; Radiation Oncology, School of MedicineBackground Sample quality is critical for biomarker detection in oncology, and platelet degradation and contamination in plasma have a remarkable impact on the ability to accurately quantify many blood-based biomarkers. Platelet factor 4 (PF4) can be used as an indicator to monitor sample quality. This multicenter study aimed to determine the impact of critical components of the blood sample handling process on platelet degradation/contamination and to establish an optimal method for collecting platelet-poor plasma samples. Methods At each of six participating centers, blood samples were drawn from 12–13 healthy volunteers. Serum and plasma samples were prepared from whole blood samples using nine different methods that have been commonly used in ongoing multicenter trials. PF4 levels in the prepared samples were measured by enzyme-linked immunosorbent assay (ELISA). Paired t-tests were used for statistical analysis. Results Blood samples were collected from 74 subjects enrolled in six centers. PF4 levels were significantly higher in serum samples than in plasma samples (P<0.001), in plasma samples from blood that sat at room temperature for 5 minutes (P=0.021), in plasma samples prepared at an insufficient centrifugal force (P<0.001), and in plasma samples prepared from blood that sat for longer than 4 hours on ice (P=0.001). For each method, the PF4 levels did not differ significantly among the centers or between Chinese and American subjects. The methods that resulted in normal levels of PF4 involved keeping blood samples on ice for 30 minutes to <4 hours and centrifugation at 2,500–3,000 ×g for 30 min. Conclusions This multicenter study evaluated multiple blood sample handling conditions for minimizing platelet degradation during plasma serum preparation and determined an optimal method for preparing platelet-poor plasma. The findings of this study can be applied in future blood biomarker studies.Item HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis(Wolters Kluwer, 2023-11-06) Huang, Yi; Liangpunsakul, Suthat; Rudraiah, Swetha; Ma, Jing; Keshipeddy, Santosh K.; Wright, Dennis; Costa, Antonio; Burgess, Diane; Zhang, Yuxia; Huda, Nazmul; Wang, Li; Yang, Zhihong; Medicine, School of MedicineBackground: High mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models. Methods: The carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention. Results: The serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix. Conclusion: We conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.Item Incidence Trends, Clinicopathologic Characteristics, and Overall Survival Prediction in Retinoblastoma Children: SEER Prognostic Nomogram Analysis(Oxford University Press, 2024) Guo, Xiaohong; Wang, Li; Beeraka, Narasimha M.; Liu, Chunying; Zhao, Xiang; Zhou, Runze; Yu, Huiming; Fan, Ruitai; Liu, Junqi; Pediatrics, School of MedicineBackground: Retinoblastoma is the most common intraocular malignant tumor occurring among children, with an incidence rate of 1/15 000. This study built a joinpoint regression model to assess the incidence trend of retinoblastoma from 2004 to 2015 and constructed a nomogram to predict the overall survival (OS) in children. Materials and methods: Patients less than 19 years diagnosed with retinoblastoma from 2004 to 2015 were selected from the SEER database. Joinpoint regression analysis (version 4.9.0.0) was performed to evaluate the trends in retinoblastoma incidence rates from 2004 to 2015. Cox Regression Analysis was applied to investigate prognostic risk factors that influence OS. Results: Joinpoint regression revealed that retinoblastoma incidence exhibited no significant increase or decrease from 2004 to 2015. As per the multiple Cox regression, tumor size, laterality, and residence (rural-urban continuum code) were correlated with OS and were used to construct a nomogram. The nomogram exhibited a good C-index of 0.71 (95% CI, 0.63 to 0.79), and the calibration curve for survival probability demonstrated that the predictions corresponded well with actual observations. Conclusions and relevance: A prognostic nomogram integrating the risk factors for retinoblastoma was constructed to provide comparatively accurate individual survival predictions. If validated, this type of assessment could be used to guide therapy in patients with retinoblastoma.Item Levels of circulating follicular helper T cells, T helper 1 cells, and the prognostic significance of soluble form of CD40 ligand on survival in patients with alcoholic cirrhosis(KeAi Communications Co., 2018-03) Hollister, Kristin; Kusumanchi, Praveen; Ross, Ruth Ann; Chandler, Kristina; Oshodi, AdePeju; Heathers, Laura; Teagarden, Sean; Wang, Li; Dent, Alexander L.; Liangpunsakul, Suthat; Microbiology and Immunology, School of MedicineBackground: Excessive drinkers (ED) and patients with alcoholic liver disease (ALD) are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations. Follicular helper T (TFH) cells are essential to select B cells in the germinal center and to produce antibodies. TFH cells express both a membrane-associated and a soluble form of CD40 ligand (sCD40L); in which the latter form is released to circulation upon T cell activation. The effect of alcohol on TFH cells has not been studied. Objectives: The goals of this study are to determine the levels of TFH and T helper 1 (Th1) cells in ED and those with alcoholic cirrhosis (AC) when compared to healthy controls and to determine the prognostic significance of sCD40L in a cohort of patients with AC. Methods: Controls, ED, and those with AC were enrolled. Baseline demographic, laboratory tests, and peripheral blood mononuclear cells (PBMCs) were isolated and assessed via flow cytometry for TFH cells. In vitro study was performed to determine the ability of PBMCs to secrete interferon (IFN)-γ upon stimulation. Serum sCD40L were also determined and its prognostic significance was tested in a cohort of AC patients. Results: The levels of circulating TFH (cTFH) cells were significantly lower in peripheral blood of subjects with ED and AC compared to controls (P<0.05). IFN-γ secretion from PBMCs upon stimulation was also lower in ED and those with cirrhosis. Serum sCD40L was significantly lower in ED and AC when compared to that in controls (P<0.0005). Its level was an independent predictor of mortality. Conclusions: Patients with AC had significantly lower level of cTFH and sCD40L. The level of sCD40L was an independent predictor of mortality in these patients.Item LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis(Wiley, 2017-08) Yang, Zhihong; Ross, Ruth A.; Zhao, Shi; Tu, Wanzhu; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineBackground: Alcoholic liver disease (ALD) is one of the leading causes of chronic liver disease. Recent studies have demonstrated the roles of long noncoding RNAs (lncRNAs) in the pathogenesis of several disease processes. However, the roles of lncRNAs in patients with ALD remain unexplored. Methods: Global profiling for human lncRNAs from peripheral blood RNA was performed in a well characterized cohort of healthy controls (HC, n=4), excessive drinkers without liver diseases (ED, n=4), and those with alcoholic cirrhosis with different severities (AC, n=12). The expression of unique lncRNA signatures were validated in a separate cohort of HC (n=17), ED (n=19), AC (n=48), and human liver tissues with ALD (n=19). Results: Detailed analysis of plasma lncRNAs in AC subjects with different severities compared to HC identified 244 commonly up-regulated lncRNAs and 181 commonly down-regulated lncRNAs. We further validated top 20 most differentially up- and down-regulated lncRNAs in ED and AC as compared to HC and also determined the expression of selected lncRNAs in human liver tissues with or without AC. Among those lncRNAs, AK128652 and AK054921 were two of the most abundantly expressed lncRNAs in normal human plasma and liver, and their levels were significantly elevated in AC. The prognostic significance of AK128652 and AK054921 was determined in 48 subjects with AC; who were prospectively followed for 520 days. The expression of AK128652 and AK054921 was inversely associated with survival in patients with AC. Conclusions: LncRNAs AK054921 and AK128652 are potential biomarkers to predict the progression to ALD in those with excessive alcohol consumption and are predictors of survival with patients with alcoholic cirrhosis.Item Long Non-coding RNA in Liver Metabolism and Disease: Current Status(Elsevier, 2017-09) Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineLong non-coding RNAs (lncRNAs) are comprised of RNA transcripts exceeding 200 nucleotides in length but lacking identifiable open reading frames (with rare exceptions). Herein, we highlight emerging evidence demonstrating that lncRNAs are critical regulators of liver metabolic function and diseases. We summarize current knowledges about dysregulated lncRNAs and outline the underlying molecular mechanisms by which lncRNAs control hepatic lipid ad glucose metabolism, as well as cholestatic liver disease. lncLSTR, Lnc18q22.2, SRA, HULC, MALAT1, lncLGR, MEG3, and H19, lncHR1, lnc-HC, APOA1-AS, DYNLRB2-2, and LeXis are included in the discussion.Item Metabolomics analysis revealed distinct cyclic changes of metabolites altered by chronic ethanol-plus-binge and Shp-deficiency(Wiley, 2016-12) Tran, Melanie; Yang, Zhihong; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineBackground Chronic ethanol consumption causes alcoholic liver disease (ALD) and disruption of the circadian system facilitates the development of ALD. Small heterodimer partner (SHP) is a nuclear receptor and critical regulator of hepatic lipid metabolism. This study aims at depicting circadian metabolomes altered by chronic ethanol-plus-binge and Shp-deficiency using high throughput Metabolomics. Methods Wild-type (WT) C57Bl/6 and Shp-/- mice were fed the control diet (CD) or Lieber De-Carli ethanol liquid diet (ED) for 10 days followed by a single bout of maltose (CD+M) or ethanol (ED+E) binge on the 11th day. Serum and liver were collected over a 24 hr light-dark (LD) cycle at Zeitgeber time ZT12, ZT18, ZT0 and ZT6 and metabolomics was performed using GC-MS. Results A total of 110 metabolites were identified in liver and of those 80 were also present in serum from pathways of carbohydrates, lipids, pentose phosphate, amino acids, nucleotides and tricarboxylic acid (TCA) cycle. In the liver, 91% of metabolites displayed rhythmicity with ED+E whereas in the serum, only 87% were rhythmic. Bioinformatics analysis identified unique metabolome patterns altered in WT CD+M, WT ED+E, Shp-/- CD+M, and Shp-/- ED+E groups. Specifically, metabolites from the nucleotide and amino acid pathway (ribose, glucose-6-phosphate, glutamic acid, aspartic acid and seduheptulose-7-P) were elevated in Shp-/- CD+M mice during the dark cycle, whereas metabolites including N-methylalanine, 2-hydroxybutyric acid, 2-hydroxyglutarate were elevated in WT ED+E mice during the light cycle. The rhythmicity and abundance of other individual metabolites were also significantly altered by both control and ethanol diets. Conclusions Metabolomics provides a useful means to identify unique metabolites altered by chronic ethanol-plus-binge.