Jiyuan Zhou

Background: Liver cirrhosis is a progressive chronic disease with high morbidity and mortality, thereby posing a major challenge to global health. Evidence suggests that thyroid dysfunction, particularly hypothyroidism, is linked to liver diseases. Hypothyroidism disrupts metabolism, immune homeostasis, and inflammatory pathways, processes central to cirrhosis pathophysiology. However, its causal role and molecular mechanisms remain unclear. Methods: The study initiated by analyzing the association between thyroid dysfunction and cirrhosis through retrospective analysis of longitudinal data obtained from the Medical Information Mart for Intensive Care clinical database. To assess genetic correlation, we applied linkage disequilibrium score regression, followed by bidirectional Mendelian randomization to explore potential causal relationships. Through transcriptome-wide association studies, we identified candidate genes, which were then prioritized using a combination of weighted gene co-expression network analysis and differential gene expression data integration. To interpret the biological relevance of these genes, we conducted functional enrichment analyses. We further explored gene function at the cellular level by leveraging single-cell RNA sequencing (scRNA) to map cell-specific expression patterns, analyze intercellular communication, and simulate gene knockouts. Finally, we performed molecular docking and phenome-wide Mendelian randomization to identify potential therapeutic compounds targeting the prioritized genes. Results: Through a combination of observational and genetic insights, we established a causal relationship between hypothyroidism and cirrhosis, identifying hypothyroidism as a risk factor for cirrhosis. Subsequent multi-omics analyses highlighted HLA-DQA1 and CD27 as potential therapeutic targets. ScRNA revealed key roles of these molecules in macrophages and CD8 ⁺ T cells, and simulated knockouts confirmed their importance in T cell activation and lymphocyte proliferation. Finally, molecular docking analysis identified glycyrrhizic acid and levothyroxine sodium as candidate drugs targeting HLA-DQA1 and CD27, while phenome-wide Mendelian randomization analysis revealed potential adverse effects associated with these targets. Conclusions: This study is the first to reveal a causal relationship between hypothyroidism and cirrhosis, potentially driven by immune dysregulation mediated by HLA-DQA1 and CD27. These findings offer novel insights into disease progression and identify HLA-DQA1 and CD27 as potential therapeutic targets, with glycyrrhizic acid and levothyroxine sodium as promising candidate drugs.

Objective This study aims to build a prognostic model of hepatocellular carcinoma (HCC) with ferroptosis-associated genes and explore their molecular function. Methods Gene expression data and clinical information were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and the International Cancer Genome Consortium (ICGC). A ferroptosis-associated gene set was obtained from the FerrDb database to identify differentially expressed genes. Then, we performed pathway enrichment analysis and immune infiltration analysis. A combined model based on ferroptosis-associated genes for predicting the overall survival of HCC was built by univariate and multivariate Cox regression analyses. Quantitative real-time polymerase chain reaction, Western blotting, colony formation, CCK-8, and EdU incorporation assays were performed to clarify the function of CAPG in the regulation of cell proliferation in human HCC. Ferroptosis was evaluated by glutathione (GSH), malondialdehyde (MDA), and total iron detection. Results Forty-nine ferroptosis-related genes were significantly correlated with HCC, 19 of which had prognostic significance. CAPG, SLC7A11 and SQSTM1 were used to construct a novel risk model. The areas under the curves (AUCs) were 0.746 and 0.720 (1 year) in the training and validation groups, respectively. The survival analysis indicated that patients with high risk scores exhibited worse survival in the training and validation groups. The risk score was also identified as an independent prognostic factor of overall survival (OS), which established and validated the predictive abilities of the nomogram. The risk score was also significantly correlated with the expression of immune checkpoint genes. In vitro data showed that CAPG knockdown dramatically suppressed HCC cell proliferation, and the underlying molecular mechanisms might be that the silencing of CAPG reduced the expression of SLC7A11 and promoted ferroptosis. Conclusion The established risk model can be used to predict the prognosis of HCC. At the mechanistic level, CAPG may drive HCC progression by regulating SLC7A11, and ferroptosis activation in HCC patients with high CAPG expression may serve as a potential therapeutic strategy.

This study was designed to explore if antiviral treatment influences the performance of serum alpha‐fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high‐risk chronic HBV‐infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non‐antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non‐antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut‐off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high‐risk population of CHB and LC patients.

Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI. To identify SNPs that indicate susceptibility to PM-DILI. We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant. The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database. rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Recent evidence suggests that athletes have microbial features distinct from those of sedentary individuals. However, the characteristics of the gut microbiota in athletes competing at different levels have not been assessed. The aim of this study was to investigate whether the gut microbiome is significantly different between higher-level and lower-level athletes. Faecal microbiota communities were analysed with hypervariable tag sequencing of the V3–V4 region of the 16S rRNA gene among 28 professional martial arts athletes, including 12 higher-level and 16 lower-level athletes. The gut microbial richness and diversity (the Shannon diversity index (p = 0.019) and Simpson diversity index (p = 0.001)) were significantly higher in the higher-level athletes than in the lower-level athletes. Moreover, the genera Parabacteroides, Phascolarctobacterium, Oscillibacter and Bilophila were enriched in the higher-level athletes, whereas Megasphaera was abundant in the lower-level athletes. Interestingly, the abundance of the genus Parabacteroides was positively correlated with the amount of time participants exercised during an average week. Further analysis of the functional prediction revealed that histidine metabolism and carbohydrate metabolism pathways were markedly over-represented in the gut microbiota of the higher-level athletes. Collectively, this study provides the first insight into the gut microbiota characteristics of professional martial arts athletes. The higher-level athletes had increased diversity and higher metabolic capacity of the gut microbiome for it may positively influence athletic performance.

Purpose: Angiopoietin-like protein 2 (ANGPTL2) is a secretory glycoprotein with various functions in vascular biology, inflammation and tumor development. As shown in our previous studies, ANGPTL2 expression positively correlates with liver fibrosis stages in chronic hepatitis B (CHB) patients. The aim of this study was further to assess whether ANGPTL2 represents a potential biomarker for detecting hepatocellular carcinoma (HCC). Patients and methods: This study enrolled 361 participants including healthy controls (HCs) and patients with CHB, liver cirrhosis (LC) and HCC. A discovery cohort consisted of 35 HCs and 55 patients with HCC. A total of 271 participants, including 45 HCs, 125 patients with CHB, 38 patients with LC, and 63 patients with HCC were enrolled in a validation cohort. Serum ANGPTL2 levels were detected using a human ANGPTL2 assay kit, and hepatic expression of ANGPTL2 was analyzed using immunohistochemistry. Results: In the discovery cohort, a significantly higher serum ANGPTL2 level was detected in HCC than in HCs (73.49±33.87 vs 30.54±9.86; pConclusions: ANGPTL2 may be used as a promising biomarker for the diagnosis of CHB-related HCC.

Brain-derived neurotrophic factor (BDNF) is one of the proteins that contributes to the survival, growth, maintenance of neurons, and plays important roles in the pathophysiology of depression. It has been reported that depression is closely associated with the pathogenesis of acne vulgaris disease. But, there is no report of serum BDNF levels in patients with acne vulgaris. The study aimed to determine the potential association between BDNF and depressive symptoms in young adults with acne vulgaris. In this analytical cross-sectional study, the serum BDNF levels were measured in peripheral blood samples of 20 consecutive acne vulgaris patients with depression and 98 consecutive acne vulgaris patients without depression and also compared it with a 59 healthy control group by using a ELISA. The potential correlation between the BDNF levels, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and depressive symptoms such as nine-item patient health questionnaire (PHQ-9) and Athens insomnia scale (AIS) were evaluated with multivariate logistic regression analysis. Our results showed that levels of BDNF expression were lower in consecutive acne vulgaris patients when compared with healthy control (P < 0.05). There was a negative correlation between levels of BDNF and the PHQ-9 scores (r = − 0.486, P < 0.001). Furthermore, acne vulgaris patients with depression showed lower serum BDNF levels (10.96 ± 2.12 ng/ml) compared with acne vulgaris patients without depression (13.85 ± 2.47 ng/ml), as well as with healthy control (14.35 ± 2.70 ng/mg; both P < 0.05). No difference was found in serum BDNF levels between healthy control and acne vulgaris patients without depressive symptoms (z = 0.964, P > 0.05). Similarly, the overall area under the curve of receiver operating characteristic was 0.82, indicating the highly conserving of serum BDNF levels as an biomarker for screening of depression in young adults with acne vulgaris (72% sensitivity and 85% specificity). Serum BDNF levels were decreased and negatively associated with depressive symptoms in young Chinese adults with acne vulgaris.

Purpose YKL-40 is a chitinase-like protein expressed in multiple tissues including liver and is reported as a fibrosis marker. This study aimed to determine whether YKL-40 could serve as a diagnostic marker for the assessment of liver fibrosis in chronic hepatitis B patients with normal and mildly elevated ALT. Methods Six hundred and eighty-five patients with chronic hepatitis B infection were enrolled in this study from October 2013 to March 2016. All patients underwent liver biopsy and then staged based on Ishak histological system. Serum YKL-40 levels were measured by Human Magnetic Luminex Assays. Results Among chronic hepatitis B patients with normal and mildly elevated ALT, almost more than 30% of patients have significant liver fibrosis. Serum YKL-40 levels increased significantly in parallel with the progression of fibrosis in patients with ALT less than two times the upper limit of normal range (P < 0.0001). Multivariate analysis revealed that serum YKL-40, hyaluronic acid, PLT, and AST were independently associated with significant fibrosis. We established a novel YKL-40-based fibrosis model for patients with ALT less than two times the upper limit of normal range (ULN). YKL-40 model was superior to APRI, FIB-4, Forns’ index, and Hui model for diagnosis of significant fibrosis in patients with ALT < 2ULN, with AUROCs of 0.786 [95% confidence interval (CI) 0.726–0.846] in the training group, 0.831 (95%CI 0.752–0.910) in the validation group and 0.801 (95%CI 0.753–0.849) in the entire cohort. Conclusion Serum YKL-40 is a feasible biomarker of liver fibrosis in chronic hepatitis B patients. YKL-40 model was superior to APRI, FIB-4, Forns’ index and Hui model for diagnosis of significant fibrosis in patients with normal and mildly elevated ALT.