TLR2 and CASP7 as the biomarkers associated with non-alcoholic fatty liver disease and chronic kidney disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are both highly prevalent worldwide. Studies have confirmed the association between them, but the underlying pathophysiological mechanisms are not clear yet. This study aims to identify the genetic and molecular mechanisms influencing both diseases through a bioinformatics approach. RESULTS: Fifty-four overlapping differentially expressed genes associated with NAFLD and CKD were obtained by analysis of microarray datasets GSE63067 and GSE66494 downloaded from Gene Expression Omnibus. Next, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Nine hub genes were screened using protein-protein interaction network and Cytoscape software, including TLR2, ICAM1, RELB, BIRC3, HIF1A, RIPK2, CASP7, IFNGR1 and MAP2K4. The receiver operating characteristic curve results showed that all hub genes have good diagnostic values for patients with NAFLD and CKD. The mRNA expression of nine hub genes was detected in NAFLD and CKD animal models, and it was found that the expression of TLR2 and CASP7 was significantly increased in both disease models. CONCLUSIONS: TLR2 and CASP7 can be used as biomarkers for both diseases. Our study provided new insights for identifying potential biomarkers and valuable therapeutic leads in NAFLD and CKD.

Identification and validation of INHBE and P4HA1 as hub genes in non-alcoholic fatty liver disease.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent type of liver disease and a worldwide disease threatening human health. This study aims to identify the novel diagnostic biomarkers of NAFLD by comprehensive bioinformatics and machine learning, and to validate our results in hepatocyte and animal models. METHODS: We used Gene Expression Omnibus (GEO) databases on NAFLD patients for differential gene expression analyses. Intersections were taken with genes from the key modules of WGCNA and differentially expressed genes (DEGs). Machine learning algorithms like LASSO regression analysis, SVM-RFE, and RandomForest were used to screen hub genes. In addition, a nomogram model and calibration curves were built in order to forecast the probability of NAFLD occurrence. Then, the relationship between hub genes and immune cells was verified using Spearman analysis. Finally, we further verified the expression of key genes by constructing a steatosis hepatocyte model and animal model. RESULTS: Key genes (INHBE and P4HA1) were identified by comprehensive bioinformatics analysis and machine learning. INHBE and P4HA1 were up-regulated and down-regulated in the steatosis hepatocyte model, respectively. Animal experiments also showed that INHBE was up-regulated in the liver of mice fed with high fat diet (HFD). CONCLUSION: INHBE and P4HA1 are the hub genes of NAFLD. Our findings may contribute to a greater understanding of the occurrence and development of NAFLD and provide potential biomarkers and possible therapeutic targets for future clinical diagnosis and treatment.

Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma: a Mendelian randomization and mediation analysis.

BACKGROUND: A previous study demonstrated that low-density lipoprotein cholesterol (LDL-C) is associated with hepatocellular carcinoma (HCC); however, the causality between them has not been proven due to conflicting research results and the interference of confounders. This study utilized Mendelian randomization (MR) to investigate the causal relationship between LDL-C and HCC and identify the mediating factors. METHODS: LDL-C, HCC, and coronary artery disease (CAD) genome-wide association study (GWAS) data were obtained from a public database. To investigate causality, inverse variance weighting (IVW) was the main analysis approach. MR‒Egger, simple mode, weighted median (WM), and weighted mode were employed as supplementary analytic methods. In addition, horizontal pleiotropy and heterogeneity were tested. To evaluate the stability of the MR results, a "leave-one-out" approach was used. Multivariate MR (MVMR) was utilized to correct the confounders that might affect causality, and mediation analysis was used to investigate the potential mediating effects. Finally, we used HCC risk to infer the reverse causality with LDL-C level. RESULTS: Random effects IVW results were (LDL-C-HCC: odds ratio (OR) = 0.703, 95% confidence interval (CI) = [0.508, 0.973], P = 0.034; CAD-HCC: OR = 0.722, 95% CI = [0.645, 0.808], P = 1.50 × 10-8; LDL-C-CAD: OR = 2.103, 95% CI = [1.862, 2.376], P = 5.65 × 10-33), demonstrating a causal link between LDL-C levels and a lower risk of HCC. Through MVMR, after mutual correction, the causal effect of LDL-C and CAD on HCC remained significant (P < 0.05). Through mediation analysis, it was proven that CAD mediated the causative connection between LDL-C and HCC, and the proportion of mediating effect on HCC was 58.52%. Reverse MR showed that HCC could affect LDL-C levels with a negative correlation (ORIVW = 0.979, 95% CI = [0.961, 0.997], P = 0.025). CONCLUSION: This MR study confirmed the causal effect between LDL-C levels and HCC risk, with CAD playing a mediating role. It may provide a new view on HCC occurrence and development mechanisms, as well as new metabolic intervention targets for treatment.

Inflammatory biomarkers in older adults with frailty: a systematic review and meta-analysis of cross-sectional studies.

BACKGROUND: Systemic chronic inflammation has been proposed as an essential mediating factor in frailty, and several studies tested its relationship with frailty. However, the issue is still controversial. OBJECTIVES: We identified observational studies and pooled their results to assess whether abnormal expression of inflammatory biomarkers is present in the blood of older adults with frailty. METHODS: We conducted a systematic search on the Medline, Embase, and Web of Science database from inception to 1st September 2021. The quality of included studies was assessed using the JBI Critical Appraisal Checklist for Analytical Cross-Sectional Studies (JBI-MAStARI). Study heterogeneity was assessed with the Cochran Q test and I2 statistic. Pooled estimates were obtained through random-effect models. Sensitivity analyses were conducted by excluding one of the studies. Egger's regression test and observation of funnel plots were used to detect small-study effects and publication bias. PROSPERO registration: CRD42020172853. RESULT: A total of 53 cross-sectional studies corresponding to 56 independent study populations were included in this analysis. There were 31 study populations with three frailty categories (3144 frailty, 14,023 pre-frailty, 10,989 robust) and 25 study populations with two frailty categories (2576 frailty, 8368 non-frailty). This meta-analysis performed pooled analyses for the inflammatory biomarker leukocyte, lymphocytes, CRP, IL-6, IL-10, and TNF-α. Older adults with frailty had lower lymphocytes and higher interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α) levels compared with the control group. However, there was no significant difference in leukocyte and IL-10 levels in the two groups. CONCLUSIONS: These findings suggest that peripheral inflammatory biomarkers lymphocytes, IL-6, CRP, and TNF-α are related to frailty status. Our findings are not conclusive regarding the causal relationship between chronic inflammation and frailty, so the development of further longitudinal and well-designed studies focused on this is necessary.

Diagnostic methods and drug therapies in patients with ischemic colitis.

PURPOSE: Ischemic colitis (IC) is the most prevalent ischemic injury of thegastrointestinal tract. Clinical features of IC such as acute abdominal pain, hematochezia,and diarrhea are similar to those of acute mesenteric ischemia, inflammatorybowel disease, or infectious bowel disease, and their relative ambiguity candelay diagnosis and treatment. To comprehensively detail the current state ofdiagnostic methods and available drug therapies for detecting and treating IC,this review aims to provide a concise and practical summary of thecorresponding literature. METHODS: PubMed and Cochrane Library were searched toretrieve all published studies reporting the diagnostic methods and drugtherapies in patients with ischemic colitis. The search strategy of drugtherapy includes human and animal data. RESULTS: Colonoscopy combined with histopathologicalbiopsy is the standard of diagnosis for the IC. Most patients respond well tothe conservative treatment, and surgical consultation is needed when conservativetreatment is ineffective. Studies of potential drug therapy have beendeveloped, including phosphodiesterase type 5 inhibitors, pentoxifylline,rebamipide, prostaglandin E1, and polydeoxyribonucleotide. CONCLUSION: Accurate diagnoses and effective treatmentshave helped reduce the mortality rate and improve prognoses for patientsafflicted with IC, and corresponding drug therapies have been constantlyupdated as new research has emerged.

Research on the circadian clock gene HNF4a in different malignant tumors.

Background: The circadian rhythm is produced by multiple feedback loops formed by the core clock genes after transcription and translation, thus regulating various metabolic and physiological functions of the human body. We have shown previously that the abnormal expression of 14 clock genes is related closely to the occurrence and development of different malignant tumors, and these genes may play an anti-cancer or pro-cancer role in different tumors. HNF4a has many typical properties of clock proteins involved in the clock gene negative feedback loop regulation process. We need to explore the function of HNF4a as a circadian clock gene in malignant tumors further. Methods: We used The Cancer Genome Atlas (TCGA) database to download the clinicopathological information of twenty malignant tumors and the corresponding RNA-seq data. The HNF4a RNA-seq data standardized by R language and clinical information were integrated to reveal the relationship between HNF4a and prognosis of patients. Results: Analysis of TCGA data showed that the prognosis of HNF4a was significantly different in BLCA, KIRC, LUSC, and READ. High HNF4a expression is correlated with good prognosis in BLCA, KIRC, and READ but poor prognosis in LUSC. However, HNF4a was associated with the stages, T stages, and lymph node status only in BLCA. Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA. The low expression of HNF4a could be a reference index for the metastasis, recurrence, and prognosis of BLCA.

Molecularly targeted anti-cancer drugs inhibit the invasion and metastasis of hepatocellular carcinoma by regulating the expression of MMP and TIMP gene families.

To investigate the effect of multi-kinase kinase inhibitors (sorafenib; regorafenib; lenvatinib) on the invasion and metastasis of human hepatocellular carcinoma (HCC) cells, and the outcome of this effect on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), yet unclarified. Cells were subjected to four different treatments: blank control group, sorafenib (10 µmol/L) treatment group, regorafenib (20 mmol/L) treatment group, and lenvatinib (4 µmol/L) treatment group. Anti-invasion and anti-metastasis effects were tested using the wound-healing assay and transwell invasion assay. Real-time PCR and Western blot analyses were used to determine the impact of sorafenib, regorafenib, and lenvatinib on the gene expression of MMPs and TIMPs in the two HCC lines (Hep3B and SMMC-7721). Results from the wound-healing and transwell invasion assays showed the three tested anti-cancer drugs to have a significant inhibitory effect on the metastasis and invasion of HCC cells. Real-time PCR and western blot analyses revealed that sorafenib down-regulated the expressions of MMP-7,10,16 and up-regulated those of TIMP-1,3,4, regorafenib down-regulated the expression of MMP-1 and up-regulated TIMP-3 gene expression, and lenvatinib down-regulated the expressions of MMP-1,2,7,9,10,16 and up-regulated those of TIMP-1,3,4. However, these three targeted anti-cancer drugs seem to have no significant regulatory effect on the expressions of other MMPs and TIMPs family genes. In conclusion, sorafenib, regorafenib, and lenvatinib inhibit the invasion and metastasis of HCC cells by regulating MMPs/TIMPs expression levels.

The correlation of expression levels of HIF-1α and HIF-2α in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients' clinical outcome.

OBJECTIVES: The roles of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in the development of hepatocellular carcinoma have not been fully elucidated. Here, we aim to uncover the relationship between the prognosis of hepatocellular carcinoma patients and the expression of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in tumor tissues. METHODS: The protein levels of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α were detected by immunohistochemistry on paraffin sections of 126 paired hepatocellular carcinoma tissue and peritumoral tissue samples. The mRNA levels of them were detected by quantitative real-time polymerase chain reaction. RESULTS: High expression of hypoxia-inducible factor-1α was found in 57.1% (72/126) of tumor specimens, compared with 5.6% (7/126) in peritumoral tissues, while high expression of hypoxia-inducible factor-2α was found in only 13.5% (17/126) of tumors, compared with 47.6% (60/126) of peritumoral tissues. There was high expression of hypoxia-inducible factor-1α protein in hepatocellular carcinoma tissues closely associated with capsular infiltration and portal vein invasion, and thus lower overall survival and disease-free survival of hepatocellular carcinoma patients (P < 0.05). No significant association has been found between the expression of hypoxia-inducible factor-2α protein and capsular infiltration, portal vein invasion, overall survival and disease-free survival (P > 0.05). However, patients with high expression of both hypoxia-inducible factor-1α and hypoxia-inducible factor-2α have a significantly worse outcome than patients with low expression of both hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (P < 0.05). CONCLUSIONS: The discordant results on expression of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression and stabilization mechanisms. The association between hypoxia-inducible factor-1α expression and unfavorable outcome indicates the importance of using hypoxia-inducible factor-1α as a treatment target in hepatocellular carcinoma.

Bacteroides fragilis aggravates high-fat diet-induced non-alcoholic fatty liver disease by regulating lipid metabolism and remodeling gut microbiota.

Gut microbiota dysbiosis is a prominent determinant that significantly contributes to the disruption of lipid metabolism. Consequently, it is essential to the occurrence and development of non-alcoholic fatty liver disease (NAFLD). Nevertheless, the connection between diet and symbiotic gut microbiota in the progression of NAFLD remains uncertain. The purpose of this study was to explore the role of supplementing commensal Bacteroides fragilis (B. fragilis) on lipid metabolism, gut microbiota, and metabolites in high-fat diet (HFD)-fed mice, elucidating the impact of gut microbiota and metabolites on the development of NAFLD. Our study revealed that supplementation with B. fragilis exacerbated both weight gain and obesity in mice. B. fragilis exacerbated blood glucose levels and liver dysfunction in mice. Furthermore, an increase in liver lipid accumulation and the upregulation of genes correlated with lipid metabolism were observed in mice. Under an HFD, supplementation of commensal B. fragilis resulted in alterations in the gut microbiota, notably a significant increase in Desulfovibrionaceae, which led to elevated endotoxin levels and thereby influenced the progression of NAFLD. It was interesting that the simultaneous examination of gut microbiota metabolites revealed a more pronounced impact of diet on short-chain fatty acids. This study represented the pioneering investigation into the impact of B. fragilis on NAFLD. Our findings demonstrated that B. fragilis induced dysregulation in the intestinal microbiota, leading to elevated levels of lipopolysaccharide and dysfunction in glucose and lipid metabolism, thereby exacerbating NAFLD.IMPORTANCESome intestinal symbiotic microbes are involved in the occurrence of the metabolic disorders. Our study investigated the impact of supplementing commensal Bacteroides fragilis on host metabolism in high-fat diet-fed mice. Research results indicated that adding a specific bacterial strain to the complex intestinal microecology can worsen metabolic conditions. This effect mainly affects the structural diversity of intestinal microorganisms, the increase in harmful bacteria in the gut, and the elevation of endotoxin levels, blood glucose, and lipid metabolism, thereby impacting the progression of non-alcoholic fatty liver disease (NAFLD). Understanding the principles that govern the establishment of microbial communities comprising multiple species is crucial for preventing or repairing dysfunctions in these communities, thereby enhancing host health and facilitating disease treatment. This study demonstrated that gut microbiota dysbiosis could contribute to metabolic dysfunction and provides new insights into how to promote gut microbiota in the prevention and therapy of NAFLD.

Nontoxigenic Bacteroides fragilis: A double-edged sword.

The contribution of commensal microbes to human health and disease is unknown. Bacteroides fragilis (B. fragilis) is an opportunistic pathogen and a common colonizer of the human gut. Nontoxigenic B. fragilis (NTBF) and enterotoxigenic B. fragilis (ETBF) are two kinds of B. fragilis. NTBF has been shown to affect the host immune system and interact with gut microbes and pathogenic microbes. Previous studies indicated that certain strains of B. fragilis have the potential to serve as probiotics, based on their observed relationship with the immune system. However, several recent studies have shown detrimental effects on the host when beneficial gut bacteria are found in the digestive system or elsewhere. In some pathological conditions, NTBF may have adverse reactions. This paper presents a comprehensive analysis of NTBF ecology from the host-microbe perspective, encompassing molecular disease mechanisms analysis, bacteria-bacteria interaction, bacteria-host interaction, and the intricate ecological context of the gut. Our review provides much-needed insights into the precise application of NTBF.

Causal association of sarcopenia with hepatocellular carcinoma risk in European population: a Mendelian randomization study.

Background: The causal association of sarcopenia with the incidence risk of hepatocellular carcinoma (HCC) in the European population, and the potential mediating role of C-reactive protein (CRP), remains unclear. This study employed a bidirectional two-sample, two-step Mendelian randomization (MR) analysis to investigate the causality and identify the mediator. Methods: Summary statistics for HCC, CRP, and sarcopenia-related traits, including appendicular lean mass (ALM), hand grip strength (HGS), and walking pace (WP), were acquired from publicly available databases. We conducted bidirectional MR and Steiger tests of directionality to check the presence of reverse causality. Additionally, a two-step MR analysis was used to assess the mediating effect of CRP in the causality between sarcopenia and HCC. Tests for heterogeneity and horizontal pleiotropy were performed. Results: As ALM increases, the risk of HCC occurrence decreases [odds ratio (OR), 95% confidence interval (CI): 0.703, 0.524-0.943; P = 0.019]. And, genetically predicted low-HGS (OR, 95%CI: 2.287, 1.013-5.164; P = 0.047) was associated with an increased incidence risk of HCC, with no reverse causality. However, we found no evidence supporting a causality between WP and HCC. CRP was identified as the mediator of the causal effect of ALM and low-HGS on HCC, with corresponding mediating effects of 9.1% and 7.4%. Conclusions: This MR study effectively demonstrates that lower ALM and low-HGS are linked to an elevated risk of HCC within the European population, and the causality was not bidirectional. Furthermore, CRP serves as a mediator in the associations. These findings may help mitigate HCC risk among individuals with sarcopenia.

Fecal Microbiota Transplantation Attenuates Frailty via Gut-Muscle Axis in Old Mice.

Targeting adverse pathogenic gut microbiota regulation through fecal microbiota transplantation (FMT) may restore health and has been validated in some aging-related diseases. However, the mechanisms of the gut microbiota's role in frailty and whether modulation of the gut microbiota can treat age-related frailty remain largely unknown. To assess the effects of FMT on frailty, we used bidirectional fecal microbiota transplantation in young and old mice. We demonstrated that fecal bacteria transplanted from old mice into young mice reduced body weight and grip strength (p=0.002), and led to elevated inflammatory factors in young mice, but had no significant effect on intestinal barrier function. Notably, FMT treatment in older mice not only improved frailty (grip strength: p=0.036, low physical activity: p=0.020, running speed: p=0.048, running time: p=0.058, frailty score: p=0.027) and muscle mass, but also improved intestinal ecological imbalances, intestinal barrier function, and systemic inflammation (serum TNF-α: p=0.002, and IL-6: p<0.001). KEGG enrichment analysis of fecal metabolites showed that FMT may ameliorate frailty through the sphingolipid metabolism pathway. In addition, aged mice given FMT treatment showed a significant increase in the abundance of SCFA-producing bacteria and increased levels of short-chain fatty acids (butyric acid: p=0.084, propionic acid: p=0.028). Subsequent further verification found that FMT ameliorating frailty may be achieved through SCFAs metabolism. Another mechanism study found that FMT reduces lipopolysaccharide levels (p<0.001), thereby inhibiting the TLR4/NF-κB signaling pathway and its downstream pro-inflammatory products. Therefore, regulating SCFAs metabolism by altering gut microbial composition and targeting the gut-muscle axis with LPS/TLR4 pathways may be potential strategies to treat frailty in older adults.

Efficacy and safety of tyrosine kinase inhibitors plus PD-1 inhibitor in patients with transarterial chemoembolization- refractory hepatocellular carcinoma: a two-center retrospective study.

Object: To investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs: sorafenib and lenvatinib) plus PD-1 inhibitor (camrelizumab) versus TKIs alone in transarterial chemoembolization-refractory (TACE-refractory) hepatocellular carcinoma (HCC). Materials and methods: Data of TACE-refractory HCC patients treated with TACE+TKIs+PD-1 inhibitor (TACE+TKIs+PD-1group) (n=57) or TACE+TKIs (TACE+TKIs group) (n=50) from January 2019 to January 2022 were retrospectively collected and analyzed. The differences in overall survival (OS), progression-free survival (PFS), tumor responses (based on modified Response Evaluation Criteria in Solid Tumors) and adverse events (AEs) were compared between the two groups. Potential factors affecting OS and PFS were evaluated by univariate and multivariate analyses. Results: Compared with the TKIs group, both PFS and OS were prolonged in the TACE+TKIs+PD-1 group (median PFS: 7 months vs. 5 months, P=0.007; median OS: 17 months vs. 11 months, P=0.002). In multivariate analysis, tumor size and treatment were independent prognostic factors for PFS and OS. The incidence and severity of AEs related to the treatment between the two groups showed no significant difference. Conclusion: The treatment of TACE combined with TKIs plus camrelizumab demonstrated promising efficacy and safety in TACE-refractory HCC.

Lower haemoglobin-to-red blood cell distribution width ratio is independently associated with frailty in community-dwelling older adults: a cross-sectional study.

OBJECTIVES: The importance of blood cell markers in frailty has been studied. However, research on haemoglobin-to-red blood cell distribution width ratio (HRR) and frailty in older persons is still limited. We investigated the association between HRR and frailty in older adults. DESIGN: Cross-sectional population-based study. SETTING: Community-dwelling older adults older than 65 years were recruited from September 2021 to December 2021. PARTICIPANTS: A total of 1296 community-dwelling older adults (age ≥65 years) in Wuhan were included in the study. MAIN OUTCOME MEASURES: The main outcome was the presence of frailty. The Fried Frailty Phenotype Scale was used to evaluate the frailty status of the participants. Multivariable logistic regression analysis was performed to determine the relationship between HRR and frailty. RESULTS: A total of 1296 (564 men) older adults were included in this cross-sectional study. Their mean age was 70.89±4.85 years. Receiver operating characteristic curve analysis showed that HRR is a good predictor of frailty in older people, the area under the curve (AUC) was 0.802 (95% CI: 0.755 to 0.849), and the highest sensitivity was 84.5% and the specificity was 61.9% with the optimal critical values 9.97 (p<0.001). Multiple logistic regression analysis indicated that lower HRR (<9.97) (OR: 3.419, 1.679 to 6.964, p=0.001) is independently associated with frailty in older people, even after adjusting confounding factors. CONCLUSION: Lower HRR is closely associated with an increased risk of frailty in older people. Lower HRR may be an independent risk factor for frailty in community-dwelling older adults.

High blood pressure mediated the effect of fasting insulin level on nonalcoholic fatty liver disease risk: A Mendelian randomization study.

Objective: The interactions between fasting insulin levels, high blood pressure and nonalcoholic fatty liver disease (NAFLD) are still unclear. We examined the causal mechanisms between these three cardiometabolic traits using Mendelian randomization (MR) approach by utilizing genetic instruments. Methods: Three different genome-wide association studies resources of European ancestry were utilized for the present study. Two-sample MRs were used to assess causal effects between fasting insulin levels, high blood pressure and NAFLD. Multivariate MR was used to calculate the mediating effect. The inverse variance-weighted method was used as the main analysis method. Results: Our study confirmed a causal effect of fasting insulin levels (IVW-OR = 9.54, P = 0.001) and high blood pressure (IVW-OR = 3.926, P = 0.005) on NAFLD risk. And fasting insulin level was positively casually associated with high blood pressure risk (IVW-OR = 1.170, P < 0.001). However, the impact of high blood pressure on fasting insulin levels was still uncertain because of the presence of horizontal pleiotropy. Reverse MR showed NAFLD had a positive correlation with fasting insulin levels (IVW-OR = 1.010, P < 0.001) and a negative causal effect on high blood pressure risk (IVW-OR = 0.997, P = 0.037). Combined the multivariate MR result revealed high blood pressure partially mediated the contribution of fasting insulin level to NAFLD risk (proportion mediated: 9.091%). Conclusions: Our study suggests there is a bidirectional causal relationship between fasting insulin levels and NAFLD. High blood pressure seems to play a mediating role in the development of NAFLD caused by changes in fasting insulin levels. However, it is uncertain whether high blood pressure is a mediator between NAFLD and the risk of fasting insulin level.

Comprehensive analysis of the tumor-promoting effect and immune infiltration correlation MAZ from pan-cancer to hepatocellular carcinoma.

BACKGROUND: Myc-associated zinc-finger protein (MAZ) is a transcription factor, which has been confirmed to be abnormally expressed in many tumors and involved in regulating the proliferation, migration, apoptosis, and autophagy of tumor cells. Currently, there is a lack of comprehensive analysis of MAZ in pan-cancer, and the mechanism of MAZ in hepatocellular carcinoma (HCC) and its association with immunotherapy remains unclear. METHODS: The expression, prognostic mutation, sCNA, and tumor immunity characteristics of MAZ in 33 types of tumors were analyzed by The Cancer Genome Atlas (TCGA), GEPIA, and TIMER databases. The association of MAZ expression levels with drug sensitivity, immunotherapy, immune checkpoints, and HLA-associated genes was further analyzed. Transwell, CCK-8, wound healing, and flow cytometry verified that MAZ affected the malignant cell behavior of HCC. The signaling pathways and cellular functions affected by MAZ in HCC were revealed by GSEA enrichment analysis. RESULTS: The expression level of MAZ was up-regulated, and the high expression of MAZ indicated a high-risk prognostic factor in most tumors, including ACC, BLCA, KIRP, LIHC, PRAD, SKCM, and THCA (p < 0.05). MAZ expression was positively correlated with the sensitivity of most chemotherapy drugs (p < 0.05). HLA-DQB2, HLA-H, and most immune checkpoint genes were remarkably up-regulated in the high MAZ expression group (p < 0.05). GSEA analysis revealed that MAZ expression was highly correlated with the intracellular immune-related functions and cancer-related signaling pathway, including the B cell receptor signaling pathway, complement activation, humoral immune response, TGF-ß signaling pathway, and Wnt signaling pathway. The overexpression of MAZ in HCC cells could promote the abilities of cell proliferation and migration and inhibit tumor cell apoptosis. CONCLUSION: Our study revealed that MAZ might play a role in promoting the progression of HCC. It was closely related to the tumor microenvironment, immune cell infiltration, and immune escape in pan-cancer. Moreover, this study provides new insights into MAZ as a prognostic marker and potential therapeutic target in HCC.

Prognostic and clinicopathological values of LINC00665 in cancers: a systematic review and China population-based meta-analysis.

BACKGROUND: Recent studies have uncovered that the aberrant expression of LINC00665 contributes to the malignant pathological process of various cancers and is closely related to the unfavorable prognosis of patients with cancer. However, a systematic analysis of the prognostic and clinicopathologic values of LINC00665 in cancers has not been conducted. OBJECTIVE: We aim to clarify the association of LINC00665 expression with patient survival and clinicopathologic phenotypes in cancers. METHODS: An electronic search of PubMed, Embase and Web of Science was performed to select eligible literature. Pooled hazard ratio (HR) and odds ratio (OR) were calculated to assess the clinical importance of LINC00665. The fixed-effects model was used to analyze the combined HR values and 95% CI when the studies had no significant heterogeneity (P > 0.1 for the Chi-square test or I2 < 50%). Begg's test and sensitivity analysis were also conducted. This study was registered in The International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42021290123). RESULTS: A total of 710 patients from 10 eligible studies were enrolled in this meta-analysis, which was based on China population. The pooled results of this analysis revealed that high-level expression of LINC00665 was notably correlated with poor overall survival (HR = 2.08, 95% CI = 1.57-2.75) and recurrence-free survival (HR = 2.49, 95% CI = 1.63-3.80) in human cancers. Elevated LINC00665 expression was also correlated with more advanced clinical stage, earlier lymph node metastasis, lower tumor differentiation, earlier distant metastasis and larger tumor size. CONCLUSION: LINC00665 expression was critically related to the cancer prognosis, which has important prognostic implications for clinical prediction.

Fecal microbial biomarkers in older adults with autoimmune diseases.

Aim: To analyze the alterations in the fecal microbiota of older adults with autoimmune disease and determine the diagnostic capabilities of microbial biomarkers. Methods: The raw data of fecal samples from 444 older adults from the publicly available American Gut Project database was analyzed. Results: It was found that there were no significant differences in the microbiota richness and evenness between older adults with autoimmune disease and healthy controls. However, significant differences were observed in the microbiota composition and structure. The subject operating characteristic curve of the eight key microbiota was obtained, and the area under curve value was 70.0%. Conclusion: Older adults with autoimmune disease showed changes in intestinal microbiota composition, which can be used as microbial biomarkers.

Comprehensive analysis of basement membrane and immune checkpoint related lncRNA and its prognostic value in hepatocellular carcinoma via machine learning.

Background: Hepatocellular carcinoma (HCC), which is characterized by its high malignancy, generally exhibits poor response to immunotherapy. As part of the tumor microenvironment, basement membranes (BMs) are involved in tumor development and immune activities. Presently, there is no integrated analysis linking the basement membrane with immune checkpoints, especially from the perspective of lncRNA. Methods: Based on transcriptome data from The Cancer Genome Atlas, BMs-related and immune checkpoint-related lncRNAs were identified. By applying univariable Cox regression and Machine learning (LASSO and SVM-RFE algorithm), a 10-lncRNA prognosis signature was constructed. The prognostic significance of this signature was assessed by survival analysis. GSEA, ssGSEA, and drug sensitivity analysis were conducted to investigate potential functional pathways, immune status, and clinical implications of guiding individual treatments in HCC. Finally, the promoting migration effect of LINC01224 was validated via in vitro experiments. Results: The multiple Cox regression, receiver operating characteristic curves, and stratified survival analysis of clinical subgroups exhibited the robust prognostic ability of the lncRNA signature. Results of the GSEA and drug sensitivity analysis revealed significant differences in potential functional pathways and response to drugs between the two risk groups. In addition, the risk level of HCC patients was distinctly correlated with immune cell infiltration status. More importantly, LINC01224 was independently associated with the OS of HCC patients (P < 0.05), suppressing the expression of LINC01224 inhibited the migration of HCC cells. Conclusion: This study developed a reliable signature for the prognosis of HCC based on BM and immune checkpoint related lncRNA, revealing that LINC01224 might be a prognostic biomarker for HCC associated with the progression of HCC.

Ferroptosis - A new target of osteoporosis.

Osteoporosis is a bone metabolic disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture, leading to enhanced skeletal fragility and susceptibility to fracture. Unbalanced bone remodeling is the primary pathogenetic factor of osteoporosis, in which osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Bisphosphonates and calcitonin are among the drugs commonly used to treat osteoporosis, in addition to the bone nutrients vitamin D and calcium supplements. The current treatments effectively prevent further bone loss by inhibiting the excessive activation of osteoclasts, accompanied by various degrees of side effects. Iron, one of the trace elements essential for life activities, has recently been recognized as an independent risk factor for osteoporosis. Abnormal iron metabolism increases the incidence of many bone diseases, especially osteoporosis. Iron metabolism does play a key role in bone homeostasis. Ferroptosis is a novel form of cell death that has been discovered in recent years. Its main features include iron overload and the accumulation of ROS. And lipid peroxidation is the key. There are increasing shreds of evidence that ferroptosis is involved in the occurrence and development of osteoporosis, and its regulation can effectively prevent osteoporosis. Therefore, this review further elucidates the role of ferroptosis in osteoporosis based on the mechanism and its relationship with osteoporosis and provides a new idea for treating osteoporosis.