Association between metabolic dysfunction-associated steatotic liver disease and risk of colorectal cancer or colorectal adenoma: an updated meta-analysis of cohort studies.

Background and aims: In recent years, the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and colorectal cancer (CRC) or colorectal adenoma (CRA) has gained widespread attention. Previous meta-analyses on this subject either incorporated numerous cross-sectional studies, which were susceptible to bias, or concentrated solely on a restricted number of cohort studies. Moreover, with the release of a substantial number of high-quality cohort studies on this subject in the past two years, the findings continue to be debated and contradictory. Therefore, we conducted an updated systematic review and meta-analysis of cohort studies to quantitatively evaluate the magnitude of the association between them. Methods: Comprehensive searches of PubMed, Web of Science, and Embase were conducted without language restrictions from the time of their creation up to December, 2023. The pooled hazard ratios (HRs) with 95% confidence interval (CIs) were calculated by the generic inverse variance based on the random-effects model. Moreover, subgroup and sensitivity analyses were performed. Results: A total of 15 cohort studies were analyzed in this meta-analysis, which included 9,958,412 participants. The meta-analysis of 13 cohort studies showed that MASLD was linked to a higher risk of CRC (HR=1.25, 95% CI: 1.15-1.36, P < 0.00001). Additionally, further subgroup analysis indicated that the combined HR remained consistent regardless of the study location, nomenclature of fatty liver disease (FLD), confirmation methods for FLD, sample size, follow-up time, and study quality. Furthermore, the meta-analysis of four cohort studies demonstrated that MASLD was correlated with an increased risk of CRA (HR=1.38, 95% CI: 1.17-1.64, P = 0.0002). The sensitivity analysis results further validated the robustness of the aboved findings. Conclusion: The results of our meta-analysis indicated that MASLD was associated with an increased risk of incident CRC/CRA. In the future, it is necessary to conduct more prospective cohort studies to thoroughly assess potential confounding factors, particularly in individuals from Europe and North America. Furthermore, related mechanism studies should be conducted to enhance our understanding of the link between MASLD and CRC/CRA. Systematic review registration: Open Science Framework registries (https://osf.io/m3p9k).

Hypoxia-Inducible Factor-1α Regulates High Phosphate-Induced Vascular Calcification via Type III Sodium-Dependent Phosphate Cotransporter 1.

Vascular calcification (VC) has a high incidence in patients with chronic kidney disease, which is a worldwide public health problem and presents a heavy burden to society. Hypoxia-inducible factor (HIF)-1α, the active subunit of HIF-1, has been reported to play a vital role in high phosphate-induced VC. However, the underlying mechanism is still undetermined, and effective treatment is unavailable. In the present study, human aortic smooth muscle cells (HASMCs) were cultured under normal or high phosphate media conditions. HIF-1α small interfering RNA and overexpression plasmids were employed to regulate HIF-1α expression. Phosphonoformic acid was employed to restrain the function of type III sodium-dependent phosphate cotransporter 1 (Pit-1). The expression levels of HIF-1α, Pit-1, runt-related transcription factor 2 (Runx2), and smooth muscle 22 alpha (SM22α) were evaluated, and the calcium contents were also examined. Cell growth was assessed using an MTT assay. High phosphate stimulation caused an upregulation in HIF-1α and Pit-1 expression levels and induced calcium depositions in HASMCs. Upregulation of Runx2 expression accompanied by downregulation of SM22α expression was observed in the high phosphate group. Following the suppression of HIF-1α expression, there was a concomitant attenuation in Pit-1 expression, calcium deposition, the alteration of phenotypic transition marker genes, and vice versa. The most serious calcium deposition was noted in HASMCs cultured under high phosphate conditions which were pretreated with a HIF-1α overexpression plasmid. However, when the biological functions of Pit-1 were restrained, the putative serious calcium deposition was not formed even in HASMCs transfected with a HIF-1α overexpression plasmid. The findings confirmed that HIF-1α regulated Pit-1 expression and exerted its pro-calcifying effect through Pit-1, which identified HIF-1α and Pit-1 as therapeutic targets for high phosphate-induced VC.

Phosphonoformic acid reduces hyperphosphatemia-induced vascular calcification via Pit-1.

OBJECTIVE: This study aimed to examine the mechanism of hyperphosphatemia-induced vascular calcification (HPVC). METHODS: Primary human aortic smooth muscle cells and rat aortic rings were cultured in Dulbecco's modified Eagle's medium supplemented with 0.9 mM or 2.5 mM phosphorus concentrations. Type III sodium-dependent phosphate cotransporter-1 (Pit-1) small interfering RNA and phosphonoformic acid (PFA), a Pit-1 inhibitor, were used to investigate the effects and mechanisms of Pit-1 on HPVC. Calcium content shown by Alizarin red staining, expression levels of Pit-1, and characteristic molecules for phenotypic transition of vascular smooth muscle cells were examined. RESULTS: Hyperphosphatemia induced the upregulation of Pit-1 expression, facilitated phenotypic transition of vascular smooth muscle cells, and led to HPVC in cellular and organ models. Treatment with Pit-1 small interfering RNA or PFA significantly inhibited Pit-1 expression, suppressed phenotypic transition, and attenuated HPVC. CONCLUSIONS: Our findings suggest that Pit-1 plays a pivotal role in the development of HPVC. The use of PFA as a Pit-1 inhibitor has the potential for therapeutic intervention in patients with HPVC. However, further rigorous clinical investigations are required to ensure the safety and efficacy of PFA before it can be considered for widespread implementation in clinical practice.

Association between hepatitis B or hepatitis C virus infection and risk of pancreatic cancer: a systematic review and meta-analysis of cohort studies.

Background and aim: With conflicting data from previous observational studies on the relationship between hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and pancreatic cancer (PC), we decided to conduct a systematic review and meta-analysis in order to evaluate any potential association. Design: This is a systematic review and meta-analysis. Methods: We conducted a search of three databases (PubMed, Embase, and Web of Science) from the time of their creation up to June 2023. The summary results, including hazard ratio (HR) with 95% confidence interval (CI), were pooled using a generic inverse variance method and a random-effects model. Furthermore, subgroup and sensitivity analyses were conducted. Results: In this meta-analysis, 22 cohort studies with a total of 10,572,865 participants were analyzed. Meta-analysis from 15 cohort studies revealed that HBV infection was correlated with an increased risk of PC (HR = 1.53, 95% CI: 1.40-1.68, p < 0.00001) with no heterogeneity (I2 = 0%, p = 0.49). Meta-analysis from 14 cohort studies showed that HCV infection was associated with an increased risk of PC (HR = 1.82, 95% CI: 1.51-2.21, p < 0.00001). Most of our subgroup analyses yielded similar results. Meta-analysis from four cohort studies indicated that co-infection with HBV and HCV was linked to an increased risk of PC (HR = 2.32, 95% CI: 1.40-3.85, p = 0.001) with no heterogeneity observed (I2 = 0%, p = 0.60). The results of sensitivity analyses were robust. Conclusion: Our meta-analysis showed that HBV/HCV infection or co-infection with HBV and HCV was associated with an increased risk of PC. Future prospective cohort studies need to take into account various ethnicities and any confounding factors, as well as investigate the potential mechanisms of PC development in those with HBV/HCV. Trial registration: Open Science Framework registries (No: osf.io/n64ua).