Dipeptidyl peptidase-4 marks distinct subtypes of human adipose stromal/stem cells with different hepatocyte differentiation and immunoregulatory properties.

BACKGROUND: Human adipose-derived stromal/stem cells (hASCs) play important roles in regenerative medicine and numerous inflammatory diseases. However, their cellular heterogeneity limits the effectiveness of treatment. Understanding the distinct subtypes of hASCs and their phenotypic implications will enable the selection of appropriate subpopulations for targeted approaches in regenerative medicine or inflammatory diseases. METHODS: hASC subtypes expressing dipeptidyl peptidase-4 (DPP4) were identified via fluorescence-activated cell sorting (FACS) analysis. DPP4 expression was knocked down in DPP4+ hASCs via DPP4 siRNA. The capacity for proliferation, hepatocyte differentiation, inflammatory factor secretion and T-cell functionality regulation of hASCs from DPP4-, DPP4+, and control siRNA-treated DPP4+ hASCs and DPP4 siRNA-treated DPP4+ hASCs were assessed. RESULTS: DPP4+ hASCs and control siRNA-treated DPP4+ hASCs presented a lower proliferative capacity but greater hepatocyte differentiation capacity than DPP4- hASCs and DPP4 siRNA-treated DPP4+ hASCs. Both DPP4+ hASCs and DPP4- hASCs secreted high levels of vascular endothelial growth factor-A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6), whereas the levels of other factors, including matrix metalloproteinase (MMP)-1, eotaxin-3, fractalkine (FKN, CX3CL1), growth-related oncogene-alpha (GRO-alpha, CXCL1), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP)-1beta, and macrophage colony-stimulating factor (M-CSF), were significantly greater in the supernatants of DPP4+ hASCs than in those of DPP4- hASCs. Exposure to hASC subtypes and their conditioned media triggered changes in the secreted cytokine profiles of T cells from healthy donors. The percentage of functional T cells that secreted factors such as MIP-1beta and IL-8 increased when these cells were cocultured with DPP4+ hASCs. The percentage of polyfunctional CD8+ T cells that secreted multiple factors, such as IL-17A, tumour necrosis factor alpha (TNF-α) and TNF-ß, decreased when these cells were cocultured with supernatants derived from DPP4+ hASCs. CONCLUSIONS: DPP4 may regulate proliferation, hepatocyte differentiation, inflammatory cytokine secretion and T-cell functionality of hASCs. These data provide a key foundation for understanding the important role of hASC subpopulations in the regulation of T cells, which may be helpful for future immune activation studies and allow them to be customized for clinical application.

Prognostic significance of GATA2 in patients with MDS/AML: a systematic review and meta-analysis.

GATA2 deficiency syndrome is a heterogeneous disorder characterized by a high risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). We conducted a meta-analysis of the literature to explore the prognostic significance of GATA2 mutations in patients diagnosed with MDS/AML, as previous studies have yielded conflicting findings regarding the impact of GATA2 mutations on patient outcomes. We conducted a comprehensive literature search of databases such as PubMed, Embase, the Cochrane Library, and the Web of Science to obtain studies on the prognostic significance of GATA2 mutations in patients with MDS/AML that were published through January 2024. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). The meta-analysis was conducted by choosing either a fixed-effect model or a random-effect model, depending on the variability observed among the studies. A total of 13 cohort studies were included in the final meta-analysis, including 2714 patients with MDS, of whom 644 had GATA2 mutations. The results revealed that GATA2 mutations had an adverse impact on OS (HR = 1.54, 95% CI = 1.08-2.18, P = 0.02) and EFS (HR = 1.32, 95% CI = 1.01-1.72, P = 0.04), but no significant effect on DFS (HR = 1.21, 95% CI = 0.89-1.64, P = 0.23). GATA2 mutations were associated with a significantly shorter OS in MDS patients (HR = 2.56, 95% CI = 1.42-4.06, P = 0.002) but not in AML patients (HR = 1.08, 95% CI = 0.92-1.26, P = 0.37). Our meta-analysis revealed that GATA2 mutations are associated with unfavourable outcomes in patients with MDS/AML. Furthermore, patients harbouring these mutations should be prioritized for aggressive therapeutic interventions.

Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain: A meta-analysis.

Background: Various prevalences of asthma in coronavirus disease 2019 (COVID-19) have been reported in different regions, and the association between asthma and COVID-19 subsequent mortality has been in debate. Thus, this study aimed to investigate whether there was a significant association between asthma and COVID-19 mortality in Spain through a meta-analysis. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were strictly complied with conducting this study. The pooled odds ratio (OR) with a corresponding 95% confidence interval (CI) was calculated by a random-effects model. The I 2 statistics for heterogeneity, sensitivity analysis for robustness, Begg's test, and Egger's test for publication bias, along with subgroup analyses for confounding bias, were also performed to support the foundation of this study. Results: The meta-analysis revealed that asthma was significantly associated with a lower risk of mortality among COVID-19 patients in Spain with a random-effects model (pooled OR = 0.78, 95% CI = 0.69-0.88, I 2 = 35%). Further subgroup analyses by male proportion and sample size also indicated that a statistically significant negative correlation did exist between asthma and COVID-19 mortality. Robustness and no publication on-bias were evidenced by sensitivity analysis, Egger's test, and Begg's test, respectively. Conclusion: In conclusion, patients with asthma were found to have a lower risk of mortality from COVID-19 in Spain, especially among elderly patients. In addition, asthmatic patients infected with COVID-19 may be at risk of death compared to non-asthmatic patients, which is not a cause for undue concern, thereby reducing the burden of medication.

Review on Long Non-Coding RNAs as Biomarkers and Potentially Therapeutic Targets for Bacterial Infections.

The confrontation between humans and bacteria is ongoing, with strategies for combating bacterial infections continually evolving. With the advancement of RNA sequencing technology, non-coding RNAs (ncRNAs) associated with bacterial infections have garnered significant attention. Recently, long ncRNAs (lncRNAs) have been identified as regulators of sterile inflammatory responses and cellular defense against live bacterial pathogens. They are involved in regulating host antimicrobial immunity in both the nucleus and cytoplasm. Increasing evidence indicates that lncRNAs are critical for the intricate interactions between host and pathogen during bacterial infections. This paper emphatically elaborates on the potential applications of lncRNAs in clinical hallmarks, cellular damage, immunity, virulence, and drug resistance in bacterial infections in greater detail. Additionally, we discuss the challenges and limitations of studying lncRNAs in the context of bacterial infections and highlight clear directions for this promising field.

Blockade of TGF-ß signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue.

BACKGROUND: Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS: The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS: We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-ß1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-ß1 signalling using an anti-TGF-ß1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS: Native ECM in obesity vWAT initiates hASC senescence through TGF-ß1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.

Comorbid asthma decreased the risk for COVID-19 mortality in the United Kingdom: Evidence based on a meta-analysis.

The study aimed to investigate the influence of comorbid asthma on the risk for mortality among patients with coronavirus disease 2019 (COVID-19) in the United Kingdom (UK) by utilizing a quantitative meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was estimated by conducting a random-effects model. Sensitivity analysis, I2 statistic, meta-regression, subgroup analysis, Begg's analysis and Egger's analysis were all implemented. Our results presented that comorbid asthma was significantly related to a decreased risk for COVID-19 mortality in the UK based on 24 eligible studies with 1,209,675 COVID-19 patients (pooled OR = 0.81, 95% CI: 0.71-0.93; I2 = 89.2%, P < 0.01). Coming through further meta-regression to seek the possible cause of heterogeneity, none of elements might be responsible for heterogeneity. A sensitivity analysis proved the stability and reliability of the overall results. Both Begg's analysis (P = 1.000) and Egger's analysis (P = 0.271) manifested that publication bias did not exist. In conclusion, our data demonstrated that COVID-19 patients with comorbid asthma might bear a lower risk for mortality in the UK. Furthermore, routine intervention and treatment of asthma patients with severe acute respiratory syndrome coronavirus 2 infection should be continued in the UK.

Significant association between HIV infection and increased risk of COVID-19 mortality: a meta-analysis based on adjusted effect estimates.

To investigate the relationship between human immunodeficiency virus (HIV) infection and the risk of mortality among coronavirus disease 2019 (COVID-19) patients based on adjusted effect estimate by a quantitative meta-analysis. A random-effects model was used to estimate the pooled effect size (ES) with corresponding 95% confidence interval (CI). I2 statistic, sensitivity analysis, Begg's test, meta-regression and subgroup analyses were also conducted. This meta-analysis presented that HIV infection was associated with a significantly higher risk of COVID-19 mortality based on 40 studies reporting risk factors-adjusted effects with 131,907,981 cases (pooled ES 1.43, 95% CI 1.25-1.63). Subgroup analyses by male proportion and setting yielded consistent results on the significant association between HIV infection and the increased risk of COVID-19 mortality. Allowing for the existence of heterogeneity, further meta-regression and subgroup analyses were conducted to seek the possible source of heterogeneity. None of factors might be possible reasons for heterogeneity in the further analyses. Sensitivity analysis indicated the robustness of this meta-analysis. The Begg's test manifested that there was no publication bias (P = 0.2734). Our findings demonstrated that HIV infection was independently associated with a significantly increased risk of mortality in COVID-19 patients. Further well-designed studies based on prospective study estimates are warranted to confirm our findings.

α5 integrin regulates hepatic tight junctions through SRC-TET1-mediated DNA hydroxymethylation.

The functional tight junctions' integrity plays an important role in liver physiology. A variety of liver diseases have been associated with the perturbation of tight junctions. Herein, we showed that the lower expression of α5 integrin in hepatocytes in patients with liver cirrhosis is associated with matrix deposition in the space of Disse. Selective silencing of α5 integrin in hepatocytes compromised the ultrastructure of tight junctions by downregulating claudin 1 in an SRC (proto-oncogene, non-receptor tyrosine kinase) signaling-dependent manner. α5 integrin signaling induced SRC-TET-mediated changes in 5-hydroxymethylcytosine and 5-methylcytosine levels in hepatocytes in vitro and in vivo. hMeDIP sequencing showed intergenic hypohydroxymethylation of the claudin 1 gene in hepatocytes after α5 integrin silencing in mice. Therefore, understanding the mechanisms regulating hepatic tight junction integrity in which α5 integrin-SRC signaling and epigenetic modifications cooperate might help advance the development of useful diagnostics and therapeutic approaches for liver disease.

The association between stroke and COVID-19-related mortality: a systematic review and meta-analysis based on adjusted effect estimates.

OBJECTIVE: To investigate the association between stroke and the risk for mortality among coronavirus disease 2019 (COVID-19) patients. METHODS: We performed systematic searches through electronic databases including PubMed, Embase, Scopus, and Web of Science to identify potential articles reporting adjusted effect estimates on the association of stroke with COVID-19-related mortality. To estimate pooled effects, the random-effects model was applied. Subgroup analyses and meta-regression were performed to explore the possible sources of heterogeneity. The stability of the results was assessed by sensitivity analysis. Publication bias was evaluated by Begg's test and Egger's test. RESULTS: This meta-analysis included 47 studies involving 7,267,055 patients. The stroke was associated with higher COVID-19 mortality (pooled effect = 1.30, 95% confidence interval (CI): 1.16-1.44; I2 = 89%, P < 0.01; random-effects model). Subgroup analyses yielded consistent results among area, age, proportion of males, setting, cases, effect type, and proportion of severe COVID-19 cases. Statistical heterogeneity might result from the different effect type according to the meta-regression (P = 0.0105). Sensitivity analysis suggested that our results were stable and robust. Both Begg's test and Egger's test indicated that potential publication bias did not exist. CONCLUSION: Stroke was independently associated with a significantly increased risk for mortality in COVID-19 patients.

Impact of asthma on COVID-19 mortality in the United States: Evidence based on a meta-analysis.

OBJECTIVE: The aim of this study was to investigate the impact of asthma on the risk for mortality among coronavirus disease 2019 (COVID-19) patients in the United States by a quantitative meta-analysis. METHODS: A random-effects model was used to estimate the pooled odds ratio (OR) with corresponding 95% confidence interval (CI). I2 statistic, sensitivity analysis, Begg's test, meta-regression and subgroup analyses were also performed. RESULTS: The data based on 56 studies with 426,261 COVID-19 patients showed that there was a statistically significant association between pre-existing asthma and the reduced risk for COVID-19 mortality in the United States (OR: 0.82, 95% CI: 0.74-0.91). Subgroup analyses by age, male proportion, sample size, study design and setting demonstrated that pre-existing asthma was associated with a significantly reduced risk for COVID-19 mortality among studies with age ≥ 60 years old (OR: 0.79, 95% CI: 0.72-0.87), male proportion ≥ 55% (OR: 0.79, 95% CI: 0.72-0.87), male proportion ＜ 55% (OR: 0.81, 95% CI: 0.69-0.95), sample sizes ≥ 700 cases (OR: 0.80, 95% CI: 0.71-0.91), retrospective study/case series (OR: 0.82, 95% CI: 0.75-0.89), prospective study (OR: 0.83, 95% CI: 0.70-0.98) and hospitalized patients (OR: 0.82, 95% CI: 0.74-0.91). Meta-regression did reveal none of factors mentioned above were possible reasons of heterogeneity. Sensitivity analysis indicated the robustness of our findings. No publication bias was detected in Begg's test (P = 0.4538). CONCLUSION: Our findings demonstrated pre-existing asthma was significantly associated with a reduced risk for COVID-19 mortality in the United States.

GSK3 inhibitor ameliorates steatosis through the modulation of mitochondrial dysfunction in hepatocytes of obese patients.

Obesity is an important risk factor and a potential treatment target for hepatic steatosis. The maladaptation of hepatic mitochondrial flexibility plays a key role in the hepatic steatosis. Herein, we found that hepatocyte-like cells derived from human adipose stem cell of obese patients exhibited the characteristics of hepatic steatosis and accompanied with lower expression of the subunits of mitochondrial complex I and lower oxidative phosphorylation levels. The GSK3 inhibitor CHIR-99021 promoted the expression of NDUFB8, NDUFB9, the subunits of mitochondrial complex I, the basal oxygen consumption rate, and the fatty acid oxidation of the hepatocytes of obese patients by upregulating the expression of the transcription factor PGC-1α, TFAM, and NRF1 involved in mitochondrial biogenesis. Moreover, CHIR-99021 decreased the lipid droplets size and the triglyceride levels in hepatocytes of obese patients. The results demonstrate that GSK3 inhibition ameliorates hepatic steatosis by elevating the mitochondrial function in hepatocytes of obese patients.