miR-208a-3p regulated by circUQCRC2 suppresses ischemia/reperfusion-induced acute kidney injury by inhibiting CELF2-mediated tubular epithelial cell apoptosis, inflammation and ferroptosis.

ABSTRACT: Background : Acute kidney injury (AKI) is a prevalent clinical syndrome with persistent kidney dysfunction. Renal ischemia/reperfusion (I/R) injury is a major cause of AKI. miR-208a-3p overexpression attenuated myocardial I/R injury. This study aims to investigate the role and mechanism of miR-208a-3p in I/R-induced AKI. Methods : AKI models were established using hypoxia/reoxygenation (H/R)-exposed tubule epithelial cell HK-2 and I/R-induced mice. The function and mechanism of miR-208a-3p were investigated by gain- or loss-of-function methods using real-time PCR, CCK-8, flow cytometry, ELISA, western blot, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, detection of Fe 2+ , reactive oxygen species, blood urea nitrogen and creatinine, and luciferase reporter assay. Results : miR-208a-3p expression was suppressed, while the expression of CELF2 and circular RNA ubiquinol-cytochrome c reductase core protein 2 (circUQCRC2) was increased in both AKI models. miR-208a-3p upregulation or circUQCRC2 silencing increased the viability, decreased the levels of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6), reduced apoptosis and contents of Fe 2+ and reactive oxygen species, elevated expression of GPX4 and SLC7A11, and reduced ACSL4 expression in H/R-stimulated HK-2 cells. In addition, miR-208a-3p improved kidney function by alleviating renal injury, apoptosis, inflammation, and ferroptosis in AKI mouse model. CELF2 was a target gene of miR-208a-3p, which was negatively modulated by circUQCRC2. Overexpression of CELF2 blocked the function of miR-208a-3p upregulation or circUQCRC2 silencing on H/R-treated HK-2 cells. Moreover, the effects of circUQCRC2 downregulation on H/R-injured cells were also reversed by miR-208a-3p inhibitor. Conclusions : miR-208a-3p regulated by circUQCRC2 could attenuate I/R-induced AKI by inhibiting CELF2-mediated tubular epithelial cell apoptosis, inflammation and ferroptosis. This study provides potential therapeutic targets for I/R-induced AKI.

Development of a high-performance label-free electrochemical immunosensor for early cancer diagnosis using anti-CEA/Ag-MOF/GO/GCE nanocomposite.

In order to detect carcinoembryonic antigen (CEA) as a tumor marker in lung cancer for early cancer diagnosis, this study aimed to develop a label-free electrochemical immunosensor based on the immobilization of an Anti-CEA antibody on a metal-organic framework (MOF)-graphene oxide nanocomposite modified glassy carbon electrode (Anti-CEA/Ag-MOF/GO/GCE). Ag-MOF/GO nanocomposite was prepared on the GCE surface using the ultrasonic irradiation method, and Anti-CEA antibody was subsequently immobilized on the surface. Analysis of the crystal structure and morphology of the modified electrode using FE-SEM and XRD revealed that the correct combination of GO nanosheets and Ag-MOF nanoparticles produced a high surface area to trap the antibodies. Electrochemical tests utilizing the CV and DPV methods revealed that the immunosensor's sensitivity, stability, and selectivity were improved by Anti-CEA/Ag-MOF/GO/GCE. Results showed that, with a detection limit of 0.005 ng/mL, the change in the reduction peak current was inversely correlated with the logarithm concentration of CEA in the range of 10-3 to 5000 ng/mL. The suggested CEA immunosensor's applicability in a human serum sample was investigated, and findings of analytical studies via standard addition technique for both ELISA and DPV assays revealed that significant agreement existed between the outcomes of the two assays. Additionally, the recoveries ranged from 99.00% to 99.25%, and all relative standard deviations (RSDs) for the sample detections were below 5.01%, indicating satisfactory accuracy in results measured with the proposed CEA immunosensor, indicating that the prepared CEA immunosensor in this study can be used in clinical applications and human fluids.

Neutrophil-Derived IL-6 Potentially Drives Ferroptosis Resistance in B Cells in Lupus Kidney.

Ferroptosis resistance is vital for B cell development, especially in inflammatory diseases, yet the underlying mechanism is still unclear. In this study, based on the scRNA-seq technique and flow cytometry, we discovered a proportion of neutrophils exhibited upregulated expression of the IL-6 and correlated with the expression of IL-6 receptor and SLC7A11 from B cells in lupus kidney. Moreover, we identified that in lupus kidney, neutrophils could provide IL-6 to facilitate ferroptosis resistance in B cells via SLC7A11, and inhibition of SLC7A11 could significantly enhance ferroptosis in B cells and could decrease B cell proliferation. This study helps understand the crosstalk between neutrophils and B cells in the kidney in the development of lupus.

Reactive oxygen species-responsive nanocarrier ameliorates murine colitis by intervening colonic innate and adaptive immune responses.

Ulcerative colitis (UC) is a chronic or relapsing inflammatory disease with limited therapeutic outcomes. Pterostilbene (PSB) is a polyphenol-based anti-oxidant that has received extensive interest for its intrinsic anti-inflammatory and anti-oxidative activities. This work aims to develop a reactive oxygen species (ROS)-responsive, folic acid (FA)-functionalized nanoparticle (NP) for efficient PSB delivery to treat UC. The resulting PSB@NP-FA had a nano-scaled diameter of 231 nm and a spherical shape. With ROS-responsive release and ROS-scavenging properties, PSB@NP could effectively scavenge H2O2, thereby protecting cells from H2O2-induced oxidative damage. After FA modification, the resulting PSB@NP-FA could be internalized by RAW 264.7 and Colon-26 cells efficiently and preferentially localized to the inflamed colon. In dextran sulfate sodium (DSS)-induced colitis models, PSB@NP-FA showed a prominent ROS-scavenging capacity and anti-inflammatory activity, therefore relieving murine colitis effectively. Mechanism results suggested that PSB@NP-FA ameliorated colitis by regulating dendritic cells (DCs), promoting macrophage polarization, and regulating T cell infiltration. Both innate and adaptive immunity were involved. More importantly, the combination of the PSB and dexamethasone (DEX) enhanced the therapeutic efficacy of colitis. This ROS-responsive and ROS-scavenging nanocarrier represents an alternative therapeutic approach to UC. It can also be used as an enhancer for classic anti-inflammatory drugs.

The Expression of ARMCX1 in Gastric Cancer Contributes to Prognosis and Influences Chemotherapy.

The altered expression of ARMCX1 in patients with gastric cancer has been reported frequently, yet its correlation to prognosis and chemotherapy needs to be unveiled. In combination of the gene expression data retrieved from TCGA database and bioinformatic analysis, this study discovered 590 differentially expressed genes in the cancerous biopsies isolated from gastric patients, compared with controls. Among which, ARMCX1 exhibited great potential to serve as a prognostic biomarker for gastric patients; furthermore, patients with low expression of ARMCX1 could be more sensitive to these 9 chemotherapeutic agents: A-770041, AMG-706, ATRA, BEZ235, bortezomib, CGP60474, dasatinib, HG-64-1, and pazopanib, rather than the other chemotherapeutic agents. This study helps the improvement of evaluating the prognosis of gastric cancer patients, and would help optimize chemotherapeutic strategies in consideration of the expression of ARMCX1.

Intestinal flora induces depression by mediating the dysregulation of cerebral cortex gene expression and regulating the metabolism of stroke patients.

Post-stroke depression (PSD) is a common cerebrovascular complication characterized by complex pathogenesis and poor treatment effects. Here, we tested the influence of differentially expressed genes (DEGs), non-targeted metabolites, and intestinal microbes on the occurrence and development of PSD. We acquired gene expression profiles for stroke patients, depression patients, and healthy controls from the Gene Expression Omnibus database. After screening for DEGs using differential expression analysis, we identified common DEGs in stroke and depression patients that were considered to form the molecular basis of PSD. Functional enrichment analysis of DEGs also revealed that the majority of biological functions were closely related to metabolism, immunity, the nervous system, and microorganisms, and we also collected blood and stool samples from healthy controls, stroke patients, and PSD patients and performed 16S rDNA sequencing and untargeted metabolomics. After evaluating the quality of the sequencing data, we compared the diversity of the metabolites and intestinal flora within and between groups. Metabolic pathway enrichment analysis was used to identify metabolic pathways that were significantly involved in stroke and PSD, and a global metabolic network was constructed to explore the pathogenesis of PSD. Additionally, we constructed a global regulatory network based on 16S rDNA sequencing, non-targeted metabolomics, and transcriptomics to explore the pathogenesis of PSD through correlation analysis. Our results suggest that intestinal flora associates the dysregulation of cerebral cortex gene expression and could potentially promote the occurrence of depression by affecting the metabolism of stroke patients. Our findings may be helpful in identifying new targets for the prevention and treatment of PSD.

Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) usually has a poor prognosis and is associated with a high mortality rate. Its etiology is mainly the result from long-term exposure to either alcohol, tobacco or human papillomavirus (HPV) infection or a combination of these insults. However, HNSCC patients with HPV have been found to show a survival advantage over those without the virus, but the mechanism that confers this advantage is unclear. Due to the large number of HPV-independent HNSCC cases, there is a possibility that the difference in prognosis between HPV-positive (HPV+) and negative (HPV-) patients is due to different carcinogens. To clarify this, we used scRNA data and viral tracking methods in order to identify HPV+ and HPV- cells in the tumour tissues of patients infected with HPV. By comparing HPV+ and HPV- malignant cells, we found a higher level of tumour stemness in HPV- tumour cells. Using tumour stemness-related genes, we established a six-gene prognostic signature that was used to divide the patients into low- and high-risk groups. It was found that HPV patients who were at low-risk of contracting HNSCC had a higher number of CD8+ T-cells as well as a higher expression of immune checkpoint molecules. Correspondingly, we found that HPV+ tumour cells expressed higher levels of CCL4, and these were highly correlated with CD8+ T cells infiltration and immune checkpoint molecules. These data suggest that the stemness features of tumour cells are not only associated with the prognostic risk, but that it could also affect the immune cell interactions and associated signalling pathways.

ADAM-10 Regulates MMP-12 during Lipopolysaccharide-Induced Inflammatory Response in Macrophages.

A disintegrin and metalloprotease 10 (ADAM-10), a member of the ADAM protease family, has biological activities related to TNF-α activation, cell adhesion, and migration, among other functions. Macrophages are important immune cells that are involved in the inflammatory response of the body. ADAM-10 is involved in inflammatory responses, but the specific regulatory mechanisms are not fully understood. In this study, we investigated the regulatory mechanism of ADAM-10 in the lipopolysaccharide-promoted proliferation (LPS) of the macrophage inflammatory response. Differentially expressed or regulated proteins were identified in interfered ADAM-10 (sh ADAM-10) macrophages using tandem mass tag (TMT) proteomics. The changes and regulatory role of ADAM-10 during LPS-induced inflammatory response in normal, interfering, and overexpressing ADAM-10 (EX ADAM-10) cells were determined. Results indicated that ADAM-10 interference affected inflammation-related pathways and reduced matrix metalloproteinase 12 (MMP-12) protein levels, as identified by TMT proteomics. In normal cells, LPS decreased ADAM-10 gene expression, but promoted ADAM-10 secretion, MMP-12 and TNF-α gene expression, and MMP-12, iNOS, IL-10, and cyclinD1 protein expression. Additionally, ADAM-10 knockdown decreased macrophage viability in sh-ADAM-10 cells. Moreover, an MMP-12 inhibitor had no impact on the viability effect of LPS on cells or the expression of ADAM-10. iNOS expression decreased, whereas IL-10 expression increased after ADAM-10 depletion. ADAM-10 knockdown decreased MMP-12, iNOS, TNF-α, IL-1ß, and FKN, while overexpression had an opposite effect. ADAM-10 overexpression further increased MMP-12, iNOS, and TNF-α gene expression in response to LPS. Cell viability was increased in EX ADAM-10 cells, and ADAM-10 secretion was further increased in the EX and LPS groups. Flow cytometry and immunofluorescence staining revealed that EX-ADAM 10 cells had increased iNOS expression, which acted as an IL-6 expression driver. In summary, we found that ADAM-10 is activated by LPS and positively participates in LPS-stimulated macrophage inflammatory responses by positively regulating MMP-12 during the inflammatory process.

Heterogeneity in NK Cell Subpopulations May Be Involved in Kidney Cancer Metastasis.

Although substantial progress has been made in the immunotherapy of kidney cancer, its efficacy varies from patient to patient, with many responding suboptimally or even developing metastases. Thus, research on the tumour immune microenvironment and immune cell heterogeneity is essential for kidney cancer treatment. In this study, natural killer (NK) cell populations were isolated using signature genes from the single-cell sequencing data of clear cell renal cell carcinoma (ccRCC) and normal kidney tissues and divided into three subpopulations according to the differences in gene expression profiles: NK(GZMH), NK(EGR1), and NK(CAPG). Gene set enrichment analysis revealed that NK(EGR1) and NK(CAPG) were closely related to tumour metastasis, as shown by kidney cancer metastasis to Hodgkin lymphoma, T-cell leukaemia, and Ki-1+ anaplastic large cell lymphoma. Thus, these two NK cell subpopulations are promising targets for inhibiting metastasis in ccRCC. Our findings revealed heterogeneity in the infiltrating NK cells of kidney cancer, which can serve as a reference for the mechanisms underlying metastasis in kidney cancer.

Tumor-Infiltrated CD8+ T Cell 10-Gene Signature Related to Clear Cell Renal Cell Carcinoma Prognosis.

Clear cell renal cell carcinoma (ccRCC) usually affects multiple organs (e.g., bone and brain), and patient prognosis is usually poor. Although it is known that CD8+ T cell infiltration can potentially alleviate ccRCC progression, few studies have concentrated on the correlation between CD8+ T cell infiltration and ccRCC prognosis. In this study, ten genes expressed by infiltrated CD8+ T cells (i.e., AMD1, CCSER2, CIB1, DRAP1, HMGB2, HMGN1, NPIPB5, PTP4A2, RORA, and SAP18) were suggested as potential ccRCC prognostic biomarkers, by using next-generation sequencing (i.e. bulk sequencing and single-cell sequencing) of ccRCC, papillary renal cell carcinoma (papRCC), and control kidney biopsies. Specifically, we identified four genes (i.e., CCSER2, DRAP1, NPIPB5, and SAP18) as potential novel prognostic biomarkers for ccRCC. It is noteworthy that SAP18 derived from CD8+ T cells negatively correlates to Atg7+ neutrophils in ccRCC, compared with papRCC, indicating a potential decreased neutrophil metabolic function in autophagy and fatty acids. This study elucidated the protective role of infiltrated CD8+ T cells in ccRCC and identified ten candidate genes related to an improved prognosis in patients with ccRCC.

Clinical Status of Cardiac Rehabilitation Manners and Models.

Cardiac rehabilitation, which combines cardiology and preventive medicine, is an important part of treatment for cardiovascular diseases. Systematically, cardiac rehabilitation, including simultaneously inhibiting endothelial injury and promoting endothelial repair, is beneficial for physical and mental recovery and reduces the risks of recurrence and death in patients with cardiovascular diseases. Cardiac rehabilitation has developed rapidly in the last 50 years. A preliminary system for cardiac rehabilitation has been developed in China. The present article mainly focuses on the progress of cardiac rehabilitation from the aspects of goals, measures, and modes of research in the current scenario.

Association of BIRC5 Gene Polymorphism with the Collateral Circulation and Severity of Large Artery Atherosclerotic Stroke.

Objectives: The collateral circulation near the cerebral artery occlusion can contribute to the relief of the symptoms and signs of stroke. Genetic factors play a decisive role in the difference in collateral circulation. Survivin, encoded by the baculoviral inhibitor of apoptosis (IAP) repeat-containing 5 gene (BIRC5), plays an important role in maintaining long-term endothelial integrity and homeostasis and as an angiogenic factor in the treatment of vascular diseases. We hypothesized that genetic variations in the BIRC5 gene may contribute to severity by influencing the collateral circulation. This study aimed at examining how the polymorphism of the BIRC5 gene correlated with the collateral circulation and severity of large artery atherosclerotic stroke. Methods: This study enrolled 428 patients with large artery atherosclerotic stroke. There are no statistical differences in age, sex, social behavior, such as smoking and drinking, between the groups classified by the collateral circulation and by the severity of stroke (P > 0.01). Direct sequencing was performed for the genotyping of single nucleotide polymorphism (SNP) of BIRC5 (rs2071214). The enrolled patients were divided into several subgroups based on the collateral flow grading system from the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR), the results of the National Institutes of Health Stroke Survey (NIHSS) (6 as a threshold), and the score of the modified Rankin scale (mRS) (for the prediction of prognosis, 2 as a threshold). Differences among subgroups were identified through logistic regression. Results: The analysis of collateral circulation revealed the significant correlation of SNP of rs2071214 with the development of poor collateral circulation of large artery atherosclerotic stroke in the additive model (GG vs. AA, odds ratio (OR) = 3.592, 95% confidence interval (CI) = 1.410-9.150, and P=0.007) and the recessive model (GG vs. AA/GA, OR = 3.313, 95% CI = 1.420-7.727, and P=0.006). The analysis of stroke severity exposed the significant role of the SNP of rs2071214 in increasing stroke severity in the dominant model (GA/GG vs. AA, OR = 1.658, 95% CI = 1.017-2.703, and P=0.043) and the additive model (GA vs. AA, OR = 1.717, 95% CI = 1.021-2.888, and P=0.042). However, the analysis of the short-term outcome indicated that three genetic models were not associated with short-term outcomes in the additive model (GA vs. AA, P=0.815, GG vs. AA, and P=0.336), the dominant model (GA/GG vs. AA and P=0.589), and the recessive model (GG vs. AA/GA and P=0.342). Conclusion: Our findings identified the SNP of rs2071214 of the BIRC5 gene as a risk factor for the poor compensatory ability of collateral circulation and a predictor of stroke severity in large artery atherosclerotic stroke, which suggested that the SNP of rs2071214 can serve as an innovative therapeutic target for patients with acute ischemic stroke.

Use of Single Cell Transcriptomic Techniques to Study the Role of High-Risk Human Papillomavirus Infection in Cervical Cancer.

High-risk human papillomavirus (hrHPV) infection has been associated with a higher probability of progression to cervical cancer. However, several extensive studies have reported that the presence of hrHPV can lead to a better prognosis, but the mechanism of how this occurs is unclear. In this study, microbiological analysis was used to identify HPV infection as a factor for the prognosis of patients with cervical squamous cell carcinoma (CSCC). Comparing the interactions of HPV+ and HPV- malignant cells with immune cells as well as the trajectory of malignant cells either with or without HPV, we found that most of the HPV+ cells are well differentiated while HPV- cells appear to be hypo-fractionated. Using transcriptomic and immunostaining data, we validated a set of unfavourable molecules in the HPV- CSCC cells, including KRT16, ITGB1, CXCR1, VEGFA, CRCT1 and TNFRSF10B/DR5. This study provides a basis for the development of a rational post-operative follow-up programme and the development of an appropriate treatment plan for patients with cervical cancer.

Overall Structural Alteration of Gut Microbiota and Relationships with Risk Factors in Patients with Metabolic Syndrome Treated with Inulin Alone and with Other Agents: An Open-Label Pilot Study.

Objective: The relative contribution of some products with prebiotic effects, such as inulin, together with medications specific to the human gut microbiome has not been comprehensively studied. The present study determined the potential for manipulating populations in the gut microbiome using inulin alone and combined with other agents in individuals with metabolic syndrome (MetS). The study also assessed whether there is relationship variability in multiple clinical parameters in response to intervention with the changes in the gut milieu. Participants/Methods. This single-centre, single-blinded, randomised community-based pilot trial randomly assigned 60 patients (mean age, 46.3 y and male, 43%) with MetS to receive either inulin, inulin+traditional Chinese medicine (TCM), or inulin+metformin for 6 months. Lipid profiles, blood glucose, and uric acid (UA) levels were analysed in venous blood samples collected after overnight fast of 8 h at baseline and at the end of the follow-up period. Microbiota from stool samples were taxonomically analysed using 16S RNA amplicon sequencing, and an integrative analysis was conducted on microbiome and responsiveness data at 6 months. Results: The results of 16S rRNA sequencing showed that inulin resulted in a higher proportion of Bacteroides at the endpoint compared with inulin+TCM and inulin+metformin (p = 0.024). More Romboutsia (p = 0.043), Streptococcus (p < 0.001), and Holdemanella (p = 0.011) were found in inulin+TCM and inulin+metformin samples. We further identified gut microbiota relationships with lipids, UA, and glucose that impact the development of MetS. Conclusion: Among the groups, inulin alone or combined with metformin or TCM altered specific gut microbiota taxa but not the general diversity. Accordingly, we analysed metabolites associated with microbiota that might provide more information about intrinsic differences. Consequently, a reliable method could be developed for treating metabolic syndrome in the future.

Alterations of the Gut Microbiome in Chinese Zhuang Ethnic Patients with Sepsis.

Objectives: Sepsis is characterized as a dysregulated host immune response to infection and has been known to be closely associated with the gut microbiome. This study was aimed at investigating the gut microbial profiles of Zhuang ethnic patients with sepsis. Method: Eleven Zhuang ethnic patients with sepsis and 20 healthy individuals (controls) were recruited at the Baise City People's Hospital, China. Their gut microbial community profiles were analyzed by 16S rRNA gene sequencing using the Illumina MiSeq system. Results: The gut microbial community of patients with sepsis was significantly altered compared to that of the healthy individuals based on the results of principal coordinate analysis and microbial ecological networks. Additionally, significantly lower microbial alpha diversity was observed in patients with sepsis than in healthy individuals. In particular, the enrichment of Bilophila, Burkholderia, Corynebacterium, and Porphyromonas, along with the reduced abundance of a large number of short-chain fatty acid-producing microbes, including Roseburia, Bifidobacterium, Faecalibacterium, Coprococcus, Blautia, Clostridium, Ruminococcus, and Anaerostipe was observed in patients with sepsis compared to the control group. Moreover, patients with sepsis could be effectively classified based on the abundance of these bacteria using a support vector machine algorithm. Conclusion: This study demonstrated significant differences in the gut microbiome between Zhuang ethnic patients with sepsis and healthy individuals. In the future, it is necessary to determine whether such alterations are the cause or consequence of sepsis.

Endothelial Cells Potentially Participate in the Metastasis of Triple-Negative Breast Cancer.

Inhibition of triple-negative breast cancer metastasis has long been a challenge, mainly due to the difficulty in identifying factors that contribute to this process. In this study, freshly isolated triple-negative breast cancer biopsied cells obtained from consenting patients were subjected to flow cytometry and bioinformatic analysis to identify three endothelial cell subclusters: EC (ATP1B3), EC (HSPA1B), and EC (KRT7) in the tumor microenvironment. These endothelial cell subclusters exhibited distinguishing biological features. Based on differentially expressed genes derived from the subclusters, gene set enrichment analysis showed that EC (ATP1B3) and EC (HSPA1B) contribute to the process of metastasis, for example, in fibrosarcoma and anaplastic carcinoma. In this study, we identified the heterogeneity of endothelial cells in the human breast cancer and have provided insights into its role in metastasis.

An Integrative Bioinformatic Analysis of Microbiome and Transcriptome for Predicting the Risk of Colon Adenocarcinoma.

The abundance of gut microbiota is significantly decreased in patients with colorectal tumors compared to healthy groups. However, few studies have been conducted to correlate the differences in gut microbiota in colon cancer patients with different prognosis. In this study, we analysed the gut microbiota among patients with colon cancer and determined the microbial characteristics of COAD and divided the overall survival of COAD data into the high- and low-risk groups. In addition, we established a microbiome-related gene map and determined the association between microbial features and immune cell infiltration in COAD. In comparison with the low-risk group, the high risk group of COAD samples exhibited a decreased proportion of activated CD4 T cells as well as an increased proportion of M2 macrophages. The current data suggested that different gut flora backgrounds lead to different gene expression profiles, which in turn affect immune cell typing and colorectal tumor prognosis.

Apelin Alleviates Meniscus Endothelial Cell Apoptosis in Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease characterized by articular cartilage and/or chondrocyte destruction, and although it has long been considered as a primary disease, the importance of meniscus endothelial cell modulation in the subchondral microenvironment has recently drawn attention. Previous studies have shown that apelin could potentially inhibit cellular apoptosis; however, it remains unclear whether apelin could play a protective role in protecting the endothelium in the OA meniscus. In this study, with the advantages of single-cell RNA sequencing (scRNA-seq) data, in combination with flow cytometry, we identified two endothelial subclusters in the meniscus, featured by high expression of Homeobox A13 (HOXA13) and Ras Protein-Specific Guanine Nucleotide Releasing Factor 2 (RASGRF2), respectively. Compared with control patients, both subclusters decreased in absolute cell numbers and exhibited downregulated APJ endogenous ligand (APLN, coding for apelin) and upregulated apelin receptor (APLNR, coding apelin receptor). Furthermore, we confirmed that in OA, decreased endothelial cell numbers, including both subclusters, were related to intrinsic apoptosis factors: one more relevant to caspase 3 (CASP3) and the other to BH3-Interacting Domain Death agonist (BID). In vitro culturing of meniscal endothelial cells purified from patients proved that apelin could significantly inhibit apoptosis by downregulating these two factors in endothelial cell subclusters, suggesting that apelin could potentially serve as a therapeutic target for patients with OA.

MHC haplotype and B cell autoimmunity: Correlation with pathogenic IgG autoantibody subclasses and Fc glycosylation patterns.

Genome-wide association studies (GWAS) have identified many genes that are associated with the development of certain autoimmune disorders, but the MHC haplotypes still represent the most prevalent genetic risk factor for many autoimmune diseases. The mechanisms by which MHC-associated genetic susceptibility translates into B cell autoimmunity and the development of autoimmune diseases are complex. There is increasing evidence that the MHC haplotype modulates autoreactive B cell responses in multiple ways. Instead of merely inhibiting the production of IgG autoantibodies and mediating complete immunological tolerance, the non-permitting MHC haplotypes seem to facilitate the production of IgG autoantibodies exhibiting Fc glycosylation patterns that are associated with reduced pathogenicity and a protective cytokine profile of T follicular helper (Tfh) cells. Here, we discuss mechanisms linking MHC haplotypes to the production of pathogenic IgG autoantibodies, which could be relevant for the development of improved diagnosis, particularly in the context of individual medicine.