The possible effect of anti-diabetic agents GLP-1RA and SGLT-2i on the respiratory system function.

Type 2 Diabetes (T2D) is a chronic disease with increasing incidence and prevalence and serious chronic complications, especially from cardiovascular system. However, other organs can be affected too. Several studies have associated T2D, especially when poorly controlled, with multiple pulmonary diseases. T2D is a common comorbidity among patients with asthma, Chronic Obstructive Pulmonary Disease (COPD), and Obstructive Sleep Apnea Syndrome (OSAS), and it is related to higher respiratory infection incidence, prevalence and severity. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are novel antihyperglycaemic agents with established cardiovascular benefits. There are also limited studies indicating their potential benefit in respiratory function. The aim of this article is to review data on the impact of GLP-1RA and SGLT-2i on respiratory function and describe the possible clinical benefits. Key findings indicate that GLP-1RA significantly improve lung function in patients with COPD, evidenced by improvements in spirometry measurements. Additionally, both GLP-1RA and SGLT-2i are associated with a decreased risk of severe and moderate exacerbations in COPD patients and have shown potential in reducing the incidence of respiratory disorders, including asthma and pneumonia. The mechanisms underlying these benefits are not yet fully understood and include multiple effects, such as anti-inflammatory action and oxidative stress reduction.

The Dispensing Error Rate in an App-Based, Semaglutide-Supported Weight-Loss Service: A Retrospective Cohort Study.

Digital weight-loss services (DWLSs) combining pharmacotherapy and health coaching have the potential to make a major contribution to the global struggle against obesity. However, the degree to which DWLSs compromise patient safety through the dispensation of Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications is unknown. This study retrospectively analysed the rate at which patients reported GLP-1 RA dispensing errors from patient-selected and partner pharmacies of Australia's largest DWLS provider over a six-month period. The analysis found that 99 (0.35%) of the 28,165 dispensed semaglutide orders contained an error. Incorrect dose (58.6%) and unreasonable medication expiry window (21.2%) were the two most common error types. Most errors (84.9%) were deemed to have been of medium urgency, with 11.1% being considered high-urgency errors. Incorrect doses (45.5%) and supplies of the wrong medication (36.3%) comprised most errors reported in high-urgency cases. Female patients reported more dispensing errors than male patients (0.41% vs. 0.12%, p < 0.001). Similarly, reported dispensing error rates were highest among patients aged 18 to 29 years (0.6%) and 30 to 39 years (0.5%). This research provides preliminary evidence that GLP-1 RA dispensing errors within comprehensive Australian DWLSs are relatively low.

ITIH4 in Rheumatoid Arthritis Pathogenesis: Network Pharmacology and Molecular Docking Analysis Identify CXCR4 as a Potential Receptor.

Elevated levels of Inter-alpha-trypsin-inhibitor heavy chain 4 (ITIH4) have grabbed attention in rheumatoid arthritis (RA) pathogenesis, though its precise mechanisms remain unexplored. To elucidate these mechanisms, a comprehensive strategy employing network pharmacology and molecular docking was utilized. RA targets were sourced from the DisGeNET Database while interacting targets of ITIH4 were retrieved from the STRING and Literature databases. Venny 2.1 was used to identify overlapping genes, followed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) through Cytoscape 3.10.2 software, and molecular docking was performed in the ClusPro server. The study identified 18 interacting proteins of ITIH4 associated with RA, demonstrating their major involvement in the chemokine signaling pathway by enrichment analysis. Molecular docking of ITIH4 with the 18 proteins revealed that C-X-C chemokine-receptor type 4 (CXCR4), a major protein associated with chemokine signaling, has the highest binding affinity with ITIH4 with energy -1705.7 kcal/mol forming 3 Hydrogen bonds in the active site pocket of ITIH4 with His441, Arg288, Asp443 amino acids. The effect of ITIH4 on CXCR4 was analyzed via knockdown studies in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), demonstrating the significant downregulation of CXCR4 protein expression validated by Western blot in RA-FLS. In conclusion, it was speculated that CXCR4 might serve as a potential receptor for ITIH4 to activate the chemokine signaling, exacerbating RA pathogenesis.

Dissecting depression symptoms: Multi-omics clustering uncovers immune-related subgroups and cell-type specific dysregulation.

In a subset of patients with mental disorders, such as depression, low-grade inflammation and altered immune marker concentrations are observed. However, these immune alterations are often assessed by only one data type and small marker panels. Here, we used a transdiagnostic approach and combined data from two cohorts to define subgroups of depression symptoms across the diagnostic spectrum through a large-scale multi-omics clustering approach in 237 individuals. The method incorporated age, body mass index (BMI), 43 plasma immune markers and RNA-seq data from peripheral mononuclear blood cells (PBMCs). Our initial clustering revealed four clusters, including two immune-related depression symptom clusters characterized by elevated BMI, higher depression severity and elevated levels of immune markers such as interleukin-1 receptor antagonist (IL-1RA), C-reactive protein (CRP) and C-C motif chemokine 2 (CCL2 or MCP-1). In contrast, the RNA-seq data mostly differentiated a cluster with low depression severity, enriched in brain related gene sets. This cluster was also distinguished by electrocardiography data, while structural imaging data revealed differences in ventricle volumes across the clusters. Incorporating predicted cell type proportions into the clustering resulted in three clusters, with one showing elevated immune marker concentrations. The cell type proportion and genes related to cell types were most pronounced in an intermediate depression symptoms cluster, suggesting that RNA-seq and immune markers measure different aspects of immune dysregulation. Lastly, we found a dysregulation of the SERPINF1/VEGF-A pathway that was specific to dendritic cells by integrating immune marker and RNA-seq data. This shows the advantages of combining different data modalities and highlights possible markers for further stratification research of depression symptoms.

Similarities and differences between osteoarthritis and rheumatoid arthritis: insights from Mendelian randomization and transcriptome analysis.

BACKGROUND: Osteoarthritis (OA) and rheumatoid arthritis (RA) are often difficult to distinguish in the early stage of the disease. The purpose of this study was to explore the similarities and differences between the two diseases through Mendelian randomization (MR) and transcriptome analysis. METHODS: We first performed a correlation analysis of phenotypic data from genome-wide association studies (GWAS) of OA and RA. Then, we performed functional and pathway enrichment of differentially expressed genes in OA, RA, and normal patients. The infiltration of immune cells in arthritis was analyzed according to gene expression. Finally, MR analysis was performed with inflammatory cytokines and immune cells as exposures and arthritis as the outcome. The same and different key cytokines and immune cells were obtained by the two analysis methods. RESULTS: GWAS indicated that there was a genetic correlation between OA and RA. The common function of OA and RA is enriched in their response to cytokines, while the difference is enriched in lymphocyte activation. T cells are the main immune cells that differentiate between OA and RA. MR analysis further revealed that OA is associated with more protective cytokines, and most of the cytokines in RA are pathogenic. In addition, CCR7 on naive CD4 + T cell was positively correlated with OA. SSC-A on CD4 + T cell was negatively correlated with RA, while HLA DR on CD33- HLA DR + was positively correlated with RA. CONCLUSION: Our study demonstrated the similarities and differences of immune inflammation between OA and RA, allowing us to better understand these two diseases.

Cost Analysis of Robot-Assisted Versus On-Pump and Off-Pump Coronary Artery Bypass Grafting: A Single-Center Surgical and 30-Day Outcomes Comparison.

OBJECTIVE: Throughout Europe, the interest in implementing robot-assisted minimally invasive direct coronary artery bypass (RA-MIDCAB) has been growing. However, concerns about additional costs have emerged concurrently. In this analysis, we aim to provide a comparison of the cumulative perioperative costs of RA-MIDCAB, on-pump coronary artery bypass grafting (CABG), and off-pump CABG (OPCAB). METHODS: We conducted a propensity score-matched analysis comparing patients undergoing RA-MIDCAB with those undergoing CABG or OPCAB at our institution from January 2016 to December 2021. After matching, we analyzed the combined intraoperative surgical costs and 30-day postoperative costs. We first compared RA-MIDCAB costs to CABG and then to OPCAB separately. Violin plots illustrated the cost distribution among individual patients. Total cost uncertainty was estimated using 1,000 bootstrapping iterations. RESULTS: Seventy-nine RA-MIDCAB patients were matched to 158 CABG patients, and 80 RA-MIDCAB patients were matched to 149 OPCAB patients. Considering both surgical and clinical outcomes, RA-MIDCAB yielded an average cost of €17,121 per patient (€16,781 to €33,294), CABG was €16,571 per patient (€16,664 to €41,860), and OPCAB was €15,463 per patient (€10,895 to €57,867). After bootstrap iterations, RA-MIDCAB was found to be €472 (2.8%) and €1,599 (10.3%) more expensive per patient than CABG and OPCAB, respectively. CONCLUSIONS: In The Netherlands, the adoption of RA-MIDCAB did not show a significant economic impact on hospital resources. The additional robotic costs for the surgery were almost entirely offset by the cost savings during the postoperative hospital stay. However, these comparisons may differ when considering hybrid coronary revascularization with its additional percutaneous coronary intervention costs.

Decreased Serum CTRP3 level was associated with connective tissue diseases.

Objective: Complement C1q tumor necrosis factor-related protein 3 (CTRP3) and 9 (CTRP9) are two of the most extensively studied adipokines, known for their diverse biological functions. However, it remains unclear whether serum levels of CTRP3 or CTRP9 are associated with connective tissue diseases (CTD). Methods: Serum CTRP3 and CTRP9 levels were measured by enzyme-linked immune sorbent assay (ELISA) and analyzed in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), ankylosing spondylitis (AS), undifferentiated connective tissue disease (UCTD), as well as in healthy controls (HCs). Results: Serum CTRP3 levels were all significantly lower in patients with RA, SLE, pSS and AS compared with HCs. However, there were no significant differences in serum CTRP9 levels between patients with RA, SLE, pSS, or AS and HCs. In pSS patients, CTRP3 showed a weak correlation with blood glucose, creatinine, and urine acid in pSS patients, while no correlations were observed between serum CTRP3 levels and clinical or laboratory indices in RA, SLE or AS patients. Stable associations between CTRP3 and RA, SLE, pSS and AS were evaluated using multivariate logistics regression analysis. Receiver operating characteristic (ROC) curves were plotted to evaluated CTRP3 as a marker for RA, SLE, pSS and AS, yielding area under curve (AUC) values of 0.691, 0.727, 0.658 and 0.694, respectively. Conclusion: Decreased serum CTRP3 levels were associated with RA, SLE, pSS and AS.

Successful treatment of rheumatoid arthritis-associated interstitial lung disease with filgotinib: A case report on janus kinase 1 inhibition.

Filgotinib, a janus kinase 1 (JAK1) inhibitor, is used in the treatment of rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) is a severe RA complication with no established effective treatment. We report the case of a patient with RA-ILD successfully treated with filgotinib. A 46-year-old woman with RA and RA-ILD, presenting with a non-specific interstitial pneumonia pattern, was refractory to abatacept and prednisolone but responded to filgotinib. Both arthritis and RA-ILD improved significantly, and the patient remained in remission for over 12 months. Basic research indicates that JAK1 plays a role in the cytokine signal transduction in ILD; however, there are no clinical reports on the efficacy of filgotinib in RA-ILD. This case suggests filgotinib as a potential treatment for patients with RA-ILD, particularly in the early stages of this disease.

SLAMF1 as a novel molecule mediating the causal association between rheumatoid arthritis and interstitial lung disease: A Mendelian randomization study combined with transcriptomics and in vivo validation.

BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a common complication of rheumatoid arthritis (RA) that result in significant morbidity and mortality. Understanding the molecular mechanisms underlying RA-ILD is crucial for effective prevention. This study aims to identify the specific molecule that mediate the causal association between RA and ILD, as well as to explore its potential mechanisms in the pathogenesis of RA-ILD. METHODS: Using two-sample Mendelian randomization (MR) analyses, we investigated the causal relationship among 16,987 blood genes, RA and ILD. Subsequently, a two-step MR technique was employed to identify significant genes that mediate the association between RA and ILD, and to quantify their proportion of mediation effect. To validate the genes as mediators, the replication MR analysis was conducted and the in vivo experiment was performed using an established animal model of RA-ILD. Furthermore, integrated bioinformatic analyses were conducted to elucidate the specific biological functions of the determined mediator in pathogenesis of RA-ILD. RESULTS: Nine genes, namely MAPK8IP2, TAF11, SLAMF1, DAB2IP, GLUL, SLC4A10, PRSS35, NFX1, and PLK3, were identified as mediators. Among them, SLAMF1 was validated as the most significant mediator, accounting for 4.693% of the mediating effect on the causal relationship between RA and ILD. Upregulated mRNA expression of SLAMF1 was observed in the animal model of RA-ILD compared to controls. Bioinformatic analyses revealed that SLAMF1 was overexpressed in patients with lung fibrosis and correlated with a poor prognosis. Specifically, SLAMF1 was found to be predominantly overexpressed in T cells in lung tissues of patients with lung fibrosis. Additionally, the functional role of SLAMF1 was associated with multiple immune cell infiltrations and the biological process of extracellular matrix synthesis in pulmonary tissues from patients with lung fibrosis. CONCLUSION: SLAMF1 may play a crucial role as a molecular mediator in the causal association between RA and ILD, and participate in multiple mechanisms underlying the pathogenesis of RA-ILD. This research provides insights into how the development of RA influences the risk of ILD and offers potential interventional targets against RA-ILD.

Association between IL-6, miRNA-146a, MALAT1 genetic polymorphisms and risk of rheumatoid arthritis.

Aim: This study aimed to investigate the associations between single nucleotide polymorphisms (SNPs) of IL-6 (-174G/C), microRNA146a (rs2910164C/G) and MALAT1 (rs619586A/G) and susceptibility to rheumatoid arthritis (RA) in Egyptians.Methods: SNPs were genotyped in 101 RA patients and 104 controls. Expression levels were evaluated either by Enzyme-linked immunosorbent assay (ELISA) for IL-6 or quantitative real-time PCR (qRT-PCR) for miR-146a and MALAT1.Results: IL-6-174 GC (OR = 3.422) genotype, IL-6-174 C allele (OR = 2.565), miR-146a (rs2910164) CG (OR = 2.190) and MALAT1 (rs619586) AA (OR = 4.125) genotypes and A allele (OR = 6.122) could be considered as risk factors for RA. An increase in the expression of IL-6, miR-146a and MALAT1 was detected in RA patients, which was independent of any SNP.Conclusion: SNPs of IL-6, miR-146a and MALAT1were linked to RA predisposition in Egyptians.

Rheumatoid arthritis (RA) is a chronic joint disorder with overexpression of inflammatory mediators. There is increasing evidence that epigenetic changes could play a prominent role in RA pathogenesis. This study was designated to explore the associations between genetic mutation of inflammatory cytokines (Interleukin (IL-6) and epigenetic modulators (miR-146a and MALAT1) and susceptibility to RA. Increased production of IL-6, miR-146a and MALAT1 is a remarkable event in RA patients. We provide evidence that certain genotypes could be used as risk factors for the disease. Our data suggest that detecting certain mutations is quite important in disease prediction. Special concern has to be directed to those persons harboring definite genotypes to achieve better clinical manipulation of patients at risk.

Successful Allogeneic Hematopoietic Cell Transplantation for Patients with IL10RA Deficiency in Japan.

BACKGROUND: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. METHODS: We retrospectively analyzed patients with IL10RA deficiency in Japan. RESULTS: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. CONCLUSION: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250).

Increased m6A RNA methylation and METTL3 expression may contribute to the synovitis progression of rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and progressive bone destruction. The tumor-like growth of fibroblast-like synoviocytes (FLSs) plays a crucial role in the pathogenesis of RA. The N6 methyladenine (m6A) mRNA methylation modification, regulated by methyltransferases (METTL3) and demethylation enzymes, is a novel epigenetic regulator in the development of RA. However, there is limited research on m6A methylation modifications in RA synovitis and a lack of mechanistic studies on their impact on the function of RA-FLSs. METHODS: This study utilized clinical synovial tissue specimens and FLSs as research subjects. The m6A methylation level and the expression of methyltransferases and demethylation enzymes were detected. RNA interference and gene overexpression methods were employed to investigate the mechanism of METTL3 in RA-FLSs. The study also examined the proliferation, apoptosis, migration, invasion, and cytokine levels of RA-FLSs, as well as the expression of METTL3 in RA animal models. RESULTS: In this study, we found that m6A methylation levels were elevated in synovial tissues and FLSs of RA patients. Immunohistochemical staining showed that METTL3 and METTL14 levels were up-regulated in synovial tissues of RA, the mRNA levels of METTL3, METTL14, WTAP, FTO, and ALKBH5 were significantly higher in synovial tissues and FLSs of RA patients. Overexpression of METTL3 could promote the proliferation, migration, and secretion of IL-6, RANKL of RA-FLSs; inhibition of METTL3 expression could inhibit the abnormal proliferation, migration, invasion, and secretion of IL-6, RANKL, at the same time promoted the apoptosis and secretion of OPG, thus inhibited RA-FLSs tumor-like growth. In CIA mice, the use of MTX and STM2457 reduced METTL3 expression, synovial hyperplasia and bone destruction. CONCLUSION: Abnormal modification of m6A methylation exists in synovial tissues and FLSs of RA patients, and inhibition of METTL3 can reduce synovitis and bone destruction. Our findings suggest that m6A methylation might control FLS-mediated tumor-like phenotype, and be a novel target for RA treatment.

Autoantibody mediated deficiency of IL-36-receptor antagonist in a subset of patients with psoriasis and psoriatic arthritis.

OBJECTIVE: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso). METHODS: In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n = 254), Pso (n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n = 100), ulcerative colitis (UC, n = 50), Crohn´s disease (CD, n = 50), and healthy controls (n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed. RESULTS: Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling. CONCLUSION: IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology.

Mechanisms of ferroptosis and glucagon-like peptide-1 receptor agonist in post-percutaneous coronary intervention restenosis.

Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.

Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD): Update on Prevalence, Risk Factors, Pathogenesis, and Therapy.

PURPOSE OF REVIEW: Rheumatoid arthritis is frequently complicated by interstitial lung disease (RA-ILD), an underappreciated contributor to excess morbidity and mortality. The true prevalence of RA-ILD is difficult to define given the variability in diagnostic criteria used. The lack of standardized screening methods, an incomplete understanding of disease pathogenesis, and dearth of validated biomarkers have limited the development of controlled clinical trials for this disease. RECENT FINDINGS: Numerous studies have focused on clinical, radiographic, genetic, molecular, and/or serologic markers of disease severity as well as risk of disease progression. In addition to defining valuable clinical biomarkers, these studies have provided insights regarding the pathogenesis of RA-ILD and potential therapeutic targets. Additional studies involving immunomodulatory and/or anti-fibrotic agents have assessed new therapeutic options for different stages of RA-ILD. RA-ILD continues to be a major contributor to the increased morbidity and mortality associated with RA. Advancements in our understanding of disease pathogenesis at a molecular level are necessary to drive the development of more targeted therapy.

Analysis of the mechanisms underlying the anticancer and biological activity of retinoic acid and chitosan nanoparticles containing retinoic acid.

Retinoic acid (RA) has been shown in earlier investigations to have anticancer properties in various cancer cells. RA's effect on breast cancer treatment remains uncertain, though. This study investigated whether RA and chitosan nanoparticles (NPs) loaded with RA could be harmful to the MCF-7 cell line. In this study, NPs with RA were used in characterization tests. Using ELISA kits, the amounts of 8-okso-2'-deoksiguanozin (8-oxo-dG), BCL-2, Bcl-2-Associated X-protein (Bax), cleaved Poly (ADP-ribose) polymerases (PARP), total oxidant and antioxidant, and cleaved caspase-3 capacities were determined. The analysis of chitosan NPs showed that their drug-release profile, encapsulation efficiency (EE), and particle size were suitable for cell culture experiment. The EE value of NPs including RA was calculated as 83.32 ± 0.04%. The IC50 value for RA was 2.89 ± 0.03 µg/mL, while the IC50 value for RA-loaded NPs was significantly lower at 2.28 ± 0.02 µg/mL. In ELISA testing, RA and chitosan NPs containing RA at a concentration of 2 µg/mL dramatically increased the concentrations of total oxidant, cleaved caspase-3. Cleaved caspase-3 levels were quantified as 614.90 ± 3.40 pg/mg protein in the control group, 826.37 ± 5.82 pg/mg protein in RA-treated cells, and 863.52 ± 4.32 pg/mg protein in RA-NP-treated cells. Interestingly, no substantial variations were observed in the levels of the anti-apoptotic protein BCL-2. Overall, studies revealed that RA and RA-NPs promoted apoptosis in MCF-7 cells by upregulating the expression of pro-apoptotic proteins Bax, cleaved caspase-3, and cleaved PARP.

GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review.

Obesity and type 2 diabetes mellitus (T2DM) present major global health challenges, with an increasing prevalence worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a pivotal treatment option for both conditions, demonstrating efficacy in blood glucose management, weight reduction, cardiovascular disease prevention, and kidney health improvement. GLP-1, an incretin hormone, plays a crucial role in glucose metabolism and appetite regulation, influencing insulin secretion, insulin sensitivity, and gastric emptying. The therapeutic use of GLP-1RAs has evolved significantly, offering various formulations that provide different efficacy, routes of administration, and flexibility in dosing. These agents reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects, making them an integral component of T2DM and obesity management. This review will discuss the currently approved medication for T2DM and obesity, and will also highlight the advent of novel agents which are dual and triple hormonal agonists which represent the future direction of incretin-based therapy. Funding: National Institutes of HealthNIDDKU24 DK132733 (FCS), UE5 DK137285 (FCS), and P30 DK040561 (FCS).

Comparison of glucagon-like peptide-1 receptor agonists vs. placebo on any cardiovascular events in overweight or obese non-diabetic patients: a systematic review and meta-analysis.

Introduction: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) have been extensively used to treat obesity in recent years. These novel drugs are effective at reducing body weight and also the risk of major adverse cardiovascular events in individuals with type 2 diabetes. However, the data of its efficacy in reducing cardiovascular events in individuals without type 2 diabetes is not as robust. We aim to update and conduct a systematic review and meta-analysis to assess the same. Methods: The study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guideline. Researchers searched PubMed, EMBASE, and Clinicaltrails.gov for English literature from inception to 2024. Randomized Controlled trails enrolling adult participants (age ≥ 18 years) who are overweight or obese (BMI > 25 Kg/m2) with a comparison of all cardiovascular events between patients taking GLP1-RA and placebo were included. The analysis was done by Revman version 5.4. Results: A total of 17 RCTs among 34,419 participants were included in the analysis. The pooled risk ratio from 17 studies illustrated that patients with GLP-1 RA had a significantly lower risk of cardiovascular events compared to patients who had a placebo (RR = 0.75; 95% confidence interval 0.64-0.89, p-value = 0.0008). Semaglutide was found to have a statistically significant greatest risk reduction than other drug types. Conclusions: This meta-analysis found that GLP-1 RA significantly reduced all types of cardiovascular events in overweight and obese patients without diabetes. Semaglutide was found to be superior to others in CV event reductions. But still, the results of ongoing trials are needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=553048, PROSPERO (CRD42024553048).

Elevated remnant cholesterol as a potential predictor for cardiovascular events in rheumatoid arthritis patients.

Objective: The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) remains inadequately defined. Consequently, this study aims to evaluate the predictive value of remnant cholesterol (RC) for assessing CVD risk in RA patients. Methods: Plasma RC levels were measured in 114 RA patients and 41 healthy controls, calculated as total cholesterol minus HDL-C and LDL-C. These levels were further analyzed using 1H-NMR lipid/metabolomics. Meanwhile, the 28-joint Disease Activity Score (DAS28) assessed RA activity. Results: RC levels were significantly elevated in RA patients (19.0 mg/dl, p < 0.001) compared to healthy controls (14.5 mg/dl). Furthermore, RC levels were significantly elevated at 37.4 mg/dl in patients who experienced cardiovascular event (CVE) compared to 17.4 mg/dl in those without CVE (p < 0.001). To enhance the precision and reliability of RC measurements, RC concentrations were further validated using 1H-NMR spectroscopy. Additionally, a positive correlation was observed between RC levels and DAS28. Multivariate analysis identified RC as a significant predictor of CVE (odds ratio = 1.82, p = 0.013). ROC curve analysis revealed superior predictive capability of RC for CVE (AUC = 0.919, p < 0.001) compared to LDL-C (AUC = 0.669, p = 0.018), with a high sensitivity of 94.7% and a specificity of 82.1%. Conclusion: Elevated RC levels demonstrate greater accuracy in predicting CVE occurrence in RA patients compared to traditional measures such as LDL-C. These findings suggest that elevated RC levels may serve as a novel predictor for occurrence of CVE in RA patients, facilitating early intervention strategies based on the risk stratification.

Corydaline attenuates osteolysis in rheumatoid arthritis via mitigating reactive oxygen species production and suppressing calcineurin-Nfatc1 signaling.

AIM OF THE STUDY: Osteolysis in Rheumatoid arthritis (RA) is principally provoked by osteoclast hyperactivity. This study aims to employ Corydaline (Cory), a plant extract, as an osteoclast inhibitor in treating RA-inflicted osteolysis while unveiling the corresponding mechanism. MATERIALS AND METHODS: Osteoclasts were derived from mouse bone marrow-derived monocytes (BMMs) stimulated with M-CSF and RANKL. Subsequently, utilizing network pharmacology, we performed a thorough analysis of Cory's molecular structure and discerned its preliminary therapeutic potential. Subsequently, LPS was used to simulate and establish an in vitro model of RA, and the biological effect of Cory on osteoclast behaviors was evaluated through various staining methods, RT-qPCR, and Western blot. In addition, a collagen-induced arthritis (CIA) mouse model was developed to evaluate the therapeutic effects of Cory in vivo. RESULTS: The results from network pharmacology indicated a significant correlation between Cory, oxidative stress, and calcium signaling. Subsequent in vitro experiments demonstrated Cory's capacity to inhibit the formation and function of osteoclast under inflammatory stimuli, thereby protecting against abnormal bone resorption. This effect is achieved by activating the Nrf2 signaling pathway, mitigating the generation of reactive oxygen species (ROS), and modulating the calcineurin-Nfatc1 signaling. Furthermore, this therapeutic effect of Cory on RA-associated osteolysis was proved in CIA mice models. CONCLUSIONS: Cory demonstrates the potential to activate the Nrf2 signaling pathway, effectively countering oxidative stress, and simultaneously inhibit the calcineurin-Nfatc1 signaling pathway to regulate the terminals of calcium signaling. These dual effects collectively reduce osteoclast activity, ultimately contributing to a therapeutic role in RA osteolysis. Therefore, our study presents Cory as a novel pharmaceutical candidate for the prevention and treatment of RA.