Potential Therapeutic Target Research Articles

A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development. We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice. Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity. Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

Nitric oxide: Potential therapeutic target in Heat Stress-induced Multiple Organ Dysfunction.

As climate change intensifies, urgent action is needed to address global warming and its associated health risks, particularly in vulnerable regions. Rising global temperature and increasing frequency of heatwaves present a hidden health risk, disrupting the body's temperature regulation and leading to severe consequences such as heat stress-induced multiple organ dysfunction (HS-MOD). Multiple organ injury triggered by heat stress involves complex molecular pathways such as nitric oxide dysregulation, inflammation, oxidative stress, mitochondrial dysfunction, calcium homeostasis disruption, and autophagy impairment that contribute to cellular damage. Understanding these molecular pathways is crucial for developing targeted therapeutic interventions to alleviate the impact of heat stress (HS). As we explore numerous therapeutic strategies, a remarkable molecule captures our attention: nitric oxide (NO). This colorless gas, mainly produced by nitric oxide synthase (NOS) enzymes, plays crucial roles in various body functions. From promoting vasodilation and neurotransmission to regulating the immune response, platelet function, cell signaling, and reproductive health, NO stands out for its versatility. Exploring it as a promising treatment for heat stress-induced multiple organ injury highlights its distinctive features in the journey towards effective therapeutic interventions. This involves exploring both pharmacological avenues, considering the use of NO donors and antioxidants, and non-pharmacological strategies, such as adopting nitrate-rich diets and engaging in exercise regimens. This review highlights the concept of heat stress, the molecular framework of the disease, and treatment options based upon some new interventions.

Gene Expression Profiling Regulated by lncRNA H19 Using Bioinformatic Analyses in Glioma Cell Lines.

Glioma, the most common type of primary brain tumor, is characterized by high malignancy, recurrence, and mortality. Long non-coding RNA (lncRNA) H19 is a potential biomarker for glioma diagnosis and treatment due to its overexpression in human glioma tissues and its involvement in cell division and metastasis regulation. This study aimed to identify potential therapeutic targets involved in glioma development by analyzing gene expression profiles regulated by H19. To elucidate the role of H19 in A172 and U87MG glioma cell lines, cell counting, colony formation, and wound healing assays were conducted. RNA-seq data analysis and bioinformatics analyses were performed to reveal the molecular interactions of H19. Cell-based experiments showed that elevated H19 levels were related to cancer cell survival, proliferation, and migration. Bioinformatics analyses identified 2,084 differentially expressed genes (DEGs) influenced by H19 which are involved in cancer progression. Specifically, ANXA5, CLEC18B, RAB42, CXCL8, OASL, USP18, and CDCP1 were positively correlated with H19 expression, while CSDC2 and FOXO4 were negatively correlated. These DEGs were predicted to function as oncogenes or tumor suppressors in gliomas, in association with H19. These findings highlight H19 and its associated genes as potential diagnostic and therapeutic targets for gliomas, emphasizing their clinical significance in patient survival.

Peripheral immune landscape of pediatric fulminant myocarditis revealed by single-cell sequencing

Abstract Fulminant myocarditis (FM) is one of the most feared diseases in children because of its fulminant nature and high mortality rate. However, the precise pathological immune subsets and molecular changes in FM are unknown. Here, we present the first comprehensive cellular and transcriptomic profiling of the peripheral blood mononuclear cells of children in FM acute and recovery phases using Single-cell RNA sequencing. 21 cell clusters are identified among 79542 cells. The proportion of T cells and NK cells increase, while myeloid cells and B cells reduce in acute phase, which were consistent with our flow cytometry data of 35 FM patients. Several unique cell types in peripheral blood are identified, including regulatory B cells, MAIT cells, adaptive NK cells and CD8+Tpex cells. The transcriptomic analysis exhibited elevated expression levels of chemokine receptor CXCR4 and S100A family genes almost in all cell types in FM acute phase, as well as MHC-II molecules in antigen-presenting cells. TCR and BCR exhibit remarkable amplification and obvious skewed usages of V genes in FM. Ligand receptor analysis show myeloid cells maintained active communication with other immune cells. Considering that CXCR4 may play an important role in myocarditis, we designed experiments to explore its function in mouse model. Vital myocarditis (VMC) mouse model was constructed using Coxsackie virus type3（CVB3）.We found that myocardial inflammation and myocardial injury of VMC mice were alleviated when treated with CXCR4 blocker. CXCR4 may be a potential therapeutic target for myocarditis. Our study will provide useful insights into key immune cell subsets and transcriptomic profiles implicated in pediatric fulminant myocarditis acute phase and recovery phase, thus providing several potential diagnostic and therapeutic targets for this disease.

Association of thyroid hormones with the severity of chronic kidney disease: a cross-sectional observational study at Tabuk, Saudi Arabia

Background The interplay between chronic kidney disease (CKD) and thyroid dysfunction is becoming more evident in the biomedical community. However, the intricacies of their relationship warrant deeper investigation to understand the clinical implications fully. Objective This study aims to systematically evaluate the correlation between thyroid hormone levels, including thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4), and markers of renal disease severity. These markers include serum creatinine, urea, and parathyroid hormone (PTH) levels in individuals diagnosed with CK). Methods We conducted a cross-sectional observational study involving a cohort of 86 participants with CKD recruited from the renal clinic at King Fahad Hospital in Tabuk. Biochemical parameters, encompassing plasma electrolytes and thyroid hormone concentrations, were quantitatively assessed. These measurements were performed with the aid of a Roche Cobas E411 analyzer. The Pearson correlation coefficient was employed to delineate the strength and direction of the associations between the thyroid function markers and renal disease indicators. Results The statistical analysis highlighted a generally weak correlation between the concentrations of thyroid hormones and the indicators of renal disease severity, with Pearson correlation coefficients between −0.319 and 0.815. Critically, no significant correlation was found between creatinine and thyroid hormones (TSH, T3, T4), nor was any substantial correlation between urea and thyroid hormones. Conversely, a robust positive correlation was noted between the levels of parathyroid hormone and serum creatinine (r = 0.718, p < 0.001). Conclusion The data suggests that thyroid hormone levels have a minimal correlation with the severity of renal disease markers. In contrast, the pronounced correlation between PTH and creatinine underscores the importance of considering PTH as a significant factor in managing and therapeutic intervention of CKD complications. These initial findings catalyze further research to thoroughly investigate the pathophysiological relationships and potential therapeutic targets concerning thyroid dysfunction in patients with renal impairment.

Impact of atrial fibrillation on progression of tricuspid regurgitation in patients undergoing transcatheter aortic valve replacement

Abstract Background Recent advancements in interventional cardiology have spurred growing interest in atrial tricuspid regurgitation (TR) as a potential therapeutic target. Atrial TR, a form of secondary TR, arises from the dilatation and dysfunction of the right atrium, frequently seen in the context of atrial fibrillation (AF). While the concept is increasingly recognized, the natural history of TR in relation to AF remains incompletely understood. Purpose This study aims to elucidate the impact of AF on the progression of TR in patients undergoing transcatheter aortic valve replacement (TAVR). Methods Utilizing data from a comprehensive single-center TAVR registry, this study included patients who underwent TAVR between 2016 and 2023, excluding those with severe TR post-TAVR. Subjects were categorized based on the presence or absence of paroxysmal or persistent/permanent AF/atrial flutter (AFL). The study employed the cumulative incidence function to depict the progression to severe TR, considering all-cause mortality as a competing risk. Results Among 981 eligible patients, 169 (17.2%) presented with AF/AFL, with 57 (5.8%) having persistent/permanent and 112 (11.4%) paroxysmal forms. Patients with AF/AFL had a higher surgical risk, a higher prevalence of significant mitral regurgitation and TR, and a lower left ventricular ejection fraction. The median follow-up period was 366 days, with an interquartile range from 36 to 1079 days. Over a 5-year period, 11.7% of patients with AF/AFL experienced progression to severe TR, with 14.2% in those with persistent/permanent AF/AFL and 10.6% in those with paroxysmal AF/AFL, compared to merely 0.8% in patients without AF/AFL (sub-distribution HR: 7.60, 95%CI: 2.86-20.0; P<0.001) (Figure 1). Multivariable Fine-Gray regression analysis showed that AF/AFL was associated with the progression of TR by at least one grade, independently of the TR grade post-TAVR and other echocardiographic parameters (sub-distribution HR: 1.38, 95% CI: 1.06-1.78; p=0.015). Other factors associated with progression included the TR grade post-TAVR (sub-distribution HR: 1.20, 95% CI: 1.05-1.38; p=0.009) and the presence of a permanent pacemaker (sub-distribution HR: 1.53, 95% CI: 1.18-1.71; p=0.001) (Figure 2). Conclusions The presence of AF/AFL significantly increases the risk of developing severe TR in the long-term following TAVR, underscoring the need for vigilant monitoring and potentially preemptive management strategies in this patient cohort.

Role of common variants and new genes associated with arrhythmogenic cardiomyopathy

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease, predominantly affecting males, characterized by fibro-fatty myocardial replacement mainly in the right ventricle. It leads to 5% sudden cardiac death in affected young adults (<25 yo) without an implantable cardioverter defibrillator. Early diagnosis is crucial for appropriate clinical management to reduce mortality and prevent disease progression. Rare variants in desmosomal genes (PKP2,DSC2,DSG2,DSP and JUP) are found in 50% of cases. However, challenges persist since we observe a low penetrance in relatives (28-58%) and a high variability in expressivity and severity annihilating any preventive strategy. Objective We aim to decipher the genetic architecture of ACM by investigating the role of common variants in disease susceptibility/severity and to idendify new genes associated to ACM. Method A Genome Wide Association Study (GWAS) was performed on 1079 ACM index patients and 7305 controls, followed by conditional analysis. New candidate genes were knocked out (KO) in Zebrafish and/or hiPSC using CRISPR/Cas9. Impedance and external field potential measurements were performed on hiPSC derived cardiomyocytes (CM-hiPSC). Results The GWAS identified 5 significant loci (Figure 1, P<5.10-8), including 2 desmosomal genes (PKP2 a n d DSG2) and 3 new candidates (KLF12, CTNNA3, and ARL17B/WNT3). Conditional analysis revealed 3 additional loci with suggestive p-values (P<1.10-6), highlighting 3 new susceptible loci. Among them, we uncovered key non-coding regulatory regions near desmosomal genes (DSC2 and DSG2). Initial findings in PKP2-KO zebrafish present hearts with structural defects, while CM-hiPS KLF12-KO(-/-) exhibited altered interbeat interval and relaxation time compared to isogenic controls. Conclusion Our findings reveal ACM's complex genetic architecture, implicating common variants in disease susceptibility. A polygenic risk score will be implemented to improve patient risk stratification. Three novel loci/genes for ACM as well as specific regulatory regions of desmosomal genes have been highlighted. Their functional studies in isogenic hiPSC and Zebrafish models will offer new insights in ACM underlying molecular mechanism and potential therapeutic targets.

Proteomic biomarkers and pathway analysis for progression to heart failure in three epidemiological representative cohorts.

Biomarkers associated with asymptomatic ventricular dysfunction might improve risk stratification and identify pathways leading to heart failure (HF). We explored the association between proteomic biomarkers and left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and incident HF in three population-based cohorts. A chip was used to measure 92 protein biomarkers in blood samples from >1500 Malmö Preventive Project (MPP) participants, of whom 514 had LVH (34%), 462 had DD (32.4%) and, over a median follow-up of 13 (11-14) years, 130 developed HF (7.7%). Findings were confirmed in the STANISLAS (n > 1500, 238 participants with LVH, 76 with DD) and HOMAGE case-control (562 cases of incident HF, 871 controls) cohorts. In multivariable logistic or Cox regression analyses adjusted for age, sex and cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with LVH, DD and incident HF in all cohorts: MPP (LVH odds ratio [OR] [95% confidence interval] 1.48 [1.28-1.71]; DD OR 1.71 [1.53-1.92]; HF HR 1.98 [1.66-2.36]); STANISLAS (LVH OR 1.20 [1.02-1.41]; DD OR 1.46 [1.12-1.90]); HOMAGE (HF HR 1.85 [1.62-2.12]). Galectin-4, growth differentiation factor 15 and suppression of tumorigenicity-2 were associated with incident HF in MPP and HOMAGE. A pathway enrichment analysis suggested that inflammation and viral infection were related to incident HF. In conclusion, our study reinforces the role of NT-proBNP as a key biomarker for asymptomatic cardiac dysfunction and incident HF, consistent with its established use in clinical practice. This underscores the value of NT-proBNP for identifying patients at high risk for HF, and provides insights into pathways leading to HF and potential therapeutic targets.

Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.

Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and ApcMin/+) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.

Association of Neutrophil extracellular traps burden with clinical and angiographic characteristics in patients with ST-elevation myocardial infarction

Abstract Background The precise triggers for arterial plaque rupture and the underlying pathophysiology of thrombogenesis remain elusive. Polymorphonuclear neutrophils (PMN), particularly their formation of Neutrophil Extracellular Traps (NETs), have garnered attention in the context of coronary atherothrombosis. This study sought to explore the association of NETs burden with clinical and angiographic characteristics in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI) and thrombus aspiration (TA). Methods This study included 336 consecutive STEMI patients undergoing pPCI and TA. Aspirated thrombi underwent histological analysis and NETs quantification via immunohistochemistry. Potential associations of clinical variables and angiographic outcomes with NETs burden were assessed. Results Manual TA was selectively performed in 72 cases with increased thrombotic burden and 60 thrombi were suitable for analysis. Most thrombi specimens displayed lytic features (63%) and almost three out of four specimens were identified as white thrombi. Increased NETs burden was significantly associated with prolonged pain-to-balloon time (&amp;gt;300 minutes) OR=10.29 (95% CI 2.11-42.22, p=0.001) and stress-induced hyperglycemia (SIH) OR=6.58 (95% CI 1.23-52.63, p=0.04) after multivariate regression analysis. Additionally, distal embolization (DE), a predictor of adverse outcomes, was more frequent among patients with an elevated NETs burden OR=16.9 (95% CI 4.23-44.52, p&amp;lt;0.001). Conversely, no significant association between NETs burden and final TIMI flow=3 was observed. Conclusion Elevated NETs burden in STEMI thrombi is linked to delayed reperfusion, SIH and increased risk of DE. Further research is needed to elucidate the role of NETs as a potential therapeutic target in acute atherothrombosis.

Effect of empagliflozin on epicardial adipose tissue volume in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF)

Abstract Background Epicardial adipose tissue (EAT) is postulated to be linked to the pathophysiology of heart failure with reduced ejection fraction (HFrEF), acting both as a biomarker and a potential therapeutic target. Investigating changes in EAT volume following treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor could provide valuable mechanistic insights. Purpose This posthoc substudy of the SUGAR-DM-HF trial aimed to assess the effect of the SGLT2 inhibitor empagliflozin on EAT volume. Methods Within a multicentre, randomised, double-blind, placebo-controlled trial, the effects of empagliflozin were evaluated in patients with HFrEF (New York Heart Association functional class II-IV, left ventricular ejection fraction (LVEF) ≤40%), and type 2 diabetes or prediabetes. Patients with atrial fibrillation/flutter were excluded to avoid image degradation. Patients were randomly assigned 1:1 to empagliflozin 10mg daily or placebo. EAT volume was quantified using cardiovascular magnetic resonance (CMR) cine imaging at baseline and week 36, and reported as: (a) total EAT volume (mL); (b) EAT volume indexed to body surface area (mL/m2); (c) % change from baseline. Observers were blinded to subject identification, scan date, clinical data, and randomization arm. Scans with major artefacts were not analysed. Results One hundred five patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% (9.8%). Baseline EAT volume was available in 101 patients (median [IQR] 85 [67-104] mL and 41 [34-52] mL/m2). Paired baseline and 36-week EAT volume was available in 90 patients. Higher baseline total EAT volume was associated with male gender, higher body mass index, coronary artery disease, elevated serum creatinine, higher left ventricular end-diastolic volume, and higher left ventricular mass (TABLE). EAT volume changed by -2.7 mL / -1.3 mL/m2 / -3.1% in the empagliflozin group versus 0.3 mL / 0.3 mL/m2 / 1.5% in the placebo group (between-group difference -3.4 mL, 95% CI -6.7 to -0.1; p=0.045 and -1.7 mL/m2, 95% CI -3.4 to -0.04; p=0.045) at 36 weeks (FIGURE). The beneficial reduction in left ventricular end-systolic volume indexed to body surface area observed with empagliflozin treatment was not modified by baseline total or indexed EAT volumes (p interaction=0.31 and 0.45, respectively). Conclusion Empagliflozin treatment significantly reduced EAT volume. This may represent an additional benefit of SGLT2 inhibition in HFrEF.

Sirt5 as a mediator of endothelial and vascular dysfunction: potential therapeutic target in aging-related vascular diseases

Abstract Background Aging is one of the most dominant cardiovascular (CV) risk factors. Sirt5 belongs to the lifespan-regulating sirtuin superfamily as a protein deacylase. However, its regulatory effects on vascular function and aging are yet unclear. Purpose We therefore aimed to investigate the roles of Sirt5 on endothelial and vascular function during aging, decipher the underlying mechanisms, and to explore its potential as a therapeutic target through in vivo and in vitro studies. Methods Aortic expression of Sirt5 were studied in C5BL/6 wild type (WT) mice during aging, followed by vascular functional and structural assessment in WT mice and Sirt5-overexpressing mice (Sirt5/Tg) using the established myograph system and histological staining respectively. Furthermore, the regulatory role of Sirt5 on endothelial function was investigated in senescent primary human aortic endothelial cells (HAECs, passages 13-15) by studying its interference with endothelial nitric oxide synthase (eNOS) expression and activity in knock-down experiments using siRNA. The therapeutic potential of Sirt5 inhibition was explored at the tissue level in myograph experiments. Results Aged WT mice had increased level of Sirt5 in aorta compared to the young ones. Overexpression of Sirt5 in vivo led to significantly reduced aortic endothelial-dependent relaxation and displayed thicker collagen deposition in the adventitia compared to aged WT controls. The reduction of vascular relaxing response in Sirt5/Tg mice was prevented by an addition of eNOS inhibitor (L-name), indicating that Sirt5 regulated vascular function through the eNOS pathway. In senescent HAECs, knock-down of Sirt5 markedly induced total eNOS expression and increased its activity (phospho-eNOS Ser1177), further confirming the regulatory role of Sirt5 on eNOS pathway. In line with the above, aorta from aged WT mice displayed improved endothelial function after pharmacological inhibition of Sirt5. Conclusion Vascular Sirt5 expression increases with age and contributes to aging-related endothelial dysfunction by downregulating the eNOS pathway. Thus, Sirt5 inhibition may represent a novel therapeutic approach to maintain vascular function during aging. Ongoing studies will investigate Sirt5 silencing in-vivo using RNA interference for its therapeutic potential to prevent aging-related vascular dysfunction.

Plasma cytokines are associated with major adverse cardiovascular events in follow-up of patients undergoing carotid endarterectomy

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) have a high risk of experiencing Major Adverse Cardiovascular Events (MACE) after surgery. The occurrence of MACE in CEA-treated patients is not predicted by common cardiovascular (CV) risk factors. Purpose We aimed to identify the association between plasma and plaque inflammatory cytokines and the incidence of MACE in the follow-up after CEA. We hypothesized that MACE is related to a higher level of circulating inflammatory cytokines at the time of surgery. Methods We prospectively enrolled patients with carotid artery disease undergoing CEA. Plasma and carotid plaques were collected during the surgery. Inflammatory cytokines (MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, VEGF) were measured in plasma and tissue homogenates using a customized 10-plex Luminex assay. Baseline demographics and clinical data for all the patients were extracted from electronic health records. MACE after CEA was defined as a composite measure of nonfatal cardiac events such as myocardial infarction with or without revascularization, cerebrovascular events (ischemic stroke, TIA, and amaurosis fugax), and all-cause mortality. Results Of 107 patients who underwent CEA with a median age of 73 (67-78) years, 57 (53.2%) experienced MACE during a median follow-up of 5.2 [2.2-9.3] years: 23 (40.3%) cardiac events, 9 (15.7%) CVA, and 25 (43.8%) all-cause mortality. Plaque cytokines levels did not differ between the groups with and without MACE in the follow-up after CEA. Instead, plasma cytokines were associated with MACE in the follow-up after CEA, as summarized in Figure 1. In the logistic regression analysis, plasma levels of MCP-1/CCL2, IFN-gamma, and TNF-alpha were independent predictors of MACE in follow-up post-CEA in univariate and multivariable models adjusted for CV risk factors such as age, BMI, systolic and diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, and glucose level: MCP1/CCL2 (HR 1.009 [1.002-1.015]; p=0.007), IFN-gamma (HR 1.368 [1.014-1.845]; p=0.040), and TNF-alpha (HR 1.121 [1.022-1.228]; p=0.015) (Table 1). Conclusions Plasma levels of CCL2, IFN-gamma, and TNF-alpha are associated with the high incidence of MACE in the follow-up after CEA, indicating that these are potential biomarkers of MACE in this patient population and potential therapeutic targets in patients' progression of systemic atherosclerosis.Plasma cytokines and MACE after CEACytokines logistic regression analysis

Autonomic response and attachment style in disruptive mood dysregulation disorder

Background: Disruptive mood dysregulation disorder (DMDD) is characterised by severe emotion regulation difficulties, particularly anger and irritability, in children. Despite the impact of attachment on emotional and behavioural regulation, the link between attachment style and DMDD is under-researched.Aim: This study investigated whether attachment style and parasympathetic regulation differentiate the response profiles to frustrating conditions between children diagnosed with DMDD and controls.Setting: Participants were assessed at schools in Johannesburg, Gauteng, South Africa.Methods: Thirty participants were divided into two matched groups (nDMDD = 15; nControl = 15) and assessed. Respiratory sinus arrhythmia (RSA) and heart period were measured during an Affective Posner Task, inducing frustration. Attachment style was assessed using the Attachment Style Classification Questionnaire for children. Parents of children with DMDD completed a social interaction problems questionnaire.Results: The DMDD group showed a higher prevalence of avoidant attachment style (p = 0.013) compared to controls. Both groups displayed adaptive vagal withdrawal and recovery during the task (p = 0.005; p = 0.021). Controls had significantly higher heart period throughout the assessment (game 1: p = 0.006; game 2: p = 0.013; game 3: p = 0.007). In the DMDD group, lower vagal tone during frustration correlated with more social interaction problems (p = 0.049).Conclusion: The study demonstrates a potential link between attachment style and altered physiological state in children with DMDD.Contribution: The findings provide insight into possible atypical vagal regulation of the heart and avoidant attachment styles in DMDD, highlighting potential therapeutic and intervention targets.

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target.

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.

Causal association between visceral fat and coronary artery disease: a large-scale mendelian randomization analysis

Abstract Background While increased body mass index (BMI) is an established risk factor, the residual risk associated with visceral fat, remains a concern. We aimed to perform a Mendelian randomization to explore the causal relationship between visceral fat and the risk of coronary artery disease (CAD), aiming to address gaps left by observational studies that may be influenced by confounding factors and reverse causation. Methods Leveraging large-scale genome-wide association study (GWAS) databases, we identified single-nucleotide polymorphisms (SNPs) associated with visceral fat. These genetic instruments were analyzed to infer causal relationships with CAD outcomes, drawing data from the CARDIoGRAMplusC4D consortium for CAD, and additional databases for related cardiovascular conditions. We performed a Two-sample Mendelian Randomization (MR) to test the genetic association between the visceral obesity and Coronary Artery Disease (CAD). Results The analysis encompassed data from a combined cohort exceeding 500,000 participants, revealing a significant causal relationship between increased levels of visceral fat and the risk of CAD. The observed odds ratio (OR) for CAD per standard deviation (SD) increase in visceral fat was [OR, 1.48 ] ([95% CI, 1.33-1.64]; P&amp;lt;0.001), indicating a robust association which remains independent from BMI on mediation analysis. Notably, the study's methodology ensured minimal risk of pleiotropy, reinforcing the validity of the findings. Conclusions This Mendelian randomization study provides compelling evidence of a genetic causal link between visceral fat and coronary artery disease. The findings suggest that beyond BMI, visceral fat represents a significant, independent risk factor for CAD, underscoring the importance of considering comprehensive lipid management in cardiovascular risk reduction strategies. Further research is warranted to explore potential mechanisms and therapeutic targets associated with visceral fat in the context of cardiovascular disease.

ND-13 preserves mitochondrial integrity via the RhoA/ROCK1/Drp1-S616 pathway providing acute cardioprotection in myocardial infarction

Abstract Background Ischemia-reperfusion injury (IRI) following acute myocardial infarction is a major contributor to heart failure and mortality worldwide. Drp1-driven mitochondrial fragmentation disrupts mitochondrial function, increases cardiomyocyte death, and aggravates cardiac dysfunction. We investigated whether ND-13, a novel DJ-1-derived peptide, can acutely protect the heart by maintaining mitochondrial homeostasis and modulating Drp1 activity during IRI. Methods The effects of ND-13 on Drp1 activity were assessed by studying mitochondrial dynamics, function and survival signalling pathways. Cardioprotective effects of ND-13 were assessed using in vitro, ex vivo and in vivo models of IRI. Results ND-13 demonstrated acute cardioprotective effects in murine adult cardiomyocytes subjected to simulated IRI by a 42% reduction in cell death. The excessive mitochondrial fission following IRI was attenuated by inhibiting Drp1 phosphorylation at the Ser616 residue by reduced activity of the RhoA/ROCK1 pathway. This in turn enhanced mitochondrial function as seen through increased mitochondrial respiration rates (basal, maximal and spare respiratory capacity), increased ATP production, maintained mitochondrial membrane potential and reduced reactive oxygen species levels. The acute cardioprotective effect of ND-13 was reproduced in both an ex vivo Langendorff based model of IRI with a 43% reduction infarct size and an in vivo murine model of IRI with a 35% reduction of infarct size. These results indicate the robust effect of the peptide and its potential for clinical translation through intravenous delivery. Conclusion In this study, we demonstrate ND-13 as a small peptide that modulates mitochondrial dynamics through the RhoA/ROCK1/DRP1-S616 pathway, which highlights a potential new therapeutic target for myocardial IRI.

Noncoding RNAs in rheumatoid arthritis: modulators of the NF-κB signaling pathway and therapeutic implications

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and gradual tissue destruction. New research has shown how important noncoding RNAs (ncRNAs) are for changing immune and inflammatory pathways, such as the WNT signaling pathway, which is important for activating synovial fibroblasts and osteoblasts to work. This article examines the current understanding of several ncRNAs, such as miRNAs, lncRNAs, and circRNAs, that influence NF-κB signaling in the pathogenesis of RA. We investigate how these ncRNAs impact NF-κB signaling components, altering cell proliferation, differentiation, and death in joint tissues. The paper also looks at how ncRNAs can be used as potential early detection markers and therapeutic targets in RA because they can change important pathogenic pathways. This study highlights the therapeutic potential of targeting ncRNAs in RA therapy techniques, with the goal of reducing inflammation and stopping disease progression. This thorough analysis opens up new possibilities for understanding the molecular foundations of RA and designing novel ncRNA-based treatments.

Skeletal and respiratory muscle weakness contributes to decreased exercise capacity in hypertrophic cardiomyopathy

Abstract Background and Aims Although decreased exercise capacity (due to dyspnea or angina-like symptoms) constitutes the fundamental characteristics of hypertrophic cardiomyopathy (HCM), the pathophysiology of these symptoms remains only partly understood. We investigated clinical and functional determinants of decreased exercise capacity in a broad range of HCM patients irrespective of primary disease aetiology (either genetic disorder or e.g. infiltrative phenocopies in the course of cardiac amyloidosis), overt heart failure (HF) and the presence of haemodynamically significant left ventricular outflow tract obstruction (LVOTO). Further, we deterimined the contribution of skeletal and respiratory muscle weakness to decresed exercise capacity. Methods We analyzed clinical data and functional assessments (skeletal and respiratory muscle strength, physical fitness) in relation to symptomatology and sub-maximal exercise capacity in 82 clinically stable patients with HCM (females: 32 %; age: 62±16 years; left ventricular ejection fraction [LVEF] 59±7%; intraventricular septum wall thickness [IVS] 19±4 mm; median plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 818 pg/mL [lower and upper quartile: 208-1917]; New York Heart Association [NYHA] class 0/I/II/III: 38/18/33/11 % [0 indicates no HF]; significant LVOTO: 29%). Results HCM patients with more severe symptomatology (NYHA class II-III vs 0-I) were older, had more frequently significant LVOTO and greater comorbidity burden, and had higher NT-proBNP and worse estimated renal function (all p≤0.03). Gender distribution, percentage of beta-blocker therapy and implanted device, body mass index, major echocardiography parameters (including LVEF, left ventricular end-diastolic diameter and IVS), high-sensitive (hs) cardiac troponin type I and hs-C-reactive protein were comparable in these 2 groups of subjects (all p&amp;gt;0.05). In multivariable linear regression models more advanced age, higher circulating natriuretic peptides (NT-proBNP) and previous coronary revascularization were independent predictors of more advanced NYHA class (standardized β-coefficient=0.30, p&amp;lt;0.01; β=0.27, p&amp;lt;0.01; and β=0.22, p&amp;lt;0.05; respectively). Similarly, more advanced age, female sex and higher NT-proBNP were independent correlates of shorter distance in 6-minute walking test (6MWT) (β=-0.46, p&amp;lt;0.001; β=-0.26, p&amp;lt;0.001; and β=-0.36, p&amp;lt;0.001; respectively). All analyzed muscle parameters (including respiratory muscle strength parameters) and objective measures of physical fitness (Functional Fitness Test for older adults) remained independently associated with 6MWT distance (all p&amp;lt;0.001) when adjusted for aforementioned clinical and laboratory correlates of 6MWT. Conclusions Muscle weakness and low physical fitness are related to decreased exercise capacity in HCM and may be potential therapeutic targets to alleviate disease symptoms also in non-obstructive HCM phenotype.

STING-mediated DNA damage response in diabetes-induced vascular complications

Abstract Background Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Methods and Results Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P &amp;lt; 0.001) and increased aortic eNOS phosphorylation (P &amp;lt; 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P &amp;lt; 0.01). Conclusion The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.