Radwan Darwish

Women with polyendocrine metabolic ovarian syndrome (PMOS) have heterogeneous metabolic risk. We investigated whether targeted circulating proteins were associated with incident type 2 diabetes (T2D) and whether the retained proteins responded to experimentally induced lipid stress. In Cohort 1, 231 women with (n = 135) or without (n = 96) PMOS had T2D outcome data, of whom 25 developed T2D during a median follow-up of 12.7 years (range 10.2–15.1); 221 women (20 incident cases) had complete covariate data for adjusted analyses. Of 44 available proteins, 27 were prespecified from prior literature; following Benjamini–Hochberg adjustment, eight biomarkers (Adiponectin (ADIPOQ), Endocan (ESM1), Mast/stem cell growth factor receptor-Kit (KIT), Chordin Like 1 (CHRDL1), Cell Adhesion Molecule L1 Like (CHL1), Cathepsin V (CTSV), L1 Cell Adhesion Molecule (L1CAM) and Delta Like Canonical Notch Ligand 4 (DLL4)) had a statistically significant association with T2D in univariate models. However, following adjustment for group, body mass index (BMI) and age, only ADIPOQ remained statistically significant. In Firth penalised logistic regression adjusted for PMOS status, age and BMI, each 1 SD higher ADIPOQ was associated with lower odds of incident T2D (OR 0.12; 95% CI 0.04–0.31); the association persisted when events were restricted to a common 10-year follow-up horizon, after adjustment for baseline fasting glucose, and after excluding women with baseline fasting glucose ≥ 7.0 mmol/L. Adding ADIPOQ to PMOS status, age and BMI increased the bootstrap optimism-corrected AUC from 0.74 to 0.87. In an independent experimental cohort (PMOS, n = 11; controls, n = 9, with SOMAscan data), ADIPOQ, neural cell adhesion molecule L1-like protein (CHL1), mast/stem cell growth factor receptor-Kit (KIT), chordin-like protein 1 (CHRDL1) and neural cell adhesion molecule L1 (L1CAM) were measured at 0, 180 and 300 min of 5 h saline and Intralipid infusions and analysed using linear mixed-effects models. Relative to saline, Intralipid lowered L1CAM, CHL1 and KIT at 180 min (differences in change from baseline −0.33, −0.30 and −0.25 log₂ units; FDR-adjusted p ≤ 0.029), with no evidence that responses differed between women with PMOS and controls, and no lipid-specific change in ADIPOQ was detected; only the L1CAM response persisted after excluding turbid or haemolysed samples. Lower adiponectin was the only protein independently associated with incident T2D, whereas L1CAM, and less robustly CHL1 and KIT, responded to acute lipid exposure. The small number of events, differential outcome ascertainment between groups, absence of external validation and the exploratory experimental cohort preclude claims of clinical prediction. These findings support further evaluation of prognostic and stress-responsive protein phenotypes in larger, independently validated cohorts.

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin–NFAT or oxygen-binding globins—offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell–derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation.

Mitochondria are essential for β-cell function, coupling glucose metabolism to ATP production and insulin secretion. In diabetes, β-cell mitochondrial dysfunction arises from oxidative stress, impaired quality control and disrupted dynamics, leading to reduced oxidative phosphorylation, defective insulin release and progressive cell loss. Key transcriptional regulators link genetic susceptibility to mitochondrial dysfunction in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These disruptions impair mitophagy, mitochondrial translation and redox homeostasis. Therapeutic strategies that restore mitochondrial function, including mitophagy enhancers, mitochondrial antioxidants, and transcriptional regulators, have shown potential in preserving β-cell integrity. As mitochondrial failure precedes β-cell loss, targeting mitochondrial pathways may represent a critical approach to modifying diabetes progression.

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications.

Introduction: Ischemic heart disease (IHD) remains a major global health burden, highlighting the urgent need for early, non-invasive diagnostic biomarkers. MicroRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression, have emerged as promising candidates due to their stability in circulation and involvement in cardiovascular processes. This systematic review aimed to evaluate the potential of specific miRNAs as early diagnostic biomarkers in IHD.Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed in PubMed, Scopus, and Web of Science databases up to June 31, 2024. Eligible studies were selected based on predefined inclusion criteria. We identified recurrently dysregulated miRNAs and used miRTarBase to retrieve experimentally validated gene targets. Subsequently, gene set enrichment analysis (GSEA) was performed using Enrichr, referencing BioPlanet, KEGG, and Panther pathway libraries. Functional annotation was further explored using TAM 2.0.Results: A total of 38 studies met the inclusion criteria. Among the reported miRNAs, miR-126, miR-21, miR-145, miR-92a, and miR-155 were the most frequently and consistently dysregulated across various IHD subtypes. Although expression patterns varied, these miRNAs were recurrently implicated in IHD-related processes. GSEA revealed enrichment of their gene targets in key pathways such as p53, TGF-β, and FoxO signaling, as well as in processes involving apoptosis and angiogenesis critical in vascular injury, remodeling, and immune activation. Several cancer-related pathways were also enriched, underscoring molecular overlaps between tumorigenesis and atherosclerosis. TAM 2.0 functional annotation supported these findings, linking the selected miRNAs to smooth muscle differentiation, cytokine signaling, and regulation by key transcription factors including SMAD4, STAT3, and AP-1.Discussion: Our findings suggest that a panel combining the identified miRNAs may offer greater diagnostic value for IHD than individual markers, given their involvement in multiple IHD-related biological processes and pathways. The recurrent dysregulation of these miRNAs across diverse studies supports their potential as components of a robust, non-invasive diagnostic tool. However, expression variability and pathway overlap with other diseases, such as cancer, indicate the need for further validation. Larger prospective studies are warranted to validate their clinical applicability in IHD screening and risk stratification.Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42024583265.

Since the World Health Organization (WHO) issued guidelines for developing a non-sputum test for active tuberculosis (TB) diagnosis that exhibits similar performance characteristics to sputum-based diagnosis, salivary diagnostic techniques have gained prominence as potential screening tools or adjuncts to existing diagnostics. We searched online databases for studies that looked at salivary diagnostic techniques. Afterwards, duplicates were removed, titles and abstracts were screened, and full-text studies were assessed for eligibility based on inclusion and exclusion criteria. The studies chosen for final analysis underwent a rigorous quality assessment following a QUADAS-2 template, and data were extracted. The primary outcome assessed the difference in mean levels of interleukins between TB+ patients and TB-controls (Hedges’ g). We then conducted two subgroup analyses: the first segregated the control group into healthy patients, and those with other respiratory diseases (ORD), and the second addressed three different interleukins separately (IL-6, IL-5, IL-17). The secondary outcome involved comparing salivary molecular diagnostic assays to WHO guidelines. This study is registered with PROSPERO, CRD42024536884. A total of 17 studies, out of an initial 1010, were chosen for the final analysis, but one was then excluded for being of poor quality. Our meta-analyses for the primary outcome revealed minimal diagnostic potential for interleukins. Our first subgroup analysis showed that interleukins were incapable of differentiating active TB patients from both healthy controls and ORD patients. Our second subgroup analysis showed that IL-17 was reduced in active TB patients. Assessment of the secondary outcome revealed that most studies relied on a GeneXpert MTB/RIF assay on saliva, but none fulfilled WHO guidelines for a non-sputum test. Individual biomarkers currently lack sufficient discriminatory power to definitively distinguish active tuberculosis from healthy individuals or those with other respiratory diseases (ORD), reinforcing the need for multi-biomarker panels. Interleukins may be alternatively used as markers for prognosis, severity, or treatment response. Our findings also suggest that assays are unable to meet WHO guidelines.

In the context of cell cycle inhibition, anti-proliferation, and the dysregulation observed in certain cancer pathologies, the protein p21 assumes a pivotal role. p21 links DNA damage responses to cellular processes such as apoptosis, senescence, and cell cycle arrest, primarily functioning as a regulator of the cell cycle. However, accumulating empirical evidence suggests that p21 is both directly and indirectly linked to a number of different metabolic processes. Intriguingly, recent investigations indicate that p21 significantly contributes to the pathogenesis of diabetes. In this review, we present a comprehensive evaluation of the scientific literature regarding the involvement of p21 in metabolic processes, diabetes etiology, pancreatic function, glucose homeostasis, and insulin resistance. Furthermore, we provide an encapsulated overview of therapies that target p21 to alleviate metabolic disorders. A deeper understanding of the complex interrelationship between p21 and diabetes holds promise for informing current and future therapeutic strategies to address this rapidly escalating health crisis.