Search Results (229)

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020–31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug–drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug–disease–drug interactions and glycemic risk, and inform individualized dosing strategies. Full article

Background/Objectives. Prostate cancer (PCa) is among the leading causes of death from cancer in men. Frequent use of androgen receptor inhibitors induces PCa transdifferentiation, leading to poorly differentiated neuroendocrine PCa (NEPC). ROR2 is critical for NEPC pathogenesis by activating ASCL1, promoting lineage plasticity. Protein lysine methylation mediated by N-lysine methyltransferases SMYD2 and its downstream effector EZH2 upregulates the NEPC marker ASCL1 and enhances c-MET signaling, promoting PCa aggression. Epidemiological studies suggest a lower incidence of certain malignancies in Mediterranean populations due to their intake of an olive-phenolics-rich diet. Methods. Cell viability, gene knockdown, and immunoblotting were used for in vitro analyses. A nude mouse NEPC xenograft model evaluated the anti-tumor efficacy of purified and crude oleocanthal. Xenograft tumors were subjected to RNA-seq, qPCR, and Western blot analyses, with clinical validation performed using tissue microarrays. Results. A tissue microarray analysis showed that SMYD2 expression was significantly elevated in PCa tissues with higher IHS versus normal prostate tissue cores. The olive phenolic S–(–)–oleocanthal (OC) suppressed the de novo NEPC NCI-H660 cells proliferation. Male athymic nude mice xenografted with the NCI-H660-Luc cells were used to assess OC effects on de novo NEPC progression and recurrence. Male NSG mice transplanted with LuCaP 93 PDX tumor tissues generated a heterogeneous in vivo model used to assess OC effects against t-NEPC progression. Daily oral 10 mg/kg OC administration significantly suppressed the NCI-H660-Luc tumor progression and locoregional recurrence after primary tumor surgical excision. OC treatments effectively suppressed the progression of LuCaP 93 PDX tumors. OC-treated tumors revealed downregulation of ROR2, ASCL1, SMYD2, and EZH2, as well as activated c-MET levels versus the placebo control. RNA sequencing of the collected treated NEPC tumors showed that OC disrupted NEPC splicing, translation, growth factor signaling, and neuronal differentiation. Conclusions. This study’s findings validate OC as a novel lead entity for NEPC management by targeting the ROR2-ASCL1-SMYD2-EZH2-c-MET axis. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is characterized by progressive β-cell dysfunction and insulin resistance. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may enhance β-cell function. Semaglutide, a long-acting GLP-1 RA, improves glycemic control and weight, but its direct effects on β-cell function remain uncertain. Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD420251034071). PubMed, Embase, and Scopus were searched through April 2025 for randomized controlled trials evaluating semaglutide’s effects on β-cell function in adults with T2DM. Primary outcomes included HOMA-B, HOMA-IR, and the proinsulin/insulin ratio; secondary outcomes included insulin secretion rate, insulinogenic index, and C-peptide. Two reviewers independently performed data extraction and risk-of-bias assessment using the Cochrane RoB 1 tool. Random-effects models were used for pooling. Certainty of evidence was evaluated using GRADE. Results: Sixteen trials (n = 6591) met inclusion criteria, with nine included in the meta-analysis. Semaglutide improved β-cell function (HOMA-B log ratio of means 1.50, 95% confidence interval [CI]: 1.25–1.80) and reduced insulin resistance (HOMA-IR ratio 0.82, 95% CI: 0.73–0.94) compared with placebo or active comparators. The pooled treatment ratio for proinsulin/insulin was 0.70 (95% CI: 0.63–0.79). However, risk of bias was generally high due to open-label designs, and certainty of evidence for all primary outcomes was rated very low. Conclusions: Semaglutide appears to improve β-cell function and insulin sensitivity in adults with T2DM, but conclusions remain uncertain given the very low certainty of evidence and substantial heterogeneity. High-quality trials with standardized β-cell outcomes are needed to confirm these findings. Full article

Background/Objectives: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. Methods: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. Results: Compounds 5a, 5g, 5h, 11a, and 11b showed strong inhibition of both kinases (IC₅₀ = 0.145–0.970 μM for VEGFR-2 and 0.181–1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound 11b (p-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, 11b induced G₂/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. Conclusions: Compound 11b was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy. Full article

Kinases, which make up 20% of the druggable genome, are thought to be essential signaling enzymes. Protein phosphorylation is induced by protein kinases. Proliferation, the cell cycle, apoptosis, motility, growth, differentiation, and other biological processes are all regulated by kinases. Their dysregulation disrupts several cellular functions, leading to a variety of illnesses, the most important of which is cancer. As a result, kinases are thought to be crucial targets in a number of malignancies and other diseases. Researchers from all over the world are hard at work developing inhibitors using various chemical structures. The scaffolds of imidazole and benzimidazole provide a versatile structure for a variety of physiologically active substances. Moreover, they serve as specialized scaffolding for the creation of target-specific pharmaceuticals to address various diseases. This article seeks to illustrate the application of imidazole and benzimidazole frameworks in the formulation of inhibitors that target various tyrosine kinases, including fibroblast growth factor receptors (FGFRs), c-Met kinase, epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), and FMS-like tyrosine kinase 3 (FLT3), from 2020 to the present. The major structure–activity correlations (SARs) of imidazole and benzimidazole derivatives were examined, and, also, a docking study highlighted the varied interactions occurring inside the active site of tyrosine protein kinases. The objective of this effort is to consolidate the fundamental structural information necessary for the synthesis of imidazole- or benzimidazole-based tyrosine kinase inhibitors with enhanced efficacy. Full article

Alzheimer’s disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-β (Aβ) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020–2025) using predefined terms related to PCSK9 and Alzheimer’s disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer’s. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies. Full article

Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers. Full article

This review addresses the growing concern of oral side effects, particularly dry mouth, associated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) widely used for diabetes and obesity. A literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (March–September 2025) identified studies on GLP-1 receptor signaling, semaglutide pharmacology, salivary gland biology, biased agonism, β-arrestin, and cAMP pathways, and reported oral adverse effects. Of 183 records screened, 78 met inclusion criteria and were narratively synthesized across 5 mechanistic domains linking the molecular mechanisms that may underly semaglutide-induced alteration in salivary function by exploring GLP-1 receptor (GLP-1R) expression and signaling in salivary glands. The available literature data shows that different GLP-1 receptor agonists exhibit distinct patterns of GLP-1R activation, engaging the cAMP- and β-arrestin–dependent pathways to varying extents, which may thus differentially regulate exocytosis and cellular protection. Furthermore, semaglutide’s strong albumin binding leads to prolonged receptor activation, and may disturb the rhythmic calcium and cAMP cross-talk essential for normal salivary secretion. Persistent stimulation may cause receptor desensitization, β-arrestin–mediated internalization, and reduced gland responsiveness. Clinical pharmacovigilance data indicate disproportionality signals, suggesting that semaglutide may be reported more frequently with oral side effects compared with other GLP-1 receptor agonists, although spontaneous-report databases cannot confirm causality. These insights underscore the need for patient counseling, preventive oral care, and further studies on receptor signaling bias, contributing to personalized approach when using GLP-1RAs. Full article

Inherited platelet function disorders (IPFDs) are rare diseases caused by defects in platelet surface receptors, enzymes, granules, or signaling proteins. In humans, GPVI and P2Y12 deficiency cause autosomal recessive bleeding disorders, while TBXAS1 deficiency is related to Ghosal hematodiaphyseal dysplasa, a rare autosomal recessive disorder characterized by increased long bone density and platelet dysfunction without bleeding. To date, at least 20 patients have been identified with molecular defects in P2RY12, 12 cases with molecular defects in GP6, and 34 cases with molecular defects in TBXAS1. Here, we report a novel nonsense and missense variants in P2RY12, a novel nonsense variant in GP6, and a novel missense variant in TBXAS1. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. P2RY12 c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas P2RY12 c.44delG [p.Ser15Ilefs*33] lead to decreased levels of the receptor in one of the patients. This was confirmed both by RT-qPCR and immunoblotting analysis. Decreased expression of both GPVI and FcRγ-chain was detected in patients carrying GPVI nonsense variant in heterozygosis. The deleterious effect of these variants was also confirmed in a transfected cell line model. TBXAS1 variant triggered decreased TxA₂ production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency. Full article

Background: Biopsy remains the gold standard for characterizing breast cancer, but it is invasive, costly, and may not fully capture tumor heterogeneity. Advances in artificial intelligence (AI) now allow for the extraction of biological and clinical information from medical images, raising the possibility of using imaging as a non-invasive alternative. Methods: A semi-systematic review was conducted to identify AI-based approaches applied to mammography (MM) and breast tomosynthesis (BT) for tumor subtyping, staging, and prognosis. A PubMed search retrieved 1091 articles, of which 81 studies met inclusion criteria (63 MM, 18 BT). Studies were analyzed by clinical target, modality, AI pipeline, number of cases, dataset type, and performance metrics (AUC, accuracy, or C-index). Results: Most studies focused on tumor subtyping, particularly receptor status and molecular classification. Contrast-enhanced spectral mammography (CESM) was frequently used in radiomics pipelines, while end-to-end deep learning (DL) approaches were increasingly applied to MM. Deep models achieved strong performance for ER/PR and HER2 status prediction, especially in large datasets. Fewer studies addressed staging or prognosis, but promising results were obtained for axillary lymph node (ALN) metastasis and pathological complete response (pCR). Multimodal and longitudinal approaches—especially those combining MM or BT with MRI or ultrasound—show improved accuracy but remain rare. Public datasets were used in only a minority of studies, limiting reproducibility. Conclusions: AI models can predict key tumor characteristics directly from MM and BT, showing promise as non-invasive tools to complement or even replace biopsy. However, challenges remain in terms of generalizability, external validation, and clinical integration. Future work should prioritize standardized annotations, larger multicentric datasets, and integration of histological or transcriptomic validation to ensure robustness and real-world applicability. Full article

Background: The emergence of the COVID-19 pandemic has accelerated research into diverse immune response mechanisms. One key area of interest is the regulation of cytotoxic activity by Natural Killer (NK) cells. These cells rely on a dynamic interplay between activating and inhibitory surface receptors that recognize specific ligands on target cells. Among these, receptors from the NKG2 family are particularly important, as maintaining their proper balance and function is essential for controlling NK cell cytotoxicity. Methods: In this study we employed qPCR to assess the genetic variability using single-nucleotide polymorphisms (SNPs) of NKG2A and NKG2D receptors and their ligands HLA-E and MICA/MICB. NKG2C deletion was determined by PCR-SSP, and serum-soluble levels of HLA-E and MICA/MICB molecules were measured by ELISA and Luminex methods. Results: Genotyping studies revealed that both NKG2A rs7301582 T and HLA-E rs1264457 A (HLA-E*01:01) alleles were predominant among infected individuals (OR = 2.21, p = 0.0258 and OR = 2.84, p = 0.0257, respectively). In contrast to MICB rs1065075 A, the MICA rs1051792 A (129Met) allele was most commonly found in hospitalized patients (OR = 14.95, p = 0.0114). The presence of the NKG2C del variant tended to be associated with an increased risk of SARS-CoV-2 infection (OR = 2.02, p = 0.0694). Moreover, higher concentrations of serum-soluble MICB was detected in infected individuals as compared to the control group (p = 0.008). Conclusions: Genetic variability of NK cell receptors and ligands as well as serum levels of their soluble forms showed associations with the risk of development of COVID-19 and the severity of its symptoms. Full article

Background and Objectives: Metabolic syndrome (MetS) is characterized by a cluster of factors, including dyslipidemia, insulin resistance, central obesity, elevated blood pressure, and impaired fasting glucose, which together elevate the risk of type 2 diabetes and cardiovascular disease. Nutraceuticals containing botanical extracts with antioxidant and metabolic activity have emerged as promising adjunctive strategies in the management of MetS. This study evaluated the clinical effectiveness and biological rationale of a standardized food supplement (QUINOLAM), containing extracts of Cydonia oblonga (quince), Olea europaea (olive leaf), and Amaranthus spp., in adults with metabolic syndrome. Materials and Methods: This was a retrospective, single-center observational study including adults with documented MetS who received one tablet daily of the QUINOLAM-based supplement for at least 12 weeks. The primary endpoint was the change in total cholesterol. Secondary endpoints included LDL-C, HDL-C, triglycerides, fasting glucose, HbA1c, HOMA-IR, CRP, and BMI. In parallel, preclinical studies were conducted using HepG2 cells to investigate QUINOLAM’s effects on LDL receptor expression, glucose uptake, antioxidant activity, and cell viability. Results: Thirty patients met the inclusion criteria. A significant reduction in total cholesterol was observed at both 6 and 12 weeks (p < 0.005), accompanied by a significant decline in LDL-C by week 12 (p < 0.05). Among patients with baseline fasting glucose ≥100 mg/dL (n = 19), a significant improvement in glycemia was recorded (p < 0.005). Trends toward improvement were noted in other metabolic indices. In vitro, QUINOLAM enhanced LDL receptor expression (p < 0.05) and glucose uptake (p < 0.01), demonstrated antioxidant activity in the TEAC assay, and showed no cytotoxicity at relevant doses. Conclusions: In a real-world setting, daily supplementation with QUINOLAM was associated with significant improvements in lipid and glycemic control among patients with MetS. Preclinical findings further support its mechanistic plausibility via modulation of LDL handling, glucose metabolism, and oxidative stress. These results warrant confirmation in larger, prospective clinical trials. Full article

Background/Objectives: Metrnl (Meteorin-like), a secreted protein identified in our lab, has been shown to promote wound healing in mice. However, current therapeutic strategies and the underlying mechanisms remain incompletely understood. This study aimed to (1) develop a recombinant human Metrnl (hMetrnl) hydrogel formulation for topical delivery, and (2) elucidate its molecular mechanism in wound repair. Methods: hMetrnl was dispersed in a thermosensitive PLGA-PEG-PLGA hydrogel (hMet-PPP) and applied topically to full-thickness skin wounds in male C57BL/6 mice. A large initial dose was administered on the day of injury, followed by a lower maintenance dose regimen. Mechanistic studies were performed using molecular/cellular assays to assess the effects of hMetrnl. Results: Administration of hMet-PPP significantly accelerated wound healing, reducing the initial wound area and shortening the overall recovery time. hMetrnl transmits signals to endothelial cells via the KIT receptor tyrosine kinase (C-Kit), a membrane receptor, thereby initiating a dual regulatory mechanism involving eNOS to promote angiogenesis: (1) rapid activation of eNOS activity within 30 min through the PI3K/AKT signaling pathway; and (2) suppression of proteasomal and lysosomal eNOS degradation, resulting in enhanced eNOS expression and prolonged functional activity under sustained treatment. Conclusions: Topical hMet-PPP administration represents a promising therapeutic strategy for enhancing early-stage wound healing. hMetrnl exerts its biological effects through C-Kit, which mediates dual regulation of eNOS, both activation and stabilization, providing a mechanistic basis for its potent angiogenic properties. These findings uncover a novel Metrnl mechanism with potential implications for the development of therapies targeting vascular dysfunction and tissue repair. Full article