Search Results (11,174)

Major depressive disorder (MDD) is clinically heterogeneous, and peripheral inflammatory biomarkers may help clarify early biological mechanisms before illness chronicity or pharmacologic treatment confound interpretation. This systematic review synthesized evidence on peripheral inflammatory biomarkers in first-episode, drug-naïve major depressive disorder (FEDN-MDD) compared with healthy controls and examined associations with clinical severity. Following PRISMA 2020, searches of PubMed/MEDLINE, Embase, PsycINFO, and Scopus from inception to 19 March 2026 identified 313 records; after screening, 16 publications were included in qualitative synthesis. Studies varied in age group, biological matrix, assay platform, and statistical reporting, precluding meta-analysis. The most frequently assessed biomarkers were IL-1β, TNF-α, IL-6, and CRP/hs-CRP. IL-6 showed the clearest recurrent tendency toward elevation in FEDN-MDD, whereas CRP/hs-CRP findings were partially positive but methodologically limited. TNF-α and IL-1β findings were mixed, and clinical correlations with depressive severity were sparse and inconsistent. Overall, the evidence supports heterogeneous early immune dysregulation in a subset of patients with FEDN-MDD rather than a single reproducible inflammatory signature. Peripheral inflammatory biomarkers should currently be considered research tools for biological stratification and mechanistic hypothesis generation, pending larger standardized longitudinal studies. Full article

Grapevine downy mildew, caused by the oomycete pathogen Plasmopara viticola (P. viticola), is one of the most devastating diseases threatening the global grape industry. The pathogen invades host plants through stomata, triggering a series of highly coordinated physiological disorders and biochemical defense events. This review systematically summarizes the dynamic changes in morphological structures (stomatal characteristics), physiological functions (photosynthesis, membrane system integrity, and carbon metabolism), and multi-level biochemical defense systems (reactive oxygen species (ROS) scavenging enzyme system, phenylpropanoid metabolic pathway, pathogenesis-related proteins, and phenolic compounds) in grapevines following infection. It focuses on analyzing the differences in the timing, intensity, and metabolic reprogramming of defense responses between resistant and susceptible cultivars, pointing out that the essence of disease resistance lies in early pathogen recognition and rapid defense induction. The conflicting conclusions regarding indicators such as soluble sugars, peroxidase (POD), and superoxide dismutase (SOD) are discussed from the perspectives of experimental systems, cultivar genetic backgrounds, and pathogen physiological race differences. Furthermore, the known physiological and biochemical alterations are linked to upstream signaling pathways, including salicylic acid and jasmonic acid (SA/JA), calcium signaling, and mitogen-activated protein kinase (MAPK) cascades. Recent advances in revealing resistance mechanisms in the omics era are also introduced. Finally, future research directions are proposed, including constructing multi-indicator dynamic evaluation models, verifying key gene functions using gene editing, exploring the potential of epigenetic regulation, and developing integrated control strategies combined with microbiome research. This review aims to provide theoretical support for grapevine downy mildew resistance breeding and sustainable disease management. Full article

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterized by high mortality and limited therapeutic options. Alginate oligosaccharide (AOS), a marine-derived bioactive polysaccharide, exhibits prebiotic, anti-inflammatory and antioxidant properties that are effective against various inflammatory diseases. In this study, a mouse model of SAP was established by intraperitoneal injection of cerulein (100 μg/kg) and lipopolysaccharide (5 mg/kg), and the mice were pretreated with AOS (200 mg/kg) by gavage for 4 consecutive weeks to explore the potential protective efficacy and underlying mechanisms. The results shown that AOS attenuated the severity of SAP, as evidenced by reduced serum amylase and lipase levels, as well as alleviated histopathological injury in both pancreatic and ileal tissues. AOS suppressed the overproduction of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in serum, pancreas, and ileum at protein or mRNA levels. Moreover, AOS effectively diminished pancreatic and ileal inflammatory infiltration and oxidative stress in SAP mice, accompanied by inhibited the TLR4/MyD88/NF-κB pathway and activated the Nrf2/HO-1 antioxidant axis. Furthermore, AOS restored intestinal barrier integrity, as manifested by upregulated expression of tight junction proteins (claudin-1, occludin, ZO-1), reduced serum diamine oxidase, and decreased bacterial translocation from the gut to the pancreas. It was revealed by 16S rRNA sequencing that AOS ameliorated SAP-induced gut dysbiosis by restoring microbial diversity, normalizing the Firmicutes/Bacteroidetes ratio, enriching beneficial genera (Lactobacillus, Blautia), and enhancing cecal short-chain fatty acid (acetic, propionic, butyric acid) production. Collectively, our findings demonstrate that AOS exerts comprehensive protective effects against SAP through suppression of inflammatory signaling and oxidative stress, as well as restoring gut homeostasis. These results suggest that AOS may serve as a promising prebiotic-based nutritional strategy for the management of SAP. Full article

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection. Full article

Tousled-like kinases 1 and 2 (TLK1 and TLK2) are paralogous serine/threonine kinases that share high sequence similarity yet exhibit functional divergence in cellular processes such as DNA replication, damage response, and chromatin organization. This study elucidates the paralog-specific co-phosphoregulatory networks underlying this divergence through a comprehensive analysis of 3825 human phosphoproteomic articles. Predominant phosphosites were identified as S134 and T38 for TLK1 and S73, S99, and S111 for TLK2, revealing context-dependent regulation across cancers and perturbations. Co-phosphoregulation analyses uncovered distinct networks: TLK1 associates with DNA damage signaling via proteins like ABRAXAS1, PML, and RAD9A, while TLK2 integrates with chromatin remodeling and replication through CHD4, DOT1L, NASP, and RNF20. Upstream kinases for TLK2, predominantly CDKs, link it to cell-cycle progression, whereas downstream substrates and binary interactors converge on genome stability pathways with paralog-specific nuances. These findings highlight the potential role of TLK1 on checkpoint activation and TLK2 on replication-coupled chromatin maintenance, providing insights into their roles in cancer amplification and therapeutic resistance, as well as neurodevelopmental disorders, where emerging evidence also support the involvement of TLK1 alongside TLK2. Full article

Background/Objectives: Tordylium trachycarpum Boiss. (Apiaceae) is traditionally used in Kurdish ethnomedicine for the management of gastrointestinal disorders; however, its pharmacological efficacy and safety profile remain insufficiently investigated. This study evaluated, for the first time, the gastroprotective activity and associated antioxidant, inflammatory, and apoptotic responses of the methanolic extract of T. trachycarpum using an ethanol-induced gastric ulcer model in Sprague–Dawley rats. Methods: Preliminary phytochemical screening revealed the presence of phenolics, flavonoids, terpenoids, tannins, coumarins, and glycosides. Acute oral toxicity testing demonstrated no signs of toxicity at doses up to 5 g/kg. Gastric ulceration was induced by absolute ethanol, and animals were pretreated with the extract (250 and 500 mg/kg) or omeprazole (20 mg/kg). Results: The extract significantly decreased the gastric lesion area from 258.50 ± 6.38 mm² in the ulcer control group to 143.70 ± 0.76 mm² and 115.50 ± 0.76 mm², corresponding to ulcer inhibition rates of 44.41% and 55.31%. Additionally, the extract increased mucus production, maintained mucosal structure, and raised stomach pH. Biochemical analysis showed a significant increase in antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] and a reduction in malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. In addition, the extract modulated pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10). Blood-based ELISA analysis demonstrated increased expression of heat shock protein 70 (HSP70) and reduced Bax levels, suggesting anti-apoptotic activity. Conclusions: These findings indicate that T. trachycarpum exerts significant gastroprotective activity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, supporting its traditional use and highlighting its potential as a natural therapeutic candidate for the management of gastric ulcers. Full article

Wilson–Turner syndrome (WTS) is an X-linked developmental disorder associated with variants in the LAS1L gene, which plays a role in ribosome biogenesis. We report a 6-year-and-5-month-old boy presenting with growth retardation, early developmental delay, and mild scoliosis. Exome sequencing analysis identified a novel hemizygous LAS1L frameshift variant, c.2082dup (p.Leu697ProfsTer59), inherited from his asymptomatic mother that was absent from population databases. Functional analysis in HEK-293T cells suggested reduced protein expression with a partial loss of function effect, while structural modeling indicated potential alteration of the C-terminal region. The patient lacked classical WTS features, including craniofacial dysmorphism, truncal obesity, hypogonadism, and neuromuscular involvement. This case expands the phenotypic spectrum of LAS1L-related disorders and highlights the consideration of LAS1L variants in children with unexplained growth failure, scoliosis, or developmental delay, even in the absence of classical WTS features. Full article

Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer’s disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders. Full article

Background: Sarcopenia is an age-related disorder characterized by loss of muscle mass, strength, and function, driven by oxidative stress, chronic inflammation, and protein imbalance. Broccoli-derived peptides (BDP) exert anti-inflammatory and myofiber-protective effects, while leucine regulates energy metabolism and redox balance. Methods: We established a D-galactose aging mouse model and treated mice with BDP alone, leucine alone, or their combination for 8 weeks. Lean mass, muscle index, grip strength, endurance, and treadmill capacity were detected, and atrophic, disorganized myofibers were observed through histology. RNA-seq was applied to screen differential signaling pathways, and qPCR was used to verify related gene expression levels. Results: D-galactose caused marked deficits in lean mass, muscle index, grip strength, endurance, and treadmill capacity, accompanied by atrophic and disorganized myofibers. Single BDP or leucine partially reversed these deficits, but the combination produced the most robust improvements. RNA-seq revealed that BDP enriched actin, chemokine, and TNF pathways; leucine enriched Apelin and ECM pathways; while the combination uniquely regulated MAPK signaling. qPCR confirmed that co-administration optimally upregulated myogenic drivers (Myod1, Myog, Mef2c), suppressed catabolic/inflammatory mediators (Mstn, Tnf, Cxcl10), and restored metabolic/adhesive regulators (Sirt3, Aplnr, Icam1). Conclusions: BDP and leucine show superior efficacy in ameliorating sarcopenia, through multimodal regulation of multiple signaling pathways, offering a promising plant-based nutritional strategy against age-related muscle decline. Full article

Parkinson’s disease and Alzheimer’s disease are currently classified as a major global health burden, sharing a defining pathological hallmark represented by insoluble protein aggregates of α-synuclein (α-syn) and amyloid-β (Aβ), respectively. A defining characteristic of all amyloids is a highly ordered, unbranched filamentous morphology, where individual β-strands align perpendicularly to the filament axis. Despite recent technological advances, direct observation of protein conformational changes and amyloid formation in biological samples remains a challenge as well as the quantification of pathological aggregates in liquid biopsies. This review critically recapitulates the major advances in the application of Raman spectroscopy (RS) and surface-enhanced Raman spectroscopy (SERS) in the investigation of pathological protein aggregates in neurological disorders, with a focus on α-syn and Aβ. We discuss both in vitro structural characterization and the applications to biological and clinical samples, outlining the main challenges for clinical translation, including the need for standardized protocols. Recent achievements in the use of RS and SERS on liquid biopsies and other clinical samples are paving the way for further implementation of Raman-based approaches for the diagnosis of neurodegenerative disorders. Full article

The edible seeds of pumpkin plants (genus Cucurbita) are becoming increasingly appreciated as functional foods for their nutritional benefits, medicinal properties, and bioactive compounds, including lipids, proteins, and antioxidants. Particularly, the naked seeds of Cucurbita pepo var. styriaca have proved to yield both an edible oil showing anti-inflammatory properties in treating skin disorders and hydro-alcoholic extracts effective in inhibiting the growth of cancer cells. In this study, a detailed and extensive analysis of the eco-friendly alcoholic extract of the seeds of this variety was accomplished by using LC-HRMSMS techniques, with the main aim to broaden the knowledge on bioactive lipids other than the already reported fatty acids. The obtained results highlighted the occurrence of numerous compounds belonging to different classes of polar and neutral lipids, such as phospholipids, sphingolipids, glycolipids, acylglycerols, and oxylipins. Noteworthily, a significant presence of Cer-(EO)LCBs, i.e., Cer-EOS-type ceramides with different long chain base (LCB) and fatty acid composition, was detected, representing a real novelty for pumpkin. Additionally, a good number of multiflorane-type triterpenoids were detected, only some of which were previously reported in this plant. These findings highlight the nutraceutical value of these edible seeds. Full article

Extracellular vesicles (EVs), particularly small extracellular vesicles (sEVs), are lipid bilayer-delimited particles involved in intercellular communication through the transfer of proteins, lipids, and nucleic acids; many products and studies in aesthetic medicine refer to these preparations as exosomes, although endosomal origin is not always demonstrated. This review examines current evidence on the mechanisms, clinical effectiveness, safety, therapeutic applications, and regulatory challenges of EV- and sEV-based interventions, complemented by an exploratory qualitative assessment of physicians’ perceptions regarding clinical implementation. A narrative review of studies indexed in Scopus and PubMed was conducted with emphasis on skin rejuvenation, hair restoration, wound healing, pigmentation disorders, and inflammatory dermatoses, and responses from 12 aesthetic physicians in Colombia were analyzed qualitatively. Available evidence suggests that EVs/sEVs may promote extracellular matrix remodeling, angiogenesis, immunomodulation, and tissue repair, with potential benefits across several aesthetic and regenerative indications. However, the literature remains heterogeneous and limited by variability in biologic sources, isolation and administration protocols, insufficient high-quality clinical trials, and unresolved regulatory issues. Reports of adverse reactions linked to unapproved products marketed as exosome-based formulations further highlight the need for stronger oversight. EVs, particularly sEVs, often referred to as exosomes in the aesthetic literature, remain a promising therapeutic platform, but safe clinical integration requires rigorous validation, technical standardization, and robust regulatory frameworks. Full article

Alzheimer’s disease is a progressive neurodegenerative disorder in which early detection remains limited by the cost and invasiveness of positron emission tomography and cerebrospinal fluid testing. We evaluated whether plasma proteomic profiles could distinguish amyloid PET-positive from amyloid PET-negative individuals using the Bio-Hermes cohort. After quality control and missing-data filtering, 988 participants and 295 proteins were analysed; 31 proteins showing group differences were used for supervised classification. Random Forest, Gradient Boosting, and Neural Network models were trained across four train/test splits with repeated cross-validation and class downsampling. Amyloid-positive and amyloid-negative groups differed across a subset of proteins, with five remaining significant after false discovery rate correction. Tree-based models performed most consistently, with Random Forest and Gradient Boosting achieving AUC values of 0.79–0.81 and balanced accuracy of 0.68–0.73. Eight proteins (SERPINA1, C3, CRP, APOE4, CFH, VTN, C1QTNF5, and PON1) emerged as recurring high-importance features. These findings indicate that discovery-driven plasma proteomics can identify multi-protein signatures associated with amyloid status and can complement established single-analyte blood biomarkers by adding pathway-level information. Full article

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction and impaired platelet production. Increasing evidence suggests that systemic inflammation plays a significant role in disease pathogenesis and clinical outcomes. This study aimed to evaluate the prognostic significance of inflammatory indices and their association with complications, mortality, treatment response, and relapse in patients with ITP. In this single-center retrospective study, 166 adult patients diagnosed with primary ITP between January 2015 and December 2024 were analyzed. Demographic, clinical, and laboratory data at diagnosis were collected. Inflammatory indices derived from complete blood count parameters, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were evaluated. Their associations with clinical outcomes were assessed using appropriate statistical methods. During the observation period based on retrospective medical records, complications occurred in 12% of patients, and mortality was observed in 6.6%. Patients with complications had significantly higher D-dimer levels and reduced bone marrow megakaryocyte production. In group comparisons, mortality was significantly associated with advanced age, male sex, and comorbidities. Laboratory findings revealed that lower hemoglobin, lymphocyte count, mean platelet volume, and albumin levels, along with higher PLR, erythrocyte sedimentation rate, bilirubin, and D-dimer levels, were significantly associated with mortality. Inflammatory indices such as NLR and PLR were not associated with complication development, but PLR was significantly associated with mortality. Response to intravenous immunoglobulin (IVIG) therapy was significantly associated with higher total protein, albumin, and fibrinogen levels, and lower erythrocyte sedimentation rate. Relapse was significantly associated in group comparisons with increased inflammatory activity, higher reticulocyte count, and positivity for antinuclear antibodies and Helicobacter pylori antigen. Systemic inflammation and impaired megakaryopoiesis play critical roles in the prognosis of ITP. While conventional inflammatory indices showed limited predictive value for complications, markers such as PLR, D-dimer, and albumin were associated with mortality and clinical outcomes. These findings suggest that readily available laboratory parameters may provide valuable insights for risk stratification and personalized management in patients with ITP. Full article

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article