Search Results (548)

Background: Antibody-drug conjugates (ADCs) have ushered in a new era of precision oncology by combining the targeting specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic drugs. However, the cellular and molecular mechanisms underlying their dose-limiting ocular toxicity remain unclear. Elahere™, the first FDA-approved ADC targeting folate receptor α (FRα), demonstrates remarkable efficacy in platinum-resistant ovarian cancer but causes keratitis and other ocular toxicities in some patients. Notably, FRα is not expressed in the corneal epithelium—the primary site of damage—highlighting the urgent need to elucidate its underlying mechanisms. The aim of this study was to identify the cell-type-specific molecular mechanisms underlying Elahere-induced ocular toxicity. Methods: Sprague-Dawley rats were treated with intravenous Elahere (20 mg/kg) or vehicle weekly for five weeks. Ocular toxicity was determined by clinical examination and histopathology. Corneal single-cell suspensions were analyzed using the BD Rhapsody single-cell RNA sequencing (scRNA-seq) platform. Bioinformatic analyses to characterize changes in corneal cell populations, gene expression, and signaling pathways included cell clustering, differential gene expression, pseudotime trajectory inference, and cell-cell interaction modeling. Results: scRNA-seq profiling of 47,606 corneal cells revealed significant damage to the ocular surface and corneal epithelia in the Elahere group. Twenty distinct cell types were identified. Elahere depleted myeloid immune cells; in particular, homeostatic gene expression was suppressed in phagocytic macrophages. Progenitor populations (limbal stem cells and basal cells) accumulated (e.g., a ~2.6-fold expansion of limbal stem cells), while terminally differentiated cells decreased in corneal epithelium, indicating differentiation blockade. Endothelial cells exhibited signs of injury and inflammation, including reduced angiogenic subtypes and heightened stress responses. Folate receptor alpha, the target of Elahere, was expressed in endothelial and stromal cells, potentially driving stromal cells toward a pro-fibrotic phenotype. Fc receptor genes were predominantly expressed in myeloid cells, suggesting a potential mechanism underlying their depletion. Conclusions: Elahere induces complex, multi-compartmental ocular toxicity characterized by initial perturbations in vascular endothelial and immune cell populations followed by the arrest of epithelial differentiation and stromal remodeling. These findings reveal a cascade of cellular disruptions and provide mechanistic insights into mitigating Elahere-associated ocular side effects. Full article

MicroRNAs (miRNAs) have emerged as important biomarkers for complex neurological conditions. Modifications in synaptic morphology characterize several of these disease states, indicating a possible role of miRNA in modulating synaptic formation and plasticity. Within the third-instar larvae of Drosophila melanogaster, we uncovered a functional role for highly human-conserved miR-92 in synaptogenesis of the glutamatergic peripheral nervous system. Loss of miR-92 results in underdeveloped synaptic architecture, coinciding with significantly reduced physiological activity. We demonstrate a novel role for miR-92 glial-specific expression to support synaptic growth function and plasticity. Modifications of miR-92 within glial tissue result in aberrant glial barrier properties, including an increased uptake of external dyes. Within the glia, miR-92 regulates a V-ATPase subunit (Vha55), impairing the glial cells from forming appropriate insulating layers around the nervous system. These modifications may impact how the nervous system adapts to its environment, increasing immature ‘ghost bouton’ budding and impairing responses to changes in environmental conditions. Our work highlights the importance of glial-specific miR-92 on synaptic development, affecting glial health and function through its downstream target Vha55, and demonstrates a novel mechanism for glia in synaptogenesis and homeostatic plasticity. Full article

Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee—wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX₁R and OX₂R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin’s role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies. Full article

Catecholamines (CA) are considered to play key roles in acute stress responses, but they also regulate important functions of the nervous, immune, and endocrine systems and are essential for body homeostasis and health. In Swiss mice (an outbred strain) with haploinsufficiency of the tyrosine hydroxylase gene (Th, TH-HZ), which encodes the rate-limiting enzyme of catecholamine synthesis, impairments in homeostatic system functions and a reduced lifespan have been reported. Moreover, these homeostatic alterations are exacerbated when these animals are exposed to acute restraint stress. Nonetheless, the effects of this genetic modification on an inbred strain, such as C57BL/6J, are undetermined. Given that the genetic background of mice can affect the phenotype of any genetic modification, this work aimed to characterize how behavioral responses, immunity, and the oxidative state in C57BL/6J mice are altered by Th haploinsufficiency under basal conditions after being subjected to 10 min of acute restraint stress. Sex differences were also considered. Compared with their WT counterparts, TH-HZ C57BL/6J animals exhibit behavioral impairments, immunosenescence, and oxidative stress under basal conditions. After stress, TH-HZ animals (both sexes) exhibit deteriorated behavior and immune functions. Therefore, Th haploinsufficiency in the inbred C57BL/6J strain triggers impairments in behavior, immunity, and the redox state. These findings corroborate the role of CA in maintaining regulatory system functions and highlight the importance of mouse strains in basic research. Full article

Surgery and anesthesia induce a stress response that provokes increased sympathetic stimulation, secretion of cortisol, hypercoagulability, and systemic inflammatory response. All these homeostatic deteriorations, especially systemic inflammation, represent a risk for organ damage. Perioperative cardiac complications have an increasing impact on morbidity and mortality, not only in cardiovascular but also in non-cardiac surgery. Surgical procedures represent a potential trigger for systemic inflammation that causes secretion of proinflammatory cytokines, activation of neutrophils, and tissue damage. Also, increased levels of preoperative inflammatory markers predict perioperative cardiovascular events. Systemic inflammatory biomarkers increase during the first days after surgical procedures and decline within a few weeks. Besides contemporary traditional biomarkers (CRP, BNP), newer biomarkers, such as galectin-3, TNF-α, and various MiRNAs, can predict inflammatory response and related cardiac injury. Determination of inflammatory markers in the perioperative period could help identify patients at risk for cardiovascular events. The reduction in perioperative inflammatory response may improve surgical outcomes. Prevention and treatment of systemic inflammation can be achieved by optimization of surgical procedures, anesthetic regimen, and pharmacological agents, especially interleukin inhibitors. Determination of inflammatory biomarkers, along with prevention and treatment of inflammation, can improve perioperative cardiac risk reduction strategies. Full article

Erythropoietin (EPO), clinically used as a therapeutic agent for patients with renal anemia, has been reported to exert tissue protective effects independently of hematopoiesis. Insulin resistance is a pathophysiological condition that causes hypertension, diabetes mellitus, and dyslipidemia, leading to vascular and renal injury. The present study investigated whether EPO would improve insulin resistance and vascular and renal injury in chronic sucrose treatment-induced insulin resistant model rats. Sucrose (12%) was given in drinking water for 10 weeks to induce insulin resistance, and EPO (75 U/kg, 3 times/week) was administered subcutaneously for the last 4 weeks. Responses to the oral glucose tolerance test and values of the homeostatic model assessment for insulin resistance indicated that EPO improved insulin resistance in sucrose-treated rats. Though there were no differences in the expression of phospho-Akt (Ser473)/total Akt among all groups, EPO increased that of phospho-STAT3 (Tyr705)/total STAT3 in the liver. Macrophage infiltration into the adventitial area of the aorta and renal overexpression of monocyte chemoattractant protein-1 in the sucrose-treated group were suppressed by EPO treatment, suggesting anti-inflammatory effects of EPO. EPO also decreased collagen I expression in the kidney. A proinflammatory M1-type macrophage marker, tumor necrosis factor-α, was decreased, and anti-inflammatory M2-type macrophage markers, arginase-1 and interleukin-10, were increased by EPO treatment. These results suggest that EPO improved insulin resistance and vascular and renal inflammation in the setting of insulin resistance. Full article

Interferon regulatory factor 5 (IRF5) plays a pivotal role in innate immune responses and macrophage polarization. Although its role in obesity-associated inflammation has been described, sex-specific differences in adipose IRF5 expression and its association with immune and metabolic markers remain poorly defined. To evaluate sex-specific associations between adipose tissue (AT) IRF5 expression and key inflammatory and metabolic markers in overweight and obese individuals. Subcutaneous AT samples from overweight/obese male and female subjects were analyzed for IRF5 expression using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Correlation and multiple linear regression analyses were performed to identify its associations with inflammatory gene expression and metabolic parameters including insulin, glucose, HOMA-IR, and adipokines. RF5 gene and protein levels were significantly elevated in the AT of overweight/obese females compared to males (p < 0.0001), with expression increasing progressively with BMI in females but not in males. Despite these sex-dependent expression levels, IRF5 demonstrated consistent, sex-independent positive correlations with several core immune and inflammatory markers, including CCR5, CD11c, CD16, CD163, FOXP3, RUNX1, and MyD88. However, distinct sex-specific patterns emerged: in males, IRF5 correlated positively with classical pro-inflammatory markers such as IL-2, IL-6, IL-8, TNF-α, and IRAK1; whereas in females, IRF5 was associated with a broader array of immune markers, including chemokines (CCL7, CXCL11), pattern recognition receptors (TLR2, TLR8, TLR9), and macrophage markers (CD68, CD86), along with anti-inflammatory mediators such as IL-10 and IRF4. Notably, IRF5 expression in overweight/obese males, but not females, was significantly associated with metabolic dysfunction, showing positive correlations with fasting blood glucose, HbA1c, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) levels. Multiple regression analyses revealed sex-specific predictors of IRF5 expression, with metabolic (HOMA-IR) and inflammatory (IRAK1, MyD88) markers emerging in males, while immune-related genes (RUNX1, CD68, CCL7, MyD88) predominated in females. These findings underscore a sex-divergent role of IRF5 in AT, with implications for differential regulation of immune-metabolic pathways in obesity and its complications. Full article

Background/Objectives: Levothyroxine (L-T4) replacement therapy is essential following total thyroidectomy. While liquid L-T4 formulations exhibit superior pharmacokinetic properties compared to tablets, their specific metabolic impact—particularly on insulin resistance—remains unclear. The aim of this study was to compare the short-term effects of liquid versus tablet L-T4 replacement therapy on insulin resistance indices in recently thyroidectomized women and to identify baseline predictors of metabolic response. Methods: A post hoc analysis included 130 women randomized to receive either liquid or tablet L-T4 after total thyroidectomy. Metabolic parameters—including the homeostatic model assessment for insulin resistance (HOMA-IR), triglycerides-glucose (TyG) index, and triglycerides-to-HDL cholesterol (TG/HDL-C) ratio—were assessed at baseline and after two months. Results: Both L-T4 formulations significantly improved insulin resistance indices over two months. Liquid L-T4 induced a more pronounced reduction in HOMA-IR (treatment effect p = 0.022) and fasting insulin levels (treatment effect p = 0.017) compared to the tablet formulation. No significant between-group differences were observed for TyG index or TG/HDL-C ratio. Changes in insulin resistance markers were independent of body mass index variations and were predicted by baseline metabolic parameters including insulin, glucose, and lipid levels. Conclusions: L-T4 replacement therapy improves insulin resistance markers shortly after thyroidectomy, with the liquid formulation exerting a greater effect on hepatic insulin sensitivity. These findings support the individualized selection of L-T4 formulations to optimize both endocrine and metabolic outcomes post-thyroidectomy. Full article

Background and Objectives: Ghrelin plays key roles in appetite regulation, involving both homeostatic and hedonic pathways. In obesity, its metabolism is affected by alterations in neural and hormonal responses. Liver-Enriched Antimicrobial Peptide 2 (LEAP2), recently identified as an endogenous ghrelin receptor antagonist, has emerged as a potential regulator of appetite and energy balance, and bariatric surgery is known to induce changes in this system. In this review, we aimed to evaluate the roles of acyl ghrelin, des-acyl ghrelin, and LEAP2 in food intake regulation and summarize findings on the alterations in their levels after bariatric surgery. Materials and Methods: We conducted a narrative review of human and animal studies published in the literature investigating the roles of acyl ghrelin, des-acyl ghrelin, and LEAP2 in food intake regulation, as well as changes in their levels in obesity and following bariatric surgery. Results: Alterations in the ghrelin system, i.e., the acyl ghrelin and des-acyl ghrelin isoforms and LEAP2, in obesity have been reported. Experimental studies have shown that LEAP2 administration reduces food intake and body weight by suppressing ghrelin-induced food intake. Most studies have found marked reductions in fasting acyl ghrelin after sleeve gastrectomy, more so than after Roux-en-Y gastric bypass. Conclusions: In obesity, altered neural and hormonal responses to food also affect ghrelin metabolism, with significant deviations in acyl ghrelin levels and impaired appetite regulation mechanisms. Unlike ghrelin, LEAP2 levels tend to be elevated in obesity. While changes in acyl ghrelin and des-acyl ghrelin isoforms, particularly after sleeve gastrectomy, are well documented, data on LEAP2 remain limited. Further research is needed to better define the role of LEAP2 in ghrelin-mediated food intake and its potential as a therapeutic target in obesity. Full article

The induction of type I interferon (IFN) via intracellular nucleic acid sensors may be useful in preventing viral infections. However, little is known about the effect of natural plant materials on sensor responses. We previously found that cardamom (Elettaria cardamomum (L.) Maton) seed extract (CSWE) enhanced type I IFN expression and prevented influenza virus infection. In this study, we investigated the effect of CSWE on type I IFN responses using intracellular nucleic acid sensor molecules. Human lung epithelial A549 cells were treated with CSWE and transfected with poly(dA:dT) or poly(I:C) using lipofection. CSWE and 1,8-cineole, the major CSWE components, dose-dependently induced type I IFNs and IFN-stimulated genes in both poly(dA:dT)- and poly(I:C)-transfected A549 cells. The type I IFN-enhancing effect of CSWE was dependent on the stimulator of interferon genes (STING), whereas the effect of 1,8-cineole was independent of STING and mediated by the down-regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-ADP-ribose polymerase expression. Our study suggests that CSWE has the potential to act as a beneficial antiviral agent by enhancing homeostatic type I IFN production. Full article

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus. This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored. Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL’s ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging. Full article

The paradigm-shift idea of murburn concept is no hypothesis but developed directly from fundamental facts of cellular/ecological existence. Murburn involves spontaneous and stochastic interactions (mediated by murzymes) amongst the molecules and unbound ions of cells. It leads to effective charge separation (ECS) and formation/recruitment of diffusible reactive species (DRS, like radicals whose reactions enable ATP-synthesis and thermogenesis) and emission of radiations (UV/Vis to ELF). These processes also lead to a chemo-electromagnetic matrix (CEM), ascertaining that living cell/organism react/function as a coherent unit. Murburn concept propounds the true utility of oxygen: generating DRS (with catalytic and electrical properties) on the way to becoming water, the life solvent, and ultimately also leading to phase-based macroscopic homeostatic outcomes. Such a layout enables cells to become simple chemical engines (SCEs) with powering, coherence, homeostasis, electro-mechanical and sensing–response (PCHEMS; life’s short-term “intelligence”) abilities. In the current review, we discuss the coacervate nature of cells and dwell upon the ways and contexts in which various radiations (either incident or endogenously generated) could interact in the new scheme of cellular function. Presenting comparative evidence/arguments and listing of systems with murburn models, we argue that the new perceptions explain life processes better and urge the community to urgently adopt murburn bioenergetics and adapt to its views. Further, we touch upon some distinct scientific and sociological contexts with respect to the outreach of murburn concept. It is envisaged that greater awareness of murburn could enhance the longevity and quality of life and afford better approaches to therapies. Full article

RNA-seq analysis of the highly differentiated human retinal pigment epithelial (RPE) cell-line ARPE-19, cultured on transwells for ≥4 months, yielded 44,909 genes showing 83.35% alignment with the human reference genome. These included mRNA transcripts of RPE-specific genes and those involved in retinopathies. Monolayers were fed photoreceptor outer segments (POS), designed to be synchronously internalised, mimicking homeostatic RPE activity. Cells were subsequently fixed at 4, 6, 24 and 48 h when POS were previously shown to maximally co-localise with Rab5, Rab7, LAMP/lysosomes and LC3b/autophagic compartments. A comprehensive analysis of differentially expressed genes involved in proteolysis revealed a pattern of gene orchestration consistent with POS breakdown in the autophagy-lysosomal pathway. At 4 h, these included elevated upstream signalling events promoting early stages of cargo transport and endosome maturation compared to RPE without POS exposure. This transcriptional landscape altered from 6 h, transitioning to promoting cargo degradation in autolysosomes by 24–48 h. Longitudinal scrutiny of mRNA transcripts revealed nuanced differences even within linked gene networks. POS exposure also initiated transcriptional upregulation in ubiquitin proteasome and chaperone-mediated systems within 4–6 h, providing evidence of cross-talk with other proteolytic processes. These findings show detailed evidence of transcriptome-level responses to cargo trafficking and processing in RPE cells. Full article

The insular cortex has emerged as a key region implicated in a wide array of cognitive, emotional, and sensory processes. The anterior part of the insula (AIC) is central to emotional awareness, decision-making, and interoception, while the posterior insula (PIC) is more associated with somatosensory processing. The insula acts as a functional hub within the salience network and integrates homeostatic, affective, and cognitive information; thus, its role in different mental disorders seems to be prominent. Altered structure and connectivity of the insular cortex are evident in several psychiatric conditions. In schizophrenia, reductions in insular volume—especially on the left—correlate with hallucinations, emotional dysregulation, and cognitive deficits. Bipolar and major depressive disorders exhibit AIC volume loss and aberrant connectivity patterns linked to impaired affect regulation and interoceptive awareness. Anxiety disorders show functional hyperactivity of the insula, especially in response to fear-inducing stimuli, though findings on structural changes are mixed. Overall, growing evidence underscores the insular cortex’s central role in psychiatric pathophysiology and highlights its potential as a target for future diagnostic and therapeutic strategies. Full article

Background/Objectives: Ulcerative colitis (UC) is characterized by the interplay between immune responses and dysbiosis in disease development. Aiming to provide additional insights into disease development and potential treatment strategies, the present study investigates the local effect of oral treatment with polysaccharides obtained from Auricularia auricula’s submerged culture in an experimental model of DSS-induced colitis and its impact on lesion resolution. Methods: The structure and monosaccharide composition of Auricularia polysaccharides were characterized through Nuclear Magnetic Resonance (NMR). To evaluate the effect of this polysaccharide on the murine model, wild-type and Dectin-1 knockout mice were treated or not with the exopolysaccharide (EPS) while under DSS consumption. During the experimental period, feces samples were collected to evaluate microbial shifts during disease development, and, finally, the colonic tissue was analyzed to assess the inflammatory process and cytokine production. Results: The EPS composition showed a polymeric mixture of glucans and fucogalactomannans. The treatment of the wild-type DSS-induced colitis group improved the inflammatory response by increasing gut–homeostatic cytokines, such as interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α). The Dectin-1 KO mice group did not show the same enhancement after EPS treatment. The microbiome analysis revealed a difference in the genotype, and the treatment modified the DSS microbiome modulation, with nine and four ASVs in WT and Dectin-1 KO mice, respectively. Conclusions: The EPS treatment demonstrated therapeutic potential in treating inflammatory intestinal diseases by modulating cytokine secretion and microbiota composition, which is dependent on the Dectin-1 receptor’s carbohydrate recognition. Full article