Search Results (11,719)

Background: Circadian disruption exacerbates type 2 diabetes mellitus (T2DM). Time-restricted feeding (TRF) and exercise (EX) improve metabolic health, but their combinatory effect remains unclear. This study investigated whether combined TRF and EX additively ameliorates metabolism via circadian reprogramming in db/db mice. Methods: Eight-week-old male db/db mice were assigned to control (Con), diabetic model (DM), TRF (8 h feeding window), EX (treadmill, 60 min/day, 5 days/week), or combined TRF + EX groups for 8 weeks (n = 8/group). Body weight, glucose/insulin tolerance, and 24 h energy metabolism (CLAMS) were assessed. Mitochondrial function, oxidative stress, inflammation, and expression of mitophagy (Pink1, Park2, Bnip3, Fundc1) and thermogenic (Ucp1, Pgc1a, Prdm16, Cidea) genes were measured. Results: Compared with the con group, DM mice showed obesity, hyperglycemia and blunted circadian metabolic rhythm. The TRF and EX groups improved these defects. Specifically, combined TRF + EX reduced fasting blood glucose from 25.3 ± 3.1 mmol/L (DM) to 13.2 ± 1.8 mmol/L (p < 0.05), body weight from 49.8 ± 2.5 g to 39.5 ± 1.7 g (p< 0.05), and body fat percentage from 45.6 ± 3.2% to 32.1 ± 2.2% (p < 0.05). GTT area under the curve (AUC) decreased from 3711.0 ± 186.5 (DM) to 2118.0 ± 112.4 (p < 0.05), and ITT AUC decreased from 2617.5 ± 135.8 to 1260.0 ± 68.9 (p < 0.05). Notably, the combination of TRF + EX produced greater effects than either intervention alone: body weight, fasting blood glucose, and glucose/insulin tolerance were greatly improved (p < 0.05). In addition, compared with the DM group, the diurnal metabolic amplitude and phase were improved in the TRF or EX group; the combination group showed further improvements in these parameters. Furthermore, TRF and EX each resulted in significantly higher expression of key thermogenic genes (Ucp1, Pgc1a, Prdm16, Cidea) in white adipose tissue (WAT) and brown adipose tissue (BAT) (p < 0.05), and the TRF + EX group showed the highest expression levels. Combined intervention also restored skeletal muscle SOD activity (31.2 ± 2.9 U/mg prot vs. DM 20.1 ± 2.5 U/mg prot, p < 0.05) and reduced serum TNF-α (28.5 ± 4.5 pg/mL vs. DM 65.8 ± 8.5 pg/mL, p < 0.05) and IL-6 (21.6 ± 3.8 pg/mL vs. DM 50.3 ± 7.1 pg/mL, p < 0.05). Conclusions: TRF + EX additively restores metabolic homeostasis in diabetes by re-entraining circadian energy rhythms, improving mitochondrial quality, and activating adipose thermogenesis, supporting further investigation of integrated lifestyle timing as a potential therapeutic strategy. Full article

Toll-like receptor 7 (TLR7) agonism offers a promising avenue for antiviral intervention. This study characterizes AXC-715, a novel small-molecule agonist that selectively targets TLR7 to elicit broad-spectrum antiviral effects. Structural analysis of the AXC-715–hTLR7 complex (PDB ID: 5GMH) elucidates the molecular basis of receptor activation. AXC-715 occupies the interface of TLR7 monomers, establishing critical hydrogen bonds with D555 and T586, alongside π-π and π-alkyl interactions with F408, V381, and L557. These interactions effectively promote and stabilize the active TLR7 dimeric conformation. Functionally, AXC-715 activates NF-κB signaling in a P65-dependent manner without inducing cytotoxicity in PK-15 or THP-1 cells. In vitro assays demonstrated that AXC-715 potently inhibits the replication of both pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) by specifically impairing viral replication, distinct from adsorption, entry, assembly, or release processes. The antiviral effect was abolished in TLR7-knockout PK-15 cells, confirming the strict dependence of AXC-715 on on-target TLR7 signaling. These findings highlight AXC-715 as a potent TLR7 agonist that stabilizes receptor dimerization to inhibit viral replication, providing a valuable framework for developing TLR7-based antiviral therapeutics. Full article

As global urbanization accelerates, biophilic urbanism has emerged as a key nature-based strategy for enhancing public health. While plants are critical active agents for psychological restoration, the specific pathways through which vegetation characteristics influence human–environment interactions remain fragmented. This knowledge gap hinders the evidence-based translation of biophilic principles into actionable urban design and governance. This study conducts a systematic bibliometric analysis of 443 peer-reviewed articles (2000–2025) at the intersection of restorative landscapes, urban settings, and plant-based interventions retrieved from the Web of Science Core Collection. Employing multiple visualization tools (VOSviewer, bibliometrix, and CiteSpace), we map publication trends, international collaborations, and thematic evolution. The results demonstrate a significant shift in the field, moving beyond the validation of foundational restorative theories (e.g., ART and SRT) to a more precise, implementation-oriented framework. This shift is characterized by the operationalization of vegetation attributes as controllable design variables, increasingly relating biophilic principles to broader nature-based solutions (NbS) agendas and evidence-informed urban governance. Thematic clustering analysis identified three core knowledge domains: (1) the role of plants as active exposure agents and behavioral mediators in psychological restoration; (2) the impact of specific plant characteristics—such as canopy structure, species diversity, and seasonal variation—on therapeutic outcomes; and (3) the integration of urban green spaces into broader governance frameworks to promote health equity and inclusive well-being. Our analysis highlights that plant-based interventions are evolving from aesthetic ornaments into precision design levers for fostering human–nature interactions. This study provides a science-based foundation for developing practical design guidelines and policy frameworks, shifting biophilic urbanism toward a robust governance strategy for creating equitable, restorative, and resilient cities. Full article

Diabetic retinopathy (DR), recognized as a progressive neurovascular and microvascular complication of diabetes, remains one of the leading causes of visual disability worldwide, within the context of a sustained increase in ophthalmic diseases and retinal vascular disorders that compromise vision. This study aimed to characterize the progression of diabetic retinopathy in a streptozotocin (STZ)-induced Wistar rat model. A single dose of 65 mg/kg body weight was administered, with follow-up periods at 2, 4, 8, and 10 weeks, compared to healthy controls. STZ-induced rats exhibited reduced weight gain compared to the control group. They also showed markedly variable hyperglycemia, with glucose concentrations ranging from 250 to 530 mg/dL. Histological analysis of retinal tissue at week 4 revealed early signs of vascular compromise, including early indications of a microenvironment conducive to neovascularization and edema. By week 8, retinal damage had progressed to hemorrhage, persistent edema, and layer-specific vascular disruption. At week 10, intensified neovascularization and exacerbated edema indicated advanced microvascular deterioration. Immunofluorescence analysis demonstrated a temporal accumulation of CD8⁺ T cells in the retina, correlating with photoreceptor degeneration. The coordinated dynamics of CD4⁺ and CD8⁺ T cells suggested transient immune activation during STZ-induced retinal degeneration. Gene expression profiling revealed a proinflammatory and pro-oxidative retinal microenvironment, characterized by the overexpression of angiogenic pathways and proliferative signals. Simultaneously, the antioxidant response appeared partially impaired. Collectively, these findings provide mechanistic perspective on the multifactorial nature of diabetic retinopathy. Oxidative stress, inflammation, and angiogenesis converge to disrupt retinal homeostasis. This experimental model may serve as a reliable platform for future studies aimed at elucidating disease pathophysiology, identifying novel therapeutic targets, and evaluating emerging ophthalmic antidiabetic interventions. Full article

Chemotherapy- and/or radiotherapy-induced oral mucositis (CRIOM) is a common complication in patients with head and neck cancer, driven largely by excessive proinflammatory cytokine signalling and treatment-associated bacterial dysbiosis. This narrative review synthesizes current mechanistic evidence and summarizes emerging therapeutic strategies targeting these pathways. Research indicates that elevated levels of IL-1β, IL-6, TNF, iNOS, and nitric oxide amplify tissue injury and ulceration, while disruption of oral and gut microbial communities, characterized by loss of beneficial commensals and enrichment of pathogenic taxa, further exacerbates mucosal inflammation. Anti-inflammatory agents, including pentoxifylline, atorvastatin, trans-caryophyllene, azilsartan, recombinant human IL-11, and low-level laser therapy have been shown in preclinical models to reduce cytokine levels and promote mucosal healing. Similarly, microbiome-targeted approaches, such as oral microbiota transplantation and multi-strain probiotic formulations, have demonstrated potential in restoring microbial balance and attenuating CRIOM severity, with current evidence including both preclinical and clinical studies. Overall, current findings highlight cytokine toxicity and dysbiosis as synergistic drivers of CRIOM and support anti-inflammatory and microbiome-modulating strategies as promising adjunctive approaches; however, further well-designed clinical studies are required to validate their efficacy and guide clinical translation. Full article

Background: Tension-type headache (TTH) is the most prevalent primary headache disorder worldwide and represents a major source of disability related to chronic pain. Despite its high prevalence, uncertainty remains regarding optimal conservative management strategies, and limited evidence is available on how physiotherapists apply existing recommendations in routine clinical practice. Objective: The objective was to explore physiotherapists’ perceptions, clinical experiences, and treatment strategies in the management of tension-type headache, with particular emphasis on commonly used interventions, clinical decision-making, and characteristics of physiotherapy care. Methods: A cross-sectional survey study was conducted using a self-administered online survey developed in accordance with the CHERRIES guidelines. One hundred Spanish physiotherapists with clinical experience in treating patients with TTH participated. Quantitative data were analyzed descriptively, while open-ended responses were examined using inductive thematic analysis following the framework proposed by Braun and Clarke. Results: Manual therapy was the most frequently reported intervention (96%), followed by therapeutic exercise (61%) and invasive techniques, primarily dry needling (48%). The suboccipital and upper cervical regions were consistently identified as primary therapeutic targets, reflecting a predominant craniocervical treatment focus. Most respondents reported individualized treatment plans, typically delivered in weekly sessions lasting 45–60 min, with expected clinical improvement within 4–6 weeks. Pain education strategies were reported infrequently. Considerable variability was observed in the selection and combination of therapeutic techniques. Conclusions: Physiotherapists managing tension-type headache commonly adopt a multimodal approach, largely centered on manual and tissue-focused interventions. Although many reported practices are aligned with current evidence, the substantial heterogeneity observed and the limited integration of biopsychosocial strategies highlight the need for consensus-based guidelines and further research addressing real-world clinical effectiveness. Full article

Ubiquitination is a reversible post-translational modification crucial for cellular homeostasis and protein degradation. It is orchestrated by a cascade of ubiquitin-activating enzymes (E1), conjugating enzymes (E2), and ligases (E3) that tag proteins with ubiquitin, and deubiquitinating enzymes (DUBs) that remove these tags. Through this tightly regulated ubiquitination/deubiquitination system, cells control protein turnover, localization, and activity, thereby governing processes ranging from cell cycle progression and DNA repair to immune and stress responses. Here, we review the structural and functional mechanisms of each class of enzymes in the ubiquitin–proteasome system, including E1, E2, E3, and DUBs, and highlight their roles in key signaling pathways and physiological processes. We further discuss how the dysregulation of these enzymes leads to diseases such as cancer, neurodegenerative disorders, and immune diseases, underlining the potential of targeting ubiquitination pathways for therapeutic intervention. Full article

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape for hepatocellular carcinoma (HCC); however, a considerable proportion of patients do not achieve durable clinical benefits. This highlights the need for reliable predictive biomarkers, which are currently lacking. The accumulated evidence supports a relevant role of the gut–liver axis in modulating immunotherapy outcomes, and several studies have identified distinct microbial features associated with either responders or non-responders. Responders to immunotherapy frequently present with higher microbial diversity and enrichment of beneficial taxa, whereas the expansion of pro-inflammatory and pathogenic bacteria has been associated with primary resistance and increased treatment-related toxicity in non-responders. However, the available findings remain heterogeneous across cohorts, likely owing to differences in geography, diet, liver disease etiology, treatment regimens, and microbiome analytical methods. Machine-learning models integrating metagenomic and metabolomic data have shown encouraging results in defining microbial signatures associated with treatment outcomes, although variability among cohorts currently limits their clinical applicability and generalizability. Beyond microbial taxonomic composition, microbiota-derived metabolites—such as short-chain fatty acids, bile acids, inosine, and tryptophan catabolites—appear to play a crucial role in shaping the tumor microenvironment and host immune responses, thus representing additional candidate biomarkers, also due to the relative ease of their measurement. Finally, microbiota-targeted interventions are emerging as potential strategies to enhance immunotherapy efficacy. Overall, the gut microbiome and its metabolic activity represent promising tools, albeit still under investigation, for patient stratification and personalized management in HCC treated with ICIs. Therefore, this review aims to summarize and critically discuss the current evidence on gut microbiota-derived biomarkers of response and resistance to ICIs in HCC, with particular focus on microbial composition, microbiota-related metabolites, and emerging microbiome-based therapeutic strategies. This narrative review provides an updated overview of the role of gut microbiota as both a biomarker and a therapeutic target in patients with hepatocellular carcinoma (HCC) receiving immune checkpoint inhibitor (ICI) therapy. Full article

Phytochemicals have attracted considerable attention as therapeutically relevant bioactive compounds due to their diverse pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and metabolic regulatory effects. However, their clinical translation is frequently hindered by unfavorable pharmaceutical properties such as poor aqueous solubility, chemical instability, rapid metabolism, and limited bioavailability. These challenges have constrained the reproducibility and therapeutic reliability of phytochemical-based interventions. In this context, nanotechnology-enabled delivery systems have emerged as effective strategies to overcome the intrinsic limitations of phytochemicals and enhance their biological performance. This review provides a comprehensive overview of recent advances in nanotechnology-based delivery platforms for phytochemicals, with emphasis on lipid-based nanocarriers, polymeric nanoparticles, nanoemulsions and self-nanoemulsifying drug delivery systems, inorganic and hybrid nanocarriers, as well as hydrogel-based and transdermal delivery systems. We discuss how rational nanocarrier design improves solubility, stability, pharmacokinetics, cellular uptake, and tissue targeting, thereby enhancing therapeutic efficacy across multiple disease areas. In addition, critical safety, toxicity, manufacturing, and regulatory considerations that influence translational potential are addressed. By adopting a delivery-centered perspective, this review highlights current challenges and future opportunities in nano-phytomedicine and underscores the importance of integrating nanotechnology, biological insight, and regulatory-conscious development to advance phytochemicals toward clinically viable therapeutic applications. Full article

Fetal alcohol spectrum disorders (FASD) encompass a continuum of developmental abnormalities caused by prenatal alcohol exposure, resulting in persistent neurodevelopmental and structural defects. Accumulating evidence indicates that redox dysregulation plays a central role in the pathogenesis of FASD. Ethanol disrupts cellular redox homeostasis by promoting excessive reactive oxygen species production and depleting endogenous antioxidants, thereby perturbing key redox-sensitive molecular networks. Dysregulation of these pathways leads to mitochondrial dysfunction, endoplasmic reticulum stress, lysosome dysfunction, and disrupted cellular processes, including proliferation, differentiation, and migration, while also promoting apoptosis and neuroinflammation, ultimately leading to the developmental abnormalities characteristic of FASD. Recent studies demonstrate that antioxidant supplementation or targeted modulation of redox-sensitive signaling can mitigate these deleterious effects in preclinical models. This review synthesizes current knowledge of the molecular networks underlying redox dysregulation in FASD and discusses emerging antioxidant and dietary interventions with therapeutic potential. Elucidating these mechanisms provides critical insight into the pathogenesis of FASD and may inform the development of effective strategies for the prevention and treatment of FASD. Full article

Background and Clinical Significance: Dentinogenesis imperfecta is a hereditary dentin disorder that compromises tooth structure, esthetics, and function. Case Presentation: We report the case of a 1.5-year-old female presenting with generalized discoloration of the primary dentition and intermittent sensitivity to thermal stimuli. The diagnosis of dentinogenesis imperfecta was established based on characteristic clinical features, radiographic findings, and a positive family history. The patient was followed longitudinally from 2020 to 2025, with documentation of diagnostic findings, radiographic changes, therapeutic interventions, and outcomes. Management included placement of composite veneers on the maxillary incisors for esthetic rehabilitation and sealants on second primary molars as a preventive measure. Although various management approaches have been described in the literature, evidence regarding optimal strategies and long-term outcomes in the primary dentition remains limited. This case highlights the occurrence of asymptomatic periapical pathology and root resorption despite minimal clinical symptoms, underscoring the challenges of relying on symptom-based assessment alone. Conclusions: Early diagnosis, regular radiographic monitoring, and individualized, risk-based treatment planning are essential in managing dentinogenesis imperfecta. This case emphasizes the importance of recognizing asymptomatic disease progression and integrating psychosocial considerations into comprehensive care. Full article

Pythiosis is a neglected infectious disease caused by the aquatic oomycete Pythium insidiosum and remains underrecognized in cattle, particularly in tropical regions. Here, we report the first molecularly confirmed outbreak of bovine pythiosis in the Amazon biome, affecting more than 400 animals raised under extensive production systems and areas with prolonged exposure to standing water. Clinically affected cattle presented ulcerative and exudative cutaneous lesions, predominantly involving the distal limbs. Given the diagnostic challenges associated with pythiosis, etiological confirmation was achieved through quantitative PCR (qPCR) targeting the internal transcribed spacer (ITS) region of P. insidiosum, providing rapid and specific molecular detection during the outbreak investigation. Therapeutic interventions were implemented as part of routine field management, including intramuscular triamcinolone combined with topical copper sulfate; this regimen was associated with clinical improvement in a substantial proportion of affected animals, though treatment efficacy was not formally evaluated. The outbreak occurred in flood-prone pastures during the rainy season, highlighting the role of aquatic environments in pathogen transmission. These findings expand the current understanding of bovine pythiosis in tropical ecosystems and underscore the importance of molecular diagnostics, outbreak surveillance, and a One Health approach for the identification and management of water-associated pathogens in livestock. Full article

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria (NSM) and synaptosomal fractions containing synaptic mitochondria from adult male rats exposed to six weeks of CSIS, an animal model of depression, compared to controls. The compartment-specific proteomic alterations reveal mechanisms underlying mitochondrial dysregulation, providing molecular insights into the depression-like phenotype. Hippocampal NSM exhibit changes in energy metabolism-related proteins, including components of the tricarboxylic acid cycle and oxidative phosphorylation, as well as mitochondrial transport proteins and alterations in chaperones, structural and translational proteins, and monoamine oxidase, further elucidating how these proteomic changes contribute to mitochondrial dysregulation. In contrast, synaptosomal proteomics reveal predominantly increased protein abundance associated with energy metabolism, signaling, cytoskeletal organization, protein quality control, and vesicle trafficking, suggesting compensatory adaptations. Together, these findings highlight compartment-specific mitochondrial proteomic changes that may underlie depression-like behaviors and represent potential targets for therapeutic intervention. Full article

Background and Clinical Significance: Retroperitoneal urinomas are uncommon complications that can arise following trauma, particularly in the context of congenital anomalies such as pyeloureteral duplication. These conditions pose significant diagnostic and therapeutic challenges, requiring a comprehensive and multidisciplinary approach to ensure optimal patient outcomes. Case Presentation: Here, we report the case of a 22-year-old male who presented to the emergency department with right lumbar and flank pain, nausea, and abrasions following a fall from a height. Initial imaging revealed a right-sided retroperitoneal urinoma and a rare congenital anomaly: complete pyeloureteral duplication with the upper pole draining into the right seminal vesicle. The patient underwent two surgical interventions, including the insertion of a ureteral stent and reimplantation of the ureter using a latero-terminal U trans U technique. Conclusions: This case highlights the complexity of managing traumatic retroperitoneal urinomas associated with congenital anomalies such as complete pyeloureteral duplication. It emphasizes the importance of timely surgical intervention to prevent complications and improve patient outcomes. Full article