Search Results (22,071)

This narrative review examines topical anti-inflammatory therapies in veterinary medicine through the lens of the One Health framework, integrating pharmacology, dermatology, ecotoxicology, food safety, and regulatory science. It discusses the interconnected roles of veterinarians, pharmacists, environmental scientists, public health authorities, and regulatory bodies in addressing antimicrobial resistance, environmental contamination, zoonotic transmission, and drug residues in food-producing animals. By emphasising cross-sector collaboration, the review highlights how coordinated strategies can enhance animal welfare, safeguard human health, and reduce ecological burden. The article analyses inflammatory conditions in companion and farm animals and compares systemic versus topical anti-inflammatory approaches. Particular attention is given to corticosteroids, NSAIDs, immunomodulators, pro-resolving lipid mediators, and plant-derived bioactives, alongside advances in vehicles such as lipid nanocarriers and biodegradable film-forming systems designed to minimise systemic absorption and environmental dispersion. Regulatory considerations, residue control, pharmacovigilance gaps, and sustainability-oriented formulation strategies are critically addressed. Topical anti-inflammatory therapies, when rationally designed and monitored under One Health principles, represent a strategic opportunity to improve therapeutic precision while limiting systemic toxicity and ecological impact. Future directions should prioritise translational research, eco-compatible formulation design, and harmonised regulatory frameworks. Full article

GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics’ Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure–activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis. Full article

Diabetes mellitus is primarily caused by the loss or malfunction of insulin-producing β-cells, and although current therapies improve glycemic control, they do not restore physiologic insulin secretion. Advances in stem cell biology and organoid engineering have led to the development of pancreatic organoids and induced pluripotent stem cell (iPSC)-derived β-cells as promising platforms for disease modeling, drug testing, and regenerative medicine. Pancreatic organoids generated from ductal, acinar, or progenitor populations can recapitulate key anatomical and functional features of native pancreatic tissue, enabling studies of development, injury, and regeneration. In parallel, improvements in iPSC differentiation protocols have produced β-like cells capable of insulin secretion in response to glucose, although achieving full functional maturity remains a challenge. Bioengineering strategies, including biomaterial scaffolds, microfluidic platforms, endothelial co-culture systems, three-dimensional bioprinting, and CRISPR-based genome editing, have enhanced the stability, vascular compatibility, and functional performance of both organoid and iPSC-derived systems. Despite these advances, variability in differentiation efficiency, limited β-cell maturity, and poor long-term survival continue to hinder clinical translation. Together, pancreatic organoids and iPSC-derived β-cells represent complementary platforms that advance fundamental research and support the development of β-cell replacement therapies, with ongoing integration of bioengineering approaches expected to accelerate progress toward reproducible, scalable, and clinically relevant β-cell regeneration. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation that leads to widespread inflammation and damage across multiple organs. B lymphocytes play a vital role in SLE, with abnormal development and activation leading to autoreactive antibody production and immune complex formation, which damages tissues. Methods: The PPARα agonist WY14643 has anti-inflammatory effects in various inflammatory conditions, including CNS diseases. We investigated whether WY14643 decreases inflammatory mediator production in CD45R⁺ cells in the MRL/lpr mouse model of SLE. Flow cytometry was used to evaluate WY14643’s impact on the expression of IFN-γ, IL-6, iNOS, MCP-1, IL-1α, IL-2, Notch-1, Notch-3, GITR, and NF-κB p65 in splenic CD45R⁺ B cells. Additionally, we assessed the effect of WY14643 on the mRNA levels of these markers in the kidney using RT-PCR. Results: WY14643 decreased inflammatory markers such as CD45R⁺IFN-γ⁺, CD45R⁺IL-6⁺, CD45R⁺iNOS⁺, CD45R⁺MCP-1⁺, CD45R⁺IL-1α⁺, CD45R⁺IL-2⁺, CD45R⁺Notch1⁺, CD45R⁺Notch3⁺, CD45R⁺GITR⁺, and CD45R⁺NF-κB p65⁺ in splenic cells from MRL/lpr mice. Furthermore, WY14643 also lowered mRNA expression of IFN-γ, IL-6, iNOS, MCP-1, IL-2, IL-1α, Notch-1, Notch-3, GITR, and NF-κB p65 in the kidney. Conclusions: This study shows that WY14643 inhibits the production of inflammatory mediators and significantly reduces autoimmune features, including kidney inflammation, in MRL/lpr mice. Our results indicate that WY14643, a PPAR-α agonist, could be a potential therapy for lupus nephritis. Full article

Autoimmune diseases arise from the failure of self-tolerance. The recognition of self-antigen peptide–MHC (pMHC) complexes by the T-cell receptor (TCR) is the fundamental event triggering autoimmune pathogenesis. While traditional immunosuppressants provide broad systemic effects, they often compromise global immunity. Emerging molecular strategies aim to selectively disrupt the trimolecular complex—comprising the TCR, the antigenic peptide, and the MHC molecule—to induce antigen-specific tolerance. This review highlights the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. We discuss the structural basis of these interactions and their potential to redefine the therapeutic landscape for autoimmune diseases (ADs). We examine the molecular drivers of tolerance breakdown—including genetic susceptibility, molecular mimicry, post-translational modifications (PTMs), and ectopic MHC II expression—that shape the autoreactive T-cell landscape. This review examines current advancements in biological and pharmacological interventions, such as pMHC-decorated nanoparticles and soluble pMHC, to reprogram pathogenic T-cell response. We also explored CAR-T therapy strategies for autoimmune diseases, such as CAR-Treg, designed to precisely modulate pMHC-TCR signaling. Collectively, these precision interventions in immunological synapse assembly during autoimmune response are considered the basis for safer, antigen-specific immunotherapy capable of restoring self-tolerance without global immunosuppression. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a systemic metabolic disorder characterized by impaired metabolic flexibility involving the liver, skeletal muscle, and adipose tissue. Although weight loss has traditionally been emphasized in its management, emerging evidence suggests that exercise exerts therapeutic effects beyond body weight reduction. This narrative review aims to examine exercise as a metabolic therapy for MASLD by integrating mechanistic insights and clinical evidence. Exercise improves hepatic steatosis, insulin resistance, mitochondrial function, and inflammatory signaling through interconnected pathways, including activation of AMPK-related signaling, enhanced fatty acid oxidation, and muscle–liver crosstalk mediated by myokines. Importantly, these benefits can occur independently of weight loss, supporting a shift from weight-centered to metabolism-focused treatment strategies. Both aerobic and resistance exercise demonstrate efficacy, with combined approaches providing complementary benefits. In conclusion, exercise should be considered a central therapeutic strategy for MASLD by restoring metabolic flexibility rather than solely promoting weight reduction. Future research should focus on optimizing individualized and sustainable exercise prescriptions to enhance long-term clinical outcomes. Full article

Hearing loss is detrimental to human health, and currently, more than 1.5 billion people are affected by hearing loss. Active military personnel and construction workers are examples of individuals in the workplace who are exposed to loud noise and are at serious risk of hearing loss. While there is currently no therapy for hearing loss, evidence supports investigating the enhancement of the Medial Olivocochlear (MOC) System, an efferent pathway for hearing that serves as a gain-control for hearing loss protection. Selectively modulating the α9α10 nicotinic acetylcholine receptor (nAChRs) found within this pathway is promising for the development of a new drug class. In this review article, we present the most current findings related to the therapeutic targeting of α9α10 nAChRs for hearing loss. We discuss the loss- or gain-of-function of the receptor, evaluate the known modulators of the receptor, examine their clinical relevance, and discuss their chemical and physical properties. Investigation of this novel pathway may aid in the development of a therapeutic for hearing loss. Full article

Over the past years, burn care has evolved from a discipline focused on survival to one centered on restoring long-term health, function, and quality of life. Significant advances in critical care, early excision and grafting, infection control, and metabolic support have transformed survival outcomes for even the most severe injuries. As a result, the field now faces a new frontier: understanding and managing the long-term physical, psychological, and systemic sequelae of survival. This review traces the evolution of burn care over the last century and outlines the challenges and priorities for the next 25 years. The first era of progress, defined by innovations in resuscitation, surgery, and critical care, has given rise to a growing cohort of long-term survivors. Research over the past decade has revealed that major burns induce chronic multisystem alterations, including metabolic, cardiovascular, neurocognitive, and immunological dysfunctions. Emerging concepts such as burn-associated heart failure exemplify this shift from acute to chronic disease understanding. Looking ahead, the future of burn medicine lies in personalized and lifelong care, supported by translational research, digital health, regenerative therapies, and interdisciplinary collaboration. Overall, burn care stands at a pivotal crossroads. By integrating precision medicine, rehabilitation science, and psychosocial care, we aim to move the field from survival toward sustained, holistic recovery over the next 25 years. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative maxillofacial disorder marked by progressive cartilage degradation and subchondral bone resorption, severely compromising patients’ quality of life. Intra-articular injection (IA), a standard route for conservative therapy, offers clinical advantages in safety and efficacy; however, outcomes remain limited due to short drug retention, poor tissue penetration, and variable agent efficacy, necessitating repeated administration. To overcome these limitations, fisetin-loaded poly (lactic-co-glycolic acid) nanoparticles (FST-PNP) were developed as a localized drug delivery system (DDS) for TMJOA treatment. Physicochemical analyses showed FST-PNP had uniform spherical morphology, excellent dispersibility, stability, high encapsulation efficiency, and substantial drug loading capacity. An in vitro study demonstrated more sustained and stable release from FST-PNP than free fisetin. The in vivo IA administration of FST-PNP preserved mandibular condylar osteochondral structures in TMJOA models. Notably, FST-PNP suppressed the expression of metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) as catabolic enzymes and downregulated p16 and p21 as senescence markers, indicating synergistic anti-inflammatory and anti-senescent effects. These findings highlight FST-PNP as a DDS integrating controlled-release with multifaceted therapeutic actions, providing a promising strategy for IA therapy of TMJOA. Full article

Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Advances in molecular diagnostics and targeted therapies have transformed treatment paradigms, yet the integration of molecular testing into routine care for resected NSCLC specimens continues to face significant challenges. This review outlines the technical, clinical, and systemic barriers that limit the effectiveness of molecular testing. Key considerations include tissue quality, the limitations of formalin-fixed paraffin-embedded (FFPE) samples, and the comparative roles of conventional methods—such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR)—versus next-generation sequencing (NGS). We also discuss the prevalence and clinical relevance of common genomic alterations, including TP53, KRAS, EGFR, and ALK, as well as their impact on prognosis and treatment selection. Real-world obstacles such as accessibility, reimbursement, delays in testing, interdisciplinary coordination, and sample adequacy are critically examined. Emerging innovations—including multi-omics integration, spatial profiling, liquid biopsy, artificial intelligence, and novel targeted therapies—offer opportunities to overcome current limitations and improve patient outcomes. Finally, practical recommendations are proposed to optimize tissue handling, testing algorithms, and access to precision-guided therapies. By addressing these challenges, molecular testing in NSCLC can be more effectively leveraged to personalize treatment strategies and enhance survival outcomes. Full article

Age-related macular degeneration (AMD) is the most common cause of blindness and vision impairment in individuals over 60 years of age in the United States (US). Despite this, current treatment options have limitations related to drug efficacy and durability. Gene therapy provides a potential solution by providing a more durable and longer- acting treatment option that can decrease treatment burden and improve long-term visual outcomes. This review presents the current treatment approaches, routes of administration, and vectors being investigated for gene therapy delivery in AMD. It also provides an update on the ongoing gene therapy clinical trials for dry and wet AMD. As these therapies advance into later-stage clinical trials, ophthalmologists need to be mindful of the many challenges pertaining to gene therapy delivery, including safety, limitations related to immunogenicity, long-term ocular and systemic side effects, and potential barriers to drug manufacturing and access. Continued efforts are required to improve precision, safety, and efficacy, including identifying the safest and most effective vectors and delivery routes, and minimizing potential adverse effects. In addition, guidelines need to be established to guide appropriate patient selection before gene therapy can be integrated into clinical practice. Full article

Background and Clinical Significance: Mechanical complications and intracavitary thrombus are both recognized causes of clinical deterioration following acute myocardial infarction, yet they require fundamentally different therapeutic approaches. Distinguishing between these entities is critical, as misdiagnosis may lead to unnecessary surgical intervention or delayed anticoagulation with serious consequences. Left ventricular (LV) thrombus typically appears as a well-defined mass; however, atypical and highly mobile morphologies may closely mimic catastrophic post-infarction mechanical complications, creating significant diagnostic uncertainty. This case highlights the pivotal role of contrast-enhanced echocardiography in resolving such ambiguity and guiding appropriate management in a high-stakes clinical setting. Case Presentation: A 60-year-old man presented with acute dyspnea and pulmonary edema ten days after an anterior myocardial infarction treated with percutaneous coronary intervention, complicated by ischemic stroke. Transthoracic echocardiography demonstrated severe LV systolic dysfunction with moderate-to-severe mitral regurgitation and an unexpected, highly mobile, irregular mass protruding into the LV apex. The mass exhibited a shredded, tissue-like appearance, raising urgent concern for post-infarction mechanical complications, including papillary muscle rupture or apical myocardial disruption, and prompting immediate consideration of surgical intervention. Contrast-enhanced echocardiography was performed and revealed a mobile LV apical thrombus. Surgical management was avoided, and systemic anticoagulation was initiated, followed by transition to rivaroxaban in combination with ongoing dual antiplatelet therapy. The patient demonstrated rapid clinical improvement with optimized heart failure treatment and was discharged after four days, with planned follow-up imaging to assess thrombus resolution. Conclusions: Left ventricular thrombus may present with atypical, misleading morphologies that closely resemble life-threatening mechanical complications after myocardial infarction. Full article

The diagnosis of type 2 diabetes using classical clinical and laboratory biomarkers (HbA1c, glucose, lipids, BMI, and blood pressure) is a classification by symptoms and does not provide insight into the underlying pathophysiological disorders (insulin resistance, ß-cell dysfunction, visceral adipose tissue hormonal secretion, and chronic systemic inflammation). A better understanding of these disorders may help in the selection of appropriate and potentially more successful personalized therapeutic interventions. Based on extensive clinical trial experience, a method for individual phenotyping and consecutive personalized diabetes therapy has been developed in our practice, which we have been using for more than 15 years and would like to share for discussion and debate. In this Part 1, the pathophysiological background and diagnostic approach to phenotyping is described. A consecutive Part 2 will present the translation of the phenotyping result into a personalized diabetes therapy, and another consecutive Part 3 will provide more comprehensive real-world patient observations when practicing this concept. This article is intended as a discussion/concept paper and does not present unpublished patient-level outcome data or formal effectiveness analyses. Prospective validation studies are needed to evaluate the clinical utility of this phenotype-based framework. Full article

Background/Objectives: Vasomotor symptoms (hot flashes) affect 70–80% of menopausal women, significantly impairing quality of life. Current treatments include hormone therapy, which is contraindicated for many patients, and non-hormonal alternatives with limited efficacy or adverse effects. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential therapeutic candidate due to its interaction with the endocannabinoid system. This study aimed to investigate whether a standardized Cannabis sativa extract containing isolated CBD attenuates heat dissipation in ovariectomized rats, a preclinical model of estrogen deficiency. Methods: Female Wistar rats were randomly assigned to sham-operated vehicle-treated (SHAM-V), ovariectomized vehicle-treated (OVX-V), or ovariectomized CBD-treated (OVX-CBD; 10 mg/kg/day, oral gavage) groups. Treatment began on postoperative day 2 and continued for 21 days. Tail-skin temperature, a surrogate marker of heat dissipation, was assessed by infrared thermography on day 14. Energy metabolism was evaluated by indirect calorimetry on day 21. Uterine weight was measured as a biomarker of estrogen depletion. Results: Ovariectomy significantly increased tail temperature compared to SHAM-V. CBD treatment completely prevented this effect, with OVX-CBD animals exhibiting thermographic profiles similar to SHAM-V. Uterine atrophy was not reversed by CBD. No differences in the calorimetry parameter were observed among groups. Conclusions: This study provides novel preclinical evidence that cannabidiol attenuates ovariectomy-induced heat dissipation in rats, without detectable effects on uterine weight or metabolic parameters. These findings suggest that CBD may represent a potential non-hormonal approach for the management of menopausal vasomotor symptoms; however, further studies are required to elucidate the underlying mechanisms and to determine its translational and clinical relevance. Full article