The journal retracts the article titled, “A Flavonoid-Rich Extract from Bergamot Juice, Alone or in Association with Curcumin and Resveratrol, Shows Protective Effects in a Murine Model of Cadmium-Induced Testicular Injury” [...]
Background: Janus kinase (JAK) inhibitors have expanded the therapeutic landscape for moderate-to-severe atopic dermatitis (AD), yet real-world comparative data on upadacitinib and abrocitinib remain limited. Objective: We aimed to compare the 24-week real-world effectiveness and safety of upadacitinib 30 mg and abrocitinib 200 mg in adult patients with moderate-to-severe AD, using EASI-75 as the primary efficacy endpoint, and to explore potential clinical factors associated with treatment response. Methods: This retrospective single-center study included adult patients with moderate-to-severe AD treated with upadacitinib 30 mg or abrocitinib 200 mg and followed for 24 weeks in routine clinical practice. A small pediatric subgroup (n = 3) receiving abrocitinib 100 mg was analyzed separately for descriptive purposes only. Clinical outcomes included Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS), EASI-50/75/90 response rates, and NRS-4 response. Safety was assessed using routinely documented adverse events. Exploratory analyses evaluated the possible influence of body mass index (BMI), baseline immunoglobulin E (IgE), and psychological stress on treatment response. Results: Both upadacitinib and abrocitinib were associated with rapid and sustained clinical improvement over 24 weeks. At month 6, EASI-75 response was 83.3% in the upadacitinib group versus 70.8% in the abrocitinib group (p = 0.27). EASI-50 response was significantly higher in the upadacitinib group (100% vs. 83.3%; p = 0.05). Exploratory findings suggested that higher BMI, elevated baseline IgE levels, and psychological stress may be associated with less favorable response trajectories. Both treatments demonstrated a generally favorable safety profile; however, one serious cerebrovascular thrombotic event occurred in a patient with pre-existing cardiovascular risk factors, highlighting the importance of individualized risk assessment when prescribing JAK inhibitors. Conclusions: In routine clinical practice, both upadacitinib and abrocitinib appeared effective for the management of moderate-to-severe AD over 24 weeks. Although upadacitinib 30 mg showed a numerically higher month-6 EASI-50 response, this finding should be interpreted cautiously given the modest sample size and the absence of broader between-group differences across other key efficacy outcomes. Larger prospective studies are needed to confirm comparative effectiveness and to clarify predictors of response and safety in real-world settings.
Background/Objectives: Anshen Bunao Oral Liquid (ABOL) is a traditional medicinal formula comprising Cornu Cervi Pantotrichum, Radix Polygoni Multiflori Preparata and other ingredients. It replenishes essence, nourishes qi and blood, and soothes the spirit. It is used in clinical practice to treat neurasthenia and insomnia (emotion-related symptoms), and its key component, glycyrrhizin, exhibits anxiolytic properties. This aligns with the holistic approach of traditional Chinese medicine (TCM) to regulating neuropsychiatric disorders. The aim of this study is to evaluate the anxiolytic efficacy of ABOL in rats with anxiety induced by chronic restraint stress (CRS), and to clarify its mechanism by focusing on modulation of the gut-brain axis (microbiota and metabolism). Methods: Sprague-Dawley rats underwent three hours of restraint per day for 28 days to induce anxiety. ABOL was administered intragastrically in three doses. Anxiety-like behaviours were assessed using OFT, EPM and SPT. Serum, tissue and faecal samples were analysed using ELISA, histopathology, immunohistochemistry, non-targeted metabolomics, 16S rRNA sequencing and RT-qPCR. Results: CRS induced anxiety-like behaviours, impaired weight gain and perturbed the balance of neurotransmitters (decreasing 5-HT, GABA, NE and DA, while increasing CORT), inducing inflammation/oxidative stress, hippocampal neuronal injury, intestinal barrier dysfunction and gut microbiota/metabolic dysregulation. ABOL effectively reversed these abnormalities by restoring the balance of neurotransmitters and the HPA axis, suppressing inflammation and oxidation, protecting neurons and the intestinal barrier, remodelling the gut microbiota (enriching Akkermansia and balancing Firmicutes/Bacteroidota) and regulating sphingolipid and glycerophospholipid pathways. The interaction between the gut microbiota and metabolites may contribute to this pharmacological effect. Conclusions: ABOL exerts anxiolytic effects by modulating the gut-brain axis at multiple targets, involving microbiota remodelling, regulation of lipid metabolism and improvement of pathology. This validates its ethnopharmacological value, linking traditional Chinese medicine to the development of modern anxiolytics.
Background/Objectives: Carvedilol is an adrenergic blocker FDA-approved to improve outcomes in heart failure with reduced ejection fraction. Clinical trials examining whether carvedilol may be cardioprotective in the setting of cancer therapy-induced heart failure have generated mixed results that may depend on the cancer regimen, tumor, or comorbidities. Methods: To investigate the therapeutic potential of carvedilol to mitigate doxorubicin cardiotoxicity in cardiomyocytes, myocardial tissue, and in vivo, independent of confounding factors in clinical studies, we utilized disease-free cardiac slices and cardiomyocytes from mice, dogs, and human in vitro, and in wildtype mice injected with doxorubicin in vivo. We further evaluated the impact of carvedilol in dogs with cancer receiving doxorubicin. Results: In primary canine and murine cardiac slices, carvedilol treatment restored autophagy and prevented apoptosis from doxorubicin. Carvedilol restored mitochondrial energetics in human, canine, and murine models. In wildtype mice challenged with doxorubicin, carvedilol prevented declines in cardiac function and alterations in cardiac structure. In pet dogs with cancer and undergoing doxorubicin treatment, carvedilol was beneficial in preserving cardiac function and structure. Conclusions: Carvedilol activates cardioprotective autophagy, arrests doxorubicin-induced cell death, and improves energetics and cardiac structure and function across species.
Background/Objectives: Ulcerative colitis is a chronic inflammatory disorder of the colon characterized by epithelial injury and excessive inflammatory responses. J2H-1802 is a newly synthesized hybrid molecule designed to combine the pharmacological properties of mycophenolate mofetil and 5-aminosalicylic acid. This study evaluated the protective and anti-inflammatory effects of J2H-1802 in a dextran sulfate sodium (DSS)-induced colitis mouse model and investigated its underlying mechanisms. Methods: Experimental colitis was induced in mice by administration of 2.5% (w/v) DSS for 7 days, followed by oral treatment with J2H-1802. Body weight, stool consistency, fecal bleeding, and disease activity index were assessed. Colon length and spleen weight were measured to evaluate macroscopic damage. Levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, and myeloperoxidase in colon tissues were quantified, and the expression of phosphorylated nuclear factor-κB and cyclooxygenase-2 was analyzed by Western blotting. Results: J2H-1802 alleviated DSS-induced body weight loss, diarrhea, and fecal bleeding, resulting in reduced disease activity index scores. It also prevented colon shortening and attenuated splenomegaly. In addition, J2H-1802 significantly suppressed the elevated levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, and myeloperoxidase in colon tissues. Western blot analysis further showed that J2H-1802 inhibited the DSS-induced upregulation of phosphorylated nuclear factor-κB and cyclooxygenase-2. Conclusions: J2H-1802 protected against DSS-induced colitis by reducing inflammatory responses and inhibiting the nuclear factor-κB/cyclooxygenase-2 signaling pathway. These findings suggest that J2H-1802 functions as a hybrid anti-inflammatory scaffold with in vivo pharmacological activity and may warrant further optimization and investigation in IBD models.
The process of drug discovery is one of the most expensive, time-consuming, and high-risk endeavors in modern science. Translating initial scientific insights into safe and effective therapies, supported by genomics, structural biology, and computational chemistry, typically requires more than a decade and substantial financial investment. Machine learning (ML) has emerged as a powerful tool for improving efficiency across the drug discovery pipeline. By enabling the analysis of large and complex datasets, ML supports target identification, lead discovery, optimization, and prediction of preclinical and clinical outcomes. Its integration with experimental validation and automation is illustrated by recent advances such as protein structure prediction, AI-driven antifibrotic compound discovery, and antibiotic identification. Despite these advances, significant challenges remain. Model generalizability is limited by data scarcity, heterogeneity, and hidden biases. In addition, the translation of in silico predictions into clinically validated outcomes remains a major bottleneck, and regulatory acceptance is constrained by limited model interpretability. Ethical considerations, including data privacy, equitable representation, and the potential misuse of generative models, further complicate adoption. This review examines the applications of ML across the drug discovery pipeline, with a focus on translational and regulatory considerations. It also discusses emerging directions, including hybrid physics–AI approaches, multimodal foundation models, federated learning, and explainable AI. The effective integration of ML will depend on rigorous validation, interdisciplinary collaboration, responsible data governance, and alignment with regulatory frameworks.
Background and Objectives: Ocrelizumab significantly reduces inflammatory activity in relapsing-remitting multiple sclerosis (RRMS), but treatment-induced brain volume change and the specific contributions of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) compartments to global atrophy and pseudoatrophy remain unclear. We aim to characterize the longitudinal and infusion-related dynamics of brain compartments in ocrelizumab-treated RRMS patients and identify the clinical and time-dependent predictors of these changes. Methods: Fifty-one RRMS patients were enrolled in a four-year prospective study. Brain volumes, including WM, GM, peripheral GM (pGRAY), CSF, ventricular CSF (vCSF), total brain volume (TBV) and their respective fractions (WMF, GMF, BPF) were evaluated by absolute time points (baseline to 4 years) and infusion-based intervals (baseline to 8th infusion), before and after each ocrelizumab cycle. Correlations between brain volume measures and the Expanded Disability Status Scale (EDSS), as well as time-dependent variables such as age, age at onset and disease duration (DD) were examined. Results: Mean age was 41.62 ± 9.76 years, mean age at onset 28.17 ± 7.85, mean DD 12.89 ± 8.55 years and mean EDSS 3.26 ± 1.5, indicating moderate disability. During the study, vCSF and CSF significantly increased, whereas WM, WMF, TBV and BPF significantly decreased. Notably, these measures exhibited marked, non-linear, and transient changes during the first year of ocrelizumab treatment, consistent with pseudoatrophy, likely reflecting early resolution of inflammation rather than irreversible tissue loss. GM and pGRAY remained relatively stable, with minor early increases. Correlation analyses revealed that higher EDSS scores, older age, later age at onset and longer DD were associated with lower GM, pGRAY and TBV, emphasizing the interplay between disease progression and development of brain volumetric patterns. Conclusions: Ocrelizumab-induced pseudoatrophy is predominantly WM-driven and age-dependent, with WM shrinkage being the main contributor to parenchymal loss and secondary widening of CSF spaces. Age remains a powerful predictor of brain atrophy and neurological impairment. These findings provide mechanistic insights into the biological basis of this modulation in RRMS.
COVID-19 has spurred much interest in complementary and alternative agents for therapeutic purposes having antiviral and immunomodulatory effects. In these, natural products and bioactive compounds from plants have been at the center of attention due to their easy access, relatively low risk and long history of use in traditional medicine. This paper reviews in detail and critically assesses the scientific data that presently proposes the use of certain cannabinoids, cannabimimetic compounds and Artemisia species in the treatment and prevention of COVID-19. It gives an account of medicinal approaches to cannabinoids like cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) alongside other minor cannabinoids and synthetic and naturally-occurring cannabimimetics. The paper reports the potential of Artemisia annua and other species as treatments, especially focusing on their antiviral, anti-regulatory, anti-inflammatory and immunomodulating properties. It highlights the molecular interactions with SARS-CoV-2 targets as well as cytokine regulation and modulation of oxidative stress pathways, with special emphasis on these areas. The paper raises multiple issues like preclinical and clinical studies, safety aspects, regulatory hurdles and drawbacks related to the use of these natural compounds. After analyzing all the available data, the article entertains the idea of a cannabinoid–Artemisia combination as a supportive or adjunct therapy in COVID-19 treatment. It also points out that the clinical trials are insufficient concerning the establishment of effectiveness, determination of the appropriate dosage and assurance of the long-term safety of the treatment.
Background: Positron emission tomography (PET) is a molecular imaging technique that exploits the β+ decay of selected radionuclides to enable non-invasive in vivo investigation of biochemical and physiological processes, including early and subclinical disease alterations. Radiotracers are designed to bind specific molecular targets with high affinity and selectivity. Among the targets to which PET devotes increasing attention are G protein-coupled receptors (GPCRs)—the largest class of transmembrane receptors—which orchestrate a wide spectrum of biological outcomes and are widely implicated in human disease. Objectives: This review analyzes patents published between 2020 and 2025 focusing on GPCR-targeted PET radiotracers, highlighting design strategies, radionuclide selection, and translational perspectives across oncology, central nervous system (CNS) disorders, and inflammatory diseases. Results: Patent activity shows that most GPCR-targeted PET tracers are derived from validated ligands adapted for imaging while preserving affinity and selectivity. Oncology patents mainly favor peptide-based or modular metal–chelator platforms enabling radionuclide flexibility and theranostic extension, whereas CNS tracers rely on drug-like small molecules optimized under strict ADME and blood–brain barrier constraints. Increasing emphasis on non-orthosteric, function-sensitive, and dual-targeting approaches reflects a shift toward interrogating GPCR signaling states, while inflammatory indications remain comparatively underrepresented despite clear biological foundations. Conclusions: Current patent trends consolidate GPCR-targeted PET tracers as well-established diagnostic tools while progressively expanding their clinical utility, both as platforms supporting translational research—informing mechanistic insight and drug development—and as components of emerging theranostic strategies across multiple disease areas.
Background: The NLRP3 inflammasome drives pathological inflammation in various diseases. PINK1/Parkin-associated mitophagy serves as a critical negative regulator of NLRP3 activation, yet pharmacological enhancers remain scarce. Muscone, a natural macrocyclic ketone with blood–brain barrier permeability, exhibits potent anti-inflammatory properties; however, its mechanistic role within the NLRP3-mitophagy axis remains undefined. Methods: LPS/ATP-stimulated macrophages were employed to assess stage-specific effects of muscone on NLRP3 priming (NF-κB signaling, NLRP3, and pro-IL-1β expression) and activation (ASC oligomerization, ASC–pro-caspase 1 complex formation, and IL-1β secretion). RNA sequencing and bioinformatic analysis were performed for pathway enrichment. Mitophagy was characterized by MitoSOX Red staining for mt-ROS detection, electron microscopy, Western blotting of LC3B-II in isolated mitochondria and PINK1 and Parkin in whole-cell lysates, and live-cell mitochondria–lysosome tracking. In vivo protective efficacy was assessed in an LPS-induced endotoxemia mouse model. Results: Muscone dose-dependently suppressed both the priming and activation stages of the NLRP3 inflammasome, maximally reducing IL-1β secretion by ~60% at 50 μM. Mechanistically, muscone amplified PINK1/Parkin-associated mitophagy, scavenging excessive mt-ROS and attenuating NLRP3 activation. These effects were corroborated by RNA-seq and comprehensive functional assays. In vivo, muscone (30 mg/kg) significantly improved survival (3/8 mice alive at 98 h when all LPS controls had died; 2/8 survived to the 132-h endpoint), with concomitant enhancement of mitophagy markers in peritoneal macrophages. Conclusions: Muscone functions as a PINK1/Parkin-associated mitophagy enhancer that maintains mitochondrial quality control during NLRP3-driven inflammatory responses. Its unique macrocyclic structure and blood–brain barrier permeability provide a promising scaffold for developing therapeutics against inflammatory disorders associated with NLRP3 inflammasome activation.
Background/Objectives: Type 2 diabetes is a group of metabolic disorders whose pathophysiological outcome is sustained hyperglycemia. Several medications are available for the treatment. SGLT2 simultaneously inhibits glucose and sodium reabsorption in the renal proximal tubule, resulting in urinary glucose excretion. This study assessed the pharmacokinetic profiles of two empagliflozin 25 mg drug products under fasting conditions in healthy Mexican subjects to establish bioequivalence. Methods: This was a randomized, open-label, two-way crossover, single-dose, prospective study with a 7-day washout period. Eligible subjects were healthy adult Mexican volunteers. The drugs were dosed orally, according to the randomization, after 10 h of fasting and 4 h before breakfast, with 250 mL of 10% glucose solution at room temperature. Serial blood samples were collected before and after dosing. Empagliflozin concentrations were analyzed using high-performance liquid chromatography–tandem mass spectrometry. Results: A total of 32 subjects were enrolled, and 30 completed the study. Pharmacokinetic parameters Cmax, tmax, AUC0–t, AUC 0–∞, and t½ of empagliflozin for test and reference formulation, expressed as mean ± SD, were 578.28 ± 125.60 ng/mL, 2.72 ± 0.85 h, 4370.88 ± 769.50 ngh/mL, 4423.93 ± 776.02 ngh/mL, 7.62 ± 0.83 h, and 593.99 ± 156.78 ng/mL, 2.86 ± 1.00 h, 4313.24 ± 885.02 ngh/mL, 4368.04 ± 887.75 ngh/mL, and 7.61 ± 0.68 h, respectively. The 90% CI for Cmax, AUC0–t, and AUC 0–∞ were 98.30 [92.72–104.22], 101.72 [98.77–104.77], and 101.64 [98.73–104.63], respectively. Serious adverse events were not observed. Conclusions: Our study demonstrated bioequivalence between the empagliflozin formulations tested in healthy subjects under fasting conditions.
Background: Toxoplasma gondii (T. gondii) is one of the most prevalent parasitic zoonoses worldwide, and the host’s immunological state significantly influences its clinical manifestations, which can be potentially fatal in immunocompromised hosts. The unavailability of a vaccine, combined with the considerable toxicity of existing medications, necessitates the urgent search for new therapies or adjunctive techniques, including regenerative and immunomodulatory approaches. Hence, the present study investigated, for the first time, the therapeutic potential of syngeneic platelet rich plasma (PRP) against T. gondii ME49 strain-induced chronic toxoplasmosis in both immunocompetent and immunosuppressed mouse models. Methods: 72 albino mice were divided into two sections, immunocompetent and immunosuppressed. Each section contained six groups: healthy, model, cotrimoxazole (CTZ)-treated, PRP-treated, half-dose of both CTZ and PRP-treated, and full-dose of both CTZ and PRP-treated. Treatment efficacy was assessed via parasitological, histological, immunohistochemical, and immunological analyses. Results: PRP, especially when coadministered with the CTZ, mitigated the consequences of toxoplasmosis by significantly reducing brain cyst counts (p < 0.0001), restoring brain tissue architecture, modulating apoptotic pathways by restoring caspase-3 expression in the brain, and normalizing systemic IFN-γ, TNF-α, and IL-10 cytokine profiles. Conclusions: The findings highlight PRP as an adjunct to the reference treatment, CTZ, for controlling toxoplasmosis in both immunocompetent and immunosuppressed conditions via anti-infective, neuroprotective, and immunomodulatory activities.
Background: Ketamine is a rapid-acting antidepressant for major depressive disorder; however, its effects are short-lasting and associated with neurotoxic side effects. Thus, identifying strategies to prolong its antidepressant effects is of critical importance. It has been shown that Dajianzhong Decoction (DJZT) prolongs the antidepressant effects of ketamine through modulation of the gut microbiota, but the underlying mechanisms remain unclear. Method: Fecal microbiota transplantation, metabolomic profiling, pharmacological interventions, and behavioral approaches were employed together with a chronic unpredictable mild stress (CUMS) mouse model to investigate how microbiota-derived signals mediate the combined effects of DJZT and ketamine. Results: Microbiota from CUMS mice induced depressive-like behaviors in recipient mice, accompanied by reduced levels of short-chain fatty acids (SCFAs), decreased FFAR2 expression in the medial prefrontal cortex, and increased neuroinflammation and synaptic deficits. These alterations were reversed by microbiota from DJZT-plus-ketamine-treated donors. Notably, acetic acid and isobutyric acid were identified as key SCFAs restored by the combined treatment and were significantly associated with behavioral outcomes. Moreover, SCFA supplementation recapitulated these effects by activating FFAR2 and suppressing NLRP3–IL-1β signaling. Importantly, pharmacological inhibition of FFAR2 using GLPG0974 abolished the antidepressant-like, anti-inflammatory, and synaptic protective effects of the microbiota from DJZT-plus-ketamine-treated donors. Conclusions: These findings demonstrate that microbiota-derived SCFAs mediate the synergistic antidepressant effects of DJZT and ketamine via a central FFAR2-dependent mechanism involving suppression of neuroinflammation. This work highlights a potential role of the SCFA–FFAR2–NLRP3– IL-1β axis in influencing ketamine efficacy and points to microbiota-modulating strategies as a possible avenue for improving antidepressant therapy.
Background/Objectives: Type 2 Diabetes Mellitus (T2DM) is characterized by insulin resistance and chronic hyperglycemia, which significantly impair vascular function. In experimental T2DM models, the vascular endothelium is compromised, showing decreased vasodilator responses. Vitamin D3 has emerged as a promising intervention for improving glycemic parameters and restoring endothelial function. This study evaluated the effects of vitamin D3 (0.25 and 0.50 µg/kg/day) administered for 4 and 8 weeks on the ex vivo aortic vascular reactivity of T2DM rats. Methods: T2DM was induced in male Wistar rats via a high-fat, normoprotein diet and streptozotocin (30 mg/kg, i.p.). Groups included normal control, diabetic control, metformin, and vitamin D3 (0.25 or 0.50 µg/kg/day). Following 4 or 8 weeks of treatment, thoracic aortic segments were isolated for ex vivo vascular reactivity studies to assess responses to vasoconstrictor and vasorelaxant agents. Results: Vitamin D3 treatment improved glycemic profiles; the 0.25 µg/kg dose reduced fasting glucose, while the 0.50 µg/kg dose lowered glycated hemoglobin at 8 weeks. Endothelium-dependent relaxation induced by acetylcholine was significantly increased in diabetic rats treated with vitamin D3 at both doses over 4 weeks compared to diabetic controls. Moreover, vitamin D3 prevented the attenuation of maximal contractile responses to phenylephrine observed in untreated diabetic rats at 8 weeks. Conclusions: Vitamin D3 supplementation restores endothelial function and improves vascular reactivity in an experimental T2DM model. These findings suggest that vitamin D3 may mitigate vascular complications by enhancing vasorelaxation and maintaining contractile integrity.
The advent of novel Human Epidermal growth factor Receptor 2 (HER2)-targeted therapies and tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in HER2-positive malignancies, particularly breast cancer. However, these agents carry a growing burden of cardiovascular adverse events, representing a critical concern in modern oncology. This narrative review explores the evolving landscape of cardiovascular toxicity associated with these therapeutic classes, integrating mechanistic insights with real-world clinical data. HER2-targeting monoclonal antibodies and antibody–drug conjugates exert off-target effects on cardiomyocytes via HER2 pathway inhibition, leading to reversible or irreversible myocardial dysfunction. In parallel, small-molecule TKIs, especially those targeting multiple kinases, have been associated with hypertension, arrhythmia, QT prolongation, and heart failure, through mechanisms such as mitochondrial dysfunction, endothelial damage, and disruption of cardioprotective signaling. We summarize clinical evidence elucidating the molecular basis of these toxicities and critically review clinical trials and post-marketing data highlighting their incidence and management. The review emphasizes the heterogeneity of cardiotoxicity profiles across different agents, underscoring the need for individualized cardiovascular risk stratification and monitoring. Finally, we address the emerging role of cardio-oncology in bridging oncologic efficacy with cardiac safety, advocating for multidisciplinary approaches, biomarker-guided surveillance, and standardized definitions of cardiotoxicity. As precision oncology advances, a parallel refinement in cardiotoxicity prediction and prevention is imperative to optimize patient outcomes.
Sonchus asper (L.) Hill is a widely distributed plant traditionally used as both a food source and a medicinal herb. In recent years, increasing interest in natural, safe, and effective cosmetic ingredients has highlighted the potential of plant-derived bioactive compounds. This review provides an overview of the biological properties of S. asper, with particular emphasis on its relevance in cosmetic applications. The plant is characterized by a rich profile of primary and secondary metabolites, including amino acids, fatty acids, vitamins, phenolic acids, flavonoids, coumarins, and terpenoids. These compounds contribute to a broad spectrum of biological activities, such as strong free radical scavenging activity, modulation of inflammatory pathways, and inhibition of the growth of selected skin-associated pathogens, suggesting its potential as a multifunctional cosmetic ingredient.
Background/Objectives: Mild traumatic brain injury (mTBI) is common and may result in persistent cognitive and affective disturbances driven, at least in part, by delayed secondary injury mechanisms, including oxidative stress, neuroinflammation, apoptosis-related signaling, and impaired neuroplasticity. Pharmacological strategies targeting these interconnected processes remain limited. The present study investigated leucovorin, also known as folinic acid, a clinically approved reduced folate, as a potential repurposing candidate in an experimental model of mTBI. Methods: Male Wistar rats were subjected to mild diffuse brain injury using a modified weight-drop model and received a single intraperitoneal dose of leucovorin (20 mg/kg). Behavioral performance was evaluated using the open field, elevated plus maze, forced swim, and novel object recognition tests. Oxidative stress markers, including total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI), as well as inflammatory mediators tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2), caspase-3, brain-derived neurotrophic factor (BDNF), and acetylcholinesterase (AChE), were measured in hippocampal tissue and plasma. Histopathological and immunohistochemical evaluations were also performed in cortical and hippocampal regions. Results: Experimental mTBI was associated with anxiety-like and depressive-like behaviors and impaired recognition memory, whereas basal locomotor activity was not significantly altered. Trauma was also associated with increased oxidative stress, elevated inflammatory and apoptosis-related markers, reduced BDNF levels, altered AChE activity, and histopathological abnormalities. Compared with untreated mTBI animals, leucovorin-treated animals showed attenuation of biochemical and tissue alterations, accompanied by improved behavioral outcomes. Immunohistochemical findings were consistent with reduced inflammatory labeling and relative preservation of tissue architecture following leucovorin treatment. Conclusions: Leucovorin attenuated behavioral, biochemical, histopathological, and immunohistochemical alterations associated with experimental mTBI. These findings suggest that leucovorin may have neuroprotective potential in this setting; however, further studies are needed to clarify the underlying mechanisms, optimal treatment paradigms, and translational relevance.
Background/Objectives: Anxiety disorders in people over 65 y of age are common. Treatment of those disorders is often based on studies involving much younger patients. Experience shows that those treatments are regularly ineffective in the elderly, due to differences in physiology and the disparate etiology of the disease. Here, we examine current trends in research to generate data for evidence-based approaches to treat anxiety disorders in the elderly. Our objective was to evaluate the scope, methodological characteristics, and therapeutic focus of current clinical trials for anxiety disorders in the elderly, and to determine whether the existing evidence pipeline is likely to meet the substantial unmet need for effective and well-tolerated treatments. Methods: We searched clinicaltrials.gov for studies addressing “Anxiety disorder” and related readouts and selected those studies that included patients older than 65 y, and that had anxiety measures as primary or secondary endpoints. Results: We find that over 99% of clinical “anxiety” trials exclude patients older than 65 y. Sixty-six trials fulfilled our inclusion criteria. Trials specifically recruiting the elderly are a rare exception. Unexpectedly, only 10 “anxiety” trials are sponsored by the pharmaceutical industry, despite the potential rewards in such investments. Discussion and Conclusions: Although most clinical trials are registered in clinicaltrials.gov., our work is limited by the fact that not all clinical trials carried out world-wide are included in that database. Our findings indicate that ongoing clinical research supporting evidence-based recommendations for the treatment of anxiety in the elderly is scarce. Detailed secondary analysis of clinical trial results for the efficacy and safety of anxiolytics in various age cohorts may at least be a useful instrument for hypothesis generation, to trigger additional clinical research specifically designed to address anxiety treatment in the elderly.
Background/Objectives: The dual inhibition of the COX-2 and 5-LOX pathways, in addition to sEH inhibition, presents a superior approach to managing inflammation while mitigating the cardiovascular adverse effects typically associated with conventional NSAIDs. These multi-target agents are safer and more efficient as they inhibit the synthesis of pro-inflammatory leukotrienes while preserving cardioprotective epoxyeicosatrienoic acids. Methods: This study reports the development of multi-target inhibitors to mitigate inflammatory and cardiovascular conditions. We examined a series of tetrahydroindazole-sulfonamide hybrids (3a–g and 4a–e) against the enzymes COX-1/2, 5-LOX, and sEH. Results: Compound 3b outperformed celecoxib as a multi-target agent, inhibiting COX-2 (IC50 = 0.08 µM, SI = 82), 5-LOX (IC50 = 0.46 µM), and sEH (IC50 = 21.95 nM) in many metrics. In cellular experiments, 3b showed strong cardioprotective and anti-inflammatory effects, significantly reducing TNF-α (65.58%), LDH (76.26%), and CK-MB (76.76%) levels compared to LPS-treated controls. Molecular docking validated these findings, indicating that 3b was comparable to celecoxib at the COX-2 site via a thorough six hydrogen-bond network and achieves considerable sEH affinity through specialized halogen bonding and aromatic stacking. These results indicate that 3b effectively provides dual anti-inflammatory and cardioprotective effects. Conclusions: Our findings suggest that targeting the COX/5-LOX/sEH pathways simultaneously offers a balanced multi-target profile for treating complex inflammatory diseases while minimizing cardiovascular risks.
Background/Objectives: Diabetes mellitus (DM) is a critical metabolic condition with escalated blood glucose levels caused by insulin resistance, restricted insulin production, and the activity of alpha-amylase and alpha-glucosidase enzymes. Methods: This current work focuses on the synthesis and evaluation of novel Pyrimidine-derived pyrazole-based thiadiazole derivatives to target DM by inhibiting α-amylase and α-glucosidase. Results: The findings exhibited that, except for three compounds, all other synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC50 values ranging from 5.17 μM to 29.84 μM on α-amylase and 7.60 μM to 31.62 μM on α-glucosidase, in comparison to the standard drug Acarbose (α-amylase IC50 = 8.25 ± 0.80 μM; α-glucosidase IC50 = 10.75 ± 1.10 μM). Analogs 8g, 8k, and 8b displayed superior or comparable inhibitory activity compared to the reference drug Acarbose. The inhibition potential of the derivatives can be attributed to their stable contacts with crucial amino acid residues of targeted enzymes, as shown through molecular docking analysis. Moreover, DFT-calculated HOMO–LUMO parameters and electrostatic potential (ESP) maps were used to gain complementary insight into the electronic characteristics, charge distribution, and potential interaction behavior of the synthesized derivatives, which supported the molecular docking observations. Conclusions: Experimental outcomes and in silico support display that these derivatives serve as potential leads for anti-diabetic drug development. These potent pyrimidine-derived pyrazole-based thiadiazole derivatives were comparable to an existing diabetic mellitus inhibitor, specifying potential for further therapeutic development and optimization against diabetic mellitus.
