Search Results (1,888)

Therapeutic phlebotomy remains a key intervention in the management of erythrocytosis and iron overload disorders, particularly polycythemia vera (PV) and hereditary hemochromatosis. Despite its historical origins as an ancient practice, venesection continues to be recommended in international guidelines for the reduction of hematocrit and iron burden, thereby mitigating thrombotic and organ-related complications. However, the evolving landscape of targeted pharmacologic therapies is reshaping the therapeutic paradigm. This review examines the current role of therapeutic phlebotomy, with a particular focus on PV, outlining its physiological rationale, clinical benefits, and well-documented limitations—including iron deficiency, procedural burden, and incomplete hematocrit control between sessions. Comparative insights are provided between phlebotomy and red cell apheresis, highlighting differences in efficacy, tolerability, and accessibility. The emergence of disease-modifying agents—such as interferons, JAK inhibitors, hepcidin mimetics, and epigenetic modulators like givinostat and bomedemstat—promises more sustained hematologic control with the potential to reduce or eliminate the need for repeated phlebotomies. While phlebotomy remains indispensable in early-stage or low-risk PV, its future utility will likely shift toward complementary or bridge therapy in the context of individualized, pharmacologically driven strategies, redefining the role of phlebotomy in the era of precision medicine. Full article

The rise in antimicrobial resistance and strict milk withdrawal regulations drive the search for safe, non-antibiotic intramammary therapies. This pilot field study focused on clinical parameters, including the somatic cell count (SCC) and the assessment of changes, as well as overall safety, which together enabled a prospective evaluation of whether the substance exerted any therapeutic effect. In this study, 48 Holstein–Friesian cows with naturally occurring clinical mastitis (somatic cell count > 400,000 cells/mL; single quarter) were randomized to receive either seven daily infusions of 10% pectin (n = 24) or two standard intramammary doses of a licensed multi-component antibiotic formulation (n = 24). The clinical severity scores (0–3) and SCC were monitored from 72 h before to 168 h after treatment initiation; the bacteriological cultures, milk TNF-α, milk yield, and blood hematology/biochemistry were also assessed. Both groups exhibited comparable and significant reductions in the mastitis scores and log₂-transformed SCC by 48 h post-treatment, with equivalent bacteriological cure rates and pathogen profiles (predominantly Streptococcus uberis, coagulase-negative staphylococci, and Escherichia coli) and no local irritation, systemic adverse effects, or alterations in the milk yield, TNF-α, or blood parameters. These findings indicate that intramammary pectin at a 10% concentration is safe and well tolerated and that it provides efficacy equivalent to standard antibiotic therapy, supporting its potential as an alternative mastitis treatment that avoids antibiotic residues and contributes to antimicrobial stewardship. Full article

Reactive oxygen species (ROS) act as double-edged swords in cancer biology—facilitating tumor growth, survival, and metastasis at moderate levels while inducing oxidative damage and cell death when exceeding cellular buffering capacity. To survive under chronic oxidative stress, cancer cells rely on robust antioxidant systems such as the glutathione (GSH) and thioredoxin (Trx), and superoxide dismutases (SODs). These systems maintain redox homeostasis and sustain ROS-sensitive signaling pathways including MAPK/ERK, PI3K/Akt/mTOR, NF-κB, STAT3, and HIF-1α. Targeting the antioxidant defense mechanisms of cancer cells has emerged as a promising therapeutic strategy. Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity. Disruption of the Trx system by agents such as PX-12 and dimethyl fumarate (DMF) impairs redox-sensitive survival signaling. Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology. Full article

Objectives: Anagrelide, an oral phosphodiesterase-3 inhibitor, is widely used to treat thrombocythemia. Evaluating the bioequivalence of low-dose formulations is essential to ensure consistent therapeutic outcomes while minimizing adverse effects, particularly cardiovascular events such as palpitations, tachycardia, and potential arrhythmias, which are known concerns with anagrelide therapy. This study aimed to compare the pharmacokinetics and bioavailability of a newly developed 0.5 mg anagrelide capsule with the reference product under fasting conditions y. Materials and Methods: In a randomized, open-label, two-period crossover design, 42 healthy Turkish male volunteers received a single oral dose (0.5 mg) of either the test or reference anagrelide capsule, with a seven-day washout period between treatments. Serial blood samples were collected over a 10 h post-dose period. Plasma concentrations of anagrelide were analyzed using a validated LC-MS/MS method. Key pharmacokinetic parameters (AUC₀–t, AUC₀–∞, Cmax, tmax, λz, t½, AUC–extrapol) were calculated and subjected to ANOVA-based bioequivalence analysis. Results: A total of 42 healthy male participants (mean age: 34.1 ± 8.9 years; BMI: 25.7 ± 2.9 kg/m²) completed the study without any protocol deviations. Pharmacokinetic analysis demonstrated that the test and reference formulations of anagrelide 0.5 mg were bioequivalent. The mean AUC₀–t values were 4533.3 ± 2379.3 pg·h/mL for the test formulation and 4515.0 ± 2392.3 pg·h/mL for the reference (p > 0.05), while the mean Cmax values were 1997.1 ± 1159.2 pg/mL and 2061.3 ± 1054.0 pg/mL, respectively (p > 0.05). The 90% confidence intervals for the geometric mean ratios of AUC₀–t (94.09–104.75%), Cmax (85.62–104.03%), and AUC₀–∞ (94.50–105.10%) were all within the predefined bioequivalence range of 80–125%, with corresponding point estimates of 99.28%, 94.37%, and 99.66%, respectively. Intra-subject variability was 14.68% for AUC₀–t and 26.98% for Cmax. No statistically significant differences were observed between the formulations for any of the primary or secondary pharmacokinetic parameters (ANOVA, p > 0.05). Regarding safety, 13 treatment-emergent adverse events were reported in 11 participants (26.2%), mostly moderate-intensity headaches, all of which resolved without complications. No serious adverse events occurred, confirming the tolerability of both formulations. Conclusions: This study demonstrates that the test and reference formulations of low-dose 0.5 mg anagrelide are bioequivalent under fasting conditions, with similar safety and tolerability profiles. The findings support the use of the test product as a safe and effective alternative. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder characterized by immune dysregulation and epidermal barrier dysfunction. Advances in understanding the interplay of genetic predisposition, cytokine signaling, and environmental triggers have led to the emergence of targeted therapies. Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options. Small molecule therapies are gaining momentum as they target intracellular pathways central to AD pathogenesis and offer oral or topical administration routes. This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule therapies into precision treatment strategies for moderate-to-severe AD. Full article

Chlorophyll, the green pigment essential for photosynthesis, abundantly found in green vegetables and algae, has attracted growing scientific interest for its potential therapeutic effects, particularly in diabetes management. Recent research highlighted that chlorophyll and its derivatives may beneficially influence glucose metabolism and oxidative stress, key factors in diabetes. This review examines current knowledge on how chlorophyll compounds could aid diabetes control. Chlorophyll and its derivatives appear to support glucose regulation primarily through actions in the gastrointestinal tract. They modulate gut microbiota, improve glucose tolerance, reduce inflammation, and alleviate obesity-related markers. While chlorophyll itself does not directly inhibit digestive enzymes like α-glucosidase, its derivatives such as pheophorbide a, pheophytin a, and pyropheophytin a may slow carbohydrate digestion, acting as α-amylase and α-glucosidase inhibitors, reducing postprandial glucose spikes. Additionally, chlorophyll enhances resistant starch content, further controlling glucose absorption. Beyond digestion, chlorophyll derivatives show promise in inhibiting glycation processes, improving insulin sensitivity through nuclear receptor modulation, and lowering oxidative stress. However, some compounds pose risks due to photosensitizing effects and toxicity, warranting careful consideration. Chlorophyllin, a stable semi-synthetic derivative, also shows potential in improving glucose and lipid metabolism. Notably, pheophorbide a demonstrates insulin-mimetic activity by stimulating glucose uptake via glucose transporters, offering a novel therapeutic avenue. Overall, the antioxidant, anti-inflammatory, and insulin-mimicking properties of chlorophyll derivatives suggest a multifaceted approach to diabetes management. While promising, these findings require further clinical validation to establish effective therapeutic applications. Full article

Technological innovation in immersive virtual reality is fostering the development of novel psychotherapeutic interventions in mental health, particularly benefiting populations with limited access to specialized services. This pilot study explores the feasibility, tolerability, and therapeutic potential of an immersive virtual reality-based psychotherapeutic intervention for adolescents and young people with eating disorders in a rural setting. A quasi-experimental pre-test/post-test design was used, with a control group (n = 5) and an experimental group (n = 5), applying weekly immersive virtual reality sessions focused on body perception and food exposure. Preliminary results showed good acceptance and a low incidence of cybersickness. However, a reduction in anxiety levels was observed in the experimental group after immersive virtual reality exposure, particularly in trait anxiety, suggesting a potential effect of the intervention on emotional regulation. While these changes were not statistically significant, the direction and magnitude of the effect warrant further investigation. Changes in body mass index were also noted during the intervention. The remotely guided sessions, conducted via fifth-generation mobile network connectivity, demonstrated technical feasibility and encouraging clinical outcomes, even in geographically isolated or underserved areas. These findings support the use of immersive VR as a complementary tool in the early stages of treatment for eating disorders, contributing to improved body perception and emotional self-regulation. This work not only reinforces the applicability of immersive technology in real-world clinical practice but also opens new avenues for the development of personalized, accessible, and emotionally meaningful interventions in child and adolescent mental health. Full article

Background/Objectives: Psychotic disorders with childhood or adolescent onset pose major therapeutic challenges due to their complex etiology and variable treatment response. While pharmacogenetics and neuroimaging biomarkers have independently shown potential for guiding therapy, their combined utility remains underexplored. This study aimed to investigate whether integrating CYP2D6 pharmacogenetic profiles with structural neuroimaging findings can enhance personalized treatment and predict clinical outcomes in pediatric psychotic disorders. Methods: This prospective observational study included 63 children and adolescents (10–18 years) with DSM-5 diagnosed psychotic disorders. All patients underwent baseline MRI and standardized clinical assessments (PANSS, CGI, GAF). CYP2D6 genotyping was performed in 31 patients (49.2%), categorizing them as extensive (EMs) or intermediate metabolizers (IMs). Patients were treated with atypical antipsychotics and followed for 18 months. Outcomes included symptom severity, global functioning, and side-effect profiles. Results: EM patients demonstrated superior clinical improvement, as evidenced by a reduction in PANSS scores (from 118 to 40) and a corresponding increase in GAF scores (from 39 to 76), compared to the IM and non-tested groups. IM patients exhibited a higher prevalence of MRI abnormalities and slower response. Significant correlations emerged between CYP2D6 genotype, MRI findings, and treatment outcomes (p < 0.001). Combined biomarker profiles enhanced the prediction of therapeutic response and tolerability. Conclusions: Integrating CYP2D6 pharmacogenetic data with neuroimaging biomarkers provides valuable guidance for personalizing antipsychotic treatment in pediatric psychosis. This approach improves clinical outcomes and reduces adverse effects. Future research should further explore the integration of multimodal biomarkers in larger, longitudinal cohorts to optimize individualized psychiatric care for this vulnerable population. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) play a crucial role in trophoblast invasion, immune tolerance, and placental angiogenesis. To delineate their diagnostic and pathological significance, we critically evaluated the evidence for correlations between circulating or placental lncRNA profiles with pregnancy complications. Methods: Five databases were searched from inception through September 2024. We included only the studies that assessed the expression of the lncRNA-complicated pregnancies versus a control group. Results: Three single-center case–control studies fulfilled the inclusion criteria. Eight serum lncRNAs that present <20 weeks of gestation were elevated in subsequent pregnancy-induced hypertension or preeclampsia. The three lncRNAs in intrahepatic cholestasis of pregnancy were consistently decreased with a negative correlation with bile acids. Gestational diabetes was characterized by the elevation of MALAT1. Conclusions: Different lncRNAs showed a potential for use as non-invasive markers as well as for risk stratification for pregnancy-induced hypertension or preeclampsia, metabolic, and hepatobiliary pregnancy complications. There is a need for large-scale, multi-ethnic, prospective cohorts to include lncRNA as screening or therapeutic targeting in obstetric practice. Full article

Background: Artocarpus heterophyllus, familiar as jackfruit, is a tropical fruit highly valued not only for its nutritional content but also for its medicinal properties, including potential antidiabetic effects. Objectives: This study aimed to evaluate the insulinotropic, β-cell proliferative and anti-hyperlipidaemic properties of the ethanol extract of unripe Artocarpus heterophyllus (EEAH) in high-fat-fed (HFF) diet-induced obese mice. Method: We evaluated acute insulin secretion and β-cell proliferation in BRIN-BD11 cells, and assessed in vitro glucose diffusion and starch digestion. In vivo, acute and chronic studies in HFF induced obese mice measured glucose tolerance, body weight, food and fluid intake, and lipid profiles. A preliminary phytochemical screening was also performed. Results: In this study, EEAH exhibited significant antidiabetic activity through multiple mechanisms. EEAH enhanced glucose-stimulated insulin secretion in BRIN-BD11 β-cells via K_ATP channel modulation and cAMP-mediated pathways, with partial dependence on extracellular calcium, and it also promoted β-cell proliferation. In vitro assays revealed its ability to inhibit starch digestion and glucose diffusion, indicating delayed carbohydrate digestion and absorption. In high-fat-fed (HFF) obese mice, the acute and chronic oral administration of EEAH improved oral glucose tolerance, reduced fasting blood glucose, decreased body weight, and normalized food and fluid intake. Lipid profile analysis showed increased HDL and reduced total cholesterol, LDL, and triglycerides, while higher doses of EEAH also enhanced gut motility. Phytochemical screening revealed the presence of bioactive compounds such as alkaloids, tannins, flavonoids, saponins, steroids, and terpenoids, which are likely responsible for these therapeutic effects. Conclusion: These findings highlight EEAH as a promising natural candidate for adjunctive therapy in managing type 2 diabetes and associated metabolic disorders and emphasize the importance of future multi-omics studies to elucidate its molecular targets and pathways. Full article

Chimeric antigen receptor-engineered mesenchymal stem cells (CAR-MSCs) represent a novel and highly adaptable platform for the targeted treatment of inflammatory and autoimmune diseases. By integrating the inflammation-homing and immunomodulatory properties of mesenchymal stem cells (MSCs) with the antigen-specific recognition and activation potential of chimeric antigen receptors (CARs), CAR-MSCs enable site-specific delivery of therapeutic agents directly to inflamed or diseased tissues. This dual functionality enhances therapeutic precision while minimizing off-target effects and systemic toxicity. Recent preclinical studies have demonstrated the efficacy of CAR-MSCs in modulating pathogenic immune responses, reducing local inflammation, and promoting tissue repair in various disease models. CAR-MSCs have been engineered to recognize and interact with disease-specific antigens or inflammatory markers, allowing them to selectively suppress the activation and proliferation of autoreactive immune cells. This targeted immunosuppression offers a promising strategy for restoring immune tolerance without the risks associated with systemic immunosuppression. In this review, we provide a comprehensive overview of recent developments in CAR-MSC design, highlight mechanisms by which CARs enhance MSC functionality, and discuss key challenges, including safety, scalability, and regulatory considerations. Collectively, these emerging approaches hold substantial promise for reshaping future therapies for inflammatory and autoimmune diseases. Full article

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread immune dysregulation and the production of autoantibodies targeting nuclear, cytoplasmic, and cell surface antigens. These autoantibodies are central to disease pathogenesis, contribute to immune complex formation and organ damage, and serve as essential diagnostic and prognostic markers. Their detection supports disease classification, guides clinical decision-making, and offers insight into disease activity and therapeutic response. Traditional markers such as anti-nuclear antibodies (ANA), anti-dsDNA, and anti-Sm antibodies remain diagnostic cornerstones, but growing attention is given to anti-C1q, anti-nucleosome antibodies (ANuA), anti-ribosomal P, antiphospholipid, and anti-cytokine antibodies due to their associations with specific disease phenotypes and activity. These markers may reflect disease activity, specific organ involvement, or predict flares. The mechanisms underlying their persistence include B cell tolerance failure and long-lived plasma cell activity. The aim of this review is to summarize current knowledge on the major autoantibodies in SLE, appraise available detection methods, highlight their clinical utility and limitations and present evidence on the association between antibodies and disease phenotypes. Full article

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication. Full article

Samphire (Crithmum matrimum), a halophyte, thrives in saline environments due to its salt tolerance, which is partly attributed to miR167. However, the functional role of miR167 in human cells is unclear. This study explores the role of extracellular vesicles (EVs) derived from C. matrimum callus in skin regeneration, highlighting the potential of miRNA tae-miR167c-5p (miR167). Calluses were successfully induced and scaled for EV isolation. Characterization confirmed the presence of plant EV biomarkers and EVs with an average size of 136.6 nm. Cm-callus EVs enhanced wound healing and skin regeneration in human fibroblasts (HFF cells and CCD-986Sk cells) by modulating key genes, in particular, by downregulating MMP1 and upregulating COL1A1 and VEGFA. Small RNA sequencing revealed an enrichment of miR167 in Cm-callus EVs. Transfection with an miR167 mimic replicated these regenerative effects. Computational predictions identified PPP3R2, which is linked to the MAPK and NFAT pathways, as a potential target of miR167. This study demonstrates the efficacy of Cm-callus EVs and miR167 in promoting skin regeneration without cytotoxicity, providing insights into their therapeutic potential and calling for further experimental validation of target interactions. Full article

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that activates the nociceptin opioid peptide (NOP) receptor, a G protein-coupled receptor structurally similar to classical opioid receptors but with distinct pharmacological properties. Unlike μ-opioid receptor (MOR) agonists, NOP receptor agonists provide analgesia with a reduced risk of respiratory depression, tolerance, and dependence. This review synthesizes current evidence from molecular studies, animal models, and clinical trials to evaluate the therapeutic potential of the N/OFQ–NOP system in pain management and anesthesia. A literature review was conducted through a PubMed search of English language articles published between 2015 and 2025 using keywords such as “nociceptin,” “NOP receptor,” “bifunctional NOP/MOR agonists,” and “analgesia.” Primary research articles, clinical trials, and relevant reviews were selected based on their relevance to NOP pharmacology and therapeutic application. Additional references were included through citation tracking of seminal papers. Comparisons with classical opioid systems were made to highlight key pharmacological differences, and therapeutic developments involving NOP-selective and bifunctional NOP/MOR agonists were examined. In preclinical models of chronic inflammatory and neuropathic pain, NOP receptor ago-nists reduced hyperalgesia by 30–70%, while producing minimal effects in acute pain as-says. In healthy human volunteers, bifunctional NOP/MOR agonists such as cebrano-padol provided significant pain relief, achieving ≥30% reduction in pain intensity in up to 70% of subjects, with lower incidence of respiratory depression compared with morphine. Sunobinop, another NOP/MOR agent, demonstrated reduced next-day residual effects and a favorable cognitive safety profile. Clinical data also suggest that co-activation of NOP and MOR may attenuate opioid-induced hyperalgesia and tolerance. However, challenges remain, including variability in receptor signaling and limited human trial data. The N/OFQ–NOP receptor system represents a promising and potentially safer target for analgesia and perioperative care. Future efforts should focus on developing optimized NOP ligands, incorporating personalized approaches based on receptor variability, and advancing clinical trials to integrate these agents into multimodal pain management and enhanced recovery protocols. Full article