Search Results (868)

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future. Full article

Mesenchymal stromal cells (MSCs) are intensively investigated in oncology owing to their intrinsic tumor-homing ability and capacity to deliver therapeutic agents directly into the tumor microenvironment (TME). Recent advances in genetic engineering have enabled precise modification of MSCs, allowing controlled expression of therapeutic genes and other cargo delivery, thus improving targeting efficiency. As cellular carriers, MSCs have been engineered to transport oncolytic viruses, suicide genes in gene-directed enzyme prodrug therapy (GDEPT), multifunctional nanoparticles, and therapeutic factors such as IFN-β or TRAIL, while engineered MSC-derived extracellular vesicles (MSC-EVs) offer a promising cell-free alternative. These strategies increase intratumoral drug concentration, amplify bystander effects, and synergize with standard therapies while reducing systemic toxicity. Conversely, accumulating evidence highlights the tumor-promoting properties of MSCs: once recruited by inflammatory and hypoxic cues, they remodel the tumor microenvironment by stimulating angiogenesis, suppressing immune responses, differentiating into cancer-associated fibroblasts, and promoting epithelial-to-mesenchymal transition (EMT), ultimately enhancing invasion, metastasis, and therapy resistance. This duality has sparked both enthusiasm and concern in the oncology field. The present review outlines the paradoxical role of MSCs in oncology—ranging from their potential to promote tumor growth to their emerging utility as vehicles for targeted drug delivery. By highlighting both therapeutic opportunities and biological risks, we aim to provide a balanced perspective on how MSC-based strategies might be refined, optimized, and safely integrated into future cancer therapies. Full article

Background: The combination of hepatic arterial infusion chemotherapy (HAIC) with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represents a potential therapeutic strategy for advanced hepatocellular carcinoma (HCC). This study aimed to compare the efficacy and safety of triple therapies combining HAIC with ICIs and either bevacizumab or tyrosine kinase inhibitors (TKIs) in these patients. Methods: This retrospective single-center study enrolled 65 consecutive patients with advanced HCC who received HAIC combined with ICIs plus either bevacizumab (bevacizumab group, n = 31) or TKIs (TKIs group, n = 34) between June 2021 and June 2023. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety profiles. Results: The bevacizumab group demonstrated significantly prolonged median PFS (10.9 vs. 7.4 months, p = 0.001) and higher ORR (83.9% vs. 61.8%, p = 0.047) compared with the TKIs group. DOR was longer in the bevacizumab group (7.9 vs. 5.3 months, p = 0.008). Median overall survival (OS) was not reached in the bevacizumab group versus 22.6 months in the TKIs group. Grade 3–4 adverse events occurred in 67.7% of the bevacizumab group and 73.5% of the TKIs group, with distinct toxicity profiles. Gastrointestinal hemorrhage (45.2%) and gastric ulcer (22.6%) predominated in the bevacizumab group, whereas the TKIs group exhibited more hepatic enzyme elevations (aspartate aminotransferase, 67.6%; alanine aminotransferase, 61.8%), proteinuria (29.4%), diarrhea (26.5%), hand-foot syndrome (20.6%), and reactive cutaneous capillary endothelial proliferation (11.8%). Conclusions: Bevacizumab-containing triplet therapy was associated with improved tumor control and delayed progression compared to TKIs-based regimens in advanced HCC. The higher bleeding risk in the bevacizumab group highlights the necessity of standardized baseline evaluation and adequate preventive measures. Full article

SARS-CoV-2, the virus responsible for coronavirus disease COVID-19, is a highly transmissible pathogen that has caused substantial global morbidity and mortality. The ongoing COVID-19 pandemic caused by this virus has had a significant impact on public health and the global economy. One approach to combating COVID-19 is the development of broadly neutralizing antibodies for prevention and treatment. In this work, we performed an in silico ligand-based screening of the PDB database to search for unique anti-SARS-CoV-2 motifs. The collected data were organized and presented in a classified SARS-CoV-2 Ligands Database, categorized based on the number of ligands and structural components of the spike glycoprotein. The database contains 1797 entries related to the structures of the spike glycoprotein (UniProt ID: P0DTC2), including both full-length molecules and their fragments (individual domains and their combinations) with various ligands, such as angiotensin-converting enzyme II and antibodies. The database’s capabilities allow users to explore various datasets according to the research objectives. To search for motifs in the receptor-binding domain (RBD) most frequently involved in antibody binding sites, antibodies were classified into four classes according to their location on the RBD; for each class, special binding motifs are revealed. In the RBD binding sites, specific tyrosine-containing motifs were found. Data obtained may help speed up the creation of new antibody-based therapies, and guide the rational design of next-generation vaccines. Full article

Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include (1) enhanced activity of anticancer drug efflux mechanisms (MRP1); (2) suppressed activity of anticancer drug influx mechanisms (ENT-1); (3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); (4) influence of the tumor microenvironment (GRP94), etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan–Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group, n = 1, 5%: AKR1B1(+)/AKR1B10(−), 5-year overall survival (OS), 100%; Intermediate prognosis-1 group, n = 9, 5%: AKR1B1(−)/AKR1B10(−) plus MRP1(−), 5-year OS, 68%; Intermediate-2 prognosis group, n = 6.3%: AKR1B1(−)/AKR1B10(−) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; and Poor prognosis group, n = 3, 16%: AKR1B1(−)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n = 2. Conclusions: The Urayasu classification for ALL is considered reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy. Full article

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants—astaxanthin and Garcinia indica (kokum)—in modulating hepatic redox status, lysosomal function, and metabolic gene expression in a murine model of diet-induced NAFLD. A total of 120 male Swiss Webster mice were allocated into control and steatotic groups, followed by a 90-day supplementation period with astaxanthin, kokum, or their combination. Liver tissue was collected post-supplementation for biochemical, antioxidant, and qRT-PCR analyses. Outcomes included lysosomal enzymes activities, superoxide dismutase (SOD), GSH, vitamin C, total polyphenols, DPPH radical-scavenging activity, and total antioxidant capacity (TAC). NAFLD induced marked oxidative stress, lysosomal overactivation, and alteration of antioxidant-related gene expression. Combined supplementation restored GSH, enhanced TAC, reduced lysosomal stress markers, and significantly upregulated nuclear factor erythroid 2-related factor 2 (Nfe2l2) while downregulating fatty acid synthase (FASN) and partially rescuing lipoprotein lipase (LpL). Correlation analyses revealed strong associations between antioxidant capacity, lysosomal function, and transcriptional regulation, supporting the therapeutic relevance of combined antioxidant therapy for concurrent redox and lysosomal dysregulation in NAFLD. These findings underscore the therapeutic potential of targeting redox and cellular degradation pathways with antioxidant-based interventions to re-establish hepatic metabolic balance in NAFLD and related disorders. Full article

Background/Objectives: Diabetes mellitus is a serious global disease characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. It represents a major health concern affecting millions of people worldwide. This condition can lead to severe complications significantly affecting patients’ quality of life. Due to the limitations and side effects of current therapies, the search for safer and more effective antidiabetic agents, particularly from natural sources, has gained considerable attention. This study investigates the antidiabetic potential of seaweed-derived compounds through structure-based virtual screening targeting α-glucosidase. Methods: A library of compounds derived from the Seaweed Metabolite Database was subjected to a hierarchical molecular docking protocol against α-glucosidase. Extra Precision (XP) docking was employed to identify the top-ranked ligands based on their binding affinities. Drug-likeness was assessed according to Lipinski’s Rule of Five, followed by pharmacokinetic and toxicity predictions to evaluate ADMET properties. Density Functional Theory (DFT) calculations were performed to analyze the electronic properties and chemical reactivity of the selected compounds. Furthermore, molecular dynamics simulations were carried out to examine the stability and dynamic behavior of the ligand–enzyme complexes. Results: Following XP docking and ADMET prediction, four promising compounds were selected: Colensolide A, Rhodomelol, Callophycin A, and 7-(2,3-dibromo-4,5-dihydroxybenzyl)-3,7-dihydro-1H-purine-2,6-dione. Molecular dynamics simulations further confirmed the structural stability and strong binding interactions of these compounds within the α-glucosidase active site. Conclusions: This investigation demonstrated the important role of seaweed-derived compounds in inhibiting α-glucosidase activity. Further experimental validation is warranted to confirm their biological activity and therapeutic potential. Full article

Overactivation of the renin–angiotensin–aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor–neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1–7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited. Full article

Background: Obesity is increasingly recognized as a complex condition characterized by the convergence of metabolic dysregulation and psychological vulnerability. Insulin resistance (IR) has been identified as a biological bridge linking metabolic imbalance with affective symptoms such as anxiety, depression, and disordered eating behaviors. Methods: Fifteen obese adults (mean age = 25 ± 4.3 years) were evaluated through clinical examination, anthropometric assessment (BMI), biochemical assays (fasting insulin, AST, ALT), and standardized psychological assessments (STAI, BDI-II). In parallel, a rapid systematic review (2019–2025) synthesized evidence on the association between IR, affective dysregulation, binge eating disorder (BED), and the clinical role of insulin-sensitizing or incretin-based therapies. Results: Participants exhibited marked hyperinsulinemia (M = 79 μU/mL, SD = 6.61) and elevated anxiety (STAI-Trait = 54.22 ± 22.4) and depression scores (BDI-II = 21.6 ± 7.5). Liver enzymes were within normal limits. Literature synthesis confirmed consistent associations between IR, mood symptoms, and BED, associated with biological processes including inflammation, HPA axis hyperactivity, and dopaminergic imbalance. Integrated treatment approaches combining cognitive-behavioral therapy, medical nutrition therapy, and insulin-sensitizing agents (metformin, GLP-1RA, and GLP-1/GIP RA) were supported as effective and safe options. Conclusions: The coexistence of insulin resistance and emotional dysregulation in obesity is consistent with the hypothesis of a bidirectional metabolic–emotional axis. Early, integrated interventions addressing both metabolic and psychological domains may improve clinical outcomes and reduce progression toward chronic metabolic and psychiatric comorbidity. Full article

Hepatic abscesses are uncommon in dogs and typically develop secondary to biliary tract disease or ascending bacterial infections. Although congenital extrahepatic portosystemic shunt (EHPSS) is known to impair hepatic perfusion and immune clearance, its potential role in predisposing geriatric dogs to hepatic abscess formation has not been previously reported. This case report describes the diagnostic approach, therapeutic decision-making, and clinical outcome of a geriatric dog in which a multidrug-resistant hepatic abscess occurred in association with congenital EHPSS, and to propose a pathophysiologic link between chronic portal hypoperfusion and intrahepatic infection. An 11-year-old neutered male Maltese dog with a known EHPSS presented with acute anorexia and lethargy. Diagnostic imaging revealed a hepatic abscess adjacent to the gallbladder, and cytology confirmed a septic process. Despite targeted meropenem therapy based on antimicrobial susceptibility testing, the abscess failed to regress and C-reactive protein levels continued to rise. Concern for persistent biliary contamination and impaired hepatic immune clearance led to surgical intervention. A combined procedure—partial hepatic lobectomy, cholecystectomy, and shunt attenuation—was performed. Postoperative hypotension was managed successfully with vasopressors and transfusion. The patient recovered uneventfully, and at four-month follow-up, hepatic enzyme activities normalized and liver size increased. These findings highlight the need to evaluate hepatic infections in dogs with EHPSS as a potential consequence of impaired hepatic immune clearance rather than an incidental finding. Full article

Boron is a trace element with multifaceted chemical and biological properties that underpin its emerging relevance in human health and medicinal chemistry. Although present in organisms at very low concentrations, boron participates in key physiological processes, including mineral metabolism, bone homeostasis, hormonal regulation, immune modulation, and redox balance. Its unique electronic structure—characterized by electron deficiency and the ability to form multi-center bonds—gives rise to diverse allotropic, cluster, and coordination chemistries, enabling the formation of biologically active complexes and therapeutic agents. Dietary boron, derived mainly from plant-based foods, is efficiently absorbed and predominantly excreted by the kidneys, showing a strong correlation between intake and urinary levels. Current evidence suggests beneficial effects of boron on bone mineral density, cognitive function, inflammation, antioxidant defenses, and metabolic regulation, although the precise molecular mechanisms remain partially understood. In medicinal chemistry, a broad spectrum of boron-containing compounds—including borates, boronic acids, boronated amino acids, carboranes, and metallacarboranes—has gained clinical and preclinical importance. These compounds serve as enzyme inhibitors, antimicrobial and anti-inflammatory agents, metabolic modulators, and critical boron carriers in boron neutron capture therapy (BNCT), which leverages the neutron-capture properties of ¹⁰B for targeted cancer treatment. Advances in synthesis, functionalization, and nanocarrier design have expanded the therapeutic potential of boron-based molecules. Ongoing research aims to optimize their selectivity, biodistribution, safety, and diagnostic integration. Overall, boron represents a versatile and rapidly developing component of modern biomedical science, with promising implications for oncology, infectious diseases, metabolic disorders, and precision medicine. Full article

Introduction: Severe acute pancreatitis (SAP) is a critical condition that affects 20–30% of people with acute pancreatitis (AP). Prompt detection and accurate classification are crucial to direct prompt interventions, increase resource allocation, and improve patient outcomes. Current scoring systems, while beneficial, frequently face challenges related to speed, complexity, and early predictive accuracy. Method: We developed and validated an effective six-parameter risk assessment scale for AP, incorporating pancreatic-specific biomarkers (trypsinogen-activating peptide [TAP], trypsin-2), systemic inflammation markers (C-reactive protein), pancreatic enzyme concentrations, blood glucose, and patient age. The study cohort included 104 patient samples. Reliability was assessed using Cronbach’s alpha and Spearman–Brown coefficients, factorial validity was determined by principal component analysis, and predictive validity was analyzed using logistic regression and receiver operating characteristic (ROC) analysis. Biotemporal changes at 24 and 48 h were assessed to classify risk scoring. Results: The scale demonstrated satisfactory internal consistency (Cronbach’s alpha = 0.72) and a distinct structure with two factors representing local pancreatic damage and systemic inflammation, explaining 65% of the variability. Logistic regression established predictive validity for serious outcomes, with TAP and trypsin-2 showing significant correlations. ROC analysis demonstrated remarkable discriminative capacity (AUC = 0.85), showing a sensitivity of 82.4% and a specificity of 76.8%. Assessment of temporal biomarkers showed a reduction in TAP, signifying resolution of the initial enzymatic activation, while trypsin-2 levels continued to increase, indicating persistent damage to the pancreatic tissue. Patients were classified into low-, moderate- and high-risk groups, facilitating practical clinical decision-making. Discussion and Conclusions: This six-parameter risk score provides a rapid, biologically based, and clinically useful method for early detection of patients at risk for SAP. Combining indicators of local pancreatic involvement with systemic inflammation allows for prompt triage, improves the allocation of intensive therapy, and supports informed prognostic conversations. Full article

Background: Antiretroviral therapy (ART) has transformed HIV into a chronic manageable condition, yet metabolic toxicities including pancreatic enzyme alterations remain concerns. While older ART regimens have been associated with hyperamylasemia, the impact of integrase strand transfer inhibitor (INSTI)-based therapies on serum amylase levels has not been specifically examined. Purpose: This study aimed to compare longitudinal patterns of serum amylase levels between people living with HIV receiving INSTI-based versus NNRTI/PI-based ART regimens. Methods: This retrospective observational study analyzed 99 HIV-positive patients at Kaplan Medical Centre, Israel (2002–2023). Participants received either INSTI-based (n = 49) or NNRTI/PI-based (n = 50) regimens for ≥24 months. Serum amylase, viral load, CD4 counts, and metabolic parameters were measured at baseline, one year, and two years. Repeated-measures ANOVA assessed longitudinal changes. Results: NNRTI/PI-treated patients maintained significantly higher mean amylase levels throughout follow-up (baseline: 122.9 ± 42.1 U/L; two years: 129.6 ± 38.0 U/L) compared to INSTI-treated patients (baseline: 78.7 ± 32.3 U/L; two years: 68.4 ± 23.4 U/L; p < 0.0001 at all timepoints). A significant linear time-by-group interaction (p = 0.037) demonstrated divergent trajectories. No clinical pancreatitis was observed in either treatment group during the follow-up period, and all observed variations in serum amylase were biochemical and asymptomatic. While these findings are reassuring regarding acute pancreatic toxicity, the clinical significance of chronic subclinical enzyme elevations remains uncertain. Conclusion: INSTI-based antiretroviral regimens suggest a favorable pancreatic and metabolic safety profile compared with NNRTI/PI-based therapies. Full article

Metabolic reprogramming is a fundamental hallmark and a key driver of malignant tumors. By reshaping glucose, lipid, and amino acid metabolism, as well as mitochondrial function, it sustains the abnormal proliferation and survival of tumor cells, making it a crucial target for anti-tumor therapy. Curcumin, a natural multi-target compound, exhibits unique advantages in intervening in tumor metabolic reprogramming due to its low toxicity and broad-spectrum regulatory properties. In various tumor models, it can directly modulate the activity of key glycolytic enzymes, such as hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2, as well as transporters like glucose transporter 1. Furthermore, it inhibits the expression of proteins related to lipid metabolism, including fatty acid synthase and stearoyl-CoA desaturase 1, while also intervening in amino acid metabolic networks, such as glutaminase and branched-chain amino acid transaminase. Additionally, curcumin targets mitochondrial function and reactive oxygen species balance, creating multi-dimensional intervention effects through various pathways, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis and modulating gut microbiota metabolism. Its mechanism of action involves the synergistic regulation of key signaling pathways, including phosphoinositide 3-kinase/Akt, NF-κB, AMP-activated protein kinase, and hypoxia-inducible factor-1alpha. Furthermore, its specific effect profile demonstrates significant dependency on cell type and tumor model. This article systematically reviews the regulatory effects of curcumin on these critical metabolic processes and pathways in tumor metabolic reprogramming, revealing its molecular mechanisms in disrupting tumor growth and progression by targeting energy and biosynthetic metabolism. These findings provide a significant theoretical foundation and a preclinical research perspective for the development of natural antitumor drugs based on metabolic regulation, as well as for optimizing combination therapy strategies. Full article

Celiac disease (CeD) is a chronic, immune-mediated enteropathy triggered by dietary gluten in genetically susceptible individuals, with environmental and epigenetic factors also contributing to its pathogenesis. Once considered a rare pediatric malabsorptive disorder, CeD is now recognized as a systemic condition that can manifest with both gastrointestinal and extraintestinal symptoms across the lifespan. Although strict adherence to a gluten-free diet (GFD) remains the cornerstone of treatment, up to 30–40% of patients experience persistent symptoms and/or ongoing mucosal injury despite reported compliance. This therapeutic gap, combined with advances in molecular understanding of disease mechanisms, has driven the development of novel strategies targeting key pathogenic pathways. Intraluminal interventions include gluten-degrading enzymes and gluten-sequestering agents, while other approaches target tissue transglutaminase 2, induce antigen-specific immune tolerance, or modulate cytokine-driven inflammation, with particular emphasis on interleukin-15 (IL-15) signaling. Additional strategies aim to inhibit lymphocyte trafficking to the intestinal mucosa and enhance intestinal barrier function through zonulin modulation. Adjunctive therapies under investigation include nutraceuticals, microbiota-targeted interventions, and vaccine-based approaches. More recently, advanced experimental and computational platforms, such as human intestinal organoids, organ-on-chip systems, and machine learning–driven analytics, are being leveraged in efforts to accelerate translational research and support the rational design of precision medicine approaches. This narrative review synthesizes current evidence for therapies beyond the GFD, examines challenges in clinical implementation, and discusses how technological innovations may reshape the future therapeutic landscape of CeD. Full article