Search Results (260)

Triple-positive breast cancer (TPBC) is characterized by the overexpression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making its management a therapeutic challenge. Despite the availability of targeted therapies, patients with TPBC often experience recurrence and poor clinical outcomes due to intrinsic and acquired resistance mechanisms. This review summarizes current therapeutic approaches and their limitations, highlights the molecular mechanisms underlying treatment resistance and recurrence, and explores opportunities for drug repurposing, particularly involving multi-target inhibitors. Special emphasis is placed on the interaction between hormone receptor and growth factor receptor pathways, compensatory signaling mechanisms, and predictive biomarkers of recurrence. Furthermore, emerging strategies for drug repurposing using clinically available drugs are analyzed, including in silico, in vitro, and clinical trial evidence, along with their translational implications. Finally, we conclude that drug repurposing and multi-target approaches offer a compelling rationale for the development of novel therapeutic strategies in triple-positive breast cancer. However, their clinical utility remains to be validated through appropriately designed experimental and clinical studies before their impact on recurrence outcomes can be established. Full article

α-synuclein (α-syn) aggregation in dopaminergic neurons is a central event in Parkinson’s disease (PD) pathogenesis. Immunotherapeutic strategies targeting α-syn, including passive and active approaches, aim to inhibit aggregation, propagation, and toxicity of pathological species while promoting their clearance via immune mechanisms. This review summarizes α-syn directed immunotherapies evaluated in in silico, in vitro, and in vivo models, as well as early phase clinical trials, focusing on how epitope selection and antibody formats influence efficacy, safety, and target engagement. Data on monoclonal antibody, peptide, and protein-based vaccines, and structure-guided immunogens were analyzed, integrating behavioral, neuropathological, proteomic, and structural outcomes alongside biomarker development for α-syn species in cerebrospinal fluid and peripheral compartments. Clinical evidence indicates that several candidates induce sustained anti-α-syn antibody responses with acceptable safety profiles and signs of pharmacodynamic engagement, including reductions in free or oligomeric α-syn. However, consistent long-term clinical benefits remain unproven, highlighting the gap between preclinical success and disease modification in humans. Advances in structural biology and proteomics support rational epitope selection and improved immunogen design, reinforcing α-syn-targeted immunotherapy as a promising yet experimental strategy for PD, and highlighting the need for mechanistically oriented, biomarker-driven clinical trials initiated in well-characterized prodromal and early-stage cohorts. Full article

Virtual reality (VR)-based rehabilitation is an established modality for upper extremity motor recovery; however, existing systems frequently rely on fixed, random, or therapist-tuned target placement that disregards patient-specific motor capacity and population-level priors. This study proposes a cross-patient collaborative swarm intelligence framework that derives zone-based patient profiles from real VR trajectories and augments them with a similarity-weighted cohort prior distilled from clinically similar patients’ successful trajectory clouds and zone-transition graphs. A hybrid Ant Colony Optimization (ACO)–Particle Swarm Optimization (PSO) algorithm optimizes 12 targets per session across a 27-zone ($3\times 3\times 3$) workspace using a five-component fitness function encompassing reachability, zone balance, movement efficiency, heatmap-guided challenge coverage, and swarm-flow consistency. The framework was evaluated retrospectively on a single-center cohort of 36 post-stroke patients and 6373 sessions under a leakage-safe simulation protocol with 70/30 chronological splits; outcomes are model-based proxy success rates derived from each patient’s profile rather than directly observed task success. The hybrid strategy achieved a mean simulated success rate of 85.5% ± 5.5%, a 36.4% relative improvement over random placement (Wilcoxon $p<{10}^{-7}$, Cohen’s $d=4.91$); the leakage-safe split yielded 80.1% on the held-out segment versus 61.1% for random, with no statistically significant train–test gap ($p=0.470$). Ablation confirmed both PSO and ACO are individually necessary ($\mathsf{\Delta }\ge 2.7$ pp, $p<0.001$). Total session-start computation is 78 ms on standard CPU hardware. These findings constitute a proof-of-concept that collaborative personalized swarm optimization can substantially outperform heuristic target placement under in silico evaluation; clinical efficacy in terms of standardized motor outcome measures remains to be established in a prospective randomized controlled trial, and the findings should be replicated across centers, task modes, and a larger cohort before generalization. Full article

The global food system faces high pressure to sustain a growing population amid climate constraints and shifting consumer demands, making the traditional trial-and-error development methodologies inadequate. Artificial Intelligence (AI) has transitioned from a simple optimization tool into a structural enabler across the entire food chain. This review examines the integration and evolution of computational architectures in food technology between 2006 and 2026, tracing the paradigm shift from the early fuzzy logic and rule-based systems to modern deep learning and generative frameworks. This review highlights breakthroughs achieved over the last five years, demonstrating how Graph Neural Networks, Transformers, and Variational Autoencoders and other architectures are accelerating the in silico discovery of bioactive ingredients, predicting complex molecular flavors, and autonomously synthesizing optimal culinary formulations. The transition to Industry 5.0 is also explored, emphasizing the integration of collaborative robotics, process-level digital twins, and federated learning to enable autonomous manufacturing and privacy-preserving precision nutrition. Finally, this review addresses critical barriers to commercialization, including severe data fragmentation, the “Innovation Paradox” in fundamental academic research, and the urgent need for multidisciplinary teams capable of translating digital predictions into physically stable, strictly regulated food matrices. Full article

Background/Objectives: Liuwei Dihuang (LWDH) is a classical plant-derived herbal formula widely used for cognitive decline. This study aimed to evaluate its efficacy and safety in cognitive disorders and to explore its potential pharmacological mechanisms using network pharmacology. Methods: We searched 11 databases through November 2024 for randomized controlled trials comparing LWDH plus conventional therapy with conventional therapy alone in cognitive disorders. Meta-analysis was performed for clinical outcomes, and herb–compound–target and disease-target datasets were integrated to identify core molecular modules. Results: Twelve randomized controlled trials involving 1137 participants were included. Adjunctive LWDH was associated with improvements in Mini-Mental State Examination scores (MD = 2.34, 95% CI 0.88–3.79), activities of daily living, and quality of life. However, substantial heterogeneity and methodological limitations, including unclear randomization and blinding, were observed across studies, indicating a potential risk of bias. Fewer adverse events were reported in the LWDH plus conventional treatment group, although reporting quality was limited. The overall risk of bias was judged as “some concerns”. Network pharmacology analysis identified a broad set of overlapping genes between LWDH-associated targets and cognitive disorder-related genes, which were further refined through filtering procedures. Subsequent analyses suggested associations with pathways related to neurodegeneration, apoptosis, and central nervous system function; however, these findings are exploratory and based on in silico predictions. Conclusions: LWDH may be associated with potential adjunctive benefits in cognitive disorders. However, given the methodological limitations and clinical heterogeneity of the included studies, the findings should be interpreted with caution. The proposed pharmacological mechanisms are exploratory and require further validation. Well-designed randomized controlled trials are needed to establish more robust evidence. Full article

This systematic review was conducted and reported according to the PRISMA 2020 statement to synthesize evidence published between January 2020 and January 2025 on food-derived antihypertensive peptides, with emphasis on mechanisms of action, molecular stability, bioavailability, and functional food applications. PubMed, Scopus, and Web of Science were searched using combined terms related to bioactive or ACE-inhibitory peptides, stability or bioavailability, and alternative protein sources. Original peer-reviewed studies in English evaluating antihypertensive or ACE-inhibitory peptides from plant, marine, insect, fungal, dairy, or terrestrial animal matrices were considered eligible when they reported experimental evidence on activity, stability, transport, or in vivo efficacy. Three reviewers independently screened records and extracted data. A total of 177 studies were included. Plant and marine matrices accounted for approximately 72% of the evidence base, with a strong focus on low-molecular-weight peptides (<3 kDa) and multistage validation pipelines integrating in silico screening, in vitro enzymatic assays, Caco-2 transport models, ex vivo assays, and spontaneously hypertensive rat studies. Overall, the evidence supports the antihypertensive potential of selected food-derived peptides, particularly through ACE inhibition and related vascular mechanisms. Encapsulation and advanced delivery approaches improved peptide stability and bioavailability in several studies. Food-derived antihypertensive peptides represent promising candidates for functional foods and nutraceuticals; however, greater methodological standardization, formal risk-of-bias assessment in primary studies, and well-designed human trials remain necessary to strengthen translation into practice. Full article

Bovine babesiosis is a tick-borne disease that poses significant economic losses to global cattle production, and diverse vaccine platforms have been developed to combat it. This work critically evaluates global research on bovine babesiosis vaccines, integrating historical milestones with recent advances in antigen discovery and immunization approaches and assessing their protective efficacy through meta-analysis. Using comprehensive database searches, we identified 413 publications on bovine babesiosis vaccines, of which 168 met the inclusion criteria, spanning from 1960 to August 2025. Analysis revealed that B. bovis dominated the research output, followed by B. bigemina and B. divergens. Five key methodological approaches emerged: field trials, controlled experiments, immunogenicity assessments, in vitro assays, and in silico antigen analyses, with a notable shift toward immunogenicity and computational studies post-2000. Frequently studied antigens included RAP-1, MSA-2c, AMA-1, 11C5, and 12D3 (B. bovis); RAP-1 and GP45 (B. bigemina); and Bd37 (B. divergens). Geographically, research was concentrated in the United States, Australia, Argentina, Mexico, and France, which were identified as the top contributors in that order, primarily focusing on live and recombinant vaccines, with minimal African participation despite high cattle populations. Bibliometric analysis showed increasing publication output, with leading journals such as Veterinary Parasitology, Infection and Immunity, and Parasites & Vectors as the top three. Thematic evolution highlighted a transition from live vaccines to recombinant and multi-epitope strategies, with increasing emphasis on conserved antigens and novel platforms. However, more field evaluations are required to determine whether these new technologies can achieve protective efficacy comparable to that of live vaccines. This work underscores the need for sustained investment, intersectoral collaboration, and validation using standardized and comparable metrics in field trials to translate laboratory innovations into effective, safe, and globally accessible vaccines against bovine babesiosis. Full article

Helichrysum odoratissimum (L.) Less. is used as a traditional medicine in South Africa to treat tuberculosis, abdominal pains, heartburn, coughs, colds, female sterility, eczema and wounds. In Uganda, the leaves are used to treat dental/oral diseases. This review aims to provide detailed information on the traditional uses, essential oils, phytochemistry, in silico studies, and pharmacological studies and propose possible future research directions on this widely investigated species. The data was gathered from various online electronic databases such as Science Direct, Scopus, Google Scholar, Web of Science, SciFinder, Wiley Online, SpringerLink, and PubMed. Reports on the essential oil composition of H. odoratissimum showed the dominance of monoterpenoids and sesquiterpenoid compounds. Several studies also reported the isolation of the non-volatile compounds, which were mainly flavonoids and terpenes. The species has been reported to have pharmacological activities such as antimicrobial, antimycobacterial, antioxidant activity, antidiabetic, antiproliferative, anti-inflammatory activity and antityrosinase activity. The most important study on H. odoratissimum was a clinical trial in human participants in South Africa addressing its in vivo irritancy potential. However, further research on the clinical and scientific aspects is needed to justify some of its other medicinal uses. Full article

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy, has significantly improved clinical outcomes and has become a standard treatment strategy in both metastatic and high-risk early-stage disease. Nevertheless, treatment resistance and disease progression remain major clinical challenges. A deeper understanding of the structural characteristics of CDK4/6 and the molecular basis of inhibitor binding is therefore essential for improving therapeutic strategies and guiding the development of new targeted agents. This review provides an integrated overview of the structural features of CDK4/6 and their role in cell cycle regulation, summarizes the clinical development and major clinical trials of currently approved CDK4/6 inhibitors, and discusses recent computational studies investigating inhibitor binding and conformational dynamics. Particular attention is given to the application of in silico approaches, including molecular docking, molecular dynamics simulations, and binding free-energy calculations, which provide insights into mechanisms of therapy resistance and potential strategies to overcome them and support the identification and optimization of novel CDK4/6-targeted therapeutic candidates. By integrating structural, clinical, and computational perspectives, this review highlights current knowledge and emerging directions in CDK4/6 research that may advance the development of more personalized therapies for HR+/HER2− breast cancer, while accounting for both intrinsic and de novo resistance mechanisms. Full article

Background/Objectives: Obesity is a global health emergency with a complex etiology, in which monogenic forms, although rare, are significantly underdiagnosed. In our clinical setting, first-tier genetic screening panels targeting LEP, LEPR, BDNF, FTO, and MC4R often fail to identify a causative variant, leaving a significant diagnostic gap. This study aimed to assess the prevalence of variants in other critical genes of the melanocortin pathway to improve diagnostic yield. Methods: We analyzed 88 patients with non-syndromic obesity (Body Mass Index, BMI > 30 kg/m²), who were first screened for our standard obesity-related genes. In those testing negative, we expanded the analysis to include the MC3R and POMC genes. In silico bioinformatic tools were used to predict the functional consequences of identified variants on protein structure and splicing. Results: We found several variants in POMC, specifically within the regions coding for alpha-, beta-, and gamma-MSH peptides. A bioinformatic analysis suggests that these variants disrupt the melanocortin signaling pathway, likely contributing to an intermediate susceptibility phenotype in our adult cohort. Additionally, a clinical follow-up of a patient carrying the rare BDNF p.Thr2Ile variant revealed a suboptimal response to high-dose tirzepatide treatment (9% weight loss over 72 weeks), notably inferior to the average response observed in clinical trials. Conclusions: Our findings demonstrate that expanding first-level routine testing to include POMC and MC3R is essential to maximize diagnostic yield and improve clinical management. Full article

Agonists of the G protein-coupled receptor TGR5 have long been sought-after for their metabolic benefits. Intestinal TGR5 activation induces secretion of the antidiabetic hormone GLP-1, which can systemically improve diabetes phenotypes in multiple organs. However, no TGR5 agonist drug candidate has succeeded in clinical trials due to their low potency and unwanted side effects. A challenge in the field has been the development of TGR5 agonists that are non-toxic, long-acting, and have functional selectivity for G protein-biased agonism. In this study, we propose a systematic pipeline for engineering optimal TGR5 agonists with antidiabetic properties. This pipeline is interdisciplinary, combining in silico, in vitro, and in vivo assays to design and validate drug candidates. We identify 2 lead compounds that outline the necessary beneficial properties for a successful TGR5 agonist against diabetes. We uncover the molecular mechanisms that allow TGR5 agonists to induce the transcription of their target, TGR5, in intestinal enteroendocrine cells. Lastly, we investigate the molecular interactions of our lead candidates in the TGR5 binding pocket to identify optimal parameters for stability and biological activity. Our strategy for TGR5 agonist design and evaluation has the potential to guide the discovery process for targeted TGR5 therapeutics for metabolic diseases. Full article

Human rhinoviruses (HRVs) are the primary cause of the common cold, a highly contagious upper respiratory tract infection characterized by nasal congestion, sneezing, and sore throat. HRV replication depends on its 3C protease (HRV-3Cpro), a key enzyme that cleaves the viral polyprotein into functional proteins essential for viral maturation. Currently, no FDA-approved inhibitors specifically target HRV-3Cpro. While rupintrivir, a synthetic inhibitor, advanced to clinical trials, it ultimately failed due to limited efficacy. This study investigated the potential of Vitex negundo (or lagundi)—a medicinal plant traditionally used in the Philippines for treating colds and respiratory ailments—as a source of natural HRV-3Cpro inhibitors through in silico molecular docking and pharmacokinetic (ADMET) evaluation. Fifteen phytochemicals were screened, with five compounds exhibiting strong binding affinities exceeding that of the reference inhibitor rupintrivir (−6.1 kcal/mol): agnuside (−6.9 kcal/mol), luteolin 7-O-glucoside (−6.7 kcal/mol), 2′-p-hydroxybenzoyl mussaenosidic acid (−6.5 kcal/mol), 6′-(p-hydroxybenzoyl) mussaenosidic acid (−6.5 kcal/mol), and luteolin (−6.2 kcal/mol). Among these, luteolin emerged as a particularly promising lead compound, forming stable hydrogen bonding and hydrophobic interactions with HRV-3Cpro. Luteolin also demonstrates a favorable ADMET and safety profile, predicted to be non-mutagenic and non-hepatotoxic. These findings position luteolin as a potential plant-based HRV-3Cpro inhibitor, warranting further in vitro and in vivo studies to validate its antiviral efficacy and pharmacokinetic properties. Full article

Background/Objectives: This study aimed to evaluate the antidiabetic potential of five extracts/sub-extracts and five known cycloartane saponins [astragalosides (AST) I, II, III, IV, and cyclocanthoside E] from Astragalus noeanus (AN), using four specific diabetes-related molecular targets. Methods: Four diabetes-associated in vitro and in silico targets—protein tyrosine phosphatase 1B (PTP1B), dipeptidyl peptidase IV (DPP IV), α-amylase, and advanced glycation end-products (AGEs)—were employed to obtain comprehensive antidiabetic activity profiles. Additionally, the antioxidant and prebiotic capacities of the extracts/sub-extracts were assessed in vitro. A cycloartane saponin was isolated and structurally characterized. Quantitative analyses of total flavonoids, total saponins, and high-performance thin-layer chromatography (HPTLC) were performed to profile the chemical constituents of the plant material. Results: Among the extracts/sub-extracts, the aqueous extract (ANW) exhibited the highest inhibitory effects against all four diabetes-related targets, with inhibition percentages ranging from 83.70% to 93.49%. The methanol extract (ANM) demonstrated significant prebiotic activity comparable to standard controls on two Lactobacillus strains. The chloroform extract (ANC) showed the highest flavonoid content and exhibited the strongest antioxidant activity across all assays. ANM yielded the highest saponin content (3250 mg escin equivalent/g). HPTLC quantification revealed that AST IV was the predominant saponin in ANM (14.28 μg/mg) after cyclocanthoside E (117.27 ± 6.71 μg/mg). Among the saponins, AST IV displayed the most potent inhibition in diabetes-related enzyme assays, surpassing reference drugs acarbose and vildagliptin at equivalent concentrations. AST III also demonstrated considerable activity, ranking just below AST IV. Molecular docking studies identified AST II and AST III as the most promising ligands, exhibiting superior binding affinities and stronger hydrogen bonding and hydrophobic interactions with target proteins. Cyclocanthoside E was isolated from A. noeanus and evaluated for its antidiabetic effects for the first time, with its structure confirmed by NMR and LC-HRMS analyses. Conclusions: This study highlights Astragalus noeanus as a promising source for safe and effective antidiabetic agents. The potent activity of the aqueous extract, along with AST IV and AST III, warrants further investigation through clinical trials to validate their therapeutic potential in diabetes management. Full article

Background/Objectives: African swine fever virus (ASFV), the causative agent of African swine fever (ASF), is a highly contagious virus affecting both domestic and feral pig populations with mortality rates approaching 100% within one week of infection. Currently, there are limited treatments or vaccines available to control the disease. Although ASF is endemic in sub-Saharan Africa, the virus has also spread widely, reaching regions of the European Union, Russia, China, Southeast Asia, and, more recently, to the Dominican Republic and Haiti, bringing the threat closer to the United States (U.S.). ASF introduction to the U.S. would have severe consequences for swine producers and the national pork industry. Consequently, there is an urgent need to develop effective vaccine strategies to manage ongoing outbreaks abroad and mitigate the risk of future ASF incursions. Recent efforts have identified several ASFV epitopes and evaluated them in experimental vaccine trials. However, these vaccine candidates have elicited limited protective immune responses and have not demonstrated full protective efficacy. Methods: In this study, we employed in silico modeling and epitope prediction tools to design a synthetic multiepitope ASF protein incorporating key immunogenic regions of ASFV. The goal was to generate a single-antigen construct capable of inducing broad and robust immune responses when formulated with an established nanoparticle-based vaccine platform. The multiepitope ASF protein was subsequently expressed and entrapped into mannose-conjugated chitosan (M-CS) nanoparticles for vaccine formulation. The candidate vaccine, formulated with M-CS nanoparticle-entrapped adjuvant (ADU S100), was administered intramuscularly to pigs, and both T- and B-cell responses were assessed following the primary (DPV 22) and booster (DPV 42) doses. Results: Our M-CS ASF protein vaccine elicited antigen-specific T- and B-cell responses, both of which are recognized as central correlates of protection against ASFV. Conclusions: These promising preliminary immunological findings suggest that this nanoparticle vaccine has the potential to confer protection against ASFV challenge, a hypothesis that will be examined in future studies. Full article

Objectives: To compare artificial intelligence (AI) crown design with expert or non-AI computer-aided (CAD) design for single-unit tooth and implant-supported crowns across efficiency, marginal and internal fit, morphology and occlusion, and mechanical performance. Materials and Methods: This systematic review was conducted and reported in accordance with PRISMA 2020. PubMed MEDLINE, Scopus, Web of Science, IEEE Xplore, and Dentistry and Oral Sciences Source were searched from 2016 to 2025 with citation chasing. Eligible studies directly contrasted artificial intelligence-generated or artificial intelligence-assisted crown designs with human design in clinical, ex vivo, or in silico settings. Primary outcomes were design time, marginal and internal fit, morphology and occlusion, and mechanical performance. Risk of bias was assessed with ROBINS-I for non-randomized clinical studies, QUIN for bench studies, and PROBAST + AI for computational investigations, with TRIPOD + AI items mapped descriptively. Given heterogeneity in settings and endpoints, a narrative synthesis was used. Results: A total of 14 studies met inclusion criteria, including a clinical patient study, multiple ex vivo experiments, and in silico evaluations. Artificial intelligence design reduced design time by between 40% and 90% relative to expert computer-aided design or manual workflows. Marginal and internal fit for artificial intelligence and human designs were statistically equivalent in multiple comparisons. Mechanical performance matched technician designs in load-to-fracture testing, and modeling indicated stress distributions similar to natural teeth. Overall risk of bias was judged as some concerns across tiers. Conclusions: Artificial intelligence crown design delivers efficiency gains while showing short-term technical comparability across fit, morphology, occlusion, and strength for single-unit crowns in predominantly bench and in silico evidence, with limited patient-level feasibility data. Prospective clinical trials with standardized, preregistered endpoints are needed to confirm durability, generalizability, and patient-relevant outcomes, and to establish whether short-term technical advantages translate into clinical benefit. Full article