Search Results (7,086)

Schistosomiasis remains one of the most significant neglected tropical diseases (NTDs) worldwide, sustained by the complex biology of Schistosoma species and the host’s immunopathological responses to tissue-trapped eggs. Despite decades of reliance on praziquantel (PZQ) as the sole chemotherapeutic option, major limitations persist, including its lack of activity against juvenile worms, incomplete protection against reinfection, and concerns regarding emerging tolerance. These challenges, together with persistent hotspots of transmission and uneven global progress toward disease elimination, underscore the urgent need for alternative or complementary therapies. Plant-derived terpenes have emerged as promising antischistosomal candidates due to their structural diversity, broad-spectrum bioactivity, and favourable safety profiles. Evidence from in vitro and in vivo studies demonstrates that monoterpenes, sesquiterpenes, diterpenes, triterpenes, and triterpenoid saponins exert multimodal effects on Schistosoma, including tegumental disruption, interference with metabolic and redox pathways, inhibition of oviposition, and modulation of host immune and fibrotic responses. Advances in mechanistic studies, supported by omics and computational approaches, further highlight their potential as leads for drug development. Additionally, nano-enabled delivery systems offer strategies to overcome pharmacokinetic limitations and enhance therapeutic performance. This review integrates current knowledge on schistosome biology, treatment challenges, and the growing evidence supporting terpenoids as viable components of a diversified antischistosomal therapeutic arsenal. Full article

Manzamine-A (MA), a complex β-carboline alkaloid isolated from various genera of marine sponges, has attracted significant attention due to its unique structure and broad spectrum of potent biological activities. Despite the therapeutic potential, its development is limited by challenging natural supply and suboptimal pharmacokinetics. To address these barriers, innovative total syntheses of its intricate polycyclic framework have been achieved, enabling the development of semi-synthetic and synthetic analogues aimed at improving potency and drug-like properties. This review comprehensively outlines the progress in understanding this marine natural product, mainly focusing on its microbial origin, biological activities, pharmacokinetic behavior, chemical synthesis, and derivatives’ and analogues’ development. By integrating these diverse yet interconnected fields of research, this review bridges the critical gap between the natural product’s discovery and its clinical translation. Additionally, it also provides a roadmap for future drug development, highlighting how interdisciplinary collaboration can unlock the therapeutic potential of MA as a viable clinical candidate. Full article

The worldwide rise in antimicrobial resistance, along with the ongoing prevalence of cancer, underscores the pressing need for novel, safe, and multifunctional therapeutic candidates. Medicinal plants continue to serve as a valuable source of chemically diverse bioactive molecules that modulate multiple biological targets. In this investigation, the preliminary screening of the antibacterial and anticancer activities of an ethanolic extract of Alhagi maurorum (A. maurorum) was comprehensively evaluated using integrated chemical characterization, in vitro bioassays, and in silico approaches. A liquid chromatography–mass spectrometry (LC-MS) analysis demonstrated a rich phytochemical profile including glucosinolates, phenolic acids, gallotannins, fatty acids, alkaloids, carotenoid derivatives, and 2-hexyldecanoic acid-associated constituents. Antibacterial efficacy was assessed by disk diffusion and minimum inhibitory concentration (MIC) testing against Escherichia coli (E. coli ) and Bacillus cereus (B. cereus), with the extract producing inhibition zones similar to those observed with streptomycin. Anticancer effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays with MCF-7 breast carcinoma cells and Hs27 normal fibroblasts over 24, 48, and 72 h., revealing a time-dependent, selective decrease in malignant cell viability with relatively limited toxicity towards normal cells. Induction of apoptosis was further verified by propidium iodide (PI) staining. A molecular docking analysis highlighted 2-hexyldecanoic acid as the principal active compound, with a strong binding affinity for critical bacterial targets (GyrA, GyrB, and RpoB). In silico toxicity and ADME (absorption, distribution, metabolism, and excretion) assessments indicated favorable drug-like properties, good gastrointestinal uptake, and acceptable safety profiles. Altogether, these results provide combined experimental and computational support for A. maurorum as a promising source of dual-purpose antibacterial and anticancer agents and lay a mechanistic foundation for subsequent preclinical studies. Full article

Background/Objectives: Rotenone (RT)-induced neurotoxicity is widely used to model Parkinsonism-like nigrostriatal injury and recapitulates several PD-relevant pathological features, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and dopaminergic neurochemical disturbance. Loganin (LG), an iridoid glycoside isolated from Cornus officinalis, has been reported to possess antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties. However, its protective effects in a unilateral stereotaxic RT lesion model have not been fully elucidated. This study aimed to investigate the neuroprotective potential of LG against RT-induced Parkinsonism-like pathology in rats and to explore the possible involvement of antioxidant-related signaling mechanisms. Methods: Adult male Wistar rats were randomly assigned to twelve experimental groups (n = 8/group), including control, sham, RT, sham + LG, RT + LG, RT + trigonelline (TG) + LG, and RT + selegiline (SL). RT was stereotaxically injected once into the right substantia nigra pars compacta (SNpc) on Day 0 to induce unilateral nigrostriatal injury. LG was administered orally once daily from Day 1 to Day 21 at doses of 3, 10, and 30 mg/kg. TG was given intraperitoneally 30 min before LG treatment, while SL served as a reference antiparkinsonian drug. Behavioral assessments and biochemical analyses were conducted to evaluate motor dysfunction, oxidative and nitrosative stress, endogenous antioxidant status, mitochondrial dysfunction, inflammatory and apoptotic responses in the SNpc, and striatal catecholamine disturbances. Results: RT lesioning produced significant motor deficits, oxidative and nitrosative stress, depletion of endogenous antioxidant defenses, mitochondrial dysfunction, inflammatory and apoptotic activation in the SNpc, and abnormalities in striatal catecholamine levels. LG treatment significantly attenuated these pathological changes, with more pronounced protective effects observed at 10 and 30 mg/kg. Co-administration of TG partially weakened the beneficial effects of LG, suggesting the possible involvement of antioxidant defense-related signaling while not providing direct proof of a single pathway. SL also ameliorated RT-induced behavioral and biochemical abnormalities. Conclusions: These findings suggest that LG confers multi-target neuroprotective effects against RT-induced Parkinsonism-like features in rats. The protective actions of LG were associated with attenuation of oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and catecholaminergic disturbances. Because the pathway analysis remains pharmacological and indirect, additional studies using direct molecular validation are warranted before LG can be considered a disease-modifying candidate for PD-related neurodegeneration. Full article

Computer-aided drug discovery increasingly depends on virtual-screening workflows that remain reliable under severe class imbalance, chemical redundancy and early-recognition constraints. In this study, we developed a leakage-aware prioritization workflow for two cancer-relevant targets, pyruvate kinase M2 (PKM2) and mitogen-activated protein kinase 1 (MAPK1/ERK2), using the LIT-PCBA benchmark. The workflow combines canonical-SMILES curation, duplicate and label-conflict auditing, scaffold-aware validation, a non-learning nearest-active Tanimoto baseline, imbalance-aware machine-learning models, repeated-seed robustness analysis, isotonic probability calibration, ensemble-disagreement estimation, absorption, distribution, metabolism, excretion and toxicity (ADMET)-aware triage, molecular docking, and residue-level contact analysis. Benchmark enrichment is interpreted alongside calibration, ADMET filtering, docking and residue-contact evidence, rather than as a standalone discovery claim. PKM2 emerged as the clearer machine-learning case, with scaffold-aware tree models improving early recognition beyond the nearest-active similarity baseline and yielding top-ranked candidates supported by calibrated activity scores, ADMET profiles, docking scores, and residue-contact fingerprints. MAPK1 provided a biologically relevant contrast target, where ligand-neighborhood similarity remained competitive and downstream structural triage became more decisive than ligand-based ranking alone. These results support a conservative drug-discovery workflow in which leakage-aware benchmarking, calibration, uncertainty, and molecular-level triage remain visible throughout candidate prioritization. Full article

Osteoarthritis (OA) remains an alarming therapeutic challenge, as conventional intra-articular interventions primarily address symptomatic relief without halting progressive cartilage and bone degeneration. In this study, we investigated the disease-modifying potential of Cyclo(His-Pro) (CHP) in a monosodium iodoacetate (MIA)-induced OA rat model. Intra-articular CHP yielded significant clinical improvements, reducing joint edema and reversing OA-induced mechanical and thermal hypersensitivity, as evidenced by lifting behavior, rotarod performance, and hot plate tests. Beyond analgesia, micro-computed tomography (micro-CT) analysis showed that CHP preserved subchondral bone architecture, restoring trabecular volume and thickness and reducing serum C-terminal telopeptide of type II collagen (CTX-2), indicative of suppressed cartilage degradation. At the molecular level, CHP reprogrammed the joint microenvironment by suppressing Cox2, Adamts5, Mmp13, Mmp1, Mmp2, and Timp2 expression and decreasing systemic prostaglandin E2 (PGE₂) levels. Moreover, CHP showed efficacy comparable to Conjuran, a polynucleotide-based mechanical supportive agent, while additionally targeting COX-2/PGE₂-driven inflammatory cascades and cartilage catabolic pathways. Collectively, these findings indicate that intra-articular CHP confers combined analgesic, chondroprotective, and osteoprotective effects, supporting its potential as a promising disease-modifying osteoarthritis drug candidate. Full article

Current treatments for choroidal neovascularization (CNV) and its associated subretinal fibrosis (SRF), major causes of vision loss, are limited by the need for frequent intravitreal injections and the emergence of drug resistance. This study evaluated the safety and efficacy of the intravitreal administration of engineered humanized anti-vascular endothelial growth factor Nanobodies, including a wild-type Nanobody (WHNb) and two mutated variants (MHNb136 and MHNb256), in a rat model of laser-induced CNV and associated SRF. Safety was assessed through in vivo electrophysiological and histopathological analyses following intravitreal injection of Nanobodies at doses of 12.5, 25, 50, and 100 µg. Efficacy was evaluated in rat models of laser-induced CNV and SRF using double immunohistochemistry for isolectin B4 and anti-collagen type I on sclerochoroidal flat mounts. Mean CNV and SRF areas in Nanobody-treated groups were compared with those in bevacizumab-treated and sham control groups. None of the Nanobodies showed retinal toxicity in safety assessments. Compared with bevacizumab, MHNb136 and MHNb256 reduced the CNV area by 1.72-fold and 1.8-fold, respectively (both p < 0.0001), whereas WHNb showed an effect nearly identical to that of bevacizumab. In addition, 12.5 µg MHNb136 and 100 µg MHNb256 reduced the SRF area by 1.3-fold (p = 0.047) and 1.6-fold (p = 0.0007), respectively, relative to bevacizumab. For CNV reduction, 12.5 µg MHNb136 was comparable to 25 µg MHNb256; both outperformed bevacizumab. For SRF reduction, 12.5 µg MHNb136 was more effective than bevacizumab and comparable to 100 µg MHNb256. These findings suggest that 12.5 µg MHNb136 may represent a cost-effective bioengineered Nanobody candidate for future clinical studies. Full article

The anti-apoptotic Bcl-2 protein family, frequently upregulated in a wide range of cancers, contributes to tumor persistence and therapeutic resistance, making these proteins attractive targets for structure-based inhibitor development. Betulinic acid-derived hybrids represent promising scaffolds for apoptosis-oriented anticancer drug discovery due to their reported antiproliferative and pro-apoptotic properties. In this study, a virtual library of 152 betulinic acid-derived hybrids was screened against Bcl-2 and Bcl-XL. This molecular docking study using AutoDock Vina identified BA–Celastrol and BA–Proanthocyanidin B2 as top-ranked ligands, with docking scores ranging from −13.00 to −8.7 kcal/mol. Both compounds were further analyzed by 100 ns molecular dynamics simulation runs, which revealed system-dependent ligand behavior rather than uniform preservation of the initial docked pose across all complexes. BA–Celastrol showed a more compact internal ligand conformation in the ligand property and RMSF analyses, whereas BA–Proanthocyanidin B2 showed greater intramolecular flexibility and conformational adaptability. Ligand displacement relative to the protein differed between targets, with BA–Proanthocyanidin B2 showing a more retained profile in the Bcl-XL model and BA–Celastrol showing more moderate positional behavior in the Bcl-2 model. MM-GBSA calculations resulted in free energy values ranging from −4.95 to −31.82 kcal/mol, indicating protein-dependent energetic differences across the investigated systems. Based on docking performance, molecular dynamics stability, and energetic data, both hybrids were ranked as computational candidates for further exploration against Bcl-2 family targets. The present findings, although confined to computational analysis, underscore the need for prioritizing betulinic acid-based hybrids for subsequent experimental evaluation. Full article

Hypoxia is a prevalent pathophysiological condition. Prolonged exposure to hypobaric hypoxia can lead to maladaptation, increasing the risk of chronic hypoxic diseases such as high-altitude polycythemia (HAPC). Dauricine, an alkaloid derived from the root of Menispermum dauricum DC, has been demonstrated to possess anti-hypoxic properties; however, its underlying molecular mechanisms remain elusive. In this study, a potential multi-target anti-hypoxic mechanism of dauricine was proposed and computationally evaluated using an integrated approach combining network pharmacology, molecular docking, and molecular dynamics simulations. Common targets between dauricine and hypoxia-related genes were identified through network pharmacology screening. A protein–protein interaction (PPI) network was constructed to identify core targets, followed by Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Molecular docking was subsequently employed to evaluate the binding affinities between dauricine and the candidate core targets, while molecular dynamics simulations were performed to assess the dynamic stability of the resulting complexes. Additionally, the drug-likeness and safety profiles of dauricine were assessed. The results suggest that dauricine may exert its anti-hypoxic effects by modulating candidate core targets, including ESR1, PIK3CA, and MTOR, and by acting on key signaling pathways such as PI3K-Akt, MAPK, and mTOR. This study provides a theoretical foundation for the further investigation of dauricine as a multi-target candidate for intervention in hypoxia and establishes a bioinformatics basis for subsequent experimental validation. Full article

Resistance formation and considerable toxicities limit the application of currently available antiparasitic drugs. Thus, new drug candidates are required. Piperlongumine-based cinnamides are promising antiparasitic compounds. In this study, new synthetic cinnamide derivatives with variable halogen substituents (F, Cl, and Br) were prepared and analyzed. They were tested for activity against Toxoplasma gondii and Leishmania major parasites. Considerable activities against T. gondii parasites were observed for certain chloro- and bromo-substituted cinnamides (IC₅₀ = 1.88–2.72 µM), while activities against L. major were less pronounced. Structure–activity relationships were investigated, which revealed notable relations of anti-toxoplasmal activity with the nature of the applied halogen substituents and a preference for chloro- and bromo-substituents in active compounds. In contrast to piperlongumine, the new active compounds have no methoxy substituents anymore and appear to be suitable for advanced antiparasitic studies. Successful docking of selected derivatives into the colchicine binding site of tubulin provided a strong hint at a possible mode of action for these cinnamides (S-scores of −6.075 and −5.993 kcal/mol). In addition, considerable drug-like properties were determined by ADME-T calculations. Thus, in conclusion, new halo-substituted cinnamides with promising activity against Toxoplasma gondii were identified. The selectivity for Toxoplasma parasites can lead to better drugs for the therapy of toxoplasmosis. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation, playing a critical role in the pathogenesis of various cardiomyopathies, including hypertrophic, dilated, diabetic, ischemic, doxorubicin-induced, and septic cardiomyopathy, as well as myocardial ischemia–reperfusion injury. This article provides a comprehensive narrative review of the molecular mechanisms of ferroptosis—centered on dysregulation of the GPX4/System Xc⁻ axis, iron metabolism, and lipid metabolism—and its role in cardiovascular diseases, with a specific focus on the cardioprotective effects of Traditional Chinese Medicine (TCM). Through a systematic analysis of recent literature, we highlight active components (e.g., baicalin, ginsenoside Rg3, resveratrol, tanshinone IIA), compound formulations (e.g., Qishen Granule, Zhilong Huoxue Tongyu Capsule), and electroacupuncture therapy, which exert effects via multi-target regulation of ferroptosis-related pathways such as Nrf2/HO-1/GPX4, p53/SLC7A11, and PI3K/AKT. Evidence indicates that TCM interventions effectively alleviate cardiomyocyte ferroptosis by activating the Nrf2 antioxidant pathway to upregulate GPX4/SLC7A11, modulating iron metabolism to reduce labile iron pools, and inhibiting ACSL4/ALOX15-mediated lipid peroxidation, with these effects validated in diverse cardiovascular disease models showing improved cardiac function. Targeting ferroptosis offers a novel therapeutic strategy for cardiovascular diseases, and TCM—with its synergistic multi-component, multi-target, multi-pathway advantages—holds significant potential in this context. Future research should prioritize elucidating complex network mechanisms and advancing clinical translation via high-quality studies to provide new theoretical foundations and drug candidates for cardiovascular disease management. Full article

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) remains an obstacle in colorectal cancer (CRC) therapy, but the upstream mechanisms enabling adaptive survival remain unclear. Angiomotin (AMOT), a Hippo-YAP regulator, is expressed as two major isoforms, p130 and p80, but the contribution of isoform-specific AMOT regulation to chemoresistance is unknown. RNA-seq of OXA-resistant cells identified AMOT as a candidate determinant, and its isoform-specific regulation and functional relevance were then examined in OXA- and 5-FU-resistant CRC sublines. AMOT-p80 was preferentially upregulated, whereas AMOT-p130 remained largely unchanged. Common AMOT pre-mRNA was elevated, whereas p130-specific pre-mRNA was unchanged, consistent with preferential transcriptional activation favoring the p80 isoform. Functionally, AMOT depletion minimally affected basal viability but significantly sensitized resistant cells to 5-FU or OXA, with increased apoptotic responses. AMOT silencing reduced nuclear YAP and lowered c-Myc and Cyclin D1 protein levels, whereas AMOT-p80 re-expression restored nuclear YAP, with recovery of c-Myc/Cyclin D1 levels and drug tolerance. YAP knockdown attenuated these outputs and blunted the additional effect of AMOT depletion. AMOT-p80 overexpression in parental cells increased c-Myc/Cyclin D1 protein levels and enhanced tolerance to 5-FU and OXA. These findings suggest that preferential AMOT-p80 upregulation is linked to YAP-associated chemoresistant phenotypes in CRC cells. Full article

Cannabidiol (CBD), a major non-psychoactive phytocannabinoid, has attracted considerable attention owing to its broad therapeutic potential. Its anti-inflammatory, antimicrobial, and antitumor properties make it a promising candidate for the treatment of mucosa-associated diseases. However, the clinical translation of CBD is significantly hindered by its unfavorable physicochemical properties, particularly high lipophilicity and poor aqueous solubility, which result in low bioavailability. To overcome these limitations, the rational selection of administration routes in combination with advanced drug delivery systems tailored to disease pathophysiology is essential. Such strategies are critical for improving the stability of CBD, enhancing mucosal permeation, and enabling controlled and targeted release at diseased sites. Nevertheless, a systematic review focusing on these aspects is still lacking. This review first summarizes the relationship between CBD and the mucosal endocannabinoid system, together with its pharmacological effects. It then discusses the therapeutic potential of CBD in mucosal disorders of the digestive and respiratory systems. In addition, current administration routes and advanced delivery systems for CBD are reviewed to provide insights for future research and clinical translation. Finally, the remaining challenges associated with the clinical application of CBD and future development directions are discussed. Full article

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article