Search Results (3,628)

Traditional drug discovery processes are typically expensive, time-consuming, and have a very high failure rate. Artificial intelligence (AI) is currently reshaping this field in unprecedented ways, promising to significantly improve the efficiency and success rate of drug development. This article systematically compares and analyzes the application of AI for two major drug types: small molecule vs. peptide drugs. It explores their applications in several key stages of drug development, including virtual screening, lead compound optimization, de novo drug design, ADMET (absorption, distribution, metabolism, excretion, and toxicity) property prediction, and chemical synthesis planning. While both drug types benefit from AI-driven approaches, fundamental differences exist in molecular representation, data availability, key challenges, and model adaptability. For small molecule drugs, AI focuses on drug efficacy, synthetic feasibility, and accurate structure–activity relationship prediction. In contrast, for peptide drugs, AI faces more unique biological challenges, such as inherent flexibility, complex biological functions, stability, and immunogenicity. Finally, this article provides a forward-looking perspective on the future of AI-driven drug discovery, highlighting the immense potential of basic models, multimodal integrated systems, and autonomous discovery platforms, which will collectively drive the next wave of precision drug development. Full article

HIV latency, driven by a complex interplay of host factors, remains a key barrier to viral clearance. Current latency-reversing agents (LRAs) demonstrate limited efficacy and specificity, and none have been approved for clinical use. Although natural products have shown promise as LRAs, the therapeutic potential of fungal metabolites remains underexplored. Candida albicans, a prevalent human commensal and opportunistic pathogen, produces diverse secondary metabolites that can influence host pathways, affecting latency dynamics. This study aimed to investigate the latency-modulating potential of secondary metabolites of C. albicans using an integrative network pharmacology and computational pipeline. C. albicans secondary metabolites were retrieved from the literature, screened for drug-likeness, and mapped to human targets and biological pathways annotated in HIV latency. Key metabolites, hub genes, and pathways were systematically characterized through network and computational analyses. Six drug-like candidates, identified from 185 absorption, distribution, metabolism, excretion, and toxicity (ADMET)-screened metabolites, collectively mapped to 369 human genes with a 6.5% overlap in HIV latency (176 shared and 20 hub genes). These overlapping genes were significantly enriched for signal transduction, membrane localization, and adaptive responses to chemical stimuli. Kyoto encyclopedia of genes and genomes (KEGG) enrichment revealed oncogenic diseases (non-small cell lung, pancreatic, and prostate cancers) and latency-associated cascades, including PD-L1/PD-1, HIF-1, Ras, PI3K-Akt, calcium, and cAMP signaling. Six hub targets (MAPK1, PIK3CA, MAPK3, EGFR, MTOR, and AKT1) were consistently annotated within the top 30 KEGG pathways and displayed strong binding affinities for MET 15 and MET 119. Molecular dynamics (MD) simulations confirmed favorable binding free energies (BFEs) and stable conformational dynamics for the top-ranked metabolite MET 15. C. albicans secondary metabolites preferentially target oncogenic signaling networks central to HIV latency maintenance, notably PI3K/AKT/MTOR and MAPK/ERK, which regulate cell survival, metabolic homeostasis, and viral transcriptional repression. MET 15 is a top-ranked candidate metabolite for HIV latency-reversing therapeutics and warrants experimental validation in established latency models. Full article

Background/Objectives: To investigate whether chronic cosmetics use near or directly on the eyelid margin contributes to tear film instability and meibomian gland dysfunction. Methods: Subjects were enrolled in one of three groups: those who rarely wear makeup (No-M), those who wear it frequently but only outside the eyelid margin (Min-M), and those who wear it frequently and directly on the eyelid margin (W-M). Subjects were assessed for dry eye signs and symptoms by a masked examiner. Lipid layer thickness (LLT), tear meniscus height, meibomian gland excreta grade, number of glands secreting, corneal and conjunctival staining and tear breakup time were assessed. Results: 10 No-M, 18 Min-M, and 21 W-M subjects completed the study. Average fluorescein breakup time was 4.6 s in each group (p = 0.839, 1-way ANOVA). There were higher scores (worse findings) in the marginal eyeliner sample for symptoms (modified Schein, OSDI, SPEED), Oxford and total NEI staining and lower lid meibomian secretions. The W-M group demonstrated a statistically significant increase in the meibomian gland excreta grade (a worsening) compared to the No-M group (mean grades 1.2 and 0.55 respectively; Tukey test, adjusted p < 0.05, 95% CI 0.055–1.187). LLT, tear breakup time, eyelid marginal signs, and meibomian gland dropout had no differences among groups. Conclusions: Eyeliner wear both outside and on the eyelid margin demonstrated increased ocular staining and decreased gland excretion quality, compared to non-makeup users. The meibomian gland excreta decrement may lead to worsening meibomian gland function and potentially glandular atrophy over time. Full article

Long-term monitoring is essential for understanding how recurring disturbances, such as hurricanes and coral bleaching, affect reef fish communities and ecosystem processes. This study evaluates temporal trends (2013–2025) in fish assemblage composition, functional diversity, and nutrient excretion proxies (C, N, and P) across three reef sites on San Andrés Island in the Colombian Caribbean. Our results reveal significant shifts in community structure following major disturbances in 2020 (Hurricanes Eta, Iota) and 2023 (mass bleaching event). Taxonomic and functional richness (TRich, FRich) fluctuated throughout the study period, whereas functional divergence (FDiv) declined earlier (2016), highlighting site-specific differences. A trait-based nutrient-excretion proxy (NPC composite score) identified key species that maintain nutrient cycling. Despite recent coral bleaching, certain sites exhibited functional resilience, sustained by the persistence of high-performing nutrient providing species. However, the overall disconnect between taxonomic recovery and functional stability suggests that ecosystem-level processes remain vulnerable, even when species richness appears to recover. This highlights the importance of integrating functional traits and nutrient recycling proxies into monitoring programs to better predict long-term variability in San Andrés Island reefs under a changing climate. Our findings provide a framework for prioritizing management efforts in the Seaflower Biosphere Reserve with emphasis on maintaining ecosystem services. Full article

Saline–alkaline water constitutes a vital strategic non-traditional fishery resource in China, characterized by high pH values, elevated carbonate alkalinity, and complex ionic compositions. These extreme environmental conditions impose significant stress on aquatic animals, mainly by inducing ionic toxicity and disrupting acid–base regulatory mechanisms. Such disruptions subsequently lead to osmotic imbalance, metabolic dysregulation, and immunosuppression, thus restricting the survival and growth of aquatic species in aquaculture systems. Consequently, the sustainable development of the saline–alkaline aquaculture is imperative for enhancing production efficiency and promoting the utilization of marginal land and water resources. This review comprehensively summarizes the current status of saline–alkaline aquaculture and highlights the stress-inducing impacts of salinity, alkalinity, and specific ionic ratios on teleost fishes and crustaceans. It further explores key adaptive mechanisms, including osmoregulatory and ionoregulatory strategies, bioenergetic trade-offs related to oxygen consumption and ammonia excretion, coordinated antioxidant and innate immune responses, as well as recent findings from multi-omics research. This review aims to offer a scientific foundation for the selection and breeding of saline–alkaline-tolerant strains, the precise regulation of aquaculture water environments, and the development of ecological aquaculture models in saline–alkaline regions, thereby facilitating the sustainable utilization of saline–alkaline land and water resources. Full article

siRNA, as a precise, specific, and highly effective gene-silencing therapy, has been extensively studied. Before reaching tumor cell targets, siRNA formulations must overcome multiple extracellular barriers, including clearance from the bloodstream, membrane impermeability, capture by the mononuclear phagocyte system (MPS), rapid renal excretion, endosomal escape, and precise recognition of target cells. These challenges limit siRNA’s clinical application. Consequently, various modifications have been applied to siRNA to enhance transfection efficiency, while researchers continue to pursue improved siRNA-targeting delivery systems. Nanotechnology offers a rational technical approach to address siRNA delivery. Nanoparticles can increase transfection efficiency while exhibiting lower cytotoxicity and reduced off-target effects. Various matrices have been employed to construct nanoparticles for targeted therapeutic delivery. This review briefly discusses siRNA nanoparticle delivery strategies, illustrates examples of various siRNA nanodelivery systems, such as lipid nanoparticles, polymeric siRNA nanoparticles, inorganic nanoparticles, hybrid nanoparticles, and conjugate-siRNA delivery systems, and introduces clinical trials of siRNA-loaded nanoparticles for cancer treatment, which can provide valuable references for further research and clinical application of siRNA nanoparticle delivery systems. Full article

Hyaluronic acid (HA) is widely used in medical, cosmetic, and nutraceutical applications, yet the systemic fate of orally administered HA, particularly non-animal forms, remains poorly characterised. This study investigates the stability, absorption, metabolism, and biological effects of a novel fungal-derived HA extracted from Tremella fuciformis using a sequential in vitro multi-barrier model simulating human physiological compartments, including gastric, intestinal, hepatic, renal, chondrocyte, and keratinocyte environments. Across the gastrointestinal stages, fungal-derived HA demonstrated high structural stability, maintained molecular weight, and exerted superior antioxidant and anti-inflammatory activity compared with sodium hyaluronate. It efficiently crossed the intestinal barrier without increasing hyaluronidase activity, indicating protection from premature enzymatic degradation. In hepatic cells, fungal-derived HA exhibited reduced intracellular uptake and greater extracellular persistence, suggesting lower first-pass metabolism and suggesting improved persistence under in vitro conditions. At peripheral targets, it increased the cluster of differentiation 44 (CD44) expression and HA internalisation in chondrocytes and keratinocytes, supporting anti-inflammatory and pro-regenerative effects. Renal assessments revealed minimal excretion and no cytotoxicity, supporting potential systemic availability. Overall, these results provide the first integrated in vitro evidence describing the absorption, distribution, metabolism, and excretion process of fungal-derived HA. This supports the conclusion that this form of HA is stable, biocompatible, and bioactive with therapeutic potential for joint and skin health, as suggested by the in vitro models. Full article

Background: Enterococcus faecalis is a major cause of complicated urinary tract infections (UTIs), characterized by intrinsic resistance and pronounced biofilm formation. Nitroxoline (NTX), a metal-chelating uroantiseptic, accumulates in urine and exhibits antibiofilm activity. Hydroquinone (HQ), the active urinary metabolite of arbutin-containing herbal preparations, is also excreted into urine and may contribute to antimicrobial activity in situ. This study investigated the antimicrobial and antibiofilm effects of NTX and HQ, individually and in combination, against uropathogenic E. faecalis isolates. Methods: Minimum inhibitory (MIC), bactericidal (MBC), and anti-adhesion (MAC) concentrations were determined using broth microdilution. Interaction was assessed by the checkerboard method and expressed as the fractional inhibitory concentration index (FICI). Biofilm inhibition was quantified by colony-forming unit (CFU) enumeration following exposure to subinhibitory concentrations. Ultrastructural alterations of E. faecalis following exposure to NTX and HQ were examined by transmission electron microscopy (TEM). Results: NTX demonstrated MIC values ranging from 0.002–0.016 mg/mL (MIC50/MIC90: 0.004/0.008 mg/mL), while HQ exhibited MIC values of 0.78–1.56 mg/mL (MIC50/MIC90: 0.78/1.56 mg/mL). Synergistic interactions (FICI ≤ 0.5) were observed in selected isolates, with up to eightfold and sixteenfold reductions in NTX and HQ concentrations, respectively. Additive effects predominated in the remaining isolates without antagonism. The combination achieved 3–5 log₁₀ reductions in adherent bacterial counts compared to untreated controls and up to 4 log₁₀ reductions compared to single-agent exposure. In several strains, complete inhibition of adhesion was observed. TEM analysis revealed marked envelope disruption, cytoplasmic condensation, and structural collapse following combined treatment. Conclusions: Given that both NTX and HQ are active within the urinary environment, their combination may represent a pharmacologically relevant strategy targeting both bacterial growth and early biofilm establishment in enterococcal UTIs. These findings support further in vivo and pharmacokinetic investigations to evaluate the clinical applicability of this combination. Full article

Beach sands may harbor human pathogens and antibiotic resistance genes, prompting the proposal of low-dose quicklime (CaO; 1–3% w/w) as a remediation strategy to improve microbiological quality in highly contaminated areas. After application, CaO is converted into calcium carbonate (CaCO₃), yet the ecological effects of this residual compound on benthic fauna remain poorly understood. This study evaluated the short-term impact of CaCO₃-enriched sediment (3% w/w) on the Manila clam, Ruditapes philippinarum, under controlled mesocosm conditions. Adult clams were exposed for one week, and survival, burrowing behavior, feeding- and metabolism-related parameters (clearance, ingestion, absorption efficiency and rate, ammonia excretion), and oxidative stress (malondialdehyde, MDA) were assessed using a hierarchical design, with a tank as the experimental unit. No significant differences were detected between control and CaCO₃-enriched treatments for any measured endpoint. Survival remained high, functional responses showed overlapping ranges, and MDA levels did not differ significantly between groups. Although limited to short-term exposure and a single concentration, these findings suggest that residual CaCO₃ derived from quicklime application did not induce detectable adverse effects in adult R. philippinarum under the tested conditions. Further long-term and multi-species studies are needed to confirm ecological safety. Full article

Nitrogen (N) utilization by ruminants affects production efficiency, feeding costs, and environmental N losses in confined production systems. Palm kernel cake (PKC), an abundant agro-industrial by-product in tropical regions, has been increasingly used in ruminant diets, although its effects on nitrogen dynamics remain inconsistent. In this study, we systematically reviewed and meta-analyzed the effects of dietary PKC inclusion on N intake, excretion, absorption, and retention in confined cattle, goats, and sheep. Eleven studies published between 1995 and 2025, comprising 44 treatment means and 322 experimental units, were included in the meta-analysis. A random-effects model was applied, and the ruminant species was used as a moderator, defining a significant level at 0.05. Overall, the pooled effects indicated that species significantly influenced N intake (p < 0.01) and N absorption (p < 0.01). Species also showed a tendency to influence N in feces (p = 0.062) and manure N (p = 0.073), whereas N in urine (p = 0.194) and N retention (p = 0.170) were not affected. In subgroup analysis, PKC inclusion reduced N intake in goats (Standardized Mean Difference (SMD)) = −0.792; 95% CI (Confidence Interval) = −1.428 to −0.155; I² (Heterogeneity) = 76.7%) and cattle (SMD = −1.576; 95% CI = −2.250 to −0.902; I² = 65.7%), N in urine in cattle (SMD = −0.478; 95% CI = −0.806 to −0.150; I² = 0%), N absorption (SMD = −0.873; 95% CI = −1.517 to −0.229; I² = 77.1%), and N retention (SMD = −0.875; 95% CI = −1.338 to −0.412; I² = 64.1%) in goats. Conversely, PKC had a positive effect on N absorption in sheep (SMD = 1.137; 95% CI = 0.016 to 2.258; I² = 72.4%). Overall, this study highlights the species-dependent responses of N dynamics to PKC inclusion, emphasizing the importance of species-specific dietary strategies when using agro-industrial by-products to improve nitrogen utilization efficiency and potentially mitigate N losses in confined ruminant systems. Full article

Barbatic acid (BA), a phenolic compound isolated from Pyrrosia petiolosa (Christ) Ching, was investigated for its diuretic effects and underlying mechanisms following oral administration in rats using UPLC-MS/MS-based metabolomics and pharmacokinetics. In a water-loaded rat model, BA (28 and 56 mg/kg) significantly increased 6 h urine output (1.5-fold vs. model, p < 0.01) and promoted urinary excretion of Na⁺, K⁺, and Cl⁻ (1.1–1.4-fold, p < 0.05–0.01). Metabolomic analysis revealed that BA modulates amino acid metabolism pathways, including cysteine and methionine metabolism (impact score 0.16), tyrosine metabolism (impact score 0.10), histidine metabolism (impact score 0.12), taurine hypotaurine metabolismand (impact score 0.43), and phenylalanine metabolism (impact score 0.14). Pharmacokinetic evaluation showed dose-dependent half-lives of 5.88, 5.23, and 2.61 h at 28, 56, and 112 mg/kg, respectively, with Cmax and AUC increasing proportionally with dose (r² > 0.99). These findings provide the first integrated evidence supporting BA as a potential novel diuretic agent with a mechanism involving amino acid metabolism regulation. Full article

Environmental scientists are increasingly monitoring therapeutic drugs and their metabolites in water systems, requiring knowledge of human drug metabolism and excretion. Many published studies, however, rely on data from small-scale human metabolism trials, typically involving around six (healthy, young, male) volunteers. Their generalizability to real-world drug users may be limited, potentially biasing environmental monitoring efforts. Here, we leveraged untargeted LC-SWATH/MS pharmacometabolomics data from 283 potential living kidney donors and 688 kidney transplant recipients to characterize the 24 h urinary excretion profiles of two widely used diuretics frequently monitored in wastewater, hydrochlorothiazide and furosemide. Both are expected to be excreted largely unchanged, which our analyses confirmed. For hydrochlorothiazide, however, we also identified (using reference standards) the previously underreported transformation products chlorothiazide and salamide. These findings highlight the relevance and capability of using untargeted metabolomics data from human excreta to provide insights from large, real-world cohorts into which chemicals enter wastewater systems, with both drugs serving as exemplary case studies for analogous analyses of other drugs. In particular, the qualitative information obtained (e.g., accurate mass, retention time, fragment spectra) may inform targeted biomonitoring and highlight cases where consensus-based estimates of excreted drug or metabolite fractions are overestimated. Full article

In search of a non-surgical alternative for male animal sterilization, this study investigated the use of gold-coated maghemite nanoparticles (γ-Fe₂O₃@Au) functionalized with citrate to produce testicular photohyperthermia (PHT). Wistar rats received an intratesticular injection of the fluid containing the nanoparticles (150 µL/testicle) followed by testicular irradiation with an LED light (808 nm). Testicular temperature was maintained at ~45 °C for 15 min. The results demonstrated a significant reduction in testicular volume and weight and sperm motility and normal morphology in PHT-treated animals, together with histopathological degeneration of seminiferous tubules. No treatment-related side effects or signs of systemic toxicity were observed. The biodistribution of the gold (Au) and iron (Fe) from the nanoparticles showed that the testes were the primary site of nanoparticle accumulation until day 56 post-treatment with possible renal excretion of Au. These findings support the prospect of testicular PHT mediated by γ-Fe₂O₃@Au nanoparticles as a neutering method for male animals. Full article

Diabetic kidney disease (DKD) persists as the leading cause of chronic kidney disease (CKD) and often leads to end-stage renal disease (ESRD). Worldwide, 30–50% of patients with diabetes are affected by DKD, while DKD contributes to about half of ESRD. Previously, DKD had been defined based on overt proteinuria—that is, a urine albumin-to-creatinine ratio (UACR) above 300 mg/g—after a stage of microalbuminuria (UACR 30–300 mg/g). However, emerging data suggest that a significant number of patients develop renal functional decline without albuminuria, suggesting that DKD can occur in the absence of protein excretion. This phenotype of normoalbuminuric or non-proteinuric DKD (NA-DKD or NP-DKD) is emerging as an important clinical entity. It is characterized by a gradual decline in renal function, commonly with an annual reduction in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m² or an eGFR < 60 mL/min/1.73 m², while the UACR remains < 30 mg/g. Growing rates of NP-DKD expose limitations inherent in traditional models of DKD pathogenesis and underscore the need for diagnostic and therapeutic paradigms that are not reliant on albuminuria-only criteria. Here, we present a comprehensive review of the NP-DKD to guide a more inclusive model of DKD pathogenesis, its diagnosis, and therapy. Full article

The present work set out to examine the antidiabetic capacity of Abelmoschus esculentus (okra) fruit extract through a combined experimental and computational framework. Enzyme inhibition assays were carried out against four metabolic targets, and IC₅₀ values stood at 7.66 ± 0.31 mg/mL for alpha-glucosidase, 5.21 ± 0.18 mg/mL for alpha-amylase, 2.11 ± 0.15 microg/mL for DPP-4, and 9.17 ± 0.54 mg/mL for pancreatic lipase. The extract showed moderate-to-weak activity relative to standard inhibitors acarbose, sitagliptin, and orlistat. Sixteen drug-like phytochemicals obtained from the IMPPAT 2.0 database were docked against the crystal structures of all four tested enzymes (PDB: 8CB1, 5E0F, 2ONC, 1LPB). Alpha-Carotene, Vitamin E, and Spiraeoside emerged as the top-ranked compounds across all targets, with alpha-Carotene recording the strongest binding affinity of −11.1 kcal/mol against pancreatic lipase, which was 4.2 kcal/mol more negative than the positive control orlistat (−6.9 kcal/mol). PLIP-based interaction profiling mapped out hydrogen bonds, hydrophobic contacts, pi-stacking, and salt bridges at the atomic level. Absorption, distribution, metabolism, and excretion (ADME) and toxicity screening of alpha-Carotene returned a favourable pharmacokinetic profile with predicted LD₅₀ of 1510 mg/kg (Class 4) and inactivity across most toxicity endpoints. A 100 ns molecular dynamics simulation of the pancreatic lipase-alpha–Carotene complex, alongside the orlistat control, showed stable root mean square deviation (RMSD) (0.15–0.22 nm), a consistent Rg (~1.97 nm), and sustained hydrogen bonding throughout the trajectory. Free-energy landscape analysis revealed a well-defined single energy basin for alpha-Carotene, suggesting a thermodynamically stable binding conformation. These findings lay the molecular basis for using okra phytochemicals as adjunctive agents in diabetes management, though in vivo validation remains necessary. Full article