Search Results (4,409)

Heavy metal pollution has become a critical concern in agricultural ecosystems driven by a complex matrix of industrial practices, high-input fertilizers, metal-based agrochemicals, and wastewater irrigation. While the previous literature typically highlights general physiological symptoms of heavy metal stress, this review provides a novel, comprehensive framework that bridges three independent pillars: specific industrial applications dictating elemental pathway, localizes active root-zone transport kinetics, and an engineering-based evaluation of emerging remediation strategies. We systematically synthesized literature from 2000 to 2026 across major databases (WoS, PubMed and Google Scholar), applying strict inclusion criteria based on data validation, experimental reproducibility, and mechanistic depth. We examine the geochemical behavior, cellular toxicity, and plant resilience mechanics of seven priority elements like cadmium, lead, arsenic, aluminum, mercury, chromium and molybdenum. Rather than merely reiterating superficial visual damage like chlorosis or stunted growth, we focus on physiological and molecular root causes of phytotoxicity, including the structural hijacking of essential nutrient networks, intracellular reduction cascades and organelle-specific oxidative disruption. This review also discussed the discovery of specialized, energy-dependent eukaryotic transport mechanisms like ABC transporters and a comparative operational blueprint evaluating physical–chemical conventional remediation techniques against advanced in situ and ex situ biotechnological approaches, including biochar assistance, microbial engineering, rhizosphere synergies, and engineered nanomaterials. By systematically linking industrial source dynamics with cellular toxicological mechanisms and field-scale engineering feasibility, this review establishes an actionable roadmap for future genetic, agronomic, and management interventions aimed at securing global food. Full article

β-hydroxy-β-methylbutyrate (HMB), a bioactive metabolite of leucine, is widely recognized for its anabolic and anti-catabolic effects in skeletal muscle. However, the molecular mechanisms underlying these effects, particularly in relation to circadian regulation, remain incompletely understood. Here, we investigated the impact of HMB on dexamethasone-induced muscle atrophy in C2C12 myotubes, with a focus on anabolic signaling and circadian clock regulation. C2C12 myotubes were treated with HMB or HMB after dexamethasone-induced atrophy. HMB treatment significantly improved cell viability, surface area and fiber diameter by reducing expression of CBL-B, MuRF1 and Atrogin1, key mediators of muscle proteolysis, and increasing myogenin expression compared with atrophic conditions. While HMB did not activate AKT or mTOR, it robustly increased phosphorylation of P70S6K and S6 through a phospholipase D (PLD)-dependent mechanism. HMB restored disrupted circadian clock gene expression induced by dexamethasone, including normalization of expression patterns. HMB also enhanced circadian rhythmic amplitude and advanced phase timing, indicating improved clock robustness. These findings identify circadian regulation as a novel target of HMB action and demonstrate that HMB preserves muscle homeostasis through coordinated modulation of anabolic signaling and intrinsic circadian machinery. This study provides mechanistic insight into how HMB protects against muscle atrophy and highlights circadian regulation as an important contributor to skeletal muscle health. Full article

Chronic inflammation and the associated dysbiosis of the gut microbiota are increasingly recognized as key factors contributing to the development of inflammatory bowel disease (IBD) and colorectal cancer (CRC). The diet–gut microbiota–immune system–cancer axis is considered a key regulator of these processes. Among the bioactive compounds found in the diet, ellagitannins have garnered significant scientific interest due to their conversion by the gut microbiota into biologically active metabolites known as urolithins. Urolithin A (UroA), one of the best characterized compounds, exhibits broad anti-inflammatory, antioxidant, immunomodulatory, and anticancer properties. It modulates signaling pathways associated with inflammation, oxidative stress, mitochondrial dysfunction, and cell proliferation. Furthermore, UroA has been shown to improve intestinal barrier integrity, regulate immune cell activity, and induce mitophagy, thereby contributing to the restoration of mitochondrial and cellular homeostasis. A growing body of evidence also suggests that UroA may inhibit cancer cell proliferation, induce apoptosis, and disrupt the molecular pathways involved in colorectal carcinogenesis. This review summarizes the current state of knowledge regarding the biosynthesis and bioavailability of UroA, its molecular mechanisms of action in IBD, and its potential role in the prevention and treatment of CRC. Furthermore, the limitations of UroA-based therapies and future research directions are discussed. Although further, well-designed clinical trials are necessary, current findings suggest that UroA may represent a promising microflora-targeted therapeutic strategy in chronic inflammatory and CRC diseases. Full article

This paper presents the synthesis and characterization of Schiff base ligands (L) derived from NH-pyrazole-indole and their ruthenium(II) complexes of the general formula [Ru(p-cymene)(L)Cl₂]. The structural characterization of the ligands and ruthenium complexes was performed using a range of analytical methods, including infrared spectroscopy (IR), Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, elemental analysis, mass spectrometry(ESI-MS), density functional theory (DFT) calculations, and single-crystal X-ray diffraction crystallography for two of the four synthesized compounds. Schiff base ligands (L) derived from NH-pyrazole-indole and their ruthenium(II) complexes were evaluated against antibiotic-resistant bacteria. The effect of substituting the ligand with methoxy groups on biological activity was assessed. The antibacterial activity, Minimal Inhibitory Concentration (MIC), and Minimal Bactericidal Concentration (MBC) of the free ligands and the ruthenium compounds were measured against six bacterial isolates (Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Shigella dysenteriae) and two control strains (Enterococcus faecalis ATCC 29212 and Enterobacter cloacae ATCC 13047) from the ESKAPE group of highly antibiotic-resistant pathogens. The free ligands were inactive, whereas all four ruthenium complexes displayed notable antibacterial activity. In particular, compounds Ru3 and Ru4 exhibited higher activity against Staphylococcus aureus than the Trimethoprim control, with MIC values of 15.60 µg/mL, compared with an MIC > 64 µg/mL for Trimethoprim. The activity of those two complexes was similar to that of Gentamicin against this strain. Molecular docking calculations suggested a possible mechanism of action through binding of the complexes to the active site of S. aureus PBP2a. Full article

Cancer remains one of the most frightening global health challenges, contributing substantially to morbidity and mortality across diverse populations. In recent years, naturally derived compounds have attracted considerable attention due to their potential therapeutic efficacy and fewer adverse effects. Among these, the flavokawain subclass of chalcones, comprising Flavokawains A, B, and C, obtained from various plant sources, has emerged as a promising group of bioactive phytochemicals exhibiting a broad spectrum of pharmacological activities, with notable anticancer potential. This review critically compiles and evaluates the existing preclinical evidence regarding the anticancer mechanisms of flavokawains across various cancer models. It was found that these compounds have significant potential to inhibit cancer cell proliferation, induce apoptosis, disrupt cell-cycle progression, and modulate multiple molecular pathways implicated in tumorigenesis, including phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), extracellular-signal regulated kinase/c-Jun N-terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK) and so on. Importantly, flavokawains exert significant modulatory effects within the tumor microenvironment by suppressing angiogenesis through downregulation of vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), attenuating epithelial-mesenchymal transition via restoration of E-cadherin and suppression of vimentin and Snail1, inhibiting matrix metalloproteinase (MMP)-mediated extracellular matrix remodeling, and disrupting cancer stem cell (CSC)-supportive niches. Preclinical toxicity profiles suggest a favorable safety margin, though further investigation is required to fully elucidate their therapeutic index. Due to their multifaceted mechanisms of action and selective cytotoxicity toward cancer cells, flavokawains are considered promising preclinical candidates for development as adjuncts or alternatives to conventional chemotherapeutic agents. Full article

The purpose of this study was the chemical design, synthesis, and evaluation of the anticonvulsant potential of 15 novel thiazolyl-methylthio-quinazolin-4(3H)-one hybrid compounds (4a-o). The compounds were designed based on a scaffold that reunited thiazole and quinazolin-4(3H)-one heterocycles of two well-known anticonvulsants, clomethiazole and methaqualone, through a condensation reaction. The compounds were evaluated in vivo for anticonvulsant activity using the pentylenetetrazole-induced seizure animal model. A Rotarod test was employed to evaluate the neuromotor coordination after the administration of the tested compounds, and a flumazenil antagonism assay was subsequently performed to investigate if the observed anticonvulsant effects were mediated through the compounds’ interaction with the GABA_A receptor. The in silico assessment consisted of molecular docking, evaluation of the druggability, and ADMETox prediction. All compounds presented anticonvulsant activity to varying degrees. The most notable activity was observed in compounds 4k (ED₅₀ = 84.313 mg/kg) and 4c (ED₅₀ = 178.165 mg/kg). The in vivo results positively correlated with the observations drawn in the molecular docking study on the human α₁β₂γ₂ GABA_A receptor and on the NR1 ligand-binding core of the NMDA receptor. The potential of anticonvulsant activity was also supported by the druggability and ADMETox predictions that highlighted an increased possibility of brain–blood barrier permeation, supported by the computed parameters TPSA, logD, and logBB. The results of the flumazenil antagonism assay additionally highlighted the possible mechanism of action of compounds 4c and 4k as positive allosteric modulators of the GABA_A receptor. Preliminary evaluation confirmed the anticonvulsant potential of the tested compounds, with further testing being necessary for a better understanding and confirmation of the activity. Full article

Cisplatin-induced acute kidney injury (AKI) remains a dose-limiting complication in cancer chemotherapy with restricted preventive measures. Carthamus tinctorius L. (safflower) is known to exhibit effective antioxidant and anti-inflammatory properties; however its potential in renoprotective mechanisms remains poorly understood. The present study utilized a cisplatin-induced AKI mouse model to evaluate the renoprotective potential of CT (Carthamus tinctorius) extract. Integrated multi-omics along with in silico and in vivo approaches were used to elucidate the underlying mechanisms of action. The results initially demonstrated a rich phytochemical profile of CT extract characterized by abundant polysaccharides and flavonoids, with Hydroxysafflor Yellow A as a dominant bioactive constituent. In a cisplatin-induced acute kidney injury (AKI) mouse model, CT extract noticeably ameliorated the abnormalities of renal injury, as suggested by improved histopathology, reduced serum creatinine and BUN levels, and regulation of redox homeostasis. Metabolically, CT extract partially reversed AKI-associated disturbances by affecting 21 key metabolites, likely associated with histidine and alanine-aspartate-glutamate biosynthesis, and modulating amino acid and energy metabolism pathways. Concurrently, CT extract improved gut microbial homeostasis, increasing microbial diversity, normalizing the Firmicutes/Bacteroidota ratio, suppressing pathogens, and enriching beneficial Ligilactobacillus. Network pharmacology and molecular docking identified AKT1, RELA, MAPK, and TP53 as central targets of core compounds (rutin and kaempferol derivatives), apparently targeting the PI3K-AKT and RELA (NF-kappaB) hubs. These results suggested that the renoprotective effects of CT extract are associated with transcriptional upregulation of the PI3K/Akt/Nrf2 pathway-related genes, increased expression of antioxidant genes (Ho-1, Sod1), and reduced expression of pro-inflammatory mediators (RelA, Cdk2) in the cisplatin-induced AKI mouse model. Full article

Background: Chagas disease, caused by the parasite Trypanosoma cruzi, remains a major neglected tropical disease, with millions of people living with the infection worldwide. Current treatments are effective in the acute stage of the disease, but are poorly tolerated and show reduced efficacy in chronic infections, highlighting an urgent need for novel therapeutic strategies. A key bottleneck in early-stage drug discovery is target identification, which is traditionally dependent on costly and low-throughput experimental methods. Computational approaches offer a cost-effective and fast alternative to traditional methods. Methods: In this study, we present an integrated in silico pipeline that combines ligand-based and structure-based computational approaches to prioritize potential molecular targets for bioactive compounds against T. cruzi. The ligand-based component performed similarity searches across curated bioactivity databases containing known ligand–protein associations, and the most similar candidates were then further evaluated using a structure-based approach through pairwise structural alignment against the T. cruzi proteome from AlphaFold. Results: The pipeline was validated using eight compounds with known targets, successfully recovering the correct target in six cases. Additionally, two compounds with anti-T. cruzi activity but unknown mechanisms of action were analyzed to hypothesize their potential targets. Conclusions: Overall, the pipeline demonstrated moderate success, with limitations arising from challenges in handling novel chemotypes and poorly annotated targets. Nevertheless, its modular nature allows for an easy adaptation to other neglected tropical diseases, providing a flexible and cost-effective framework for early-stage target prioritization. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Background/Objectives: Shashen Maidong Decoction (SMD) has a long history of use within the traditional Chinese medicine (TCM) system and is currently employed in modern clinical practice for the treatment of various diseases. The characterization of the chemical constituents of TCM drugs is a prerequisite and foundation for research into bioactive compounds and quality control. However, no study has yet undertaken a comprehensive identification of its chemical constituents. Therefore, it is necessary to establish suitable analytical methods to comprehensively and systematically characterize the chemical constituents of SMD. Methods: Ultra-performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q Exactive orbitrap HRMS) and the Global Natural Products Social Molecular Networking (GNPS) technology were employed. The chemical constituents in SMD were systematically identified by comparing mass spectrometry data with reference standards, databases and relevant literature, and by analyzing mass spectrometry fragmentation patterns. Results: A total of 86 compounds were identified in SMD, including 27 flavonoids, 2 homoisoflavonoids, 34 organic acids, 2 alkaloids, 4 amino acids, 5 saccharides, 3 triterpenes and 9 other constituents. Conclusions: This study represents the first relatively comprehensive and systematic characterization of the chemical constituents in SMD, enriching modern understanding of SMD and laying the foundation for the identification of bioactive compounds, the elucidation of mechanisms of action, and further development and utilization. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

Satureja nepeta essential oil (EO) is gaining prominence for its multifaceted pharmacological and biotechnological potential. This study aimed to characterize its volatile profile and evaluate its functional capacity as an antioxidant, antibacterial, and antiproliferative agent. Gas Chromatography Mass Spectrometry (GC–MS) profiling was conducted to identify the volatile constituents of the EO. Antioxidant activity was assessed using DPPH, ABTS, TAC, and FRAP assays. Antibacterial activity was evaluated against Gram-positive and Gram-negative pathogens using disk diffusion and MIC determination. In silico molecular docking against bacterial DNA gyrase B was performed to explore potential mechanisms of action. Antiproliferative activity was assessed on the P3X63Ag8.653 myeloma cell line. Chemical profiling identified nine major constituents, dominated by pulegone (68.63%), menthol (6.64%), and cis-pulegol (2.04%). The EO demonstrated significant free radical-scavenging activity, particularly in the TAC assay (EC₅₀ = 3.747 ± 0.577 µg/mL). Antimicrobial evaluations revealed robust inhibitory effects, with Pseudomonas aeruginosa and Salmonella enterica exhibiting the highest susceptibility. In silico modeling corroborated these findings, identifying menthol as the lead ligand (ΔG = −6.09 kcal/mol), suggesting a synergistic mechanism of action. Notably, the EO displayed potent antiproliferative activity (LC₅₀ = 14.060 ± 1.364 µg/mL), falling well within the high-cytotoxicity threshold. Collectively, these findings underscore the pharmacological significance of S. nepeta EO as a potent reservoir of bioactive monoterpenes with antioxidant, antimicrobial, and anticancer properties, meriting further in vivo validation and mechanistic exploration toward its development as a therapeutic or nutraceutical candidate. Full article

Background: Solar dermatitis (SD) is an inflammatory skin disease caused by excessive exposure to ultraviolet (UV) radiation. Gastrodia elata (GE) is a medicinal and edible plant with broad pharmacological activities; however, the polarity distribution of its active components and their specific mechanisms of action in SD remain incompletely understood. Methods: Different polarity fractions of GE-petroleum ether extract (PEE), ethyl acetate extract (EAE), and n-butanol extract (NBAE) were prepared and evaluated in a UVB-induced SD mouse model. We integrated metabolomics, network pharmacology, molecular docking, molecular dynamics simulations, and molecular biology techniques to identify key active ingredients and regulatory mechanisms. Results: The EAE group significantly ameliorated epidermal thickening and collagen damage in SD mice. Mechanistically, EAE and its active component luteolin (LUT) likely suppressed abnormal activation of the JUN pathway (binding energy: −9.1 kcal/mol), leading to downregulation of the pro-inflammatory cytokines tumour necrosis factor-alpha and inerleukin-1 beta. Conclusions: The EAE fraction alleviates SD through multi-component, multitarget synergistic effects, with LUT as a core bioactive component that inhibits the JUN pathway to mitigate skin inflammation and oxidative damage. EAE also accelerated SD recovery by modulating critical metabolic pathways, including arginine biosynthesis and terpenoid backbone biosynthesis. These findings identify EAE and LUT as promising candidate therapeutics for SD. Full article

Stroke remains one of the leading causes of death and disability worldwide, yet its clinical management is constrained by substantial biological heterogeneity that single-biomarker and single-omics approaches fail to resolve. The integration of multiple molecular data layers, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and immunomics, offers a transformative framework for investigating the underlying neuroinflammatory mechanisms of different stroke subtypes and endotypes. In this review, we synthesize the current multi-omics evidence in stroke by examining how genetic variants propagate through regulatory and immune pathways and generate measurable molecular signatures and clinically relevant biomarkers. We investigate the roles of microglia, infiltrating monocyte-derived macrophages, astrocytes, neutrophils, T cells, and endothelial cells as interacting nodes in the neuroimmune network after stroke, and analyze how spatially resolved single-cell transcriptomics illuminate state-specific programs previously undetectable in bulk tissue analyses. We discuss how proteomics and metabolomics translate these cellular programs into actionable circulating biomarkers and examine emerging evidence on blood–brain barrier disruption and neurovascular unit remodeling as multi-omics-defined targets. We then explore AI and machine learning frameworks enabling the integration of heterogeneous, high-dimensional datasets for endotype classification, patient stratification, and therapeutic response prediction. Finally, we address translational barriers, including analytical standardization, multi-ancestry generalizability, and regulatory readiness, and propose a roadmap for precision stroke medicine based on systems immunology. The core conceptual point of this review is the shift from describing omics findings in stroke cases to redefining biologically meaningful neuroinflammatory endotypes and using multi-omics to enable precision cerebrovascular medicine. Full article