Search Results (4,771)

Background: Geraniol is an acyclic monoterpene widely distributed in the essential oils of aromatic species such as Cymbopogon citratus, Pelargonium graveolens, and Rosa damascena, It is known for its antioxidant, anti-inflammatory, neuroprotective, and antitumor activities. Methods: This study aimed to investigate, through network pharmacology and computational ADMET modeling, the molecular mechanisms and pharmacological potential of geraniol, integrating drug-likeness parameters, toxicity prediction, and multitarget interactions. Results: A total of 25 core targets were identified, mainly involved in inflammation, oxidative stress, apoptosis, and transcriptional regulation. Geraniol exhibited a favorable drug-likeness profile, high predicted intestinal absorption, and low systemic toxicity, supporting its pharmaceutical applicability. Mechanistically, it modulates the Nrf2/HO-1 ↔ NF-κB axis, reducing reactive oxygen species, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and apoptotic markers (caspases, Bax), while enhancing antioxidant enzymes (SOD, CAT, GPx) and antiapoptotic proteins (Bcl-2). Conclusions: These findings confirm its multitarget and pleiotropic nature, highlighting its potential as a therapeutic candidate for inflammatory, metabolic, and neurodegenerative disorders. Furthermore, this study provides a robust mechanistic rationale for future in vitro and in vivo validation, as well as for the design of nanostructured formulations to improve geraniol’s bioavailability and therapeutic safety. Full article

The demand for sustainable nutrients and bioactive compounds has increased interest in underutilized wild plants. Forestiera tomentosa, a Mexican drupe-bearing species, is largely unexplored. This study evaluated the proximate composition, physicochemical and functional properties, phenolic profile, antioxidant capacity, and toxicological safety of F. tomentosa fruit. The fruit showed high carbohydrate content [71.94% dry weight (DW)], with notable crude fiber (7.90% DW), protein (7.39% DW), and lipid (4.30% DW) contents. Analysis revealed a mildly acidic pH (5.66), titratable acidity of 0.32%, and total soluble solids of 2.33 °Brix. The fruit powder had a low water activity (0.42) and a favorable water solubility index (56.10%), oil absorption (4.54%), and foaming capacity (19.71%). The fruit contained high levels of soluble phenols (280.42 mg GAE/g DW), flavonoids (98.89 mg CE/g DW), anthocyanins (54.53 mg C3G/g DW), and condensed tannins (94.05 mg CE/g DW). High-performance liquid chromatography identified 20 phenolic compounds, with 3-(4-hydroxyphenyl) propionic acid, syringic acid, catechin, epicatechin, and gallocatechin being predominant. The fruit showed significant radical scavenging and reducing potential (DPPH, ABTS, and FRAP). Toxicological evaluation using the Artemia salina bioassay showed a 100% survival rate across all concentrations, indicating no acute toxicity. In silico ADMET predictions revealed favorable pharmacokinetic properties, including high intestinal absorption and compliance with Lipinski’s rule of five. These findings position F. tomentosa as a promising, non-toxic source of functional ingredients for the food, nutraceutical, and pharmaceutical industries, supporting biodiversity conservation and sustainable resource utilization. Further studies are needed to evaluate the potential health benefits of this fruit in vitro and in vivo. Full article

Toxoplasmosis remains a major global health concern, particularly in immunocompromised individuals and pregnant women, while currently available therapies are associated with significant toxicity and limited efficacy against chronic infection. Drug repurposing represents an attractive strategy for the identification of safer and more effective anti-Toxoplasma gondii agents. This study investigated the antiparasitic potential of loratadine, a second-generation antihistamine, using an integrated in silico, in vitro, and in vivo approach. The anti-T. gondii activity of loratadine was evaluated through β-galactosidase-based proliferation assays, reversibility assays, and experiments using pretreated tachyzoites. In vivo efficacy was assessed in murine models of acute and chronic toxoplasmosis. Disease progression, survival, parasite burden, and cerebral cyst formation were analyzed following treatment. Loratadine inhibited the intracellular proliferation of T. gondii tachyzoites in a concentration-dependent manner and induced partially irreversible effects on parasite viability after drug withdrawal. Pretreatment of extracellular tachyzoites produced limited effects, suggesting that loratadine predominantly acts during the intracellular stage of infection. In the acute toxoplasmosis model, loratadine treatment delayed disease progression, prolonged animal survival, and significantly reduced the number of tachyzoites recovered from the peritoneal cavity. In the chronic infection model, treatment significantly decreased both the number and size of cerebral cysts, although these findings do not demonstrate cyst eradication or direct bradyzoite killing. Despite its measurable biological activity, loratadine exhibited a relatively low in vitro selectivity index, highlighting the need for further optimization. These exploratory findings identify loratadine as a promising lead compound (hit) for further optimization rather than an immediately translatable therapeutic candidate. Additional medicinal chemistry, pharmacokinetic, mechanistic, and confirmatory preclinical studies will be required to determine its potential for anti-T. gondii drug development. Full article

Conventional antibiotics exhibit limited ability to penetrate host cell membranes, making intracellular bacterial infections difficult to eradicate completely. As naturally derived nanoscale membrane structures, bacterial extracellular vesicles (EVs) possess excellent biocompatibility and intrinsic transmembrane transport capability, thereby demonstrating unique advantages for in vivo drug delivery. The present study investigated the feasibility of using EVs derived from the avirulent Streptococcus suis T15 as novel carriers for ciprofloxacin delivery. We also comprehensively evaluated the biosafety and anti-infective efficacy of this nanodrug delivery system in vitro and in vivo. Cytotoxicity assays, live/dead cell staining, and hemolysis analyses demonstrated that T15-derived EVs at concentrations below 50 μg/mL did not cause significant cellular damage or hemolysis. Serum biochemical analyses in mice further confirmed the absence of obvious organ toxicity, indicating favorable biosafety within the tested concentration range. Ciprofloxacin was successfully loaded into EVs using a combination of ultrasonication and electroporation, achieving a drug concentration of 438.6 μg/mL and a loading efficiency of 10.96%. The ciprofloxacin-loaded EVs (EV-CIP) exhibited significantly greater antibacterial activity than free ciprofloxacin against both intracellular bacteria and fluoroquinolone-resistant strains exhibiting efflux pump activity. Evaluation in animal infection models showed that EV-CIP markedly reduced mortality in infected Galleria mellonella larvae. It also decreased bacterial burdens in multiple mouse organs and significantly alleviated histopathological damage. These results collectively suggest that EVs derived from the avirulent S. suis T15 were safe and effective within the tested concentration range and experimental conditions. The EV-based ciprofloxacin delivery system substantially enhanced the clearance of intracellular pathogens and fluoroquinolone efflux pump-positive bacteria, suggesting its potential application in the treatment of difficult-to-treat bacterial infections. This study provides a theoretical and experimental basis for the further development of novel EV-based anti-infective drug delivery strategies for livestock and poultry. Full article

Fumonisins, a class of mycotoxins produced primarily by Fusarium fungi, pose significant health risks to humans and animals through contamination of the food and feed chains. They rank among the most prevalent mycotoxins contaminating maize and maize-derived feeds worldwide, resulting in chronic dietary exposure of both humans and livestock populations across many regions. Their core mechanism of action is the inhibition of ceramide synthases (CerS), which disrupts the essential balance of sphingolipid metabolism by causing an accumulation of free sphingoid bases and a depletion of complex sphingolipids. Both sphingolipids and steroidogenesis are metabolically linked to mitochondrial, membrane and kinase-cascade mechanisms; hence this metabolic disruption may consequently affect steroid hormone biosynthesis, triggering toxicity phenotypes marked by impaired gametogenesis hormonal imbalances, and compromised pregnancy outcomes across mammalian species. Despite the established link between fumonisins and sphingolipid disruption, there is a gap in the literature, as no study to date has integrated sphingolipid disruptions with steroid hormone levels in a dose-dependent manner within reproductive tissues in vivo. This review synthesizes current scientific knowledge across mammalian species to highlight the risks fumonisins pose to reproductive physiology and to identify directions for future research. Full article

Hesperidin is a natural flavonoid derived from citrus plants, which can be hydrolyzed into hesperetin in vivo. Both compounds have anti-inflammatory, antioxidant and antitumor activities. At present, there is a lack of reviews focusing on the epigenetic regulation of cancer stem cells (CSCs) mediated by hesperidin and hesperetin. This review summarizes the molecular crosstalk between hesperidin/hesperetin and CSCs mediated via three major epigenetic pathways, including direct regulatory effects, indirect modulatory actions, and mechanistic relationships proposed based on scientific hypotheses. We elaborate their effects on inhibiting the self-renewal, invasion and metastasis of CSCs as well as reversing chemoresistance, and analyze the crosstalk between epigenetic networks and classical signaling pathways of CSCs. Furthermore, we discuss the core bottlenecks restricting the clinical transformation of these two compounds and introduce improvement strategies such as nanodelivery systems. Current research is still confronted with problems including CSC heterogeneity and the potential off-target toxicity of drugs. In conclusion, hesperidin and hesperetin may serve as potential candidate agents for epigenetic regulation targeting CSCs, which can offer novel theoretical basis for comprehensive tumor therapy. Full article

Background/Objectives: Geranylgeraniol (GGOH), an isoprenoid intermediate of the mevalonate pathway, regulates bone cell viability and function, particularly by mitigating cellular toxicity induced by nitrogen-containing bisphosphonates (N-BPs). Despite this, its role in osteoporosis remains underexplored. This scoping review synthesises evidence on the effects of GGOH in in vitro and in vivo models of osteoporosis. Methods: PubMed, Scopus, and Ovid were searched using GGOH- and osteoporosis-related terms. Primary studies evaluating GGOH exposure in cellular or animal osteoporosis models were eligible. Twenty-nine studies met the inclusion criteria. Results: In vitro findings demonstrate that GGOH reverses N-BP-induced depletion of geranylgeranyl pyrophosphate, restoring protein prenylation which is essential for osteoclast and osteoblast survival, cytoskeletal organisation, and differentiation. GGOH reduced osteoclast apoptosis, restored nuclear factor of activated T-cells 1 and carbonic anhydrase II expression, and prevented N-BP-associated suppression of bone resorption. In osteoblasts and mesenchymal stem cells, GGOH improved viability, upregulated osteogenic markers including runt-related transcription factor 2, alkaline phosphatase, collagen type I, and bone morphogenetic proteins, and rescued mineralisation impaired by alendronate or zoledronate. Independent of N-BPs, GGOH exerted divergent effects on osteoclasts, by inhibiting osteoclastogenesis or promoting retinoic acid receptor-mediated bone resorption and attenuating zoledronate protection in vascular calcification settings in a model-specific manner. In vivo, dietary GGOH supplementation improved trabecular and cortical bone parameters and reduced serum C-terminal telopeptide of type I collagen in obese mice, indicating suppression of bone resorption. Conclusions: Overall, although GGOH shows osteoprotective potential, its capacity to antagonise N-BP efficacy limits systemic co-administration. Current evidence suggests that local delivery may warrant future investigation as a strategy to mitigate N-BP-induced skeletal toxicity. However, studies evaluating bone tissue exposure, pharmacokinetics, and clinically achievable concentrations are required before this approach can be translated. Full article

Triazole fungicides are ubiquitous environmental contaminants. However, their specific effects on the male reproductive system remain unclear. We investigated the toxicological effects of hexaconazole (HEX) on testicular function and elucidated its underlying molecular mechanisms. Although 8 weeks of HEX administration in mice did not affect body weight or gross testicular morphology, it significantly reduced sperm motility and circulating testosterone levels. Correspondingly, HEX exposure markedly downregulated germ cell (DDX4) and meiotic markers (SYCP3) as well as key steroidogenic related gene, including 3β-HSD, Cyp11a1, and Star. HEX induced the excessive production of reactive oxygen species (ROS) and elicited molecular and biochemical features consistent with ferroptosis, an iron-dependent form of regulated cell death, predominantly in interstitial Leydig cells. This process is characterized by increased intracellular labile iron accumulation, enhanced lipid peroxidation (BODIPY fluorescence), and pronounced dysregulation of ferroptosis-associated regulators, including the upregulation of Tfrc, Slc11a2, and Acsl4, concomitant with substantial depletion of Gpx4, an antioxidant related gene. Consistent with in vivo findings, in vitro experiments using primary Leydig cells demonstrated that HEX-induced oxidative stress directly compromised cell viability and steroidogenic function. Thus, Leydig cell ferroptosis is associated with underlying HEX-induced reproductive toxicity, linking endocrine disruption to impaired spermatogenesis. Furthermore, we identified the ferroptosis-mediated antioxidant defense system as a potential molecular target for mitigating reproductive risks associated with triazole fungicide exposure. Full article

Curcumin, a natural polyphenol with well-established antioxidant and anti-inflammatory properties, was evaluated for its protective effects against glyphosate (GLY)-induced mammary toxicity. Pregnant mice received GLY (50 or 250 mg/kg/day) with or without curcumin (150 mg/kg/day) by oral gavage; GLY dose-dependently disrupted alveolar architecture, caused marked inflammatory infiltration, and downregulated tight-junction proteins. In parallel, goat mammary epithelial cells (GMECs) were treated with GLY (1 or 7 mM) and curcumin (1 µM) to dissect acute cellular stress pathways. These complementary models address distinct aspects of GLY toxicity: the in vivo system reflects defined oral exposure, whereas the in vitro setting employs high concentrations to probe mechanistic events. Transcriptomic profiling combined with functional assays demonstrated that GLY triggered oxidative stress, endoplasmic reticulum stress, and intracellular Ca²⁺ overload, activated the TNFα/MAPK axis, suppressed STAT3 phosphorylation, and ultimately promoted apoptosis. Curcumin co-treatment alleviated these alterations at both structural and molecular levels. These findings indicate that curcumin can combat GLY-induced mammary injury by restoring cellular homeostasis and inhibiting apoptotic and inflammatory signaling, thereby protecting breast health. Full article

Background: Humans have long consumed lactic acid bacteria-based fermented foods, and this empirical experience has led to the development of probiotic-based functional foods and therapeutics. However, conventional development strategies have largely focused on commonly used probiotic strains to prioritize development efficiency and safety, resulting in limited functional innovation. Although research on next-generation probiotics (NGPs) has expanded in recent years, there is an increasing need for post-next-generation probiotic (Post-NGP) strategies that address subsequent stages of microbiome modulation. Methods: In this study, Phocaeicola vulgatus PMC94 was isolated and characterized as a Post-NGP candidate, and its effects on gut microbiome balance were evaluated using ex vivo human gut microbiota culture (ex vivo HGMC). Results: Dysbiosis induced by commonly encountered therapeutic agents was significantly alleviated by co-administration of PMC94. This restorative effect on gut microbiome imbalance was more pronounced than that observed with conventional probiotic strains. To elucidate the mechanistic basis underlying these effects, additional analyses were conducted using a human gut microbiome simulator (HGMS). PMC94 selectively suppressed Proteobacteria while promoting balanced proliferation of Bacteroidetes and Firmicutes, thereby restoring gut microbial homeostasis. This pattern of microbiome modulation was consistently supported by in vivo mouse experiments. Furthermore, these changes were associated with increased production of short-chain fatty acids (SCFAs), as well as immune modulation and reinforcement of gut barrier function. The safety of PMC94 was confirmed through a 2-week repeated-dose toxicity study. Conclusions: Collectively, these findings demonstrate that P. vulgatus PMC94 is a promising Post-NGP candidate capable of restoring and strengthening gut microbial homeostasis. Full article

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin profiling, transwell migration assays, β-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with β-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify β-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders. Full article

Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. & Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays—including cell viability, caspase 3/7 activity, flow cytometry, and colony formation—in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB/c-nu/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy. Full article

Inflammatory bowel disease (IBD) is characterized by intestinal barrier dysfunction and excessive inflammation, in which STAT3 signaling plays a critical role. Berberine is clinically effective against colitis; its application is limited by low bioavailability and toxicity. Berberrubine, a major metabolite of berberine, exhibits improved pharmacological properties; however, its therapeutic potential in IBD remains unclear. The efficacy and mechanisms of berberine and berberrubine were evaluated in DSS-induced colitis mice, LPS-stimulated cells and intestinal organoids. STAT3 knockout cell lines were generated using CRISPR-Cas9 to assess the role of STAT3 in mediating the pharmacological activities of both compounds. We found that berberrubine significantly alleviated colitis, reduced pro-inflammatory cytokines (IL-6 and TNF-α), and restored intestinal barrier integrity by upregulating ZO-1 and claudin-1 in vivo and in organoids, demonstrating superior efficacy and safety to berberine. Mechanistically, both compounds inhibited STAT3 activation and nuclear translocation. STAT3 deficiency attenuated their anti-inflammatory, anti-tumor, and barrier-protective effects. Notably, berberrubine exhibited selective cytotoxicity to cancer cells over normal epithelial cells, suggesting a favorable therapeutic window. Collectively, berberrubine ameliorates intestinal barrier dysfunction and inflammation through inhibition of the STAT3 signaling pathway. Its superior efficacy and favorable safety profile compared to berberine support its potential as a novel therapeutic agent for IBD. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Background: Bisphenol F (BPF), a widely used bisphenol A substitute and emerging endocrine disruptor, has been implicated in bone loss; however, its underlying mechanisms remain unclear. Curcumin (CUR) has shown beneficial effects on bone metabolism, but its protective role against BPF-induced osteogenic impairment requires further validation. This study investigated the involvement of the PI3K/AKT signaling pathway in BPF-induced osteoporosis and osteogenic dysfunction, and whether CUR could alleviate these effects through modulation of this pathway. Methods: Network toxicology, network pharmacology, and molecular docking were first used to predict potential targets and signaling pathways. A rat model of BPF-induced osteoporosis and a BPF-treated MC3T3-E1 osteogenic impairment model were then established to evaluate the effects of CUR. Bone mineral density, trabecular microarchitecture, serum bone metabolism markers, and osteogenic protein expression were assessed in vivo. In vitro, alkaline phosphatase activity, mineralization, and key signaling proteins were measured. The PI3K/AKT inhibitor LY294002 was used to verify pathway involvement. Results: Computational analyses suggested that BPF and CUR were closely associated with the PI3K/AKT pathway. Experimentally, BPF reduced bone mass, disrupted trabecular structure, and suppressed osteogenic differentiation, accompanied by downregulation of osteogenic markers and PI3K/AKT signaling. Notably, BPF reduced femoral BMD by 10.8%, whereas CUR restored approximately 43.5% of the BPF-induced loss. CUR significantly reversed these effects, whereas LY294002 abolished the protective actions of CUR. Conclusions: BPF may impair bone formation and promote osteoporosis by suppressing PI3K/AKT signaling, while CUR alleviates these effects through pathway activation. These findings provide mechanistic evidence supporting CUR as a potential intervention against BPF-related bone toxicity. Full article