Search Results (24,079)

Background: MYC dysregulation is frequent in ocular adnexal sebaceous carcinoma (SebCA), an aggressive malignancy without precision therapy. Fatty acid synthase (FASN) expression and lipid metabolism are commonly perturbed in high-MYC-expressing tumors; however, the role of MYC and FASN in the coregulation of lipid biosynthesis and tumorigenesis in SebCA is unknown. Methods: The aim of this study was to characterize the effects of FASN inhibition on MYC expression, oncogenic processes, and lipid profiles in vitro, using non-neoplastic human Meibomian gland epithelial cells (HMGECs) and three primary SebCA cell lines, and in vivo, utilizing a conditionally MYC-overexpressing mouse model. Results: FASN inhibition reduced cell viability, proliferation, and clonogenicity and altered the saturation profile of fatty acids across multiple lipid classes. The relative saturation of ceramides was the most variable between treatment conditions. MYC overexpression in the murine Meibomian gland promoted proliferation while suppressing sebaceous differentiation. Subsequent topical FASN inhibition further reduced sebaceous differentiation, attenuated PLIN2 expression, and induced apoptotic cell death. Conclusions: Collectively, these findings suggest that MYC expression in SebCA is responsive to FASN inhibition. Pharmacologic targeting of FASN reveals a metabolic vulnerability that may serve as a target for future therapeutic development. Full article

Background: Vasicine (Vas) is a quinazoline alkaloid derived from Adhatoda vasica Nees, which has good anti-allergic asthma and anti-inflammatory effects. However, its specific functional mechanism on allergic asthma is unclear. This study aims to investigate the protective effect of Vas on allergic asthma and its underlying mechanisms. Methods: Initially, the therapeutic effects of Vas were assessed in ovalbumin-sensitized BALB/c mice using airway hyperresponsiveness (AHR), histopathological examinations, immunohistochemistry, and enzyme-linked immunosorbent assays (ELISA). Subsequently, a non-targeted metabolomic analysis was performed to examine the influence of Vas on lung metabolites, while molecular docking was utilized to clarify the mechanisms by which Vas intervenes in allergic asthma. Lastly, RBL-2H3 cells were employed in vitro to validate the metabolomic findings by measuring intracellular Ca²⁺ concentrations, in addition to conducting ELISA and Western blot analyses. Results: In vivo, Vas alleviates AHR in mice with allergic asthma, enhances histopathological conditions, and reduces inflammatory factors. Non-targeted metabolomics analyses indicate that the primary pathway implicated in its intervention in allergic asthma may be the FcεRI pathway. Furthermore, molecular docking techniques were utilized to evaluate the binding affinity between Vas and proteins associated with this pathway. In vitro, Vas effectively inhibits degranulation in RBL-2H3 cells and diminishes the release of inflammatory factors by modulating the FcεRI/Lyn + Syk/MAPK pathway. Conclusions: These findings indicate that Vas may effectively alleviate allergic asthma by reducing inflammatory responses, decreasing AHR, and improving histopathological features. Furthermore, Vas seems to inhibit mast cell degranulation and modulate the FcεRI/Lyn + Syk/MAPK pathway. Full article

Chinese rice-field eel rhabdovirus (CrERV), an emerging viral pathogen, causes massive death in rice-field eels (Monopterus albus), thus threatening the industry’s development. There is currently no established treatment strategy for CrERV. This study evaluated the anti-CrERV effects of schisandrin B (Sch B) in vitro and in vivo. The results indicated that Sch B at 20 mg/L could inhibit the expression of the CrERV G protein, with a maximum inhibition rate of 69.5%. Additionally, Sch B mitigated the nuclear damage and mitochondrial membrane potential decline induced by CrERV, thereby preserving cellular morphology. A time-of-addition study suggested that Sch B might exert its antiviral effects during the mid-stage of viral replication. In vivo, Sch B exhibited promising preventive and therapeutic effects against CrERV infection in rice-field eels, enhancing their survival rate by 57% and 51%, when added at 0.075% and 0.025%, respectively. Overall, the natural product Sch B was proven to have excellent anti-CrERV activity, with broad prospects for application in aquaculture. Full article

Background: Myocardial fibrosis, a central pathological process leading to heart failure, lacks specific mechanism-based therapies. Although the anti-inflammatory activity of the natural compound protocatechuic acid is recognized, its direct anti-fibrotic mechanism, particularly concerning the critical role of endothelial–mesenchymal transition (EndMT), remains unexplored. This study aimed to investigate the protective effects and underlying mechanisms of protocatechuic acid. Methods: The study employed both in vivo and in vitro models. For in vivo evaluation, a rat model of myocardial fibrosis was induced by isoproterenol hydrochloride (ISO). For in vitro analysis, human umbilical vein endothelial cells (HUVECs) were stimulated with angiotensin II (Ang II) and subjected to siRNA-mediated histone deacetylase 1 (HDAC1) knockdown, alongside a co-culture model involving HUVECs and the AC16 human cardiomyocyte cells. Additionally, molecular docking and dynamics simulations were performed to evaluate the binding affinity and stability of protocatechuic acid with the target protein, HDAC1. Results: In vivo, protocatechuic acid significantly improved cardiac function, attenuated pathological injury, and reduced collagen deposition in ISO-induced fibrotic rats. It also potently suppressed inflammatory responses and inhibited the EndMT process. These beneficial effects were associated with decreased HDAC1 and increased GATA binding protein 4 (GATA4) expression in perivascular regions, which suggests the modulation of the HDAC1/GATA4 pathway. In vitro, protocatechuic acid suppressed Ang II-induced endothelial inflammation in HUVECs. This effect was replicated by HDAC1 knockdown, thus confirming that the HDAC1/GATA4 pathway mediates its anti-inflammatory action at the cellular level. Furthermore, molecular docking and dynamics simulations indicated that protocatechuic acid stably binds to a key target, HDAC1. Conclusions: Protocatechuic acid alleviates inflammation and EndMT by inhibiting the HDAC1/GATA4 signaling pathway, thereby preserving cardiac function and retarding the progression of myocardial fibrosis. These findings provide a theoretical and experimental foundation for the potential application of protocatechuic acid in treating cardiovascular diseases. Full article

It is broadly realized that the body’s metabolism has a profound impact on tumor progression. However, pathophysiological mechanisms underlying the metabolic modulation of the tumor immune microenvironment remain incompletely understood. Here, we report that long-chain fatty acids (LCFAs) can directly modulate the function of myeloid-derived suppressor cells (MDSCs), a central component of establishing the tumor immune microenvironment. In vitro or in vivo exposure to LCFAs significantly reduces the expression levels of signature immunosuppressive genes of both monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). As a result, mice fed with a diet of high LCFA content exhibit delayed tumor progression and prolonged survival in different cancer models. Furthermore, this LCFA-mediated inhibition of M-MDSCs and PMN-MDSCs correlates with enhanced CD8⁺ T antitumor immunity, which is abolished in tumor-bearing nude mice. These results have revealed a previously under-recognized role of LCFAs in the tumor immune microenvironment, implicating novel therapeutic strategies for cancer treatment. Full article

Taurine metabolism is emerging as an important player in cancer progression, yet its precise roles remain incompletely understood. Our study revealed that elevated serum Taurine levels and concomitant upregulation of its transporter, Slc6a6, are associated with enhanced tumor growth. Functionally, Slc6a6 overexpression drives tumor progression in vivo and accelerates cancer cell proliferation in vitro. Mechanistically, we identified a dual pro-oncogenic function for Slc6a6. First, Slc6a6 possesses intrinsic antioxidant regulatory capacity and further enhances cellular redox homeostasis by mediating the uptake of the antioxidant molecule Taurine. Second, beyond its metabolic role, Slc6a6 directly interacts with the cell cycle regulator Rprd1b to promote the G1/S phase transition, leading to uncontrolled proliferation. Clinically, bioinformatics analyses correlate high SLC6A6 expression with poor prognosis in breast cancer patients, underscoring its potential as a therapeutic target. Full article

Background: Diabetic wound healing is hampered by persistent inflammation and excessive neutrophil extracellular traps (NET) formation. Peptidylarginine deiminase 4 (PAD4) is a key enzyme driving this pathology. This study developed a thermosensitive chitosan/β-glycerophosphate hydrogel for the local delivery of a novel PAD4 inhibitor, YJ-2, to promote diabetic wound repair. Methods: A YJ-2-loaded hydrogel (CGY) was synthesized and characterized. In vitro studies used HaCaT cells and macrophages to assess proliferation, migration, NETs (via H3cit), and polarization. Efficacy was evaluated in diabetic C57 mouse wound models. Results: CGY exhibited temperature-sensitive gelation and sustained YJ-2 release. In vitro, YJ-2 inhibited NETs formation, reduced pro-inflammatory markers, promoted HaCaT migration, and induced M2 macrophage polarization. In vivo, CGY treatment significantly accelerated wound closure. Conclusions: Local hydrogel delivery of the PAD4 inhibitor YJ-2 effectively mitigates inflammation and NETs, promoting healing in diabetic wounds. This strategy represents a promising targeted therapy for diabetic wounds. Full article

The interaction between the gut microbiota and human health has gained increasing recognition, accelerating advances in microbiome research. While early studies have emphasized probiotics, concerns regarding antibiotic resistance and adverse effects, such as sepsis, have shifted research interest towards heat-treated microbial cells or postbiotics. This study investigated the therapeutic potential of heat-killed postbiotic Enterococcus faecalis EF-2001—one of the most widely used postbiotics worldwide—for the prevention and treatment of muscle atrophy. In vitro, mouse C2C12 myotubes were pretreated with heat-killed postbiotic EF-2001 (50–500 μg/mL) for 48 h and then treated with dexamethasone (100 μM) to induce muscle atrophy. In vivo, male Sprague Dawley rats were treated with low-dose (3 mg/kg) and high-dose (30 mg/kg) EF-2001 for efficacy studies. Heat-killed postbiotic EF-2001 attenuated cellular and DNA damage in dexamethasone-induced C2C12 myotubes. Specifically, heat-killed postbiotic EF-2001 increased AKT phosphorylation while suppressing Atrogin-1 expression, thereby alleviating muscle atrophy. In a Sprague Dawley rat model, heat-killed postbiotic EF-2001 significantly reduced dexamethasone-induced muscle loss by regulating muscle atrophy-associated signaling pathways, including Atrogin-1 expression. Collectively, these findings demonstrate that heat-killed EF-2001 alleviates dexamethasone-induced muscle atrophy and support its potential as a postbiotic. This study provides a solid foundation for future human clinical studies by establishing preclinical evidence for the biological activity of heat-killed EF-2001. Full article

The gut microbiome is defined as the collective assembly of microbial communities inhabiting the gut, along with their genes and metabolic products. The gut microbiome systematically regulates host metabolism, immunity, and neuroendocrine homeostasis via interspecies interaction networks and inter-organ axes. Given the importance of the gut microbiome to the host, this review integrates the composition, function, and genetic basis of the gut microbiome with host genomics to provide a systematic overview of recent advances in microbiome–host interactions. This encompasses a complete technological pipeline spanning from in vitro to in vivo models to translational medicine. This technological pipeline spans from single-bacterium CRISPR editing, organoid–microbiome co-culture, and sterile/humanized animal models to multi-omics integrated algorithms, machine learning causal inference, and individualized probiotic design. It aims to transform microbiome associations into precision intervention strategies that can be targeted and predicted for clinical application through interdisciplinary research, thereby providing the cornerstone of a new generation of precision treatment strategies for cancer, metabolic, and neurodegenerative diseases. Full article

The removal of protein-bound uremic toxins (PBUTs) from the blood of kidney failure patients with conventional dialysis is limited. However, as their harmful effects and association with morbidity and mortality in dialysis patients are increasingly recognized, PBUTs have become important therapeutic targets. In this review, PBUT removal with current state-of-the-art dialysis technologies and future perspectives are discussed. Strategies to enhance PBUT clearance include methods that interfere with PBUT–albumin binding, such as chemical displacers, high ionic strength, pH changes, or electromagnetic fields, thereby increasing the free fraction available for dialysis. While these methods have shown promise in vitro, and some also in vivo, long-term safety data are lacking. PBUT removal can also be increased by adsorption, either directly via hemoperfusion, or indirectly, e.g., via sorbents incorporated in a mixed-matrix membrane or dissolved in the dialysate. In the kidney, PBUTs are secreted in the proximal tubules; hence, a cell-based bioartificial kidney (BAK) that secretes PBUTs is proposed as an add-on to current dialysis. Yet both PBUT adsorption strategies and, in particular, BAKs face considerable challenges in upscaling and mass production at acceptable costs. In conclusion, many novel technologies are under development, all requiring further (pre)clinical testing and upscaling before these strategies can be applied in the clinic. Full article

Background: Ganoderma lucidum triterpenes are bioactive compounds with recognized anti-inflammatory, antitumor, and immunomodulatory properties. This systematic review synthesizes evidence regarding the anti-inflammatory activity of these triterpenes based on studies from the last two decades. Methods: A systematic search was performed in PubMed, Medline, and Embase (2003–2025) for original in vitro and in vivo (non-clinical) studies evaluating G. lucidum triterpene extracts or isolated compounds. Clinical trials, reviews, and multi-species extracts were excluded. The review is registered on PROSPERO (CRD42024510982), and animal study quality was assessed using the SYRCLE Risk of Bias tool. Findings: From over 3000 records, 23 articles were included. Studies utilized diverse models, including macrophages, human PBMCs, and various animal strains (mice, rats, chickens). All studies reported significant anti-inflammatory effects via reduction in pro-inflammatory markers (TNF-α, IL-1β, IL-6), primarily through downregulation of MAPK and TLR-4/NF-κB signaling pathways. Meta-analysis of in vitro data confirmed significant reductions in NO levels (−3.29 [95% CI: −5.21, −1.37]; p = 0.0008), IL-6 (−3.51 [−4.73, −2.29]; p < 0.00001), and TNF-α (−2.20 [−2.93, −1.48]; p < 0.00001). Similar anti-inflammatory profiles were observed in vivo across hepatic and splenic tissues. Interpretation: Evidence consistently demonstrates the potent anti-inflammatory activity of G. lucidum triterpenes, highlighting their potential as therapeutic candidates for inflammatory diseases. However, the structural complexity and isomer diversity of these compounds remain significant barriers to pharmacological standardization. Future research must prioritize clinical translation by investigating compound synergism, bioavailability, and long-term toxicity profiles, which were notably absent in current non-clinical literature. Full article

Background: Gold (Au) complexes have emerged as promising anticancer candidates due to their distinct coordination chemistry and ability to modulate thiol-dependent and redox-regulated cellular pathways, particularly thioredoxin reductase (TrxR). In recent years, structurally diverse Au(I) and Au(III) complexes have been reported with potent in vitro anticancer activity; however, cross-study comparability and design principles remain unclear. Aim: This systematic review critically evaluates anticancer Au(I/III) complexes reported since 2016, with the specific aim of identifying how oxidation state, coordination geometry, and ligand class influence in vitro potency, selectivity, and translational potential. Methods: A PRISMA-guided literature search was performed in Scopus, Web of Science, PubMed, and ScienceDirect for studies published between January 2016 and March 2025. Two independent reviewers screened titles/abstracts and full texts according to predefined inclusion criteria. Only original studies reporting anticancer activity of structurally characterized Au(I/III) complexes in human cancer models were included. After the removal of duplicates, 1100 records were screened at the title and abstract level. Of these, 240 articles were assessed in full text for eligibility. Ultimately, 128 studies reporting anticancer activity of structurally characterized Au(I/III) complexes met the inclusion criteria and were included in the qualitative synthesis. Biological potency data were harmonized to μM units where applicable, and results were synthesized qualitatively due to heterogeneity in experimental design. Results: A total of 128 studies met the inclusion criteria. Au(I) complexes—particularly phosphine- and N-heterocyclic carbene (NHC)-based compounds—consistently showed sub-micromolar cytotoxicity in TrxR-dependent cancer cell lines, whereas Au(III) complexes displayed greater structural diversity but variable stability and redox behavior. In vivo efficacy was reported for a limited subset of compounds and was frequently constrained by solubility, systemic toxicity, or metabolic instability. Conclusions: The available evidence indicates that anticancer activity of gold complexes is strongly dependent on oxidation state, ligand environment, and redox stability. While Au(I) scaffolds show more reproducible in vitro potency, successful translation to in vivo models remains limited. This review defines structure–activity and structure–liability relationships that can guide the rational design of next-generation gold-based anticancer agents. Full article

Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K–Akt–Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17–19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K–Akt inhibition and caspase-3–mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments. Full article

Clinical reports have shown that administration of Nauclea officinalis (Danmu in Chinese, DM) preparations may cause significant gastrointestinal discomfort. This study aimed to systematically evaluate the adverse effects of DM and its primary active constituent, strictosamide, on gastrointestinal motility, intestinal barrier integrity, and gut microbiota homeostasis. Furthermore, we sought to investigate the potential role of the bitter taste receptor (T2R) signaling pathway in mediating these effects. In vitro cell cultures and ex vivo intestinal tissues were employed to assess cell viability and molecular alterations. In vivo studies involved short-term (2 weeks) gavage of DM (0.54 and 1.08 g/kg) and long-term (16 weeks) intervention (0.4, 0.8, and 1.2 g/kg) in rodents. Evaluations included histopathological examination, serum levels of cytokines and oxidative stress markers (ELISA), expression of tight junction proteins (Western blot and qPCR), and 16S rDNA sequencing of cecal microbiota. Mechanistic analyses focused on α-defensin secretion and T2R-associated gene and protein expression. Administration of DM resulted in significant gastrointestinal dysfunction, characterized by delayed intestinal propulsion and increased gastric retention. Dose-dependent histopathological damage, disruption of the intestinal barrier (reduced occludin and claudin-1 expression), and elevated levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), oxidative stress markers (MDA, SOD, and GSH-Px), and immune mediators (IFN-γ) were observed. Gut microbiota analysis revealed dysbiosis, marked by a decline in beneficial genera (e.g., Mucispirillum, Butyricicoccus, Roseburia) and an increase in potentially pathogenic bacteria (e.g., Citrobacter, Helicobacter). Mechanistically, DM suppressed α-defensin secretion and downregulated the expression of TAS2R108, TAS2R138, and Gα-gustducin both in vitro and in vivo. DM and strictosamide disrupt gut microbiota composition and compromise intestinal barrier function, likely through inhibition of the T2R/α-defensin pathway. These findings provide important mechanistic insights into drug-induced gastrointestinal toxicity and underscore the potential risks associated with prolonged use of DM-containing preparations. Full article