Search Results (105)

Gastric cancer (GC), also known as stomach adenocarcinoma (STAD), remains a highly lethal malignancy due to late diagnosis, limited therapeutic efficacy, and frequent metastasis. Although extensive molecular profiling has been performed, post-transcriptional regulatory mechanisms underlying GC progression are still incompletely characterized. In this study, we applied an integrative multi-omics framework to elucidate the regulatory roles and clinical relevance of circular RNAs (circRNAs) in GC. Transcriptomic data of mRNAs, microRNAs, and circRNAs from eight independent GEO datasets were jointly analyzed, resulting in the identification of 249 differentially expressed genes (DEGs), 8 differentially expressed microRNAs (DEmiRNAs), and 4 differentially expressed circRNAs (DEcircRNAs). These molecules were integrated into a competing endogenous RNA (ceRNA) network, enabling systems-level characterization of GC-associated regulatory interactions. Network topology and survival analyses prioritized 13 hub molecules, including IGF2BP3, COL4A1, MMP14, and TGM2, which showed both central network positions and significant associations with patient survival. To explore therapeutic implications, transcriptomics-guided drug repositioning combined with molecular docking analysis identified five candidate compounds—celastrol, fedratinib, pevonedistat, tozasertib, and withaferin A—predicted to target key network hubs. Overall, this in silico study provides a ceRNA-centered regulatory framework for GC and prioritizes biologically informed biomarkers and repositioned drug candidates with potential applicability across other malignancies to converge precision oncology. Full article

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition resulting from dysregulation of the intestinal immune system. CD4⁺FoxP3⁺ regulatory T cells (Tregs) play a crucial role in regulating this immune response. The heat shock response (HSR) regulates the inflammatory cascade, preventing misfolding of proteins and regulating immune responses. We have previously shown that Heat Shock Factor 1 (HSF1), the master regulator of the HSR, regulates Tregs in inflammation. Based on this finding, we hypothesized that targeting HSF1 with celastrol, a pentacyclic triterpenoid that activates HSF1, would activate Treg cells and ameliorate intestinal inflammation. To test this, we investigated the impact of celastrol on Tregs both in vitro and in vivo, evaluating its efficacy in HSF1^fl/fl-CD4^cre mice, and in two murine models of IBD: the adoptive transfer colitis, and TNF^ΔARE+/− ileitis. Our results demonstrate that celastrol activates HSF1 in Tregs, enhances Treg suppressive function, increases Treg populations in vivo, and ameliorates intestinal inflammation. Full article

(1) Aminoglycosides remain indispensable in modern medicine but share a serious dose-limiting adverse effect: irreversible cochleovestibular ototoxicity. (2) This scoping review systematically maps experimental and clinical strategies aimed at preventing aminoglycoside-induced hearing loss, integrating mechanistic insights across preclinical and translational domains. (3) Preclinical evidence, encompassing in vitro and in vivo studies, delineates three principal mechanistic ways of protection: (A) antioxidant and redox modulation, including N-acetyl-L-cysteine (NAC), vitamin C, edaravone, and selected phytochemicals, which counteract reactive oxygen species-mediated hair cell apoptosis; (B) mitochondrial stabilization with compounds such as mitoquinone, celastrol, and histone deacetylase inhibitors restoring bioenergetic and proteostatic balance; and (C) restriction of aminoglycoside entry through partial blockade of the mechano-electrical transduction channel, notably by ORC-13661 and related modulators. Additional strategies involve nitric oxide modulation, vasodilatory agents, and iron chelation. Efficacy, however, remains compound- and antibiotic-specific, with paradoxical effects observed for several drugs. Clinical evidence remains limited and methodologically diverse. Of the investigated pharmacologic interventions, aspirin provides the most robust and reproducible evidence of protection against gentamicin-induced hearing loss, whereas NAC demonstrates a consistent, but population-specific benefit among dialysis patients. In contrast, vitamin E—despite promising experimental findings—has failed to show clinically significant otoprotective effects in randomized human studies. (4) In conclusion, while experimental data establish a strong mechanistic basis for pharmacologic otoprotection, clinical studies remain few, underpowered, and methodologically inconsistent. Standardized, adequately powered, and mechanistically informed clinical trials are urgently needed to translate experimental promise into actionable otoprotective strategies. Full article

Background: Parkinson’s disease (PD) is a complex neurodegenerative disorder in aged people with multifaceted molecular underpinnings. It poses a severe threat to millions of older adults worldwide. The understanding of the molecular mechanisms of PD development and the performance of its therapeutic strategies has not yet reached a satisfactory level. Methods: This study integrated six transcriptomic datasets to uncover key genes (KGs) and their underlying pathogenic mechanisms, providing insights into potential therapeutic strategies for PD. We designed a comprehensive computational pipeline using various bioinformatics tools and databases to investigate PD-causing KGs, focusing on their functions, pathways, regulatory mechanisms, and potential therapeutic drug molecules. Results: In order to explore PD-causing KGs, we initially identified 303 differentially expressed genes (DEGs) between PD and control samples with 204 upregulated and 99 downregulated DEGs using the LIMMA approach with threshold values at Adj. p-value < 0.05 and abs (log₂FC) ≥ 1.0. Then, protein–protein interaction (PPI) network analysis pinpointed seven top-ranked DEGs (GAPDH, PTEN, CCND1, APOE, ESR1, MAPK3/ERK1, and SNCA) as KGs or central modulators of PD pathogenesis. Regulatory network analysis of KGs identified 3 top-ranked transcription factors (FOXC1, NFKB1, and TFAP2A) and 6 microRNAs (hsa-let-7b-5p, hsa-mir-16-5p, and others) as the pivotal regulators of KGs. Gene Ontology (GO) terms and KEGG pathway enrichment analyses with KGs revealed several crucial biological processes, molecular functions, cellular components, and neurodegenerative pathways associated with the development of PD. Finally, the top five molecules guided by KGs (Nilotinib, Bromocriptine, Withaferin-A, Celastrol, and Donepezil) were identified as promising drug candidates against PD and validated computationally through ADME/T analysis and molecular dynamics simulation studies. Conclusions: The findings of this study may serve as valuable resources for developing effective treatment strategies for PD patients. Full article

Nasopharyngeal carcinoma (NPC) is a head and neck malignancy strongly associated with Epstein–Barr virus (EBV) infection and characterized by high radiosensitivity but frequent therapy resistance. Despite advances in radiotherapy, chemotherapy, and immunotherapy, relapse and metastasis remain major challenges, underscoring the need for novel therapeutic approaches. This review aims to provide an integrated overview of the molecular mechanisms governing ferroptosis in NPC and to clarify how these pathways contribute to therapy resistance while revealing potential therapeutic vulnerabilities. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising target in NPC. Core regulators include the system xCT–GSH–GPX4 antioxidant axis, iron metabolism, and lipid remodeling enzymes such as ACSL4, with epigenetic modifiers (METTL3, IGF2BP2, HOXA9) and EBV-driven signaling further shaping ferroptosis responses. EBV-driven oncogenic programs substantially reshape ferroptosis sensitivity in NPC by activating the Nrf2/Keap1 antioxidant axis, stabilizing SLC7A11 and GPX4, and modulating iron and redox metabolism. These viral mechanisms suppress ferroptotic stress and contribute to both radioresistance and chemoresistance. Suppression of ferroptosis underlies both radioresistance and chemoresistance, whereas restoration of ferroptosis re-sensitizes tumors to treatment. Natural compounds including solasodine, berberine, cucurbitacin B, and celastrol-curcumin combinations, as well as pharmacologic modulators such as HO-1 inhibitors and GPX4 antagonists, have shown ferroptosis-inducing effects in preclinical models, although their translational potential remains to be clarified. Nanotechnology-based platforms (e.g., Bi₂Se₃ nanosheet hydrogels) further enhance efficacy and reduce toxicity by enabling controlled drug delivery. Biomarker discovery, encompassing ferroptosis-related gene signatures, epigenetic regulators, immune infiltration patterns, EBV DNA load, and on-treatment redox metabolites, provides a foundation for patient stratification. Integration of ferroptosis modulation with radiotherapy, chemotherapy, and immunotherapy represents a compelling strategy to overcome therapy resistance. In synthesizing these findings, this review highlights both the mechanistic basis and the translational promise of ferroptosis modulation as a strategy to overcome treatment resistance in NPC. Future directions include biomarker validation, optimization of drug delivery, early-phase clinical trial development, and multidisciplinary collaboration to balance ferroptosis induction in tumors while protecting normal tissues. Collectively, ferroptosis is emerging as both a vulnerability and a therapeutic opportunity for improving outcomes in NPC. Full article

Tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs) contain reactive cysteines that can be exploited by targeted covalent inhibitors. In this exploratory computational study, we asked whether selected natural-product-like (NP-like) electrophiles bearing Michael-acceptor (MA) motifs could adopt geometries consistent with covalent approaches to these cysteines, in a manner analogous to approved covalent TKIs. Using AutoDockFR with cysteine-centered grids and explicit side-chain flexibility, we performed pocket-focused, within-receptor covalent docking for EGFR, VEGFR2/KDR, PDGFRβ (via PDGFRα surrogate), BTK, CDK7, and CDK12. Reference inhibitors (osimertinib–EGFR, ibrutinib–BTK, THZ1–CDK7, and THZ531–CDK12) reproduced the expected geometries and served as internal controls. NP-like electrophiles (parthenolide, withaferin A, celastrol, and curcumin as a low-reactivity geometry probe) displayed pocket-compatible orientations in several targets, particularly EGFR and BTK, suggesting feasible pre-reaction alignment toward the reactive cysteine. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds. Full article

Organic anion transporting polypeptide 1B1 (OATP1B1) is specifically expressed at the basolateral membrane of human liver cells and transports a wide range of endogenous compounds, toxins, and drugs, making it a crucial factor in determining the pharmacokinetics of many clinically important medications. Triptergium wilfordii Hook. f. (TWHF) is a traditional Chinese medicine known for its long history of therapeutic effects. A previous study conducted in our laboratory found that major components of TWHF, including wilforine (WFR), wilforgine (WFG), celastrol (CL), and triptolide (TPL), directly suppressed the function of OATP1B1. In the current study, we investigated the long-term (24 h) effects of these TWHF components on the transporter. It was found that TPL was the most potent compound exhibiting inhibitory effects. Mechanistically, TPL accelerated the degradation of OATP1B1, which is likely mediated by serum and glucocorticoid-induced kinase 1 (SGK1). TPL downregulated the mRNA expression of SGK1 and reduced the nuclear accumulation of nuclear factor kappa B (NFκB). Further analysis of the upstream sequence of SGK1 identified three potential binding sites for NFκB. Both luciferase activity assays and chromatin immunoprecipitation (ChIP) analyses confirmed the binding of NFκB to two specific sites located at −1015 bp~−1006 bp and −319 bp~−310 bp. Full article

Equine herpesvirus (EHV) infections represent a significant global veterinary and economic challenge affecting both horses and donkeys across all inhabited continents. This narrative review comprehensively examines the nine distinct EHV species (EHV-1 through EHV-9), their taxonomic classification within Alphaherpesvirinae and Gammaherpesvirinae subfamilies, and their diverse host tropism patterns. The complex molecular pathogenesis involves sophisticated viral glycoproteins (gK, gB, gC, gH, gM, gL, gG, gD, gI, gE) that orchestrate cellular invasion, immune evasion, and intercellular transmission. Clinical manifestations vary considerably, ranging from respiratory diseases and reproductive failures to severe neurological disorders, with EHV-1 demonstrating the most severe presentations including myeloencephalopathy. Global distribution analysis reveals widespread circulation across Europe, Asia, Africa, the Americas, and Oceania, with species-specific clinical patterns. Current therapeutic options remain largely supportive, with experimental compounds like berbamine and cepharanthine, celastrol, blebbistatin, and hyperoside showing promise in preclinical studies. Vaccination programs demonstrate limited effectiveness, failing to prevent transmission at population levels despite inducing individual immune responses. The sophisticated immune evasion strategies employed by EHVs, including the “Trojan horse” mechanism utilizing infected leukocytes, highlight the complexity of host–pathogen interactions and underscore the urgent need for innovative prevention and treatment strategies. Full article

Honey is a valuable natural product prized for its nutritional and therapeutic properties, including antioxidant, antimicrobial, and anti-inflammatory effects. However, in addition to health-promoting compounds, honey may also contain plant-derived toxins, contaminants, and degradation products. Certain phytotoxins—such as pyrrolizidine alkaloids, grayanotoxins, triptolide, celastrol, gelsedine-type alkaloids, and tutin—can be transferred to honey from specific plant sources and pose health risks, particularly at high doses or with long-term exposure. Furthermore, compounds like 5-hydroxymethylfurfural, trace metals, pesticide residues, and Clostridium botulinum spores may present additional risks, especially to sensitive groups such as infants. Consumers often assume that natural products are inherently safe, which may lead to unintentional exposure to harmful substances. Adverse effects can range from chronic toxicity to, in extreme cases, death. Therefore, raising awareness among consumers and vendors is essential to reduce the intake of honey from unverified sources. Continuous monitoring of honey composition and further studies on the toxicodynamics of rare contaminants are crucial to ensuring safety while preserving the therapeutic benefits of this remarkable natural substance. Full article

Background: Based on our previous study, Celastrol-based proteolysis-targeting chimeras (Celastrol-PROTACs) were shown to induce apoptosis in 4T1 cells by selectively degrading GRP94 and CDK1/4 through the endogenous ubiquitin–proteasome system. However, their clinical translation is limited by poor solubility, low targeting efficiency, and liver and kidney toxicity. Methods: To address these limitations, we developed a pegylated liposomal formulation of Celastrol-PROTACs (Lip-Celastrol-PROTACs) and evaluated its therapeutic efficacy and safety profile. Results: The tumor volume of the mice in the Celastrol-PROTACs solution group (286 ± 79 mm³) was significantly larger than that of those in the Lip-Celastrol-PROTACs group (229 ± 49 mm³) on day 18 after intravenous administration (p < 0.01). This difference between the two groups was statistically significant (p < 0.01). Notably, the Celastrol-PROTACs group exhibited significantly greater weight loss compared to the Lip-Celastrol-PROTACs group (p < 0.001). In vivo toxicity assessments revealed that the levels of AST and BUN in the Celastrol-PROTACs group were 27.93 ± 4.88 U/L and 12.36 ± 1.33 μmol/L, respectively, whereas those in the Lip-Celastrol-PROTACs group were found to be 7.92 ± 0.94 U/L and 8.19 ± 0.67 μmol/L, respectively. These findings indicate a statistically significant difference between the two formulations (p < 0.01). Conclusions: Our research demonstrated that pegylated liposomes could improve the targeting efficiency and minimize the toxicity of PROTACs, thereby improving overall therapeutic efficacy. These findings indicated that Lip-Celastrol-PROTACs represent a promising strategy for future clinical applications. Full article

In this report, we describe the synthesis of a compound derived from the natural compound celastrol, which is connected to a phthalimide moiety via an ester linkage. The compound was fully characterized by proton (¹H), carbon-13 (¹³C), heteronuclear single-quantum coherence (HSQC), and distortionless enhancement by polarization transfer (DEPT) NMR. Ultraviolet–visible spectroscopy (UV-Vis), Fourier-transform infrared (FTIR), and elementary analysis were also performed. Full article

Avian colibacillosis causes significant economic losses and raises concerns for human health due to food safety risks, a problem exacerbated by the increase in antibiotic resistance. This study aimed to develop novel antibacterial strategies using fermented liquid of Sini decoction dregs to address these challenges. We analyzed the transcriptome of the chicken thymus sample GSE69014 in the GEO database to identify immune-related genes, performed molecular docking to assess compound interactions, and experimental validation via Western blot and ELISA to evaluate anti-inflammatory effects. Results revealed 11 core genes, including TLR4, critical for immune responses against the infection, with TLR4 activating key inflammatory pathways. Fermented liquid with probiotics enhanced bioactivity, and natural compounds Dioscin and Celastrol from the fermented liquid inhibited inflammation by targeting the TLR4-MD2 complex. In animal models, fermented liquid outperformed individual compounds, likely due to synergistic effects, significantly reducing inflammatory markers. These findings demonstrate that fermented liquid of Sini decoction dregs offers a promising, sustainable approach to control avian colibacillosis, mitigate antibiotic resistance, and improve poultry health, providing a scientific foundation for its application in farming to reduce economic losses and enhance food safety. Full article

Background: Celastrol, a pentacyclic triterpenoid active component isolated from the root bark of the traditional medicinal plant Tripterygium wilfordii, displays significant anti-inflammatory, antioxidant, and immunomodulatory properties. However, its clinical application remains limited due to inadequate bioavailability. Methods: Regarding these issues, we innovatively developed a novel peanut cultivar (cel-peanut) enriched with celastrol through distant hybridization combined with metabolomics screening. Guided by the research concept of “natural anti-inflammatory diets for metabolic disease management”, we established a high-fat diet-induced ApoE^−/− atherosclerotic mouse model to systematically evaluate the anti-atherosclerosis effects and mechanisms of cel-peanut. Results: Our results revealed that cel-peanut significantly reduced serum levels of triglycerides (TGs) and increased high-density lipoprotein cholesterol (HDL-C). Concurrently, cel-peanut markedly decreased the atherosclerotic lesion area and enhanced collagen content within plaques. Mechanistic investigations demonstrated that cel-peanut reduced serum malondialdehyde (MDA) levels and suppressed the concentration of pro-inflammatory cytokine IL-6 in atherosclerotic lesions. Furthermore, cel-peanut promoted intestinal health by modulating the composition and functionality of gut microbiota, thereby attenuating atherosclerosis progression. Conclusions: Overall, these findings indicate that cel-peanut exerts therapeutic effects against atherosclerosis through its anti-inflammatory, antioxidant, and gut microbiota-modulating properties. This study proposes a novel nutritional intervention strategy for atherosclerosis and provides a promising adjuvant strategy for clinical atherosclerosis treatment. Full article

Background: Celastrol (Cela), a phytochemical extracted from Tripterygium wilfordii, has been extensively investigated for its potential anti-inflammatory, anti-psoriatic, antioxidant, neuroprotective, and antineoplastic properties. However, its clinical translation is limited due to poor bioavailability, low solubility, and nonspecific toxicity. This study aimed to develop and evaluate an inhalable Cela-loaded nanoemulsion (NE) formulation to enhance targeted drug delivery and therapeutic efficacy in non-small cell lung cancer (NSCLC). Methods: The NE formulation was optimized using Capmul MCM (25%), Tween 80 (20%), Transcutol HP (5%), and water (50%) as the oil, surfactant, co-surfactant, and aqueous phase, respectively. Physicochemical characterization included globule size, zeta potential, and drug release in simulated lung fluid. In vitro aerosolization performance, cytotoxicity in NSCLC cell lines (A549), scratch and clonogenic assays, and 3D tumor spheroid models were employed to assess therapeutic potential. Results: The NE showed a globule size of 201.4 ± 3.7 nm and a zeta potential of −15.7 ± 0.2 mV. Drug release was sustained, with 20.4 ± 5.5%, 29.1 ± 10%, 64.6 ± 4.1%, and 88.1 ± 5.2% released at 24, 48, 72, and 120 h, respectively. In vitro aerosolization studies indicated a median aerodynamic particle size of 4.8 ± 0.2 μm, confirming its respirability in the lung. Cell culture studies indicated higher toxicity of NE-Cela in NSCLC cells. NE-Cela significantly reduced A549 cell viability, showing a ~6-fold decrease in IC₅₀ (0.2 ± 0.1 μM) compared to Cela alone (1.2 ± 0.2 μM). Migration and clonogenic assays demonstrated reduced cell proliferation, and 3D spheroid models supported its therapeutic activity in tumor-like environments. Conclusions: The inhalable NE-Cela formulation improved Cela’s physicochemical limitations and demonstrated enhanced anti-cancer efficacy in NSCLC models. These findings support its potential as a targeted, well-tolerated therapeutic option for lung cancer treatment. Full article