Search Results (413)

Cholangiocarcinoma (CCA) is highly prevalent in the Greater Mekong sub-region, especially northeastern Thailand, where infection with the liver fluke Opisthorchis viverrini is a major etiological factor. Limited therapeutic options and the absence of reliable early diagnosis tools impede effective disease control. Atractylodes lancea (Thunb.) DC.—long used in Thai and East Asian medicine, contains atractylodin (ATD), a potent bioactive compound with anticancer potential. Here, we developed ATD-loaded poly(lactic co-glycolic acid) nanoparticles (ATD PLGA NPs) and evaluated their antitumor efficacy against CCA. The formulated nanoparticles had a mean diameter of 229.8 nm, an encapsulation efficiency of 83%, and exhibited biphasic, sustained release, reaching a cumulative release of 92% within seven days. In vitro, ATD-PLGA NPs selectively reduced the viability of CL-6 and HuCCT-1 CCA cell lines, with selectivity indices (SI) of 3.53 and 2.61, respectively, outperforming free ATD and 5-fluorouracil (5-FU). They suppressed CL-6 cell migration and invasion by up to 90% within 12 h and induced apoptosis in 83% of cells through caspase-3/7 activation. Micronucleus assays showed lower mutagenic potential than the positive control. In vivo, ATD-PLGA NPs dose-dependently inhibited tumor growth and prolonged survival in CCA-xenografted nude mice; the high-dose regimen matched or exceeded the efficacy of 5-FU. Gene expression analysis revealed significant downregulation of pro-tumorigenic factors (VEGF, MMP-9, TGF-β, TNF-α, COX-2, PGE₂, and IL-6) and upregulation of the anti-inflammatory cytokine IL-10. Collectively, these results indicate that ATD-PLGA NPs are a promising nanotherapeutic platform for targeted CCA treatment, offering improved anticancer potency, selectivity, and safety compared to conventional therapies. Full article

Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article

Chrysanthemum × morifolium (Ramat) Hemsl. (Hangbaiju), which has been widely consumed as a herbal tea for over 3000 years, is renowned for its biosafety and diverse bioactivities. This study investigates the impact of polyphenol-rich Hangbaiju extracts (HE) on high-fat diet-induced obesity in mice. HE contains phenolic acids and flavonoids with anti-obesity properties, such as apigenin, luteolin-7-glucoside, apigenin-7-O-glucoside, kaempferol 3-(6″-acetylglucoside), etc. To establish the obesity model, mice were randomly assigned into four groups (n = 8 per group) and administered with either HE or water for 42 days under high-fat or low-fat dietary conditions. Administration of low (LH) and high (HH) doses of HE both significantly suppressed body weight growth (by 16.28% and 16.24%, respectively) and adipose tissue enlargement in obese mice. HE significantly improved the serum lipid profiles, mainly manifested as decreased levels of triglycerides (28.19% in LH and 19.59% in HH) and increased levels of high-density lipoprotein cholesterol (44.34% in LH and 54.88% in HH), and further attenuated liver lipid deposition. Furthermore, HE significantly decreased the Firmicutes/Bacteroidetes ratio 0.23-fold (LH) and 0.12-fold (HH), indicating an improvement in the microecological balance of the gut. HE administration also elevated the relative abundance of beneficial bacteria (e.g., Allobaculum, norank_f__Muribaculaceae), while suppressing harmful pathogenic proliferation (e.g., Dubosiella, Romboutsia). In conclusion, HE ameliorates obesity and hyperlipidemia through modulating lipid metabolism and restoring the balance of intestinal microecology, thus being promising for obesity therapy. Full article

Background: Heat therapy (HT) and electroacupuncture (EA) are widely utilized pain relief methods, but the analgesic mechanisms of their combined application remain unclear. Methods: In acetic acid (AA)-induced writhing test and complete Freund’s adjuvant (CFA)-induced inflammatory pain tests, mice received one of three treatments: EA at bilateral ST36, HT via a 45 °C heating pad, or the combination (EA + HT). To probe underlying pathways, separate groups were pretreated with caffeine, DPCPX (a selective adenosine A₁ receptor antagonist), or naloxone (an opioid receptor antagonist). Spinal expression of glial fibrillary acidic protein (GFAP) and phosphorylated p38 (p-p38) was examined by Western blot and immunofluorescence. Results: Both EA and HT individually reduced AA-induced writhing, with the combination (EA + HT) exhibiting the greatest analgesic effect. EA’s analgesic effect was reversed by caffeine and DPCPX and partially by naloxone, while HT’s effect was reversed by caffeine and DPCPX but was unaffected by naloxone. AA injection elevated spinal p-p38 and GFAP expression, which were attenuated by either EA or HT, with the most substantial suppression observed in the EA + HT group. In the CFA model, both treatments alleviated mechanical allodynia, while the combined treatment resulted in significantly greater analgesia compared to either treatment alone. Conclusions: EA combined with HT synergistically enhances analgesia in both AA and CFA pain models, accompanied by reduced spinal inflammation and astrocyte activation. EA’s analgesic effects appear to involve adenosine A₁ receptor pathways and, to a lesser extent, opioid receptor mechanisms, whereas HT’s effects involve adenosine A₁ receptor pathways. Full article

Polyomaviruses are a family of small DNA viruses capable of establishing persistent infections, and they can pose significant pathogenic risks in immunocompromised hosts. While traditionally studied in the context of viral reactivation and immune suppression, recent evidence has highlighted the gut microbiota as a critical regulator of host immunity and viral pathogenesis. This review examines the complex interactions between polyomaviruses, the immune system, and intestinal microbiota, emphasizing the role of short-chain fatty acids (SCFAs) in modulating antiviral responses. We explore how dysbiosis may facilitate viral replication, reactivation, and immune escape and also consider how polyomavirus infection can, in turn, alter microbial composition. Particular attention is given to the Firmicutes/Bacteroidetes ratio as a potential biomarker of infection risk and immune status. Therapeutic strategies targeting the microbiota, including prebiotics, probiotics, and fecal microbiota transplantation (FMT), are discussed as innovative adjuncts to immune-based therapies. Understanding these tri-directional interactions may offer new avenues for mitigating disease severity and improving patient outcomes during viral reactivation. Full article

Background: Short-chain fatty acids (SCFAs), microbial metabolites also known as postbiotics, are essential for maintaining gut health. However, their antiproliferative effects on gastric cancer cells and potential interactions with conventional therapies remain underexplored. This study aimed to investigate the effects of three SCFA salts—magnesium acetate (A), sodium propionate (P), and sodium butyrate (B)—individually and in combination (APB), as well as in combination with dexamethasone (Dex), on AGS gastric adenocarcinoma cells. Methods: AGS cells were treated with PB, AP, AB, APB, Dex, and APB+Dex. Cell viability was assessed to determine antiproliferative effects, and the IC₅₀ of APB was calculated. Flow cytometry was used to evaluate apoptosis and necrosis. Reactive oxygen species (ROS) levels were measured to assess oxidative stress. Proteomic analysis via LC-MS was performed to identify differential protein expression and related pathways impacted by the treatments. Results: SCFA salts showed significant antiproliferative effects on AGS cells, with APB exhibiting a combined IC₅₀ of 568.33 μg/mL. The APB+Dex combination demonstrated strong synergy (combination index = 0.76) and significantly enhanced growth inhibition. Both APB and APB+Dex induced substantial apoptosis (p < 0.0001) with minimal necrosis. APB alone significantly increased ROS levels (p < 0.0001), while Dex moderated this effect in the combination group APB+Dex (p < 0.0001). Notably, the APB+Dex treatment synergistically targeted multiple tumour-promoting mechanisms, including the impairment of redox homeostasis through SLC7A11 suppression, and inhibition of the haemostasis, platelet activation network and NF-κB signalling pathway via downregulation of NFKB1 (−1.34), exemplified by increased expression of SERPINE1 (1.99) within the “Response to elevated platelet cytosolic Ca²⁺” pathway. Conclusions: These findings showed a multifaceted anticancer mechanism by APB+Dex that may collectively impair cell proliferation, survival signalling, immune modulation, and tumour microenvironment support in gastric cancer. Full article

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment (TME), interacting with cancer cells and other components to promote tumor growth. Given the influence of TAMs on tumor progression and resistance to therapy, regulating the activity of these macrophages is crucial for improving cancer treatment outcomes. TAMs often exhibit immunosuppressive phenotypes (commonly referred to as M2-like macrophages), which suppress immune responses and contribute to drug resistance. Therefore, inhibiting immunosuppressive polarization offers a promising strategy to impede tumor growth. This study revealed retinoic acid receptor gamma (RARγ), a nuclear receptor, as a key regulator of immunosuppressive polarization in THP-1 macrophages. Indeed, the inhibition of RARγ, either by a small molecule or gene silencing, significantly reduced the expression of immunosuppressive macrophage markers. In a three-dimensional tumor spheroid model, immunosuppressive macrophages enhanced the proliferation of HCT116 colorectal cancer cells, which was significantly hindered by RARγ inhibition. These findings suggest that targeting RARγ reprograms immunosuppressive macrophages and mitigates the tumor-promoting effects of TAMs, highlighting RARγ as a promising therapeutic target for developing novel anti-cancer strategies. Full article

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect Full article

The tumor microenvironment plays an important role in tumor incidence, metastasis, and chemotherapy resistance. Novel therapeutic strategies targeting the tumor microenvironment have become a research focus in the field of biomedicine. In this study, we developed a smart small-molecule probe, TZ2, featuring pH/GSH dual-responsive characteristics. TZ2 exhibits a unique pH-dependent reaction mechanism: GSH is preferentially covalently modified with maleimide groups in acidic microenvironments (pH < 7), while specifically activating nucleophilic substitutions under alkaline conditions (pH > 7). It is worth noting that TZ2 effectively eliminates intracellular glutathione (GSH) in a time and concentration-dependent manner, demonstrating significant GSH depletion ability in various tumor cell lines. Pharmacodynamic studies have shown that TZ2 not only inhibits the cell cycle by regulating the expression of cell cycle-related proteins, but also effectively suppresses the cloning ability of cancer cells. Furthermore, TZ2 significantly increases the sensitivity of drug-resistant cancer cells to cisplatin. By integrating microenvironment modulation, real-time monitoring, and synergistic therapy, TZ2 provides a novel molecular tool and theoretical basis for tumor theranostics integration. Full article

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H₂O₂-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD⁺/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H₂O₂-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases. Full article

Malignant pleural effusion (MPE) can lead to pleural organization with loculation and impaired drainage. This condition is becoming increasingly more common due to advancements in cancer therapy and extended patient survival. Factors such as repeated thoracentesis through an indwelling pleural catheter (IPC), intrapleural bleeding, and tumor progression contribute to MPE organization. Loculated MPE causes breathlessness and reduced quality of life, and current therapies, including intrapleural fibrinolytic or enzymatic therapy (IPFT/IET), have limitations in efficacy and safety. Identifying new therapeutic targets is crucial for improving treatment outcomes. Research is needed to understand the role of profibrogenic factors in pleural neoplasia, their regulation, and their impact on different stages of pleural organization. The development of a rabbit model of organizing MPE could provide insights into underlying mechanisms and novel interventions. Comparative studies of pleural tissues and effusions from MPE patients and other forms of pleural organization may reveal valuable information. Cellular and molecular profiling, assessment of biomarkers, and personalized IPFT dosing are potential areas of investigation. Suppression of PAI-1 activity and the role of hyaluronic acid in malignant mesothelioma are also important research directions. Understanding the profibrogenic capacity of pleural mesothelial cells undergoing mesenchymal transition (MesoMT) and identifying key contributors and effectors involved in this process are essential for developing effective treatments for loculated MPE. Full article

Background: Allergic rhinitis (AR) is a prevalent allergic disorder characterized by a complex pathogenesis. Drawing on traditional Chinese medicine theory and contemporary pharmacological principles, this study developed an inhalation-based herbal formulation, ZHW, to explore a novel non-invasive therapeutic approach. Objective: To investigate the therapeutic effects of ZHW on AR and elucidate its underlying mechanisms and potential targets through an integrated analysis of network pharmacology and proteomics. Materials and Methods: The volatile components of ZHW were analyzed by gas chromatography–mass spectrometry (GC-MS). The mouse model of AR was induced by OVA sensitization. The therapeutic efficacy of ZHW was assessed based on nasal symptom scores, histopathological examination, and inflammatory cytokine levels. Furthermore, the underlying mechanisms and potential targets of ZHW were investigated through integrated network pharmacology and proteomics analyses. Results: GC-MS analysis identified 39 bioactive compounds in ZHW. Inhalation treatment with ZHW demonstrated significant anti-allergic effects in OVA-sensitized mice, as evidenced by (1) reduced sneezing frequency and nasal rubbing behaviors; (2) decreased serum levels of IL-4, histamine, and OVA-specific IgE; (3) attenuated IL-4 concentrations in both nasal lavage fluid and lung tissue; (4) diminished nasal mucosal thickening; and (5) suppression of inflammatory cell infiltration. Integrated network pharmacology and proteomics analyses indicated that ZHW’s therapeutic effects were mediated through the modulation of multiple pathways, including the PI3K-Akt signaling pathway, the B cell receptor signaling pathway, oxidative phosphorylation, and the FcεRI signaling pathway. Key molecular targets involved Rac1, MAPK1, and SYK. Molecular docking simulations revealed strong binding affinities between ZHW’s primary bioactive constituents (linalool, levomenthol, linoleic acid, Linoelaidic acid, and n-Valeric acid cis-3-hexenyl ester) and these target proteins. Conclusions: The herbal formulation ZHW demonstrates significant efficacy in alleviating allergic rhinitis symptoms through multi-target modulation of key signaling pathways, including PI3K-Akt- and FcεRI-mediated inflammatory responses. These findings substantiate ZHW’s therapeutic potential as a novel, non-invasive treatment for AR and provide a strong basis for the development of new AR therapies. Future clinical development will require systematic safety evaluation to ensure optimal therapeutic outcomes. Full article

Vitamin C, also known as L-ascorbic acid (AA), functions as a pro-oxidant in cancer at high doses and exerts anticancer effects by generating reactive oxygen species (ROS) and selectively inducing damage to cancer cells. However, AA at low doses promotes cancer cell proliferation. The efficacy of high-dose AA therapy is frequently restricted by inadequate intracellular AA uptake, resulting from low expression of sodium-dependent vitamin C transporter 2 (SVCT2). In this study, we investigated whether valproic acid (VPA), a histone deacetylase inhibitor, could circumvent this constraint by increasing the expression of SVCT2 in colorectal cancer cells, including HCT-116 and DLD-1 with low SVCT2 levels. We found that VPA increased SVCT2 expression in both cell lines. Co-treatment with AA and VPA increased the number of apoptotic cells and enhanced intracellular AA uptake via VPA-upregulated SVCT2, followed by increased ROS production in both cell lines. Furthermore, the combination increased the synergistic anticancer effects and suppressed the hormetic dose response of AA in both cell lines. In a xenograft mouse model, co-treatment decreased tumor size and increased the tumor growth inhibition ratio compared to treatment with AA or VPA alone. Accordingly, VPA treatment enhanced SVCT2 expression in colorectal cancer cells, suppressed the hormetic dose-response effect of AA, and improved the potential of high-dose AA therapy as an anticancer agent. Full article

Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury (DILI) globally, which necessitates effective therapies. Gallic acid (GA), a naturally abundant polyphenol, possesses potent antioxidant and anti-inflammatory properties that may overcome the limitations of N-acetylcysteine (NAC), such as its narrow therapeutic window. This study systematically investigated the hepatoprotective effects and underlying molecular mechanisms of GA against APAP-induced acute liver injury (ALI). Mice received an intraperitoneal injection of APAP (300 mg/kg), followed by an oral administration of GA (50 or 100 mg/kg) or NAC (150 mg/kg) 1 h post-intoxication. Both GA and NAC significantly ameliorated hypertrophy and histopathological damage, as evidenced by reduced serum ALT/AST levels and inflammatory cytokines. TUNEL staining revealed a marked suppression of apoptotic and necrotic cell death, further supported by the downregulation of pro-apoptotic Bax and the upregulation of anti-apoptotic Bcl-2 mRNA expression. GA and NAC treatment restored hepatic glutathione (GSH) content, enhanced antioxidant enzyme gene expression, and reduced malondialdehyde (MDA) accumulation. Mechanistically, GA and NAC inhibited MAPK phosphorylation while activating AMPK signaling. Taken together, these findings demonstrate that GA mitigates APAP-induced ALI by modulating oxidative stress and inflammation through the regulation of MAPK/AMPK signaling proteins. Full article