Search Results (5,308)

Reactive oxygen species (ROS) act as double-edged swords in cancer biology—facilitating tumor growth, survival, and metastasis at moderate levels while inducing oxidative damage and cell death when exceeding cellular buffering capacity. To survive under chronic oxidative stress, cancer cells rely on robust antioxidant systems such as the glutathione (GSH) and thioredoxin (Trx), and superoxide dismutases (SODs). These systems maintain redox homeostasis and sustain ROS-sensitive signaling pathways including MAPK/ERK, PI3K/Akt/mTOR, NF-κB, STAT3, and HIF-1α. Targeting the antioxidant defense mechanisms of cancer cells has emerged as a promising therapeutic strategy. Inhibiting the glutathione system induces ferroptosis, a non-apoptotic form of cell death driven by lipid peroxidation, with compounds like withaferin A and altretamine showing strong preclinical activity. Disruption of the Trx system by agents such as PX-12 and dimethyl fumarate (DMF) impairs redox-sensitive survival signaling. Trx reductase inhibition by auranofin or mitomycin C further destabilizes redox balance, promoting mitochondrial dysfunction and apoptosis. SOD1 inhibitors, including ATN-224 and disulfiram, selectively enhance oxidative stress in tumor cells and are currently being tested in clinical trials. Mounting preclinical and clinical evidence supports redox modulation as a cancer-selective vulnerability. Pharmacologically tipping the redox balance beyond the threshold of cellular tolerance offers a rational and potentially powerful approach to eliminate malignant cells while sparing healthy tissue, highlighting novel strategies for targeted cancer therapy at the interface of redox biology and oncology. Full article

This study investigated the immunomodulatory effects and underlying mechanisms of total flavonoid of Spatholobus suberectus Dunn (TFSD) and its primary constituent formononetin (FMN) in immunosuppressed mouse models. Spatholobus suberectus Dunn (S. suberectus Dunn) was first analyzed qualitatively and quantitatively by broadly targeted metabolomics using Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Integrated network pharmacology and molecular docking approaches were used to investigate the potential mechanisms underlying S. suberectus Dunn’s immunomodulatory effects. Subsequently, mice were pretreated with TFSD and FMN for seven days before constructing an immunosuppression model through intraperitoneal injection of 200 mg/kg.bw cyclophosphamide (CTX). In vivo experiments validated the findings and investigated the mechanisms underlying the effects of TFSD and FMN on immunosuppression. Metabolomic analysis identified 501 distinct flavonoids in S. suberectus Dunn, with FMN exhibiting the highest relative abundance among all detected compounds. The primary active components of S. suberectus Dunn against immunosuppression are flavonoids, including FMN and vestitol. The core targets of these components were identified as NF-κB and IKKβ, with the NF-κB signaling pathway being suggested as the most probable mechanism of action. FMN exhibited strong binding affinity to the core targets, NF-κB p65 and IKKβ. In vivo experiments indicated that pretreatment with TFSD and FMN prevented CTX-induced pathological damage in the spleen and thymus and increased immune cell counts and immunoglobulin levels. Additionally, it significantly upregulated the secretion and expression of key cytokines and the mRNA expression of NF-κB p65, IKKα, and IKKβ (p < 0.05 or p < 0.01). In conclusion, TFSD and FMN can protect mice from CTX-induced immunosuppression by regulating the NF-κB signaling pathway, making them promising drug candidates for preventing and treating immunosuppression-related diseases. Full article

Hederagenin, a pentacyclic triterpenoid saponin from various medicinal plants, shows immense therapeutic potential; however, its inherent low bioavailability severely hinders its clinical translation. This comprehensive review synthesizes recent studies on the health benefits of hederagenin and its glycosides, critically the chemical modification strategies and pharmacological mechanisms aimed at optimizing its bioactivity. Key findings reveal that its broad anticancer and anti-inflammatory activities largely stem from its capacity to modulate crucial cellular signaling pathways, including the NF-κB, PI3K/Akt, and MAPK. Structural modification, particularly intelligent derivatization at the C-28 position, is a central strategy to overcome its pharmacokinetic deficiencies and significantly boost cytotoxicity. Furthermore, its unique pro-oxidant function within cancer cells, achieved by inhibiting the Nrf2-ARE antioxidant pathway, offers a novel approach for selective chemotherapeutics. For the clinical translation of hederagenin, we propose a strategic focus on derivatization through multi-target hybrids and sophisticated delivery systems. This approach is essential for addressing its pharmacokinetic barriers while strategically leveraging its context-dependent pro-oxidant effects. Full article

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by high intratumoral heterogeneity, therapy resistance, and poor prognosis. Nuclear factor-κB (NF-κB) signaling plays a pivotal role in GBM pathogenesis by promoting proliferation, invasion, inflammation, immune evasion, and treatment resistance. This review provides a comprehensive overview of canonical and non-canonical NF-κB signaling pathways and their molecular mechanisms in GBM, with a focus on their regulation in glioma stem-like cells (GSCs), interactions with key oncogenic factors (including STAT3, FOSL1, and TRPM7), and roles in maintaining tumor stemness, metabolic adaptation, and angiogenesis. We further discuss the reciprocal regulatory dynamics between NF-κB and non-coding RNAs (ncRNAs), particularly microRNAs, highlighting novel ncRNA-mediated epigenetic switches that shape GBM cell plasticity and subtype specification. Additionally, we examine the influence of NF-κB in modulating the tumor microenvironment (TME), where it orchestrates pro-tumorigenic cytokine production, immune cell reprogramming, and stromal remodeling. Finally, we review current NF-κB-targeting therapeutic strategies in GBM, including clinical trial data on small-molecule inhibitors and combinatorial approaches. Understanding the multifaceted roles of NF-κB in GBM offers new insights into targeted therapies aimed at disrupting tumor-promoting circuits within both cancer cells and the TME. Full article

This study investigates the effect of walnut green husk extract (WE) on gut microbiota, metabolites, and immune-antioxidant changes in fattening pigs through gut microbiota-metabolite interactions. A total of 60 healthy fattening pigs (Duroc × Landrace × Yorkshire) with an initial body weight of 65.2 ± 3.1 kg were randomly assigned to two groups (n = 30 per group): the control group (NC), which was fed a basal diet, and the WE group, which was fed the basal diet supplemented with 0.1% walnut green husk extract (WE). Dietary supplementation with 0.1% WE significantly increased the relative abundances of beneficial bacteria (e.g., Firmicutes, Lactobacillus) and reduced pathogenic bacteria (e.g., Proteobacteria, Shigella). Untargeted metabolomics identified 170 differentially accumulated metabolites, among which propionic acid—a key short-chain fatty acid with immunomodulatory effects—was significantly upregulated by 1.09-fold (p = 0.03) and showed a positive correlation with beneficial microbial abundances. These metabolites were enriched in glycerophospholipid and α-linolenic acid metabolism pathways, where eicosadienoic acid inhibited the nuclear factor kappa-B (NF-κB) pathway for anti-inflammatory effects, and methyl cinnamate synergistically regulated mitogen-activated protein kinase (MAPK) signaling with Lactobacillus. Serum analyses showed that WE significantly enhanced IgA, IgM, and IgG levels by 3.97-fold, 4.67-fold, and 4.43-fold (p < 0.01), reduced malondialdehyde (MDA) concentration by 82.8% (p < 0.01), and trended to improve antioxidant capacity via glutamine. Mechanistically, WE promoted short-chain fatty acid production by beneficial bacteria, forming a “microbiota–metabolite–immunity” cascade to enhance lipid metabolism and alleviate intestinal inflammation. These findings highlight that WE provides multi-omics evidence for its application as a functional feed additive. Full article

Background: Previously, we established gemcitabine (Gem)-resistant pancreatic cancer (PaCa) cell lines and showed that the acquisition of Gem resistance is accompanied by enhanced activation of the inflammatory transcription factor nuclear factor-κB (NF-κB). In this study, we focus on CalebinA, a natural compound derived from the rhizomes of turmeric, known for its potent anti-inflammatory properties. It has been suggested that this compound may exert anticancer effects by downregulating the NF-κB signaling cascade. Therefore, we collaborated with Sabinsa Corporation, Japan, to explore its potential application in pancreatic cancer therapy. Methods: We used gemcitabine-resistant pancreatic cell lines to demonstrate the effect of CalebinA on cell toxicity, invasiveness, cytokine levels, NF-κB p65 activity, and tube formation in angiogenesis. Tumor volume and histopathological analysis were used to analyze the effects of CalebinA on tumors induced by the subcutaneous injection of pancreatic cell lines in mice. Results: Treatment with 10 μM CalebinA significantly inhibited NF-κB activity. Gem-resistant PaCa cells exhibited higher invasive and angiogenic capacities than non-resistant parental cells; however, these capacities were markedly suppressed by CalebinA. In vivo, intraperitoneal CalebinA administration every 3 days led to a significant reduction in tumor volume in mice bearing subcutaneous xenografts of the AsPC-1 pancreatic cancer cell line. Immunohistochemical analysis revealed that CalebinA suppressed the expression of Ki-67, CD31-positive microvessel density, and NF-κB p65. Conclusions: These findings suggest that CalebinA holds promise as a novel therapeutic agent for Gem-resistant pancreatic cancer and may be a strong candidate for clinical application. Full article

Background/Objectives: Doxorubicin (DOXO) is effective against various types of cancer; however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Methods: Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Results: Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-κB and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1α and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-β1 and α-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Conclusions: Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-κB and IL-17A/STAT3/HIF-1α/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis. Full article

Histamine can damage the antioxidant and immune systems in fish and crustaceans. Rutin, a natural substance with a diverse phenolic structure, has demonstrated antioxidant and anti-inflammatory properties. However, whether rutin can mitigate histamine-induced negative effects remains uninvestigated in fish models. This study investigated the effect of 0.1–100 μM rutin preincubation on histamine (29.5 mM)-induced cytotoxicity in zebrafish liver cells (ZFL) and its potential mechanisms. Results showed that 0.1–100 μM rutin significantly improved ZFL cell survival following histamine stimulation and protected cellular morphology. Rutin inhibited the adverse effects of histamine on ZFL by scavenging or suppressing the accumulation of reactive oxygen species (ROS), H₂O₂, and malondialdehyde (MDA), while increasing the activities of superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC). At the protein level, 10 μM rutin significantly promoted Nrf2 protein expression. HO-1 protein was significantly up-regulated after preincubation with 0.1–10 μM rutin, whereas IL-1β protein levels were significantly down-regulated. The mechanism may involve activation of the Nrf2 antioxidant signaling pathway and inhibition of the NF-κB inflammatory signaling pathway. In summary, within the experimental concentration range, 10 μM rutin showed the strongest inhibitory effects on histamine-induced ZFL cell death and oxidative stress. This study provides a theoretical basis and data support for evaluating rutin’s feasibility as a green aquatic feed additive. Full article

Liver cirrhosis represents the end-stage of chronic hepatic injury, arising from a diverse range of etiologies including viral hepatitis, alcohol abuse and non-alcoholic fatty liver disease. A key driver of cirrhosis is hepatic fibrogenesis, a multifaceted process involving hepatic stellate cell activation, inflammatory signaling and extracellular matrix accumulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, have emerged as pivotal regulators in this context, modulating gene expression networks that govern inflammation, fibrosis and hepatocarcinogenesis. This review synthesizes current evidence on the role of miRNAs in liver cirrhosis, emphasizing specific miRNAs such as miR-21, miR-122, miR-125, miR-146 and miR-155. These miRNAs influence pathways involving TGF-β, NF-κB and PI3K/Akt signaling, contributing to either fibrogenic progression or its suppression. The unique expression profiles and stability of miRNAs in biological fluids position them as promising non-invasive biomarkers for cirrhosis diagnosis and monitoring. Moreover, therapeutic modulation of miRNA activity through mimics or inhibitors holds future potential, though delivery and safety challenges remain. Advancing our understanding of miRNA-mediated regulation in cirrhosis could transform current diagnostic and therapeutic strategies, enabling more precise and personalized liver disease management. Full article

Gastric ulcer (GU) is a common gastrointestinal disorder that impacts quality of life. Currently, several drugs are available for GU treatment, including proton pump inhibitors like omeprazole (OMP); however, their use is limited by numerous potential adverse effects. Glycyrrhizic acid (GLY), a natural anti-inflammatory agent, exhibits promising gastroprotective properties; however, its use is likewise limited by numerous potential adverse effects. This study aimed to synthesize GLY nanoparticles (GLY-NPs) to enhance their therapeutic potential and to comparatively evaluate their efficacy against OMP in an ethanol-induced GU in male Wistar rats. GLY-NPs were synthesized via a hydrothermal method and characterized using TEM, XRD, FTIR, and zeta potential analyses. In vivo, GLY-NPs significantly attenuated gastric mucosal damage compared to OMP, as evidenced by macroscopic and histopathological analyses. Biochemical assays revealed that GLY-NPs markedly improved antioxidant defenses by elevating SOD, catalase, and glutathione peroxidase activities while reducing MDA levels, surpassing the effects of OMP. Furthermore, GLY-NPs modulated inflammatory responses by downregulating p38 MAPK, NF-κB, and TNF-α expression, concomitant with upregulation of the anti-inflammatory cytokine IL-10. Mechanistic insights indicated that GLY-NPs favorably regulated key signaling pathways implicated in gastric mucosal protection, including suppression of the JAK2/STAT3 and TGF-β1/Smad3 pathways, alongside activation of the SIRT1/FOXO1/PGC-1α axis. In conclusion, these findings indicate that GLY-NPs offer higher gastroprotective effects relative to traditional OMP therapy through comprehensive modulation of oxidative stress, inflammation, and molecular signaling pathways. This study highlights GLY-NPs as a potent nanotherapeutic candidate for the effective management of GU. Full article

Background/Objectives: Perilla frutescens var. acuta Kudo, a member of the Lamiaceae family, has been previously reported to reduce neuroinflammation and potentially decrease Aβ plaque accumulation in 5XFAD mice. In this study, we aimed to evaluate the anti-neuroinflammatory potential of a standardized 60% ethanol extract of Perilla leaves (PE), optimized for commercial application. Methods: The inflammatory response was assessed in LPS-stimulated BV2 microglial cells, and the cognitive improvement was evaluated in an AD animal model induced by intracerebroventricular injection of Aβ. Results: Using LPS-stimulated BV2 microglial cells and an Aβ-injected ICR mouse model of Alzheimer’s disease, we found that PE significantly suppressed the LPS-induced production of nitric oxide and pro-inflammatory mediators, including IL-6, TNF-α, NF-κB, iNOS, and COX-2, along with inhibition of JNK and p38 MAPK activation. Furthermore, PE upregulated CREB and BDNF expression. In vivo, PE administration alleviated Aβ-induced cognitive deficits, which were associated with reduced expression of JNK, NF-κB, iNOS, and COX and increased CREB/BDNF signaling in the hippocampus. Behavioral assessments—including passive avoidance, Morris water maze, novel object recognition, and Y-maze tests—confirmed the improvement in cognitive function. Conclusions: Collectively, these findings demonstrate that PE exerts significant anti-neuroinflammatory and neuroprotective effects, supporting its potential as a functional ingredient for cognitive enhancement. Full article

Dancong tea is a representative type of oolong tea typically stored for over six months before sale to reduce gastrointestinal irritation. The effects and mechanisms of this storage on gastrointestinal damage remain unclear. Therefore, this study investigated hydrochloric acid and ethanol (HCl/EtOH)-induced gastric injury in mice. The results indicate that six-month-stored Dancong tea (OldT) alleviated gastric injury at low doses but showed no protective effect at high doses; in fact, high-dose OldT exacerbated injury. In contrast, fresh tea (NewT) aggravated gastric injury at both low and high doses. Hematoxylin and eosin (H&E) staining revealed that low-dose OldT significantly attenuated gastric histopathological injury. Mechanistically, low-dose OldT reduced injury via antioxidant and anti-inflammatory pathways (Nrf-2/HO-1 activation and NF-κB inhibition), and inhibiting lipid peroxidation, reactive oxygen species (ROS), nitric oxide (NO), and inflammatory mediators (iNOS, COX-2, IL-6, TNF-α). These findings suggest that storage reduces the gastrointestinal irritant properties of fresh Dancong tea, providing a scientific basis for industrial practice and guiding consumption. Full article

Postpartum metritis in dairy cows compromises reproductive performance and leads to substantial economic losses. This study investigated the molecular mechanisms underlying metritis by integrating high-throughput circulating microRNA (miRNA) profiling with systems-level bioinformatics. Previously, 30 differentially expressed miRNAs, 16 upregulated and 14 downregulated, were identified in metritis-affected cows compared to healthy controls. Building on these findings, this study predicted miRNA target genes and constructed regulatory networks involving miRNAs, mRNAs, circRNAs, lncRNAs, and snRNAs, alongside protein–protein interaction networks. Functional annotation and KEGG pathway analysis revealed that upregulated miRNAs influenced genes involved in immune activation, apoptosis, and metabolism, while downregulated miRNAs were associated with angiogenesis, immune suppression, and tissue repair. Hub genes such as AKT3, VEGFA, and HIF1A were central to immune and angiogenic signaling, whereas UBE3A and ZEB1 were linked to immune inhibition. Interferon-stimulated genes (e.g., ISG15, RSAD2, CXCL chemokines) were shown to regulate solute carriers, contributing to immune dysregulation. Key pathways included PI3K-Akt, NF-κB, JAK-STAT, insulin resistance, and T cell receptor signaling. Noncoding RNAs such as NEAT1, KCNQ1OT1, and XIST, along with miRNAs like bta-miR-15b and bta-miR-148a, emerged as pro-inflammatory regulators, while bta-miR-199a-3p appeared to exert immunosuppressive effects. These findings offer new insights into the complex regulatory networks driving metritis and suggest potential targets for improving fertility in dairy cows. Full article

Oxidative stress plays a central role in numerous conditions, including cancer, cardiovascular and neurodegenerative diseases, diabetes, chronic inflammation, and organ transplantation. In transplantation, oxidative stress leads to mitochondrial dysfunction, DNA and protein damage, lipid peroxidation, and activation of pro-inflammatory pathways such as NF-κB, ultimately impairing cell viability and organ function. A Kinase-Interacting Protein 1 (AKIP1) has been linked to oxidative stress regulation in transgenic mouse models. To investigate this further in a livestock setting, we generated AKIP1 transgenic pigs and assessed AKIP1’s protective role against oxidative-stress-induced cell death, including apoptosis, necrosis, and ferroptosis in vitro. Our cellular analyses revealed reduced apoptosis (caspase-3/7 activity), suppressed MPTP-mediated necrosis, and decreased lipid peroxidation, suggesting protection from ferroptosis. Additionally, we observed lower mitochondrial superoxide production and enhanced mitochondrial respiration and recovery following H₂O₂-induced oxidative challenge. This is the first study to examine AKIP1 in porcine cells, providing a unique and translational platform for studying oxidative injury in a physiologically relevant species. Our in vitro data reveal that AKIP1 overexpression enhances antioxidant defenses and mitochondrial stability, offering future potential for improving graft survival in xenotransplantation. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder affecting 10–20% of the population. In this study, we investigate the anti-inflammatory effect on the skin of eight compounds isolated from Digitalis purpurea L., using tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-stimulated human keratinocytes (HaCaT cells) and a three-dimensional (3D) reconstructed human skin model. Among the tested compounds, desrhamnosyl acteoside exhibited the most potent activity, significantly reducing the secretion of pro-inflammatory cytokines (IL-6, IL-8) and chemokines (CCL17, CCL22), suppressing the expression of inflammatory proteins, and modulating key signaling pathways, including NF-κB, JAK2/STAT1, and MAPK. Notably, this is the first report demonstrating that desrhamnosyl acteoside simultaneously targets all three pathways, indicating a multi-modal mechanism distinct from conventional single-target approaches. In the 3D skin model, desrhamnosyl acteoside further exhibited barrier-protective effects by downregulating inflammatory mediators and upregulating epidermal differentiation markers such as involucrin and loricrin. These findings reveal a previously uncharacterized phytochemical with dual anti-inflammatory and barrier-restorative activities, supporting its potential as a novel therapeutic candidate for AD and other inflammatory skin diseases. Full article