Search Results (2,416)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LDs) as key drivers of disease progression, although their interaction remains poorly characterized. This review provides an integrative and stage-dependent synthesis of current mechanistic insights into how bidirectional crosstalk between CS and LD regulation shapes the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, including upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can activate peroxisome-proliferator-activated receptor alpha (PPARα), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent CS under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid oxidation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor—kappa B (NF-κB) signaling, promotes chronic hepatic inflammation. By framing LDs as active modulators of senescence-associated signaling rather than passive lipid stores, this review highlights how disruption of senescence–lipid feedback loops may represent a disease-modifying opportunity in MASLD progression. Full article

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, characterized by progressive neurodegeneration and cognitive decline. Early diagnosis remains critical for enabling timely intervention. However, detecting the earliest pathological changes is challenging due to the limited availability of reliable biomarkers that reflect early disease pathology in experimental models. This study evaluated molecular markers associated with AD-related processes in a rat model inoculated with human amyloid β (Aβ)_1-42 peptides. We assessed the levels of biomarkers: Aβ_1-42, Aβ₄₂, phosphorylated tau, monocyte chemoattractant protein-1 (MCP-1), nuclear factor kappa B (NF-κB p65) and superoxide dismutase 1 (SOD1) in hippocampal tissue and serum using enzyme-linked immunosorbent assay. A treatment group receiving Kelulut honey was included to evaluate biomarker responsiveness. Results showed significant elevation in hippocampal Aβ_1-42 and phosphorylated tau in diseased rats, with changes in inflammatory markers MCP-1 and NF-κB p65, whereas no significant change was observed in oxidative stress marker SOD1. Serum levels of Aβ_1-42 and MCP-1 did not differ significantly between groups, indicating limited peripheral sensitivity after a month of disease induction. These findings suggest that amyloid-, tau-, and inflammation-related markers in hippocampal tissue may be informative for early pathological changes in this acute model, while serum markers showed limited sensitivity. Full article

Sasa quelpaertensis, a multipurpose bamboo plant endemic to Jeju Island in South Korea, is used by the population in traditional medicine for its anti-inflammatory, anti-diabetic, anti-gastritis, and diuretic activities. Studies have shown the potential of S. quelpaertensis against various diseases; its effects include anticancer, anti-obesity, anti-diabetic, anti-inflammatory, antibacterial, antiviral, antioxidant, antidepressant, immunomodulating, and hepatoprotective effects. Several bioactive phytochemicals, including p-coumaric acid, tricin, naringenin, and vanillic acid, have been identified in S. quelpaertensis, further emphasizing its pharmacological potential. Molecular studies have identified crucial pharmacological targets of S. quelpaertensis, such as adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) signaling. The major challenges are that most pharmacological activities have been observed only in the preclinical stage, and that a compilation of its phytochemicals and pharmacological activities is missing from the literature. The studies with incomplete extract characterization or standardization limit the comparability across studies. Identification of active phytochemicals for specific activities and large-scale clinical trials for the majority of pharmacological effects are suggested. This review not only compiles the phytochemicals and pharmacological properties of S. quelpaertensis but also highlights current gaps and proposes solutions for its development as a therapeutic agent and/or supplement against major diseases. Full article

Background: Pulmonary fibrosis (PF) currently lacks effective therapeutic interventions. Roxadustat, an oral small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase, has been shown in several studies to attenuate the progression of fibrotic diseases. However, its therapeutic efficacy in PF remains to be fully elucidated. The aim of this study was to evaluate roxadustat’s therapeutic benefits on PF as well as the underlying mechanisms of action. Methods: Bleomycin was administered intraperitoneally to establish a PF mouse model. H&E staining, Masson staining, and immunohistochemistry (IHC) were used to assess histopathological and fibrotic changes. Changes in the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Network pharmacology combined with transcriptomic analysis was employed to identify potential target genes and associated signaling pathways. Subsequently, RT-qPCR and Western blot analyses were carried out to experimentally validate the predicted targets and pathways and to verify the protective effects of roxadustat in PF mice. Results: Roxadustat markedly ameliorated bleomycin-induced pulmonary fibrosis in mice. The therapeutic effect was evidenced by a reduction in alveolar damage, thinner alveolar septa, diminished infiltration of inflammatory cells, and decreased collagen deposition. Concomitantly, the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were significantly lowered. Integrated network pharmacology and transcriptomic analyses revealed the involvement of critical signaling pathways, specifically nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor (PPAR). Experimental validation further demonstrated that roxadustat downregulated the expression of key genes (S100A8, S100A9, and Fos) in murine lung tissues. It also suppressed the protein ratios of phosphorylated p65 to total p65 and phosphorylated IκBα to total IκBα. Moreover, roxadustat treatment upregulated PPARγ protein expression. Conclusions: These data indicate that roxadustat ameliorates bleomycin-induced PF in mice, an effect associated with modulation of the NF-κB and PPAR signaling pathways. The findings provide a preclinical rationale for further investigation of roxadustat as a potential treatment for PF. Full article

Inositol is a natural carbocyclic sugar that plays an essential role in regulating the vital cellular functions of plants and animals. Existing research has explored methyl derivatives of inositol, reporting on their various biological activities, including antitumor, anti-inflammatory, and anti-osteoporosis activities. Our previous study demonstrated that L-quebrachitol, a methyl derivative of inositol, enhances osteoblastogenesis and bone formation; however, its effect on osteoclastogenesis remains unclear. Consequently, we aimed to investigate the effect of L-quebrachitol on receptor activator of nuclear factor-κB ligand-induced osteoclastogenesis in pre-osteoclastic RAW 264.7 cells, and bone resorption in an ovariectomized rat model. The results revealed that L-quebrachitol suppressed RANK-mediated signaling, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Fos proto-oncogene (cFOS) pathways, at both the gene and protein levels. Moreover, the critical transcription factor for osteoclastogenesis, nuclear factor of activated T cells c1 (NFATc1), was downregulated. Inhibition of osteoclast-associated marker genes encoding proteolytic enzymes, such as tartrate-resistant acid phosphatase (TRAP), matrix metallopeptidase 9 (MMP-9), and cathepsin K, led to reduced formation of TRAP-positive multinucleated cells and resorption pits. In addition, proteasome subunit alpha type-5 (PSMA5), which is involved in the degradation of the NF-κB inhibitor, was also suppressed. In particular, the animal study clearly supported the bone homeostasis property of the agent by increasing the BV/TV (bone volume/total volume) and Tb.Th (trabecular thickness) in ovariectomized rats. These findings demonstrate the dose-dependent inhibitory effect of L-quebrachitol on osteoclastogenesis through the modulation of RANK-mediated signaling pathways and prevention of bone loss in an animal model. However, further exploration of the potential of L-quebrachitol as an effective approach for osteoporosis is required. Full article

Background: Cytokine oncostatin M (OSM) is implicated in inflammatory conditions. The plant sterol stigmasterol (ST) is found in diverse plant foods and exerts various benefits, such as antitumor, antioxidant, and anti-inflammatory effects. However, the inhibitory mechanism of ST on OSM production in neutrophils needs to be elucidated. Methods: To evaluate the modulatory effects of ST, this investigation employed neutrophil-like differentiated (d)HL-60 cells. ELISA, real-time PCR, Western blotting, and immunofluorescence staining were conducted. dHL-60 cells were pretreated with ST (0.02 to 2 µg/mL) for 1 h, and then stimulated with GM-CSF (5 ng/mL). Results: Our results showed that addition of granulocyte–macrophage colony-stimulating factor (GM-CSF) leads to up-regulation of OSM mRNA and protein in dHL-60 cells, while pretreatment with ST reduces OSM mRNA and protein levels. Mechanistically, the highest dose (2 µg/mL) of ST significantly decreased phosphorylation of phosphatidylinositol 3-kinase, protein kinase B (Akt), and nuclear factor-κB. Conclusions: Our findings suggest that the plant sterol ST shows potential and warrants in vivo validation on OSM regulation via suppressing PI3K/Akt/NF-κB Signaling Processes. Full article

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)–Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log₂ fold-change (|log₂FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP’s molecular effects in breast cancer and suggest potential applications in biomarker perioperative management. Full article

Gut microbial metabolites play a crucial role in modulating cognitive function. In a previous animal study, oral administration of Lactiplantibacillus plantarum MWFLp-182 (L. plantarum MWFLp-182) significantly increased inosine levels in both the serum and feces of D-galactose (D-gal)-induced mice, which was accompanied by improved cognitive performance. Building on this finding, we further investigated the neuroprotective mechanisms of inosine derived from L. plantarum MWFLp-182 in alleviating D-gal-induced neuronal damage in HT-22 cells. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze the addition of inosine (250 μg/mL, 500 μg/mL), which considerably reduces oxidative stress induced by D-gal (20 mg/mL), on the regulation of mRNA expression of the nuclear factor erythroid 2-related factor (Nrf2)/hemeoxygenase 1 (HO-1) signaling pathway factors. Compared to the D-gal group, the inosine-treated group exhibited a 4.3-fold and 8.7-fold increase in HO-1 and Nrf2 levels, respectively. Furthermore, inosine alleviates neuroinflammation by modulating the mRNA expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Compared to the D-gal group, the inosine-treated group showed reductions of 41.75%, 28.29%, and 32.17% in TLR4, MyD88, and NF-κB levels, respectively. Moreover, immunofluorescence staining revealed that inosine exhibits anti-apoptotic properties by enhancing the levels of neurotrophic factors, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), while simultaneously lowering the expression of the pro-apoptotic protein bcl-2-associated X (Bax). These findings suggest that inosine, a differentially expressed metabolite identified in a probiotic-intervention mouse model, alleviates D-gal-induced neuronal damage in HT-22 cells by modulating oxidative, inflammatory, and apoptotic pathways, providing mechanistic insights into the neuroprotective effects of this metabolite. Full article

Atherosclerosis (AS) is a disease characterized by chronic vascular wall inflammation and lipid deposition. Although lipid-lowering drugs such as statins have significantly reduced cardiovascular event rates, “residual inflammatory risk” remains a key factor driving disease progression and plaque rupture. As a central regulator of the inflammatory response, the nuclear factor-κappaB (NF-κB) signaling network comprises both canonical pro-inflammatory pathways and functionally more complex non-canonical pathways. Increasing evidence in recent years indicates that abnormal and sustained activation of the non-canonical NF-κB signaling pathway plays a pivotal role in driving plaque rupture. This review first elaborates on the shift in AS strategies from “lipid-lowering” to “anti-inflammatory” approaches, followed by an in-depth analysis of the molecular activation mechanisms of the NF-κB signaling pathway and its distinctiveness in the AS pathological process, along with its epigenetic regulation. It emphasizes how this pathway drives pathological angiogenesis and regulates vascular smooth muscle cell (VSMC) phenotypic switching and macrophage function, thereby forming a vicious cycle that amplifies inflammation and structural damage, ultimately leading to acute cardiovascular events. Finally, we systematically summarize current progress and challenges in drug development targeting the NF-κB pathway (e.g., targeting key kinases like NIK and IKKα), aiming to provide theoretical foundations and future directions for novel therapeutic strategies to stabilize coronary plaques and prevent acute coronary syndromes. Full article

Parkinson’s disease is a neurodegenerative disorder that affects the elderly population worldwide. Rotenone (ROT) is an environmental toxin that impairs mitochondrial dynamics by inhibiting respiratory chain complex I and thus inducing oxidative stress. Farnesol (FSL) is a dietary sesquiterpene with antioxidant and anti-inflammatory properties reported in various in vivo models. To evaluate the efficacy of FSL in the management of PD, Wistar rats were injected with ROT (2.5 mg/kg, i.p) and pretreated with FSL. Immunohistochemical staining measured tyrosine hydroxylase-positive cells in the substantia nigra and striatum. Western blotting was employed to determine protein expression of inflammatory, apoptotic, and autophagic markers. Our results indicate that FSL significantly protected against ROT-induced inflammation by suppressing microglial and astrocytic activation through the downregulation of Toll-Like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B (IkB), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), matrix metalloproteinase-9 (MMP-9) expression. FSL has also demonstrated an antioxidant effect by enhancing the activity of superoxide dismutase and catalase while reducing the level of Malondialdehyde and nitric oxide. Moreover, it restored homeostasis in ROT-induced imbalance between pro- and anti-apoptotic proteins. Impaired autophagy observed in ROT-injected rats was corrected by FSL treatment, which upregulated phosphorylated mammalian target of rapamycin (p-mTOR) expression and downregulated P62, an autophagosome marker. The protective effect of FSL was further supported by preserving the brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase in the brain. These findings demonstrate the neuroprotective ability of FSL and its potential to be developed as a pharmaceutical or nutraceutical agent for the prevention and treatment of PD by mitigating neuropathological changes observed in dopaminergic neurodegeneration. Full article

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

Background/Objectives: Surfactin is a biosurfactant with various biological activities, including antibacterial and anti-inflammatory properties; however, its effects on bone metabolism remain poorly understood. This study aimed to investigate the effects of surfactin on osteoclast differentiation and elucidate its underlying molecular mechanisms. Methods: RAW264.7 cells were treated with receptor activator of nuclear factor-kappa B ligand (RANKL) and surfactin, and osteoclast differentiation and maturation were evaluated by tartrate-resistant acid phosphatase and F-actin staining, respectively. Gene expression of differentiation markers was assessed using real-time reverse transcription-quantitative polymerase chain reaction, while the kinetics of intracellular signaling molecules and transcription factors were analyzed using Western blot analysis. Results: Surfactin treatment significantly inhibited osteoclast differentiation and maturation, as well as the mRNA expression of Nfatc1, Acp5, and Cathepsin K. Although surfactin did not markedly affect RANKL-induced activation of the NF-κB or MAPK-mediated signaling, it significantly suppressed the expression of c-Fos at both the mRNA and protein levels. Furthermore, surfactin attenuated the phosphorylation of Elk1, a transcription factor involved in c-Fos induction. Conclusions: Surfactin inhibits RANKL-induced osteoclast differentiation by negatively regulating the Elk1-AP-1-NFATc1 axis. Surfactin may thus be a promising therapeutic candidate for the treatment of metabolic bone disorders and inflammatory bone destruction. Full article

Silicosis is an irreversible and progressive pulmonary fibrotic disease caused by the long-term inhalation of silica dust. The precise molecular mechanisms underlying the disease remain incompletely understood, and effective early diagnostic biomarkers are still lacking. In this study, we used a silicosis mouse model and transcriptomic sequencing to identify 2950 mRNAs, 461 lncRNAs, 81 miRNAs, and 44 circRNAs that were differentially expressed in lung tissue. Enrichment analysis revealed that these differentially expressed genes were significantly enriched in the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) signaling pathway, nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway, and tumor necrosis factor (TNF) signaling pathway. The constructed competing endogenous RNA (ceRNA) network highlighted extensive regulatory interactions among lncRNAs/circRNAs, miRNAs, and mRNAs. Human validation showed that the expression levels of hsa-miR-215-5p and hsa-miR-146b-5p were significantly upregulated in the peripheral blood of early-stage pneumoconiosis patients, while hsa-miR-485-5p was downregulated. Logistic regression analysis revealed that hsa-miR-215-5p (OR = 1.966, 95% CI: 1.6938–2.2796, p < 0.001) and hsa-miR-146b-5p (OR = 1.9367, 95% CI: 1.697–2.201, p < 0.001) were independent risk factors for pneumoconiosis (p < 0.001). ROC curve analysis showed that both miRNAs demonstrated good diagnostic efficacy for pneumoconiosis, with AUC values of 0.9563 and 0.8876, respectively. These results provide novel insights into the complex ceRNA regulatory network involved in silicosis pathogenesis and suggest potential early, non-invasive diagnostic biomarkers. Full article

Background/Objectives: Endometrial cancer is one of the most common gynecological malignancies, with increasing incidence and mortality rates, particularly in developed countries. L1 cell adhesion molecule (L1CAM) has been identified as a poor prognostic factor for human endometrial cancer; however, the molecular mechanisms underlying its role in tumor progression remain unclear. Methods: We investigated the biological significance of L1CAM in human endometrial cancer using multiple cell lines. Functional analyses, including cell proliferation, cell cycle, and apoptosis assays, were performed after L1CAM knockdown or overexpression. Results: L1CAM promoted the transition of endometrial cancer cells from the G0/G1 phase and enhanced cell proliferation. L1CAM knockdown inhibited NF-κB signaling by reducing NF-κB (p65) phosphorylation and downregulating the expression of downstream targets such as TNF. Overexpression of constitutively active IKKβ restored the proliferation defect caused by L1CAM knockdown, supporting the role of NF-κB as a key downstream effector of L1CAM. Immunohistochemical analysis revealed a significant correlation between L1CAM expression and nuclear NF-κB (p65) positivity rates in human patient samples. Furthermore, combination therapy with cisplatin and an IKK inhibitor enhanced the anti-proliferative effect. Conclusions: Our study demonstrated that L1CAM promotes proliferation and chemotherapy resistance in human endometrial cancer through activation of the NF-κB signaling pathway. Therapeutic strategies targeting the L1CAM-NF-κB pathway may represent a promising treatment option for improving prognosis in L1CAM-positive human endometrial cancer. Full article

Chronic sleep deprivation (CSD) disrupts redox homeostasis and enhances neuroinflammatory activation, contributing to progressive cognitive impairment. Propyl gallate (PG), a lipophilic ester of gallic acid with established antioxidant activity, has not been investigated in the context of prolonged sleep deprivation. The current study examined whether PG alleviates CSD-induced oxidative imbalance, inflammatory activation, and associated behavioral deficits. Male ICR mice were subjected to 14 days of CSD using a rolling-drum apparatus and received oral PG (50, 100, or 200 mg/kg) or Ginkgo biloba extract (GBE, 40 mg/kg). Behavioral outcomes were assessed through a battery of tests, including the open-field, novel-object recognition, step-through, and Morris water maze paradigms. Oxidative and inflammatory biomarkers were assessed in serum and hippocampus, and Western blotting quantified the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2). PG improved CSD-induced impairments in exploration, recognition memory, and spatial learning; restored antioxidant capacity; reduced lipid peroxidation; enhanced Nrf2-associated antioxidant signaling; and suppressed NF-κB-mediated inflammatory activation. These findings indicate that PG alleviates cognitive deficits induced by CSD through the modulation of redox homeostasis and neuroinflammatory responses, supporting its potential as an antioxidant derivative under chronic sleep-deprivation conditions. Full article