We have previously demonstrated that ovarian tumor (Otu) domain-containing ubiquitin aldehyde-binding protein 2 (Otub2), a deubiquitinating enzyme, exerts anti-apoptotic effects in primary human islets. The present study aims to further elucidate the molecular mechanisms underlying the role of Otub2 as a regulator of insulin secretion and β-cell function.
Otub2 overexpression or silencing was employed to study its effects on cultured MIN6 cells and dispersed human islets. To evaluate its in vivo effects, Otub2 knockout (KO) mice were employed, as well as a pancreata-specific Otub2 overexpression model. RNA sequencing was performed on pancreatic tissue from Otub2-KO and control mice to study its effects on gene expression patterns. Co-immunoprecipitation followed by mass spectrometry identified Otub2-interacting proteins.
Overexpression of Otub2 inhibited NF-κB activity and enhanced glucose-stimulated insulin secretion (GSIS) in cultured MIN6 cells and primary human islets. Otub2 KO mice exhibited impaired glucose tolerance and upregulation of NF-κB target genes. Conversely, selective in vivo overexpression of Otub2 in pancreata of C57BL wild-type mice resulted in significantly lower (~30%) blood glucose levels, post glucose injection, compared to control mice. Transcriptomic analysis of KO pancreata revealed downregulation of K+ transporter-related genes and upregulation of oxidative phosphorylation genes, consistent with defective insulin secretion. Mass spectrometry identified the voltage-gated potassium channel subunit Kv9.3 as a major Otub2 binding partner, along with paternally expressed 3 (Peg3) and calcium/calmodulin dependent protein kinase II delta (Camk2d) proteins known to promote NF-κB signaling and β-cell apoptosis.
Otub2 is a critical regulator of β-cell function, acting through modulation of NF-κB signaling and K+ channel-associated complexes. By deubiquitinating components such as Peg3 and Camk2d, Otub2 may protect β-cells from cytokine-induced apoptosis and sustain insulin secretory capacity. These findings position Otub2 as a potential therapeutic target for preserving β-cell function in diabetes.
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease defined by exocrine gland infiltration and systemic involvement. The management of pSS is hampered by three persistent challenges: seronegativity, heterogeneity, and delayed diagnosis. Up to one-third of patients lack anti-Sjögren’s-syndrome-related antigen A/B (SSA/SSB) autoantibodies, contributing to misclassification and delayed recognition. Recent studies have expanded the autoantibody repertoire, identifying novel targets such as anti-D-aminoacyl-tRNA deacylase 2 (DTD2), anti-retroelement silencing factor-1 (RESF1), and anti-calreticulin (CALR), as well as multiplex panels including anti-salivary protein-1 (SP-1), anti-parotid secretory protein (PSP), and anti-carbonic anhydrase VI (CA6). These can detect disease before conventional seroconversion, thus offering diagnostic value for seronegative cases. The greatest challenge remains early detection, as the current reliance on biopsy and late-appearing serologies overlooks subclinical disease. In this context, non-invasive fluid biomarkers are transformative, with salivary and tear fluid proteomics (β2-microglobulin, clusterin, matrix metalloproteinase-9), exosomal micro ribonucleic acid (miRNAs), and metabolomic fingerprints providing sensitive indicators of glandular dysfunction and immune activation. When combined with machine learning, integrated multi-omics panels can achieve diagnostic accuracies comparable to biopsy while enabling prognostic stratification. Emerging approaches also leverage artificial intelligence (AI) to refine biomarker discovery and clinical translation. AI-assisted ultrasonography enables reproducible quantification of glandular inflammation, while the application of integrative AI models to multi-omics datasets can identify biomarker signatures with superior predictive accuracy. Such tools have the potential to accelerate early diagnosis, automate risk prediction, and guide precision therapeutics in real time. The future use of biomarker panels in clinical practice should reduce the time to diagnosis, thereby facilitating the anticipation of risk and the provision of therapy based on the underlying cause. In this review, we describe how pSS exemplifies some of the problems inherent in contemporary autoimmunity. This multifaceted and diverse condition is now well-positioned to benefit from integrative, biomarker-driven methodologies, which should lead to improved patient outcomes.
The gut microbiome is increasingly recognized as a modifiable contributor to coronary artery disease (CAD). This narrative review integrates mechanistic and clinical evidence regarding short-chain fatty acids (SCFAs), trimethylamine-N-oxide (TMAO), and bile acids, and appraises therapeutic modulation via diet; probiotics, prebiotics, and synbiotics; fecal microbiota transplantation (FMT); and drug–microbiome interactions. SCFAs generally confer anti-inflammatory and lipid-regulatory effects, whereas bile acid signaling exhibits context-dependent metabolic actions. Findings regarding TMAO are inconsistent; in several cohorts, associations with cardiovascular risk become null or attenuated after adjustment for renal function (estimated glomerular filtration rate [eGFR]) and dietary patterns. Most interventional studies are small, use surrogate endpoints, and vary in strains and dosing, limiting certainty. Microbiome profiles differ across geographic regions, racial and ethnic groups, and dietary patterns, underscoring the need for stratified approaches. Routine FMT in CAD remains constrained by safety, feasibility, and ethical and logistical considerations. Overall, the microbiome represents a promising yet unproven therapeutic target in CAD. Future trials should standardize interventions, rigorously control for confounders, evaluate drug–microbiome interactions, and be adequately powered to detect clinical events to enable precision medicine.
Mast cells, traditionally recognized for their roles in allergy and host defense, have recently been implicated in the pathogenesis of atherosclerosis. Their strategic localization in vascularized tissues and capacity to release a wide array of bioactive mediators position them as crucial contributors to both early and advanced stages of plaque development. This review summarizes the current understanding of mast cell functions in vascular homeostasis and immunity, with a special focus on their mechanistic involvement in atherogenesis and their potential as therapeutic targets in atherosclerosis. We conducted a comprehensive literature review of experimental, preclinical, and clinical studies addressing mast cell biology in the context of atherosclerosis. Particular emphasis was placed on molecular mechanisms, mast cell-derived mediators, and emerging pharmacologic interventions. Mast cells promote key atherogenic processes, including endothelial dysfunction, low-density lipoprotein (LDL) retention, monocyte recruitment, foam cell formation, fibrous cap thinning, and plaque rupture. Mechanistically, this involves the release of proteases (chymase and tryptase), histamine, and proinflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)). Additionally, mast cells contribute to caspase-1-mediated IL-1β production, which activates NF-κB signaling cascades leading to enhanced inflammatory cytokine production and adhesion molecule expression. Therapeutic strategies targeting mast cell activation, degranulation, metabolic activity, and specific receptors have demonstrated efficacy in preclinical models. Emerging approaches include dual protease inhibitors, personalized therapies guided by mast cell phenotyping, and advanced delivery systems. Mast cells are significant drivers of atherogenesis and plaque destabilization. Targeting mast cell-specific pathways represents a promising avenue for therapeutic intervention in atherosclerosis and the prevention of acute cardiovascular events.
Diabetes mellitus leads to chronic, multi-organ complications, most notably diabetic nephropathy, peripheral neuropathy, and retinopathy. While hyperglycemia serves as the initiating insult, disease progression involves a complex interplay of molecular mechanisms, including oxidative stress, mitochondrial dysfunction, inflammation, and impaired antioxidant defenses. This focused review examines how these shared pathways contribute to organ-specific damage and how they are reflected in experimental mouse models. Key regulatory networks—including nuclear factor kappa B (NF-κB), transforming growth factor-β (TGF-β), protein kinase C (PKC), the advanced glycation end product (AGE)–receptor for AGE (RAGE) axis, and nuclear factor erythroid 2-related factor 2 (Nrf2)—link metabolic stress to fibrosis, vascular dysfunction, and neural injury. Mitochondrial dysfunction is also a commonly shared pathological feature across affected tissues. To investigate these mechanisms in vivo, this review outlines the characteristics of widely used mouse models—streptozotocin (STZ)-induced, Akita mice (harboring the Ins2Akita mutation), db/db, and Black and Tan Brachyury (BTBR) ob/ob—in relation to specific diabetic complications. STZ-induced and Akita mice effectively model hyperglycemia-induced injury, while db/db and BTBR ob/ob mice recapitulate insulin resistance, dyslipidemia, and systemic inflammation. We describe how each model reflects distinct pathogenic features—such as TGF-β–mediated podocyte loss in nephropathy, aldose reductase activation and mast cell dysfunction in neuropathy, and PKC-dependent pericyte apoptosis in retinopathy. Therapeutic strategies targeting these conserved molecular pathways—including Nrf2 activation, NF-κB inhibition, or mitochondrial restoration—have demonstrated efficacy across multiple models. By aligning pathophysiological mechanisms with appropriate experimental systems, this review provides a practical framework for selecting preclinical tools and developing multi-targeted interventions to prevent or slow the progression of diabetic complications.
Alzheimer’s disease (AD) is a neurodegenerative disorder primarily affecting the geriatric population, characterized by progressive cognitive impairment and behavioral abnormalities. Due to the absence of effective disease-modifying therapies, AD imposes a substantial burden on patients and their families. The etiology and pathogenesis of AD have not been fully elucidated; multiple pathological alterations have been implicated, including the deposition of β-amyloid (Aβ) plaques, abnormal tau phosphorylation, and neuroinflammatory responses. These pathological changes contribute to neuronal damage, synaptic dysfunction, and neuronal death, ultimately leading to brain atrophy. Recent studies have identified PANoptosis as a critical regulatory mechanism of programmed cell death that influences the pathological progression of AD through multiple pathways, including modulation of Aβ plaque deposition and regulating neuroinflammatory responses. However, the precise mechanisms of these effects remain unclear. This review aims to comprehensively analyze recent research findings, focusing on the regulatory role of PANoptosis in AD, exploring the specific manifestations of the intricate network of cell death regulation in AD pathogenesis. By providing a systematic overview of emerging findings, this review offers new insights into the pathogenesis of AD and highlights potential directions for the development of targeted therapeutic strategies.
Breast cancer is the most prevalent malignant tumor among women worldwide. Its progression is driven, in part, by mitochondrial metabolic dysregulation, which can also contribute to therapeutic resistance. Although targeting mitochondrial metabolism offers new opportunities for treatment, significant therapeutic challenges remain. These include metabolic heterogeneity among subtypes and individual patients, drug resistance arising from metabolic plasticity, and suboptimal clinical translation of metabolic therapies. This review systematically synthesizes the mitochondrial metabolic mechanisms underlying different breast cancer subtypes, emphasizing the spatial network regulatory functions of mitochondrial metabolism. It further critically evaluates combined therapeutic strategies targeting metabolic vulnerabilities. By integrating current research limitations with emerging breakthroughs, we outline novel therapeutic frameworks to advance the development of precision medicine approaches focused on mitochondrial metabolism.
DNA methylation is a key epigenetic modification catalyzed by DNA methyltransferases (DNMTs) and predominantly occurs at cytosine-phosphate-guanine (CpG) islands, which are often located in gene promoter regions. Hypermethylation of CpG islands within gene promoters can silence tumor suppressor gene expression, thereby disrupting normal cellular functions, including maintenance of genomic stability and regulation of cell growth, and contributing to tumor initiation and progression. In contrast, global hypomethylation may promote genomic instability and oncogene activation. This review discusses the molecular mechanisms underlying DNA methylation and evaluates its functional and clinical significance in colorectal and gastric cancers, with emphasis on its potential application as a noninvasive biomarker for diagnosis.
Alzheimer’s disease (AD) involves a progressive deterioration of cognitive abilities, memory loss, and persistent brain inflammation. Emerging evidence indicates that pyroptosis mediated by the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, contributes significantly to AD development. Docosahexaenoic acid (DHA) has demonstrated neuroprotective properties; however, the precise mechanisms by which it modulates pyroptosis in AD have yet to remained incompletely elucidated.
To explore the role of DHA in modulating microglial pyroptosis via the HOXA9-NLRP3 pathway in an AD model.
Effects of DHA on Aβ25–35-induced pyroptosis were assessed in human microglial clone 3 (HMC3) human microglial cells using CCK-8, western blotting, immunofluorescence, and Enzyme-linked Immunosorbent Assay (ELISA) assays. The role of homeobox A9 (HOXA9) in pyroptosis regulation was evaluated through overexpression and knockdown experiments. Dual-luciferase reporter assays together with chromatin immunoprecipitation (ChIP) were used to verify the interaction of HOXA9 to NLRP3 promoter. Amyloid precursor protein / Presenilin-1 double-transgenic (APP/PS1) transgenic AD mice underwent DHA treatment in vivo, and cognitive performance was assessed using the Morris water maze paradigm. Expression of HOXA9, NLRP3, and pyroptosis-related proteins were analyzed by Quantitative Real-time Reverse Transcription PCR (qRT-PCR), Western blotting, and immunofluorescence.
DHA treatment significantly reduced Aβ25–35-induced microglial pyroptosis, as indicated by decreased levels of p30-Gasdermin D (GSDMD), cleaved-caspase-1, IL-1β, and IL-18. HOXA9 overexpression reversed the protective effects of DHA, whereas NLRP3 inhibition by MCC950 enhanced DHA inhibition of pyroptosis. Dual-luciferase and ChIP assays confirmed that HOXA9 directly regulates NLRP3 transcription. In APP/PS1 mice, DHA administration enhanced cognitive performance while simultaneously decreasing the expression of pyroptosis-related markers and inflammatory mediators in brain. Inhibition of NLRP3 signaling by MCC950 further strengthened the neuroprotective actions of DHA.
DHA ameliorates AD-related cognitive decline and reduces microglial pyroptosis through suppressing the HOXA9-NLRP3 axis. These results offer novel insights into the molecular basis of DHA-mediated neuroprotection and highlight potential therapeutic targets for AD.
Transcription factor acetylation is a critical yet often overlooked regulator of cell fate. Although traditionally studied in the context of histone modifications, many acetyltransferases and deacetylases also modify transcription factors directly, thereby controlling lineage-specific transcriptional programs. At the molecular level, acetylation fine-tunes transcription factor activity by modulating DNA binding, protein stability, cofactor interactions, and nucleo-cytoplasmic trafficking. These molecular effects frequently intersect with other post-translational modifications, establishing acetylation as a versatile molecular switch of transcriptional output. These molecular effects scale into cellular outcomes that determine identity and plasticity. In pluripotent stem cells, defined acetylation events on core regulators stabilize the pluripotency network and prime lineage-specific enhancers. In hematopoiesis, transcription factor acetylation modulates transitions from stem and progenitor states to committed lineages, while in myogenesis, it governs progenitor differentiation and regenerative capacity. Importantly, differential acetylation of distinct lysine residues can yield context-dependent outcomes, underscoring the precision and adaptability of this modification in controlling cell identity. Recognizing transcription factor acetylation as a central axis of epigenetic regulation reframes our understanding of lineage specification and cellular plasticity. Beyond developmental biology, it provides a mechanistic rationale for therapeutic strategies that target acetylation dynamics, not only altering chromatin states but also reprogramming transcription factor function. This review synthesizes current knowledge of transcription factor acetylation in hematopoietic and myogenic contexts, highlighting its significance as a bridge between molecular mechanisms and cellular identity, and as a promising target in disease intervention.
Dendrobium spp. has traditionally been used to improve visual function, and related formulations, such as Dendrobium Glow in dark pills, are currently used in the management of dry eye disease (DED). This study investigated the positive effects and underlying mechanisms of 3-O-methylgigantol, an active compound from Dendrobium spp., against DED using network pharmacology and in vitro experimental validation.
Active compounds and targets were identified through database screening, and network analysis was used to identify the key compounds and targets. Molecular docking and dynamic simulations were performed to verify the binding of 3-O-methylgigantol to the epidermal growth factor receptor (EGFR). An in vitro DED model was established using hyperosmotic sodium chloride (550 mOsm) in human corneal epithelial cells (HCECs). The effects of 3-O-methylgigantol, with or without the EGFR inhibitor (erlotinib), on cell viability, apoptosis, reactive oxygen species, and inflammatory cytokines were assessed.
Network pharmacology predicted 3-O-methylgigantol as a key active compound and EGFR as a core target. Molecular simulations confirmed stable binding. In vitro experiments showed that 3-O-methylgigantol significantly increased HCEC viability and reduced apoptosis, reactive oxygen species accumulation, and inflammatory cytokine release under hyperosmotic conditions. The EGFR inhibitor erlotinib attenuated these protective effects.
3-O-methylgigantol, an active compound from Dendrobium spp., alleviates hyperosmolarity-induced corneal epithelial cell damage, oxidative stress, and inflammation by activating the EGFR signaling pathway. This compound may represent a potential therapeutic candidate for DED management, demonstrating its efficacy in restoring tear film homeostasis in in vitro models.
Developing therapy resistance and exhibiting high invasiveness are significant challenges in treating aggressive cancers, such as glioblastoma, where intercellular communication plays a crucial role in cellular organization, survival, and resistance to treatment. Tunneling nanotubes (TNTs), nanometer-sized membranous channels that connect distant cells, have emerged as an efficient form of intercellular communication that may enable cancer cells to evade therapeutic interventions.
In this study, we investigated the responses of TNT networks to low linear energy transfer (low-LET) X-ray irradiation in two established glioblastoma cell lines, U87 MG and LN229. Initially, we assessed radiosensitivity using colony formation assays to measure cell survival. Then, we used confocal live-cell microscopy to monitor TNT network dynamics over a 24-hour period following irradiation and performed co-staining experiments to identify cargoes transported through TNTs.
We observed a significant increase in TNT-mediated cellular connectivity 6 to 10 hours after 1.8 Gy X-ray irradiation in both cell lines. In contrast, cells treated with a higher radiation dose (3.9 Gy) exhibited reduced TNT connectivity; however, it remained slightly elevated compared to sham-irradiated controls. The co-staining experiments revealed the presence of calcium and mitochondria within TNTs. These cargoes are known to facilitate cancer cell migration and survival, potentially contributing to treatment resistance.
Taken together, these results strongly suggest that TNT-mediated intercellular communication may be a critical mechanism that supports glioblastoma resistance to radiotherapy.
The clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR/Cas9) system has emerged as a versatile platform for genome editing, transcriptional regulation, and chromosomal imaging. Recent advances in synthetic biology have enabled the engineering of single guide RNA (sgRNA) to confer conditional responsiveness on the CRISPR/Cas9 system. By integrating functional nucleic acid elements, such as aptamers, ribozymes, and aptazymes, into specific structural regions of the sgRNA, researchers have developed systems that respond to a variety of molecular signals, including small molecules, proteins, and endogenous metabolites. These engineered sgRNAs enable spatiotemporal control of gene editing, activation, repression, and imaging in both prokaryotic and eukaryotic cells. This review summarizes the structural principles, design strategies, and applications of condition-responsive CRISPR/Cas9 systems, highlighting their potential in synthetic biology, disease modeling, and therapeutic development. Current challenges and future directions for improving the specificity, efficiency, and applicability of these systems are also discussed.
Gastric cancer (GC) is among the most frequently diagnosed malignancies worldwide. Identifying novel therapeutic targets is of great significance.
GC-related RNA-seq data and matched clinical information were retrieved from the publicly available The Cancer Genome Atlas (TCGA) database. The epithelial-mesenchymal transition (EMT) scores of GC and normal tissues were calculated using the gene set variation analysis (GSVA) package. Weighted gene coexpression network analysis (WGCNA) was applied to identify modules associated with EMT. The survival and clinical relevance of EMT-related core genes were analyzed, and carbohydrate sulfotransferase 1 (CHST1) was selected for further investigation. CHST1 expression was validated in patient-derived GC tissues and GC cell lines. Subsequently, CHST1 expression and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway activity were modulated in AGS cells to evaluate their effects on cell proliferation, apoptosis, migration, and EMT. In vivo experiments were conducted to elucidate the involvement of CHST1 expression in GC growth.
The EMT score was markedly higher in GC tissues than in normal tissues. Within the EMT-related module, 7 hub genes (CHST1, GPR176, OLFML2B, P4HA3, PDGFRB, SPARC, and VCAN) were closely associated with GC prognosis. CHST1 expression was strongly correlated with both the EMT score and T stage. As revealed by survival analysis, patients with high CHST1 expression had shorter overall survival than those with low expression. A marked up-regulation of CHST1 protein expression was observed in clinical GC tissues compared with normal tissues. In vitro, CHST1 expression was significantly elevated in GC cell lines. Inhibiting CHST1 expression in AGS and HGC27 cells suppressed cell proliferation, migration, as well as EMT, while simultaneously promoting apoptosis. In AGS cells, CHST1 regulated cell proliferation, apoptosis, migration, and EMT through the MAPK/ERK signaling pathway. In vivo, CHST1 significantly promoted GC growth and increased the activity of the MAPK/ERK signaling pathway.
CHST1 is highly expressed in GC and may influence GC progression by regulating the MAPK/ERK signaling pathway.
Atherosclerosis is a chronic inflammatory disease characterized by lipid-driven immune dysregulation. Argininosuccinate synthase 1 (ASS1) has been implicated in macrophage inflammation, yet its precise mechanistic role in foam cell-mediated vascular injury during atherosclerosis remains unclear. This study investigates whether ASS1 promotes disease progression via the NLRP3/IL-33/ST2 axis.
An in vitro foam cell model was established using phorbol 12-myristate 13-acetate (PMA)-differentiated U937 macrophages treated with oxidized low-density lipoprotein (ox-LDL). The role of ASS1 was assessed via knockdown (si-ASS1) and overexpression (ASS1 overexpression) plasmids. Co-culture systems with human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (HAVSMCs) were used to evaluate endothelial apoptosis and VSMC proliferation/migration. In vivo, atherosclerosis was induced in apolipoprotein E‑deficient (ApoE)-deficient mice via a 12-week high-fat diet, and ASS1 expression was modulated using AAV9 vectors. Molecular analyses included ROS detection, enzyme-linked immunosorbent assay (ELISA), qPCR, western blot, and immunofluorescence. Plaque burden was assessed via Oil Red O staining.
Ox-LDL treatment significantly upregulated ASS1 expression in U937-derived foam cells. ASS1 overexpression enhanced intracellular ROS production, NLRP3 inflammasome activation, STAT3 phosphorylation, and IL-33 secretion. These effects were reversed by ASS1 knockdown. Rescue experiments demonstrated that STAT3 is required for ASS1-mediated NLRP3 activation and IL-33 upregulation. ASS1 altered IL-33 receptor ST2 signaling by increasing the soluble decoy isoform (sST2) and decreasing the membrane-bound signaling isoform (ST2L). In co-culture, ASS1-overexpressing foam cells promoted HUVEC apoptosis (via mitochondrial pathway) and HAVSMC proliferation, migration, and dedifferentiation. NLRP3 overexpression alone mimicked the pro-inflammatory effects of ASS1 and reversed the anti-inflammatory effects of ASS1 knockdown. In vivo, ASS1 knockdown in ApoE-/- mice reduced plaque lipid deposition, serum levels of IL-33 and IL-1β, and vascular expression of NLRP3 and p-STAT3, while ASS1 overexpression exacerbated these parameters.
ASS1 drives atherosclerosis by activating the STAT3/NLRP3 inflammasome axis, shifting the IL-33/ST2 balance toward a pro-inflammatory state, and amplifying foam cell–mediated endothelial injury and smooth muscle cell dysfunction. Targeting ASS1 may offer a novel therapeutic strategy for inflammatory vascular disease.
Hyperlipidemia is highly prevalent worldwide and can affect cardiac pathophysiology. This study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the molecular mechanisms of myocardial stress and pathological remodeling in non-obese apolipoprotein E knockout (ApoE⁻/⁻) mice with hypercholesterolemia.
Thirty-five 8-week-old male ApoE⁻/⁻ mice were randomly assigned to four groups as follows: control (normal diet); HFD (high-fat diet); HFD+MICT (60% maximal running speed); and HFD+HIIT (85% maximal running speed). After a 12-week intervention, serum levels of blood lipids and B-type natriuretic peptide (BNP) as well as pathological changes in the myocardial tissue (hematoxylin and eosin staining and Masson’s trichrome staining) were detected. Protein expression analyses of lipid metabolism markers (CD36, CD68 (Cluster of Differentiation 36/68), lectin-type oxidized low-density lipoprotein receptor 1 and peroxisome proliferator-activated receptor-gamma), antioxidant regulators (sirtuin 1/3 [SIRT1/3], nuclear factor erythroid 2-related factor 2 [NRF2], and superoxide dismutase 2 [SOD2]), inflammatory cytokines (interleukin [IL]-6 and IL-18), and fibrosis-related proteins (transforming growth factor-beta 1 [TGF-β1], collagen I/III) was performed using immunohistochemistry and western blotting.
The HFD condition increased serum total cholesterol (TC) and triglyceride (TG) levels, but did not increase body weight, consistent with a lean hyperlipidemia model. Compared with the MICT condition, the HIIT condition demonstrated superior efficacy in reducing HFD-induced TC, TG and BNP levels (p < 0.05). Histologically, HIIT reduced myocardial fibrosis and inflammation. HIIT downregulated lipid transporters CD36/CD68, upregulate the antioxidant SIRT1/3-NRF2-SOD2 axis, inhibit pro-inflammatory factors IL-1β, IL-6, and IL-18, and reduce the deposition of fibrotic TGF-β1 and collagen I and III (p < 0.05).
In a non-obese, hypercholesterolemic ApoE⁻/⁻ model, HIIT elicited more favorable molecular signatures than MICT for ameliorating myocardial stress and pathological remodeling in terms of lipid deposition, oxidative stress, inflammation and fibrosis pathways.
Ultraviolet A (UVA) radiation is a major environmental factor contributing to melanoma development. Melanocytes synthesize melanin, which provides partial protection against UVA-induced oxidative damage; however, these cells remain highly susceptible to oxidative and pro-inflammatory effects of UVA exposure.
In melanocytes, the following parameters were assessed: total antioxidant status (TAS-photometrically), reactive oxygen species (ROS-ESR), lipid peroxidation (4-HNE-GC-MS/MS), 4-HNE-protein adducts, and the expression/localization of key signaling proteins including phosphorylated nuclear factor erythroid 2-related factor 2 (pNrf2) and nuclear factor kappa B (NFκB) subunits [ELISA/fluorescence microscopy].
Cannabigerol (CBG) is a cytoprotective phytocannabinoid. In vitro studies showed that CBG attenuated UVA-induced oxidative stress in human melanocytes exposed to UVA radiation and significantly reduces lipid peroxidation, as measured by the levels of 4-hydroxynonenal (4-HNE) and its protein adducts. The biosynthesis of antioxidants was also regulated by CBG, even when administered post-irradiation. CBG attenuated the effects of UVA radiation by downregulating Nrf2, Kelch-like ECH-associated protein 1 (Keap1), BTB domain and CNC homolog 1 (Bach1), potent cyclin-dependent kinase inhibitor (p21), KRAB-associated protein 1 (KAP1), and multifunctional adaptor protein (p62). CBG also partially inhibited the pro-inflammatory NFκB signaling pathway by reducing the level of the activator (pIκB) and increasing the levels of the inhibitors (IKKα/β).
These results suggest that CBG may protect melanocytes from UVA-induced oxidative changes and lipid peroxidation by activating the Nrf2-dependent antioxidant system and inhibiting NFκB-based pro-inflammatory signaling. CBG can therefore create favorable conditions for the physiological functioning of melanocytes after UVA exposure, ultimately reducing the risk of inflammatory skin responses and neoplastic transformation.
Acute myeloid leukemia (AML) is an aggressive and molecularly diverse hematologic malignancy with unfavorable clinical outcomes and limited options for targeted therapy. This study investigated whether polypyrimidine tract-binding protein 1 (PTBP1), an RNA-binding protein (RBP), affects AML progression by binding to WNK lysine-deficient protein kinase 1 (WNK1).
We first determined the level of WNK1 in AML using the Gene Expression Profiling Interactive Analysis (GEPIA) database and verified it by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB) assay. AML cell migration and invasion were analyzed using Transwell assays following WNK1 modulation. Epithelial-to-mesenchymal transition (EMT) marker level was confirmed by WB assay. The influence of WNK1 on the in vivo metastasis of AML was verified via tail vein injection of WNK1-knockdown AML cells into Non-Obese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) mice. Mechanistically, RNA pull-down and RNA immunoprecipitation (RIP) assays were utilized to interpret the relationship between PTBP1 and WNK1 and to determine whether PTBP1 affects AML cell migration and invasion by regulating WNK1, using rescue experiments.
WNK1 was highly expressed in AML. WNK1 inhibition hindered AML cell migration, invasion, and the expression of EMT markers. WNK1 depletion markedly suppressed the metastasis of AML cells in vivo. Mechanistically, PTBP1 directly bound to WNK1 and increased its mRNA stability. Furthermore, PTBP1 facilitated AML cells migration, invasion, and the expression of EMT markers via WNK1.
We demonstrate that PTBP1 promotes AML progression by modulating WNK1. PTBP1 may therefore represent a potential therapeutic target in AML.
Acupuncture has emerged as a promising complementary therapy for allergic asthma, but the molecular mechanisms underlying its therapeutic effects remain unclear. This study aimed to investigate whether Clara cell 10-kDa protein (CC10), an airway epithelial immunoregulatory protein, mediates the anti-inflammatory actions of acupuncture through the modulation of pulmonary dendritic cells (DCs).
We conducted a clinical study in patients with allergic asthma who underwent acupuncture at GV14 (Dazhui), BL12 (Fengmen), and BL13 (Feishu) acupoints to evaluate changes in asthma control, leukocyte counts, and serum CC10 levels. Parallelly, a house dust mite (HDM)-induced murine asthma model was used to examine the effects of acupuncture on airway hyperresponsiveness, pulmonary inflammation, T helper type 2 (Th2) cytokine production, and CC10 expression. To confirm the role of CC10, wild-type and CC10-deficient mice were compared, focusing on DC subsets analyzed by flow cytometry.
Clinically, acupuncture significantly improved Asthma Control Test (ACT) scores, reduced peripheral leukocyte counts, and elevated serum CC10 concentrations. Consistent with these clinical findings, acupuncture attenuated airway hyperresponsiveness, suppressed eosinophilic infiltration, downregulated Th2 cytokines, and restored pulmonary CC10 expression in HDM-challenged mice. Notably, these protective effects were largely abrogated in CC10-deficient mice, which displayed heightened airway inflammation, mucus hypersecretion, and enhanced Th2 responses. Mechanistic studies revealed that acupuncture reduced pro-inflammatory CD11b+ DCs in a CC10-dependent manner, thereby contributing to airway immune homeostasis.
Acupuncture attenuates allergic airway inflammation by upregulating CC10 and subsequently modulating pulmonary DC subsets, specifically CD11b+ DCs. These findings elucidate a novel mechanistic basis for the therapeutic efficacy of acupuncture and underscore CC10 as a viable therapeutic target for the management of allergic asthma.
NCT01931696, https://clinicaltrials.gov/study/NCT01931696.
The progression of periodontitis is accompanied by destruction of keratinized epithelium, while members of the tumor necrosis factor receptor superfamily (TNFRSF) play critical roles in epithelial repair. This study aimed to elucidate the role of TNFRSF in the pathogenesis and progression of periodontitis. Furthermore, we investigated the mechanisms underlying the repair of epithelial keratinization, with the ultimate aim of translating these insights into clinical therapeutic applications.
Single-cell RNA sequencing was used to investigate the TNFRSF expression profiles in the gingival epithelium of patients with severe periodontitis. Gingival tissues were collected from healthy individuals and those with periodontitis. An in vitro model was also established using retinoic acid to inhibit keratinization and BMS493 to promote keratinization. Bulk RNA sequencing was performed to further substantiate the model and validated the findings by gene knockdown and overexpression experiments. Protein–protein interaction (PPI) analysis and immunoprecipitation identified key protein interactions. In addition, a TNFRSF21 overexpression plasmid and a full-thickness dorsal skin wound mouse model were used to confirm regulatory processes during keratinization.
TNFRSF21 expression, along with epithelial keratinization-related genes were significantly reduced in clinical periodontitis tissues. However, TNFRSF21 increased significantly during epithelial repair following initial periodontal therapy for severe periodontitis, particularly in proliferative keratinocytes and basal layer cells. An in vitro keratinization model revealed that TNFRSF21, Keratin 8 (KRT8), and KRT18, were downregulated during the inhibition of keratinization and upregulated during its promotion. Importantly, the expression levels of KRT8, KRT18, and Claudin-1 were consistently downregulated in the TNFRSF21 knockdown group and upregulated in the TNFRSF21 overexpression group. Single-cell RNA sequencing combined with PPI analysis revealed a significant interaction between TNFRSF21 and amyloid precursor protein (APP). This was validated by STRING database analysis and immunoprecipitation. Mice treated with TNFRSF21 overexpression plasmids showed accelerated wound healing and increased keratin expression on dorsal skin.
Our findings indicate that TNFRSF21 is a pivotal regulator of epithelial keratinization and tight junction integrity in oral epithelial keratinocytes. Targeting TNFRSF21 may represent a novel therapeutic strategy to restore oral epithelial function.
Melanoma, an aggressive cancer with a poor prognosis, is difficult for early diagnosis, and there are limited drug treatments. Biologically active molecules, especially polyphenols and flavonoids, have a great therapeutic potential; however, their applications are limited by low aqueous solubility and bioavailability.
The mixture of usnic acid and curcumin was loaded into the polymer matrices based on hyaluronic acid, with the following polymeric film casting. The anticancer activity of the dual-molecule-loaded polymeric films was evaluated against lightly pigmented human melanoma SK-MEL 28 and unpigmented melanoma CVCL-7036 in comparison with the immortalized human keratinocytes HaCaT.
Usnic acid/curcumin-loaded biopolymer matrices demonstrated a high selective antitumor toxicity against melanoma SK-MEL 28 and CVCL-7036 cell lines with high biocompatibility with immortalized human keratinocytes HaCaT.
Results highlight the potential of the obtained dual-molecule-loaded thin films based on hyaluronic acid as topical and safe antitumor therapy systems for local administration for the melanoma treatment. Moreover, due to the intrinsic properties of usnic acid and curcumin, and the biological activity of native hyaluronic acid, it is supposed that the obtained matrices possess the anti-inflammatory, antioxidant, antibacterial, and wound-healing activities, which are planned to be confirmed in further investigations.
Anticancer therapeutics have evolved from small-molecule drugs to monoclonal antibodies and, more recently, to cell and gene therapies (CGTs). This progress has been driven by the pursuit of greater drug specificity, potency, and safety. Recent breakthroughs in chimeric antigen receptor T-cell (CAR-T) therapy for B-cell hematologic malignancies have accelerated the development of CAR-X CGTs, including CAR-T, CAR-natural killer (CAR-NK), and CAR-macrophage approaches. In this article, we compare candidate CAR-X platforms for T-cell–related diseases, such as T-cell hematologic malignancies, and propose the most suitable modality. Therefore, we analyzed the advantages and limitations of CAR-T, CAR-NK, and CAR-macrophage therapies. In T-cell-related diseases, CAR-T therapy faces multiple challenges, including fratricide, T-cell aplasia, and substantial barriers to the generation of allogeneic CAR-T products. CAR-macrophage therapies, in contrast, are constrained by relatively limited efficacy. In contrast, CAR-NK cells do not cause fratricide or T-cell aplasia and can be manufactured efficiently as allogeneic, “off-the-shelf” products. Collectively, to sustain and extend the advances in CGT initiated by CAR-T cells in B-cell malignancies, prioritizing CAR-NK research infrastructure for T-cell–related diseases represents a rational and strategic approach.
N7-methylguanosine (m7G) is an important RNA modification involved in the regulation of gene expression during transcription. While its roles in mRNAs and tRNAs are increasingly understood, the distribution and function of m7G in long non-coding RNAs (lncRNAs), particularly in oral squamous cell carcinoma (OSCC), remain poorly understood. This study aimed to systematically characterize the m7G methylation landscape of lncRNAs in OSCC and investigate the oncogenic function and regulatory mechanism of the m7G-modified lncRNA DPY19L1P1.
Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed on three pairs of OSCC and adjacent normal tissues to identify differentially m7G-modified and differentially expressed lncRNAs. Motif prediction, its potential functions are identified through analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. DPY19L1P1 was prioritized based on its high level of m7G modification and upregulation. Its clinical relevance was assessed using TCGA-HNSC datasets. In vitro and in vivo functional assays were performed to evaluate its oncogenic roles. The regulatory effects of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) on DPY19L1P1 were examined using expression correlation, MeRIP quantitative real-time PCR (qPCR), and splicing efficiency analyses.
A total of 5486 OSCC-specific m7G peaks and 5135 modified lncRNAs were identified. Compared to normal tissues, OSCC tissues exhibited broader distribution and higher levels of m7G modifications. Among 15,085 hyper-m7G-modified lncRNAs detected in OSCC, 80 were also upregulated. They are enriched in metabolic pathways associated with lncRNA cell adhesion and migration. DPY19L1P1 displayed the most prominent m7G methylation and expression levels, and was significantly associated with advanced clinical stage and poor differentiation, indicating its diagnostic potential. Mechanistically, METTL1 and WDR4 cooperatively enhanced both the m7G modification and expression of DPY19L1P1 by promoting its splicing efficiency. Furthermore, METTL1/WDR4 and DPY19L1P1 synergistically promoted OSCC progression, with DPY19L1P1 functioning as a key downstream effector. Functionally, DPY19L1P1 facilitated OSCC cell proliferation, migration, glycolysis-driven metabolic reprogramming, and epithelial–mesenchymal transition (EMT).
This study provides a comprehensive profile of m7G-modified lncRNAs in OSCC and identifies DPY19L1P1 as a hyper-m7G-modified oncogenic lncRNA regulated by the METTL1/WDR4 complex. As a key downstream effector, DPY19L1P1 promotes OSCC progression through metabolic reprogramming and EMT, and may serve as a potential diagnostic biomarker and therapeutic target.
Centromere protein A (CENPA) is a histone H3 variant essential for centromere function and has been implicated in tumorigenesis in several cancers. However, its clinical significance and biological role in endometrial cancer (EC) remain poorly characterized. This study aimed to elucidate the oncogenic function and underlying mechanisms of CENPA in EC progression.
CENPA expression and its correlation with patient survival were analyzed using clinical datasets and tissue samples. Gain- and loss-of-function assays were performed to evaluate the effects of CENPA on EC cell proliferation, migration, and invasion. Metabolic assays, protein interaction studies, and in vivo xenograft models were utilized to investigate the molecular mechanisms driving CENPA-mediated tumorigenesis.
CENPA was significantly upregulated in EC tissues compared to normal endometrium, and high expression correlated with poor overall survival. Functionally, CENPA overexpression promoted, while its silencing suppressed, EC cell growth and metastasis. Mechanistically, CENPA facilitated metabolic reprogramming by enhancing aerobic glycolysis. We identified Yin Yang 1 (YY1) as a direct binding partner of CENPA. CENPA stabilized YY1 protein levels by inhibiting its proteasomal degradation. Importantly, YY1 knockdown rescued the glycolytic and tumorigenic phenotypes induced by CENPA both in vitro and in vivo.
Our findings establish CENPA as a critical oncogenic driver in EC that functions by stabilizing YY1 to promote metabolic reprogramming. The CENPA-YY1 axis may represent a potential therapeutic target for EC.
Collagen type XI alpha 1 (COL11A1) is overexpressed in pancreatic cancer and is often associated with poor survival, chemoresistance, and tumor recurrence. However, the role of COL11A1 in pancreatic cancer remains poorly understood.
We explored the correlation between COL11A1 and overall survival in pancreatic cancer patients using Kaplan-Meier survival analysis and validated COL11A1’s regulatory role in the viability of pancreatic cancer cell line PANC-1 using Cell Counting Kit-8 and colony formation assays. To clarify the underlying mechanisms, we further examined COL11A1’s modulation of ferroptosis and autophagy in PANC-1 cells by western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence assays. Moreover, autophagy agonist rapamycin, inhibitor 3-methyladenine (3-MA), and AKT/Beclin 1 pathway inhibitors were employed to dissect the regulatory crosstalk between COL11A1, autophagy, and ferroptosis.
COL11A1 expression was negatively correlated with pancreatic cancer patients’ survival rate. Its overexpression significantly enhanced the viability and clonogenic capacity of erastin- and rapamycin-treated PANC-1 cells. Our data showed that COL11A1 reduced intracellular iron levels, suppressed reactive oxygen species accumulation, downregulated malondialdehyde and microtubule—associated protein 1 light chain 3—II/I (LC3II/I) expression, while increasing glutathione (GSH), ferritin heavy chain 1 (FTH1) and solute carrier family 7 member 11 (SLC7A11) levels. Furthermore, COL11A1-mediated ferroptosis inhibition was attenuated by the autophagy agonist Rapamycin but enhanced by the inhibitor 3-MA. Notably, COL11A1 promoted AKT and Beclin 1 phosphorylation, and blocking the AKT/Beclin 1 pathway abrogated its ability to suppress autophagy and ferroptosis in pancreatic cancer cells.
The study demonstrated that COL11A1 exerts its oncogenic effects by suppressing autophagy via the AKT/Beclin 1 pathway, consequently inhibiting ferroptosis in pancreatic cancer cells. These findings reveal a novel molecular mechanism through which COL11A1 promotes tumor progression and provide a potential therapeutic target for pancreatic cancer treatment.
Optimizing culture conditions is essential for enhancing embryonic developmental potential. During the early developmental stages of preimplantation embryos, pyruvate is preferentially consumed in the lower-glucose environment of the fallopian tube, whereas glucose becomes the primary energy substrate in the higher-glucose uterine environment following compaction. However, the specific effects of glucose exposure on autophagy during early development of preimplantation mouse embryos remained unclear. This study used chloroquine (CQ), an autophagy inhibitor in preimplantation embryos. Furthermore, the effects of glucose exposure on the early embryo were investigated, with a focus on changes in autophagy and mitochondrial dependency during the process of embryo development.
We examined the sensitivity of in vivo–fertilized embryos (1-cell and 2-cell flushed embryos; 1-CF and 2-CF, respectively) and in vitro–fertilized (IVF) embryos to CQ, and to rotenone, a mitochondrial respiration inhibitor, from the 2-cell stage. Furthermore, using glucose-free CZB medium and glucose-containing modified CZB (mCZB), comparisons were made of development rates, autophagy activity measured with DAPGreen, and mitochondrial activity measured with MitoTracker. Additionally, we examined the effects of O-GlcNAc transferase (OGT) inhibition using the OGT inhibitor OSMI-1.
Under CQ treatment, the blastocyst formation rate decreased significantly in IVF embryos and 1-CF embryos cultured in mCZB compared to 2-CF embryos, starting at 2.0 μM CQ treatment and this was accompanied by reduced cell numbers. Interestingly, autophagy activity detected by DAPGreen was significantly higher at the morula stage in IVF embryos compared with in 2-CF embryos. Oppositely, under rotenone treatment, the blastocyst formation rate increased significantly in IVF embryos and 1-CF embryos compared to 2-CF embryos, starting at 1.0 μM rotenone treatment. Next, glucose-deprived IVF embryos, which cultured in CZB for 24 hours starting at 2 hours after insemination, exhibited increased sensitivity to rotenone during development and elevated mitochondrial activity at the 2-cell stage, followed by decreased autophagy activity at the 4/8-cell stage. Finally, OSMI-1 treatment in mCZB for 24 hours starting at 2 hours after insemination showed an increased mitochondrial activity at the 2-cell stage but, unexpectedly, these embryos showed a tendency toward increased CQ sensitivity.
Our data indicate that, regardless of fertilization conditions, glucose exposure immediately after fertilization begins to shift preimplantation mouse embryos towards a more autophagy-dependent and less mitochondria-dependent mode of development. This shift is accompanied by increased autophagy activity and reduced mitochondrial activity, potentially mediated in part by O-GlcNAc modification.
Neuronal growth regulator 1 (NEGR1) is an IgLON cell adhesion molecule significantly associated with depression risk in genome-wide association studies. Since the role of NEGR1 in depression pathophysiology remains incompletely understood, we investigated changes in NEGR1-associated gene expression levels in stress-susceptible male mice exposed to chronic restraint stress.
Mice were subjected to 21 consecutive days of restraint stress, and stress-induced maladaptive phenotypes were evaluated by tail suspension, forced swim, splash, and open field tests. After sacrifice, the hippocampi were collected, and the levels of NEGR1-associated genes were assessed by quantitative polymerase chain reaction (qPCR).
In the stress-exposed group, weight was significantly reduced, and immobility time was significantly higher in the tail suspension and the forced swim tests, while grooming bouts in the splash test were reduced. No changes were observed in the open field test. A z-score normalization integrating all behavioural parameters was applied to classify the animals as resilient or susceptible to restraint stress. In stress-susceptible mice, NEGR1, Fibroblast Growth Factor Receptor 2 (FGFR2), Limbic System-Associated Membrane Protein (LSAMP), and Neurotrimin (NTM) mRNA levels were significantly higher compared to controls, while ADAM Metallopeptidase Domain 10 (ADAM10), a metalloprotease releasing NEGR1 from neuronal membranes, was significantly reduced. Interestingly, ADAM10 expression negatively correlated with the behavioural z-score, whereas NEGR1 and LSAMP expression showed positive correlations.
These findings indicate a potential role for NEGR1 in depressive-like behaviors elicited in a stress-susceptible phenotype. Considering NEGR1 genetic association with depression, our results suggest that the NEGR1 pathway may contribute to depression pathophysiology by modulating the interplay between genetic predisposition and exposure to stress as a crucial environmental precipitating factor.
Alzheimer’s disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.
Thyroid collision tumors (TCTs) are rare thyroid malignancies characterized by the coexistence of distinct tumor types. We investigated the histopathology, immunohistochemistry, and gene mutations to comprehensively characterize the heterogeneity of TCTs.
Immunohistochemistry (IHC), hematoxylin and eosin (HE) staining, and Congo red staining were performed to characterize tumor markers. DNA concentrations of all samples were measured using the Qubit DNA Assay Kit in the Qubit 2.0 fluorometer. Somatic mutations were analyzed using the Genomic Identification of Significant Targets in Cancer (GISTIC) and the NCBI-ClinVar, dbSNP, COSMIC, and HGMD databases. Bioinformatic enrichments were constructed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases, the OncodriveCLUST software, Cytoscape, and Circos.
Immunohistochemistry staining of papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) samples showed several distinct biomarkers. According to whole-exome sequencing, a total of 76 single-nucleotide variants (SNVs), 12 insertion–deletion variants (INDELs), and 99 copy-number variations (CNVs) were identified in the TCTs. Moreover, an OTU deubiquitinase, ubiquitin aldehyde–binding protein 2 (OTUB2), with a deletion mutation enhanced the proliferation of thyroid cancer cells in both in vitro and in vivo experiments.
HRas proto-oncogene (HRAS) and STAG2 cohesin complex component (STAG2) were synchronously identified as the driver genes, while the OTUB2 deletion mutation may contribute to tumor proliferation and disease progression in TCTs.
Cadmium (Cd), a widespread environmental pollutant, poses significant risks to human health due to its high bioaccumulation potential and prolonged biological half-life. Selenium (Se) has been reported to exert protective effects against Cd-induced organ toxicity; however, the underlying molecular mechanisms, particularly those associated with lipid metabolism and inflammatory regulation, remain insufficiently elucidated.
The hepatoprotective effects of Se, administered as selenomethionine (SeMet) and Se-enriched Cardamine enshiensis extract (CE), were investigated against Cd-induced hepatic injury using both in vitro (L-02 hepatocytes) and in vivo (C57BL/6J mice) models.
SeMet significantly attenuated Cd-induced cytotoxicity, lipid accumulation, and metabolic dysregulation in L-02 cells. In Cd-exposed mice, treatment with SeMet or CE significantly mitigated hepatic injury, steatosis, and inflammation, as evidenced by normalized serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and total cholesterol (TC) levels, improved hepatic histoarchitecture, and reduced lipid droplet deposition. Integrated lipidomic and transcriptomic analyses demonstrated that Se supplementation restored Cd-perturbed polyunsaturated fatty acid metabolism, downregulated lipogenic genes (SCD1, Pparγ, Fasn), and suppressed pro-inflammatory mediators (Cxcl2, Ccl2).
Se confers hepatoprotection against Cd toxicity not only through its classical antioxidant activity but also through coordinated modulation of lipid metabolic pathways and inflammatory signaling. This study provides mechanistic insights into Se-mediated defense against Cd-induced hepatotoxicity and highlights the therapeutic potential of Se-enriched phytochemicals for mitigating the adverse effects of environmental Cd exposure.