搜索结果：Frontiers in bioscience (Landmark edition)

Chronic pancreatitis (CP) is an independent risk factor for pancreatic cancer (PC). Investigation of the pathological progression of CP may help to elucidate the mechanisms underlying the progression of preneoplastic lesions in CP. Interleukin-6 (IL-6)and Tumor necrosis factor-alpha (TNF-α) were used to induce inflammatory mouse pancreatic acinar carcinoma cell line 83 (MPC-83) cells, followed by RNA-sequencing to identify differentially expressed genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to assess mRNA expression and protein levels, respectively. Flow cytometry was used to quantify CD86- and CD206-positive cells, and the Transwell assays were used to assess cell migration. Methylation-specific PCR (MSP-PCR) was used to assess DNA methylation, and enzyme-linked immunosorbent assay (ELISA) to measure Interferon-gamma (IFN-γ), IL-10, spermine, and spermidine levels. Hematoxylin-Eosin (HE) and Masson staining were used to assess pathological changes and collagen deposition in pancreatic tissues, and immunohistochemistry was used to detect alpha-smooth muscle actin (α-SMA), cluster of differentiation 86 (CD86), and cluster of differentiation 206 (CD206) expression. Spermine and spermidine levels were elevated in inflammatory MPC-83 cells and the serum and pancreatic tissues of a CP mouse model, respectively. IL-6 and TNF-α increased the mRNA expression of Ornithine decarboxylase (ODC), Spermine synthase (SMS), and Spermidine synthase (SRM), and decreased Spermidine/spermine N1-acetyltransferase 1 (SAT1) mRNA expression. Spermine further increased the mRNA expression of SRY-box 9 (SOX9) and Keratin 19 (KRT19) in inflammatory MPC-83 cells and reduced the DNA methyltransferase 3b (DNMT3B) protein level. Spermine also reduced the methylation of SOX9 and KRT19 in MPC-83 cells. The enhanced migration and M2 polarization of RAW264.7 cells induced by spermine-treated inflammatory MPC-83 cells were reversed by DNMT3B overexpression in inflammatory MPC-83 cells. Finally, in vivo experiments revealed that spermine aggravated CP progression and increased M2 macrophage infiltration into the pancreatic tissues of CP mice. Our results suggest that increased spermine levels in inflammatory MPC-83 cells aggravated CP progression by promoting macrophage migration and M2 polarization of macrophages, possibly through reduced DNA methylation of SOX9 and KRT19. These findings suggest a novel mechanism underlying the progression of preneoplastic lesions in CP.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent tissue remodeling, but the mechanisms underlying impaired fibrinolysis were not fully understood. SERPIN family B member 2 (SERPINB2/plasminogen activator inhibitor type 2 [PAI-2]) is a known inhibitor of tissue plasminogen activator (tPA). However, its role in CRSwNP pathogenesis remains unclear. This study investigated whether SERPINB2 contributes to fibrinolytic dysfunction in CRSwNP. tPA and SERPINB2 expression levels were assessed in nasal polyp and control turbinate tissues using qRT-PCR, Western blot, and immunofluorescence. Primary human nasal epithelial cells were stimulated with IFN-γ, IL-13, or IL-17A to evaluate cytokine-mediated regulation. The direct effects of SERPINB2 on tPA expression were examined using recombinant protein treatment and siRNA-mediated knockdown. tPA enzymatic activity and fibrinolytic function were measured using a fluorometric substrate assay and D-dimer ELISA, respectively. tPA expression was significantly reduced in nasal polyp tissues compared to control turbinate and inversely correlated with SERPINB2 levels. Immunofluorescence analysis revealed decreased tPA-positive and increased SERPINB2-positive cells in the nasal epithelium. Both the Th1 cytokine IFN-γ and the Th2 cytokine IL-13 downregulated tPA while upregulating SERPINB2 in primary nasal epithelial cells, whereas IL-17A showed no significant effect. Notably, recombinant SERPINB2 dose-dependently suppressed epithelial tPA expression, while SERPINB2 knockdown rescued cytokine-induced tPA downregulation. Functionally, SERPINB2 inhibited tPA enzymatic activity in a dose-dependent manner and significantly impaired fibrinolytic function. This study identifies a novel SERPINB2-tPA regulatory axis in nasal epithelial cells. The convergent regulation by both Th1 and Th2 cytokines suggests that fibrinolytic dysfunction occurs across different CRSwNP inflammatory endotypes. These findings provide mechanistic insights into fibrin accumulation in nasal polyps and identify SERPINB2 as a potential therapeutic target for the prevention of polyp formation and recurrence.

Icariin, a bioactive flavonoid, exhibits significant neuroprotective properties and has emerged as a promising candidate for preventing neurodegenerative diseases, including Parkinson's disease (PD). However, the mechanism underlying its action is not fully understood. Enhancing the function and frequency of peripheral regulatory T cells (Tregs) may mitigate dopaminergic degeneration. This study investigates the role of Tregs in icariin's neuroprotective effects in a rodent model of PD. PD was induced in mice via stereotactic injection of 6-hydroxydopamine (6-OHDA). Mice underwent pretreatment with saline, icariin, an androgen receptor inhibitor (ARI), or a combination of icariin and ARI. Motor function was assessed in each experimental group, and dopaminergic neuronal injury was evaluated using immunohistochemistry (IHC) staining for tyrosine-hydroxylase (TH) in the substantia nigra (SN) and striatum. IHC was used to quantify CD4+ T-cell infiltration in the SN. Neuroinflammation was assessed through mRNA levels of the pro-inflammatory M1 phenotype of microglia, the anti-inflammatory M2 phenotype of microglia, and the levels of indicated pro-inflammatory cytokines in the SN. The frequency of Tregs among peripheral blood mononuclear cells (PBMCs) was analyzed by flow cytometry, and with Tregs were depleted using PC61 monoclonal antibodies. In vitro androgen receptor (AR) knockdown using shRNA in naïve CD4+ T cells was performed to validate the AR-dependent mechanism. The results revealed that icariin significantly alleviated dopaminergic degeneration. Mechanistically, icariin promotes the expansion of peripheral neuroprotective and immunosuppressive Tregs, thereby restricting CD4+ T cell migration into the SN. This improvement in the inflammatory microenvironment reduced neuroinflammation and mitigated neurodegeneration. However, the neuroprotective and anti-inflammatory effects of icariin were lost when combined with ARI. Additionally, Treg depletion before 6-OHDA injection reversed the positive effects observed in the PD model. Icariin protects against neurodegeneration and neuroinflammation by boosting Tregs expansion in an androgen receptor-dependent manner.

This study aimed to elucidate the protective effects of β-ecdysterone (β-Ecd) against premature senescence in human aortic smooth muscle cells (HASMCs) and to unravel the underlying mechanisms. HASMCs' senescence was induced with angiotensin II (Ang II), and cells were then treated with β-Ecd. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Cellular senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining, cell cycle analysis, and western blotting for the senescence-associated proteins ‌tumor protein p53 (p53) and cyclin-dependent kinase inhibitor 1A (p21). IL-6 and MCP-1 levels in culture supernatants were measured using enzyme-linked immunosorbent assay (ELISA). Autophagy was assessed by microtubule-associated protein 1A/1B light chain 3 (LC3) immunofluorescence, autolysosome staining, and western blotting for LC3 and sequestosome 1 (p62). Intracellular reactive oxygen species (ROS) were quantified by flow cytometry. Transcriptomic profiling using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA), along with analyses and molecular docking, was used to explore potential mechanisms, with key findings validated by western blot. Ang II induced pronounced senescence in HASMCs, characterized by increased SA-β-gal activity, elevated p53 and p21 expression, G0/G1 cell cycle arrest, impaired autophagic flux, increased ROS accumulation, and elevated secretion of IL-6 and MCP-1. CCK-8 assays confirmed that β-Ecd did not affect HASMCs' viability at concentrations up to 200 μM. Treatment with 200 μM β-Ecd effectively attenuated Ang II-induced senescence, restoring cell cycle distribution, reducing p53 and p21 expression, and suppressing IL-6 and MCP-1 secretion. β-Ecd also enhanced autophagic activity, as evidenced by increased LC3II levels, reduced p62 accumulation, and enhanced autophagosome-lysosome fusion, while significantly decreasing intracellular ROS levels. Inhibition of autophagy with bafilomycin A1 abolished the protective effects of β-Ecd. Transcriptomic and bioinformatics analyses revealed enrichment for pathways related to autophagy regulation, with a prominent role for the PI3K/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling axis. Consistently, western blot analysis showed that β-Ecd suppressed Ang II-induced phosphorylation of AKT and mTOR. Modulation of AKT activity further supported its involvement in β-Ecd-mediated protection, as AKT inhibition mimicked this effect. In contrast, AKT activation counteracted the pro-autophagic and anti-senescent effects of β-Ecd. Molecular docking further suggested favorable interactions between β-Ecd and AKT isoforms as well as mTOR. β-Ecd attenuates Ang II-induced premature senescence in HASMCs by enhancing autophagy and limiting oxidative stress, a process mediated by suppressed AKT/mTOR signaling.

Inositol hexaphosphate (IP6), a natural polyphosphorylated carbohydrate widely present in grains, legumes, and mammalian cells, has been increasingly recognized as a key regulator of cellular metabolism. This review examines how IP6 modulates metabolic reprogramming and plasticity in stem cells and disease states and discusses the implications of these mechanisms for translational medicine. IP6 influences central metabolic circuits, including glycolysis, mitochondrial oxidative phosphorylation, and redox balance. In stem cells, IP6 modulates energy utilization, enhances antioxidant defenses, and stabilizes pluripotency networks, thereby helping maintain self-renewal and delay premature differentiation. In pathological settings, such as cancer, IP6 acts as a metabolic checkpoint by attenuating aerobic glycolysis, modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway, and restoring mitochondrial integrity, which leads to growth arrest and apoptosis. These cancer-associated metabolic effects provide a framework for interpreting the IP6-mediated regulation of metabolic thresholds in stem and progenitor cells. Emerging evidence further suggests that IP6 can influence epigenetic landscapes through metabolite-dependent chromatin remodeling, thereby establishing a link between metabolic state and the transcriptional regulation of stemness and lineage commitment. In summary, IP6 is a versatile metabolic rheostat that preserves stem cell function while counteracting maladaptive metabolic reprogramming in disease states. Its pleiotropic effects are also implicated in neurodegeneration, hearing loss, and metabolic syndromes. Future studies should focus on defining IP6-regulated metabolic checkpoints, identifying direct molecular targets, and addressing pharmacokinetic and delivery challenges to help translate IP6-based strategies into regenerative and disease-modifying applications.

SPI1 is a hub gene associated with intracranial aneurysms (IA) and is highly expressed in IA tissues. However, its functional role in IA formation remains unclear. This study aimed to investigate the effect of SPI1 on IA development and its underlying mechanisms. An in vitro IA cell model was established using Platelet-Derived Growth Factor BB (PDGF-BB)-induced vascular smooth muscle cells (VSMCs). SPI1 expression was silenced via sh-SPI1 plasmids to assess its effects on VSMC phenotypic switching and the Wnt pathway. The binding of SPI1 to the Wnt5a promoter was verified by chromatin immunoprecipitation (ChIP) assays. Furthermore, to investigate whether SPI1 influences the contractile-to-synthetic phenotypic transition of VSMCs via the Wnt pathway, the cells were treated with the Wnt5a inhibitor Box5. The in vivo effects of SPI1 knockdown were assessed using an IA mouse model. Compared with the control group, PDGF-BB treatment increased the expression of SPI1, synthetic phenotype markers (MMP3/9), and Wnt pathway-related proteins (β-catenin and c-Myc), while reducing the expression of contractile markers (α-SMA and SM22α) and Wnt5a. Silencing of SPI1 reversed these changes. ChIP assays further confirmed that SPI1 could bind directly to the Wnt5a promoter. Moreover, treatment with the Wnt5a inhibitor Box5 reversed the SPI1 knockdown-induced changes in Wnt5a, β-catenin, and c-Myc in VSMCs. In vivo, SPI1 knockdown alleviated vascular wall thickening in the cerebral artery ring of IA mice, improved the loss of elastic fibers, and suppressed inflammatory responses. In addition, SPI1 knockdown promoted Wnt5a expression while restoring the expression of β-catenin, c-Myc, and phenotypic markers toward control levels. This study suggests that SPI1 promotes intracranial aneurysm formation by inhibiting Wnt5a transcription, thereby promoting activation of the canonical Wnt/β-catenin pathway and driving VSMC phenotypic switching toward a synthetic phenotype. In vivo, SPI1 knockdown alleviated vascular wall injury and inflammation. These findings indicate that the SPI1/Wnt5a signaling axis may represent a potential therapeutic target for intracranial aneurysms.

Colorectal cancer (CRC) progression is frequently driven by metabolic reprogramming and immune evasion. A crucial metabolic enzyme, argininosuccinate synthetase 1 (ASS1), is dysregulated in a number of malignancies; however, its role in CRC and its effects on the tumor immune microenvironment remain poorly understood. Carnitine palmitoyltransferase 1A (CPT1A)-mediated fatty acid oxidation and post-translational modifications, including succinylation, are emerging as important regulators of tumor behavior. ASS1 expression was analyzed using The Cancer Genome Atlas (TCGA) database and further validated in 40 paired clinical CRC specimens and cell lines. Functional roles were assessed through knockdown and overexpression experiments in CRC cells, evaluating proliferation, colony formation, migration, and invasion. Mechanisms were explored via co-immunoprecipitation, succinylation assays, protein stability measurements, and co-culture systems with CD8+ T cells. Additionally, in vivo tumor growth and changes in the immune milieu were evaluated using a mouse CT26 transplantation model. ASS1 was markedly upregulation in both cultured cell lines and CRC tissues. ASS1 knockdown decreased programmed cell death protein-1 (PD-1) expression and T cell fatigue while enhancing interferon-γ, tumor necrosis factor-α, perforin, and granzyme B secretion, which in turn increased CD8+ T cell cytotoxicity and inhibited malignant phenotypes in vitro. Mechanistically, ASS1 transcriptionally activated CPT1A, which promoted S100 calcium-binding protein A10 (S100A10) succinylation at lysine 47, thereby stabilizing S100A10 protein. Overexpression of either CPT1A or S100A10 reversed the tumor growth suppression and impaired immune activation resulting from ASS1 knockdown. In vivo, ASS1 knockdown inhibited tumor growth, downregulated CPT1A and S100A10 expression, and increased CD8+ T cell infiltration while reducing PD-1 levels. ASS1 promotes CRC progression and immune escape by regulating the CPT1A-mediated succinylation and stabilization of S100A10. These findings highlight the ASS1/CPT1A/S100A10 axis as a potential therapeutic target for CRC.

Current osteoporosis (OP) therapies predominantly suppress osteoclastic bone resorption, highlighting a critical unmet need for anabolic strategies that directly stimulate bone formation. Meteorin-like (Metrnl) is a recently identified adipokine whose role in bone metabolism remains poorly defined and controversial. This study systematically investigated the expression profile, physiological function, and molecular mechanism of Metrnl in skeletal biology. An integrated approach combining clinical bone marrow specimen analysis, proteomics, single-cell RNA sequencing, and conditional genetic ablation mouse models was utilized. Skeletal phenotypes were evaluated via Micro-CT and bone histomorphometry. Intracellular molecular interactions were determined through co-immunoprecipitation and transcriptional activity assays. Clinically, Metrnl expression was significantly diminished in bone marrow samples from postmenopausal women with OP, suggesting potential relevance to human disease. In mice, Metrnl was predominantly expressed in osteoprogenitor cells, and its expression declined progressively with age. Unexpectedly, systemic knockout (n = 6 per group) of Metrnl resulted in a marked increase in trabecular bone mass (bone volume to total volume ratio [BV/TV]: 4.11 &#xb1; 0.08% vs. 3.89 &#xb1; 0.12%, p < 0.01) and bone formation rate (Bone formation rate per bone surface [BFR/BS]: 0.50 &#xb1; 0.03 vs. 0.38 &#xb1; 0.03 &#x3bc;m/day*100, p < 0.05) without affecting osteoclast activity. This anabolic phenotype was fully recapitulated in osteoblast-specific (Ocn-Cre) and osteoprogenitor-specific (Prx1-Cre) conditional knockout mice (n = 6 per group), which both exhibited significantly higher BV/TV (4.13 &#xb1; 0.06% and 4.04 &#xb1; 0.05%, respectively) compared to controls (3.88 &#xb1; 0.08%; p < 0.001 and p < 0.01, respectively), establishing a cell-autonomous inhibitory role of Metrnl in osteogenesis. Mechanistically, intracellular Metrnl directly interacts with the scaffold protein Receptor for activated C kinase 1 (Rack1), thereby disrupting the PKC-&#x3b1;-Rack1 complex, reducing Brain and Muscle ARNT-Like 1 (Bmal1) phosphorylation, and facilitating its nuclear translocation. This process subsequently upregulates transcription of the circadian clock gene Cryptochrome 2 (Cry2), thereby suppressing osteoblast differentiation. Collectively, these findings identify Metrnl as a previously unrecognized negative regulator of bone formation and uncover a Rack1-PKC&#x3b1;-Bmal1-Cry2 signaling axis that links circadian regulation to osteogenesis. These results establish a conceptual framework for targeting Metrnl-mediated pathways in the development of anabolic therapies for OP.

Non-muscle-invasive bladder cancer (NMIBC) accounts for roughly 75% of all bladder cancer cases. For patients with intermediate- and high-risk disease, intravesical Bacillus Calmette-Gu&#xe9;rin (BCG) remains the standard treatment, yet it fails in up to 40% of cases. While radical cystectomy is the most effective salvage option, it carries significant morbidity and long-term quality-of-life consequences, highlighting the urgent need for bladder-sparing alternatives. Advancing such therapies requires a deep understanding of the immunologic mechanisms within the tumor microenvironment (TME). This review offers a concise overview of the immunologic mechanisms underlying BCG therapy, along with a detailed examination of the multifactorial immune evasion mechanisms that contribute to its failure in NMIBC. Within the TME, ten principal mechanisms of immune suppression have been identified. These include the activity of myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, and tolerogenic dendritic cells, as well as signaling pathways such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1), the natural killer group 2A/human leukocyte antigen-E (NKG2A/HLA-E) checkpoint, and the release of immunomodulatory molecules within the TME. Further contributors to immune evasion include cluster of differentiation 6/activated leukocyte cell adhesion molecule (CD6-ALCAM) signaling, effector T cell exhaustion, and cancer-associated fibroblasts. Collectively, these mechanisms disrupt antigen presentation, suppress cytotoxic immune responses, and facilitate tumor progression, ultimately undermining the efficacy of BCG therapy. In parallel, we highlight emerging intravesical immunotherapies for BCG-unresponsive NMIBC with carcinoma in situ, including nadofaragene firadenovec (Adstiladrin), nogapendekin alfa inbakicept-pmln (Anktiva), cretostimogene grenadenorepvec (CG0070), and detalimogene voraplasmid (EG-70). These agents employ diverse platforms, including gene therapy, cytokine stimulation, oncolytic virotherapy, and plasmid-based immune activation, to enhance antitumor responses. While early and late-phase clinical trials have shown promising response rates and favorable safety profiles for these novel agents, direct comparisons remain limited due to the reliance on single-arm study designs. The lack of comparative data, coupled with the absence of predictive biomarkers of response, complicates treatment selection. Our review underscores that developing effective therapies for BCG-unresponsive disease will require combination strategies targeting multiple immune escape mechanisms that shape immune dynamics within the TME.

Nitric oxide (NO) is a key bioactive signaling molecule produced primarily by L-arginine by inducible NO synthase (iNOS), which is involved in signal transduction and performs a variety of biological functions. As the mainstay of the immune response, macrophage polarization is a dynamic and reversible process, allowing them to shift their functional states and immune-inflammatory properties in response to changing environmental cues. M1-type macrophages are polarized by stimuli such as lipopolysaccharide or interferon gamma. These pro-inflammatory cells secrete tumor necrosis factor alpha, interleukin-1&#x3b2; (IL-1&#x3b2;), IL-6, and other pro-inflammatory factors, which serve to initiate and amplify the inflammatory response. By contrast, M2-type macrophages are induced by IL-4 or IL-13 and express high levels of anti-inflammatory mediators such as IL-10 and transforming growth factor beta, which inhibit inflammation and promote tissue repair. Macrophages in the tumor immune microenvironment produce NO via arginine metabolism, with important impacts on tumorigenesis and immune escape. In turn, NO production regulates macrophage function by inducing a shift from the M2 type (which promotes tumor growth) to the M1 type (which suppresses tumor growth). In addition, NO affects the tumor immune response by regulating T-cell activity. Relevant therapeutic strategies for targeting NO include arginase (ARG) inhibitors, NO donors, and iNOS overexpression. This review summarizes the complex role of NO in tumor immunity and related therapeutic strategies. While the findings provide new directions for cancer immunotherapy, further research is needed to fully understand specific mechanisms, such as the dynamic regulation of the NO concentration threshold, the clinical translation of these findings, and the seemingly contradictory role of NO in immune cell function, ultimately leading to more effective treatment options.

Heart failure (HF) is characterized by mitochondrial dysfunction and immune dysregulation. However, the underlying molecular mechanisms remain unclear. Functional enrichment analyses study aimed to identify key mitochondrial genes involved in HF pathogenesis and to explore their association with immune cell infiltration. Differentially expressed genes related to HF were identified and subjected to functional enrichment analyses. Summary data-based Mendelian randomization (SMR) was used to evaluate the diagnostic potential of candidate genes. Immune cell infiltration analysis was performed to assess associations between gene expression and immune profiles. Single-cell RNA sequencing data (GSE145154) were analyzed to determine cell-specific expression patterns. A transverse aortic constriction (TAC)-induced HF mouse model was established, and cardiac function was assessed by echocardiography. Histopathological analyses were conducted to evaluate myocardial injury, fibrosis, and apoptosis. Immune cell populations were further examined in vivo. Functional enrichment analysis revealed that HF-related genes were significantly associated with mitochondrial organization and pathways such as mechanistic target of rapamycin (mTOR) signaling and cardiomyopathy. SMR analysis identified NADH: ubiquinone oxidoreductase core subunit S2 (NDUFS2) and NME/NM23 nucleoside diphosphate kinase 6 (NME6) as having diagnostic relevance. Immune infiltration analysis showed correlations between these genes and immune cell populations. Single-cell RNA sequencing revealed that NME6 was predominantly expressed in T cells and neutrophils, indicating potentially important significance. Clinical data suggested that brain natriuretic peptide (BNP), C-reactive protein (CRP), neutrophils, monocytes, and inflammatory factor levels tended to increase with HF severity. Echocardiography determined that in HF mice, NME6 knockdown lessened the left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) while boosting the left ventricular ejection fraction (LVEF) and fractional shortening (LVFS). Histopathological analysis further demonstrated that NME6 knockdown alleviated myocardial damage and fibrosis, and inhibited cardiomyocyte apoptosis in HF mice. In-depth studies indicated that NME6 knockdown mitigated HF by increasing the proportion of CD4+ T cells and decreasing the proportions of CD8+ T cells and CD44+CD62L+ T cells. NME6 may act as a regulator of immune responses and a potential therapeutic target in HF, providing new insights into the molecular mechanisms of HF.

Dehydrogenases function as metabolic gatekeepers, regulating carbon flux, redox balance, and biosynthetic capacity at critical branch points in cellular metabolism. This narrative review examines six key dehydrogenases, namely glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH), pyruvate dehydrogenase complex (PDHC), malate dehydrogenase (MDH1/2), isocitrate dehydrogenase (IDH1/2/3), and glucose-6-phosphate dehydrogenase (G6PDH), that collectively orchestrate the partitioning of nutrients among energy production, biosynthesis, and redox homeostasis. These enzymes share common features, including cofactor-dependent catalysis (NAD+/NADH or NADP+/NADPH), strategic positioning at metabolic nodes, and integration of compartmentalized metabolism between the cytosol and mitochondria. Under physiologic conditions, these dehydrogenases enable metabolic flexibility, allowing cells to adapt nutrient utilization to changing energetic demands and biosynthetic requirements. However, their dysregulation drives pathogenesis across diverse human diseases. In cancer, altered dehydrogenase activity supports metabolic reprogramming, exemplified by the Warburg effect mediated by LDHA, oncometabolite production (mutant IDH1/2), and enhanced biosynthetic capacity associated with G6PDH activity. Metabolic syndrome and diabetes feature PDHC suppression via pyruvate dehydrogenase kinase (PDK) upregulation, contributing to metabolic inflexibility and impaired glucose oxidation. Inherited enzymopathies, including G6PDH and PDHC deficiencies, underscore the essential roles of these enzymes and their tissue-specific requirements. In neurodegenerative disorders, oxidative modification of GAPDH promotes protein aggregation, whereas age-related decline in NAD+ compromises the activity of multiple NAD+-dependent dehydrogenases in a tissue- and context-dependent manner. The central importance of these enzymes has generated substantial therapeutic interest. Successful clinical translation includes mutant IDH inhibitors that reverse oncometabolite-driven epigenetic reprogramming in cancer. However, targeting essential metabolic enzymes presents challenges, including narrow therapeutic windows, metabolic compensation, and tissue-specific toxicities. Future therapeutic strategies will likely focus on exploiting disease-specific vulnerabilities, developing isoform-selective inhibitors, and combining metabolic interventions with conventional therapies. Understanding these six dehydrogenase gatekeepers provides crucial insights into metabolic regulation and highlights opportunities for precision-medicine approaches targeting the metabolic dependencies of human disease.

Type 2 diabetes mellitus (T2DM) is a major public health challenge. This study aimed to explore the molecular mechanisms underlying the effects of semaglutide on lipid metabolism in visceral white adipose tissue in a mouse model of T2DM. Male C57BL/6J mice were given a normal diet, a high-fat diet with streptozotocin, or a high-fat diet with semaglutide. Blood samples, liver tissue, and adipose tissue were collected for analysis. Serum adipokines, inflammatory cytokines, liver function, and lipid profiles were assessed. White adipose tissue and liver sections were processed for hematoxylin and eosin (H&E) staining or immunohistochemistry (IHC) staining for the macrophage marker F4/80. High-throughput targeted lipidomic analysis of epididymal white adipose tissue from these animals was performed using liquid chromatography-tandem mass spectrometry to characterize changes in lipid composition and function. Furthermore, the expression of genes related to adipokines, inflammation, and lipid metabolism in epididymal adipose tissue was determined by reverse transcription-quantitative PCR (RT-qPCR). Semaglutide significantly improved systemic metabolism in mice with T2DM, as demonstrated by reductions in body weight, blood glucose, serum lipid levels, and insulin resistance indices homeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance index (Adipo-IR). Serum Leptin, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-&#x3b1;) levels were downregulated, while Adiponectin levels were elevated. Histological analysis revealed that semaglutide effectively reduced adipocyte size, suppressed macrophage infiltration in adipose tissue, and decreased liver lipid accumulation. Targeted lipidomic profiling identified 24 lipid subclasses, of which 50 lipid molecules were significantly changed after semaglutide treatment. Enrichment analysis identified 15 metabolic pathways, with glycerophospholipid metabolism being the most prominently affected. RT-qPCR results confirmed that semaglutide altered the expression of key genes involved in glycerolipid, glycerophospholipid, fatty acid, and cholesterol metabolism. These results shed light on the comprehensive remodeling of semaglutide in improving lipid metabolism in epididymal white adipose tissue mice with T2DM.

Immunomodulators play a central role in the treatment of cancer and immune-mediated disorders. Small-molecule immunomodulators are particularly attractive due to their structural diversity, pharmacological versatility, and potential for oral administration. This study aimed to investigate the immunomodulatory potential of newly synthesized aza-spirocyclic derivatives. A series of novel aza-spirocyclic compounds was evaluated for cytotoxicity in RAW264.7 murine macrophages. Immunomodulatory activity was assessed by quantifying nitric oxide (NO) production and profiling pro- and anti-inflammatory cytokines in macrophages and murine splenocytes. In vitro anti-inflammatory effects were further examined using a lipopolysaccharide (LPS)-induced inflammation model. Mechanistic insights were explored using molecular docking and immuno-informatics analyses. All compounds were non-toxic at the tested concentrations. Most derivatives failed to induce NO production, indicating an absence of danger-associated molecular pattern (DAMP)-like activity. Several compounds significantly reduced the pro-inflammatory cytokine interleukin-6 (IL-6) while increasing the anti-inflammatory cytokine IL-10 in vitro. In the LPS-induced inflammation model, four compounds notably suppressed IL-6 and enhanced IL-10 expression. The binding affinities obtained from docking, along with in vitro validation of these compounds on Janus kinases (JAKs) signaling, suggested that compounds AS8 and AS10 modulated inflammatory signaling pathways. The synthesized aza-spirocyclic derivatives exhibit promising anti-inflammatory profiles, characterized by IL-6 suppression and IL-10 enhancement. These findings position aza-spirocyclic scaffolds as candidates for the development of next-generation small-molecule immunomodulators.

The use of manganese oxide nanoparticles (MnOxNPs) in biomedicine increases the risk of their accumulation in the body, potentially leading to toxicity in various organs and tissues. In addition, occupational exposure to MnOxNPs-containing aerosols may also occur. MnOxNPs have been shown to accumulate in the brain and induce neurobehavioral alterations. However, the specific mechanisms of MnOxNPs toxicity in the brain and other tissues remain incompletely understood. Therefore, the objective of this review is to summarize existing data on the toxicity of MnOxNPs in the brain and other tissues, and to discuss the molecular mechanisms underlying their neurotoxic effects. It has been shown that MnOxNPs induce neuronal death through induction of mitochondrial dysfunction and subsequent apoptosis, and overaccumulation of tau protein and amyloid-&#x3b2;. Neurotoxic effects of MnOxNPs may also be mediated by blood-brain barrier disruption, and dysregulation of dopaminergic and glutaminergic signaling. Exposure to MnOxNPs induces neuroinflammation through activation of nuclear factor kappa B (NF-&#x3ba;B) and p38 mitogen-activated protein kinase (p38 MAPK) pathways in a reactive oxygen species-dependent manner. In vitro studies further demonstrate that MnOxNPs exhibit a dose-dependent cytotoxic effects in alveolar macrophages, as well as in respiratory, colonic, and other epithelial cells, through the promotion of oxidative stress and an inflammatory response. Overexposure to MnOxNPs has significant nephrotoxic, hepatotoxic, and immunotoxic effects, as well as affecting the reproductive system. Smaller particles exhibit more pronounced toxic effects in the brain and other tissues than larger nanoparticles or microparticles. However, the mechanisms underlying the different toxicities of MnOxNPs of different sizes, shapes, and surface modifications remain unclear. These observations highlight the potential of MnOxNP exposure to contribute to neurological disorders and dysfunction of other systems, underscoring the need for further mechanistic studies to ensure their safe application in biomedicine.

Cardiovascular diseases remain a leading cause of mortality worldwide, with myocardial infarction (MI) being the most severe form. Despite advances in treatment, MI is still associated with an estimated mortality rate of approximately 35%, and survivors frequently develop heart failure and arrhythmias, underscoring the need for new therapeutic strategies. Growing evidence indicates that mitochondrial dysfunction in cardiomyocytes (CMCs) is a major driver of post-MI remodeling. Consequently, targeting mitochondrial dynamics and subpopulation-specific responses has emerged as a promising cardioprotective approach. While acute-phase mitochondrial changes after MI have been extensively studied, remodeling during the subacute and chronic stages remains less understood, despite its critical role in scar expansion and the progression of heart failure. In this study, we investigated functional and morphological alterations in distinct mitochondrial subpopulations of left ventricular CMCs two weeks after MI. MI was induced in adult rats by permanent ligation of the left anterior descending coronary artery. Mitochondrial morphology was analyzed by transmission electron microscopy. Mitochondrial function and oxidative stress were assessed in live isolated CMCs using fluorescence and confocal microscopy. Two weeks after MI, CMCs exhibited a reduction in total mitochondrial membrane potential (MMP) and an increase in reactive oxygen species levels. Herewith, mitochondrial activity differed among mitochondrial subpopulations. The MMP of perinuclear (PNM) and subsarcolemmal mitochondria (SSM) decreased by ~30% more than that of intermyofibrillar mitochondria (IFM). These functional impairments were accompanied by reductions in mitochondrial size: IFM area decreased by 22%, whereas PNM and SSM decreased by 32% and 29%, respectively. At the same time, mitochondrial volume density decreased in SSM and IFM regions but remained unchanged in PNM regions. Consequently, the overall functional alterations in the PNM regions were comparable to those observed in IFM regions. Our data demonstrate a decrease in the activity of CMC mitochondria associated with their fragmentation and reduced volume density two weeks after MI, with the most pronounced changes in SSM. These findings underscore the importance of subpopulation-specific mitochondrial analysis for understanding subacute post-infarction remodeling and for identifying novel therapeutic targets.

Climate change, along with the increasing incidence of drought, salinity, nutrient depletion, and extreme temperatures, is severely constraining global agricultural productivity. In recent years, nanoparticles (NPs) have emerged as effective modulators of plant physiology; however, a comprehensive understanding of their comparative performance across different stress conditions remains limited. This review synthesizes recent advances on silicon dioxide (SiO2), zinc oxide (ZnO), copper oxide (CuO), iron oxide (FeO), silver (Ag), and titanium dioxide/titania (TiO2) NPs, emphasizing their mechanistic roles and quantifying their effectiveness in enhancing plant resilience. Evidence indicates that SiO2 NPs primarily enhance antioxidant defense, regulate ion homeostasis, improve water-use efficiency, and promote root development under drought and salinity stress. For example, SiO2 NPs at 250 mg L-1 increased chlorophyll content and boosted antioxidant enzyme activity. ZnO NPs contribute to stress tolerance by strengthening antioxidant systems, maintaining membrane stability, improving osmotic adjustment, and enhancing nutrient uptake under drought, salinity, and nutrient-deficient conditions. Their effects on antioxidant defenses are consistently strong: plants treated with 100 mg L-1 ZnO NPs exhibited marked increases in pigment concentrations (+58-73% for chlorophyll a, +142-149% for chlorophyll b, and +176-193% for carotenoids). Cu NPs also demonstrated protective effects: doses of 20 mg L-1 can reduce cadmium (Cd) accumulation in leaves (-12.6%) and roots (-38.6%). Iron(II) oxide NPs (FeO NPs), applied at 20-100 mg L-1, promote better growth and photosynthesis in barley by regulating gene expression. Additionally, TiO2 NPs at 200 ppm have been shown to enhance salt tolerance in eggplant by improving antioxidant defense, protecting photosynthetic function, and reducing oxidative damage. By integrating these quantitative results with mechanistic insights, this review clarifies how NPs modulate plant performance under stress. It also identifies key knowledge gaps related to dose optimization, long-term environmental fate, and safety assessment. Overall, the findings highlight both the potential and the challenges of incorporating nanotechnology into future strategies aimed at strengthening crop resilience under accelerating climate stress.

Diabetic retinopathy (DR) is increasingly recognized as a complex neurovascular degenerative disorder driven by intertwined immune and metabolic disturbances within the retinal microenvironment. Chronic hyperglycemia induces metabolic stress, mitochondrial dysfunction, and oxidative imbalance, which, in turn, activate innate and adaptive immune pathways. Key mechanisms-including complement dysregulation, microglial activation, leukostasis, cytokine and chemokine signaling, and advanced glycation end-product-mediated inflammation-contribute to endothelial injury, barrier breakdown, and progressive neuronal loss. Parallel alterations in lipid metabolism, amino acid utilization, and mitochondrial bioenergetics further amplify inflammatory cascades and shape the retinal immune landscape. This review synthesizes current evidence on how immune-metabolic crosstalk orchestrates early and late stages of DR, integrating findings from transcriptomic, proteomic, metabolomic, and epigenetic studies. We examine core signaling hubs that couple metabolic dysfunction to inflammatory amplification, including complement components, the advanced glycation end product (AGE)-receptor for AGE (RAGE) pathway, cytokine networks, and immune response regulation. Adopting a systems biology perspective, we highlight how convergent mechanisms can unify vascular, neuronal, and glial pathology under a shared framework of immune-metabolic imbalance. An extensive literature search was conducted (PubMed, accessed December 2025). By positioning DR as a model of inflammatory retinal degeneration, this review outlines a conceptual foundation for network-based diagnostics and therapeutics. Understanding the dynamic interactions among immune signaling, metabolic stress, and neurovascular instability may inform future strategies to restore retinal homeostasis and prevent vision-threatening disease progression.

The molecular mechanisms underlying obstructive jaundice (OJ)-induced liver injury and subsequent repair after biliary recanalization (R-OJ) remain incompletely elucidated. This study aimed to identify and validate core gene involved in regulating OJ-related liver injury and repair via integrated in vitro and in vivo models. Animal models (OJ and R-OJ groups) and cell models (OJ serum (OJS) and OJ serum depletion (OJSD) groups) were established. Liver function and histopathologic changes were evaluated. Differentially expressed genes (DEGs) were screened by RNA sequencing (RNA-seq), and candidate genes were selected by intersecting DEGs with functional gene sets associated with "injury" and "repair". Key genes were identified via protein-protein interaction (PPI) network and pathway enrichment analyses. Fibroblast growth factor receptor 2 (FGFR2) expression was validated by quantitative reverse transcription PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC). Functional involvement of FGFR2 was assessed by siRNA-mediated knockdown followed by assessment of downstream AKT signaling, proliferation (proliferating cell nuclear antigen, PCNA), and apoptosis maker cleaved caspase-3. OJ induced significant liver dysfunction and tissue damage, which partially recovered after R-OJ. Bioinformatic analyses identified FGFR2 as a core regulatory gene among 20 candidates. FGFR2 was downregulated during injury (OJS vs. Con, p < 0.05) and upregulated during repair (OJSD vs. OJS, p < 0.05) both in vivo and in vitro. FGFR2 knockdown in BRL-3A cells markedly reduced p-AKT levels by approximately 50% under all serum conditions (p < 0.01), significantly decreased PCNA expression, and altered cleaved caspase-3 levels, suggesting that FGFR2 may contribute to hepatocyte proliferation and survival, potentially through the phosphoinositide 3-kinase (PI3K)/AKT signaling. FGFR2 exhibits a dynamic expression pattern of downregulation during cholestatic injury and upregulation during repair, and is associated with hepatocyte proliferation and apoptosis, potentially through AKT signaling. These findings suggest that FGFR2 may represent a potential therapeutic target for improving liver repair in obstructive jaundice.