搜索结果：Cell biochemistry and function

Adolescence is a metabolically vulnerable period, during which rapid physiological maturation coincides with the dynamic remodelling of the gut microbiome. This narrative review summarises evidence from 2015 to 2025 to clarify how disturbances to the gut-liver axis driven by dysbiosis contribute to the development and progression of non-alcoholic fatty liver disease (NAFLD) in young people. Based on a systematic search of the databases PubMed, Scopus and Web of Science, we outline the basis of bidirectional communication between the gut and liver and emphasise how microbial imbalance alters the handling of lipids in the liver by enhancing de novo lipogenesis, impairing fatty acid oxidation and disrupting AMPK signalling and mitochondrial function. Consistent findings from clinical and experimental studies show that adolescents with NAFLD exhibit reduced microbial diversity, the enrichment of ethanol- and LPS-producing taxa, and altered short-chain fatty acid profiles. Each of these is associated with hepatic inflammation and metabolic reprogramming. Microbial molecules, including LPS, secondary bile acids and branched-chain amino acid metabolites, activate TLR4-NF-κB pathways, promote Kupffer cell activation and intensify oxidative stress. These mechanisms intersect with factors specific to adolescence, such as increased adiposity, hormonal shifts and diet-induced metabolic strain. Dietary patterns emerge as key modulators of these processes. Westernised diets promote dysbiosis and endotoxemia, whereas Mediterranean, fibre-rich and plant-based diets enhance SCFA production, strengthen epithelial integrity and modulate adiponectin-dependent hepatic metabolism. Micronutrient-sensitive epigenetic regulation, particularly that involving folate, choline and polyphenols, also plays a role in shaping lipid homeostasis and inflammatory tone. We also highlight emerging evidence that the activation of cytoprotective pathways, especially Nrf2, is dependent on lifestyle factors and links antioxidant-rich functional foods and physical activity to improved mitochondrial resilience and microbiome stability. We evaluate therapies targeting the microbiome, including probiotics, prebiotics, synbiotics and postbiotics, which reduce endotoxemia, restore microbial balance and complement dietary strategies. Thus, these findings emphasise the importance of age-specific, mechanistically informed interventions that integrate diet quality, microbial ecology, and the molecular pathways that govern metabolic health in adolescents with NAFLD.

The present study aimed to evaluate the effect of apigenin (Api) on the differentiation of adipose tissue-derived mesenchymal stem cells (ASCs) into insulin-producing cells (IPCs) via inducing autophagy. ASCs were isolated from fresh adipose tissues using mechanical and enzymatic digestion and characterized using flow cytometry. ASCs were treated with Api (0, 5, 10, 25, and 50 µM) for 48 and 72 h, to determine the Api optimum dose using the MTT test. ASCs were exposed to optimal Api doses (5 and 10 µM) and differentiated into IPCs by cultivating them in a differentiation medium in a two-step manner. The expression of IPC and autophagy genes and proteins was evaluated using real-time PCR and Western blot, and glucose-stimulated insulin and C-peptide secretion were assessed using colorimetric methods. Autophagy and β cell-specific protein interactions were analyzed using the STRING database. 94% of ASCs expressed CD73, CD90, and CD105, while 99% didn't express CD34 and CD45. Api treatment increased the expression of PDX1, GLUT2, Insulin, LC3A, ATG5, and ATG7 genes, as well as LC3-1 and LC3-II proteins in a dose-dependent manner. Glucose-stimulated insulin and C-peptide secretion were significantly higher in Api-treated groups. Bioinformatic analysis revealed that MAPK and FOXO3 were central proteins that interacted with and connected β cell-specific and autophagy functional clusters. Api increased the differentiation of ASCs into IPCs by inducing autophagy and can be considered a novel strategy for enhancing differentiation efficiency.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are urgently needed. Transforming Growth Factor-β (TGF-β) plays a central role in IPF pathogenesis by activating lung fibroblasts. Inhibitor of DNA binding (ID) proteins are regulated by TGF-β; however, their role in IPF remains poorly understood. We aimed to evaluate the regulation of ID proteins in IPF and to determine their functional role in human lung fibroblasts (HLF) in vitro and pulmonary fibrosis in vivo. ID protein expression was assessed in lungs and lung fibroblasts from mice and patients with pulmonary fibrosis. In vitro, the effects of ID1/ID3 inhibition and overexpression on HLF proliferation, migration and differentiation into myofibroblasts were evaluated. Genetic and pharmacological approaches were used in vivo to determine the role of ID1/ID3 in pulmonary fibrosis. ID1/ID3 levels were elevated in lungs and lung fibroblasts from mice and patients with pulmonary fibrosis, as well as in HLFs treated with TGF-β. ID1/ID3 knockdown reduced proliferation, migration and differentiation of healthy and IPF-derived HLFs. Bleomycin-exposed ID1/ID3 double KO mice exhibited improved lung function and reduced fibrosis compared with WT mice. Pharmacological inhibition of ID1/ID3 decreased HLF proliferation, migration and differentiation in vitro and attenuated pulmonary fibrosis in vivo. Lung-specific inhibition of ID1/ID3 using adeno-associated viruses expressing short hairpins targeting ID1 and ID3 also reversed pulmonary fibrosis in mice. Mechanistically, ID1/ID3 inhibition reduced fibroblast proliferation through regulation of cell cycle genes and attenuated fibroblast differentiation via the MEK/ERK pathway. Simultaneous inhibition of ID1 and ID3 attenuates pulmonary fibrosis. Targeting ID1/ID3 represents a potential novel therapeutic strategy for IPF.

Nanotechnology plays a crucial role in vaccine development, enabling the design of functional nanoparticles (NPs) that act as both antigen carriers and adjuvants to enhance immune responses. In this study, we evaluated complex coacervate-like NPs composed of poly(allylamine hydrochloride) (PAH) and tripolyphosphate (TPP) as a biocompatible and biosafe platform for systemic and mucosal subunit vaccines. We assessed NP-induced activation of antigen-presenting cells and their adjuvanticity in BALB/c and knockout mice immunized intraperitoneally and intranasally with NP-OVA. In vitro, NPs increased CD86 and MHC II expression and promoted interleukin-1β (IL-1β) and IL-18 secretion via NLRP3 inflammasome activation in macrophages and dendritic cells co-incubated with LPS. Cytokine release occurred through an unconventional autophagosome-dependent pathway, as inhibition of autophagy with 3-methyladenine reduced LPS/NP-induced IL-1β secretion. In vivo, NP-OVA administration induced robust OVA-specific IgG and IgG2a responses, increased IFN-γ secretion by splenocytes, and elevated frequencies of CD4⁺IFN-γ⁺ and CD8⁺IFN-γ⁺ T cells. Comparable responses were observed following intranasal immunization, highlighting the versatility of these NPs as vaccine platforms. Overall, PAH/TPP NPs activate the NLRP3 inflammasome in innate immune cells, promote antigen-presenting cell maturation, enhance cytokine secretion, and induce strong Th1-biased humoral and cellular immune responses. These findings support their potential as a safe dual-function nanoplatform for preventive and therapeutic vaccines against infectious and non-infectious diseases.

Breast cancer (BC) is the most prevalent cancer among women, and retrieving the anti-tumor function of the immune system seems a promising treatment approach for its crucial role in combating cancer cells. In this study, we evaluated the impact of a combination therapy containing a TAK1 inhibitor, Takinib (Tak), a metabolic regulator, Metformin (Met), and an immunostimulant, Lentinula edodes mycelia extract (LEME) on enhancing the immune system's anti-tumor activity in BALB/c mice bearing triple-negative breast cancer (TNBC). BALB/c mice were used to induce TNBC tumors and evaluate tumor growth inhibition. The number of CD8+ CD28+ T cells was determined by immunofluorescence assay, the expression of MUC1 protein was assessed by Western blot, while the expression of TOX, NR4A1, and TIM-3 genes was evaluated by real-time PCR in mouse-derived tumor tissues. MTT assay was performed on different BC cell lines to assess cell viability. Molecular docking results revealed significant interactions between Tak and Met with TOX and NR4A1. The combination treatments of Tak, Met, and LEME significantly decreased tumor volume/weight in mice and also significantly increased the number of infiltrated CD8+ CD28+ T cells, reduced MUC-1 protein expression, and decreased the expression of TOX, NR4A1, and TIM-3 genes in mouse tumor tissue. Tak, Met, and their combination significantly decreased the cell viability of different BC cell lines. This study suggests that the Tak-Met-LEME combination treatments may inhibit BC progression by increasing CD8+ CD28+ T cell population in tumor tissue and decreasing tumor progression.

The specific targeting of therapeutic agents to tumor cells remains a pivotal challenge in cancer treatment. While antibody-directed enzyme prodrug therapy (ADEPT) offers a promising approach by delivering enzymes such as carboxypeptidase G2 (CPG2) to the tumor microenvironment, achieving efficient targeting and multifunctionality remains a significant hurdle. This study developed a novel bifunctional fusion protein by integrating an anti-PD-L1 nanobody with CPG2, enabling specific immune checkpoint targeting and localized prodrug activation. The fusion protein was computationally engineered using in silico analyses to optimize structural stability and linker flexibility. Molecular modeling and docking simulations were performed to evaluate binding to the PD-L1 receptor, and the construct exhibiting the most favorable binding energy and strongest intramolecular interactions was selected for experimental validation. The optimized fusion protein was expressed in E. coli BL21 (DE3) and purified. Cell-ELISA revealed values for the Nb and fusion protein against MDA-MB-231 (12.97 vs. 25.86 nM) and RKO (11.75 vs. 24.36 nM) cells, respectively. Despite a moderate shift in Kd values, the fusion protein maintained nanomolar binding affinity, with negligible binding to PD-L1-low HEK-293 cells. Enzymatic activity assays demonstrated that the fusion protein preserved significant catalytic efficiency (24.83 vs. 31.82 μM-1·min-1 for native CPG2). In addition, cell-based viability analyses indicated minimal intrinsic cytotoxicity, supporting the functional integrity of the bifunctional construct. Overall, these findings demonstrate that the engineered CPG2-anti-PD-L1 fusion protein preserves both antigen-binding and enzymatic activities, highlighting its potential as a dual-function platform that integrates immune checkpoint targeting with site-specific prodrug activation for targeted cancer therapy.

The metabolic reprogramming of cancer cell has recently gained heightened attention in the field of tumor metastasis. This metabolic reprogramming helps the cancer cells to meet increased energy and biosynthetic requirements. Beyond their structural role in membrane integrity, fatty aids are also crucial for the energy requirement of cancer cell which ultimately helps epithelial to mesenchymal transition and metastatic progression. There is urgent need for identifying the varied role of fatty acid metabolism in the tumor microenvironment (TME), that includes tumor cell, immune cells and stromal cells. Understanding how the tumor cells alter their lipid metabolism after their interaction with other cells in the TME can present a promising therapeutic strategy against cancer. This metabolic interaction between cancer cells and other cells of the TME (like immune cells and stromal cells) which supply fatty acids that helps in the formation of metastatic niche. In this review, we discussed in detail the role of exogenous fatty acid uptake and endogenous fatty acid synthesis in tumor cells and the mechanism through which cancer cells regulate lipid metabolism. Also, the involvement of immune and stromal cell in the metabolic reprogramming and the molecules or drugs that can affect the receptor or enzymes involved in lipid metabolism are identified. This review underscores the importance of further research focusing on targeting fatty acid metabolism to identify susceptibilities and enhance cancer therapy.

Landmark epidemiological studies and clinical trials, such as the Seven Countries Study, the Lyon Diet Heart Study, the PREDIMED Study and the CORDIOPREV Study, have shown significant reductions in cardiovascular events in those following the Mediterranean diet (MD). The aim of the present work is to summarize the most robust available evidence and the major biological pathways underlying the protective effects of the MD, with particular emphasis on the role of PAF inhibitors. Mechanistically, MD functions through a complex synergy of antioxidant, anti-inflammatory, and antithrombotic effects that collectively improve lipid profiles, enhance endothelial function, optimize postprandial metabolism and cell membrane signaling, making it a functional model for human longevity. The PAF-Implicated Atherosclerosis Theory has emerged as a key unifying framework, proposing that Platelet-Activating Factor (PAF)-a highly potent lipid inflammatory mediator-plays a central role in the initiation and progression of atherosclerosis. Oxidized LDL promotes the production of PAF and PAF-like lipids, leading to endothelial dysfunction, vascular inflammation, and atherosclerotic plaque formation. Traditional Mediterranean foods are rich in natural PAF inhibitors, particularly the polar lipid fractions of extra virgin olive oil, as well as wine, fish, vegetables, onions, and garlic. Animal studies demonstrate that these compounds can reduce or even regress atherosclerotic lesions, independently of serum cholesterol levels. Human dietary interventions have further shown that MD-based meals and functional foods enriched with PAF inhibitors reduce PAF activity and improve thrombosis-related biomarkers. This mechanistic framework helps explain phenomena such as the "French Paradox" and the cardio-protective effects associated with fish consumption. Moreover, the extraction of PAF inhibitors from Mediterranean food by-products, such as olive pomace, offers promising ecological and economic advantages. Collectively, targeting PAF and increasing dietary intake of PAF inhibitors represent promising strategies for the prevention and management of atherosclerosis and other inflammatory diseases, supporting the view that PAF may function as a major, modifiable risk factor in these conditions.

Atopic Dermatitis (AD) is a prevalent chronic inflammatory skin disorder with incompletely understood pathogenesis and limited therapeutic options. T-Lymphokine-Activated Killer Cell-Originated Protein Kinase (TOPK) is known to promote inflammation, its specific role in AD remains unclear. This study sought to elucidate the function of TOPK in AD pathogenesis and to delineate its underlying molecular mechanisms. TOPK expression in AD patients was analyzed using the Gene Expression Omnibus (GEO) database. The functional role of TOPK in AD pathogenesis was investigated through genetic knockdown and pharmacological inhibition in a relevant disease model. Mechanistic insights were obtained via phosphoproteomic profiling, interaction assays (co‑immunoprecipitation and pull‑down), and kinase assays. The cellular function of the TOPK‑driven pathway was further validated by inhibiting TOPK in both HaCaT keratinocytes and mast cells. Bioinformatics analysis revealed that TOPK was significantly upregulated in AD patients. Genetic or pharmacological inhibition of TOPK markedly attenuated AD-like pathological features and reduces the levels of IgE, IL-6, IL-8 and IL-33, suggesting that TOPK contributes to AD pathogenesis. Mechanistically, TOPK was found to directly interact with and phosphorylate STAT3 at Ser727. Inhibition of TOPK in both HaCaT keratinocytes and mast cells decreased STAT3 phosphorylation at Ser727, thereby alleviating AD-related inflammatory responses. These findings validate the central role of the TOPK-STAT3 signaling pathway in regulating key inflammatory responses in AD. In summary, TOPK drives AD pathogenesis by phosphorylating STAT3 at Ser727, highlighting its promise as a therapeutic target. Genetic or pharmacological inhibition of TOPK suppresses this signaling axis, alleviates AD‑associated inflammation, and provides a promising new strategy for clinical intervention.

Mitochondrial dysfunction, oxidative stress, and neuroinflammation play a critical role in the occurrence and progression of Alzheimer's disease (AD). MicroRNAs (miRNAs) have been studied recently as potential therapeutic approaches for AD. In this study, we examined the function and underlying mechanism of microRNA-25802 (miR-25802), a newly discovered miRNA in an AD model. In order to evaluate the levels of oxidative stress, mitochondrial damage and neuroinflammation in neuroblastoma cells, four experimental groups were created: control group (neuroblastoma cells, SH-SY5Y), amyloid beta (Aβ)-induced neuroblastoma cells (SY5Y-Aβ), small extracellular vesicles (sEVs)-only group and miR-25802-loaded small extracellular vesicles (sEV-miR25802) administered group. Neuroinflammation, oxidative stress, mitochondrial damage, tau hyperphosphorylation, and Aβ accumulation were evaluated in Aβ-induced neuroblastoma cells. Oxidative stress was analyzed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPX1). Inflammatory markers such as tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM1), and brain-derived neurotrophic factor (BDNF) mRNA levels, a neurotrophic factor, were evaluated by RT-qPCR. Neurofilament light chain (NfL), vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) and cytochrome c (Cyt-c), mitochondrial transcription factor A (TFAM), PTEN-induced kinase 1 (PINK1) and dynamin-1-like protein (DNM1L) protein levels were determined by ELISA. Mechanistically, sEV-miR25802 were shown to provide anti-inflammatory and neuroprotective effects by regulating neuroinflammation, mitochondrial dysfunction, and oxidative stress. These findings reveal the regulatory role of miR-25802 on neuroinflammation, mitochondrial damage, and oxidative stress and suggest that it may be a potential therapeutic target for AD.

In head and neck squamous cell carcinoma (HNSCC), solute carrier family 16 member 1 (SLC16A1) is associated with tumor advancement and reduced sensitivity to ferroptosis, yet the molecular basis of these effects remains unclear. This study seeks to uncover how SLC16A1 contributes to HNSCC tumorigenesis. To elucidate how SLC16A1 drives HNSCC progression via ferroptosis resistance, we performed RNA sequencing on SLC16A1-knockdown HNSCC cells and controls, followed by functional validation. We next systematically assessed the role of the candidate molecule solute carrier family 7 member 11 (SLC7A11) in HNSCC progression and resistance to ferroptosis using loss- and gain-of-function experiments in vitro and xenograft-based assays in vivo. Finally, we applied RNA interference and validated expression changes by quantitative real-time polymerase chain reaction and immunoblotting to map the signaling pathway by which SLC16A1 controls SLC7A11 expression. Integrated RNA sequencing and functional assays identified SLC7A11 as a key downstream effector of SLC16A1. SLC7A11 mediates SLC16A1-driven tumor cell proliferation, ferroptosis resistance, and tumorigenesis. Mechanistically, SLC16A1 activates signal transducer and activator of transcription 3 (STAT3) to transcriptionally upregulate SLC7A11 expression. Our study defines a novel SLC16A1-STAT3-SLC7A11 signaling axis that promotes HNSCC progression by conferring robust resistance to ferroptosis. This axis may be leveraged as a therapeutic target to mitigate treatment resistance.

Protective role of Quercetin against the possible harmful effects of Tartrazine, which is widely used. These doses have been studied for the first time in the literature. Rats were divided: Control, Tartrazine, Quercetin, and Tartrazine + Quercetin. The substances were administered for 30 days. Afterward, liver tissues and blood samples were collected and biochemically and histopathologically analyzed. An increase was noted in oxidant (MDA, SOD) and oxidative stress index parameters (TOS, OSI) while decreases were seen in antioxidant parameters (GSH, CAT, TAS), inflammation markers (TNF-α, IL-6), apoptosis (Caspase 3) and histopathological deterioration (heterochromatic with pyknotic nuclei, pericentral hepatocyte necrosis, and inflammatory cell infiltration) in liver tissue. There was also an increase in oxidative stress index, inflammation markers, and liver function tests (ALT, AST, ALP, Direct and Total Bilirubin) in serum samples of the tartrazine group. In the quercetin group, antioxidant parameters in liver tissue increased, whereas oxidant parameters, inflammation markers, and liver function tests in serum samples decreased. Improvements in both biochemical, blood, and histopathological parameters were observed with the concomitant administration of quercetin compared to the tartrazine group. Tartrazine caused hepatotoxicity by increasing oxidative stress, inflammation, and apoptosis in the liver tissues. Additionally, it led to widespread damage by elevating inflammation and worsening liver function test results in blood samples. Quercetin, however, showed strong antioxidant, anti-inflammatory, and apoptotic effects. We recommend daily use of quercetin to protect the liver from the harmful effects of tartrazine.

The retina is highly influenced by mechanical cues such as intraocular fluid movement and blood flow, generating shear stress implicated in both retinal development and pathology. Müller glia, as retinal mechanosensors, are uniquely positioned to respond to such forces. This study examined Müller glia responses to flow-induced shear stress. Primary adult rat Müller glia were cultured in a single-channel microfluidic system and exposed to fluid shear stress (10-3 dyn/cm2) for 24 h. Müller glia survival, morphology, and extracellular matrix (ECM) remodelling were evaluated. Expression of the mechanosensitive ion channel TRPV4, phosphorylated focal adhesion kinase (pFAK), and the pro-fibrotic cytokine TGF-β1 was analysed. TRPV4 and TGF-β1 were pharmacologically inhibited to assess their functional roles. The results showed that shear stress enhanced Müller glia survival and reduced cell area. TRPV4 expression increased under flow, and its inhibition decreased survival and reversed morphological changes. Shear stress also elevated pFAK levels in a TRPV4-dependent manner. Similarly, TGF-β1 expression increased with flow, and its inhibition decreased survival and altered cell morphology under both static and flow conditions. ECM remodelling involved increased intracellular collagen I and IV levels and enhanced fibronectin deposition, both regulated by TGF-β1. In conclusion, shear stress induces Müller glia survival, cytoskeletal remodelling, and selective ECM regulation via TRPV4 and TGF-β1. TRPV4 acts upstream through pFAK signalling, while TGF-β1 controls ECM remodelling. Together, these pathways initiate early remodelling and contraction, potentially driving retinal fibrosis post-injury. Targeting TRPV4 and TGF-β1 may offer therapeutic strategies to limit glial scarring and preserve retinal structure.

Phthalates are often called "everywhere chemicals" because they are widely used in consumer products and are detectable in the environment and humans. One of the most studied phthalates, di-2-ethylhexyl phthalate (DEHP), is metabolized to mono-(2-ethylhexyl) phthalate (MEHP), which is known to disrupt metabolic processes through peroxisome proliferator-activated receptor (PPAR) signaling. However, accumulating evidence suggests that lipophilic phthalates also affect mitochondria, key regulators of oxidative metabolism, autophagy, and apoptosis. Based on previous observations that undifferentiated cells are more sensitive to a mitotoxic agent, we hypothesized that MEHP differentially affects mitochondrial function and mitochondrial DNA (mtDNA) maintenance across hepatic cell states. To test this, we used the human HepaRG hepatoma-derived cell line, which can be cultured in undifferentiated and differentiated states, and assessed viability and mitochondrial function following prolonged 6- and 12-d high-concentration MEHP treatments. Prolonged treatments reduced viability and altered bioenergetics in both states. Short treatments (1 to 3 d) reduced viability only in differentiated cultures and were associated with mtDNA depletion in undifferentiated cultures. In both states, MEHP increased the expression of the low-molecular-weight mitochondrial genome maintenance exonuclease (MGME1) isoform, altered the levels of autophagy-related factors, and induced apoptosis. In another mitochondrial-competent myoblast model (C2C12 cells), a high concentration of MEHP was associated with mtDNA depletion, whereas lower concentrations were associated with modest reductions in cell density without detectable mtDNA loss. These results demonstrate state-dependent mitochondrial responses to MEHP and indicate that a reduced endpoint cell density is a sensitive outcome occurring independently of, and at lower concentrations than, mtDNA depletion in undifferentiated cells.

Soil bacteria of the genus Streptomyces are natural producers of over two-thirds of clinically used antibiotics. Their ability to generate these valuable metabolites is tightly linked to a developmental program involving the transition from vegetative hyphae to spores. The second messenger cyclic di-GMP (c-di-GMP) stabilizes effector complexes that block sporulation, including the RsiG-σWhiG complex leading to sequestration of the developmental sigma factor by its anti sigma factor. How signal termination and disruption of effector complexes is achieved to allow sporulation, remains poorly understood. Here, we identify the phosphodiesterase RmdB as a dual-function regulator that terminates c-di-GMP signaling both globally and locally. We show that deletion of the rmdB gene leads to increase of the global c-di-GMP pool and delayed development. Using genetic complementation, we demonstrate that both the EAL motif and the GGDEF domain are essential for the physiological function of RmdB. Our co-immunoprecipitation and co-elution assays revealed that RmdB interacts directly with the sigma factor σWhiG via its GGDEF domain, thus preventing binding of the anti sigma factor RsiG to σWhiG and promoting sporulation. Our bacterial two-hybrid analyses identify RmdB as an interaction hub connecting to multiple diguanylate cyclases (DGCs), including CdgE, which also interacts with σWhiG. These findings establish a novel principle of bacterial signaling in which a phosphodiesterase serves as an antagonist of an anti sigma factor, integrating global second messenger degradation with local effector complex formation to control cell fate decisions.

Tumor cells rely heavily on vascular nutrient supply and glucose metabolism to sustain proliferation, while maintaining redox homeostasis through reprogrammed antioxidant systems, making it difficult for single starvation therapy or chemodynamic therapy (CDT) alone to achieve durable and effective antitumor efficacy. To address these limitations, we developed a cancer cell membrane (CMC)-coated core-shell biomimetic nanoplatform, termed ACuA@CMC, for synergistically enhanced dual-starvation therapy and CDT. The nanoplatform consisted of a gold nanoparticle (Au NPs) core and a Cu2O shell. The Au NPs exhibited glucose oxidase-like (GOx-like) activity, enabling continuous glucose depletion and in situ H2O2 generation within tumor cells, while the Cu2O shell further catalyzed H2O2 into highly reactive ·OH under the tumor microenvironment, thereby amplifying oxidative stress. Meanwhile, the loaded apatinib (Apa) inhibited tumor angiogenesis and nutrient supply, which synergized with Au NPs-mediated glucose consumption to establish a dual-starvation therapeutic strategy. In addition, CMC coating endowed ACuA@CMC with favorable homologous targeting ability and enhanced cellular uptake efficiency. Experimental results demonstrated that ACuA@CMC possessed favorable physicochemical properties, stability, and hemocompatibility. Moreover, ACuA@CMC significantly enhanced the uptake of nanodrugs by A549 cells, effectively inhibited cell viability, induced apoptosis, elevated intracellular ROS levels, and triggered oxidative stress. Furthermore, the nanoplatform markedly suppressed tumor cell migration and downregulated VEGF expression, exhibiting synergistic anti-migration and anti-angiogenic effects. In summary, this study proposes a synergistic therapeutic strategy for lung cancer based on dual-starvation therapy and cascade CDT-mediated ROS amplification. This work provides a new approach for the development of multifunctional synergistic antitumor nanotherapeutic systems with potential clinical translational value.

Endometriosis is a chronic, estrogen-dependent inflammatory disorder and a leading cause of female infertility. Ovarian endometriomas, a common manifestation of endometriosis, are commonly associated with diminished ovarian function; however, the mechanisms underlying endometrioma-induced follicular dysregulation remain poorly understood. Thus, we aimed to determine whether endometrioma fluid (EmF) compromises preantral follicle development via oxidative stress and tissue fibrosis. EmF was collected from six patients during laparoscopic cystectomy or transvaginal ethanol sclerotherapy for endometriomas. Large preantral follicles (diameter: 130-160 µm) were isolated from 14-day-old rats and cultured in the presence or absence of 0.5% EmF and 10 ng/mL follicle-stimulating hormone (FSH). Follicular growth, steroidogenesis, and the expression of granulosa cell (GC) and theca cell (TC) markers were evaluated using morphometric analysis, hormone assays, and quantitative real-time PCR. Oxidative stress and fibrosis were assessed by measuring intracellular reactive oxygen species (ROS) levels and by performing immunostaining for fibrosis markers. In addition, the potential protective effects of pharmacological agents, including antioxidants, antifibrotic drugs, iron chelators, and androgens, were investigated. EmF inhibited GC proliferation, suppressed FSH-induced estradiol production, and downregulated the expression of FSH receptor, anti-Müllerian hormone, and aromatase. Conversely, EmF promoted TC proliferation while downregulating LH receptor expression and androgenic enzyme levels. EmF also increased ROS generation in GC and induced the expression of the fibrotic markers, including transforming growth factor beta 1 and collagen type III, in TC. Androgen supplementation partially restored GC proliferation and FSH receptor expression, whereas antioxidants, antifibrotic agents, and iron chelators showed no significant effects. EmF disrupts preantral follicle development by inducing oxidative stress in GC and promoting fibrosis in TC, thereby impairing GC-TC crosstalk. These findings reveal a novel pathogenic mechanism underlying endometrioma-associated infertility and underscore the need for therapeutic strategies targeting both oxidative stress and fibrotic remodeling within the ovaries.

Double-stranded DNA coming from, for example, viruses, bacteria, or apoptotic cells is recognized by the cGAS-STING signaling pathway comprising the cyclic GMP-AMP synthase (cGAS) and the stimulator of interferon genes (STING) receptors. The pathway induces type I interferon response and activates transcription of interferon-stimulated genes and proinflammatory cytokines. Though the brain is an immune-privileged site, the blood-brain barrier (BBB) elicits inflammatory immune response in neurodegenerative diseases. Parkinson's disease is characterized by α-synuclein oligomer (αSO) aggregates, neurodegeneration, and mitophagy, which potential can activate the cGAS-STING pathway. Here, we studied the cGAS-STING pathway in a co-culture model of the rat BBB treated with and without α-synuclein monomers (αSM) or oligomers (αSO). Activation of the cGAS-STING pathway did not change barrier integrity and junctional protein staining, but it induced the transcription of the interferon-stimulated gene Viperin and the proinflammatory cytokine tumor necrosis factor-α in brain endothelial cells. Furthermore, STING activation increased the protein level of Viperin in astrocytes. The treatment with αSO, but not αSM, decreased barrier tightness and induced the transcription of Viperin and tumor necrosis factor-α in brain endothelial cells. In astrocytes, αSO treatment increased not only Viperin and tumor necrosis factor-α mRNA levels, but also interleukin-1β and interleukin-6. In conclusion, cGAS-STING pathway and downstream immune signaling pathways can be activated in the cells of a co-culture model of the BBB without influencing barrier integrity. However, αSO disrupts the BBB integrity and activates the cGAS-STING immune pathway in brain endothelial cells and astrocytes supporting the idea of using cGAS-STING as a therapeutic target in neuroinflammation.

Genetically modified chimeric antigen receptor (CAR) T cells eliminate tumors by recognizing specific antigens on the cell surface. T cell ion channels (e.g. Kv1.3, KCa3.1) influence activation, proliferation, and effector functions such as target cell killing, through the regulation of Ca2+ signaling. We showed that CAR-expressing cells (Jurkat) specifically eliminate tumor cells (Raji B cells) in monolayer culture and inhibition of KCa3.1 by TRAM34 increased the tumor cell-killing ability of KCa3.1+ Jurkat CARs. Blockage of KCa3.1 facilitated the migration of KCa3.1+ Jurkat CARs (mean speed, displacement and distance). The application of TRAM34 lowered the baseline Ca2+ level in mCherry-KCa3.1+ Jurkat CARs. Finally, TRAM34 significantly reduced the time needed to eliminate tumor cells. We concluded that expression and modification of KCa3.1 ion channels shifts the intracellular Ca2+ concentration into the range where cytotoxicity dominates. Hence, modification of KCa3.1 channels could contribute to a more effective anticancer immunotherapy.