Search Results (358)

High-glucose exposure impairs intestinal metabolic homeostasis and barrier integrity in fish, but the transcriptional responses associated with high-glucose adaptation in fish intestinal epithelial cells remain incompletely understood. This study investigated whether exogenous 5-methylcytosine (5MC) alleviates high-glucose-induced metabolic and epithelial stress in grass carp (Ctenopharyngodon Idella) intestinal epithelial cells and whether these responses are associated with changes in DNA methyltransferase 3 beta (dnmt3b) expression and Caudal type homeobox 1b (cdx1b)/Sodium-glucose cotransporter 1 (sglt1)-related transcriptional responses. As exploratory in silico information, molecular docking predicted candidate complex conformations of DNMT3B with CDX1B and SGLT1, with binding energies of −37.2 and −25.9 kcal/mol, respectively. Functionally, dnmt3b knockdown significantly reduced dnmt3b, Interleukin 6 (il6), and Nuclear factor kappa B (nfκb) expression, while increasing cdx1b, sglt1, Solute carrier family 2 member 3a (slc2a3a), 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4a (pfkfb4a), and Amine oxidase copper containing 1 (aoc1) expression (p < 0.05). CDX2/CDX1B-like immunoreactive protein and SGLT1 protein levels were also increased after dnmt3b knockdown (p < 0.05). Under high-glucose stress, exogenous 5MC exerted concentration-dependent effects. Specifically, 6 mM 5MC significantly reduced residual extracellular glucose, lactate dehydrogenase and diamine oxidase activities, and malondialdehyde content, while increasing glutathione content, cell viability, and cell migration (p < 0.05). These effects remained detectable after replacement with high-glucose medium for an additional 12 h. By contrast, 24 mM 5MC markedly increased lactate dehydrogenase activity and reduced cell viability, suggesting potential cytotoxicity (p < 0.05). S-adenosylmethionine (SAM) levels were significantly lower in the NC and 6 mM groups than in the HG, 12 mM, and 24 mM groups, suggesting changes in SAM-related one-carbon metabolic status rather than direct evidence of altered DNA methylation (p < 0.05). Exogenous 5MC, particularly at 6 mM, alleviated high-glucose-induced metabolic and epithelial stress in grass carp intestinal epithelial cells. These effects were accompanied by changes in several glucose metabolism- and inflammation-related genes. However, the cellular uptake, metabolic fate, DNA incorporation, methylation consequences, and causal roles of these gene-expression changes remain to be further verified. Full article

Solute carrier family 25 (SLC25) is known to facilitate the transport of diverse metabolites across the mitochondrial and peroxisomal membranes. SLC25A17 is the only member of the SLC25 protein localized to peroxisomes; formerly known as PMP34, it also shares conserved sequence features with other SLC families. SLC25A17 was first described as an ATP transporter, but conflicting results regarding cofactor specificity in various experimental models obscure its precise function. Similarly, phenotypic differences between experimental models, such as mice and zebrafish, complicate the application of animal studies to humans. In particular, SLC25A17 deficiency is associated with peroxisomal dysfunction, and SLC25A17 expression is affected in various cancers and bipolar disorder, while the underlying molecular mechanisms remain unknown. Furthermore, it remains unclear whether altered SLC25A17 expression is a cause or consequence of human disease. This review provides an overview on current knowledge of SLC25A17, focusing on its known functions and emerging roles in human diseases. This may also help future studies in understanding its metabolic significance and disease pathogenesis. Full article

Regulated cell death is essential for tissue homeostasis, immune defense, and disease progression, yet the lipid-based regulatory mechanisms that coordinate cell death signaling remain incompletely understood. Protein palmitoylation is a dynamic and reversible lipid post-translational modification that controls protein membrane association, trafficking, stability, and signaling complex assembly. This review summarizes the regulatory roles of palmitoylation and depalmitoylation in major forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-related cell death. Particular attention is given to representative palmitoylated substrates, including Fas cell surface death receptor (Fas), receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), autophagy-related 16 like 1 (ATG16L1), and Beclin1. These substrates illustrate how palmitoylation links membrane organization, metabolic status, inflammatory signaling, and cell fate decisions. Disease-oriented evidence further indicates that dysregulated palmitoylation contributes to cancer, neurodegenerative diseases, and inflammatory or immune-related disorders by modulating cell death resistance, inflammatory amplification, immune evasion, or impaired proteostasis. Current challenges include limited quantitative information on palmitoylation dynamics, incomplete evidence for some enzyme–substrate relationships, and insufficient distinction between disease-driving and secondary palmitoylation events. Targeting zinc finger Asp-His-His-Cys (zDHHC) palmitoyl acyltransferases, depalmitoylating enzymes, or specific palmitoylated substrates may provide new therapeutic opportunities. Overall, this review positions protein palmitoylation as a dynamic molecular switch linking lipid metabolism, membrane signaling, regulated cell death, and disease remodeling. Full article

Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death. Full article

Wound healing remains a persistent health problem with no definitive solution. It is crucial to characterize the complex wound healing process and the various growth factors, cytokines, and polypeptides involved. Transforming growth factor beta1 (rhTGF-β1) stimulates different cell types, providing multifunctionality in the wound healing process. Since proteins are sensitive to proteases, drug delivery systems are needed. Developed polymeric carrier systems are as important as the active substance. The carrier systems used in our study aim to contribute to wound healing in addition to the rhTGF-β1. We hypothesized that PLGA nanoparticles embedded in PVA/Chitosan (PVA/Chi) hydrogels could enhance the therapeutic effect of rhTGF-β1. PVA/Chitosan hydrogels were prepared by the freezing/thawing method. Several characterization studies (Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), texture analysis, and cell culture) were performed to investigate the potential of the prepared formulations to enhance the therapeutic effect of rhTGF-β1. Hydrogel formulations reduced the inhibitory effect of rhTGF-β1 on keratinocytes. The H5 hydrogel exhibited a proliferative effect on fibroblast cells, which play a crucial role in wound healing, resulting in a 78.8% increase compared to the control. As the PVA content in the hydrogel formulations increased, bioadhesion and viscosity also increased. Although TGF-β1 inhibited keratinocytes, it induced migration of both NIH-3T3 and HACAT cell lines. The formulations developed exhibit the potential to improve the therapeutic efficacy of rhTGF-β1 in wound healing. A small amount of the protein can have the same therapeutic efficacy and fewer side effects because the developed polymeric carrier systems contribute to the therapeutic efficacy. Full article

Background/Objectives: The gene solute carrier family 52 member 3 (SLC52A3) encodes riboflavin transporter-3, a transmembrane protein essential for riboflavin absorption. Emerging evidence suggests that metabolic transporters may play a role in tumor biology. This study aimed to investigate the expression patterns, prognostic significance, genetic alterations, and functional associations of SLC52A3 in gynecological cancers. Methods: A comprehensive bioinformatic analysis was conducted using multi-omics datasets from The Cancer Genome Atlas (TCGA). Gene expression and survival analyses were performed via GEPIA3. Genetic alterations, including mutations and copy number variations, were assessed using cBioPortal. Immune infiltration correlations were analyzed through TIMER3. Protein–protein interactions and gene enrichment analyses were performed using STRING and GEPIA2, followed by Gene Ontology (GO) and KEGG pathway analyses. Results: SLC52A3 expression was significantly upregulated in ovarian, cervical, and endometrial cancers. Reduced expression of SLC52A3 was associated with poorer overall survival and shorter progression-free interval specifically in endometrial cancer. Genetic alterations in SLC52A3 were not significantly associated with survival outcomes (OS, DFS, and PFS). Functional enrichment analysis indicated that SLC52A3 is involved in biological processes such as cell junction organization and protein localization to the plasma membrane. Additionally, SLC52A3 expression showed positive correlations with genes implicated in tumor progression and metastasis, including NECTIN4, PROM2, TACSTD2, PKP3, SEMA4B, and CD46. Conclusions: These findings suggest that SLC52A3 may serve as a potential prognostic biomarker in endometrial cancer and could play a role in tumor progression pathways. Its functional associations highlight its potential relevance as a therapeutic target, warranting further experimental validation. Full article

Background: Brain microvascular endothelial cells (BMECs) form the blood–brain barrier (BBB), a highly selective interface that restricts paracellular diffusion and regulates the transport of nutrients and drugs into the central nervous system via specialized transporters and receptors. Tight junction-associated protein 1 (Tjap1), also termed protein incorporated later into tight junctions (Pilt), has been localized to tight junctions (TJs) in epithelial cells and to the trans-Golgi network in fibroblasts; however, its expression, subcellular localization, and functional significance in BMECs are still unknown. Methods: We characterized Tjap1 subcellular localization in mouse and human BMEC cell lines as well as primary mouse BMECs by immunofluorescence with and without pharmacological Golgi disruption by treatment with Brefeldin A, Golgicide A or Pitstop 2. CRISPR/Cas9-mediated Tjap1 knockout cells were generated and examined with regard to their Golgi morphology using immunostaining. Tjap1 mRNA localization was examined by RNAscope in situ hybridization. Quantitative real-time PCR and Western blot was performed to assess the expression of BBB-associated efflux transporters, solute carrier transporters, and cellular receptors in control and Tjap1 knockout cells. Results: Tjap1 predominantly localized to the cis-Golgi compartment, co-localizing with Gm130 rather than Tgn38, and was absent from TJs in BMECs. Tjap1 knockout induced pronounced Golgi fragmentation BMECs. Importantly, Tjap1 knockout significantly downregulated mRNA-expression of Abcb1a, Abcb1b, Abcc4, Slc2a1, Slc7a1, Slc7a5 and Tfrc, while Abcg2 was upregulated. At the protein level, a decrease in the protein levels of Abcb1, Abcc4, Slc2a1, Slc7a1, and Tfrc was observed in Tjap1 knockout cEND cells. Conclusions: In BMECs, Tjap1 is a cis-Golgi-associated protein required for the structural integrity of the Golgi apparatus. Its deletion is associated with Golgi fragmentation and significant alterations in the mRNA and protein expression of drug transporters and receptors at the BBB. These findings identify Tjap1 as a candidate regulator of both Golgi architecture and the BBB transporter profile in vitro, with potential implications for modulating drug transport across the BBB. Full article

Cancer progression is closely linked to the enhanced uptake of extracellular amino acids, mediated by specific transporters that support biosynthesis, metabolic activity, and energy production through the tricarboxylic acid cycle. By increasing the expression of these transporters, tumor cells secure a continuous amino acid supply that sustains the proliferation, metabolic balance, and activation of major signaling pathways. While most studies have emphasized post-translational control of amino acid transporters, such as phosphorylation, ubiquitination, glycosylation, and palmitoylation, emerging evidence highlights regulatory crosstalk between these transporters and other membrane proteins, including G protein-coupled receptors and receptor tyrosine kinases. This review summarizes the current literature on the receptor-mediated mechanisms governing amino acid uptake and explores how interactions among families of membrane proteins contribute to the regulation of transporter activity. Full article

Background/Objectives: Calcium–phosphorus metabolism is critical for skeletal development in weaned piglets. This study evaluated the effects of dietary 25-hydroxyvitamin D₃ (25-OH-VD₃) in combination with phytase and probiotics on mineral metabolism, bone development, and related molecular mechanisms in weaned piglets. Methods: Sixty 28-day-old weaned piglets (7.1 ± 1.30 kg) were randomly assigned to four dietary treatments for 31 days (including 3 days of acclimation): CON (basal diet + 50 µg/kg 25-OH-VD₃), HI (CON + 50 mg/kg phytase), CY (CON +10 mg/kg probiotics), HICY (CON + 50 mg/kg phytase + 10 mg/kg probiotics). Apparent calcium digestibility, serum biochemical indices, bone mineral density (BMD), and mRNA and protein expression of calcium–phosphorus transport- and metabolism-related genes in jejunal mucosa and kidney were assessed. Results: Compared with CON, piglets in the HI, CY, and HICY groups showed higher apparent calcium digestibility (p < 0.05). Serum transforming growth factor-β was elevated in CY and HICY (p < 0.05). HI enhanced metatarsal and toe BMD (p < 0.05) and upregulated jejunal solute carrier family 34, member 2 (SLC34A2) and SLC34A3 mRNA expression (p < 0.05). In contrast, HICY reduced mRNA expression of transient receptor potential cation channel subfamily V member 6 and calcium-binding protein D28k, as well as of calcium-binding protein D9k and cytochrome P450 27B1 in the kidney (p < 0.05). Renal calcium-sensing receptor protein abundance increased in CY (p < 0.05). Conclusions: Supplementation of 25-OH-VD₃ with phytase and/or probiotics improved calcium utilization and modulated key transport pathways, contributing to enhanced bone development in weaned piglets. These findings highlight coordinated nutritional regulation of mineral metabolism during early post-weaning growth. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related death, and resistance to chemotherapy and radiotherapy continues to limit durable disease control. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has therefore emerged as a potential therapeutic strategy. However, models focused solely on glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) do not fully explain why CRC cells differ in their sensitivity to ferroptosis. In this review, we examine how ferroptosis in CRC is shaped by iron trafficking and selenium-dependent antioxidant defense. We first discuss the poly(rC)-binding proteins 1 and 2 (PCBP1/2)-nuclear receptor coactivator 4 (NCOA4) axis, which regulates iron storage, trafficking, and ferritinophagy. We then review the AlkB homolog 8 (ALKBH8)-directed selenoprotein network, which supports the detoxification of lipid peroxides and maintenance of redox homeostasis. We next consider how these two systems intersect and how their interplay influences ferroptosis sensitivity. We also discuss why concurrent disruption of iron handling and selenium-dependent defense mechanisms may enhance therapeutic efficacy. Finally, we outline potential clinical applications, including combination strategies and biomarker development. Full article

Cancer remains a major global health challenge, characterized by abnormal cell growth and metastasis. Current limitations of conventional therapies, particularly non-specific toxicity harming healthy cells, highlight the need for more targeted approaches. Nanotechnology offers a revolutionary solution, utilizing nanoparticles (NPs) for precise drug delivery to tumor sites while minimizing off-target effects. These nanometer-scale particles enable superior binding to cancer cell membranes, the tumor microenvironment, or nuclear receptors, facilitating significantly higher local concentrations of therapeutic agents. NPs, synthesized via physical, chemical, or biological methods, are categorized as organic (organic material-based) or inorganic (metallic particle-based). Key delivery mechanisms include the Enhanced Permeability and Retention (EPR) effect and Active Transport and Retention (ATR). This review specifically examines NP applications for the most prevalent cancers in the US (2025): breast, prostate, and lung. Gold and magnetic NPs show significant promise for early breast cancer detection. For lung cancer, polymeric NPs like PCL, PLA, and PLGA are effective carriers for peptides, proteins, and nucleic acids. BIND-014, a docetaxel-loaded NP formulation, represents an emerging strategy for prostate cancer. Clinically established examples include liposomal doxorubicin and albumin-bound paclitaxel. We comprehensively discuss the synthesis methods, delivery mechanisms, and the current landscape of NPs in research and clinical trials for these cancers. This analysis underscores the potential of nanotechnology to provide more effective and targeted therapeutic options for cancer patients in the future. A distinctive feature of this review is its comparative cancer-specific analysis of NP platforms in breast, prostate, and lung cancers. Unlike previous generalized reviews, this work integrates synthesis strategies, delivery mechanisms, translational challenges, and clinically relevant formulations to provide a bench-to-bedside perspective on the future of nanomedicine in oncology. Full article

Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article

Fish oil (FO) has been shown to confer beneficial effects on hepatic diseases in both humans and animals. This study aimed to investigate whether dietary fish oil (FO) supplementation alleviates deoxynivalenol (DON)-induced liver injury by modulating the ferroptosis signaling pathway in weaned piglets. Twenty-four weaned piglets were allocated to a 2 × 2 factorial design, with the main factors consisting of dietary treatment (5% corn oil or 5% FO supplementation) and DON exposure (basal diet or diet contaminated with 4 mg/kg DON). After 21 days of dietary treatment, piglets were euthanized for collection of blood and liver samples. Dietary FO significantly attenuated DON-induced hepatic structural damage and inflammatory infiltration. Specifically, FO supplementation reduced the activities of aspartate transaminase (AST) and alkaline phosphatase (ALP), as well as the AST/alanine aminotransferase (ALT) ratio following DON exposure. Dietary FO also decreased malondialdehyde (MDA) concentrations in both the liver and serum, lowered hepatic 4-hydroxynonenal (4-HNE) level and Fe²⁺ content, and increased hepatic glutathione (GSH) content. Moreover, dietary FO ameliorated ultrastructural liver damage induced by DON. Furthermore, DON significantly downregulated the mRNA levels of multiple genes associated with iron metabolism and ferroptosis, including heat shock protein beta-1 (HSPB1), acyl-CoA synthetase long chain family member 4 (ACSL4), and arachidonate 15-lipoxygenase (ALOX15), and upregulated the mRNA levels of transferrin (TF), ferritin heavy chain (FTH), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Dietary FO counteracted these alterations by decreasing the mRNA of SLC7A11, TFR1, FTH, and TF after DON exposure. Finally, FO significantly decreased the protein expression of SLC7A11, iron-responsive element-binding protein 2 (IREB2), and FHT1 and increased the GPX4 protein expression following DON exposure. These findings suggest that FO may ameliorate DON-induced liver injury in weaned piglets, possibly through suppressing the ferroptosis signaling pathway. Full article

Mitochondrial dysfunction plays a central role in the pathogenesis of bronchopulmonary dysplasia (BPD). Solute carrier family 25 member 28 (SLC25A28) is an iron transporter located in the inner mitochondrial membrane. In this study, we aimed to explore the role and underlying molecular mechanisms of SLC25A28 in BPD. Hyperoxia (85% O₂) was used to establish a neonatal murine model of BPD, and mouse lung epithelial cells (MLE-12 cells) were used in vitro. SLC25A28 expression and activity were downregulated under hyperoxic conditions, both in vivo and in vitro. SLC25A28 overexpression restored hyperoxia-induced mitochondrial oxidative phosphorylation (OXPHOS) dysfunction, and further enhanced the proportion of Ki67-positive cells by 37% (p < 0.05) and increased migration by 33% (p < 0.01) in MLE-12 cells. In contrast, SLC25A28 knockdown exacerbated these impairments in MLE-12 cells, with reduced the proportion of Ki67 positive cells by 71% (p < 0.01) and a 35% reduction in the migration rate. SLC25A28 was also knocked down in vivo, which further aggravated alveolar simplification in BPD mice. Furthermore, the mitochondrial-targeted peptide SS-31 could potentially interact with SLC25A28 and preserve its protein abundance. SS-31 administration mitigated hyperoxia-induced alveolar simplification, with the radical alveolar count (RAC) increasing by 28% (p < 0.05) and the mean linear intercept (MLI) decreasing by 20% (p < 0.001). In summary, this study revealed that SLC25A28 ameliorated hyperoxic lung injury by improving mitochondrial OXPHOS in alveolar epithelial cells, suggesting that it may serve as a potential therapeutic target for BPD. Full article

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. The Shen-Kang Recipe (SKR) is a traditional Chinese medicine formula used clinically to slow DKD progression, but its bioactive constituents and molecular targets remain unclear. Solute carrier family 15 member 2 (SLC15A2/PEPT2), a high-affinity peptide transporter expressed in renal proximal tubules, has been implicated in kidney pathophysiology, yet its potential role in mediating the therapeutic effects of the SKR has not been explored. Here, we evaluated the effects of the SKR in db/db mice and found that SKR treatment significantly improved renal function, attenuated glomerulosclerosis, and reduced interstitial collagen deposition. Wide-target metabolomics and quantitative proteomics revealed that the SKR broadly reversed DKD-associated metabolic and proteomic disturbances, particularly in pathways related to energy and amino acid metabolism. Proteomic analysis identified SLC15A2 as a key proximal tubule protein downregulated in DKD and selectively restored by the SKR. UPLC-Q-TOF/MS-based serum pharmacochemistry and network pharmacology highlighted quercetin as a principal bioactive component of the SKR. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) confirmed direct, high-affinity binding between quercetin and SLC15A2 (KD = 7.5 µM). In TGF-β1-stimulated HK-2 cells, quercetin suppressed epithelial-mesenchymal transition (EMT), as evidenced by restored E-cadherin and reduced N-cadherin, vimentin, and α-SMA expression; this effect was abrogated by siRNA-mediated SLC15A2 knockdown, demonstrating the functional necessity of this axis. Collectively, these findings identify a quercetin-SLC15A2 axis through which the SKR inhibits EMT and alleviates renal fibrosis in DKD, providing a mechanistic basis for its clinical application and nominating SLC15A2 as a potential therapeutic target. Full article