Search Results (475)

Preclinical bladder cancer models are often judged by tumor take, tumor growth or treatment inhibition, yet these endpoints do not reveal which bladder-specific constraints a given model preserves or bypasses. The bladder is shaped by a specialized urothelial barrier, urine exposure, cyclic filling and emptying, inflammatory injury, metabolic stress and intravesical treatment pressure. In this review, we use susceptibility engineering as an organizing framework for model selection and validation. We define susceptibility engineering as the deliberate definition, perturbation and reporting of model states that alter tumor initiation, adhesion, colonization, survival or therapeutic exposure. This framework groups cell lines, patient-derived organoids, cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models, orthotopic transplantation, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced tumors, genetically engineered mouse models and large-animal platforms according to the biological constraints they test. We focus on three linked dimensions: urothelial barrier integrity and uroplakin-related tools; local colonization thresholds under bladder-specific selection; metabolic susceptibility involving peroxisome proliferator-activated receptor gamma (PPARG)-associated differentiation programs and candidate solute carrier family 25 (SLC25)-linked mitochondrial stress nodes. We further distinguish large-animal systems as platforms for local delivery, imaging, device testing and procedural scale rather than universal substitutes for mouse models. A susceptibility-based validation framework could improve model selection, explain divergent responses across systems and support tiered platforms that connect patient-derived biology, mechanistic mouse studies and clinically realistic intravesical evaluation. Full article

Congenital disorders of glycosylation (CDG) are a group of inherited metabolic diseases rapidly growing due to the discovery of new subtypes. As with many genetic conditions, their diagnosis can be challenging, impairing proper patient care and causing additional suffering to patients and their families. We have developed an N-glycomics strategy that can provide insightful information towards diagnosing CDG type II (CDG-II). N-glycans released from the plasma of healthy individuals were labeled with deuterated iodomethane, mixed with samples from known or suspected CDG-II individuals, which were derivatized with standard iodomethane, and analyzed by liquid chromatography–mass spectrometry. After identification, relative quantification of 65 glycans was performed, revealing considerable alterations in the N-glycome of several patients. Notably, reduced fucosylation was observed in patients with FUT8-CDG and SLC35C1-CDG. Additionally, individuals with mutations in the MAN1B1 gene exhibited increased amounts of hybrid and oligomannosidic structures, whereas patients with the Golgi homeostasis disorders COG1-CDG and ATP6V0A2-CDG presented marked increases in hypogalactosylated and hyposialylated structures. Multivariate statistical analysis indicated two undiagnosed patients with alterations similar to ATP6V0A2-CDG patients and another two with a profile similar to MAN1B1-CDG patients. Genetic sequencing (targeted gene panel or whole exome sequencing) of these undiagnosed patients revealed variants in the corresponding genes, confirming the diagnosis obtained from the N-glycomics analysis. Our results demonstrate how the analysis of total plasma N-glycans can be used to identify metabolic disorders and diagnose conditions based on their molecular effects on the glycoproteome. Full article

Rs9939609 marker in FTO Alpha-Ketoglutarate-Dependent Dioxygenase (FTO) gene, rs7895307 in Transcription Factor 7-Like 2 (TCF7L2) gene, and rs75493593 in Solute Carrier Family 16 Member 11 (SLC16A11) gene have been associated with anthropometric, metabolic, and clinical variables, but have not been concurrently studied in Mexican children and adolescents with adiposity or mental disorders. In this cross-sectional association study, we genotyped these markers by means of TaqMan real-time polymerase chain reaction in two at-risk pediatric cohorts recruited in Mexico City. Group 1 (n = 175) comprised children and adolescents with overweight/obesity. Group 2 (n = 296) consisted of non-medicated adolescents meeting the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for Attention Deficit/Hyperactivity Disorder or a mood disorder. Anthropometric measurements (body mass index —BMI—, waist circumference, body fat percentage), metabolic indices (fasting glucose, lipid profile, Homeostatic Model Assessment for Insulin Resistance), and psychiatric diagnoses were evaluated. In Group 1, the FTO A allele (genotypes AA/AT) was significantly associated with severe obesity according to BMI Z scores (p = 0.004, O.R. 3.33, 95% CI [1.42–7.77]), and it was a predictor of waist circumference (B = 6.16, 95% CI [1.78–10.55], p = 0.006) and muscle percentage (B = 4.21%, 95% CI [0.91–7.51%], p = 0.013) using linear regression models adjusted for age and sex. In Group 2, TCF7L2 AA genotype was associated with increased odds of depression (B = 0.83, p = 0.003, OR = 2.29, 95% CI [1.32–3.96]). While SLC16A11 G allele showed a possible association with insulin resistance or glucose levels, confirmation is needed. These exploratory results highlight the need for larger, well characterized cohort studies to confirm the associations. Full article

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

Enlarged vestibular aqueduct (EVA) is a common inner ear malformation that causes sensorineural hearing loss. It is frequently associated with pathogenic variants in the SLC26A4 gene. This study aimed to investigate the genetic basis of hearing loss in Mongolian patients with EVA. Whole-exome sequencing was performed in 19 Mongolian patients from 15 unrelated families diagnosed with EVA with or without cochlear incomplete partition type II. All patients underwent high-resolution computed tomography of the temporal bone to confirm the diagnosis. Biallelic SLC26A4 pathogenic variants were identified in all 15 families, achieving a 100% diagnostic yield. The most frequent variant was c.919-2A>G (40%), followed by c.2027T>A (23.3%) and c.1318A>T (16.7%). The spectrum of variants includes population-specific variants found in East Asians (c.919-2A>G), North Asians (c.2027T>A), and Southwest Asians (c.716T>A), suggesting a unique mutation spectrum in this Mongolian cohort characterized by variants prevalent across various Eurasian populations, which remains to be confirmed in larger studies. Furthermore, correlation analyses on multi-ethnic allele frequencies of biallelic SLC26A4 genotypes demonstrated positive correlations with deaf cohorts of East Asian, North Asian, Northeast Asian, and Western Asian groups. Digenic inheritance (with pathogenic variants in FOXI1, KCNJ10, or EPHA2) was not observed, and there was no clear genotype–phenotype correlation between specific SLC26A4 genotypes and hearing levels or inner ear malformations. This study provides a comprehensive overview of the genetic landscape of EVA in the Mongolian population. The identification of biallelic SLC26A4 pathogenic variants in all families underscores the clinical role of this gene in EVA pathogenesis. The observed pan-ethnic mutation spectrum likely reflects the genetic diversity resulting from historical migrations of Mongolians. 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

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

The Na⁺/I⁻ symporter (NIS) is the plasma membrane (PM) protein that actively mediates iodide (I⁻) transport into the thyroid gland. Pathogenic variants in the SLC5A5 gene cause iodide transport defects (ITDs). A heterozygous G288S NIS variant was identified in a Spanish family in which female carriers developed thyroid dysfunction during pregnancy. Here, we characterized the functional significance of the G288S variant and other substitutions at residue 288 of human NIS. Human NIS (hNIS) expression and maturation were analyzed by immunoblotting, its subcellular localization was analyzed by immunofluorescence and flow cytometry, and its activity was analyzed by radioiodide uptake assays. The G288S variant does not affect hNIS maturation, membrane trafficking, or I⁻ uptake capacity, but significantly reduces I⁻ affinity while preserving substantial transport activity. In contrast, substitutions introducing charged residues (arginine, aspartic acid, or glutamic acid) or proline severely disrupted NIS maturation, plasma membrane targeting, and iodide transport. Because the variant was identified in heterozygosity, we evaluated residue 288 substitutions under heterozygous-like conditions. Co-expression of the patient-derived G288S variant with WT NIS produced an intermediate apparent K_m without reducing V_max compared with WT, consistent with a modest co-expression-dependent kinetic effect rather than a strong dominant-negative mechanism. In contrast, the severely disruptive G288E substitution reduced cell-surface NIS expression under co-expression conditions, providing proof-of-principle evidence that severe alteration of residue 288 can impair NIS plasma membrane delivery. These findings highlight residue 288 as a key determinant of hNIS functionality and underscore the need to carefully evaluate heterozygous SLC5A5/NIS variants, as they may become clinically relevant under conditions of increased physiological iodine demand and contribute to partial iodide transport impairment. Full article

Background: Zinc homeostasis regulated by ZIP transporters is critical for tumor glycolytic reprogramming and progression, yet the role of specific ZIP family members in lung adenocarcinoma (LUAD) remains unclear. This study aimed to identify the key ZIP transporter in LUAD and elucidate its molecular mechanisms and therapeutic value. Methods: siRNA-based functional screening of the ZIP family was performed in A549 and PC9 cells. A combination of in vitro cellular assays, in vivo animal models, clinical sample analysis and bioinformatics was used to validate the function of ZIP7 and explore its regulatory mechanisms. Results: ZIP7 (SLC39A7) was identified as a critical driver of glycolysis and proliferation in LUAD. It was significantly upregulated in LUAD tissues and cell lines. Mechanistically, ZIP7 increased inhibitory phosphorylation of GSK3β at Ser9 to stabilize NRF2, maintained low intracellular ROS levels, and sustained mTOR signaling to promote glycolytic flux. ZIP7-induced lactate secretion also drove M2-like macrophage polarization and PD-L1 upregulation to establish an immunosuppressive microenvironment. Notably, genetic or pharmacological inhibition of ZIP7 markedly enhanced the antitumor efficacy of anti-PD-1 therapy in vivo. Conclusions: ZIP7 is a pivotal oncogenic zinc transporter in LUAD that drives tumor progression via metabolic reprogramming and immune remodeling. Targeting ZIP7 represents a promising strategy to improve the efficacy of anti-PD-1 immunotherapy for LUAD. Full article

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by epithelial barrier disruption, oxidative stress, immune dysregulation, and defective mucosal healing. Recent studies have identified ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, as a key mechanism linking these processes. This review summarizes the current progress in understanding the role of ferroptosis in colitis. Available evidence shows that ferroptosis occurs in both human UC and experimental colitis models, with intestinal epithelial cells representing the best-established target compartment. Recent studies have further expanded this concept to reparative immune cells, particularly type 2 (M2) macrophages, thereby indicating that ferroptosis contributes not only to barrier injury but also to impaired mucosal healing. Mechanistically, colitis-associated ferroptosis is governed by interconnected networks involving solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) failure, acyl-CoA synthetase long chain family member 4 (ACSL4)-dependent lipid remodeling, iron overload, mitochondrial reactive oxygen species (ROS) amplification, inflammatory signaling, and N6-methyladenosine (m6A)-mediated post-transcriptional regulation. In parallel, microbiota-derived metabolites and dietary factors can either suppress or exacerbate ferroptotic injury. Therapeutically, ferroptosis-targeted strategies, including iron chelation, nutrient-based interventions, natural products, exosomes, and nanoplatforms show promising preclinical efficacy. Overall, ferroptosis provides a connected framework for understanding colitis pathogenesis and provides new opportunities for biomarker development and mechanism-based therapies. Full article

Background: The regulation of inorganic phosphate (Pi) homeostasis is predominantly mediated by the Pi transporters belonging to the SLC34 and SLC20 families of solute carriers. However, not all Pi handling can be explained by these transporters. In this study, we sought to identify novel Pi transporters in accordance with prior findings on inhibition patterns. Methods: We have performed a functional screening of new Pi carriers using the Xenopus laevis oocyte expression system, focusing on the SLC26 family, and corroboration in cell culture. Results: Both SLC26A7 and SLC26A9 have been shown to express sodium-activated Pi uptakes with approximately 200 µmol/L Pi affinity. In both cases, Pi transport is inhibited by increasing pH and by phosphonoformate, arsenate, bicarbonate, sulfate, the chloride channel inhibitor 5-nitro-2-[(3-phenylpropyl)amino]-benzoate, and several transport site and translocation inhibitors of bicarbonate exchangers. In addition, the CFTR inhibitor GlyH-101 and the SLC4 inhibitors DIDS, SITS, and phloretin exhibited partial inhibition of SLC26A9-mediated Pi uptake. The endogenous expressions of both SLC26A7 and SLC26A9 in the renal cell lines LLC-PK1 and MDCK were primarily intracellular, colocalizing with endosomes, lysosomes, and the trans-Golgi network markers. Conversely, plasma membrane expression was found to be minimal. Pi transport in MDCK cells was sodium-independent, but when either SLC26A7 or SLC26A9 was overexpressed, sodium-activated Pi uptake was observed, along with increased expressions of SLC26A7 or SLC26A9 in the plasma membrane. Conclusions: Sodium-activated Pi transport is a novel function of the SLC26A7 and SLC26A9 multifunctional anion transporters. Further research is necessary to ascertain the relevance to Pi homeostasis in vivo. Full article