Search Results (193)

Endometrial stromal cells (EnSCs) undergo decidualization in response to progesterone. Decidualization facilitates spiral artery remodeling, immune tolerance in the endometrium, and fetal cell invasion and placentation—all essential for successful embryo implantation. Therefore, we aimed to investigate whether ergothioneine (EGT) plays a role in reproduction, particularly in decidualization and implantation. In this study, we found that solute carrier family 22 member 4 (SLC22A4), a specific transporter of EGT—a functional food ingredient with strong anti-aging properties—is upregulated in decidualized EnSCs. The effects of EGT were examined using uterine tissues from patients, primary cultured EnSCs, EnSC cell lines, and co-cultures with a fetal cell line. We observed a significant increase in SLC22A4 expression in secretory-phase human uterine tissue, decidualized EnSCs, and EnSC cell lines. We also found that EGT regulates insulin-like growth factor binding protein 1 expression, which promotes placentation. In co-cultures of EnSC and fetal cell lines, EGT upregulated ectonucleoside triphosphate diphosphohydrolase 1 and major histocompatibility complex, class I, G expression in fetal cell lines—both critical for placentation. These findings suggest that EGT is crucial to regulating decidualization and its markers, particularly insulin-like growth factor-binding protein 1, which contributes to placentation. Full article

Plasma membrane transporters are increasingly recognized as potential drug targets for oral cancer, particularly oral squamous cell carcinoma (OSCC). These transporters play crucial roles in cancer cell metabolism, drug resistance, and the tumor microenvironment, making them attractive targets for therapeutic intervention. Among the two main families of plasma membrane transporters, ATP-binding cassette (ABC) transporters have long been known to be involved in drug efflux and contribute to chemoresistance in cancer cells. On the other hand, solute carriers (SLCs) are also a family of transporters that facilitate the transport of various substrates, including nutrients and drugs, and have recently been shown to contribute to cancer chemosensitivity, metabolism, and proliferation. SLC transporters have been identified as potential cancer biomarkers and therapeutic targets, and their expression profiles suggest that they could be utilized in precision oncology approaches. We summarize previous reports on the expression and role of ABC and SLC transporters in oral cancer and discuss their potential as therapeutic targets. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC), a challenging and malignant cancer, primarily originates from the exocrine cells of the pancreas. The superfamily of solute carrier (SLC) transporters, consisting of more than 450 proteins divided into 65 families, is integral to various cellular processes and represents a promising target in precision oncology. As therapeutic targets, SLC transporters are explored through an integrative analysis. Materials and Methods: The expression profiles of SLCs were systematically analyzed using mRNA data from The Cancer Genome Atlas (TCGA) and protein data from the Human Protein Atlas (HPA). Survival analysis was examined to evaluate the prognostic significance of SLC transporters for overall survival (OS) and disease-specific survival (DSS). Genetic alterations were examined using cBioPortal, while structural studies were performed with AlphaFold and AlphaMissense to predict functional impacts. Furthermore, Gene Set Enrichment Analysis (GSEA) was carried out to identify oncogenic pathways linked to SLC transporter expression. Results: SLC transporters were significantly upregulated in tumors relative to normal tissues. Higher expression levels of SLC39A10 (HR = 1.89, p = 0.0026), SLC22B5 (HR = 1.84, p = 0.0042), SLC55A2 (HR = 2.15, p = 0.00023), and SLC30A6 (HR = 1.90, p = 0.003) were strongly associated with unfavorable OS, highlighting their connection to poor prognosis in PDAC. GSEA highlighted that these four transporters are significantly involved in key oncogenic pathways, such as epithelial–mesenchymal transition (EMT), TNF-α signaling, and angiogenesis. Conclusions: The study identifies four SLCs as therapeutic targets in PDAC, highlighting their crucial role in essential metabolic pathways. These findings lay the groundwork for developing next-generation metabolic anti-cancer treatment to improve survival for PDAC patients. Full article

Variations within the serotonin transporter gene, SLC6A4 (solute carrier family 6 member 4), particularly the 5-HTTLPR (serotonin-transporter-linked promoter region), have been extensively studied in relation to behavioral and psychological traits. The aim of our study is to examine the relationship between the 5-HTTLPR polymorphism located in the SLC6A4 gene and personality traits, as assessed using the NEO-FFI (NEO Five Factor Inventory). The MANOVA model demonstrated a significant overall association, accounting for approximately 8% of the variance in the data (Wilk’s λ = 0.847, F_10,342 = 2.979, p = 0.0013, η² = 0.08). Subsequent ANOVAs revealed statistically significant 5-HTTLPR polymorphism associations with the Neuroticism (p = 0.0018, R² = 0.070), Openness (p = 0.0364, R² = 0.037), and Conscientiousness (p = 0.0020, R² = 0.068) dimensions. The post-hoc analysis revealed that individuals with the LL genotype obtained significantly lower Neuroticism scores compared to the S/S (p = 0.0011) and SL genotype (p = 0.0086) carriers. Similarly, individuals with the L/L genotype had lower Openness scores compared to those with SS genotype (p = 0.0107). LL and SL genotype carriers had higher Conscientiousness scores compared to those with the SS genotype (p = 0.0004 and p = 0.0109, respectively). In conclusion, our study provides further data regarding the implications of 5-HTTLPR polymorphism in the complex genetic architecture of human personality. The observed associations with Neuroticism, Openness, and Conscientiousness, while modest in effect size, contribute to our understanding of how genetic variation at the SLC6A4 locus may subtly shape individual personality differences. Full article

Forensic DNA phenotyping (FDP) has emerged as an essential tool in criminal investigations, enabling the prediction of physical traits based on genetic information. This review explores the genetic factors influencing skin pigmentation, particularly within Asian populations, with a focus on Thailand. Key genes such as Oculocutaneous Albinism II (OCA2), Dopachrome Tautomerase (DCT), KIT Ligand (KITLG), and Solute Carrier Family 24 Member 2 (SLC24A2) are examined for their roles in melanin production and variations that lead to different skin tones. The OCA2 gene is highlighted for its role in transporting ions that help stabilize melanosomes, while specific variants in the DCT gene, including single nucleotide polymorphisms (SNPs) rs2031526 and rs3782974, are discussed for their potential effects on pigmentation in Asian groups. The KITLG gene, crucial for developing melanocytes, includes the SNP rs642742, which is linked to lighter skin in East Asians. Additionally, recent findings on the SLC24A2 gene are presented, emphasizing its connection to pigmentation through calcium regulation in melanin production. Finally, the review addresses the ethical considerations of using FDP in Thailand, where advances in genetic profiling raise concerns about privacy, consent, and discrimination. Establishing clear guidelines is vital to balancing the benefits of forensic DNA applications with the protection of individual rights. Full article

Background: In humans, vitamin D₃ synthesis follows a day–night rhythm due to its UV-B-dependent production. Results: As part of the VitDHiD intervention study, we identified 87 in vivo vitamin D target genes with circadian expression patterns in immune cells, forming a regulatory network centered on transcription factors and membrane receptors. These genes exhibit a narrow basal expression range, with 80% downregulated upon vitamin D₃ supplementation. Clustering analysis revealed six distinct gene groups, with the two most prominent clusters driven by the transcription factor CSRNP1 (cysteine- and serine-rich nuclear protein 1) and GAS7 (growth arrest-specific 7), a known differentiation inducer. Among the 25 VitDHiD study participants, we identified two subgroups distinguished by significant differences in the responsiveness of 14 in vivo vitamin D target genes. These genes encode transcription factors like CSRNP1, as well as metabolic enzymes and transporters, including NAMPT (nicotinamide phosphoribosyltransferase), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), and SLC2A3 (solute carrier family 2 member 3). Notably, all 14 genes possess a vitamin D receptor-binding enhancer within a reasonable distance of their transcription start site. Conclusions: These findings highlight a novel link between vitamin D signaling and circadian gene regulation, with potential implications for personalized supplementation strategies. Full article

Solute carrier family 25 member A22 (SLC25A22) is a glutamate transporter in the inner mitochondrial membrane that is known to suppress ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase, and we previously demonstrated that targeting SIRT3 sensitized glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11. The purpose of this study was to analyze the effect of SIRT3-mediated deacetylation of mitochondrial SLC25A22 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in lung adenocarcinoma (LUAD). We found that the expression of SLC25A22 and SIRT3 had a high positive correlation and that their expression was greater in LUAD tissues than in adjacent tissues. The RSL3-induced ferroptosis of LUAD led to upregulation of SLC25A22 and SIRT3, and SIRT3 protected RSL3-induced LUAD from ferroptosis in vitro and in vivo. At the molecular level, SIRT3 bound with SLC25A22 and deacetylated this protein. Targeting SIRT3 enhanced the acetylation of SLC25A22, decreased its ubiquitination, and promoted 26S proteasome degradation in LUAD cells. Therefore, our results demonstrated that SIRT3 protected LUAD cells from RSL3-induced ferroptosis, and this effect is at least partially due to its deacetylation of SLC25A22, revealing that the SIRT3-SLC25A22 axis has an important role in regulating the ferroptosis of LUAD cells. Full article

Reprogramming of metabolic pathways is crucial to guarantee the bioenergetic and biosynthetic demands of rapidly proliferating cancer cells and might be related to treatment resistance. We have previously demonstrated the deregulation of the succinate pathway in head and neck squamous cell carcinoma (HNSCC) and its potential as a diagnostic and prognostic marker. Now we aim to identify biomarkers of resistance to radiotherapy (RT) by analyzing the expression of genes related to the succinate pathway and nutrient flux across the cell membrane. We determined the transcriptional expression of succinate receptor 1 (SUCNR1), succinate dehydrogenase A (SDHA), and the solute carrier (SLC) superfamily transporters responsible for the influx or efflux of a wide variety of nutrients (SLC2A3 and SLC16A3) in tumoral tissue from 120 HNSCC patients treated with RT or chemoradiotherapy (CRT). Our results indicated that the transcriptional expression of the glucose transporter SLC2A3 together with SDHA had the best predictive capacity for local response after treatment with RT or CRT. High SLC2A3 and SDHA expression predicted poor outcomes after RT or CRT, with these patients having a 4.2 times higher risk of local recurrence compared to the rest of the patients. These results might indicate that tumors that shifted toward a higher glucose influx and a higher oxidation of succinate via mitochondrial complex II present an ideal environment for radioresistance development. Patients with a high transcriptional expression of both SLC2A3 and SDHA had a significantly higher risk of local recurrence after treatment with RT or CRT. Full article

The solute carrier family 1 member 4 (SLC1A4) gene encodes a neutral amino acid transporter, also referred to as alanine-serine-cysteine transporter 1, ASCT1, that helps maintain amino acid balance in the brain and periphery. In the brain, SLC1A4 plays an important role in transporting levo (L) and dopa (D) isomers of serine. L-serine is required for many cellular processes, including protein and sphingolipid synthesis, while D-serine is a co-agonist required for normal neurotransmission through N-methyl-D-aspartate receptors. Through its roles transporting L-serine across the blood–brain barrier and regulating synaptic D-serine levels, SLC1A4 helps establish and maintain brain health across the lifespan. This review examines the role of SLC1A4 in neurodevelopment and neurodegeneration and assesses the therapeutic potential of serine supplementation to treat neurodevelopmental symptoms associated with mutations in SLC1A4, as well as schizophrenia, depression, traumatic brain injury, and Alzheimer’s and Parkinson’s diseases. Full article

Background: Recent studies have identified solute carrier family 19 member 1 (SLC19A1) as a second messenger transporter that regulates massive immune-related signaling cascades, but current studies provide limited information. This study aims to evaluate its role and the potential mechanisms across various cancers. Methods: We analyzed multi-omics data from a pan-cancer cohort to evaluate SLC19A1 expression and its association with multiple features, including prognosis, tumor stemness, genome instability, and immune infiltration. Immunofluorescence staining was performed to validate SLC19A1 expression in tumor tissues and its relationship M2 macrophages. In addition, we used web tools such as ROCplotter to evaluate the association between SLC19A1 and response to chemotherapy and immunotherapy. Results: SLC19A1 was found to be overexpressed in multiple cancer types compared to normal tissues, correlating with poor prognosis. High SLC19A1 levels were associated with increased genomic instability and immune suppression. In addition, SLC19A1 was negatively correlated with CD8+ T-cell infiltration and positively correlated with M2 macrophage infiltration. The association of SLC19A1 with M2 macrophages was confirmed in multiple immunofluorescence staining. Finally, SLC19A1 was associated with the response to chemotherapy and immunotherapy in a variety of tumors. Conclusions: Our findings position SLC19A1 as a novel unfavorable prognostic marker in cancer, closely linked to immune suppression and genomic instability. This study highlights the need for further exploration of SLC19A1 as a therapeutic target and its implications in cancer treatment strategies. Full article

Background/Objectives: The solute carrier family 26, member 2 (SLC26A2) gene, which belongs to the family of SLC26 transporters, can be detected in multiple tissues. However, the studies of SLC26A2 in colon-related diseases are still limited and incompletely understood, especially in ulcerative colitis (UC). Methods: In this study, we attempted to search and identify putative UC candidate genes within a large number of known genes by multiple bioinformatics analyses. The potential cellular characteristics and biological functions of SLC26A2 in the pathogenesis of UC were also elucidated. Results: Notably, SLC26A2 was representative and down-regulated in the intestinal mucosa of patients with active UC, compared to healthy controls. Decreased levels of SLC26A2 were proved to have a more value in diagnosis of UC patients, and closely correlated with some UC characteristics, including the Mayo score and Paediatric Ulcerative Colitis Activity Index (PUCAI). Mechanistically, subsequent results from published datasets and our validated clinical data all strongly implied that SLC26A2 was negatively correlated with the IL-17 signaling pathway, and positively associated with the tight junction, which led to abnormal immune cell infiltration and inflammatory injuries. After establishing the UC mice models in vivo by orally administration of DSS in portable water, SLC26A2 was significantly down-regulated at the mRNA or protein level, when compared to that in the control groups. Furthermore, the correlation analyses confirmed that SLC26A2 was positively associated with CLDN3, and negatively correlated with IL-17A expression in colon tissues. In addition, according to the SLC26A2 expression, UC patients were divided into different subgroups. The potential target drugs for UC treatment, such as progesterone, tetradioxin, and dexamethasone, were initially predicted and exerted anti-inflammatory effects via the common molecule-SLC26A2. Conclusions: SLC26A2 might be served as a protective candidate in the UC pathogenesis as well as a potential drug target for UC treatment. Full article

Background: Type 2 diabetes mellitus (T2DM) and its associated complications are of public health concern. Metformin is the most common pharmacological T2DM treatment, distributed through organic cation transporters (OCTs). The solute transporter family 22A1 (SLC22A1) gene encodes OCT1, and its variants may play a role in glycemic control. This study analyzed seven SLC22A1 gene variants and their potential association with glycemic control in patients from Northern Mexico with T2DM undergoing metformin monotherapy. Methods: This cross-sectional study included 110 patients. We analyzed HbA1c values as a continuous variable and according to glycemic control categories (<7% vs. ≥7%). DNA from blood samples was genotyped using genotyping assays based on real-time PCR and PCR-RFLP. Results: Patients with GG or AA rs628031 genotypes were 2.7 times more likely to have inadequate glycemic control than those with the GA genotype (p = 0.042). We analyzed the combination of rs628031 and rs622342 as diplotypes. The relation between HbA1c and these diplotypes was influenced by BMI and the metformin dose. Carriers of at least one minor allele of A-rs628031 and C-rs622342 had lower HbA1c values than individuals homozygous for the major allele in both genes. Conclusions: The rs628031 and rs622342 variants are associated with lower HbA1c levels in T2DM patients. Larger studies are needed to confirm these associations. Full article

Microplastics represent a threat due to their ability to enter the food chain, with harmful consequences for living organisms. The riskiness of these particles is also linked to the release of other contaminants, such as heavy metals. Solute Carriers (SLCs) represent eminent examples of first-level targets of heavy metals due to their localization on the cell surface. Putative targets of heavy metals are the organic cation transporters that form a sub-clade of the SLC22 family. Besides the physiological role in the absorption/release of endogenous organic cations, these transporters are crucial in drug disposition and their interaction with xenobiotics. In this work, the human SLC22A4, commonly known as OCTN1, was used as a benchmark to test interactions with heavy metals released by microplastics, exploiting the proteoliposome tool. The potency of metals to interfere with the OCTN1 function has been evaluated by measuring IC50 values calculated in the micromolar range. The molecular mechanism of interaction has been defined using site-directed mutagenesis and computational analyses. Finally, some chemical and physiological thiol-reacting compounds show the capacity to rescue the metal-inhibited OCTN1 function. The conclusions drawn on OCTN1 can be extended to other members of the SLC22 family and orthologous transporters in fish. Full article

The ATP-binding cassette (ABC) and solute carrier (SLC) transporters play pivotal roles in cellular transport mechanisms, influencing a wide range of physiological processes and impacting various medical conditions. Recent advancements in structural biology and computational modeling have provided significant insights into their function and regulation. This review provides an overview of the current knowledge of human ABC and SLC transporters, emphasizing their structural and functional relationships, transport mechanisms, and the contribution of computational approaches to their understanding. Current challenges and promising future research and methodological directions are also discussed. Full article

This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq^®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug. Full article