Solute Carrier Research Articles

On the potential of Zn@B38 superatom as a drug delivery vehicle for several anticancer drugs: A DFT study

The interaction between a boron-based Zn@B38 superatom and five drugs, including cisplatin (DDP), 5-fluorouracil (FU), mercaptopurine (MP), hydroxyurea (HU) and nitrogen mustard (CM) have been investigated. The adsorption of these anticancer drugs onto Zn@B38 reduces the energy gap of this superatom. Except for DDP, these drugs exhibit strong covalent interaction with the vertex of Zn@B38 because the lone pair of N/O atom of FU, MP, HU, and CM can fill into the empty atomic orbital of the electron-deficient boron atom of Zn@B38 to form polar covalent bonds, resulting in the charge transfer from drugs to Zn@B38. Hence, the adsorption energies of drug@[Zn@B38] (drug = FU, MP, HU, and CM) are −37.67 ∼ −57.21 kcal/mol, but can be significantly decreased to −8.63 ∼ 5.48 kcal/mol upon protonation, suggesting that these drugs can be efficiently adsorbed by the Zn@B38 carrier in neutral aqueous solution but are easily released in the acidic tumor microenvironment.

SLC12A9 is an immunological and prognostic biomarker for glioma

BackgroundGlioma is one of the most common malignant brain tumors. It has a high rate of progression and a poor prognosis, and effective biomarkers still need to be identified. The solute carrier family 12 (SLC12) family has been reported to be involved in various physiological and pathological processes, but their functional roles in glioma remain unclear. MethodsUsing public datasets, we studied the mutation and expression level of SLC12 family genes in glioma and identified the significantly differentially expressed member solute carrier family 12 member 9 (SLC12A9). We further predicted the prognostic role of SLC12A9 in glioma by using the Kaplan–Meier method and Cox regression analysis. Then, we performed biological functional enrichment analysis. We focused on the relationships between SLC12A9 expression and immune infiltration in glioma. Meanwhile, we conducted in vitro experiments to evaluate the effect of SLC12A9 expression on glioma cells. ResultsAmong the members of the SLC12 family, SLC12A9 had the highest mutation rate in glioma, with gene amplification as the major mutation type, and its expression was significantly upregulated in glioma. Higher SLC12A9 expression was significantly associated with older age, higher grade, wild-type isocitrate dehydrogenase (IDH), and a worse prognosis. The functional enrichment analysis indicated that SLC12A9 is mainly related to ion channel annotation. Gene set enrichment analysis (GSEA) revealed that SLC12A9 was mainly related to the DNA replication pathway. Furthermore, we found that SLC12A9 correlated with tumor-infiltrating immune cells and immune checkpoints. Thus, SLC12A9 may be involved in regulating the immune response of glioma. Finally, our in vitro experiments revealed that silencing SLC12A9 dramatically inhibited glioma cell growth and migration. ConclusionsWe showed that SLC12A9 may be a new predictive biomarker for glioma diagnosis, prognosis, and immunotherapy response, offering helpful guidelines to advance glioma treatment.

NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism

Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.

Role of solute carrier transporters in ovarian cancer (Review).

Solute carrier (SLC) transporters are involved in various biological processes associated with metabolic reprogramming and cancer, supporting the increased requirement of nutrients and energy. Over the past decade, there have been significant advancements in understanding the expression and function of SLCs in ovarian cancer (OC). This gynecological condition has a high mortality rate and limited treatment options; thus, early diagnosis remains a target clinically. OC exhibits complexity and heterogeneity, resulting in different clinical characteristics, resistance to chemotherapy drugs and poor prognosis. Additionally, SLCs have a different expression pattern between healthy and tumor tissue, and consequently, their inhibition or activation could modify signaling pathways involved in the tumor growth process, such as cell proliferation, apoptosis and drug accumulation. The present review aims to consolidate current data to provide a comprehensive understanding of the potential importance of SLCs in OC. Additionally, it seeks to offer guidance for further research on utilizing SLCs as prognostic biomarkers and therapeutic targets.

ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches

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.

Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody-Drug Conjugate for Enhanced Anti-Tumor Efficacy in Solid Tumors.

Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADCs), which combine the targeting capabilities of BsAbs with the cytotoxic potential of ADCs, offer a novel approach to overcoming several challenges associated with ADCs, including limited internalization, off-target toxicity, and drug resistance. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as a highly expressed protein in a variety of solid tumors, making it a promising therapeutic target. We developed a bispecific antibody targeting SLC3A2 and PD-L1, and conjugated it to monomethyl auristatin E (MMAE) to create the SLC3A2/PD-L1 BsADC. The SLC3A2/PD-L1 BsAb effectively blocked PD-1 binding to PD-L1 and activated T cells, while also facilitating lysosomal targeting and degradation of poorly internalized PD-L1 antibodies. The SLC3A2/PD-L1 BsADC demonstrated superior anti-tumor efficacy in PD-L1 low-expressing tumor cells compared to single-target ADCs in both in vitro studies and in multiple xenograft and immunocompetent mouse models. Overall, our engineered SLC3A2/PD-L1 BsADC exhibited enhanced internalization and improved tumor cell targeting, highlighting the potential of lysosome-targeting BsAbs in advancing ADC therapeutic strategies for solid tumors.

Identification of SLC35A1 as an essential host factor for the transduction of multi-serotype recombinant adeno-associated virus (AAV) vectors.

We conducted a genome-wide CRISPR/Cas9 screen in suspension 293 F cells transduced with rAAV5. The highly selected genes revealed after two rounds of screening included the previously reported KIAA0319L, TM9SF2, and RNF121, along with a cluster of genes involved in glycan biogenesis, Golgi apparatus localization, and endoplasmic reticulum penetration. In this report, we focused on solute carrier family 35 member A1 (SLC35A1), a Golgi apparatus-localized cytidine 5'-monophosphate-sialic acid (CMP-SIA) transporter. We confirmed that SLC35A1 knockout (KO) significantly decreased rAAV5 transduction to a level lower than that observed in KIAA0319L or TM9SF2 KO cells. Although SLC35A1 KO drastically reduced the expression of α2,6-linked SIA on the cell surface, the expression of α2,3-linked SIA, as well as the cell binding and internalization of rAAV5, was only moderately affected. Moreover, SLC35A1 KO significantly diminished the transduction of AAV multi-serotypes, including rAAV2 and rAAV3, which do not utilize SIAs for primary attachment. Notably, the SLC35A1 KO markedly increased transduction of rAAV9 and rAAV11, which primarily attach to cells via binding to galactose. Further analyses revealed that SLC35A1 KO significantly decreased vector nuclear import. More importantly, although the C-terminal cytoplasmic tail deletion (∆C Tail) mutant of SLC35A1 did not drastically decrease SIA expression, it significantly decreased rAAV transduction, as well as vector nuclear import, suggesting that the C-tail is critical in these processes. Furthermore, the T128A mutant significantly decreased SIA expression but still supported rAAV transduction and nuclear import. These findings highlight the involvement of the CMP-SIA transporter in the intracellular trafficking of rAAV vectors post-internalization.IMPORTANCErAAV is an essential tool for gene delivery in the treatment of genetic disorders; however, the mechanisms of rAAV transduction remain partially understood. GPR108 is vital for the transduction of most rAAV vectors, but not for rAAV5. We aimed to identify host factors that impact AAV5 transduction akin to GPR108. Using a genome-wide CRISPR/Cas9 screen in 293 F cells, we identified SLC35A1, a Golgi apparatus-localized CMP-sialic acid transporter that transports CMP-sialic acid from the cytoplasm into the Golgi apparatus for sialylation, is essential to rAAV transduction. Further studies across various AAV serotypes showed SLC35A1 significantly affects vector nuclear import post-internalization. These results underscore the crucial role of SLC35A1 in intracellular trafficking beyond the initial cell attachment of rAAV.

Lactate Dehydrogenase A Is a Novel Positive Regulator of Vascular Smooth Muscle Cell Ferroptosis During Aortic Dissection.

Aims: Vascular smooth muscle cell (VSMC) ferroptosis is a pivotal event in the process of aortic dissection (AD), and a number of agents have a protective role against AD by inhibiting VSMC ferroptosis. While glycolysis is an ancient pathway related to almost all biological processes, its precise involvement in VSMC ferroptosis and AD remains unclear. Results: In this study, bioinformatics analysis revealed that glycolysis-related molecules and pathways were involved in VSMC ferroptosis and AD. We focused on the key enzyme of glycolysis, lactate dehydrogenase A (LDHA), and found that LDHA overexpression promoted ferroptosis and lipid peroxidation in cystine deprivation- or imidazole ketone erastin-treated VSMCs and vice versa. Clinical specimens showed a negative correlation between elevated LDHA levels in dissected aortae and ferroptosis-related molecules glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and ferroptosis suppressor protein 1 (FSP1). In VSMC ferroptosis, LDHA overexpression led to the suppression of GPX4, SLC7A11, and FSP1. Furthermore, the interaction between LDHA and nuclear factor (erythroid-derived 2)-like 2 (NRF2) was identified, and the overexpression or agonist of NRF2 reversed the contribution of LDHA on VSMC ferroptosis and lipid peroxidation. Innovation and Conclusion: These results highlight a significant association between LDHA and VSMC ferroptosis in AD development mediated through NRF2. These findings present LDHA as a potential target for AD intervention by inhibiting its expression. Antioxid. Redox Signal. 00, 000-000.

Increased rumen Prevotella enhances BCAA synthesis, leading to synergistically increased skeletal muscle in myostatin-knockout cattle

Myostatin (MSTN) is a negative regulator of muscle growth, and its relationship with the gut microbiota is not well understood. In this study, we observed increase muscle area and branched-chain amino acids (BCAAs), an energy source of muscle, in myostatin knockout (MSTN-KO) cattle. To explore the link between increased BCAAs and rumen microbiota, we performed metagenomic sequencing, metabolome analysis of rumen fluid, and muscle transcriptomics. MSTN-KO cattle showed a significant increase in the phylum Bacteroidota (formerly Bacteroidetes), particularly the genus Prevotella (P = 3.12e-04). Within this genus, Prevotella_sp._CAG:732, Prevotella_sp._MSX73, and Prevotella_sp._MA2016 showed significant upregulation of genes related to BCAA synthesis. Functional enrichment analysis indicated enrichment of BCAA synthesis-related pathways in both rumen metagenomes and metabolomes. Additionally, muscle transcriptomics indicated enrichment in muscle fiber and amino acid metabolism, with upregulation of solute carrier family genes, enhancing BCAA transport. These findings suggest that elevated rumen Prevotella in MSTN-KO cattle, combined with MSTN deletion, synergistically improves muscle growth through enhanced BCAA synthesis and transport.

Dissecting the novel molecular interactions of solute carrier family 4 member 4 (SLC4A4) for prostate cancer (PCa) progression

Prostate cancer (PCa) is the most common malignancy diagnosed in men. The purpose of this study was to report the molecular pathways of Homo sapiens solute carrier family 4 member 4 (SLC4A4) in the progression of PCa. Here, we report our findings from clinical specimens of prostatic acinar adenocarcinoma collected from patients. We found that low-grade prostate cancers have higher SLC4A4 expression. We investigated the role of SLC4A4 and the signaling mechanism underlying its role in modulating the PCa progression. Firstly, we reported the SLC4A4/GSK-3β/β-catenin signaling axis, which regulates the clonogenic potential, invasiveness, and metastasis. In this, we found reduced phosphorylation of GSK at serine 21 of α and serine 9 of the β subunit in shSLC4A4 cells of PCa, which ultimately relieved the activity of GSK-3β. This activated GSK-3β phosphorylates β-catenin at Ser33/37 with a subsequently reduced β-catenin level in PCa cells. Our functional analysis revealed that SLC4A4 knockdown retards tumor growth and lowers invasion and migration potential. Secondly, we investigated the SLC4A4/RB axis, which acts to drive cell proliferation. SLC4A4 knockdown decreases the interaction between these molecules with hypophosphorylation of RB protein and cell cycle arrest. Likewise, transcriptome sequencing using the SLC4A4 knockdown in DU145 cells regulates differentiated expressed genes and multiple metabolic pathways. Our results suggest that SLC4A4 may serve as a potential therapeutic target for prostate cancer patients in the future.

Dexmedetomidine inhibits ferroptosis and attenuates sepsis-induced acute kidney injury via activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway

ABSTRACT Objectives The molecular mechanism underlying the protective effects of DEX against sepsis-induced acute kidney injury (SAKI) remains to be elucidated. Methods We established S-AKI models in vivo via CLP and in vitro with LPS-induced HK-2 cells. Results The Nrf2/SLC7A11/FSP1/CoQ10 pathway was inhibited in S-AKI both in vitro and in vivo. The overexpression of Nrf2 inhibited LPS-induced ferroptosis by activating the SLC7A11/FSP1/CoQ10 pathway. DEX ameliorated kidney tissue damage, as determined by a decrease in BUN, Cr, and inflammatory factor levels, along with renal tubule vacuolation and inflammatory cell infiltration in S-AKI mice. Additionally, DEX treatment significantly ameliorated ferroptosis in S-AKI in vitro and in vivo, as indicated by an improvement in mitochondrial shrinkage and disruption of cristae, a decrease in iron, ROS, MDA, and 4-HNE levels, and an increase in GSH and GPX4 levels. Mechanistically, DEX treatment restored the reduction of Nrf2 expression and nuclear translocation in S-AKI, as well as, the levels of downstream SLC7A11, FSP1, and CoQ10. Knocking down Nrf2 in vitro and administering brusatol in vivo eliminated the protective effect of DEX against S-AKI. Conclusions DEX mitigated ferroptosis and attenuated S-AKI by activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway. Abbreviation: CLP: Cecal ligation puncture; LPS: Lipopolysaccharide; Nrf2: Nuclear factor-erythroid- 2-related factor 2; SLC7A11: Solute carrier family 7 member 11; FSP1: Ferroptosis suppressor protein 1; CoQ10: Coenzyme Q10; BUN: Blood urea nitrogen; Cr: Serum creatinine; ROS: Reactive oxygen species; MDA: Malondialdehyde; 4-HNE: 4-hydroxynonenal; GSH: Hlutathione; GPX4: Glutathione peroxidase 4.

Aberrant expression of solute carrier family transporters in placentas associated with pregnancy complications

IntroductionSolute carrier family transporters (SLCs), crucial for nutrient and trace element uptake in the placenta, play a significant role in fetal growth and development. Their dysregulation is associated with various pregnancy disorders. However, a comprehensive understanding of their role and regulation in placental function and pregnancy complications is still a largely unexplored area, making this study novel and significant. MethodsWe performed a rigorous meta-analysis of publicly available NCBI GEO microarray and RNA-Seq datasets followed by bioinformatics analysis of differentially expressed SLCs in PE and IUGR. The identified SLCs were then validated using qPCR on PE placental samples, ensuring the reliability and validity of the findings. ResultsBioinformatics analysis of preeclampsia (PE) and Intrauterine Growth restriction (IUGR) datasets revealed significant associations between specific SLC transporters with disease pathology, identified by studying differentially expressed SLCs. Subsequent validation using qPCR on placental samples confirmed considerable downregulation of SLC6A8, SLC16A10, SLC25A3, and SLC29A3, highlighting their dysregulation in the pathogenesis of PE and IUGR. DiscussionThe significant downregulation of SLC6A8, SLC16A10, SLC25A3, and SLC29A3 observed by bioinformatics analyses and validated by qPCR indicates atypical expression of these SLCs in gestational disorders. Our findings underscore the potential contribution of multiple SLC gene families to the development of placental pathologies associated with diverse pregnancy complications.

Clinical Phenotypic Characterization of the SLC26A4 Mutation in Pendred Syndrome/Nonsyndromic Enlarged Vestibular Aqueduct.

To summarize the Solute Carrier Family 26 Member 4 (SLC26A4) mutations and clinical phenotypic characteristics of patients with Pendred syndrome/nonsyndromic enlarged vestibular aqueduct (PS/NSEVA). A retrospective cohort study for the Chinese population was performed to analyze the hearing test results of 406 patients with PS/NSEVA who had a SLC26A4 mutation and the relationship between inner ear imaging and audiology. There was a significant difference in the mean hearing threshold in patients with biallelic mutations (M2), monoallelic mutations (M1), and nonallelic mutations (M0) and between patients with isolated vestibular aqueduct enlargement (IEVA) and patients with IEVA combined with Mondini malformation. There was no significant difference between patients with different gene mutation types or different sexes, or between the width of the vestibular aqueduct (VA) and the mean hearing threshold. The degree of hearing loss was linearly correlated with age. We propose that the presence and absence of SLC26A4 mutation, whether combined with Mondini malformation and patient age, are essential factors affecting the degree of hearing loss in the Chinese population. However, the number and type of mutations, degree of VA expansion, and sex of the patients did not affect the clinical audiological phenotype. 3 Laryngoscope, 2024.

Structural basis for the reaction cycle and transport mechanism of human Na+-sulfate cotransporter NaS1 (SLC13A1).

Sulfate (SO42-) is a pivotal inorganic anion with essential roles in mammalian physiology. NaS1, a member of solute carrier 13 family and divalent anion/sodium symporter family, functions as a Na+-sulfate cotransporter, facilitating sulfate (re)absorption across renal proximal tubule and small intestine epithelia. While previous studies have linked several human disorders to mutations in the NaS1 gene, its transport mechanism remains unclear. Here, we report the cryo-electron microscopy structures of five distinct conformations of the human NaS1 at resolutions of 2.7 to 3.3 angstroms, revealing the substrates recognition mechanism and the conformational change of NaS1 during the Na+-sulfate cotransport cycle. Our studies delineate the molecular basis of the detailed dynamic transport cycle of NaS1. These findings advance the current understanding of the Na+-sulfate cotransport mechanism, human sulfate (re)absorption, and the implications of disease-associated NaS1 mutations.

The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development.

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/- offspring and to altered DNA hypermethylation in Tet1-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.

Effects of short-term salt exposure on gill damage, serum components and gene expression patterns in juvenile Largemouth bass (Micropterus salmoides)

The Largemouth bass (Micropterus salmoides; LMB) is a freshwater fish that plays a significant role in aquaculture, and its cultural base is expanding into inland saline water areas. To study the effect of short-term salt exposure on LMB, fish with an average body weight of 11.69 (±1.82) g were cultured for 14 days at three different salt concentrations (0 ‰, 6 ‰, and 12 ‰). After 14 days, the second gill arch was collected for tissue sectioning and transcriptome sequencing, while serum samples were collected to analyze serum components. The results showed that the mortality rate in the 0 ‰ and 6 ‰ groups was 0 %, whereas the mortality rate in the 12 ‰ group was 62 %. In the gill tissue sections, no apparent damage was observed in the 0 ‰ and 6 ‰ groups. However, in the 12 ‰ group, the secondary lamellae became shorter, thicker, and exhibited a disordered arrangement. The serum component test results showed that osmolality and K+ significantly increased in the 12 ‰ group, while Na+, K+, and Cl− concentrations showed slight increases, but the differences were not significant. Comparative transcriptome analysis revealed that, along the salinity gradient, gene expression exhibited five profiles. Genes related to ion transport and immunity were highly expressed in the 6 ‰ and 12 ‰ groups, while genes associated with biosynthesis and ATP production showed decreased expression levels as salinity increased. Notably, seven solute carrier genes, two Na+/K+-ATPase genes, and two insulin-like growth factor genes were significantly highly expressed in the 12 ‰ salinity group, playing important roles in the transmembrane transport of ions. Based on the results, the LMB can acclimatize to a salt concentration of at least 6 ‰. However, exposure to 12 ‰ salinity can lead to a series of adverse effects, including organ damage, reduced energy metabolism efficiency, and disruption of ion homeostasis.

Citrus rhoifolin alleviated DSS-induced acute colitis by activating CEMIP/SLC7A11-mediated cystine uptake and inhibiting epithelial ferroptosis.

Pharmacological inhibition of ferroptosis, a specific form of regulated cell death, has emerged as a promising therapeutic strategy for alleviating symptoms and enhancing endoscopic outcomes in patients suffering from ulcerative colitis. Rhoifolin, a prominent bioactive constituent abundant in the widely consumed fruit Citrus grandis (grapefruit), has garnered attention for its ability to diminish the levels of reactive oxygen species (ROS), which are key inducers of ferroptosis across diverse cellular contexts. In this study, we aimed to investigate whether rhoifolin exerts its beneficial effects on colitis by modulating the process of epithelial ferroptosis. Colitis model was successfully established in C57BL/6 mice through the administration of 2.5% dextran sulfate sodium (DSS) solution for a duration of 9days, which was freely accessible for drinking. RNA sequencing was conducted to delve into the mechanisms underlying the rhoifolin-mediated effects on colitis. To evaluate the impact of rhoifolin on ferroptosis in epithelial cells, several key indicators were measured, including mitochondrial morphology, colonic glutathione (GSH) levels, lipid peroxidation product contents, and ROS levels. The results indicated that rhoifolin exhibited profound anti-colitis properties and effectively curbs ferroptosis in epithelial cells of mice subjected to DSS treatment. The RNA sequencing analysis further revealed that rhoifolin stimulated a remarkable upregulation of colonic cell migration-inducing protein (CEMIP) expression by approximately 2.4-fold in colitis-affected mice. Notably, depletion of CEMIP significantly blocked the rhoifolin-induced increase in the cystine transporter solute carrier family 7 member 11 (SLC7A11, from 1.9-fold to approximately 1.1-fold), as well as the elevation of cystine uptake (from 1.72-fold to 1.2-fold) and glutathione (GSH) biosynthesis (from 2.1-fold to 1.2-fold), and the suppression of epithelial ferroptosis (from 0.51-fold to 0.94-fold) in mice with colitis. Molecular docking investigations have pinpointed crucial amino acid residues within CEMIP, specifically His267, His289, and Phe265, as the primary interaction sites (docking score: -7.8kcal/mol), facilitating the engagement of rhoifolin via hydrogen bonding interactions. Rhoifolin significantly mitigated DSS-induced colitis primarily through inhibiting epithelial ferroptosis. The activation of CEMIP by citrus-derived rhoifolin led to a notable upregulation of SLC7A11 expression, thereby enhanced cystine uptake and facilitated GSH biosynthesis, ultimately suppressed the occurrence of ferroptosis in epithelial cells.

High plant protein diet impairs growth performance and intestinal integrity in greater amberjack (Seriola dumerili): Molecular and physiological insights

The Mediterranean aquaculture industry that produces mainly seabream and seabass is exploring alternative plant-based protein sources for fish feeds together with the diversification of fish species. Effective plant-based formulations require diverse sources and additives to maintain fish welfare and growth, which is especially important for carnivorous species. In this scenario, the objective of the present study was to evaluate the impact of a high percentage of fishmeal replacement with protein of plant origin in Seriola dumerili, a fast-growing species with a high protein requirement. Two diets were developed: MAP (marine animal protein) with a protein content of 92 % of animal origin and PPB (plant protein blend) with a 50 % replacement of protein of animal origin with plant protein. We combined electrophysiology measurements with expression analysis of claudins and members of the SLC superfamily of solute carriers to unravel and characterise putative markers of intestinal integrity and absorption. The replacement resulted in shorter and lighter fish with a reduction in growth rate (SGR) from 2.6 to 2. We simultaneously observed lower transepithelial tissue resistance (TER), lower permeability, and decreased cld12 expression in the anterior intestine. In addition, we demonstrated a strong region-dependent electrogenic transport of essential amino acids, with the mid-intestine having the highest transport capacity. The comparative study performed in the mid-intestine with fish fed the MAP or the PPB diets exposed a negative effect of dietary replacement with plant protein. No significant dietary impact on di- and tri-peptide transporters (SLC15) was found at the molecular level. However, a clear region-dependent expression pattern of slc15a1, slc15a2, and slc15a4 was observed, which warrants further investigation. The expression pattern of slc7a5 showed the effect of the diet, but in contrast, the diet and intestinal region affected the expression of its functionally associated slc3a1 and slc3a2 for amino acid antiport, with the strongest effects in the posterior intestine. The integrity and absorption impairments detected in response to protein source replacement will likely underlie the significant growth differences observed between the two dietary regimes.

West African cattle share non-random heterozygosity-rich region islands enriched on adaptation-related genes despite their different origins

MethodsUp to 237 individuals belonging to 10 different taurine (Bos taurus), zebu (B. indicus), and taurine × zebu sanga cattle populations sampled in Benin, Burkina Faso, and Niger were typed using the BovineHD BeadChip of Illumina to ascertain the patterns and importance of heterozygosity-rich regions (HRRs) in West African cattle. To account for among-population gene flow, individuals were further classified into three groups (Qtaurine, Qzebu, and admixed) according to maximum likelihood estimates of individual ancestries (q^) obtained using the program Admixture v1.23.Results and discussionThe 967 HRRs identified on 27 out of 29 bovine chromosomes in 231 cattle individuals were further summarized into 103 HRR islands, covering 40.7 Mb of the bovine genome. Only HRR islands identified in at least 10% of the animals typed or 10% of the individuals classified according to cattle type or admixture class were considered relevant to characterize the West African cattle genomic background. Only one and three HRR islands were considered taurine- and zebu-specific, respectively. Most (14) relevant HRR islands identified were present in cattle individuals despite the cattle type or admixture class into which they were classified (waHRR), suggesting that HRR can give advantages for adaptation to harsh environments. A total of 202 potential candidate genes were identified on the 14 waHRR islands. Most of them belonged to gene families coding zinc finger, protocadherin, adhesion G protein-coupled receptors, solute carrier, and arachidonate lipoxygenase proteins, involved in immune response, with a putative role in adaptation. Furthermore, waHRRs were also enriched on 18 and 11 different genes coding olfactory receptors and pregnancy-associated glycoproteins, respectively, giving additional support to the suggested importance of the HRR islands identified for the adaptive ability of West African cattle. Our research identified new genomic areas that can be targeted for further research in cattle adaptive ability.

Polyamine-Enriched Exosomes from Leishmania donovani Drive Host Macrophage Polarization via Immunometabolism Reprogramming.

Leishmania donovani (Ld) promastigotes secrete exosomes that are crucial in host-pathogen interactions and intercellular communication by carrying parasite-specific molecules. Although the composition of cargos in Leishmania exosomes is known, the effects of the unique metabolic repertoire on immunometabolism rewiring of macrophage polarization are poorly understood. Interestingly, we found the enrichment of polyamines (PAs) such as spermidine and putrescine in the Ld-exosomes. Herein, we investigate the critical polycationic molecules and their crucial role in parasite survival. Our study shows that PA inhibition or depletion significantly impairs parasite growth and fitness, particularly in drug-resistant strains. Furthermore, we aimed to elucidate the impact of PAs-enriched Ld-exosomes on host macrophages. The data demonstrated that macrophages efficiently internalized these exosomes, leading to heightened phagocytic activity and infectivity. In addition, internalized Ld-exosomes induced M2 macrophage polarization characterized by elevated Arginase-1 expression and activity. The increased expression of the solute carrier gene (SLC3A2) and elevated intracellular spermidine levels suggest that Ld-exosomes contribute to the host PAs pool and create an anti-inflammatory milieu. These findings highlight the essential role of PAs-enriched Ld-exosomes in parasite survival and establishing a pro-parasitic environment in the host macrophage.