Explore the vast range of titles available.

Vitamin C plays important roles as a cofactor in many enzymatic reactions and as an antioxidant against oxidative stress. As some mammals including humans cannot synthesize vitamin C de novo from glucose, its uptake from dietary sources is essential, and is mediated by the sodium-dependent vitamin C transporter 1 (SVCT1). Despite its physiological significance in maintaining vitamin C homeostasis, the structural basis of the substrate transport mechanism remained unclear. Here, we report the cryo-EM structures of human SVCT1 in different states at 2.5–3.5 Å resolutions. The binding manner of vitamin C together with two sodium ions reveals the counter ion-dependent substrate recognition mechanism. Furthermore, comparisons of the inward-open and occluded structures support a transport mechanism combining elevator and distinct rotational motions. Our results demonstrate the molecular mechanism of vitamin C transport with its underlying conformational cycle, potentially leading to future industrial and medical applications. Vitamin C is an essential nutrient for our daily life, but how it is transported into our bodies remained unclear. Here, authors revealed multiple structures of human vitamin C transporter, providing insights into its molecular mechanisms.

Vitamin C (L-ascorbic acid) is an essential nutrient for human health, and its deficiency has long been known to cause scurvy. Sodium-dependent vitamin C transporters (SVCTs) are responsible for vitamin C uptake and tissue distribution in mammals. Here, we present cryogenic electron microscopy structures of mouse SVCT1 in both the apo and substrate-bound states. Mouse SVCT1 forms a homodimer with each protomer containing a core domain and a gate domain. The tightly packed extracellular interfaces between the core domain and gate domain stabilize the protein in an inward-open conformation for both the apo and substrate-bound structures. Vitamin C binds at the core domain of each subunit, and two potential sodium ions are identified near the binding site. The coordination of sodium ions by vitamin C explains their coupling transport. SVCTs probably deliver substrate through an elevator mechanism in combination with local structural arrangements. Altogether, our results reveal the molecular mechanism by which SVCTs recognize vitamin C and lay a foundation for further mechanistic studies on SVCT substrate transport. Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.

Genomic loss of 5-hydroxymethylcytosine (5hmC) accompanies malignant cellular transformation in breast cancer. Vitamin C serves as a cofactor for TET methylcytosine dioxygenases to increase 5hmC generation. Here we show that the transcription of SVCT2, a major vitamin C transporter, was decreased in human breast cancers (113 cases) compared to normal breast tissues from the same patients. A decreased SVCT2 expression was also observed in breast cancer cell lines. Treatment with vitamin C (100 μM) increased the 5hmC content in MDA-MB-231 breast cancer cells and markedly altered the transcriptome. The vitamin C treatment induced apoptosis in MDA-MB-231 cells, which was verified in two additional breast cancer cell lines. This pro-apoptotic effect of vitamin C appeared to be mediated by TRAIL, a known apoptosis inducer. Vitamin C upregulated TRAIL transcripts (2.3-fold increase) and increased TRAIL protein levels. The upregulation of TRAIL by vitamin C was largely abolished by siRNAs targeting TETs and anti-TRAIL antibody abrogated the induction of apoptosis. Furthermore, the apoptosis promoted by vitamin C was associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, these results suggest a potential role of physiological doses of vitamin C in breast cancer prevention and treatment.

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase. In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins.

Neurodegeneration in Huntington disease (HD) contributes to dopaminergic system dysfunction via the loss of striatal medium spiny neurons expressing dopamine receptors. Given the key role for ascorbic acid (vitamin C) in dopamine synthesis and neurotransmission, we investigated whether mild cellular ascorbate deficiency accelerates dopaminergic dysfunction in the development of HD pathology and behavioral deficits. YAC128 mice expressing mutant human huntingtin were crossed with SVCT2+/− mice, which carry a heterozygous knockout of the sodium‐dependent vitamin C transporter, to generate mice with approximately 30% decreased neuronal vitamin C as well as progressive changes in dopamine signaling. Behavioral and neurochemical outcomes were assessed at early disease stages. At 14 and 20 weeks, YAC128 and SVCT2+/− YAC128 mice showed similar deficits in grip strength, locomotor activity, and rotarod performance compared to controls, suggesting modest ascorbate deficiency did not accelerate motor phenotypes. Gene expression analysis revealed six significantly upregulated genes in the striatum of SVCT2+/− YAC128 mice, including those involved in dopamine synthesis, packaging, and transport. Notably, striatal dopamine and serotonin and their metabolites were decreased in both single mutant mouse lines (YAC128 and SVCT2+/−) but without a compounding effect of the double mutation (SVCT2+/− YAC128). These results indicate that while moderate ascorbate deficiency may not worsen early behavioral phenotypes in the YAC128 model, it does impact dopamine system regulation at the molecular level. These findings highlight the potential importance of ascorbate in modifying disease progression and suggest that humans with HD, who cannot synthesize ascorbate, may be particularly vulnerable to vitamin C deficiency effects on dopamine dynamics.

Vitamin C is implicated in various bodily functions due to its unique properties in redox homeostasis. Moreover, vitamin C also plays a great role in restoring the activity of 2-oxoglutarate and Fe2+ dependent dioxygenases (2-OGDD), which are involved in active DNA demethylation (TET proteins), the demethylation of histones, and hypoxia processes. Therefore, vitamin C may be engaged in the regulation of gene expression or in a hypoxic state. Hence, vitamin C has acquired great interest for its plausible effects on cancer treatment. Since its conceptualization, the role of vitamin C in cancer therapy has been a controversial and disputed issue. Vitamin C is transferred to the cells with sodium dependent transporters (SVCTs) and glucose transporters (GLUT). However, it is unknown whether the impaired function of these transporters may lead to carcinogenesis and tumor progression. Notably, previous studies have identified SVCTs’ polymorphisms or their altered expression in some types of cancer. This review discusses the potential effects of vitamin C and the impaired SVCT function in cancers. The variations in vitamin C transporter genes may regulate the active transport of vitamin C, and therefore have an impact on cancer risk, but further studies are needed to thoroughly elucidate their involvement in cancer biology.

The solute carrier (SLC) protein family, traditionally recognized for transporting molecules across cell membranes, is gaining attention for its broader roles, including signaling. Among SLC proteins, the ascorbate transporter SVCT2 remains poorly understood, particularly in relation to estrogen receptor alpha (ERα), a key regulator in breast cancer cells. Here, we investigate how ERα regulates SVCT2 and its implications for chemoresistance. Our results demonstrate that ERα knockdown significantly reduces SVCT2 protein levels, impairing cellular ascorbic acid uptake. Mechanistically, ERα directly interacts with SVCT2. We show that X-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, targets SVCT2 for ubiquitination and subsequent proteasomal degradation in ERα-deficient conditions. Notably, silencing XIAP restored SVCT2 stability, underscoring its regulatory role. Functionally, ERα or SVCT2 knockdown decreases doxorubicin-induced cytotoxicity, accompanied by increased expression of ATP-binding cassette (ABC) transporter genes, which mediate drug efflux and contribute to chemoresistance. These findings uncover a novel regulatory axis between ERα and SVCT2, mediated by XIAP, and establish SVCT2 as a critical factor in maintaining cellular ascorbic acid levels and drug sensitivity. Targeting XIAP or modulating SVCT2 may represent promising therapeutic strategies for overcoming resistance in ERα-positive breast cancer. This study advances our understanding of the interplay between nutrient transport and cancer therapy, offering new avenues for intervention.

Huntington’s disease has been associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. Using an electrophysiological approach in R6/2 HD slices, we observe an abnormal ascorbic acid flux from astrocytes to neurons, which is responsible for alterations in neuronal metabolic substrate preferences. Here using striatal neurons derived from knock-in mice expressing mutant huntingtin (STHdhQ cells), we study ascorbic acid transport. When extracellular ascorbic acid concentration increases, as occurs during synaptic activity, ascorbic acid transporter 2 (SVCT2) translocates to the plasma membrane, ensuring optimal ascorbic acid uptake for neurons. In contrast, SVCT2 from cells that mimic HD symptoms (dubbed HD cells) fails to reach the plasma membrane under the same conditions. We reason that an early impairment of ascorbic acid uptake in HD neurons could lead to early metabolic failure promoting neuronal death. Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al. show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.

Background/Objectives: The guinea pig is a unique experimental model because of the evolutionary loss of the GULO gene, which encodes an enzyme involved in vitamin C synthesis. Since vitamin C plays an essential role in collagen biochemistry, numerous studies have investigated the effects of pre- and postnatal vitamin C deficiency. However, only a few studies, including ours, have indicated a possible link between vitamin C deprivation and potential weakening of the basement membrane, which may lead to significant alterations in brain structure. Methods: The experiment included guinea pig foetuses completely deprived from the 10th (E2 group) and the 20th (E1 group) to the 50th day of intrauterine life. Tissue samples from the cerebrum and cerebellum were taken for biochemical, molecular, and immunohistochemical analyses. Results: In the E2 group alone, we found marked gross changes: cerebral bleeding, porencephaly, and a lissencephalic cerebellar surface. Microscopic examination revealed diffuse bleeding in the cerebrum along with a loss of neurons in the area of the defect, specifically in the E2 group. The complete maturation of ectopic neurons characterised dysplastic changes in the cerebellum. Hydroxyproline analysis of both the cerebrum and cerebellum showed no significant differences among the E1, E2, and control groups. However, decreased expression of COL1, COL4A1, and SLC23A1 was observed solely in the cerebellar tissue of the E1 group. Conclusions: The morphological, biochemical, and molecular results represent preliminary associations with vitamin C deficiency, but require further validation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a rising global incidence in recent years. Dengzhan shengmai (DZSM), a plant-based formulation clinically used in the management of cerebrovascular diseases, possesses documented anti-inflammatory and antioxidant properties; however, its effects on UC are unclear. In this study, we investigated the therapeutic potential and underlying mechanism of DZSM in a dextran sulfate sodium (DSS)-induced murine colitis model. Our results showed that DZSM significantly alleviated UC-related parameters. Mechanistically, DZSM remodeled gut microbiota dysbiosis, specifically enriching the abundance of short-chain fatty acid (SCFA)-producing bacteria and elevating colonic levels of SCFAs. Notably, butyrate upregulated the expression of the sodium-dependent vitamin C transporter 1 (SVCT1) in colonic epithelial cells, thereby enhancing cellular vitamin C (VitC) uptake. The accumulated VitC synergized with butyrate to exert potent antioxidant and anti-inflammatory effects, further reinforcing epithelial barrier function. Importantly, fecal microbiota transplantation (FMT) confirmed that the protective effects of DZSM on UC were achieved by modulating gut microbiota, at least partially. Collectively, our findings demonstrate for the first time that DZSM alleviates DSS-induced colitis in mice through a novel butyrate-SVCT1-VitC axis driven by gut microbiota remodeling, providing new mechanistic insights into the microbiota-dependent efficacy of plant-based medicine.