Gestational exposure to air pollutants perturbs metabolic and placenta-fetal phenotype.

Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16-19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5'-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5'-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5'-hydroxymethylation, gene expression, and associated injury.

Saturated fatty acids inhibit unsaturated fatty acid induced glucose uptake involving GLUT10 and aerobic glycolysis in bovine granulosa cells.

Fatty acids have been shown to modulate glucose metabolism in vitro and in vivo. However, there is still a need for substantial evidence and mechanistic understanding in many cell types whether both saturated and unsaturated fatty acids (SFAs and UFAs) pose a similar effect and, if not, what determines the net effect of fatty acid mixes on glucose metabolism. In the present study, we asked these questions by treating granulosa cells (GCs) with the most abundant non-esterified fatty acid species in bovine follicular fluid. Results revealed that oleic and alpha-linolenic acids (UFAs) significantly increased glucose consumption compared to palmitic and stearic acids (SFAs). A significant increase in lactate production, extracellular acidification rate, and decreased mitochondrial activity indicate glucose channeling through aerobic glycolysis in UFA treated GCs. We show that insulin independent glucose transporter GLUT10 is essential for UFA driven glucose consumption, and the induction of AKT and ERK signaling pathways necessary for GLUT10 expression. To mimic the physiological conditions, we co-treated GCs with mixes of SFAs and UFAs. Interestingly, co-treatments abolished the UFA induced glucose uptake and metabolism by inhibiting AKT and ERK phosphorylation and GLUT10 expression. These data suggest that the net effect of fatty acid induced glucose uptake in GCs is determined by SFAs under physiological conditions.

Revisiting the roles of glucose transporters in skeletal muscle physiology: is GLUT10 a novel player?

Skeletal muscle is the largest metabolic tissue responsible for systemic glucose handling. Glucose uptake into skeletal tissue is highly dynamic and delicately regulated, in part through the controlled expression and subcellular trafficking of multiple types of glucose transporters. Although the roles of GLUT4 in skeletal muscle metabolism are well established, the physiological significance of other, seemingly redundant, glucose transporters remain incompletely understood. Nonetheless, recent studies have shed light on the roles of several glucose transporters, such as GLUT1 and GLUT10, in skeletal muscle. Mice experiments suggest that GLUT10 could be a novel player in skeletal muscle metabolism in the context of mechanical overload, which is in line with the meta-analytical results of gene expression changes after resistance exercise in humans. Herein we discuss the knowns, unknowns, and implications of these recent findings.

Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients.

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised by tortuosity and elongation of the aorta and medium-sized arteries. It is considered an extremely rare disease; only 106 individuals with genetically confirmed ATS have been identified to date. Four cases of ATS from two families are described, contributing to the clinical delineation of this condition. A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed. Regarding the vascular involvement, a predominant supra-aortic involvement stands out and only 1 patient with significant arterial stenoses was described. All presented severe tortuosity of the intracranial arteries. To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed. A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was detected in a proband; it has an allegedly deleterious effect in compound heterozygous state with the pathogenic variant c.417T>A (p.Tyr139Ter). The other 3 patients, siblings born to healthy consanguineous parents, had a variant in homozygous state: c.510G>A (p.Trp170Ter).

Glut10 restrains neointima formation by promoting SMCs mtDNA demethylation and improving mitochondrial function.

Neointimal hyperplasia is a major clinical complication of coronary artery bypass graft and percutaneous coronary intervention. Smooth muscle cells (SMCs) play a vital roles in neointimal hyperplasia development and undergo complex phenotype switching. Previous studies have linked glucose transporter member 10(Glut10) to the phenotypic transformation of SMCs. In this research, we reported that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via promotion of mtDNA demethylation in SMCs. Glut10 is significantly downregulated in both human and mouse restenotic arteries. Global Glut10 deletion or SMC-specific Glut10 ablation in the carotid artery of mice accelerated neointimal hyperplasia, while Glut10 overexpression in the carotid artery triggered the opposite effects. All of these changes were accompanied by a significant increase in vascular SMCs migration and proliferation. Mechanistically, Glut10 is expressed primarily in the mitochondria after platelet-derived growth factor-BB (PDGF-BB) treatment. Glut10 ablation induced a reduction in ascorbic acid (VitC) concentrations in mitochondria and mitochondrial DNA (mtDNA) hypermethylation by decreasing the activity and expression of the Ten-eleven translocation (TET) protein family. We also observed that Glut10 deficiency aggravated mitochondrial dysfunction and decreased the adenosinetriphosphate (ATP) content and the oxygen consumption rate, which also caused SMCs to switch their phenotype from contractile to synthetic phenotype. Furthermore, mitochondria-specific TET family inhibition partially reversed these effects. These results suggested that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via the promotion of mtDNA demethylation in SMCs.

GLUT10 is a novel immune regulator involved in lung cancer immune cell infiltration and predicts worse survival when transcriptionally downregulated.

Background: Glucose transporter 10 (GLUT10) is encoded by the SLC2A10 gene. Our recent investigations have shown that GLUT10 is not only involved in glucose metabolism but also involved in the body's immune response to cancer cells. However, the role of GLUT10 in tumor prognosis and in tumor immunity has not been reported. Methods: We knocked down SLC2A10 and performed transcriptome sequencing to analyse the biological function of GLUT10 and found that GLUT10 may be involved in immune signaling. Then, we studied the expression level of SLC2A10 in cancers by the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We also evaluated the prognostic potential of SLC2A10 in different cancers using the Kaplan‒Meier plotter database and PrognoScan online software. The correlations between SLC2A10 expression and immune infiltrates were analysed by TIMER. In addition, correlations between SLC2A10 expression and gene marker sets of immune infiltrates were analysed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). Immunofluorescence staining of cyclooxygenase-2 (COX-2) and GLUT10 in lung cancer tissue and adjacent tissue was performed to confirm our findings from the database research. Results: Knocking down SLC2A10 widely activated immune and inflammatory signaling. SLC2A10 was abnormally expressed in several tumors. The expression level of SLC2A10 was closely correlated with cancer prognosis. Low SLC2A10 expression was related to poorer prognosis and increased malignancy of lung cancer. Lung cancer patients with low expression of SLC2A10 have a much shorter median survival time than patients with high expression of SLC2A10. SLC2A10 expression is closely related to the infiltration of different types of immune cells, particularly macrophages. Both database research and lung cancer sample research revealed that GLUT10 might modulate immune cell infiltration via the COX-2 pathway. Conclusions: By transcriptome experiments, database studies, and human sample studies, we found that GLUT10 is a new immune signaling molecule involved in tumor immunity, especially in the immune cell infiltration of lung adenocarcinoma (LUAD). GLUT10 may modulate the immune cell infiltration of LUAD via the COX-2 pathway.

H22954, a long non-coding RNA, inhibits glucose uptake in leukemia cells in a GLUT10-dependent manner.

OBJECTIVES: To investigate the performance of H22954, a novel long non-coding RNA (lncRNA), in inhibiting glucose uptake in leukemia cells. METHODS: 18F-FDG uptake, RNA half-life quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase assays were performed to detect the glucose uptake in the condition of leukemia. Microarrays and qRT-PCR analyses were used to identify the related genes or proteins and elucidate the underlying these processes. RESULTS: H22954, a novel lncRNA, inhibited glucose uptake in leukemia cells. Using bioinformatics and microarray analyses, GLUT10 was identified as a possible target molecule of H22954. H22954 targeted the 3'untranslated region of GLUT10. In the luciferase assay, the luciferase activity of pGL3-GLUT10 was inhibited by H22954. Consistently, H22954 expression levels were inversely correlated with GLUT10 expression in cell lines and acute myeloid leukemia (AML) samples. Conversely, the degradation rate of GLUT10 mRNA was increased after H22954 overexpression. Moreover, glucose uptake was recovered when the GLUT10-interaction sites in H22954 were mutated. CONCLUSION: The lncRNA H22954 regulated GLUT10 expression to inhibit glucose uptake in leukemia cells. Our findings provide potentially valuable data for designing new targeted strategies based on H22954.

El síndrome de tortuosidad arterial y su relevancia en cirugía pediátrica. A propósito de un caso / Arterial tortuosity syndrome: relevance in pediatric surgery. A case report

Introducción: El síndrome de tortuosidad arterial (STA) es untrastorno autosómico recesivo del tejido conectivo muy infrecuente,caracterizado por tortuosidad y elongación de arterias de medio y grancalibre y múltiples trastornos derivados de la afectación generalizadadel tejido conectivo. Caso clínico: Neonato diagnosticado de STA, con múltiples malfor-maciones vasculares, hernia de hiato y hernia inguinal bilateral.Intervenido a los tres meses, practicándose cierre de hernia de hiatoy herniorrafia inguinal bilateral. Estas últimas requirieron hasta cuatrointervenciones por recidiva. Durante el seguimiento presentó hernia diafragmática retrocardiaca,siendo intervenida, con posterior eventración.A los ocho años ingresó por shock séptico secundario a oclusiónintestinal. Se intervino urgente objetivando herniación gástrica en ca-vidad pleural derecha con perforación en fundus. El paciente fallecióen la UCI tras 24 horas. Comentarios: El cirujano pediátrico debe conocer el STA debidoa la múltiple patología quirúrgica que puede presentar, difícil manejo,riesgo de recidiva y complicaciones.(AU)

Introduction: Arterial tortuosity syndrome (ATS) is an extremelyrare autosomal recessive disorder of the connective tissue. It is charac-terized by tortuosity and elongation of medium and large arteries, withmultiple disorders associated with the widespread involvement of theconnective tissue. Clinical case: Newborn diagnosed with ATS, with multiple vascularmalformations, hiatal hernia, and bilateral inguinal hernia. He underwent surgery at three months of age. The hiatal hernia wasclosed, and bilateral inguinal hernia repair was performed. The inguinalhernias required up to 4 surgeries as a result of recurrences.During follow-up, the patient had retrocardiac diaphragmatic hernia.It was operated on, with subsequent incisional hernia.8 years later, he was admitted as a result of septic shock secondaryto intestinal occlusion. Emergency surgery was scheduled, demonstrating gastric herniation in the right pleural cavity, with perforation of thefundus. The patient died at the ICU 24 hours later. Discussion: The pediatric surgeon should be familiar with ATS,since it may cause multiple surgical pathologies, it is difficult to manage,and it is associated with a high risk of recurrence and complications.(AU)

Arterial tortuosity syndrome: relevance in pediatric surgery. A case report. / El síndrome de tortuosidad arterial y su relevancia en cirugía pediátrica. A propósito de un caso.

INTRODUCTION: Arterial tortuosity syndrome (ATS) is an extremely rare autosomal recessive disorder of the connective tissue. It is characterized by tortuosity and elongation of medium and large arteries, with multiple disorders associated with the widespread involvement of the connective tissue. CASE REPORT: Newborn diagnosed with ATS, with multiple vascular malformations, hiatal hernia, and bilateral inguinal hernia. He underwent surgery at three months of age. The hiatal hernia was closed, and bilateral inguinal hernia repair was performed. The inguinal hernias required up to 4 surgeries as a result of recurrences.During follow-up, the patient had retrocardiac diaphragmatic hernia. It was operated on, with subsequent incisional hernia. 8 years later, he was admitted as a result of septic shock secondary to intestinal occlusion. Emergency surgery was scheduled, demonstrating gastric herniation in the right pleural cavity, with perforation of the fundus. The patient died at the ICU 24 hours later. DISCUSSION: The pediatric surgeon should be familiar with ATS, since it may cause multiple surgical pathologies, it is difficult to manage, and it is associated with a high risk of recurrence and complications.

INTRODUCCION: El síndrome de tortuosidad arterial (STA) es un trastorno autosómico recesivo del tejido conectivo muy infrecuente, caracterizado por tortuosidad y elongación de arterias de medio y gran calibre y múltiples trastornos derivados de la afectación generalizada del tejido conectivo. CASO CLINICO: Neonato diagnosticado de STA, con múltiples malformaciones vasculares, hernia de hiato y hernia inguinal bilateral. Intervenido a los tres meses, practicándose cierre de hernia de hiato y herniorrafia inguinal bilateral. Estas últimas requirieron hasta cuatro intervenciones por recidiva. Durante el seguimiento presentó hernia diafragmática retrocardiaca, siendo intervenida, con posterior eventración. A los ocho años ingresó por shock séptico secundario a oclusión intestinal. Se intervino urgente objetivando herniación gástrica en cavidad pleural derecha con perforación en fundus. El paciente falleció en la UCI tras 24 horas. COMENTARIOS: El cirujano pediátrico debe conocer el STA debido a la múltiple patología quirúrgica que puede presentar, difícil manejo, riesgo de recidiva y complicaciones.

Arterial Tortuosity Syndrome: An Ascorbate Compartmentalization Disorder?

Significance: Cardiovascular disorders are the most important cause of morbidity and mortality in the Western world. Monogenic developmental disorders of the heart and vessels are highly valuable to study the physiological and pathological processes in cardiovascular system homeostasis. The arterial tortuosity syndrome (ATS) is a rare, autosomal recessive connective tissue disorder showing lengthening, tortuosity, and stenosis of the large arteries, with a propensity for aneurysm formation. In histopathology, it associates with fragmentation and disorganization of elastic fibers in several tissues, including the arterial wall. ATS is caused by pathogenic variants in SLC2A10 encoding the facilitative glucose transporter (GLUT)10. Critical Issues: Although several hypotheses have been forwarded, the molecular mechanisms linking disrupted GLUT10 activity with arterial malformations are largely unknown. Recent Advances: The vascular and systemic manifestations and natural history of ATS patients have been largely delineated. GLUT10 was identified as an intracellular transporter of dehydroascorbic acid, which contributes to collagen and elastin cross-linking in the endoplasmic reticulum, redox homeostasis in the mitochondria, and global and gene-specific methylation/hydroxymethylation affecting epigenetic regulation in the nucleus. We revise here the current knowledge on ATS and the role of GLUT10 within the compartmentalization of ascorbate in physiological and diseased states. Future Directions: Centralization of clinical, treatment, and outcome data will enable better management for ATS patients. Establishment of representative animal disease models could facilitate the study of pathomechanisms underlying ATS. This might be relevant for other forms of vascular dysplasia, such as isolated aneurysm formation, hypertensive vasculopathy, and neovascularization. Antioxid. Redox Signal. 34, 875-889.

Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules.

OBJECTIVES: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. METHODS: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. RESULTS AND DISCUSSION: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. CONCLUSION: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

GLUT10-Lacking in Arterial Tortuosity Syndrome-Is Localized to the Endoplasmic Reticulum of Human Fibroblasts.

GLUT10 belongs to a family of transporters that catalyze the uptake of sugars/polyols by facilitated diffusion. Loss-of-function mutations in the SLC2A10 gene encoding GLUT10 are responsible for arterial tortuosity syndrome (ATS). Since subcellular distribution of the transporter is dubious, we aimed to clarify the localization of GLUT10. In silico GLUT10 localization prediction suggested its presence in the endoplasmic reticulum (ER). Immunoblotting showed the presence of GLUT10 protein in the microsomal, but not in mitochondrial fractions of human fibroblasts and liver tissue. An even cytosolic distribution with an intense perinuclear decoration of GLUT10 was demonstrated by immunofluorescence in human fibroblasts, whilst mitochondrial markers revealed a fully different decoration pattern. GLUT10 decoration was fully absent in fibroblasts from three ATS patients. Expression of exogenous, tagged GLUT10 in fibroblasts from an ATS patient revealed a strict co-localization with the ER marker protein disulfide isomerase (PDI). The results demonstrate that GLUT10 is present in the ER.

Glucose transporter type 10-lacking in arterial tortuosity syndrome-facilitates dehydroascorbic acid transport.

Loss-of-function mutations in the gene encoding GLUT10 are responsible for arterial tortuosity syndrome (ATS), a rare connective tissue disorder. In this study GLUT10-mediated dehydroascorbic acid (DAA) transport was investigated, supposing its involvement in the pathomechanism. GLUT10 protein produced by in vitro translation and incorporated into liposomes efficiently transported DAA. Silencing of GLUT10 decreased DAA transport in immortalized human fibroblasts whose plasma membrane was selectively permeabilized. Similarly, the transport of DAA through endomembranes was markedly reduced in fibroblasts from ATS patients. Re-expression of GLUT10 in patients' fibroblasts restored DAA transport activity. The present results demonstrate that GLUT10 is a DAA transporter and DAA transport is diminished in the endomembranes of fibroblasts from ATS patients.