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Objective: To investigate the relationship of synaptic loss with glucose metabolism and dopaminergic transporters in Parkinson's disease (PD) patients. Methods: A total of 16 patients with PD and 11 age-matched healthy controls underwent positron emission tomography (PET) with the tracers [18F]SynVesT-1, a ligand for the presynaptic terminal marker synaptic vesicle protein 2 A (SV2A), and FDG. PD patients also underwent PET with the dopamine transporter (DAT) ligand [18F]FP-CIT. The difference in synaptic density between PD patients and age-matched normal controls(NCs) was determined in the selected regions of interest, and the correlations of the [18F]SynVesT-1 PET SUVRs with [18F]FP-CIT PET SUVRs and [18F]FDG PET SUVRs were evaluated. Results: Compared with that in the NC group, the synaptic density in the caudate region was significantly lower in the PD group (SUVR: 2.51 ± 0.36 vs. 3.18 ± 0.32, p < 0.001), especially in the pre-commissural caudate and post-commissural caudate (SUVR: 2.42 ± 0.29 vs. 2.63 ± 0.32, p < 0.01; 0.76 ± 0.31 vs. 0.97 ± 0.33, p < 0.001). A reduced synaptic density was significantly correlated with DAT (r = 0.61, p < 0.001) and glucose metabolism (r = 0.73, p < 0.001) in the post-commissural caudate. In the post-commissural regions of the caudate, there was a partial mediating effect of synaptic density on the relationship between glucose metabolism and DAT availability (indirect effect: β4 = 0.039, p = 0.024). Conclusion: [18F]SynVesT-1 binds specifically to SV2A, reflecting synaptic density, and there is a positive correlation metabolic pattern related to the changes reflected by [18F]SynVesT-1 and [18F]FDG. [ABSTRACT FROM AUTHOR]

Background: In patients with advanced glaucoma, lesions frequently extend beyond the eye and affect other organs. However, early distal consequences of elevated intraocular pressure (IOP) remain unclear. This study aimed to observe glucose uptake in the optic cortex during the early stages of elevated IOP and to investigate the mechanism by which Apelin13 exerts neuroprotective effects. Methods: This study used a single anterior chamber injection of polystyrene microbeads and triblock copolymer hydrogel in 6- to 8-week-old male C57BL/6J mice and observed glucose uptake in the optic cortex during the initial phase of IOP elevation using micro-positron emission tomography/magnetic resonance imaging (PET/MRI). Pathological changes in the optic nerve and optic cortex were assessed by immunofluorescence, reactive oxygen species (ROS) kit, and and nicotinamide adenine dinucleotide phosphate (NADPH) kit. Expression of glucose transporter proteins (GLUTs) and key enzymes of the pentose phosphate pathway (PPP) was evaluated using immunofluorescence and western blot. The activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B signaling pathway was analyzed via western blot. Results: On day 1 of elevated IOP, the modeled eye exhibited reduced glucose uptake in the corresponding visual cortex compared with the contralateral visual cortex. Over time, the condition gradually improved, with no discernible difference between the two sides by day 21. Concurrently, along with abnormal activation of microglia and progressive reduction of retinal ganglion cells, we noted abnormal expression of glucose transporter proteins in visual cortical neurons. Additionally, elevated levels of ROS and NADPH were observed in both the retinal and brain tissues following IOP elevation. In contrast, administration of the neuroprotectant Apelin-13 mitigated the pathology induced by IOP elevation. Conversely, treatment with a PI3K inhibitor significantly diminished the protective effects of Apelin-13. Conclusions: These findings imply that altered glucose metabolism in the visual center may be an early sign of optic nerve damage in patients with glaucoma. Apelin-13 may rely on the PI3K/Akt signaling pathway to regulate the redistribution of energy metabolism in the retina and visual centers, thereby mitigating oxidative stress and safeguarding neuronal cells. [ABSTRACT FROM AUTHOR]

Background: Stevia glycosides (SGs) have been widely used as an ideal sugar alternative in the food industry. However, the potential application of SGs mixture in the diets of weaned piglets remains unexplored. This study aimed to investigate the effect of dietary SGs mixture supplementation on growth performance, gene expression of gut chemoreceptors, and antioxidant capacity in weaned piglets. Methods: A total of 216 weaned piglets (Duroc × Landrace × Yorkshire, 7.36 ± 0.04 kg body weight) were randomly assigned to 6 groups (6 pens/group with 6 piglets/pen), and were fed with the basal diet supplemented with 0, 100, 150, 200, 250, or 300 mg/kg SGs mixture for 42 days. The serum, liver, longissimus thoracis, and jejunal samples were collected on day 43. Results: The results showed that inclusion the SGs mixture in the diet did not have a significant impact on growth performance from days 1 to 28 (P > 0.05). But increasing the concentration of SGs mixture tended to linearly decrease the average daily gain from days 1 to 42 (P = 0.052). However, 150 mg/kg SGs mixture supplementation significantly increased the mRNA expression of taste receptor family 1 member 2 (T1R2) and glucose transporters 2 (GLUT2) in the jejunum (P < 0.05), while 150 and 200 mg/kg SGs mixture supplementation significantly increased T1R3 mRNA expression (P < 0.05). Moreover, 150 mg/kg SGs mixture supplementation significantly reduced serum malondialdehyde content (P < 0.05). Increasing the concentration of SGs mixture linearly and quadratically increased serum total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activity, as well as hepatic T-SOD, GSH-Px activity, and muscle total antioxidant capacity contents (P < 0.05). Furthermore, piglets fed a diet supplemented with 100 mg/kg SGs mixture had higher serum T-SOD, CAT, and GSH-Px activities compared with the other treatments (P < 0.05). Conclusions: Therefore, our results suggest that dietary 100 ~ 150 mg/kg SGs mixture supplementation modulates gene expression of sweet taste recognition receptors and glucose transporters, while also enhancing the antioxidant capacity of weaned piglets. [ABSTRACT FROM AUTHOR]

Gestational Diabetes Mellitus (GDM) is an emerging maternal health problem with increasing incidences. The lack of complete understanding of its pathophysiological mechanisms and novel regulatory biomarkers makes early diagnosis difficult. High-throughput RNA sequencing and computational bioinformatics analyses were conducted to identify novel hub genes, and their regulatory mechanisms were validated through qRT-PCR, western blot, and siRNA-mediated knockdown studies. Intermediate metabolites and circulatory levels of amino acids in the serum of GDM patients and healthy controls were measured. Transcriptomic studies identified SNW1 as the most sensitive and specific biomarker, significantly up-regulated in GDM (fold change = 1.09; p < 0.001). Metabolomic studies indicated significantly elevated gluconeogenesis in GDM, evidenced by decreased levels of alanine and increased levels of pyruvate and glucose compared to controls. siRNA-mediated knockdown of SNW1 in PANC1 cells resulted in significant down-regulation of alanine aminotransferase (ALT/GPT) and insulin receptor substrate (IRS1), while glucose transporters (GLUT2/GLUT4) and insulin (INS) were significantly up-regulated at both mRNA and protein levels. This study identified SNW1 as a novel insulin-resistant gene that induces hyperglycemia by elevating gluconeogenesis and decreasing glucose uptake. SNW1 may be considered a potential therapeutic target with clinical utility for the management of GDM. [ABSTRACT FROM AUTHOR]

Pancreatic islet b-cells express the Cpt1a gene, which encodes the enzyme carnitine palmitoyltransferase 1A (CPT1A), an enzyme that facilitates entry of long-chain fatty acids into the mitochondria. Because fatty acids are required for glucosestimulated insulin secretion, we tested the hypothesis that CPT1A is essential to support islet b-cell function and mass. In this study, we describe genetic deletion of Cpt1a in pancreatic tissue (Cpt1aPdx1-/-) using C57BL/6J mice. Islet morphology, b-cell transcription factor abundance, islet ATP levels, glucose transporter 2 abundance, and expression of the dedifferentiation marker ALDH1A3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance were assessed to investigate the metabolic status of genetic reductions in Cpt1a. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. Pancreatic deletion of Cpt1a reduced glucose tolerance but did not alter insulin sensitivity. Glucose-stimulated insulin secretion was reduced both in vivo and in islets isolated from Cpt1aPdx1-/-mice relative to control islets. Pancreatic islets from Cpt1aPdx1-/- mice displayed elevations in ALDH1A3, a marker of dedifferentiation, but no reduction in nuclear abundance of the b-cell transcription factors MafA and Nkx6.1 or the GLUT2 glucose transporter. However, intracellular ATP abundance was markedly decreased in islets isolated from Cpt1aPdx1-/- relative to littermate control mice. We conclude that there is an important physiological role for pancreatic CPT1A to maintain whole body glucose homeostasis by supporting glucosestimulated insulin secretion and maintaining intracellular ATP levels in male mice. [ABSTRACT FROM AUTHOR]

Hyperuricemia arises from imbalanced uric acid metabolism, contributing to gout and related chronic diseases. When traditional drugs are used to treat hyperuricemia, side effects are inevitable, which promotes the exploration of new bioactive compounds. Protein hydrolysates and peptides are gradually showing potential in the treatment of hyperuricemia. This study investigated the uric acid inhibitory activity of peptides extracted from Trachurus japonicus using in silico and in vitro methods. We employed in silico virtual enzymolysis and experimental validation to identify bioactive peptides from Trachurus japonicus proteins. Four peptides (DF, AGF, QPSF, and AGDDAPR) were comprehensively screened by molecular docking and database analysis. After solid-phase synthesis, the inhibitory effects of these peptides on hyperuricemia were further verified in vitro and at the cellular level. The results showed that all four peptides have good hyperuricemia-inhibiting activities. Molecular docking and molecular dynamics revealed that peptides DF and AGDDAPR affect the production of uric acid by binding to the active sites of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), and xanthine oxidase (XOD), while peptides QPSF and AGF mainly influence the XOD active site, confirming that it is feasible to rapidly screen hyperuricemia-inhibiting peptides by molecular docking. [ABSTRACT FROM AUTHOR]

Lignocellulosic biomass is a reliable renewable feedstock for citric acid fermentation. Low product titer is the bottleneck in the large scale production of cellulosic citric acid by Yarrowia lipolytica. Herein, multiple genetic engineering strategies were explored to construct an engineered Y. lipolytica strain that can efficiently produce citric acid with a high titer and yield. Genes related to TCA cycles were overexpressed to increase citric acid production. Subsequently, genes in the downstream lipid synthesis pathway were deleted to decrease citric acid consumption. The mitochondrial transporter of isocitric acid was also deleted to minimize by-product secretion. Next, six glucose transporter genes, a hexose kinase gene, and a heterologous 6-phosphofructo-1-kinase gene were tested to enhance the efficiency of citric acid production. Consequently, the optimized engineered strain produced 88.2 g L−1 and 73.6 g L−1 citric acid from a pure sugar medium and 30% solid loading hydrolysate, respectively. Finally, in a 3 L bioreactor, 83.6 g L−1 citric acid was produced from 35% solid loading of corn stover hydrolysate via fed-batch fermentation. In this work, an efficient robust yeast cell method was developed for the production of citric acid in a sustainable manner. [ABSTRACT FROM AUTHOR]

Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses a significant threat to patient survival due to its treatment resistance and rapid recurrence.Current treatment options, including maximal safe surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into the pivotal role of glycolytic metabolic reprogramming in GBM, with a particular focus on the multifaceted roles of lactate, a key metabolic product, within the tumor microenvironment (TME). Lactate has been implicated in promoting tumor cell proliferation, invasion, and immune evasion. Additionally, this review systematically analyzes potential therapeutic strategies targeting key molecules within the glycolytic pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), and the Lactate Dehydrogenase A (LDHA). These studies provide a novel perspective for GBM treatment. Despite progress made in existing research, challenges remain, including drug penetration across the blood-brain barrier, side effects, and resistance. Future research will aim to address these challenges by improving drug delivery, minimizing side effects, and exploring combination therapies with radiotherapy, chemotherapy, and immunotherapy to develop more precise and effective personalized treatment strategies for GBM. [ABSTRACT FROM AUTHOR]

Background: Sepsis-induced cardiomyopathy (SICM) often occurs in the acute phase of sepsis and is associated with increased mortality due to cardiac dysfunction. The pathogenesis remains poorly understood, and no specific treatments are available. Although SICM is considered reversible, emerging evidence suggests potential long-term sequelae. We hypothesized that metabolic and inflammatory cardiac changes, previously observed in acute sepsis as potential drivers of SICM, partially persist in prolonged sepsis. Methods: In 24-week-old C57BL/6J mice, sepsis was induced by cecal ligation and puncture, followed by intravenous fluid resuscitation, subcutaneous analgesics and antibiotics, and, in the prolonged phase, by parenteral nutrition. Mice were killed after 5 days of sepsis (prolonged sepsis, n = 15). For comparison, we included acutely septic mice killed at 30 h (acute sepsis, n = 15) and healthy controls animals (HC, n = 15). Cardiac tissue was collected for assessment of inflammatory and metabolic markers through gene expression, metabolomic analysis and histological assessment. Results: In prolonged sepsis, cardiac expression of IL-1β and IL-6 and macrophage infiltration remained upregulated (p ≤ 0.05). In contrast, tissue levels of Krebs cycle intermediates and adenosine phosphates were normal, whereas NADPH levels were low in prolonged sepsis (p ≤ 0.05). Gene expression of fatty acid transporters and of the glucose transporter Slc2a1 was upregulated in prolonged sepsis (p ≤ 0.01). Lipid staining and glycogen content were elevated in prolonged sepsis together with increased gene expression of enzymes responsible for lipogenesis and glycogen synthesis (p ≤ 0.05). Intermediate glycolytic metabolites (hexose-phosphates, GADP, DHAP) were elevated (p ≤ 0.05), but gene expression of several enzymes for glycolysis and mitochondrial oxidation of pyruvate, fatty-acyl-CoA and ketone bodies to acetyl-CoA were suppressed in prolonged sepsis (p ≤ 0.05). Key metabolic transcription factors PPARα and PGC-1α were downregulated in acute, but upregulated in prolonged, sepsis (p ≤ 0.05 for both). Ketone body concentrations were normal but ketolytic enzymes remained suppressed (p ≤ 0.05). Amino acid metabolism showed mild, mixed changes. Conclusions: Our results suggest myocardial lipid and glycogen accumulation and suppressed mitochondrial oxidation, with a functionally intact Krebs cycle, in the prolonged phase of sepsis, together with ongoing myocardial inflammation. Whether these alterations have functional consequences and predispose to long-term sequelae of SICM needs further research. [ABSTRACT FROM AUTHOR]

The initial interzone cells for synovial joints originate from chondrocytes, but such critical transition is minimally understood. With single-cell RNA sequencing (scRNA-seq) of murine embryonic knee joint primordia, we discovered that heightened expression of glycolysis genes characterized developing interzone cells when compared to flanking chondrocytes. Conditional deletion of the glucose transporters Glut1 and/or Glut3, in either the incipient pre-skeletal mesenchyme with Prx1Cre or in chondrocytes with Col2Cre, disrupted interzone formation dose-dependently. In contrast, deletion of Glut1/3 in established interzone cells with Gdf5Cre did not have similar severe disruption of joint development. scRNA-seq revealed that Glut1/3 deletion by Prx1Cre impeded Tgfβ signaling in the developing interzone cells. Direct elimination of Tgfβ signaling with Prx1Cre partially phenocopied the deletion of Glut1/3 in impairing interzone formation. Tgfβ stimulated glycolysis in chondrocytes via activation of mTOR and Hif1a in vitro. The data support that the essential conversion of chondrocytes to interzone cells requires a transient elevation of glycolysis partly dependent on Tgfβ signaling. [ABSTRACT FROM AUTHOR]

ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer's core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors. [ABSTRACT FROM AUTHOR]

Background: Hepatoblastoma (HB) is the most common malignant solid tumor of the liver in children and is a fatal disease with a poor prognosis. Therefore, indicators that can be used for the early prediction of the HB prognosis are necessary. Sodium glucose cotransporter 2 (SGLT2) is a glucose transporter protein present in the proximal renal tubules. Studies have shown that SGLT2 is associated with the occurrence of tumors and is upregulated in various tumors. Peroxiredoxin 4 (PRDX4) is an antioxidant enzyme with a secretory function and is located in the cytoplasmic endoplasmic reticulum. Recent reports have suggested that it is closely related to the development and prognosis of various cancers. To some degree, this is highly suggestive of the interplay between SGLT2 and PRDX4. Methods: In the present study, clinical data and post-surgical paraffin-embedded specimens from 75 HB patients were collected, and hematoxylin and eosin and immunohistochemical staining of SGLT2 and PRDX4 were used to analyze their expression and correlation with the clinicopathological features and prognosis. Results: We found that low SGLT2 and high PRDX4 expression predicted a significantly shorter survival and worse clinical condition in HB patients. Furthermore, when low SGLT2 expression was combined with high PRDX4 expression, the event-free survival and overall survival were significantly reduced. Univariate and multivariate Cox proportional hazards analyses showed that low SGLT2 and high PRDX4 expression in HB were independent prognostic factors for the survival after surgical resection. Conclusion: The immunohistochemical combination of low SGLT2 and high PRDX4 expression can independently predict a poor prognosis in HB patients. [ABSTRACT FROM AUTHOR]

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the "Drug of Miracles and Wonders," as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: lb analyze the correlation of glucose transporter 4 (GLUT4), leptin receptor (LEPR), and tumour necrosis factor-α (TNF-α) with endometrial receptivity (ER) in patients with polycystic ovarian syndrome (PCOS)-induced infertility to provide clinical evidence for future diagnosis and treatment of PCOS-induced infertility. Methods: We prospectively enrolled 109 study subjects admitted to The Second Hospital Affiliated of Shandong University of Traditional Chinese Medicine from June 2020 to August 2023, including 42 patients with PCOS-induced infertility (research group), 35 nonpregnant patients with simple PCOS (control group), and 32 nonpregnant healthy women (normal group). GLUT4, LEPR, and TNF-α levels in the peripheral blood were detected in all participants, and their diagnostic value for PCOS in healthy women and PCOS-induced infertility in PCOS patients was analyzed. In addition, the endometrial thickness and endometrial blood flow pulsation index (PI) and resistance index (Rl) of patients in the research group were measured. Furthermore, the correlation of GLUT4, LEPR, and TNF-α with ER was discussed. Results: GLUT4 was lower in the research group compared with the control and normal groups, while LEPR and TNF-α were higher (P<0.05); the control group showed lower GLUT4 and higher LEPR and TNF-α levels than the normal group (P<0.05). The diagnostic sensitivity and specificity of GLUT4, LEPR, and TNF-α combined assay for PCOS-induced infertility in PCOS women were 88.57% and 75.00%, respectively, and those for PCOS in healthy women were 78.57% and 60.00%, respectively (P<0.05). In the research group, GLUT4 was positively correlated with endometrial thickness and negatively linked to Rl and PI. At the same time, LEPR and TNF-α were negatively associated with endometrial thickness and positively correlated with Rl and PI (P<0.05). Conclusions: GLUT4, LEPR, and TNF-α are closely related to ER in patients with PCOS-induced infertility, and their combined detection can effectively evaluate the occurrence of PCOS and PCOS-induced infertility. [ABSTRACT FROM AUTHOR]

Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). However, the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment. Herein, the synergistic inhibition of FLS' survival, proliferation, and activation by combining two glucose metabolism inhibitors, diclofenac (DC) and lonidamine (LND) was first verified. Subsequently, DC and LND were individually conjugated to cystamine-modified hyaluronic acid (HA) to prepare two polymer-prodrug conjugates. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (HAP−1NP DC+LND) was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms. Upon targeted uptake by FLS in inflamed joints, HAP−1NP DC+LND released DC and LND within the intracellular reductive microenvironment, where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically. Additionally, the secretion of lactic acid and pro-inflammatory factors from FLS were reduced, thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages. Finally, HAP−1NP DC+LND demonstrated promising efficacy in a mouse model of collagen-induced arthritis (CIA). Overall, this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS. A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system (HAP-1NP DC+LND) is tailored for targeted and synergistic metabolic modulation of FLS, remodeling crosstalk between FLS and pro-inflammatory macrophages for effective RA treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Placental glucose transport is regulated by glucose transporter proteins (GLUTs). The study aimed to examine placental expression of GLUT‐1, GLUT‐3, and GLUT‐4 mRNA in patients with type 1 diabetes, early gestational diabetes (eGDM), and healthy controls, and to investigate correlations between GLUTs expression and clinical parameters. Additionally, we compared placental transcriptome profiles in recruited subgroups. Materials and Methods We recruited 59 pregnant women: 23 with type 1 diabetes, 17 with eGDM, and 19 controls. Patients with diabetes attended follow‐up visits at each trimester. Transcriptome studies were performed in 4 patients per subgroup. Results The mean age was similar across all subgroups. eGDM patients had significantly higher BMI and were predominantly obese. We observed a significant 2‐fold (P = 0.009) decrease in placental GLUT‐3 mRNA expression in the type 1 diabetes and eGDM groups. GLUT‐4 mRNA expression was significantly lower in the eGDM group compared to type 1 diabetes (3‐fold) and controls (6‐fold) (P = 0.007). There was a significant negative correlation between GLUT‐3 (R = −0.29) and GLUT‐4 (R = −0.27) mRNA expression and neonatal birth weight. GLUT‐4 expression was negatively correlated with 1st trimester HbA1c (R = −0.72) and OGTT 120′ (R = −0.82) results in eGDM patients, and 3rd trimester glycemic variability (R = −0.49) in type 1 diabetes. Microarray analysis revealed significant transcriptomic changes, with 45 down‐regulated and 365 up‐regulated genes in type 1 diabetes, and 21 significant changes in eGDM. Conclusions Placental samples from patients with diabetes exhibit changes in GLUTs expression, which correlates with neonatal growth and several glycemic parameters. Additionally, multiple changes in transcriptomic profiles are observed in hyperglycemic patients.

Dual-template epitope imprinted nanoparticles specifically targeting GLUT1 and HK2 separately, achieving inhibition of glucose uptake and HK2 activity for anti-glycolytic tumor-targeted treatment. [Display omitted] • D-MIP synthesized by epitope imprinting can specifically recognize GLUT1 and HK2 simultaneously. • D-MIP can selectively hinder glucose uptake and inhibit HK2 activity. • New therapeutic strategy for tumor metabolism with dual-target regulation of glycolysis. • Precision-targeted therapy of tumors with nontoxic and bioreliable dual-template nanoparticles. Glycolysis provides tumors with abundant nutrients through glucose (Glu) metabolism. As a therapeutic target, precise targeting and effective inhibition of the glycolysis process remains a major challenge in anti-metabolic therapy. In this study, a novel dual-template molecularly imprinted polymer (D-MIP), capable of specifically recognizing glucose transporter member 1 (GLUT1) and hexokinase-2 (HK2) was prepared for anti-glycolytic tumor therapy. The imprinting factors of D-MIP for the recognition of the template molecules, the GLUT1 epitope and the HK2 epitope, were 2.1 and 2.5, respectively, enabling specific recognition of the entire target protein. Targeting GLUT1 with D-MIP could impede its Glu uptake, while simultaneously inhibiting the activity of cytoplasmic HK2, thereby reducing the metabolic rate of Glu. Cell experiments demonstrated that inhibition of HK2 resulted in downregulation of the downstream, products glucose-6-phosphate (6PG) and lactate (LA). In vitro and in vivo experimental results indicated that D-MIP exhibited significant targeting and inhibitory effects on GLUT1 and HK2, respectively, which suppressed tumor glycolysis and induced apoptosis in MCF-7 cells. Furthermore, mouse tumor models and hematoxylin-eosin (H&E) staining confirmed the excellent anti-tumor efficacy and favorable biocompatibility of D-MIP. This work represents the first design and development of a dual-template imprinted polymer targeting key transport channels and metabolic enzymes involved in glycolysis, advancing the research and application of anti-glycolytic tumor therapy. [ABSTRACT FROM AUTHOR]

The preovulatory luteinizing hormone surge is known to increase glucose uptake in ovulating follicles, but the underlying mechanisms have not been explored. Members of the Slc2a family of proteins called glucose transporters mediate glucose uptake in various cell types. Our objective was to characterize the expression pattern and temporal relationship with glucose uptake of the four best-characterized glucose transporters, Slc2a1-4 in mouse ovarian granulosa cells. Analyses of mRNA levels showed that Slc2a1 was induced in granulosa cells with a peak expression at 4h after human chorionic gonadotropin (hCG) treatment. We then examined signaling cascades involved in Slc2a1 expression by pharmacological inhibitors of the ERK1/2 and mTOR pathways. Inhibition of the ERK1/2 pathway by PD0325901 reduced Slc2a1 mRNA abundance demonstrating that the ERK1/2 signaling pathway is required for Slc2a1 expression. Conversely, inhibition of the mTOR pathway with rapamycin increased the Slc2a1 transcript level, which could be attributed to the compensatory hyperactivation of ERK1/2 activity. Bioinformatic analysis followed by chromatin immunoprecipitation showed that the transcription factor Cebpb binds to the Slc2a1 promoter in hCG-stimulated granulosa cells. Finally, the glucose uptake was higher in granulosa cells collected at 4h post-hCG than those collected at 0h hCG. These results indicate that the preovulatory LH surge increases glucose uptake in granulosa cells of the ovulating follicle by inducing Slc2a1 expression through the ERK1/2 pathway and its downstream effector transcription factor Cebpb. [ABSTRACT FROM AUTHOR]

Diabetes is a pandemic disease that causes the loss of control of glucose regulation in the organism, in consequence of dysfunction of insulin production or functionality. In this work, the antidiabetic bioactivity of 182 fractions from 19 cyanobacteria strains derived from the LEGE Culture Collection were analysed using the 2-NBDG assay in zebrafish larvae. From this initial screening, two fractions (57 (06104_D) and 107 (03283_B)) were identified as promising insulin mimetics. These were further characterized by measuring glucose levels in whole larvae, the expression of glucose transporters (GLUT 1–3) using western blot, and the mRNA expression levels of the glut2, pepck, and insa genes using real-time qPCR. Both fractions showed a decrease in free glucose levels. Furthermore, exposure to fraction 06104_D decreased GLUT1 and increased insa mRNA levels. The chemical composition of these fractions was determined using LC-HRESIMS/MS and compared to inactive fractions of the same polarity in order to identify the unique bioactive molecules. The molecular networks constructed using the GNPS platform revealed that fraction 06104_D contained mass clusters primarily composed of chlorins, lipids, and terpenoids, while fraction 03283_B contained xanthophylls, peptides, and terpenoids. To correlate the observed activity with the chemical composition of fraction 06104_D, pheophorbide a was chosen as a representative of chlorophyll derivatives. Exposure to zebrafish larvae at 10 and 20 µM confirmed the increased glucose uptake on the 2-NBDG assay. These findings highlight the bioactivity of chlorophyll derivatives as insulin mimetic compounds, as well as cyanobacteria as a source of potential therapeutic diabetes applications. [ABSTRACT FROM AUTHOR]

Flo8 is a main transcriptional regulator of flocculation and pseudohyphal growth in yeast. Disruption of FLO8 in the popular recombinant protein production host Komagataella phaffii (Pichia pastoris) prevents pseudohyphal growth and reduces cell-to-surface adherence, making the mutant an interesting platform for research and industry. However, knowledge of the physiological impact of the mutation remained scarce. In-depth analysis of transcriptome data from FLO8 -deficient K. phaffii revealed that Flo8 affects genes involved in cell cycle, mating, respiration, and catabolite repression additionally to flocculation targets. One gene with considerably increased expression in flo8 was GTH1 , encoding a high-affinity glucose transporter in K. phaffii. Its promoter (P G1) was previously established as a strong, glucose-regulatable alternative to methanol-induced promoters. P G1 and its improved derivatives P G1 - 3 , D-P GS4 and D-P GS5 , proved to be promising candidates for controlling recombinant protein production in the FLO8 -deficient background. In small-scale screenings, P G1 3 -controlled intracellular EGFP levels were 2.8-fold higher, and yields of different secreted recombinant proteins were up to 4.8-fold increased. The enhanced productivity of the flo8 mutant in combination with the P G1 variants was transferrable to glucose-limited fed-batch processes and could largely be attributed to higher transcriptional activity of the promoter, leading to a much higher productivity per chromosomally integrated gene copy. K. phaffii flo8 has many advantageous characteristics, such as reduced surface growth and increased transcriptional strength of glucose-regulatable promoters. These features turn the flo8 strain into a valuable new base strain for various experimental designs and establish flo8 as an excellent strain background for methanol-free recombinant protein production processes. • The yeast Komagataella phaffii is a powerful host for production of recombinant proteins. • K. phaffii flo8 Δ is an efficient novel background strain for methanol-free production. • Up to 7-fold higher secretion of recombinant proteins controlled by P G1 -promoter variants in K. phaffii flo8 Δ. • Enhanced productivity of the flo8 mutant is due to higher transcriptional activity of the P G1 promoters. • Higher titers per gene copy number enhance strain robustness during production processes. [ABSTRACT FROM AUTHOR]

Emerging evidence recognizes aberrant glycosylation as the malignant characteristics of cancer cells, but little is known about glycogenes' roles in endometrial carcinoma (EC), especially the most aggressive subtype carrying TP53 mutations. Using unsupervised hierarchical clustering, an 11‐glycogene cluster is identified to distinguish an EC subtype associated with frequent TP53 mutation and worse prognosis. Among them, MGAT4A (alpha‐1,3‐mannosyl‐glycoprotein 4‐β‐N‐acetylglucosaminyltransferase A) emerges as the most consistently overexpressed glycogene, contributing to EC aggressiveness. In the presence of galectin‐9, MGAT4A increases EC cell proliferation and invasion via promoting glucose metabolism. N‐glycoproteomics further revealed GLUT1, a glucose transporter, as a glycoprotein modified by MGAT4A. Binding of galectin‐9 to the MGAT4A‐branched N‐glycan on GLUT1 enhances its cell membrane distribution, leading to glucose uptake increase. In addition, oncogenic mutations of TP53 gene in EC cells upregulate MGAT4A expression by disrupting the regulatory oversight exerted by wild‐type p53 on tumor‐suppressive miRNAs, including miR‐34a and miR‐449a/b. The findings highlight a new molecular mechanism involving MGAT4A‐regulated N‐glycosylation on the key regulator of glucose metabolism in p53 mutants‐driven EC aggressiveness, which may provide a strategic avenue to combat advanced EC. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance and type 2 diabetes impair cellular regeneration in multiple tissues including skeletal muscle. The molecular basis for this impairment is largely unknown. Glucose uptake via glucose transporter GLUT4 is impaired in insulin resistance. In healthy muscle, acute injury stimulates glucose uptake. Whether decreased glucose uptake via GLUT4 impairs muscle regeneration is presently unknown. The goal of this study was to determine whether GLUT4 regulates muscle glucose uptake and/or regeneration following acute injury. Methods: Tibialis anterior and extensor digitorum longus muscles from wild-type, control, or muscle-specific GLUT4 knockout (mG4KO) mice were injected with the myotoxin barium chloride to induce muscle injury. After 3, 5, 7, 10, 14, or 21 days (in wild-type mice), or after 7 or 14 days (in control & mG4KO) mice, muscles were isolated to examine [3H]-2-deoxyglucose uptake, GLUT4 levels, extracellular fluid space, fibrosis, myofiber cross-sectional area, and myofiber centralized nuclei. Results: In wild-type mice, muscle glucose uptake was increased 3, 5, 7, and 10 days post-injury. There was a rapid decrease in GLUT4 protein levels that were restored to baseline at 5–7 days post-injury, followed by a super-compensation at 10–21 days. In mG4KO mice, there were no differences in muscle glucose uptake, extracellular fluid space, muscle fibrosis, myofiber cross-sectional areas, or percentage of centrally nucleated myofibers at 7 days post-injury. In contrast, at 14 days injured muscles from mG4KO mice exhibited decreased glucose uptake, muscle weight, myofiber cross sectional areas, and centrally nucleated myofibers, with no change in extracellular fluid space or fibrosis. Conclusions: Collectively, these findings demonstrate that glucose uptake via GLUT4 regulates skeletal myofiber regeneration following acute injury. [ABSTRACT FROM AUTHOR]

This study investigated the effects of dietary 5-hydroxytryptophan (5-HTP) supplementation on growth performance, apparent total tract digestibility (ATTD), blood profile, intestinal morphology, transcriptomics, and microbial composition in weaned piglets. A total of twenty-four 28-day-old weaned piglets (Landrace × Large Yorkshire, 8.28 ± 1.09 kg) were randomly divided into 3 dietary treatments with 8 replicates. The dietary treatments include basal diet (CON), CON diet containing 250 or 500 mg/kg 5-HTP. The results revealed that supplementation with 250 mg/kg 5-HTP significantly increased (P < 0.05) the average daily gain (ADG) and resulted in a lower (P < 0.05) feed conversion ratio (FCR), while also decreased (P < 0.05) the diarrhea rate compared to the CON group. The ATTD of crude protein (CP) was lower in the 500 mg/kg group (P < 0.05) compared with the 250 mg/kg group. Furthermore, supplementation with 5-HTP led to significantly increased (P < 0.05) plasma albumin (ALB) and total protein (TP). In addition, supplementation with 5-HTP, particularly in the 250 mg/kg group, significantly increased (P < 0.05) serum serotonin (5-HT), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, and improved the ratio of villus height to crypt depth in the jejunum and ileum. The transcriptomic analysis revealed that the majority of differentially expressed genes (DEGs) induced by 5-HTP were related to digestion and immunity in the ileum, and 5-HTP enhanced (P < 0.05) intestinal glucose transporter 2 (GLUT2), solute carrier family 1 member 1 (SLC1A1) and solute carrier family 7 member 7 (SLC7A7) mRNA expression in weaned piglets. Furthermore, supplementation with 250 mg/kg 5-HTP increased (P < 0.05) abundance of Firmicutes, Actinobacteriota, Lachnospiracea, Ruminococcaceae and Megasphaera and decreased (P < 0.05) abundance of Spirochaetes and Treponema. Collectively, the study demonstrated that 5-HTP supplementation, particularly at 250 mg/kg, positively impacted growth performance, gut health, and microbiome composition in weaned piglets. These findings suggest the potential of using 5-HTP as a dietary supplement to enhance the health and productivity of weaned piglets. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a risk factor for mucosal homeostasis and enhances the susceptibility to inflammation, in which neutrophils have been increasingly appreciated for their role. Here, barrier disruption and inflammation are observed at oral mucosa (gingiva) of T2D patients and mice. It is demonstrated that neutrophils infiltrate the gingival mucosa of T2D mice and expel obvious neutrophil extracellular traps (NETs), while removal of NETs alleviates the disruption of mucosal barrier. Mechanistically, gingival neutrophils released NETs are dependent of their metabolic reprogramming. Under hyperglycemic condition, neutrophils elevate both glucose incorporation and glycolysis via increased expression of GLUT1. Moreover, significantly increased levels of NETs are observed in local gingival lesions of patients, which are associated with clinical disease severity. This work elucidates a causative link between hyperglycemia and oral mucosal immunopathology, mediated by the altered immuno‐metabolic axis in neutrophil, thereby suggesting a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Summary: The mutualistic interaction between ectomycorrhizal fungi and trees is characterized by the coordinated exchange of soil nutrients with soluble sugars. Despite the importance of this process, the precise mechanism by which sugars are transported from host roots to colonizing hyphae remains unclear.This study aimed to identify the specific membrane transporters responsible for the unloading of sugars at the symbiotic interface, with a focus on the role of the root Sugars Will Eventually Be Exported Transporter (SWEET) uniporters.Our study used RNA sequencing and quantitative PCR to identify PtaSWEET gene expression in Populus tremula × alba–Laccaria bicolor ectomycorrhizal root tips. Our results suggest that symbiosis‐induced PtaSWEET1c is primarily responsible for transporting glucose and sucrose, as demonstrated by the yeast assays. Moreover, we used a promoter‐YFP reporter to confirm the localization of the PtaSWEET1c expression in cortical cells of ectomycorrhizal rootlets, supporting its major role in supplying glucose at the symbiotic interface. Furthermore, our observations confirmed the localization of PtaSWEET1c‐GFP in the plasma membrane. The inactivation of PtaSWEET1c reduced ectomycorrhizal root formation and 13C translocation to ectomycorrhizal roots.Our findings highlight the crucial role of PtaSWEET1c in facilitating glucose and sucrose transport at the symbiotic interface of Populus–L. bicolor symbiosis. [ABSTRACT FROM AUTHOR]

Colon cancer (CC) is the second most common cause of cancer deaths and the fourth most prevalent cancer in the United States. Recently cholesterol metabolism has been identified as a potential therapeutic avenue due to its consistent association with tumor treatment effects and overall prognosis. We conducted differential gene analysis and KEGG pathway analysis on paired tumor and adjacent-normal samples from the TCGA Colon Adenocarcinoma project, identifying that bile secretion was the only significantly downregulated pathway. To evaluate the relationship between cholesterol metabolism and CC prognosis, we used the genes from this pathway in several statistical models like Cox proportional Hazard (CPH), Random Forest (RF), Lasso Regression (LR), and the eXtreme Gradient Boosting (XGBoost) to identify the genes which contributed highly to the predictive ability of all models, ADCY5, and SLC2A1. We demonstrate that using cholesterol metabolism genes with XGBoost models improves stratification of CC patients into low and high-risk groups compared with traditional CPH, RF and LR models. Spatial transcriptomics (ST) revealed that SLC2A1 (glucose transporter 1, GLUT1) colocalized with small blood vessels. ADCY5 localized to stromal regions in both the ST and protein immunohistochemistry. Interestingly, both these significant genes are expressed in tissues other than the tumor itself, highlighting the complex interplay between the tumor and microenvironment, and that druggable targets may be found in the ability to modify how "normal" tissue interacts with tumors. [ABSTRACT FROM AUTHOR]

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Sex differences in brain metabolism and their relationship to neurodegenerative diseases like Alzheimer's are an important emerging topic in neuroscience. Intrinsic anatomic and metabolic differences related to male and female physiology have been described, underscoring the importance of considering biological sex in studying brain metabolism and associated pathologies. The hippocampus is a key structure exhibiting sex differences in volume and connectivity. Adult neurogenesis in the dentate gyrus, dendritic spine density, and electrophysiological plasticity contribute to the hippocampus' remarkable plasticity. Glucose transporters GLUT3 and GLUT4 are expressed in human hippocampal neurons, with proper glucose metabolism being crucial for learning and memory. Sex hormones play a major role, with the aromatase enzyme that generates estradiol increasing in neurons and astrocytes as an endogenous neuroprotective mechanism. Inhibition of aromatase increases gliosis and neurodegeneration after brain injury. Genetic variants of aromatase may confer higher Alzheimer's risk. Estrogen replacement therapy in postmenopausal women prevents hippocampal hypometabolism and preserves memory. Insulin is also a key regulator of hippocampal glucose metabolism and cognitive processes. Dysregulation of the insulin-sensitive glucose transporter GLUT4 may explain the comorbidity between type II diabetes and Alzheimer's. GLUT4 colocalizes with the insulin-regulated aminopeptidase IRAP in neuronal vesicles, suggesting an activity-dependent glucose uptake mechanism. Sex differences in brain metabolism are an important factor in understanding neurodegenerative diseases, and future research must elucidate the underlying mechanisms and potential therapeutic implications of these differences. [ABSTRACT FROM AUTHOR]

It has been shown that the jejunum represents the most important site for the nutrient's absorption in several species. However, in pigs, this information seems to be controversial and limited information are available about differences in intestinal physiology between female and castrated male pigs. The trans-epithelial electrical resistance (TEER) and the active uptake of L-glutamate (L-Glu), L-arginine (L-Arg), L-methionine (L-Met) and D-glucose (D-Glu) in the jejunum and ileum of female (n = 5) and castrated male (n = 7) pigs fed a protein-restricted grower and finisher diet (128 and 112 g of crude protein/kg dry matter) were investigated. The intestine segments were collected at slaughter and mounted in Ussing chambers. Results were further investigated by protein expression analysis of the D-Glu transporter Sodium-dependent Glucose Transporter 1 (SGLT1) and using serum creatinine, non-esterified fatty acids (NEFAs) and serum glucose concentrations measurements as indicators of muscle mass deposition and metabolic status of the animals. A linear mixed-effects regression (Lme4) model was used for data analysis. Independent of sex, the uptake of both L-Met and D-Glu was higher (p < 0.001) in the ileum than in the jejunum (2.1- and 3.6-fold increases, respectively). The L-Arg uptake was higher (p = 0.001) in females compared to castrates (1.9-fold increase). No significant differences were observed between the segments in the SGLT1 protein expression, regardless of sex. Serum measurements were also not significantly different between the female and castrates. This study suggests that the ileum has an important role in the active uptake of amino acids and D-Glu uptake and differences exist between female and castrated finishing pigs. HIGHLIGHTS: The L-Arginine uptake is higher in female compared to castrated pigs. The uptake of L-methionine and D-glucose is higher in the ileum than in the jejunum. The ileum has an important role in the active uptake of amino acids and D-glucose. [ABSTRACT FROM AUTHOR]

Not much is currently known about disturbances in insulin signaling and glucose transport in leukocytes of women with gestational diabetes mellitus (GDM) during and after pregnancy. In this study, the expression of insulin signaling (INSR, IRS1, IRS2 and PIK3R1)- and glucose transporter (SLC2A1, SLC2A3 and SLC2A4)-related genes in the leukocytes of 92 pregnant women was assayed using quantitative RT-PCR. The cohort consisted of 44 women without GDM (NGT group) and 48 with GDM (GDM group) at 24–28 weeks of gestation. GDM women were then tested again one year after childbirth (pGDM group: 14 women (29.2%) with abnormal glucose tolerance (AGT) and 34 women (70.8%) with normoglycemia). The GDM and NGT groups were closely matched for gestational age and parameters of obesity, such as pre-pregnancy body mass index (BMI), pregnancy weight, and gestational weight gain (GWG) (p > 0.05). Compared to the NGT group, the GDM and pGDM groups were hyperglycemic, but the GDM group featured a more highly insulin-resistant condition than the pGDM group, as reflected by higher fasting insulin (FI) levels and the values of the homeostasis model assessment for insulin resistance (HOMA-IR) (p < 0.05). In leukocytes from the GDM and pGDM groups, PIK3R1, SLC2A1, and SLC2A3 were upregulated and IRS1 was downregulated, with a larger magnitude in fold change (FC) values for PIK3R1 and IRS1 in the GDM group and for SLC2A1 and SLC2A3 in the pGDM group. The expression of SLC2A4 was unchanged in the GDM group but upregulated in the pGDM group, where it was inversely correlated with HOMA-IR (rho = −0.48; p = 0.007). Although the INSR and IRS2 levels did not significantly differ between the groups, the IRS2 transcript positively correlated with pregnancy weight, fasting plasma glucose, FI, and HOMA-IR in the GDM group. Our findings indicate that pronounced quantitative changes exist between the GDM and pGDM groups with respect to the expression of certain genes engaged in insulin signaling and glucose transport in leukocytes, with insulin resistance of a variable degree. These data also highlight the relationship of leukocyte SLC2A4 expression with insulin resistance in the postpartum period. [ABSTRACT FROM AUTHOR]

Although single treatment with sodium‐glucose cotransporter‐2 inhibitors (SGLT2i) or vitamin D3 (VD3) inhibited metabolic dysfunction‐associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD3 against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD3, and SGLT2i + VD3 groups. All animals, except the NC group, received high‐fructose/high‐fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high‐fructose/high‐fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD3 (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non‐alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP‐1/PPARγ), oxidative stress (MDA/H2O2), inflammation (IL1β/IL6/TNF‐α), fibrosis (TGF‐β1/α‐SMA), and apoptosis (TUNEL/Caspase‐3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin‐dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti‐inflammatory (IL‐10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD3, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose‐transporting and lipid‐regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD3 co‐therapy against diabetes‐induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti‐inflammatory, anti‐oxidative, and anti‐fibrotic pathways. [ABSTRACT FROM AUTHOR]

Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D. [ABSTRACT FROM AUTHOR]

Background. Several research findings suggest that sodium–glucose co-transporter 1 (SGLT1) is implicated in the progression and control of infections and inflammation processes at the pulmonary level. Moreover, our previous works indicate an engagement of SGLT1 in inhibiting the inflammatory response induced in intestinal epithelial cells by TLR agonists. In this study, we report the anti-inflammatory effects observed in the lung upon engagement of the transporter, and upon the use of glucose and BLF501, a synthetic SGLT1 ligand, for the treatment of animal models of lung inflammation, including a model of allergic asthma. Methods. In vitro experiments were carried out on human pneumocytes stimulated with LPS from Pseudomonas aeruginosa and co-treated with glucose or BLF501, and the production of IL-8 was determined. The anti-inflammatory effect associated with SGLT1 engagement was then assessed in in vivo models of LPS-induced lung injury, as well as in a murine model of ovalbumin (OVA)-induced asthma, treating mice with aerosolized LPS and the synthetic ligand. After the treatments, lung samples were collected and analyzed for morphological alterations by histological examination and immunohistochemical analysis; serum and BALF samples were collected for the determination of several pro- and anti-inflammatory markers. Results. In vitro experiments on human pneumocytes treated with LPS showed significant inhibition of IL-8 production. The results of two in vivo experimental models, mice exposed to aerosolized LPS and OVA-induced asthma, revealed that the engagement of glucose transport protein 1 (SGLT1) induced a significant anti-inflammatory effect in the lungs. In the first model, the acute respiratory distress induced in mice was abrogated by co-treatment with the ligand, with almost complete recovery of the lung morphology and physiology. Similar results were observed in the OVA-induced model of allergic asthma, both with aerosolized and oral BLF501, suggesting an engagement of SGLT1 expressed both in intestinal and alveolar cells. Conclusions. Our results confirmed the engagement of SGLT1 in lung inflammation processes and suggested that BLF501, a non-metabolizable synthetic ligand of the co-transporter, might represent a drug candidate for therapeutic intervention against lung inflammation states. [ABSTRACT FROM AUTHOR]

【Objective】Microbial production of L-malic acid is currently an extremely efficient producing method. In order to reveal the biosynthetic mechanism of L-malic acid production by Aspergillus niger, the differential changes of key genes in the metabolic regulation process were explored with the help of transcriptomic analysis.【Method】The acid production level of MA-1 strain reached 88.27 g/L at 144 h of fermentation, and three time points (48, 72, and 120 h) with different acid production rates were selected for transcriptome analysis.【Result】 GO analysis showed that the regulation of biological processes, RNA binding and ribosome-related secondary entries under the significant genes were the most differentiated and the largest number. Transcriptome analysis revealed that transcriptional regulators such as HacA, Ace1, and Rpn4 were consistently at high levels during fermentation from 48 to 120 h, with FPKM values reaching 20181.64-94573.00, and that glucose transporter protein (Rco-3), and ketoglutarate/malate transporter protein Yhm1 showed relatively high transcript levels, with FPKM values reaching 4971.83-6 575.46; in the glycolytic EMP pathway, its important rate-limiting enzyme pyruvate kinase (FPKM values of 13109.15- 25649.30) and ANI_1_1984024 among the six hexokinase enzymes (FPKM values up to 4111.68-7325.43) showed relatively high transcript levels, and then the pathway for the conversion from glucose to pyruvate. The transcript levels of other enzymes in the glucose-to- pyruvate pathway showed a decreasing trend at 120 h. The transcript levels of the whole genes in the TCA cycle were maintained at a high level to provide sufficient energy for cellular metabolism, and the highest level of citrate synthase in the rTCA pathway, followed by malate dehydrogenase, and the level of the glyoxylate cycle was low.【Conclusion】The main pathways of L-malate synthesis in A. niger MA-1 strain were presumed to be rTCA and pyruvate carboxylation pathway. [ABSTRACT FROM AUTHOR]

Background: Renoprotective effects of sodium glucose transporter 2 (SGLT2) inhibitors, including dapagliflozin, were observed in randomized controlled trials (RCTs). The suspected underlying mechanism is a correction of hyperfiltration, observed as an "initial dip". Whether SGLT2 inhibitors can attenuate the rate of decline in the estimated glomerular filtration rate (eGFR) in clinical settings, even when considering the pre-treatment decline rate, is unknown. Although several RCTs identified an association between the initial dip and long-term renal prognoses, a conclusion has not been reached. Methods: We collected the eGFR data of patients for whom dapagliflozin was initiated in our hospital and then calculated their eGFR slopes before and after the start of the treatment. We investigated the changes in the eGFR slopes (ΔeGFR slope) and the association between the ΔeGFR slope and the initial dip. Risks for rapid eGFR decliners (eGFR slope < − 3 mL/min/1.73 m2/year) were also examined. Results: The eGFR slope was significantly milder after dapagliflozin treatment (p < 0.01). A deeper initial dip was associated with a milder rate of eGFR decline (adjusted beta: − 0.29, p < 0.001). Dapagliflozin treatment reduced the proportion of rapid eGFR decliners from 52.9 to 14.7%, and a smaller initial dip was identified as a significant risk for post-treatment rapid eGFR decline (adjusted odds ratio: 1.73, p < 0.05). Conclusions: Compared to before the administration of dapagliflozin, the rate of eGFR decline was significantly milder after its administration. The initial dip was significantly associated with long-term renoprotective effects and may be a useful predictor of treatment response. [ABSTRACT FROM AUTHOR]

1. Two experiments were conducted, the first was to investigate the effect of increasing digesta viscosity by dietary carboxymethyl cellulose (CMC) on the growth performance and intestinal morphology and characteristics of healthy birds. The second experiment evaluated the impact of increased digesta viscosity in birds during an Eimeria spp. challenge. 2. In experiment 1, a corn-soybean meal-based basal diet was supplemented with 0, 10 or 20 g/kg CMC at the expense of cornstarch and offered to seven birds in each of eight replicate cages per diet from d 8 to 22 post hatching. 3. Increasing digesta viscosity due to dietary CMC linearly reduced (p < 0.05) body weight (BW) gain and the apparent ileal digestibility of nutrients. The relative lengths of the duodenum, jejunum and ileum linearly increased (p < 0.01) with dietary CMC inclusion. 4. In experiment 2, on d 14, 256 broiler chickens were randomly assigned to eight replicate cages in a 2 × 2 factorial arrangement of treatments with two CMC concentrations (0 or 10 g CMC/kg of diet), with or without an Eimeria challenge. On d 15, birds in the challenge groups were orally gavaged with a 1 ml solution containing 25,000, 25,000 or 125,000 oocysts of E. maxima, E. tenella and E. acervulina; or 1% PBS, respectively. 5. Increasing digesta viscosity in Eimeria-challenged birds decreased the total tract digestibility of dry matter and gross energy (p < 0.05). The ileal gene expression of glucose transporters was upregulated (p < 0.05) in challenged birds that received the CMC-supplemented diet. 6. In summary, increased digesta viscosity induced changes in the expression of nutrient transporter genes and decreased nutrient utilisation in Eimeria-challenged birds. [ABSTRACT FROM AUTHOR]

Hyperglycaemia is one condition related to inflammation leading to insulin signalling impairment. This study was conducted to investigate the insulin sensitivity improvement of Sambiloto (Andrographis paniculata (Burm. f.)) Nees extract in insulin resistance-induced HepG2 (IR-HepG2) cells by stimulating insulin sensitivities and inhibiting inflammatory response. Sambiloto extract at 2 µg/mL revealed glucose uptake stimulation and up-regulating GLUT-2 and IRS-1 gene expression, and inhibited pro-inflammatory cytokine IL-6 gene expression in IR-HepG2 cells. Phytochemical analysis showed that the total phenolic level and andrografolide content of Sambiloto extract were 2.91 ± 0.04% and 1.95%, respectively. This result indicated that Sambiloto extract ameliorated insulin resistance in high glucose-induced IR-HepG2 cells via modulating the IRS-1/GLUT-2 pathway due to IL-6 inhibition. These findings suggested that Sambiloto extract had potency as an anti-inflammatory and insulin-resistance improvement in IR-HepG2 cells. [ABSTRACT FROM AUTHOR]

The poor prognosis of triple‐negative breast cancer (TNBC) results from its high metastasis, whereas inflammation accompanied by excessive reactive oxygen species (ROS) is prone to aggravate tumor metastasis. Although photothermal therapy (PTT) has extremely high therapeutic efficiency, the crafty tumor cells allow an increase in the expression of heat shock proteins (HSPs) to limit its effect, and PTT‐induced inflammation is also thought to be a potential trigger for tumor metastasis. Herein, myricetin, iron ions, and polyvinylpyrrolidone were utilized to develop nanomedicines by self‐assembly strategy for the treatment of metastatic TNBC. The nanomedicines with marvelous water solubility and dispersion can inhibit glucose transporter 1 and interfere with mitochondrial function to block the energy supply of tumor cells, achieving starvation therapy on TNBC cells. Nanomedicines with excellent photothermal conversion properties allow down‐regulating the expression of HSPs to enhance the effect of PTT. Interestingly, the broad spectrum of ROS scavenging ability of nanomedicines successfully attenuates PTT‐induced inflammation as well as influences hypoxia‐inducible factors‐1α/3‐phosphoinositide‐dependent protein kinase 1 related pathway through glycometabolism inhibition to reduce tumor cell metastasis. Moreover, the nanomedicines have negligible side effects and good clinical application prospects, which provides a valuable paradigm for the treatment of metastatic TNBC through glycometabolism interference, anti‐inflammation, starvation, and photothermal synergistic therapy. [ABSTRACT FROM AUTHOR]

Mimosa pudica)M(and Abutilon indicum)A(are used as an antidiabetic mixture at a ratio of 1:1)MA11(in traditional Thai medicine. However, the mechanisms by which these plants exhibit antidiabetic effects have not been clearly elucidated. In this study, RINm5F insulinoma cells were treated with 6 mM streptozotocin (STZ) for 1 h to induce cellular damage and generate an in vitro model of diabetes. Extracts from M and A and mixtures of M and A extracts contain several phytochemicals, including flavonoids, tannins and saponins. All the extract samples at a concentration of 1,000 µg/mL exhibited antioxidant activity without cytotoxicity to RINm5F and L6 myotube cells. Pretreatment with M or A or with a mixture of the two prevented STZ-induced RINm5F cell death in a concentration-dependent manner. The greatest recovery effect was found in MA12, followed by MA11 and MA21. In addition, the M and A extracts and the mixtures of M and A extracts (100,000 μg/mL) exhibited insulin secretory activity in RINm5F cells that was similar to that of glibenclamide. Furthermore, all the plant extracts induced glucose uptake in L6 myotube cells. The induction of glucose uptake by M, A, and mixtures of M and A was derived from the upregulation of GLUT1 and GLUT4 synthesis in L6 myotube cells. These results indicate that M. pudica and A. indicum are potential sources of antidiabetic agents. In conclusion, the antidiabetic formula of M and A at a ratio of 2:1 (MA21) has the greatest potential for therapeutic use as an antidiabetic herbal mixture. [ABSTRACT FROM AUTHOR]

Administering propolis delays the liver's release into the bloodstream and stimulates insulinsensitive glucose transporters. The purpose of this study is to assess propolis' impact on insulin resistance in mice that are PCOS model users. The control group design was restricted to post-test in laboratory experimental research. Twenty-five female Wistar rats, three months old, weighing between 100 and 130 grams, were utilised as research subjects in this study. The rats were in good health, had normal activity levels, had normal vaginal swabs, were not pregnant, and had no anatomical abnormalities. Groups K1 (negative control), K2 (positive control PCOS), P1 (PCOS + propolis 50 mg/kgBW), P2 (PCOS + propolis 100 mg/kgBW), and P3 (PCOS + propolis 200 mg/kgBW) were the five groups into which the subjects were split. kgBB). After a 21-day High Fat, High Fructose (HFHF) diet and intramuscular testosterone propionate (1.8 mg/kgBW) injection, the treatment group received propolis interventions at doses of 50 mg/kgBW (P1), 100 mg/kgBW (P2), and 200 mg/kgBB (P3) for 14 days. On the 36th day GDP, insulin, HOMA-IR, and HOMA-B values were measured. The data obtained were analysed with One-way ANOVA and the Kruskal-Wallis test and p<0.001 values were regarded as statistically significant. Propolis treatment significantly (p<0.001) lowers the levels of FBS and HOMA-IR (p<0.05), raises insulin levels and dramatically (p<0.001) raises HOMA-ß values. The highest effective dose of propolis that significantly reduced insulin resistance in PCOS mice was 100 mg/kgBW. The study concluded that in PCOS model mice, propolis significantly reduced insulin resistance. [ABSTRACT FROM AUTHOR]