Enhanced Glucose Metabolism Research Articles

Enhanced glucose metabolism mediated by CD147 is associated with 18 F-FDG PET/CT imaging in lung adenocarcinoma.

BackgroundLung adenocarcinoma (LUAD) is one of the most deadly thoracic tumors. Reprogrammed glycolytic metabolism is a hallmark of cancer cells and significantly affects several cellular functions. In the current study, we aimed to investigate cluster of differentiation 147 (CD147)‐mediated glucose metabolic regulation in LUAD and its association with 18F‐FDG PET/CT imaging.MethodsThe expression profile and prognostic potential of CD147 in LUAD were analyzed using UALCAN and a Kaplan‐Meier plotter. Tissue immunohistochemical analyses and PET metabolic parameters were used to identify the relationship between CD147 expression and reprogrammed glycolysis. The role of CD147 in glucose metabolic reprogramming was assessed by radioactive uptake of 18F‐FDG through γ‐radioimmunoassays in vitro and micro‐PET/CT imaging in vivo. Western blotting assays were used to determine the expression level of monocarboxylate transporter 1 (MCT1) and MCT4 in established human LUAD cell lines (ie, HCC827 and H1975) with different CD147 expression levels via lentiviral transduction.ResultsCD147 was highly expressed in LUAD. A significant positive correlation existed between CD147 expression and PET metabolic parameters(SUVmax,SUVmean, SUVpeak). CD147 could promote radioactive uptake of 18F‐FDG in vitro and in vivo, suggesting the ability of CD147 to enhance glycolytic metabolism. Furthermore, as an obligate chaperone for MCT1 and MCT4, CD147 positively correlated with MCT1 and MCT4 expression in LUAD tissues and established cell lines with different CD147 expression.ConclusionsOur study revealed that CD147 is a promising novel target for LUAD treatment and CD147‐mediated glucose metabolism demonstrated its contribution to the predictive role of 18F‐FDG PET/CT imaging for targeted therapeutic efficacy.

Glycoconjugation as a Promising Treatment Strategy for Psoriasis.

Despite the progress in the development of novel treatment modalities, a significant portion of patients with psoriasis remains undertreated relative to the severity of their disease. Recent evidence points to targeting the glucose transporter 1 and sugar metabolism as a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases. In this review, we discuss glycoconjugation, an approach that facilitates the pharmacokinetics of cytotoxic molecules and ensures their preferential influx through glucose transporters. We propose pathways of glycoconjugate synthesis to increase effectiveness, cellular selectivity, and tolerability of widely used antipsoriatic drugs. The presented approach exploiting the heightened glucose requirement of proliferating keratinocytes bears the potential to revolutionize the management of psoriasis. SIGNIFICANCE STATEMENT: Recent findings concerning the fundamental role of enhanced glucose metabolism and glucose transporter 1 overexpression in the pathogenesis of psoriasis brought to light approaches that proved successful in cancer treatment. Substantial advances in the emerging field of glycoconjugation highlight the rationale for the development of glucose-conjugated antipsoriatic drugs to increase their effectiveness, cellular selectivity, and tolerability. The presented approach offers a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases.

MUC1 promotes glycolysis through inhibiting BRCA1 expression in pancreatic cancer.

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.

Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma.

From a metabolic perspective, cancer may be considered as a metabolic disease characterized by reprogrammed glycolytic metabolism. The aim of the present study was to investigate CD147-mediated glucose metabolic regulation in hepatocellular carcinoma (HCC) and its contribution to altered immune responses in the tumor microenvironment. Several HCC cell lines and corresponding nude mice xenografts models differing in CD147 expressions were established to directly investigate the role of CD147 in the reprogramming of glucose metabolism, and to determine the underlying molecular mechanisms. Immunohistochemistry (IHC) analyses and flow cytometry were used to identify the relationship between reprogrammed glycolysis and immunosuppression in HCC. Upregulated CD147 expressions were found to be associated with enhanced expressions of GLUT1, MCT1 in HCC tumorous tissues. CD147 promoted the glycolytic metabolism in HCC cell lines in vitro via the PI3K/Akt/mTOR signaling pathway. A positive correlation existed between a profile of immunosuppressive lymphocytes infiltration and CD147 expression in HCC tissues. Accumulation of FOXP3-expressing regulatory T cells was induced under a stimulation with lactate in vitro. In conclusion, CD147 promoted glycolytic metabolism in HCC via the PI3K/Akt/mTOR signaling pathway, and was related to immunosuppression in HCC.

KDM4B facilitates colorectal cancer growth and glucose metabolism by stimulating TRAF6-mediated AKT activation

BackgroundHistone lysine demethylase 4B (KDM4B) has been implicated in various pathological processes and human diseases. Glucose metabolism is the main pattern of energy supply in cells and its dysfunction is closely related to tumorigenesis. Recent study shows that KDM4B protects against obesity and metabolic dysfunction. We realized the significant role of KDM4B in metabolism. However, the role of KDM4B in glucose metabolism remains unclear. Here, we sought to delineate the role and mechanism of KDM4B in glucose metabolism in colorectal cancer (CRC).MethodsWe first analyzed the role of KDM4B in glucose uptake and CRC growth. We then investigated the consequences of KDM4B inhibition on the expression of GLUT1 and AKT signaling, also explored the underlying mechanism. Finally, we detected the mechanism in vivo and assessed the potential correlation between the expression of KDM4B and CRC prognosis.ResultsWe found that KDM4B promoted glucose uptake and ATP production by regulating the expression of GLUT1 via the AKT signaling pathway. KDM4B could interact with TRAF6 and promote TRAF6-mediated ubiquitination of AKT for AKT activation. Furthermore, we demonstrated that KDM4B was overexpressed in CRC specimens and high level of KDM4B was associated with a poor survival rate in CRC patients.ConclusionsThese findings reveal that KDM4B plays an important role in promoting CRC progression by enhancing glucose metabolism.

Three-Dimensional Graphene Enhances Neural Stem Cell Proliferation Through Metabolic Regulation.

Graphene consists of two-dimensional sp2-bonded carbon sheets, a single or a few layers thick, which has attracted considerable interest in recent years due to its good conductivity and biocompatibility. Three-dimensional graphene foam (3DG) has been demonstrated to be a robust scaffold for culturing neural stem cells (NSCs) in vitro that not only supports NSCs growth, but also maintains cells in a more active proliferative state than 2D graphene films and ordinary glass. In addition, 3DG can enhance NSCs differentiation into astrocytes and especially neurons. However, the underlying mechanisms behind 3DG's effects are still poorly understood. Metabolism is the fundamental characteristic of life and provides substances for building and powering the cell. Metabolic activity is tightly tied with the proliferation, differentiation, and self-renewal of stem cells. This study focused on the metabolic reconfiguration of stem cells induced by culturing on 3DG. This study established the correlation between metabolic reconfiguration metabolomics with NSCs cell proliferation rate on different scaffold. Several metabolic processes have been uncovered in association with the proliferation change of NSCs. Especially, culturing on 3DG triggered pathways that increased amino acid incorporation and enhanced glucose metabolism. These data suggested a potential association between graphene and pathways involved in Parkinson's disease. Our work provides a very useful starting point for further studies of NSC fate determination on 3DG.

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1

BackgroundProtein kinase D1 (PKD1) is a serine–threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance.MethodsPKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes.ResultsPKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations.ConclusionThis study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.

The influence of PFK-II overexpression on neuroblastoma patients\u2019 survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4

Background/AimDuring cancer progression metabolic reprogramming is observed in parallel to the alternation in transcriptional profiles of malignant cells. Recent studies suggest that metabolic isoenzymes of phosphofructokinase II (PFK-II) – PFKFB3 and PFKFB4, often induced in hypoxic environment, significantly contribute to enhancement of glucose metabolism and in consequence cancer progression.Materials and methodsUsing the publicly available data deposited in the R2 data base we performed a Kaplan–Meyer analysis for cancer patients divided into groups with high and low expression levels of PFKFB3/4, determined based on the median.ResultsOur data showed that high PFKFB3/4 expression significantly correlates with shorter overall survival in several cancers. Moreover, we found that neuroblastoma patients with poor overall survival and evidence free survival are characterized by high PFKFB3 and at the same time low PFKFB4 expression, whereas patients with high PFKFB4 expressions are characterized by significantly better overall survival/evidence free survival rates.ConclusionOur analysis clearly indicates that expression of PFKFB3/4 isoenzymes may have a key prognostic value for several cancers. What’s more, it seems that in neuroblastoma the prognostic value of PFK-II may be dependent on the relation between PFKFB3 and PFKFB4 isoenzyme expression, indicating that further studies analyzing the role of both cancer specific PFK-II isoenzymes are highly desired.

LncRNA-XIST/microRNA-126 sponge mediates cell proliferation and glucose metabolism through the IRS1/PI3K/Akt pathway in glioma.

Abnormal glucose metabolism may contribute to cancer progression. Glioma represents a cancer resulting from an imbalance between glucose metabolism and tumor growth. However, the molecular mechanisms responsible for dysregulated brain glucose metabolism and lactate accumulation in glioma remain to be elucidated. The present study identified a long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) as a candidate to mediate glucose metabolism in glioma. Cell viability, migration, invasion, and resistance to apoptosis were evaluated in lncRNA-XIST-depleted glioblastoma cells by short hairpin RNA. Glucose uptake, lactate production, as well as levels of glucose transporter 1 (GLUT1) and GLUT3, were measured. Luciferase assay, RNA pull-down, and RNA immunoprecipitation were performed to validate the interactions among lncRNA-XIST, microRNA-126 (miR-126), and insulin receptor substrate 1 (IRS1). An in vivo analysis was carried out in nude mice bearing glioblastoma cell xenografts. The study found that lncRNA-XIST knockdown inhibited cell viability, migration, invasion, resistance to apoptosis, and glucose metabolism of glioblastoma cells. LncRNA-XIST functioned as a competing endogenous RNA of miR-126 and then regulated IRS1/PI3K/Akt pathway in glioblastoma cells. In vivo results demonstrated lncRNA-XIST knockdown reduces the tumorigenicity of glioblastoma cells. Taken together, we demonstrated a novel cellular mechanism that was dependent of the lncRNA-XIST/miR-126/IRS1/PI3K/Akt pathway in enhanced glucose metabolism in glioma.

Abstract 4367: Protein kinase D1 induces metabolic switch in pancreatic cancer via modulation of mTORC1

Abstract Objective: Pancreatic cancer (PanCa) is the third most common cause of cancer-related deaths in the US. Protein Kinase D1 (PKD1) is a kinase molecule which is involved in various important cellular signaling processes. While PKD1 has been reported to play a role in PanCa progression, the molecular mechanisms involved have not been adequately studied. Herein, we investigate the underlying mechanisms which enable PKD1 in enhancing glucose metabolism and further contribute to PanCa aggressiveness. Methods: PanCa cells with high PKD1 expressing (Panc-1 and AsPC-1) and low PKD1 (HPAF-II and BXPC-3) were used in the study. Immunohistochemistry and confocal immunofluorescence were performed to analyze the expression of PKD1 in pancreatic cancer/normal tissues and cells, respectively. The effect of PKD1 gain/loss-in function was investigated on glucose uptake and lactate production in PanCa cells using commercially available kits. Western blotting and real-time PCR experiments were performed to analyze the expression of protein and mRNA levels. MTT assay was conducted to access the influence of PKD1 on cell proliferation. Boyden chamber migration assay and Matrigel invasion assays were performed to determine the migratory and invasive abilities of PanCa cells. The gene silencing was performed using specific siRNAs in the study. Results: Our results demonstrate that PKD1 upregulates glucose metabolism in PanCa cells as indicated by enhanced glucose consumption and lactate production. The invasive characteristics of PKD1 expressing cells are augmented in presence of L-Lactate and reduced in presence of 2DG. PKD1 overexpression demonstrated enhanced phosphorylation of mTOR (ser-2448), 4EBP1, s6kinase and AKT, suggesting the role of PKD1 in the activation of mTOR pathway. We further observed that the phosphorylation of mTOR (ser-2448) and ps6kinase was attenuated on silencing PKD1 or in presence of Rapamycin, suggesting the role of PKD1 in activation of mTORC1 complex, both being the main effectors of mTORC1. Additionally, the inhibition in the phosphorylation of mTOR (ser-2448) in presence of kinase dead PKD1 suggests that PKD1 phosphorylates/activates mTORC1 in PanCa. Decrease in glucose uptake and lactate production in presence of PKD1 overexpression was observed on silencing raptor but not rictor in the cells, further suggesting the involvement of mTORC1 in PKD1 induced metabolic reprogramming in PanCa. PKD1 induced enhanced phosphorylation of mTOR resulted in an activation of HIF-1α and Glut-1 proteins, involved in abberant glucose metabolism. Additionally, our results also demonstrate that altered glucose metabolism leads to chemoresistance and silencing of PKD1 expression sensitizes PanCa cells to gemcitabine. Conclusion: Our studies indicate that PKD1 acts as a key regulator of the glucose metabolism via mTOR activation and facilitates proliferation and invasion of PanCa cells. Citation Format: Sonam Kumari, Sheema Khan, Murali Yallapu, Subhash Chauhan, Meena Jaggi. Protein kinase D1 induces metabolic switch in pancreatic cancer via modulation of mTORC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4367.

Relationships between hypoxia induced factor-1α and 18F-FDG PET/CT parameters in colorectal cancer

AimThe hypoxia-inducible factor 1 (HIF-1) has a critical role in oxygen homeostasis and it is a transcriptional activator of angiogenesis, erythropoiesis, iron and glucose metabolism. Glucose metabolism rate is increased in some tumours via HIF-1α. Our aim is to evaluate the relationship between hypoxia in colorectal cancer, PET parameters, necrotic tissue size and pathologic prognostic factors via using HIF-1α. Materials/Methods70 patients (28female/42male; median age: 63 years) who were diagnosed with colorectal cancer via biopsy were staged with preoperative PET/CT and operated subsequently. Immunohistochemical evaluation scoring was done according to nuclear HIF-1α expression, staining density and intensity.Metabolic tumour volume (MTV), total lesion glycolysis (TLG) and tumour volume (TV) were calculated by using volume of an ellipsoid formula via CT images, and percentage of tumour necrosis (%TmNcr) that was calculated by the difference between TV and recorded MTV. ResultsThere was a moderately meaningful positive correlation between tumour SUVmax and TV and %TmNcr (r=0.403, p=0.001 and r=0.500, p=0.0001, respectively). There were no statistically significant relationships between HIF-1α expression levels and tumour SUVmax, TLG, MTV, TV, %TmNcr, tumour stage, lymphovascular invasion, perineural invasion and extracapsular/capsular lymph node involvement. On the other hand, strong nuclear immunohistochemical staining was seen in tumour cells adjacent to invasive border, inflammatory cells. Although not statistically significant, moderate or strong nuclear staining were seen in 64.9% of metastatic patients. ConclusionAlthough the presence of a positive correlation between tumour SUVmax and %TmNcr shows that there are hypoxic cells in cancer tissue with high FDG uptake, the relationship between the presence of HIF-1α and enhanced glucose metabolism and pathological prognostic factors of tumour was not shown. Strong nuclear immunohistochemical staining in tumour cells adjacent to invasive border and inflammatory cells leads us to believe that HIF-1α plays a role in the invasion area of tumour microenvironment.

Islet β-cell-produced NUCB2/nesfatin-1 maintains insulin secretion and glycemia along with suppressing UCP-2 in β-cells.

Nesfatin-1 is a hypothalamic anorexigenic peptide processed from nucleobindin 2 (NUCB2). Central and peripheral administration of NUCB2/nesfatin-1 enhances glucose metabolism and insulin release. NUCB2/nesfatin-1 is also localized in pancreatic islets, while its function remains unknown. To explore the role of pancreatic β-cell-produced NUCB2/nesfatin-1, we developed pancreatic β-cell-specific NUCB2 knockout (βNUCB2 KO) mice and NUCB2 gene knockdown (shNUCB2) MIN6 β-cell line. In βNUCB2 KO mice, casual blood glucose was elevated from 12weeks of age. In a glucose tolerance test at 12weeks, insulin secretion at 15min was reduced and blood glucose at 2h increased in βNUCB2 KO mice fasted 8h. In islets isolated from βNUCB2 KO mice, high glucose-stimulated insulin secretion (GSIS) was impaired. In shNUCB2 MIN6 cells, GSIS was reduced and UCP-2 mRNA expression was elevated. These results show impaired GSIS possibly associated with UCP-2 overexpression in NUCB2-silenced β-cells, suggesting that β-cell-produced NUCB2/nesfatin-1 maintains GSIS and thereby glycemia.

Drug repurposing in alternative medicine: herbal digestive Sochehwan exerts multifaceted effects against metabolic syndrome

New drug development is a challenging process that requires high-risk, huge costs and long lead times. Therefore, drug repurposing is considered a strategic and economic way towards successful drug development. Sochehwan (SCH) is a herbal formula well known as a digestive aid in traditional oriental medicine, is referred to in classic medical texts, and is available as an over-the-counter drug for indications of digestive ailments. Interestingly, another medical text written in earlier age describes different indication of SCH yet to be examined. We conducted a series of investigations using maturated adipocytes, free fatty acid (FFA) induced hepatic steatosis model in vitro and high-fat diet (HFD) mice model in vivo. Exposure to SCH regulated expression of adipogenic genes and proteins, significantly inhibiting formation of lipid droplets in 3T3-L1 cells. Similarly, SCH treatment modulated proteins related with energy metabolism decreasing lipid accumulation in FFA induced HepG2 cells. Furthermore, HFD-fed c57BL/6 J mice supplemented with SCH exhibited significant changes in serum glucose and lipid profiles. Histologic analysis of mice liver and adipose tissue showed that SCH administration attenuated hepatic steatosis and hypertrophy of adipose tissue. In overall, the results show that SCH can potentially be used to treat metabolic syndrome (MetS) by enhancing glucose metabolism and inhibiting lipogenesis through activating AMP-activated protein kinase (AMPK) and its downstream signaling. Furthermore, it seems to be a feasible drug repurposing strategy for drugs originating from alternative medicine to revise the value for buried indications of some herbal prescription in old traditional Chinese Medicine (TCM) classics.

Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U-13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 μmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 μmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 μmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 μmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 μmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.

Autophagy Regulation of Metabolism Is Required for CD8+ T Cell Anti-tumor Immunity

Autophagy is a cell survival process essential for theregulation of immune responses to infections. However, the role of Tcell autophagy in anti-tumor immunity is less clear. Here, we demonstrate a cell-autonomous role for autophagy in the regulation of CD8+ T-cell-mediated control of tumors. Mice deficient for the essential autophagy genes Atg5, Atg14, or Atg16L1 display a dramatic impairment in the growth of syngeneic tumors. Moreover, Tcells lacking Atg5 have a profound shift to an effector memory phenotype and produce greater amounts of interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α). Mechanistically, Atg5-/- CD8+ Tcells exhibit enhanced glucose metabolism that results in alterations in histone methylation, increases in H3K4me3 density, and transcriptional upregulation of both metabolic and effector target genes. Nonetheless, glucose restriction is sufficient to suppress Atg5-dependent increases in effector function. Thus, autophagy-dependent changes in CD8+ Tcell metabolism directly regulate anti-tumor immunity.

Effect of the Combination of Whole-Body Neuromuscular Electrical Stimulation and Voluntary Exercise on Metabolic Responses in Human.

PurposeSince neuromuscular electrical stimulation (NMES) can recruit high-threshold motor units and enhance glucose metabolism, the combination of NMES and voluntary low-intensity exercise would induce both anerobic and aerobic energy consumptions and this type of exercise could be more efficient and effective than conventional exercise regimens. We aimed to investigate metabolic responses and muscle fatigue during whole body NMES (WB-NMES), voluntary exercise, and their combination.MethodsThe blood lactate concentration and maximal voluntary contraction were measured before and after specified exercises: WB-NMES (E), voluntary exercise (V), and their combination (VE), and expired gas was sampled during the exercises in thirteen healthy young men. Each exercise was conducted for 15 min and interval between exercise was > 48h.ResultsEnergy expenditure and relative to the body mass during VE were significantly higher than during V and E (p < 0.05). The Respiratory gas exchange ratio (RER) during both E and VE was higher than during V (p < 0.05), and the blood lactate concentration after VE was significantly higher than after V and E (p < 0.05). Although relative to the body mass was 18.6 ± 3.1 ml/min/kg and the metabolic equivalent was 5.31 ± 0.89 Mets, the blood lactate concentration reached 7.5 ± 2.7 mmol/L after VE.ConclusionThese results suggest that the combination of WB-NMES and voluntary exercise can enhance the metabolic response to a level equivalent to high intensity exercise under the net physiological burden of low-middle intensity exercises.

Ajuba overexpression regulates mitochondrial potential and glucose uptake through YAP/Bcl-xL/GLUT1 in human gastric cancer

Ajuba dysregulation has been reported in several human cancers. However, its expression patterns and biological roles in human gastric cancers have not yet been characterized. In the current study, we found that Ajuba protein was increased in gastric cancer tissues and in cell lines. High Ajuba expression positively correlated with the tumor-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis. The Cancer Genome Atlas (TCGA) and Oncomine microarray data mining also suggested that Ajuba mRNA upregulation in gastric cancer tissues. We used SGC-7901 and NCI-N87 cell lines for Ajuba overexpression and siRNA knockdown respectively. MTT and colony formation assays indicated that Ajuba overexpression increased proliferation rate and colony formation ability while Ajuba siRNA inhibited proliferation rate and colony formation ability. AnnexinV and JC1 staining showed that Ajuba downregulated cisplatin induced apoptosis while it upregulated mitochondrial membrane potential. Ajuba overexpression also inhibited caspase-3 and PARP cleavage, while Ajuba depletion showed the opposite effects. Notably, Ajuba enhanced glucose metabolism by upregulating glucose uptake, glucose consumption, lactate production and ATP production. We further revealed that Ajuba positively regulated cyclin D1, Bcl-xL and GLUT1 at both mRNA and protein levels. Analysis of TCGA dataset revealed that there were positive correlations between Ajuba and cyclin D1, Bcl-xL, GLUT1 at the mRNA levels. Further investigation demonstrated that Ajuba overexpression inhibited Hippo signaling by upregulating YAP protein expression. Depletion of YAP by siRNA abolished the effect of Ajuba on cyclin D1, Bcl-xL and GLUT1. Together, our study showed that Ajuba was overexpressed in human gastric cancers, where it increased cell growth and chemoresistance. Our data also identified novel roles of Ajuba in gastric cancer progression involving regulating glucose uptake and mitochondrial function through the YAP-GLUT1/Bcl-xL axis, making it a potential therapeutic target.

Combination of honey with metformin enhances glucose metabolism and ameliorates hepatic and nephritic dysfunction in STZ-induced diabetic mice.

Honey is a natural sweetener that contains a large amount of monosaccharides such as glucose and fructose, as well as small amounts of disaccharides and trisaccharides such as sucrose and pine trisaccharides. In addition to carbohydrates, honey also contains vitamins, minerals, enzymes, amino acids, and polyphenols including phenolic acids and flavonoids. The polyphenols in honey have been proved to have great antioxidant activity, besides inhibiting α-glycosidase activity and improving blood-lipid metabolism. However, whether it is safe for diabetic patients to consume honey remains controversial. This study investigated the effects of honey, metformin and their combination on the characteristic pathological changes and glucose metabolism in STZ-induced diabetic mice over five weeks. Our results showed that honey and its combination with metformin could prevent hyperglycemia, stimulate insulin secretion, reduce liver fat accumulation, attenuate liver injury and kidney damage in STZ-induced diabetic mice. Moreover, treatment with honey or combination of honey and metformin significantly enhanced glucokinase (GK) activity (p < 0.05), and meanwhile suppressed the activities of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase (PC) and pyruvate dehydrogenase kinases (PDK) (p < 0.05) in diabetic mice.

Transplantation of Autologous Bone Marrow-Derived Stromal Cells into Injured Spinal Cord Enhances Glucose Metabolism and Promotes Functional Recovery

Transplantation of Autologous Bone Marrow-Derived Stromal Cells into Injured Spinal Cord Enhances Glucose Metabolism and Promotes Functional Recovery

Wnt-induced activation of glucose metabolism mediates the invivo neuroprotective roles of Wnt signaling in Alzheimer disease.

Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose-6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP-activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt-mediated improvements in neuronal glucose metabolism.