Role In Glucose Metabolism Research Articles

Dichloroacetate, a pyruvate dehydrogenase activator, alleviates high-fat-induced impairment of myogenic differentiation in skeletal muscles.

Obesity-induced impairment of myogenic differentiation leads to muscle loss and sarcopenia. Pyruvate dehydrogenase (PDH) plays a crucial role in glucose metabolism and is associated with muscle differentiation. However, the effect of dichloroacetate (DCA), a PDH activator, on obesity-induced impairment of myogenic differentiation remains unknown. Here, we evaluated the effects of DCA treatment on high-fat intake-induced impairment of myogenic differentiation in C2C12 cells and C57BL/6 mice. In C2C12 cells, DCA treatment improved PDH activity that was reduced by palmitate (PAL) and decreased the lactate concentrations in the media. Additionally, DCA reversed PAL- and high-fat diet (HFD)-induced decrease in the expression of myoblast determination protein 1 (MyoD), myogenin (MyoG) and myosin heavy chain (MyHC) in C2C12 cells and C57BL/6 mice. To explore the possible mechanism, DCA treatment restored the levels of p-Akt, p-FoxO1, p-FoxO3a and p-p38 MAPK levels in PAL-treated C2C12 cells. Moreover, the protective effects of DCA were reversed by treatment with the Akt inhibitor MK2206 in C2C12 cells. In summary, DCA treatment alleviated high-fat intake-induced impairment of myogenic differentiation via Akt signalling, suggesting its potential in treating obesity-associated muscle loss and sarcopenia.

Study on the Function of Leptin Nutrient Acquisition and Energy Metabolism of Zebrafish (Danio rerio).

Leptin plays an indispensable role in energy homeostasis, and its involvement in metabolic activities has been extensively explored in fish. We generated mutant lines of leptina (-5 bp) and leptinb (+8 bp) in zebrafish using CRISPR/Cas9 technology to explore the metabolic characteristics of lepa and lepb mutant zebrafish in response to high glucose nutritional stress induced by high levels of carbohydrates. The results were as follows: the body weight and food intake of adult zebrafish of the two mutant species were increased; the visceral fat accumulation, whole-body crude lipid, and crude protein contents of lepb-/- were increased; and the visceral fat accumulation and crude lipid in lepa-/- zebrafish were decreased. The blood glucose levels of the two mutant zebrafish were increased, the mRNA expression levels of glycolytic genes pk and gck were decreased in the two mutant zebrafish, and there were differences between lepa-/- and lepb-/- zebrafish. The expressions of glycogen synthesis and decomposition genes were inhibited and promoted, respectively. The expression of adipose synthesis genes in the liver and muscle was stimulated in lepb-/- zebrafish but suppressed in lepa-/- zebrafish. Lipolysis and oxidation genes were also stimulated in lepa-/- zebrafish livers, while the livers of lepb-/- zebrafish were stimulated but muscle was inhibited. In conclusion, the results indicate that lepa plays a major role in glucose metabolism, which is conducive to promoting glucose utilization and lipogenesis, while lepb mainly promotes lipolysis and oxidation, regulates protein generation, and plays a minor role in glucose metabolism.

Alginate-Based Microbeads from Encapsulated Cosmos Caudatus K. Extracts: In Vitro Release Profiles

This study aims to investigate the microencapsulation of C. caudatus K. leaves extract under optimal conditions, focusing on its potential as a therapeutic option for type 2 diabetes. In order to determine the inhibitory effect on the α-amylase enzyme, which plays a crucial role in glucose metabolism, biological activity assays were performed. The procedure of effectively encapsulating the substance was achieved at a pH level of 6 using sodium alginate at a concentration of 2% (w/v), resulting in a 77.2% percentage of encapsulation. The experiment involving the inhibition of α-amylase exhibited an IC50 value of 69.44 ± 0.924 μg/mL, demonstrating the significant biological activity of the microcapsules. The bioactive substances encapsulated in the microcapsules were released during intervals 30-120 min, at pH conditions of 2.2 and 7.4. The release of bioactive substances was only 2.32 % after 120 minutes at a pH of 2.2, whereas it increased to 64.54 % at a pH of 7.4. This discovery indicates that the microcapsules contain the capability to be utilized for the regulated delivery of drugs. The findings of this research demonstrate the potential to develop herbal medicines with therapeutic properties through microencapsulation, providing an excellent opportunity for managing type 2 diabetes.

A DISEASE-BASED PERSPECTIVE OF THE RELATIONSHIP BETWEEN NEUROINFLAMMATION AND IMPAIRED GLUCOSE METABOLISM

Neuroinflammation is a significant contributor to the pathogenesis of several central nervous system disorders including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, and amyotrophic lateral sclerosis. Neuroinflammation is the immune response of the central nervous system against central or peripheral abnormalities disturbed by foreign agents, molecules, metabolic activities, or various diseases. Astrocytes and microglia activation are the main activators of neuroinflammation. The polarization changes of these defender cells have some key roles in bodily metabolism as much as neuronal behavior. The blood-brain barrier is known as the first defender of brain parenchyma. Neuroinflammation disrupts blood-brain barrier integrity and may cause blood-brain barrier breakdown. Glucose is the main energy source of brain and glucose uptake is achieved through the blood-brain barrier. Altered glucose metabolism may have detrimental effects on brain functions and may cause brain disorders. Also, it has been suggested that neuroinflammation may have crucial roles in glucose metabolism. The distribution of the blood-brain barrier in vascular endothelial cells of neurons, astrocytes, and microglia contributes to the transport of glucose to the cells of brain. Microglia and astrocyte polarization are suggested as the two main underlying mechanisms in neuroinflammation. It’s obviously determined that neuroinflammation-caused neurodegenerative diseases are tightly linked with the brain insulin resistance and disrupted cerebral and peripheral glucose metabolism. However, there is lacking knowledge about glucose metabolism deficiencies and microglia/astrocyte polarization. Herein this review, we summarized the neuroinflammation and glucose metabolism with the most common neurological diseases and the possible effects of microglia/astrocyte polarization on glucose metabolism.

Gintonin Stimulates Glucose Uptake in Myocytes: Involvement of Calcium and Extracellular Signal-Regulated Kinase Signaling.

Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, glucose transporter (GLUT) 4 expression, and adenosine triphosphate (ATP) content in C2C12 myotubes. Gintonin (3-30 μg/mL) dose-dependently stimulated glucose uptake in myotubes. The expression of GLUT4 on the cell membrane was increased by gintonin treatment. Treatment with 1-3 μg/mL of gintonin increased glycogen content in myotubes, but the content was decreased at 30 μg/mL of gintonin. The ATP content in myotubes increased following treatment with 10-100 μg/mL gintonin. Gintonin transiently elevated intracellular calcium concentrations and increased the phosphorylation of extracellular signal-regulated kinase (ERK). Gintonin-induced transient calcium increases were inhibited by treatment with the lysophosphatidic acid receptor inhibitor Ki16425, the phospholipase C inhibitor U73122, and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate. Gintonin-stimulated glucose uptake was decreased by treatment with U73122, the intracellular calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester, and the ERK inhibitor PD98059. These results show that gintonin plays a role in glucose metabolism by increasing glucose uptake through transient calcium increases and ERK signaling pathways. Thus, gintonin may be beneficial for glucose metabolism control.

Pyruvate dehydrogenase kinase 1 controls triacylglycerol hydrolysis in cardiomyocytes.

Pyruvate dehydrogenase kinase (PDK) 1 is one of four isozymes that inhibit the oxidative decarboxylation of pyruvate to acetyl-CoA via pyruvate dehydrogenase. PDK activity is elevated in fasting or starvation conditions to conserve carbohydrate reserves. PDK has also been shown to increase mitochondrial fatty acid utilization. In cardiomyocytes, metabolic flexibility is crucial for the fulfillment of high energy requirements. The PDK1 isoform is abundant in cardiomyocytes, but its specific contribution to cardiomyocyte metabolism is unclear. Here we show that PDK1 regulates cardiomyocyte fuel preference by mediating triacylglycerol turnover in differentiated H9c2 myoblasts using lentiviral shRNA to knockdown Pdk1 . Somewhat surprisingly, PDK1 loss did not affect overall PDH activity, basal glycolysis, or glucose oxidation revealed by oxygen consumption rate experiments and 13 C 6 glucose labelling. On the other hand, we observed decreased triacylglycerol turnover in H9c2 cells with PDK1 knockdown, which was accompanied by decreased mitochondrial fatty acid utilization following nutrient deprivation. 13 C 16 palmitate tracing of uniformly labelled acyl chains revealed minimal acyl chain shuffling within triacylglycerol, indicating that the triacylglycerol hydrolysis, and not re-esterification, was dysfunctional in PDK1 suppressed cells. Importantly, PDK1 loss did not significantly impact the cellular lipidome or triacylglycerol accumulation following palmitic acid treatment, suggesting that effects of PDK1 on lipid metabolism were specific to the nutrient-deprived state. We validated that PDK1 loss decreased triacylglycerol turnover in Pdk1 knockout mice. Together, these findings implicate a novel role for PDK1 in lipid metabolism in cardiomyocytes, independent of its canonical roles in glucose metabolism.

Hexokinase Domain Containing 1 (HKDC1) Gene Variants and Their Association With Gestational Diabetes Mellitus: A Mini-Review

Abstract Gestational diabetes mellitus (GDM) is the most common metabolic disorder during the gestational period. Maternal glucose metabolism differs significantly from nonpregnant levels during pregnancy, with increased insulin resistance being the main physiological response. Maternal glucose levels during pregnancy, have a significant impact on the development of early and long-term metabolic health of the offspring. Therefore, a better understanding of the GDM pathophysiology is needed. Hexokinase domain containing 1 (HKDC1) gene was discovered as a gene related to glucose metabolism during pregnancy compared with nongravid state. HKDC1 plays a critical role in glucose homeostasis during pregnancy. Haplotypes of HKDC1 genetic variants associated with 2-h plasma glucose (2hPG) in pregnancy, disrupt regulatory element activity, thereby reducing HKDC1 expression in different tissues. The association of HKDC1 variants with gestational diabetes and 2hPG was investigated in several ethnic groups. These studies suggested that HKDC1 plays a more important role in glucose metabolism during pregnancy than outside of it and also demonstrated that while GDM and type 2 diabetes mellitus have many similarities, there are differences in at least one underlying pathway. This review focuses on the findings of the genetic studies on HKDC1 and GDM.

Sirtuin Expression in Insulin-Sensitive Tissues of Rats with Impaired Glucose Tolerance is not Affected by Resistance Training or Zinc Supplementation.

While physical activity and zinc supplementation have shown benefits in diabetes management, little is known about their effect on less severe glucose homeostasis disorders, such as impaired glucose tolerance. On the other hand, sirtuins have an important role in glucose metabolism and insulin sensitivity, but to date, there is no information about the impact of zinc supplementation or physical activity on their regulation in individuals with impaired glucose homeostasis. The aim of this study was to assess the effect of supplemental zinc, muscle-resistance training, and their combination on the expression of selected sirtuins in insulin-sensitive tissues of rats with impaired glucose tolerance. Thirty male Wistar rats with impaired glucose tolerance were fed a high-fat diet for 12 weeks while subjected to zinc supplementation, resistance training, both, or none. Morphometric and metabolic evaluations were performed at the end of the experimental period, and gene expression of sirtuins 1, 2, 4, and 7 was assessed in liver, gastrocnemius muscle, and white adipose tissue. Results showed that zinc supplementation and/or resistance training did not improve metabolic parameters of rats with impaired glucose tolerance, nor did they affect the expression of selected sirtuins in any of the tissues evaluated. However, the expression of some sirtuins was associated with metabolic parameters in a tissue-specific manner. Additional studies are needed to evaluate whether zinc supplementation and/or resistance training can improve metabolic status or modulate sirtuins expression in advanced stages of impaired glucose homeostasis.

Ameliorated lipid distribution in prediabetes - Effects of 12 weeks traditional Chinese YiJinJing exercise plus TheraBand: A randomized controlled trial

ObjectiveLipid distribution plays a crucial role in glucose metabolism, and this study aimed to investigate the effects of 12 weeks traditional Chinese YiJinJing exercise on specific lipid distributions in patients with prediabetes. MethodsSixty participants with prediabetes were randomly allocated to either a control group (Con, n = 30) or an exercise group (Ex, n = 30). The Ex group underwent YiJinJing exercise plus Theraband, engaging in 1-h sessions, 3 times per week, over a total period of 12 weeks. Dual-energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI) were used to measure lipid distribution in different body segments and organs. Additionally, a body composition analyser was employed to measure visceral fat, and laboratory tests were conducted to measure indicators related to glycolipid metabolism. ResultsFollowing a 12-week intervention with Exercise, 37 % of prediabetic patients in the Ex group achieved normal blood glucose levels. Significant reductions were observed in upper limb fat (ULF), trunk fat (TrF) and liver fat (LF) values in the Ex group compared to the Con group. Additionally, within the Ex group, there were notable decreases in triglyceride (TG) levels, body mass index (BMI), waist-hip ratio (WHR), android fat (AF), ULF, thigh fat (ThF), renal sinus fat (RSF), and LF compared to baseline. ConclusionsTraditional Chinese YiJinJing plus TheraBand exercise can significantly reduce blood glucose levels through improved lipid distribution and metabolism in prediabetic patients. Hence, YiJinJing can serve as a crucial intervention for individuals with prediabetes.

Exploring the Potential of Isoindole‐1,3‐Dione Derivatives as Novel Inhibitors of Aldose Reductase: An In Silico and In Vitro Insight into Therapeutic Strategies for Diabetic Complications

AbstractThis study explores the potential of isoindole‐1,3‐dione derivatives as novel inhibitors of aldose reductase (AR), focusing on their in silico and in vitro effects for therapeutic strategies against diabetic complications. Aldose reductase, a critical enzyme in the polyol pathway, plays a significant role in glucose metabolism and has been linked to diabetic complications. In this comprehensive study, isoindole‐1,3‐dione derivatives were synthesized and evaluated for their inhibitory effects on the recombinant human AR enzyme. The compounds’ inhibitory activities were measured both in vitro and through in silico techniques, employing molecular docking and free binding energy calculations and ADME studies. The newly synthesized compounds demonstrated varied inhibitory effects, with ethyl and phenyl substituents at specific positions enhancing inhibitory activity. Notably, compounds with carboxylic acid derivatives exhibited potent inhibitory effects, especially compound 6 with an IC50 value of 1.649 μM. In conclusion, this study provides valuable insights into the inhibitory potential of isoindole‐1,3‐dione derivatives against AR, suggesting their potential therapeutic application in mitigating diabetic complications. The combination of experimental and computational approaches offers a comprehensive understanding of the compounds’ interaction mechanisms and pharmacokinetic profiles, supporting their further exploration as antidiabetic agents.

In Silico Screening of Sulfonamide Derivatives against Glycolytic Enzymes Reveals Mutation‐Independent Interactions of Sulfisoxazole and Sulfamethazine

AbstractGlycolysis is a highly conserved biochemical process that involves the sequential conversion of glucose to pyruvate and the generation of adenosine triphosphate (ATP), generating energy for cellular functions. This is carried out by several enzymes that play an important role in glucose metabolism. The sulfonamide group of drugs is commonly used as an antibiotic that inhibits the bacterial folic acid production pathway, although its effects on glycolytic enzymes are unclear. Since altered glycolytic enzyme expression is linked to a variety of metabolic disorders as well as cancer, the quest for new ligands against glycolytic enzymes is never over. We revealed that different sulfonamide derivatives interact with glycolytic enzymes with varying binding affinities. Among the selected sulfonamides, sulfisoxazole and sulfamethazine had greater binding scores to certain glycolytic enzymes than others. In silico point mutation analysis predicts that sulfisoxazole and sulfamethazine interact with certain glycolytic enzymes in a residue‐independent manner. This research generates a repository of the 2D interactions of sulfonamide derivatives with glycolytic enzymes, binding energies, impacts of induced point mutations on the local environment, and changes in protein structural flexibility. In the future, sulfisoxazole and sulfamethazine may be repurposed as specific glycolytic enzyme inhibitors to combat a variety of glycolysis‐related metabolic disorders.

The Intake of Dietary Lipids Improves Glucose Tolerance via Modulating Gut Microbiota.

The composition of gut microbiota is determined not only by genetic factors but also by environmental factors, such as diet, exercise, and disease conditions. Among these factors, diet is crucial in changing the gut microbial composition. Dietary lipids composed of different fatty acids not only alter host metabolism but also have a significant impact on the composition of gut microbiota. However, the molecular mechanisms underlying the relationship between these host effects and their impact on gut microbiota remain unclear. Here, we demonstrated that intake of different dietary lipids improved glucose tolerance by modulating gut microbiota. The results of our analysis show that the taxa of bacteria that increase in number as a result of dietary lipid intake play an important role in glucose metabolism. Thus, we have identified a new mechanism underlying the function of dietary lipids in regulating glucose homeostasis. Our findings contribute to possible new methods to prevent and treat metabolic disorders by modifying the composition of gut microbiota.

Fabrication of a Near-Infrared-Emissive Probe for Detecting Dipeptidyl Peptidase 4 in the Liver of Diabetic Mice and Clinical Serum.

Dipeptidyl peptidase 4 (DPP4) plays a key role in glucose metabolism, which has been a close target for diabetes pathology and treatment. It is significant for the evaluation of cellular DPP4 activity in various biological systems. Fluorescence imaging technology is currently a popular method for detecting enzymes in living cells due to its advantages of high selectivity, high sensitivity, high spatiotemporal resolution, and real-time visualization. Herein, a near-infrared (NIR)-emissive probe NEDP with a large Stokes shift (153 nm) was developed for the assay of DPP4 activity. Upon addition of DPP4, NEDP can emit a significant turn-on NIR fluorescence signal (673 nm) with high sensitivity and specificity. Moreover, NEDP can successfully be used for imaging of intracellular DPP4, confirming the regulation of DPP4 expression in hyperglucose and its treatment in living cells. Most importantly, NEDP can not only monitor the changes of DPP4 in vivo but also show that DPP4 in diabetes is mainly up-regulated in the liver, and the level of DPP4 is positively correlated with the pathological damage of the liver. In addition, NEDP can identify the serum of diabetic patients from healthy people through the fluorescence response to DPP4. These results demonstrated that the designed probe NEDP provides a prospective visual tool to explore the relationship between DPP4 and diabetes and would be applied for detecting serum of diabetes in the clinic.

TINGKAT KEPATUHAN PENGGUNAAN OBAT ANTIDIABETES DI RS PKU AISYIYAH BOYOLALI

Diabetes mellitus or DM is a degenerative disease that is often found in society. This disease is characterized by high blood sugar caused by impaired insulin production which plays a role in glucose metabolism in pancreatic function. If someone is diagnosed with diabetes, the only treatment is to control blood sugar. This treatment requires compliance because it is carried out over a long and unlimited period of time. However, there is a problem of compliance with treatment because many conditions are neglected. This study aims to determine the level of compliance of outpatients in the internal medicine polyclinic at PKU Aisyiyah Boyolali Hospital in undergoing treatment for diabetes mellitus. This research is a descriptive research. Data collection used the Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire to measure patient compliance. The sample used was 60 respondents with a sampling technique using purposive sampling. The results of the study showed that 14 patients (23%) had a high level of compliance, 40 patients (67%) had a medium level of compliance, and 6 patients (10%) had a low level of compliance.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

BackgroundGlucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.MethodsUsing publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).ResultsGenetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57–46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78–4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54–0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.ConclusionsImpaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Angiopoietin-like protein 4 induces growth hormone variant secretion and aggravates insulin resistance during pregnancy, linking obesity to gestational diabetes mellitus.

Angiopoietin-like protein 4 (ANGPTL4) is a secretory glycoprotein involved in regulating glucose homeostasis in non-pregnant subjects. However, its role in glucose metabolism during pregnancy and the pathophysiology of gestational diabetes mellitus (GDM) remains elusive. Thus, this study aimed to clarify the relationship between ANGPTL4 and GDM and investigate the pathophysiology of placental ANGPTL4 in glucose metabolism. We investigated this issue using blood and placenta samples in 957 pregnant women, the human 3A-sub-E trophoblast cell line, and the L6 skeletal muscle cell line. We found that ANGPTL4 expression in the placenta was higher in obese pregnant women than in lean controls. Palmitic acid significantly induced ANGPTL4 expression in trophoblast cells in a dose-response manner. ANGPTL4 overexpression in trophoblast cells resulted in endoplasmic reticulum (ER) stress, which stimulated the expression and secretion of growth hormone-variant (GH2) but not human placental lactogen. In L6 skeletal muscle cells, soluble ANGPTL4 suppressed insulin-mediated glucose uptake through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases 1/2 (ERK 1/2) pathways. In pregnant women, plasma ANGPTL4 concentrations in the first trimester predicted the incidence of GDM and were positively associated with BMI, plasma triglyceride, and plasma GH2 in the first trimester. However, they were negatively associated with insulin sensitivity index ISI0,120 in the second trimester. Overall, placental ANGPTL4 is induced by obesity and is involved in the pathophysiology of GDM via the induction of ER stress and GH2 secretion. Soluble ANGPTL4 can lead to insulin resistance in skeletal muscle cells and is an early biomarker for predicting GDM.

Transcriptional and hormonal control of adipose Treg heterogeneity and function.

Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.

Abstract LB295: Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma

Abstract Dysregulated metabolism is a hallmark of cancer. While the role of glucose metabolism in cancer has been extensively studied, relatively little has been done to understand the role of poly-unsaturated fatty acids in cancer biology. To gain insight into their contribution to cancer progression we determined the expression patterns and outcome associations of both saturated and unsaturated fatty acid synthesis (UFAS) genes in pediatric neuroblastoma (NB), and fatty acid levels in NB cell lines derived from high-risk tumors. MYCN amplification and disruption of tumor suppressor miRNAs (TSmiR) function are central drivers of poor outcomes in NB. MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in UFAS remains poorly understood. Using complementary analysis of publicly available genomic datasets and cultured NB cell measurements we examined the potential regulation of UFAS genes through MYCN and MYC activity and posttranscriptional regulation by TSmiRs. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. Additionally, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, using mass spectrometry analysis we found NB cells to be high in de novo synthesized omega 9 (ω9) unsaturated fatty acids and low in both ω6 and ω3. This finding provides a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers. Citation Format: Dennis A. Sheeter, Secilia Garza, Hui Gyu Park, Lorraine-Rana Benhamou, Nikki R. Badi, Erika C. Espinosa, Kumar Kothapalli, J. Thomas Brenna, John T. Powers. Unsaturated fatty acid synthesis is associated with poor prognosis and is differentially regulated by MYCN and tumor suppressor microRNAs in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB295.

Characterization of Plant-Derived Natural Inhibitors of Dipeptidyl Peptidase-4 as Potential Antidiabetic Agents: A Computational Study.

Diabetes, characterized by elevated blood sugar levels, poses significant health and economic risks, correlating with complications like cardiovascular disease, kidney failure, and blindness. Dipeptidyl peptidase-4 (DPP-4), also referred to as T-cell activation antigen CD26 (EC 3.4.14.5.), plays a crucial role in glucose metabolism and immune function. Inhibiting DPP-4 was anticipated as a potential new therapy for diabetes. Therefore, identification of plant-based natural inhibitors of DPP-4 would help in eradicating diabetes worldwide. Here, for the identification of the potential natural inhibitors of DPP-4, we developed a phytochemicals library consisting of over 6000 phytochemicals detected in 81 medicinal plants that exhibited anti-diabetic potency. The library has been docked against the target proteins, where isorhamnetin, Benzyl 5-Amino-5-deoxy-2,3-O-isopropyl-alpha-D-mannofuranoside (DTXSID90724586), and 5-Oxo-7-[4-(trifluoromethyl) phenyl]-4H,6H,7H-[1,2]thiazolo[4,5-b]pyridine 3-carboxylic acid (CHEMBL3446108) showed binding affinities of -8.5, -8.3, and -8.3 kcal/mol, respectively. These compounds exhibiting strong interactions with DPP-4 active sites (Glu205, Glu206, Tyr547, Trp629, Ser630, Tyr662, His740) were identified. ADME/T and bioactivity predictions affirmed their pharmacological safety. Density functional theory calculations assessed stability and reactivity, while molecular dynamics simulations demonstrated persistent stability. Analyzing parameters like RMSD, RG, RMSF, SASA, H-bonds, MM-PBSA, and FEL confirmed stable protein-ligand compound formation. Principal component analysis provided structural variation insights. Our findings suggest that those compounds might be possible candidates for developing novel inhibitors targeting DPP-4 for treating diabetes.

The Role of Acyl-CoA Synthetase 1 in Bioactive Lipid Accumulation and the Development of Hepatic Insulin Resistance.

The liver plays a crucial role in glucose metabolism. Obesity and a diet rich in fats (HFD) contribute to the accumulation of intracellular lipids. The aim of the study was to explore the involvement of acyl-CoA synthetase 1 (ACSL1) in bioactive lipid accumulation and the induction of liver insulin resistance (InsR) in animals fed an HFD. The experiments were performed on male C57BL/6 mice divided into the following experimental groups: 1. Animals fed a control diet; 2. animals fed HFD; and 3. HFD-fed animals with the hepatic ACSL1 gene silenced through a hydrodynamic gene delivery technique. Long-chain acyl-CoAs, sphingolipids, and diacylglycerols were measured by LC/MS/MS. Glycogen was measured by means of a commercially available kit. The protein expression and phosphorylation state of the insulin pathway was estimated by Western blot. HFD-fed mice developed InsR, manifested as an increase in fasting blood glucose levels (202.5 mg/dL vs. 130.5 mg/dL in the control group) and inhibition of the insulin pathway, which resulted in an increase in the rate of gluconeogenesis (0.420 vs. 0.208 in the control group) and a decrease in the hepatic glycogen content (1.17 μg/mg vs. 2.32 μg/mg in the control group). Hepatic ACSL1 silencing resulted in decreased lipid content and improved insulin sensitivity, accounting for the decreased rate of gluconeogenesis (0.348 vs. 0.420 in HFD(+/+)) and the increased glycogen content (4.3 μg/mg vs. 1.17 μg/mg in HFD(+/+)). The elevation of gluconeogenesis and the decrease in glycogenesis in the hepatic tissue of HFD-fed mice resulted from cellular lipid accumulation. Inhibition of lipid synthesis through silencing ACSL1 alleviated HFD-induced hepatic InsR.