Glucose Analogue Research Articles

Development of 3D Muscle Cell Culture-Based Screening System for Metabolic Syndrome Drug Research.

Developing effective drug screening methods for type 2 diabetes requires physiologically relevant models. Traditional 2D cell cultures have limitations in replicating invivo conditions, leading to challenges in assessing drug efficacy. To overcome these issues, we developed a 3D artificial muscle model that induces insulin resistance, a hallmark of type 2 diabetes. Using C2C12 myoblasts cultured in a scaffold of 1% alginate and 1 mg/mL collagen type 1, we optimized conditions for differentiation and structural stability. Insulin resistance was induced using palmitic acid (PA), and glucose uptake was assessed using the fluorescent glucose analog 2-NBDG. The 3D model demonstrated superior glucose uptake responses compared with 2D cultures, with a threefold increase in insulin-stimulated glucose uptake on days 4 and 8 of differentiation. Induced insulin resistance was observed with 0.1 mM PA, which maintained cell viability and differentiation capacity. The model was validated through comparative drug screening using rosiglitazone and metformin, as well as 165 candidate compounds provided by Korea Chemical Bank. Drug screening revealed that three out of five hit compounds identified in both 2D and 3D models exhibited greater efficacy in 3D cultures, with results consistent with ex vivo assays using mouse soleus muscle. This model closely mimics invivo conditions, offering a robust platform for type 2 diabetes drug discovery while supporting ethical research practices.

Nanoparticles modified with glucose analogs to enhance the permeability of the blood-brain barrier and their accumulation in the epileptic brain.

Drug delivery for epilepsy treatment faces enormous challenges, where the sole focus on enhancing the ability of drugs to penetrate the blood-brain barrier (BBB) through ligand modification is insufficient because of the absence of seizure-specific drug accumulation. In this study, an amphipathic drug carrier with a glucose transporter (GLUT)-targeting capability was synthesised by conjugating 2-deoxy-2-amino-D-glucose (2-DG) to the model carrier DSPE-PEG2k. A 2-DG-modified nano drug delivery system (NDDS) possessing robust stability and favourable biocompatibility was then fabricated using the nanoprecipitation method. The results showed that the 2-DG-modified NDDS exhibited enhanced cellular uptake by brain capillary endothelial cells and neuronal cells. Most importantly, the 2-DG-modified NDDS exhibited enhanced BBB penetration and brain accumulation, especially in the epileptic brain, thus achieving seizure-based on-demand drug delivery. Our study provides a simple and smart strategy for the delivery of anti-seizure medicines.

In vitro evaluation of silver-zinc oxide-eugenol nanocomposite for enhanced antimicrobial and wound healing applications in diabetic conditions

Diabetic wounds with chronic infections present a significant challenge, exacerbated by the growing issue of antimicrobial resistance, which often leads to delayed healing and increased morbidity. This study introduces a novel silver-zinc oxide-eugenol (Ag+ZnO+EU) nanocomposite, specifically designed to enhance antimicrobial activity and promote wound healing. The nanocomposite was thoroughly characterized using advanced analytical techniques, confirming its nanoscale structure, stability and chemical composition. The Ag+ZnO+EU nanocomposite demonstrated potent antimicrobial efficacy against a range of wound associated pathogens, including standard and clinical isolates of Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. Minimum inhibitory concentrations of Ag+ZnO+EU for standard and clinical isolates were significantly lower than those of the individual components, highlighting the synergistic effect of the nanocomposite. Time-kill assays revealed rapid microbial eradication, achieving complete sterility within 240-min. Importantly, the nanocomposite effectively eliminated persister-like cells, which are typically resistant to conventional treatments, suggesting a potential solution for persistent infections. In vitro scratch assays using human keratinocyte cells demonstrated that the Ag+ZnO+EU nanocomposite significantly accelerated wound closure, with near-complete healing observed within 24-h, indicating enhanced cell migration and tissue regeneration. Additionally, the nanocomposite showed potential antidiabetic effects by increasing glucose uptake up to 97.21% in an in vitro assay using 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose, a fluorescent glucose analog, suggesting potential applications beyond wound healing. These findings highlight the Ag+ZnO+EU nanocomposite as a promising candidate for addressing both antimicrobial resistance and impaired wound healing in diabetic contexts.Graphical

Metabolic Differences in Neuroimaging with [18F]FDG in Rats Under Isoflurane and Hypnorm-Dormicum.

Anesthesia can significantly impact positron emission tomography (PET) neuroimaging in preclinical studies. Therefore, understanding these effects is crucial for accurate interpretation of the results. In this experiment, we investigate the effect of [18F]-labeled glucose analog fluorodeoxyglucose ([18F]FDG) uptake in the brains of rats anesthetized with two commonly used anesthetics for rodents: isoflurane, an inhalation anesthetic, and Hypnorm-Dormicum, a combination injection anesthetic. Female adult Sprague Dawley rats were randomly assigned to one of two anesthesia groups: isoflurane or Hypnorm-Dormicum. The rats were submitted to dynamic [18F]FDG PET scan. The whole brain [18F]FDG standard uptake value (SUV) and the brain voxel-based analysis were performed. The dynamic [18F]FDG data revealed that the brain SUV was 38% lower in the isoflurane group after 40 min of image (2.085 ± 0.3563 vs. 3.369 ± 0.5577, p = 0.0008). In voxel-based analysis between groups, the maps collaborate with SUV data, revealing a reduction in [18F]FDG uptake in the isoflurane group, primarily in the cortical regions, with additional small increases observed in the midbrain and cerebellum. The observed differences in [18F]FDG uptake in the brain may be attributed to variations in metabolic activity. These results underscore the necessity for careful consideration of anesthetic choice and its impact on neuroimaging outcomes in future research.

Total-body positron emission tomography: a tool for systemic, quantitative evaluation of the inflammatory burden of psoriatic arthritis.

To test the hypothesis that recently-developed total body-positron emission tomography (TB-PET) imaging with integrated computed tomography (CT) will enable low-dose, quantitative, domain-specific evaluation of the total inflammatory burden of psoriatic arthritis (PsA), and associate with established outcome measures of the clinical domains of PsA. Seventy-one adult participants (40 with PsA, 16 with rheumatoid arthritis (RA), and 15 with osteoarthritis (OA)) underwent 20-min TB-PET/CT scans using [18F]FDG, a glucose analogue radiotracer. [18F]FDG uptake was assessed qualitatively and quantitatively. Rheumatological examinations were performed prior to the scan. For both evaluations, domain-specific assessments included 68 joints, 6 entheses, 20 nails, axial disease and dactylitis. [18F]FDG PET uptake consistent with joint involvement and enthesitis were noted in 100% of participants with PsA. Other features included nail matrix pathology (53%), spinal involvement (60%), active sacroiliitis (13%) and dactylitis (10%). Patterns of [18F]FDG uptake in PsA differed from those in participants with RA or OA. There was a high concordance between TB-PET measures and the domain-specific assessments of joint (75%), entheseal (79%) and nail (65%) pathology. TB-PET was positive for an additional 15% joints, 20% entheses and 13% nails that were negative on clinical assessments. TB-PET/CT identified inflammatory pathologies characteristic to all clinical domains of PsA and thus provided an in vivo evaluation of systemic PsA inflammatory burden. This promising tool may further contribute to identifying pathologies that may be occult, provide biomarkers to diagnose and differentiate PsA at an early stage, and to monitor early treatment response.

Application effect of enhanced recovery after surgery on patients with hepatolithiasis undergoing hepatectomy

ObjectiveTo explore the application effect of enhanced recovery after surgery (ERAS) for patients with hepatolithiasis undergoing hepatectomy.MethodsA retrospective comparative analysis was performed on the clinical data of 120 patients with hepatolithiasis who were admitted to the Department of Hepatobiliary Surgery in our hospital between December 2017 and May 2022 using convenience sampling.ResultsThere were differences in the impact of different management modes on blood glucose and visual analogue scale (VAS) scores between the two groups of patients (Fblood glucose = 32.581, FVAS = 41.472, all P < 0.001). The average blood glucose levels in the traditional group were higher than those in the ERAS group at two time points, and the VAS scores in the former group were higher than those in the latter at 6, 12 and 24 h after surgery. The remifentanil dosage (49.89 ± 12.12 vs 57.84 ± 11.43 mL, t = − 2.475, P = 0.016), patient-controlled analgesia frequency (3.83 ± 2.23 vs 5.57 ± 3.52 times, t = − 2.481, P = 0.015) and analgesic supplementation frequency (0.57 ± 0.73 vs 1.07 ± 1.02 times, t = − 2.653, P = 0.010) in the ERAS group were all lower than those in the traditional group. Different management modes had different effects on the levels of procalcitonin (PCT), interleukin-6 (IL-6), C-reactive protein (CRP) and white blood cell count (WBC) in the two groups of patients (FPCT = 45.371, FIL-6 = 43.466, FCRP = 51.364, FWBC = 65.674, all P < 0.001). The levels of PCT, IL-6, CRP and WBC in the ERAS group were lower than those in the traditional group at three time points: postoperative day 1, 7 and 14. The postoperative hospital stay (8.41 ± 2.55 vs 11.61 ± 3.34 d, t = − 7.812, P < 0.001) and proportion of postoperative complications (9.61% vs 26.47%, χ2 = 5.403, P = 0.020) in the ERAS group were lower than those in the traditional group.ConclusionThe application of ERAS effectively reduces the perioperative stress response, shortens the postoperative length of hospital stay and lowers the overall incidence of postoperative complications in patients with hepatolithiasis.

Abstract A016: Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality

Abstract Non-small cell lung cancer (NSCLC) is a primary type of lung cancer and a leading cause of cancer-related mortality worldwide. The Warburg effect, characterized by increased glycolysis and reduced oxidative phosphorylation, is a hallmark of NSCLC and presents a therapeutic target. Annonacin, a natural compound found in fruits from the Annonaceae family, interferes with oxidative phosphorylation by inhibiting mitochondrial complex I. 2-deoxy-d-glucose (2DG), a glucose analog, disrupts glycolysis. This study examines the effects of Annonacin and 2DG on NSCLC A549 cells, both individually and in combination, with the hypothesis that inhibiting both metabolic pathways simultaneously will lead to more effective cancer treatment. In addition, we explored how these treatments might alter the tumor microenvironment, oxidative stress, and effects on normal epithelial bronchial cells. A549 NSCLC cells were exposed to different concentrations of Annonacin (0, 1, 2, 4, 6 µM) and 2DG (0,1.25, 2.5, 5, 10 mM), separately and together. Cell viability was measured using the MTT assay. Genotoxicity was assessed through the Comet Assay, and oxidative stress was evaluated by measuring superoxide dismutase and glutathione peroxidase activities. The long-term ability of the cells to proliferate was tested using colony-forming assays. The NL20 bronchial epithelial cell line was tested as a parallel control. Both Annonacin and 2DG showed a dose-dependent ability to kill A549 cells. However, when used together, these substances had a stronger effect, significantly lowering the number of surviving cells compared to when each was used alone. The response of this combination treatment on genotoxicity using Comet Assay is being pursued. Changes in oxidative stress responses were found, as shown by the altered superoxide dismutase and glutathione peroxidase enzyme activities. The ability of A549 cells to form colonies was greatly reduced following combination treatment, indicating a reduction in their long-term proliferative capacity. The combination of Annonacin and 2DG effectively inhibits the growth of NSCLC A549 cells by targeting their metabolic weaknesses, which may lead to increased DNA damage and oxidative stress. These results suggest simultaneous targeting glycolysis and oxidative phosphorylation could be a promising new approach for treating NSCLC. Future in vivo studies will evaluate this combination in live models and can offer insights into efficacy and possible translation to clinical application. Citation Format: Bhoj Raj Bhattarai, Cora Teets, Avinash Tope. Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A016.

Impairment of Glucose Uptake Induced by Elevated Intracellular Ca2+ in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice.

Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca2+ concentration ([Ca2+]i) in their muscle cells. We have reported that the muscle dysregulation of [Ca2+]i impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca2+]i and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca2+]i was recorded using a Ca2+-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca2+]i and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca2+]i using a Ca2+-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca2+]i below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca2+]i was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca2+]i within a specific range (100-130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).

The potato sugar transporter SWEET1g affects apoplasmic sugar ratio and phloem-mobile tuber- and flower-inducing signals.

The main phloem loader in potato, sucrose transporter StSUT1, is coexpressed with 2 members of the SWEET gene family: StSWEET11b, a clade III member of SWEET carriers assumed to be involved in sucrose efflux, and StSWEET1g, a clade I member involved in glucose efflux into the apoplast, that physically interacts with StSUT1. We investigated the functionality of SWEET carriers via uptake experiments with fluorescent glucose or sucrose analogs. Inhibition or overexpression of StSWEET1g/SlSWEET1e affected tuberization and flowering in transgenic potato plants. Isolation of the apoplasmic fluid by vacuum infiltration centrifugation revealed changes in the apoplasmic hexose composition and mono-to-disaccharide ratio, affecting sink strength. Downregulation of StSWEET1g expression affected the expression of SP6A, a tuberigen, and miR172 under long-day conditions, leading to early flowering and tuberization. A systematic screen for StSWEET1g-interacting protein partners revealed several proteins affecting cell wall integrity and strengthening. StSWEET1g and the main interaction partners were strongly downregulated during tuber development. We discuss whether StSWEET1g activity might be linked to cell wall remodeling during tuber development and the switch from apoplasmic to symplasmic phloem unloading.

Phytochemistry, antioxidant and anti-diabetic activities of Sterculia villosa in-vitro

ObjectiveAs ongoing research continues, many anti-diabetic agents still have a multitude of side effects which is the reason why more and more people resort to traditional medicines such as Traditional Chinese Medicine (TCM). There are many Therapeutic Species of Sterculia spp. that are commonly used in TCM practices. Here, we have studied one of such TCM herbal plants, namely Sterculia villosa Roxb. (Chinese: 绒毛苹婆), for its anti-diabetic potential. In this way, the study intends to assess its effectiveness and examine its suitability as a raw natural medicine for diabetes management in traditional medicine. MethodIn-vitro anti-diabetic property was evaluated by α-amylase and α-glucosidase enzyme inhibition and glucose uptake assays. Metabolomic profiling by GC–MS was conducted to determine the probable phyto-constituents in S. villosa. These phyto-compounds were further subjected to in-silico molecular docking studies, identifying stigmasterol as the most potent anti-diabetic phyto-compound. Glucose uptake efficacy was estimated by a fluorescence microplate reader employing glucose analog, 2-NBDG. Molecular dynamic studies (MDS) were carried out with GROMACS to comprehend the protein-ligand binding stability. ResultsStigmasterol showed enhanced enzyme inhibition for both α-amylase (IC50 23.84±1.37 μM) and α-glucosidase (IC50 39.56±1.5 μM). Line-weaver Burk plot revealed competitive and mixed modes of inhibition for α-amylase and α-glucosidase, respectively. The GC-–MS analysis identified 23 vital phyto-compounds present in the methanolic extract of the S. villosa leaves. Upon screening against crucial anti-diabetic proteins by in-silico molecular docking, stigmasterol followed by lupeol, Stigmasta-3,5-diene, and γ-sitosterol were found to be the most effective lead compounds. Stigmasterol also showed potent hypoglycaemic efficacy, as evidenced by augmentation of 2-NBDG glucose uptake in 3T3-L1 cells. The docking and simulation studies against four crucial anti-diabetic targets, α-amylase, α-glucosidase, GLUT 4, and IRS-1, predicted that stigmasterol exhibits a multi-pronged anti-diabetic activity mediated by α-amylase inhibition and activation of IRS1 pathway, simultaneously. The MDS studies highlighted that stigmasterol showed stable interactions with these four proteins, as evidenced by the RMSD, RMSF and hydrogen bond analysis. ConclusionThe results of this study are intriguing, as they identify stigmasterol, sourced from the medicinal plant S. villosa, as a potential breakthrough in the field of diabetic remediation. This discovery paves the way for further research and development of stigmasterol as a more effective and safer treatment for diabetes.

Xylooligosaccharide interferes with the cell cycle and reduces the antibiotic tolerance of avian pathogenic Escherichia coli by associating with its potential antimetabolic actions

This study aimed to probe if xylooligosaccharide (XOS) could act as an antimetabolite to impact the cell cycle and antibiotic tolerance of avian pathogenic Escherichia coli (APEC). We firstly measured the bacteriostasis of XOS against APEC O78 and its effect on the growth of APEC O78 growing on different medium. Afterwards, the effects of XOS on xylose operon activation along with the cell cycle and antibiotic tolerance of APEC O78 were analyzed. The results showed that XOS caused no inhibitory circle against APEC O78 and did not affect (P > 0.05) the growth of APEC O78 growing on LB medium. Besides, APEC O78 was unable to grow on M9 medium (carbon-free) added with XOS. However, XOS exerted a similar role as xylose in increasing (P < 0.05) the expression of certain xylose operon genes including xylose isomerase (XylA)-encoding gene (xylA) and xylose-binding periplasmic protein (XylF)-encoding gene (xylF) in APEC O78. The molecular docking simulation revealed that the major monomer components (xylobiose, xylotriose and xylotetraose) of XOS had stable binding potentials to both XylA and XylF proteins of E. coli, as supported by the low binding free energy and the formation of considerable hydrogen bonds between them. The subsequent analysis showed that XOS altered certain cell cycle-related genes expression, especially elevated (P < 0.05) nrdB expression and decreased ihfB expression to a degree. Moreover, XOS played a similar role as 2-deoxy-glucose (a glucose analogue serving as a typical antimetabolite) in lowering (P < 0.05) the number of ampicillin-tolerant APEC O78. Collectively, XOS had no direct bacteriostasis against APEC and could not be metabolized/utilized by APEC O78. However, it might become an analogue of xylose and then activate xylose transport- and metabolism-related proteins in APEC O78, thus functioning as a potential antimetabolite and exerting anti-metabolic actions. This could at least partially interpret the observed roles of XOS in interfering with the cell cycle and diminishing the antibiotic tolerance of APEC O78. The above findings expand the knowledges about the functions of XOS and provide a basis for exploring novel strategies to reduce the antibiotic tolerance of APEC.

TSH Stimulation before PET/CT as Our Frenemy in Detecting Thyroid Cancer Metastases-Final Results of a Retrospective Analysis.

Introduction: Non-iodine avid metastases of differentiated thyroid cancer (DTC) can be found using PET/CT with a fluorine-18-labeled glucose analog ([18F]FDG). There are ongoing discussions on the appropriateness of using exogenous thyrotropin (TSH) stimulation before this examination. Material and Methods: In a retrospective study, 73 PET/CT scans with [18F]FDG performed after exogenous stimulation with recombinant human TSH (rhTSH) and without such stimulation were analyzed. All analyzed patients were suspected of having non-iodine-avid foci of DTC. Results: The stimulation with rhTSH before the PET/CT did not affect the percentage of positive results: 37.5% (18/48) with rhTSH and 40% (10/25) without rhTSH (p = 0.83). The analysis of the ROC curves established the cut-off thyroglobulin point for a positive PET/CT result separately for both subgroups. There was no statistically significant difference between obtaining a positive PET/CT result and the baseline thyroglobulin concentration (both stimulated and unstimulated). The exogenous stimulation of TSH prior to the PET/CT had no effect on the [18F]FDG uptake in the PET/CT lesions. Conclusions: PET/CT with [18F]FDG remains a useful method for the diagnosis of non-iodine-avid DTC lesions; in the presented group, a positive effect of rhTSH stimulation on the number of DTC foci visible in the PET/CT was found, but without affecting its effectiveness.

A-063 Correlation of 1,5-anhydroglucitol (AG) with A1c: understanding this relationship in terms of an established physiological model for AG mass balance as a function of [glucose

Abstract Background Diet-derived 1,5-anhydroglucitol (AG) is an unmetabolizable glucose analogue present in plasma (reference interval: 7.4-32.5 µg/mL). In diabetes, hyperglycemia can accelerate AG excretion, producing an inverse relationship between A1c and AG. There are no established guidelines regarding use or interpretation of AG in diabetes, but it is often described as being useful for detection of short-term variation in [glucose]. We examined AG usage at our institution, and, additionally, analyzed the information content of AG as derived from an established model for the relationship between AG and [glucose]. Methods Medical records were scanned for all combined orders for AG and A1c between September 2020 and August 2023. Estimated average glucose (eAG) was calculated from A1c [PMID: 18540046]. AG vs. A1c data were compared to calculations for AG vs. eAG using an established physiological model for AG mass balance [PMID: 9357814]. Results Among 104 AG measurements, there were 93 AG/A1c measurement pairs (see Figure). 70% had elevated A1c (n=65). 43% had decreased AG (n=40), all with elevated A1c. Among all AG/A1c pairs, 66% (closed points; n=61) were within the boundaries of model calculations for AG when assuming a simple steady-state [glucose] equal to eAG, a normal glomerular filtration rate, and a normal AG ingestion rate. AG outside of these boundaries (34%; open points, n=32) were almost entirely above the upper boundary (32%; n=30), where results are consistent either with increased AG ingestion rate, decreased glomerular filtration rate, or a discrepancy between eAG and A1c. Only two points (2.2%) were compatible with interpretation of variation in prevailing glucose from eAG. Conclusions For our data, paired AG/A1c measurements were in majority well characterized by a physiological model based simply on steady-state (invariant) [glucose] equal to eAG as derived from A1c alone. Only a small fraction of AG results suggested possible variation in [glucose].

Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma.

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

Impaired exploration induced by type 1 diabetes is related to locomotor activity rather than a reduction in motivation

Type 1 diabetes mellitus (T1D) is associated with cognitive impairments in humans. A well-established animal model of T1D is induced through the administration of streptozotocin (STZ), a glucose analog that induces pancreatic β-cell death, resulting in hyperglycemia and cognitive impairment linked to neuroinflammation and oxidative stress. Tumor necrosis factor (TNF)-α, a key inflammatory mediator, is elevated in the central nervous system (CNS) of diabetic animals. In this study, we utilized TNFR1 knockout mice to investigate the role of TNFR1 signaling in short-term T1D-related cognitive impairment. Our findings showed that diabetic animals did not develop cognitive damage within the first 2 weeks of T1D but exhibited reduced exploration in all behavioral tests. Our findings suggest that this reduction in exploration was attributable to motor impairment, as there was no reduction in motivated novelty-seeking behavior. Additionally, deletion of TNFR1 signaling attenuated gait speed impairment in diabetic mice, but did not affect other motor-related or exploratory behaviors.

Discovery of tetrahydro γ-carboline based novel glucose uptake agent for the treatment of diabetes and Alzheimer’s diseases

The emergence of diabetes mellitus (DM), one of the prevalent metabolic disorders, has increased at alarming rates around the globe in the past few decades. The early discovery of insulin paved the way for the broadened non-invasive anti-hyperglycemic drug therapies to manage and treat diabetes. Recently, insulin resistance in brain tissues has been considered a new hallmark of disease progression, leading to neurodegeneration. Tetrahydro γ-carbolines are privileged scaffolds with various activities against obesity, cancer, and central nervous system (CNS) diseases. The failure of Latrepirdine in clinical phase trials as anti-AD, prompted us to explore further the γ-Carboline derivatives with anti-diabetic activity. To address this, we have leveraged our expertise in drug design to develop tetrahydro γ-carboline derivatives and studied their effect on glucose uptake. All the compounds exhibited low cytotoxicity towards the mammalian cell line 3T3-L1. Next, we screened the 10 derivatives to identify the novel anti-diabetic activities using a fluorescent glucose analog 2-NBDG (2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)-2-deoxy-D-glucose) based on a glucose-uptake assay in differentiated 3T3-L1 adipocytes. Compound 11a has significantly increased glucose uptake at 100 µM compared to rH-Insulin. The dose optimization (1 nM-100 nM) of lead compounds for 2-NBDG-glucose uptake clearly indicated that 11a is superior compared to Insulin. The 11a is the close analog of Latrepirdine, an anti-histamine drug, reported for Alzheimer disease (AD). Further, to understand its anti-AD potential we carried out in silico docking studies with its probable targets, Acetylcholinesterase (AChE), 5-hydroxytryptamine (5HT6) receptor, Butyrylcholinesterase (BChE), and N-methyl-D-aspartate (NMDA) receptor. The docking studies revealed that 11a had stronger binding to these targets than Latrepirdine, correlating with the glucose uptake assay. Thus, 11a is a potential lead disease-modifying agent and could be considered for the management and treatment of type 2 DM and AD.

Nuclear Imaging Modalities in the Diagnosis and Management of Thyroid Cancer.

In this review we have brought forward various nuclear imaging modalities used in the diagnosis, staging, and management of thyroid cancer. Thyroid cancer is the most common endocrine malignancy, accounting for approximately 3% of all new cancer diagnoses. Nuclear imaging plays an important role in the evaluation of thyroid cancer, and the use of radioiodine imaging, FDG imaging, and somatostatin receptor imaging are all valuable tools in the management of this disease. Radioiodine imaging involves the use of Iodine-123 [I-123] or Iodine-131 [I-131] to evaluate thyroid function and detect thyroid cancer. I-123 is a gamma-emitting isotope that is used in thyroid imaging to evaluate thyroid function and detect thyroid nodules. I-131 is a beta-emitting isotope that is used for the treatment of thyroid cancer. Radioiodine imaging is used to detect the presence of thyroid nodules and evaluate thyroid function. FDG imaging is a PET imaging modality that is used to evaluate the metabolic activity of thyroid cancer cells. FDG is a glucose analogue that is taken up by cells that are metabolically active, such as cancer cells. FDG PET/CT can detect primary thyroid cancer and metastatic disease, including lymph nodes and distant metastases. FDG PET/CT is also used to monitor treatment response and detect the recurrence of thyroid cancer. Somatostatin receptor imaging involves the use of radiolabeled somatostatin analogues to detect neuroendocrine tumors, including thyroid cancer. Radiolabeled somatostatin analogues, such as Indium-111 octreotide or Gallium-68 DOTATATE, are administered to the patient, and a gamma camera is used to detect areas of uptake. Somatostatin receptor imaging is highly sensitive and specific for the detection of metastatic thyroid cancer. A comprehensive search of relevant literature was done using online databases of PubMed, Embase, and Cochrane Library using the keywords "thyroid cancer," "nuclear imaging," "radioiodine imaging," "FDG PET/CT," and "somatostatin receptor imaging" to identify relevant studies to be included in this review. Nuclear imaging plays an important role in the diagnosis, staging, and management of thyroid cancer. The use of radioiodine imaging, thyroglobulin imaging, FDG imaging, and somatostatin receptor imaging are all valuable tools in the evaluation of thyroid cancer. With further research and development, nuclear imaging techniques have the potential to improve the diagnosis and management of thyroid cancer and other endocrine malignancies.

Influence of endomorphins-1, 2 on glucose uptake by T and B lymphocytes &lt;i&gt;in vivo&lt;/i&gt;

The main method of treating pain syndrome is the use of morphine and its analogues, which have a wide range of side effects. In this regard, many modern studies are aimed at finding safer analgesic compounds. Currently, among morphine analogues, much attention is paid to endogenous opioid peptides, which, along with an analgesic effect, have pronounced immunoregulatory properties. It is now known that the functional activity of immune cells is ensured by metabolism. This process supplies cells with the energy necessary for activation, differentiation, proliferation, apoptosis, etc. Glucose metabolism plays a key role in ensuring the functions of immune cells. The aim of this work is to evaluate the effect of endomorphins-1, 2 on the characteristics of glucose uptake by T and B lymphocytes in vivo. The subjects of the study were white male mice, peptides were administered to mice intraperitoneally at a dose of 100 ìg/kg, and glucose uptake by cells was assessed using fluorescent analogues of glucose (2-NBDG). It was found that endomorphin-1 did not affect at the intensity of glucose consumption in both T and B cells. Administration of endomorphin-2, on the contrary, led to a significant increase in glucose uptake in T lymphocytes. However, the level of glucose consumption in B cells after administration of endomorphin-2 did not change significantly. In a study of two subsets of T lymphocytes, it was noted that endomorphin-2 leads to an increase in glucose uptake in both CD4+ and CD4-T cells. Administration of endomorphin-1 had no significant effect on the level of uptake of this substrate in both subsets of T lymphocytes. Proliferating B lymphocytes increased glucose consumption in the presence of LPS after administration of endomorphin-2. Both endomorphins did not have a significant effect on glucose consumption in proliferating CD4+ and CD4-T cells. Thus, endomorphin-1, unlike endomorphin-2, does not have a significant effect on glucose metabolism in T and B cells. Taking into account the role of glycolysis in the functioning of immune cells and inflammation, it can be concluded that the use of endomorphin-1 may be associated with a lower risk of immune system-related side effects.

Brain Glucose Metabolism and COMT Val 158 Met Polymorphism in Female Patients with Work-Related Stress.

Stress is a ubiquitous challenge in modern societies. Symptoms range from mood swings and cognitive impairment to autonomic symptoms. This study explores the link between work-related stress and the neurobiological element of brain processing, testing the hypothesis that patients with occupational stress have altered cerebral glucose consumption compared to healthy controls. The participants' present conditions were evaluated using an adapted WHO SCAN interview. Neural activity at rest was assessed by positron emission tomography (PET) with the glucose analogue [18F]fluorodeoxyglucose. Participants were genotyped for the Val158Met polymorphism of the COMT gene, believed to influence stress resilience. This study included 11 women with work-related stress and 11 demographically comparable healthy controls aged 28-62 years, with an average of 46.2 years. The PET scans indicated clusters of decreased glucose consumption primarily located in the white matter of frontal lobe sub-gyral areas in stress patients. COMT Val158Met polymorphism detection indicated no immediate relation of the homozygous alleles and stress resilience; however, healthy controls mainly had the heterozygous allele. In conclusion, the results support that work-related stress does affect the brain in the form of altered glucose metabolism, suggesting neurobiological effects could be related to white matter abnormalities rather than gray matter deterioration. Genotyping indicates a more complex picture than just that of the one type being more resilient to stress. Further studies recruiting a larger number of participants are needed to confirm our preliminary findings.

The spleen assumes a major role in blood glucose regulation in type 1 diabetes patients treated with BCG

The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells’ glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG’s systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas.