Metabolic Type Research Articles

TWIST1/miR-199a axis promotes tumor aggressiveness through inhibiting oxidative phosphorylation in carcinomas

Background Metabolic reprogramming has emerged as a key hallmark of cancer progression, though its role in tumor aggressiveness is still evolving. Here, using a pan-cancer genome approach, we aimed to comprehensively assess the metabolic reprogramming involved in tumor aggressiveness in carcinomas and identify metabolic hubs which can be therapeutically targeted to treat aggressive tumors in the clinic. Methods In this study, we employed a stringent pan-cancer multi-omic metabolism-targeted differential expression approach to identify the metabolic hubs regulating tumor aggressiveness. mRNA, miRNA, DNA methylation and mutation profiling data of tumors representing 14 different types of carcinomas was downloaded from TCGA database. Cell line expression profiling and drug response data was downloaded from CCLE database. Pathway enrichment, GSEA, String protein-protein interaction, miRNA-mRNA prediction, network random-walk and CCLE drug response analyses were carried out. Results We identified downregulated expression of enzymes involved in oxidative phosphorylation as a key common factor across carcinomas, aligning with the Warburg effect. Additionally, we established that the decreased dependence on oxidative phosphorylation is driven by elevated expression of miR-199 family miRNAs that inhibit their expression at the post-transcriptional level. Furthermore, we identified the epithelial-to-mesenchymal transition-related transcription factor, TWIST1, as a master regulator of tumor aggressiveness by controlling miR-199a-3p and -5p expression. Random walk analysis of established miRNA-mRNA network identified NDUFA2, DLD, COX15, NDUFB5, and TIMM13 as crucial metabolic hubs downregulated as tumors become aggressive. Drug response analysis suggested that targeting PDGFR signaling may offer a novel therapeutic approach to counteract the aggressiveness driven by the loss of oxidative phosphorylation. Conclusion We identified TWIST1/miR-199a axis mediated suppression of oxidative phosphorylation as major metabolic contributor towards tumor aggressiveness in carcinomas. These insights underscore the critical interplay between metabolic reprogramming and tumor aggressiveness, opening avenues for potential metabolic therapies in clinical settings.

Bench to Any Side—The Pharmacology and Applications of Natural and Synthetic Alkylated Hydroxy Cinnamates and Cinnamides

Natural alkylated hydroxy cinnamates (AHCs) isolated from medicinal plants and the thereby designed and synthesized cinnamides are derivatives of hydroxy cinnamic acids such as p-coumaric, sinapic, ferulic, and caffeic acids, which are naturally derived from human dietary sources. The pharmacological properties displayed by AHCs based on their inherent structure range include antioxidant, antimicrobial, antiplasmodial, anti-tyrosinase, Alzheimer’s and Parkinson’s disease therapy, anticancer therapy, metabolic disease therapy, and biopesticides, which have not been reviewed together. Based on their inherent antioxidant, antimicrobial, and UV absorption and their structure–activity relationships, these cinnamyl esters and amides can be used for food preservation in emulsions and oils, as sun-protective components of skin care formulations, and in many other multifunctional applications. In conclusion, the fine-tuning of the structural features such as the type of hydroxy cinnamic acid used, the length of alkyl chains for variable lipophilicity, conversion from cinnamic to propanoic for antioxidants, the increase in methoxy or the change to amino groups to increase the molar absorption coefficient and loss of absorption values, the substitution by halides or amino groups for potent biopesticides, and conversion from esters to amide bonds leads to different AHCs for biomedical, cosmetic, and agriculture applications as an emerging field of investigation that can overall provide natural, safe, biodegradable, and sustainable molecules.

Rosiglitazone-induced white adipocyte browning is regulated by actin and Myh9

AimsThis study investigates the role of actin polymerization and Myh9 in mediating lipid droplet (LD) fission during rosiglitazone-induced browning of white adipocytes. The aim is to understand how LD splitting might contribute to the beige conversion of white adipose tissue, providing insights into adipocyte plasticity and metabolic regulation. Materials and methodsC3H10 T1/2-differentiated adipocytes were used as a classical model to study white adipocyte browning. Rosiglitazone was applied to induce browning, and the interactions between LDs and actin, as well as the distribution of Myh9, were assessed using immunofluorescence and Western blotting. In vivo, we employed a microfilament inhibitor to block actin polymerization in cold-stimulated mice and evaluated changes in LD morphology and browning. Furthermore, dynamic live-cell imaging using confocal microscopy was conducted to observe the real-time behavior of LDs during the browning process and to determine whether they undergo fission. Main findingsOur results demonstrate that rosiglitazone significantly induces LD size reduction, a process correlated with the increased contact of LDs with microfilaments. Inhibition of actin polymerization prevented both the reduction in LD size and the browning of white adipocytes, indicating that actin plays a critical role. Myh9 was enriched at the LD fission sites, forming a structure resembling a contractile ring. Overexpression of Myh9 promoted the shrinkage of LD, suggesting that it may be involved in LD fission. SignificanceThis study identifies actin and Myh9 as key regulators of LD fission in rosiglitazone-induced browning of white adipocytes, offering new insights into the cellular mechanisms of adipocyte plasticity. The findings propose a novel pathway by which LD dynamics contribute to the beige conversion of white fat, with potential implications for metabolic disease therapies targeting adipocyte function and energy expenditure.

Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy

Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic and transcriptomic levels, comprehensive proteomic characterization and its implications remain largely unexplored. In this study, we perform proteomic profiling of gliomas using 343 formalin-fixed and paraffin-embedded tumor samples and 53 normal-appearing brain samples from 188 patients, integrating these data with genomic panel information and clinical outcomes. The proteomic analysis uncovers two distinct subgroups: Subgroup 1, the metabolic neural subgroup, enriched in metabolic enzymes and neurotransmitter receptor proteins, and Subgroup 2, the immune subgroup, marked by upregulation of immune and inflammatory proteins. These proteomic subgroups show significant differences in prognosis, tumorigenesis, microenvironment dysregulation, and potential therapeutics, highlighting the critical roles of metabolic and immune processes in glioma biology and patient outcomes. Through a detailed investigation of metabolic pathways guided by our proteomic findings, dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) emerge as potential prognostic biomarkers linked to the reprogramming of nucleotide metabolism. Functional validation in patient-derived glioma stem cells and animal models highlights nucleotide metabolism as a promising therapy target for gliomas. This integrated multi-omics analysis introduces a proteomic classification for gliomas and identifies DPYD and TYMP as key metabolic biomarkers, offering insights into glioma pathogenesis and potential treatment strategies.

Abstract A018: Endothelial pyrimidine synthesis deficiency promotes tumor growth

Abstract The tumor microenvironment plays a crucial role in cancer progression and treatment response. Systemically administered metabolic cancer therapies target not only malignant but also stromal cells, including immune cells - the only stromal population previously addressed in this context. However, how such treatments impact other non-malignant cell types in tumors remains poorly understood. Here we show that inhibition of de novo pyrimidine synthesis in endothelial cells accelerates tumor growth and alters tumor immune repertoire. We found that whole-body de novo pyrimidine synthesis deficiency in mice, caused by the inducible whole-body ablation of DHODH, accelerates the growth rate of orthotopic lung tumors. Single-cell transcriptomic analysis of tumor-bearing lungs revealed that DHODH deficiency in the stroma impacts multiple cell populations, including immune and, surprisingly, endothelial cells. To explore the endothelial-specific effects, we generated a mouse model with inducible DHODH deficiency restricted to endothelial cells. The endothelium-specific model recapitulates the accelerated lung tumor growth observed in the whole-body DHODH deficiency model. Single-cell transcriptomics analysis of tumor-bearing lungs in the endothelium-specific model pointed to changes in the immune repertoire, particularly an enrichment of monocytes. We confirmed these results on the protein level using spectral flow cytometry, and we are currently in the process of uncovering the mechanism by which endothelial deficiency of pyrimidine synthesis affects the immune landscape of tumors. Inhibitors of pyrimidine de novo synthesis have been tested in clinical trials but failed due to their low efficiency. Our findings indicate that systemic treatment targeting pyrimidine synthesis may be hampered by its pro-tumorigenic effects in the endothelium, highlighting the unexpected role of endothelial metabolism in this context. Citation Format: Petra Hyrossova, Isidora Milisav, Silvia Novais, Mirko Milosevic, Jakub Rohlena, Katerina Rohlenova. Endothelial pyrimidine synthesis deficiency promotes tumor growth [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 A018.

CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking. METHODS We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index < 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.

TMET-27. MACHINE LEARNING-BASED IDENTIFICATION OF METABOLIC FLUXES IN PATIENT BRAIN TUMORS

Abstract Personalized oncology aims to match effective treatments for individual cancer patients based on the biology of an individual tumor. This approach is not possible for metabolic therapies due to our inability to quantify metabolic activity in patient tumors, even when patients are infused with 13C-glucose. We overcame this challenge by generating training data with a prior knowledge of 13C-glucose infused patient data and implementing a machine learning model to predict fluxes. We trained a convolutional neural network (CNN) to predict flux ratios. To validate our model, we compared predicted flux ratios to the experimental 13C-glucose-infused mouse models to predict treatment responses for: (1) pharmacologic inhibition of de novo GMP synthesis and (2) environmental serine restriction. Our GMP synthesis model predicted elevated GMP synthesis in GBM compared to cortex in a mouse model and discriminated between sources of GMP synthesis in patients. These findings allow prediction of potential responders to mycophenolate mofetil (MMF), which inhibits de novo but not salvage GMP synthesis. Furthermore, we previously showed that circulating serine uptake is higher in GBM than normal cortex, and a serine- and glycine-restricted diet slows tumor growth in mice. While de novo serine synthesis, circulating and microenvironmental-derived serine could account for serine sources in GBM, our model can distinguish between serine sources in patients, hence potentially predict response to dietary serine depletion. Thus, we have shown that our model may identify patients who will benefit from MMF treatment or a serine- and glycine-restricted diet, potentially enabling administration of highly effective personalized metabolic treatments for GBM patients.

NIMG-69. INTERROGATION OF GLIOBLASTOMA FATTY-ACID SYNTHESIS AND METABOLISM WITH DEUTERIUM METABOLIC IMAGING

Abstract Glioblastoma, an invariably lethal brain tumor, undergoes marked metabolic alterations during tumorigenesis and is extraordinarily difficult to treat. Detecting recurrence after treatment and understanding metabolic alterations within the tumor microenvironment are extremely challenging. An exciting and emerging imaging methodology, deuterium metabolic imaging (DMI), detects metabolic adaptations via non-radioactively labeled deuterated substrates. This study developed approaches to image lipid synthesis with deuterium oxide (D2O) and metabolism with D31-palmitate (D31-Pal) in glioblastoma. A fatty-acid phantom was generated for characterization of lipid DMI signal at 12 T. DMI was performed in mice orthotopically implanted with GL261 glioblastoma utilizing either orally administered D31-Pal or D2O and was correlated with pharmacokinetic metabolic measurements from mouse serum. Mice were either orally gavaged with an emulsion of D31-Pal prior to imaging or provided 16% D2O for ad libitum consumption following tumor implantation. Although D2O administration resulted in robust enrichment of lipid signal in GBM, D31-Pal uptake and metabolism were not significantly detected within intracranial tumors. Interestingly, D31-Pal uptake and metabolism were detected in normal tissues, indicating preferential utilization of fatty acids in non-neoplastic tissues. These findings suggest de novo lipogenesis within GBM, rather than uptake of administered long chain fatty acids, is the preferential pathway for cellular lipids. DMI can assist in interrogating GBM fatty-acid synthesis and metabolism, as well as furthering our understanding of lipid distribution within the body by providing a non-invasive scaffold for dynamic interrogation of fatty-acid distribution in an oncologic model. Developing a non-invasive method for characterization of tumor fatty-acid synthesis and metabolism may improve our understanding of tumor metabolism and could dynamically guide selection of patient-tailored metabolic therapies in the future.

Targeting Disulfidptosis with Potentially Bioactive Natural Products in Metabolic Cancer Therapy.

Metabolic cancers are defined by metabolic reprogramming. Although this reprograming drives rapid tumour growth and invasion, it also reveals specific metabolic vulnerabilities that can be therapeutically exploited in cancer therapy. A novel form of programmed cell death, known as disulfidptosis, was identified last year; tumour cells with high SLC7A11 expression undergo disulfidptosis when deprived of glucose. Natural products have attracted increasing attention and have shown potential to treat metabolic cancers through diverse mechanisms. We systematically searched electronic databases involving PubMed, Web of Science, Gooale Scholar. To ensue comprehensive exploration, keywords including metabolic reprogramming, metabolic cancer, disulfidptosis, natural products and some other words were employed. In this review, we focus on the shared characteristics and metabolic vulnerabilities of metabolic cancers. Additionally, we discuss the molecular mechanisms underlying disulfidptosis and highlight key regulatory genes. Furthermore, we predict bioactive natural products that target disulfidptosis-related genes, offering new perspectives for anticancer strategies through the modulation of disulfidptosis. By summarizing current research progress, this review mainly analyzed the potential mechanisms of natural products in the treatment of metabolic cancer.

Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms.

Neutrophils are key mediators of the immune response and play essential roles in the development of tumors and immune evasion. Emerging studies indicate that neutrophils also play a critical role in the immunotherapy resistance in cancer. In this review, firstly, we summarize the novel classification and phenotypes of neutrophils and describe the regulatory relationships between neutrophils and tumor metabolism, flora microecology, neuroendocrine and tumor therapy from a new perspective. Secondly, we review the mechanisms by which neutrophils affect drug resistance in tumor immunotherapy from the aspects of the immune microenvironment, tumor antigens, and epigenetics. Finally, we propose several promising strategies for overcoming tumor immunotherapy resistance by targeting neutrophils and provide new research ideas in this area.

Dual-function natural products: Farnesoid X receptor agonist/inflammation inhibitor for metabolic dysfunction-associated steatotic liver disease therapy

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, with only one Food and Drug Administration (FDA)-approved drug for its treatment. Given MASLD’s complex pathophysiology, therapies that simultaneously target multiple pathways are highly desirable. One promising approach is dual-modulation of the farnesoid X receptor (FXR), which regulates lipid and bile acid metabolism. However, FXR agonists alone are insufficient due to their limited anti-inflammatory effects. This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD. Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger (2018) for molecular docking. Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance (SPR) binding assay, reporter gene analysis, and reverse transcription-polymerase chain reaction (RT-PCR). The anti-inflammatory properties of these compounds were evaluated in AML12 cells treated with tumor necrosis factor-alpha (TNF-α). Dual-function compounds with FXR agonism and inflammation inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α. The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid. Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists, with 15 exhibiting a strong affinity for FXR recombinant protein. Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb. Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones. Three compounds (2, 6, and 8) were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors, while one compound (12) acted as an FXR agonist to inhibit inflammation. These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and inflammation. In conclusion, compounds 2, 6, and 8 (genistein, biochanin A, and 7-methoxyisoflavone, respectively) were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation, serving as potential candidates or lead compounds for MASLD therapy.

Targeting Glycolytic Reprogramming in Cholangiocarcinoma: A Novel Approach for Metabolic Therapy.

Cholangiocarcinoma (CCA) is a highly aggressive and poorly prognostic tumor. Due to the lack of early symptoms, diagnosing CCA remains challenging, often occurring at an advanced stage. Therefore, exploring the underlying mechanisms of CCA development and identifying potential biomarkers and therapeutic targets is crucial. Recently, metabolic reprogramming in cancer cells has emerged as a hallmark of the disease. Glycolysis has been identified as a central component of metabolic reprogramming in CCA, with multiple signaling pathways and key enzymes playing significant roles. Additionally, non-coding RNAs (ncRNAs) and post-translational modifications of proteins are also involved in regulating glycolysis in CCA. In this review, we provide a comprehensive summary of the alterations in cancer metabolism and the diverse signaling pathways involved, as they might exert an impact on the development of CCA. Overall, targeting glycolysis holds considerable promise as a crucial strategy for enhancing the therapeutic outcomes of CCA. In addition, we performed a bioinformatic analysis of the relationship between CCA and glycolysis to identify and investigate potential targets. The purpose of this study is to provide a theoretical basis for the development of CCA targets.

Endocrine disorders in Kearns-Sayre syndrome with different severity of symptoms: two case reports and a literature review.

Kearns-Sayre Syndrome (KSS) is a variant of mitochondrial disorder caused by a Mitochondrial Deoxyribonucleic Acid (mtDNA) deletion. Clinical manifestations of KSS can include different organ and system involvement. Different organ malfunctions, more often cardiac dysfunction, can lead to death. No effective treatment of this condition exists to date. Here, we report two patients with KSS. Female patient with a large-scale deletion of 7,020 base pairs (bp) suffered from hypogonadism, diabetes mellitus with fluctuating glucose levels, and had poor general health. A male patient with a common 4,977 bp deletion did not have diabetes mellitus but had impaired glucose tolerance. He also had a higher level of general health than our female patient. Both patients had reduced Bone Mineral Density (BMD). In female patients, calcium and vitamin D supplementation combined with metabolic therapy and nutritional drink supplements helped increase BMD (up to 32% in L1-L4). Comparing these two patients suggests that the larger the mtDNA deletion is, the more severe the course of the disease is. Not only does the size of the mtDNA deletion probably determine the severity of the disease, but also such factors as mtDNA heteroplasmy level, presence of mtDNA duplications, and pleioplasmy. Moreover, continuous nonconsecutive metabolic therapy and nutritional supplements are helpful in the prevention of deterioration of symptoms and general health.

Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in preclinical individuals with an HCM sarcomeric gene mutation

Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic gene variants, i.e. mutations in genes encoding sarcomere proteins. Previous studies have shown that preclinical asymptomatic individuals with a heterozygous sarcomere mutation have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Purpose In the ENERGY trial, preclinical individuals with an HCM sarcomere gene mutation without hypertrophy were treated with the metabolic anti-anginal drug trimetazidine (TMZ) to determine whether the reduced MEE can be corrected at an early pre-hypertrophic disease stage. Methods 40 MYBPC3 and MYH7 asymptomatic mutation carriers without hypertrophy were treated for eight weeks with TMZ or placebo in a double-blind randomized study design. Directly before and after treatment, study participants underwent an [11C]-acetate PET/CT-scan and cardiac magnetic resonance imaging to measure MEE. A cardio-pulmonary exercise test was performed to measure the influence of TMZ on exercise parameters. Results Eight weeks of treatment with TMZ 20mg three times daily did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3±3.8 percent to 29.8±4.3 percent in the placebo group and from 30.1±4 percent to 29.1±4 percent in the TMZ group. After adjustment for baseline, the TMZ group did not have a significantly different MEE (95% CI, -2.863 to 1.986, P=0.68) compared to placebo. Exercise parameters VO2max and respiratory exchange ratio were not significantly altered by treatment with TMZ. Conclusion The ENERGY trial is the first proof-of-concept randomized controlled trial with well-matched (age, sex, mutation) groups to test the hypothesis that TMZ improves MEE at a preclinical disease stage. We conclude that metabolic therapy does not correct reduced MEE in an early disease stage of HCM.methodsprimary outcome

Metabolic and Epigenetic Mechanisms in Hepatoblastoma: Insights into Tumor Biology and Therapeutic Targets.

Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments.

Nanomaterial-Enhanced Microneedles: Emerging Therapies for Diabetes and Obesity.

Drug delivery systems (DDS) have improved therapeutic agent administration by enhancing efficacy and patient compliance while minimizing side effects. They enable targeted delivery, controlled release, and improved bioavailability. Transdermal drug delivery systems (TDDS) offer non-invasive medication administration and have evolved to include methods such as chemical enhancers, iontophoresis, microneedles (MN), and nanocarriers. MN technology provides innovative solutions for chronic metabolic diseases like diabetes and obesity using various MN types. For diabetes management, MNs enable continuous glucose monitoring, diabetic wound healing, and painless insulin delivery. For obesity treatment, MNs provide sustained transdermal delivery of anti-obesity drugs or nanoparticles (NPs). Hybrid systems integrating wearable sensors and smart materials enhance treatment effectiveness and patient management. Nanotechnology has advanced drug delivery by integrating nano-scaled materials like liposomes and polymeric NPs with MNs. In diabetes management, glucose-responsive NPs facilitate smart insulin delivery. At the same time, lipid nanocarriers in dissolving MNs enable extended release for obesity treatment, enhancing drug stability and absorption for improved metabolic disorder therapies. DDS for obesity and diabetes are advancing toward personalized treatments using smart MN enhanced with nanomaterials. These innovative approaches can enhance patient outcomes through precise drug administration and real-time monitoring. However, widespread implementation faces challenges in ensuring biocompatibility, improving technologies, scaling production, and obtaining regulatory approval. This review will present recent advances in developing and applying nanomaterial-enhanced MNs for diabetes and obesity management while also discussing the challenges, limitations, and future perspectives of these innovative DDS.

Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.

Elevating ketone levels with therapeutic nutritional ketosis can help to metabolically manage disease processes associated with epilepsy, diabetes, obesity, cancer, and neurodegenerative disease. Nutritional ketosis can be achieved with various dieting strategies such as the classical ketogenic diet, the modified Atkins diet, caloric restriction, periodic fasting, or the consumption of exogenous ketogenic supplements such as medium-chain triglycerides (MCTs). However, these various strategies can be unpleasant and difficult to follow, so that achieving and sustaining nutritional ketosis can be a major challenge. Thus, investigators continue to explore the science and applications of exogenous ketone supplementation as a means to further augment the therapeutic efficacy of this metabolic therapy. Here, we describe a structurally new synthetic triglyceride, glycerol tri-acetoacetate (Gly-3AcAc), that we prepared from glycerol and an acetoacetate precursor that produces hyperketonemia in the therapeutic range (2-3 mM) when administered to mice under both fasting and non-fasting conditions. Animal studies were undertaken to evaluate the potential effects of eliciting a ketogenic response systemically. Acute effects (24 h or less) were determined in male VM/Dk mice in both fasted and unfasted dietary states. Concentration levels of β-hydroxybutyrate in blood were elevated (βHB; 2-3 mM) under both conditions. Levels of glucose were reduced only in the fasted state. No detrimental side effects were observed. Pending further study, this novel compound could potentially add to the repertoire of methods for inducing therapeutic nutritional ketosis.

CHARACTERISATION OF THE RESPONSE OF PRE-CLINICAL MODELS OF GLIOMA TO METABOLIC THERAPIES USING IN VIVO MAGNETIC RESONANCE SPECTROSCOPY

Abstract AIMS Magnetic resonance imaging (MRI) is routinely used to diagnose and monitor brain tumours. Magnetic resonance spectroscopy (MRS) allows us to record the metabolic profile of tumours in situ. This provides a non-invasive method to monitor the response of tumours to metabolic therapies. We aimed to characterise the response of pre-clinical models of glioma to metabolic therapies such as arginine deprivation and the ketogenic diet (KD) by MRS, to better understand what metabolic changes are occurring in the tumour. METHOD We performed orthotopic injection of three different cell lines, including the syngeneic models GL261 and CT2A, as well as a primary GBM cell line, into the striatum of C57BL/6 and athymic nude mice respectively. Mice were randomised to either arginine deprivation treatment using pegylated arginine deiminase (ADI), or KD, plus controls. In each animal, we collected single voxel MRS data using STEAM on both the tumour itself, and healthy brain. MRS data was exported in jMRUI format and analysed in R using the spant package, followed by PCA and OPLS-DA. RESULTS PCA showed that there is clear distinction between healthy and tumour spectra across all models. OPLS-DA indicated that the lipid and choline spectral regions were significantly associated with tumour, whereas the NAA and glutamine/glutamate regions were significantly associated with healthy brain. Integration of specific peaks associated with these metabolites confirmed these results. Subset analysis indicated distinct metabolic signatures between the syngeneic models and the primary GBM model. Furthermore, there is evidence to suggest that tumours in animals treated with arginine deprivation have a unique metabolic signature. CONCLUSION This data indicates that the tumour specific response to metabolic therapies can be measured by routine MRS screening. This would allow a non-invasive method by which clinicians could monitor the effectiveness of metabolic therapies in patients with gliomas.

UNVEILING THE MECHANISTIC INSIGHTS OF ARGININE DEPRIVATION COMBINED WITH RADIOTHERAPY FOR THE TREATMENT OF GLIOBLASTOMA

Abstract AIMS Glioblastoma is a lethal form of primary brain tumour in adults. Despite surgery, radiation and chemotherapy, life expectancy is short rendering the need for novel therapeutic approaches. Metabolic therapies provide a multifaceted effect in the heterogeneous glioblastoma microenvironment as they target its reprogrammed metabolism while overcoming therapeutic obstacles such as the blood brain barrier. We have shown that arginine deprivation combined with radiation eliminates the tumours in vivo, however, the exact mechanism of action is yet unknown. Here, using spatial transcriptomics we explore the effects of arginine deprivation and radiation, alone and combined, on the glioblastoma microenvironment. METHOD Brains collected from CT2A immunocompetent mice 6 days after treatment with ADI-PEG20 (5 IU) for arginine depletion, radiation (8 Gy) or their combination were analysed by 10X Genomics Spatial Transcriptomics. Bioinformatic analysis was performed using the R package Seurat and the Ingenuity Pathway Analysis (Qiagen). RESULTS The induction of innate immune response was observed with all treatments, however, it was the prevailing element only in the combination treatment. Upregulated pathways in all treatments involved the activation of antigen presentation cells. The pro-inflammatory cascades included key molecules of an immune response such as Type I IFNs, IFN-γ, STAT1, ISG15 and IRFs. Protein translation pathways indicating resistance to treatment dominated the changes caused by the two monotherapies, while they were absent in the combination group. The upregulation of CXCL10 and CCL5 signified the transition to adaptive immune response. Cytosolic DNA sensing by the cGAS-STING was enriched in the radiation and combination groups providing a possible trigger for the innate immune response. Pyroptosis and extracellular matrix remodelling were uniquely presented in the combination group. CONCLUSION Our analysis indicates that arginine deprivation and radiation when combined enhance each other’s effect leading to a fortified immune response that is possibly initiated by cytosolic DNA sensing.

Comparative analysis of post-procedural symptom patterns after intragastric balloon and endoscopic sleeve gastroplasty

Aim: Endoscopic bariatric and metabolic therapies (EBMTs) offer minimally invasive approaches for obesity management, with intragastric balloon (IGB) and endoscopic sleeve gastroplasty (ESG) being amongst the most prominent interventions. While both are effective, their comparative impact on post-procedural gastric symptoms remains underexplored. Methods: Single-center retrospective study was designed to evaluate the incidence of post-procedure symptoms in patients undergoing IGB and ESG. Incidence and severity of gastric symptoms were assessed using visual analog scales at various time points. Weight outcomes and medication usage were also recorded. Changes at different time points (baseline, one and four months) were compared by means of Mann-Whitney U Test. Bivariate correlations were carried out through Pearson correlation. Results: Thirty patients undergoing IGB placement and 13 patients undergoing ESG were included in the analysis. ESG group showed a significant reduction in BMI at four months compared to IGB (32.2 ± 4.2 vs . 34.4 ± 5.3, P = 0.05). ESG demonstrated significantly lower rates of post-procedural gastric symptoms compared to IGB, including nausea, regurgitation, vomiting, and abdominal cramps and greater satiety (P < 0.001) in the early postoperative period. Medication usage differed between groups, with higher usage of antispasmodics and antiemetics among IGB patients during the first week (P < 0.001). Symptom severity correlated with the need for antiemetics and antispasmodics. Conclusion: This study provides insights into the management of gastric symptoms following two prominent EBMTs. While both endoscopic interventions offer viable options for obesity management, ESG emerges as a favorable choice due to its significantly lower incidence of early post-procedural gastric symptoms. Further research is warranted to refine symptom management strategies and elucidate differences in symptom profiles between IGB and ESG procedures, ultimately aiming to optimize treatment efficacy and patient satisfaction in the field of endoscopic obesity interventions.