PubMed

Clin Cancer Res. 2024 Feb 16. doi: 10.1158/1078-0432.CCR-23-3433. Online ahead of print.ABSTRACTINTRODUCTION: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will impact therapeutic efficacy.METHODS: We performed in vivo and in vitro experiments employing PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow cytometric data to investigate these alterations.RESULTS: FF improved anti-tumor efficacy of high dose per fraction radiotherapy in HNC murine models, while the OAD reversed this effect. FF treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36.CONCLUSION: Metabolic intervention with increased FA catabolism improves efficacy of HNC therapy and enhance anti-tumoral immune response.PMID:38363297 | DOI:10.1158/1078-0432.CCR-23-3433

J Agric Food Chem. 2024 Feb 16. doi: 10.1021/acs.jafc.3c08429. Online ahead of print.ABSTRACTCombining nanoselenium (nano-Se) and melatonin (MT) was more effective than treatment alone against abiotic stress. However, their combined application mitigated the toxic effects of bensulfuron methyl, and enhanced wheat growth and metabolism has not been studied. Metabolomics and proteomics revealed that combining nano-Se and MT markedly activated phenylpropanoid biosynthesis pathways, elevating the flavonoid (quercetin by 33.5 and 39.8%) and phenolic acid (vanillic acid by 38.8 and 48.7%) levels in leaves and roots of wheat plants. Interstingly, beneficial rhizosphere bacteria in their combination increased (Oxalobacteraceae, Nocardioidaceae, and Xanthomonadaceae), which positively correlated with the enhancement of soil urease and fluorescein diacetate enzyme activity (27.0 and 26.9%) and the allelopathic substance levels. To summarize, nano-Se and MT mitigate the adverse effects of bensulfuron methyl by facilitating interactions between the phenylpropane metabolism of the plant and the beneficial microbial community. The findings provide a theoretical basis for using nano-Se and MT to remediate herbicide-contaminated soil.PMID:38363203 | DOI:10.1021/acs.jafc.3c08429

Pediatr Allergy Immunol. 2024 Feb;35(2):e14084. doi: 10.1111/pai.14084.ABSTRACTThe increasing prevalence of IgE-mediated cow's milk allergy (CMA) in childhood is a worldwide health concern. There is a growing awareness that the gut microbiome (GM) might play an important role in CMA development. Therefore, treatment with probiotics and prebiotics has gained popularity. This systematic review provides an overview of the alterations of the GM, metabolome, and immune response in CMA children and animal models, including post-treatment modifications. MEDLINE, PubMed, Scopus, and Web of Science were searched for studies on GM in CMA-diagnosed children, published before 1 March 2023. A total of 21 articles (13 on children and 8 on animal models) were included. The studies suggest that the GM, characterized by an enrichment of the Clostridia class and reductions in the Lactobacillales order and Bifidobacterium genus, is associated with CMA in early life. Additionally, reduced levels of short-chain fatty acids (SCFAs) and altered amino acid metabolism were reported in CMA children. Commonly used probiotic strains belong to the Bifidobacterium and Lactobacillus genera. However, only Bifidobacterium levels were consistently upregulated after the intervention, while alterations of other bacteria taxa remain inconclusive. These interventions appear to contribute to the restoration of SCFAs and amino acid metabolism balance. Mouse models indicate that these interventions tend to restore the Th 2/Th 1 balance, increase the Treg response, and/or silence the overall pro- and anti-inflammatory cytokine response. Overall, this systematic review highlights the need for multi-omics-related research in CMA children to gain a mechanistic understanding of this disease and to develop effective treatments and preventive strategies.PMID:38363041 | DOI:10.1111/pai.14084

J Cell Biochem. 2024 Feb 16. doi: 10.1002/jcb.30542. Online ahead of print.ABSTRACTFerroptosis is a form of regulated cell death that is induced by inhibiting glutathione peroxidase 4 (GPX4), which eliminates lipid peroxidation. Ferroptosis induction is influenced by the cell environment. However, the cellular states altering ferroptosis susceptibility remain largely unknown. We found that melanoma cell lines became resistant to ferroptosis as cell density increased. Comparative transcriptome and metabolome analyses revealed that cell density-dependent ferroptosis resistance was coupled with a shift toward a lipogenic phenotype accompanied by strong induction of stearoyl-CoA desaturase (SCD). Database analysis of gene dependency across hundreds of cancer cell lines uncovered a negative correlation between GPX4 and SCD dependency. Importantly, SCD inhibition, either pharmacologically or through genetic knockout, sensitized melanoma cells to GPX4 inhibition, thereby attenuating ferroptosis resistance in cells at high density. Our findings indicate that transition to an SCD-inducing, lipogenic cell state produces density-dependent resistance to ferroptosis, which may provide a therapeutic strategy against melanoma.PMID:38362828 | DOI:10.1002/jcb.30542

FEBS J. 2024 Feb 16. doi: 10.1111/febs.17083. Online ahead of print.ABSTRACTNeuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.PMID:38362803 | DOI:10.1111/febs.17083

Expert Rev Proteomics. 2024 Feb 16. doi: 10.1080/14789450.2024.2320166. Online ahead of print.NO ABSTRACTPMID:38362700 | DOI:10.1080/14789450.2024.2320166

Front Cell Infect Microbiol. 2024 Feb 1;14:1258246. doi: 10.3389/fcimb.2024.1258246. eCollection 2024.ABSTRACTPulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of fibroblasts, excessive deposition of extracellular matrix (ECM), and concomitant inflammatory damage. Its characteristics include short median survival, high mortality rate, and limited treatment effectiveness. More in-depth studies on the mechanisms of PF are needed to provide better treatment options. The idea of the gut-lung axis has emerged as a result of comprehensive investigations into the microbiome, metabolome, and immune system. This theory is based on the material basis of microorganisms and their metabolites, while the gut-lung circulatory system and the shared mucosal immune system act as the connectors that facilitate the interplay between the gastrointestinal and respiratory systems. The emergence of a new view of the gut-lung axis is complementary and cross-cutting to the study of the mechanisms involved in PF and provides new ideas for its treatment. This article reviews the mechanisms involved in PF, the gut-lung axis theory, and the correlation between the two. Exploring the gut-lung axis mechanism and treatments related to PF from the perspectives of microorganisms, microbial metabolites, and the immune system. The study of the gut-lung axis and PF is still in its early stages. This review systematically summarizes the mechanisms of PF related to the gut-lung axis, providing ideas for subsequent research and treatment of related mechanisms.PMID:38362497 | PMC:PMC10867257 | DOI:10.3389/fcimb.2024.1258246

iScience. 2024 Jan 26;27(2):108999. doi: 10.1016/j.isci.2024.108999. eCollection 2024 Feb 16.ABSTRACTExercise, an intervention with wide-ranging effects on the whole body, has been shown to delay aging. Due to aging and exercise as modulator of metabolism, a picture of how exercise delayed D-galactose (D-gal)-induced aging in a time-resolved manner was presented in this paper. The mapping of molecular changes in response to exercise has become increasingly accessible with the development of omics techniques. To explore the dynamic changes during exercise, the serum of rats and D-gal-induced aging rats before, during, and after exercise was analyzed by untargeted metabolomics. The variation of metabolites was monitored to reveal the specific response to D-gal-induced senescence and exercise in multiple pathways, especially the basal amino acid metabolism, including glycine serine and threonine metabolism, cysteine and methionine metabolism, and tryptophan metabolism. The homeostasis was disturbed by D-gal and maintained by exercise. The paper was expected to provide a theoretical basis for the study of anti-aging exercise.PMID:38362265 | PMC:PMC10867647 | DOI:10.1016/j.isci.2024.108999

Front Pharmacol. 2024 Feb 1;15:1257941. doi: 10.3389/fphar.2024.1257941. eCollection 2024.ABSTRACTBackground: Small extracellular vesicles (sEVs) mediate intercellular communication in the tumor microenvironment (TME) and contribute to the malignant transformation of tumors, including unrestricted growth, metastasis, or therapeutic resistance. However, there is a lack of agents targeting sEVs to overcome or reverse tumor chemotherapy resistance through sEVs-mediated TME reprogramming. Methods: The paclitaxel (PTX)-resistant A549T cell line was used to explore the inhibitory effect of alpha-hederin on impeding the transmission of chemoresistance in non-small cell lung cancer (NSCLC) through the small extracellular vesicles (sEVs) pathway. This investigation utilized the CCK-8 assay and flow cytometry. Transcriptomics, Western blot, oil red O staining, and targeted metabolomics were utilized to evaluate the impact of alpha-hederin on the expression of signaling pathways associated with chemoresistance transmission in NSCLC cells before and after treatment. In vivo molecular imaging and immunohistochemistry were conducted to assess how alpha-hederin influences the transmission of chemoresistance through the sEVs pathway. RT-PCR was employed to examine the expression of miRNA and lncRNA in response to alpha-hederin treatment. Results: The resistance to PTX chemotherapy in A549T cells was overcome by alpha-hederin through its dependence on sEV secretion. However, the effectiveness of alpha-hederin was compromised when vesicle secretion was blocked by the GW4869 inhibitor. Transcriptomic analysis for 463 upregulated genes in recipient cells exposed to A549T-derived sEVs revealed that these sEVs enhanced TGFβ signaling and unsaturated fatty acid synthesis pathways. Alpha-hederin inhibited 15 types of unsaturated fatty acid synthesis by reducing the signaling activity of the sEVs-mediated TGFβ/SMAD2 pathway. Further, we observed that alpha-hederin promoted the production of three microRNAs (miRNAs, including miR-21-5p, miR-23a-3p, and miR-125b-5p) and the sorting to sEVs in A549T cells. These miRNAs targeted the TGFβ/SMADs signaling activity in sEVs-recipient cells and sensitized them to the PTX therapy. Conclusion: Our finding demonstrated that alpha-hederin could sensitize PTX-resistant NSCLC cells by sEV-mediated multiple miRNAs accumulation, and inhibiting TGFβ/SMAD2 pathways in recipient cells.PMID:38362150 | PMC:PMC10867254 | DOI:10.3389/fphar.2024.1257941

Front Nutr. 2024 Feb 1;10:1358428. doi: 10.3389/fnut.2023.1358428. eCollection 2023.NO ABSTRACTPMID:38361955 | PMC:PMC10867326 | DOI:10.3389/fnut.2023.1358428

iScience. 2024 Jan 29;27(3):108959. doi: 10.1016/j.isci.2024.108959. eCollection 2024 Mar 15.ABSTRACTMucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.PMID:38361619 | PMC:PMC10864807 | DOI:10.1016/j.isci.2024.108959

Front Cardiovasc Med. 2024 Feb 1;11:1247472. doi: 10.3389/fcvm.2024.1247472. eCollection 2024.ABSTRACTOBJECTIVE: Cold-inducible RNA binding Protein (CIRBP) has been shown to be a potent inflammatory mediator and could serve as a novel biomarker for inflammation. Systemic inflammatory response syndrome (SIRS) and capillary leak syndrome (CLS) are frequent complications after pediatric cardiac surgery increasing morbidity, therefore early diagnosis and therapy is crucial. As CIRBP serum levels have not been analyzed in a pediatric population, we conducted a clinical feasibility establishing a customized magnetic bead panel analyzing CIRBP in pediatric patients undergoing cardiac surgery.METHODS: A prospective hypothesis generating observational clinical study was conducted at the German Heart Center Berlin during a period of 9 months starting in May 2020 (DRKS00020885, https://drks.de/search/de/trial/DRKS00020885). Serum samples were obtained before the cardiac operation, upon arrival at the pediatric intensive care unit, 6 and 24 h after the operation in patients up to 18 years of age with congenital heart disease (CHD). Customized multiplex magnetic bead-based immunoassay panels were developed to analyze CIRBP, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Monocyte chemotactic protein 1 (MCP-1), Syndecan-1 (SDC-1), Thrombomodulin (TM), Vascular endothelial growth factor (VEGF-A), Angiopoietin-2 (Ang-2), and Fibroblast growth factor 23 (FGF-23) in 25 µl serum using the Luminex MagPix® system.RESULTS: 19 patients representing a broad range of CHD (10 male patients, median age 2 years, 9 female patients, median age 3 years) were included in the feasibility study. CIRBP was detectable in the whole patient cohort. Relative to individual baseline values, CIRBP concentrations increased 6 h after operation and returned to baseline levels over time. IL-6, IL-8, IL-10, and MCP-1 concentrations were significantly increased after operation and except for MCP-1 concentrations stayed upregulated over time. SDC-1, TM, Ang-2, as well as FGF-23 concentrations were also significantly increased, whereas VEGF-A concentration was significantly decreased after surgery.DISCUSSION: Using customized magnetic bead panels, we were able to detect CIRBP in a minimal serum volume (25 µl) in all enrolled patients. To our knowledge this is the first clinical study to assess CIRBP serum concentrations in a pediatric population.PMID:38361581 | PMC:PMC10867162 | DOI:10.3389/fcvm.2024.1247472

Br J Nutr. 2024 Feb 16:1-31. doi: 10.1017/S0007114524000473. Online ahead of print.ABSTRACTElevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analyzed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (food frequency questionnaire) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS, or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol, and total energy intake. Average (geometric mean [95% prediction interval]) intake was 49 (38, 63) energy percent (E%) from carbohydrate, 31 (22, 45) E% from fat, and 17 (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e., with higher plasma pyridoxal 5'-phosphate (PLP) (% change [95% confidence interval] 3.1 [2.1, 4.1]), cobalamin (2.9 [2.1, 3.7]), riboflavin (2.4 [1.1, 3.7]), and folate (2.1 [1.2, 3.1]), and lower total homocysteine (tHcy) (-1.4 [-1.9, -0.9]) and methylmalonic acid (MMA) (-1.4 [-2.0, -0.8]). Substitution analyses replacing mono- or polyunsaturated with saturated fatty acids demonstrated higher plasma concentrations of riboflavin (5.0 [0.9, 9.3] and 3.3 [1.1, 5.6]), tHcy (2.3 [0.7, 3.8] and 1.3 [0.5, 2.2]), and MMA (2.0 [0.2, 3.9] and 1.7 [0.7, 2.7]), and lower PLP (-2.5 [-5.3, 0.3] and -2.7 [-4.2, -1.2]). In conclusion, a higher protein intake, and replacing saturated with mono- and polyunsaturated fatty acids, was associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.PMID:38361451 | DOI:10.1017/S0007114524000473

Nat Genet. 2024 Feb 15. doi: 10.1038/s41588-024-01662-5. Online ahead of print.ABSTRACTClear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.PMID:38361033 | DOI:10.1038/s41588-024-01662-5

Iran J Med Sci. 2024 Feb 1;49(2):121-129. doi: 10.30476/IJMS.2023.96413.2795. eCollection 2024 Feb.ABSTRACTBACKGROUND: Stem cell-derived secretome (SE) released into the extracellular space contributes to tissue repair. The present study aimed to investigate the impact of isolated secretome (SE) from adipose-derived mesenchymal stem cells (ASCs) on Leishmania major (L. major) lesions in BALB/c mice.METHODS: This experimental study was conducted at Ahvaz University of Medical Sciences (Ahvaz, Iran) in 2021. Forty female BALB/c mice were infected with stationary phase promastigotes through intradermal injection in the bottom of their tail and randomly divided into four groups (n=10 per group). The mice were given SE (20 mg/mL), either alone or in combination with Glucantime (GC, 20 mg/mL/Kg), meglumine antimoniate (20 mg/mL/Kg) for the GC group, and phosphate-buffered saline (PBS) for the control group. After eight weeks, the lesion size, histopathology, the levels of Interleukin 10 (IL-10), and Interleukin 12 (IL-12) were assessed. For the comparison of values between groups, the parametric one-way ANOVA was used to assess statistical significance.RESULTS: At the end of the experiment, the mice that received SE had smaller lesions (4.56±0.83 mm versus 3.62±0.59 mm, P=0.092), lower levels of IL-10 (66.5±9.7 pg/mL versus 285.4±25.2 pg/mL, P<0.001), and higher levels of IL-12 (152.2±14.2 pg/mL versus 24.2±4.4 pg/mL, P<0.001) than the control. Histopathology findings revealed that mice treated with SE had a lower parasite burden in lesions and spleen than the control group.CONCLUSION: The current study demonstrated that ADSC-derived SE could protect mice infected with L. major against leishmaniasis.PMID:38356483 | PMC:PMC10862109 | DOI:10.30476/IJMS.2023.96413.2795

Physiol Plant. 2024 Jan-Feb;176(1):e14220. doi: 10.1111/ppl.14220.ABSTRACTMyrtaceae species are abundant in tropical Atlantic rainforests, but 41% of the 5500 species of this family are of extreme conservation concern. Eugenia astringens and E. uniflora are native Brazilian Myrtaceae species that occur in the same habitats and produce desiccation-sensitive (DS) seeds. We hypothesized that their seed desiccation-sensitivity degree is associated with specific metabolic signatures. To test it, we analyzed the germination and metabolic profiles of fresh and desiccated seeds. The water content (WC) at which at least half of the seeds survived desiccation was lower in E. astringens (0.17 g H2 O g-1 DW) than in E. uniflora (0.41 g H2 O g-1 DW). We identified 103 annotated metabolites from 3261 peaks in both species, which differed in their relative contents between E. astringens and E. uniflora seeds. The main differences in seed metabolic profiles include several protective molecules in the group of carbohydrates and organic acids and amino acid contents. The relative contents of monosaccharides and disaccharides, malic and quinic acids, amino acids and saturated fatty acids may have taken part in the distinct DS behaviour of E. astringens and E. uniflora seeds. Our study provides evidence of the relationship between desiccation sensitivity, seed viability and metabolic profile of tropical seeds by comparing two closely related Eugenia species with different DS degrees.PMID:38356368 | DOI:10.1111/ppl.14220

Leukemia. 2024 Feb 15. doi: 10.1038/s41375-024-02137-6. Online ahead of print.ABSTRACTSubtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.PMID:38360865 | DOI:10.1038/s41375-024-02137-6

Mol Pharmacol. 2024 Feb 15;105(3):118-120. doi: 10.1124/molpharm.124.000866.ABSTRACTLong thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, including lysosomal storage disorders, multiple sclerosis, inflammation, and cancer as well as metabolic syndrome and obesity. In addition, the indications for many of these lipids to potentially serve as biomarkers for disease continue to emerge with increasing metabolomic and lipidomic studies. The implications of these studies have, in turn, led to the examination of SL enzymes and their bioactive lipids as potential therapeutic targets and as markers for therapeutic efficacy. SIGNIFICANCE STATEMENT: Many sphingolipids (SLs) and their metabolizing enzymes have been implicated in disease. This perspective highlights the potential for SLs to serve as therapeutic targets and diagnostic markers and discusses the implications for the studies and reviews highlighted in this Special Section on Therapeutic Implications for Sphingolipids in Health and Disease.PMID:38360837 | DOI:10.1124/molpharm.124.000866

Sci Rep. 2024 Feb 15;14(1):3841. doi: 10.1038/s41598-024-53305-8.NO ABSTRACTPMID:38360824 | DOI:10.1038/s41598-024-53305-8

Sci Rep. 2024 Feb 15;14(1):3823. doi: 10.1038/s41598-023-45608-z.ABSTRACTZebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.PMID:38360784 | DOI:10.1038/s41598-023-45608-z