Metabolic Impact Research Articles

Comparison of Fasting Blood Sugar Levels and Ureum Levels In Diabetes Mellitus Patients and Diabetic Nephropathy Patients

General Background: Diabetes Mellitus (DM) is a chronic disease characterized by hyperglycemia. Specific Background: A severe complication of DM is diabetic nephropathy, marked by progressive kidney function decline. Blood sugar and urea levels serve as crucial indicators in diagnosing DM and its complications. Knowledge Gap: Limited comparative studies exist on fasting blood sugar and urea levels between diabetes mellitus patients and diabetic nephropathy patients. Aims: This study aims to compare fasting blood sugar levels and urea levels in diabetes mellitus patients and diabetic nephropathy patients. Results: Conducted from April to June 2024, this quantitative, laboratory experimental study sampled 30 diabetes mellitus patients and 30 diabetic nephropathy patients from RSUD dr. Wahidin Sudiro Husodo, Mojokerto City. Using the SPSS Mann-Whitney test, the study found significant differences (p=0.000) in fasting blood sugar levels (125.20±20.348 mg/dL vs. 221.07±65.545 mg/dL) and urea levels (13.30±2.059 mg/dL vs. 54.10±26.699 mg/dL) between the two patient groups. Novelty: This study provides novel insights into the metabolic differences between diabetes mellitus and diabetic nephropathy patients, emphasizing the progressive impact of high blood sugar on kidney function. Implications: The findings underscore the importance of early intervention and continuous monitoring of blood sugar and urea levels to prevent or mitigate diabetic nephropathy in DM patients. Highlights : Significant Differences: The study found significant differences in fasting blood sugar and urea levels between diabetes mellitus and diabetic nephropathy patients. Metabolic Insights: Provides insights into the metabolic impact of high blood sugar on kidney function in diabetic nephropathy patients. Clinical Implications: Highlights the need for early intervention and continuous monitoring to prevent or mitigate diabetic nephropathy in DM patients. Keywords : Diabetes Mellitus, Diabetic Nephropathy, Fasting Blood Sugar Levels, Urea Levels, Kidney Function

Study of a painful diabetic peripheral neuropathy model induced by streptozotocin: conclusions before investigating non-paralytic botulinum molecules

Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes characterized by peripheral nerve dysfunction and debilitating pain symptoms. This article investigates the streptozotocin (STZ)-induced model of PDPN (45 mg/kg i.p.) to evaluate whether it can be further used to study the efficacy of non-paralytic botulinum molecules in pain control. In the study changes in relative weight, glucose levels, and mechanical and temperature sensitivity in the experimental group compared to the control group of rats were assessed. The obtained data indicate the reliability of the model. The results showed a significant decrease in relative weight and alterations in glucose levels in the experimental group, highlighting the metabolic impact of PDPN. Moreover, the rats in the experimental group exhibited heightened mechanical and temperature sensitivity, mirroring the neuropathic pain experienced by patients with PDPN. These findings support the suitability of the STZ-induced PDPN model for preclinical studies investigating non-paralytic botulinum molecules as analgesics. In conclusion, this model provides a valuable platform for future research aimed at understanding the underlying mechanisms and developing effective interventions for PDPN.

Mouse vascularized adipose spheroids: an organotypic model for thermogenic adipocytes.

Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues' thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by environmental factors like cold exposure or by pharmacology, share metabolic mechanisms that drive non-shivering thermogenesis. Understanding these two cell types requires advanced, yet broadly applicable in vitro models that reflect the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue, a tissue with 'beiging' capacity in mice and humans. We show that adding a scaffold improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers, thus reflecting increased adipocyte maturity. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to classical 2D cultures, which was enhanced by β-adrenergic receptor stimulation correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.

Multi-omic validation of the cuproptosis-sphingolipid metabolism network: modulating the immune landscape in osteosarcoma.

The current understanding of the mechanisms by which metal ion metabolism promotes the progression and drug resistance of osteosarcoma remains incomplete. This study aims to elucidate the key roles and mechanisms of genes involved in cuproptosis-related sphingolipid metabolism (cuproptosis-SPGs) in regulating the immune landscape, tumor metastasis, and drug resistance in osteosarcoma cells. This study employed multi-omics approaches to assess the impact of cuproptosis-SPGs on the prognosis of osteosarcoma patients. Lasso regression analysis was utilized to construct a prognostic model, while multivariate regression analysis was applied to identify key core genes and generate risk coefficients for these genes, thereby calculating a risk score for each osteosarcoma patient. Patients were then stratified into high-risk and low-risk groups based on their risk scores. The ESTIMATE and CIBERSORT algorithms were used to analyze the level of immune cell infiltration within these risk groups to construct the immune landscape. Single-cell analysis was conducted to provide a more precise depiction of the expression patterns of cuproptosis-SPGs among immune cell subtypes. Finally, experiments on osteosarcoma cells were performed to validate the role of the cuproptosis-sphingolipid signaling network in regulating cell migration and apoptosis. In this study, seven cuproptosis-SPGs were identified and used to construct a prognostic model for osteosarcoma patients. In addition to predicting survival, the model also demonstrated reliability in forecasting the response to chemotherapy drugs. The results showed that a high cuproptosis-sphingolipid metabolism score was closely associated with reduced CD8 T cell infiltration and indicated poor prognosis in osteosarcoma patients. Cellular functional assays revealed that cuproptosis-SPGs regulated the LC3B/ERK signaling pathway, thereby triggering cell death and impairing migration capabilities in osteosarcoma cells. The impact of cuproptosis-related sphingolipid metabolism on the survival and migration of osteosarcoma cells, as well as on CD8 T cell infiltration, highlights the potential of targeting copper ion metabolism as a promising strategy for osteosarcoma patients.

Resveratrol Induces Myotube Development by Altering Circadian Metabolism via the SIRT1-AMPK-PP2A Axis.

Resveratrol is a polyphenol known to have metabolic as well as circadian effects. However, there is little information regarding the metabolic and circadian effect of resveratrol on muscle cells. We sought to investigate the metabolic impact of resveratrol throughout the circadian cycle to clarify the associated signaling pathways. C2C12 myotubes were incubated with resveratrol in the presence of increasing concentrations of glucose, and metabolic and clock proteins were measured for 24 h. Resveratrol led to SIRT1, AMPK and PP2A activation. Myotubes treated with increasing glucose concentrations showed higher activation of the mTOR signaling pathway. However, resveratrol did not activate the mTOR signaling pathway, except for P70S6K and S6. In accordance with the reduced mTOR activity, resveratrol led to advanced circadian rhythms and reduced levels of pBMAL1 and CRY1. Resveratrol increased myogenin expression and advanced its rhythms. In conclusion, resveratrol activates the SIRT1-AMPK-PP2A axis, advances circadian rhythms and induces muscle development.

Air speed and direction affect metabolic and thermoregulatory responses during walking and running in a temperate environment.

Revisiting classical experiments on the impact of air resistance on metabolic rate, we aimed to overcome limitations of previous research, notably: low participant numbers (n = 1-3), highly turbulent wind, and confounding effects of rising body temperature. In a custom-built wind tunnel with reduced turbulence, 14 participants (8 males, 6 females) walked (5 km·h-1) and ran on a treadmill (70%V̇o2max) at 0, 2, 4, and 6 m·s-1 headwind or tailwind in a counterbalanced design, with rest breaks between each exposure to avoid rises in body core temperature. Oxygen consumption (V̇o2) exhibited strong linear relationships versus wind direction, dynamic pressure, and air speed squared (Vwr2), lower in magnitude for headwind than tailwind. A moderate linear relationship was observed between heart rate, wind direction, dynamic pressure, and Vwr2. Below 4 m·s-1, the effect of wind was well within inter- and intraindividual variation and equipment uncertainty, and only at wind speeds ≥4 m·s-1 did the differences in physiological responses reach statistical significance. Our data indicate that at running speeds below 4 m·s-1 (14.4 km/h), indoor treadmills and outdoor running are comparable in terms of the metabolic impact of air movement relative to the person. However, this does not extend to the thermoregulatory effect of wind, with outdoor running providing a higher cooling rate due to the self-generated wind created during running. By removing the confounding impact of core temperature rises, the observed effects of headwind were lower and those of tailwind larger than observed previously. In the context of middle-distance running, the headwind created by running at 21.5 km·h-1 would result in a 2.2% increase of V̇o2. A relative tailwind of the same speed would lead to a 3.1% reduction.NEW & NOTEWORTHY Revisiting classical work by Pugh and Davies on the metabolic effects of air speed and direction, shortcomings in the original studies were addressed. Using more participants, less turbulent wind, and avoiding confounding effects of work-induced core temperature increases, new equations describing the impact of air speed/direction were developed. This study observed a lower impact of headwind and a larger impact of tailwind in the absence of an exercise-induced core temperature increase.

Lipomatoses

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.

Specific human CYP enzymes-dependent mutagenicity of tris(2-butoxyethyl) phosphate (an organophosphorus flame retardant) in human and hamster cell lines

Tris(2-butoxyethyl) phosphate (TBOEP) is an organophosphorus flame retardant ubiquitously present in the environment and even the human body. TBOEP is toxic in multiple tissues, which forms dealkylated and hydroxylated metabolites under incubation with human hepatic microsomes; however, the impact of TBOEP metabolism on its toxicity, particularly mutagenicity (typically requiring metabolic activation), is left unidentified. In this study, the mutagenicity of TBOEP in human hepatoma cell lines (HepG2 and C3A) and the role of specific CYPs were studied. Through molecular docking, TBOEP bound to human CYP1A1, 1B1, 2B6 and 3A4 with energies and conformations favorable for catalyzing reactions, while the conformations of its binding with human CYP1A2 and 2E1 appeared unfavorable. In C3A cells (endogenous CYPs being substantial), TBOEP exposing for 72 h (2-cell cycle) at low micromolar levels induced micronucleus, which was abolished by 1-aminobenzotriazole (inhibitor of CYPs); in HepG2 cells (CYPs being insufficient) TBOEP did not induce micronucleus, whose effect was however potentiated by pretreating the cells with PCB126 (CYP1A1 inducer) or rifampicin (CYP3A4 inducer). TBOEP induced micronucleus in Chinese hamster V79-derived cell lines genetically engineered for stably expressing human CYP1A1 and 3A4, but not in cells expressing the other CYPs. In C3A cells, TBOEP selectively induced centromere protein B-free micronucleus (visualized by immunofluorescence) and PIG-A gene mutations, and elevated γ-H2AX rather than p-H3 (by Western blot) which indicated specific double-strand DNA breaks. Therefore, this study suggests that TBOEP may induce DNA/chromosome breaks and gene mutations in human cells, which requires metabolic activation by CYPs, primarily CYP1A1 and 3A4.

Essential oils in post-harvest disease management: Metabolic impact on Narince (Vitis vinifera L. cv) grapes against Botrytis cinerea

There is an urgent need for alternative, environmentally friendly post-harvest disease management solutions because of the growing concern over the use of chemical fungicides in agriculture and their detrimental impact on human health and the environment. This study examines the effects of thymol, eugenol, and 1,8-cineole essential oils on the sugar, organic acid, and amino acid profiles of 'Narince' grape berries as well as their effectiveness against gray mold (Botrytis cinerea). Our study has noted that the application of EOs, particularly eugenol, significantly alters the metabolic profile of 'Narince' grapes, enhancing sugar content and modifying the levels of organic acids and amino acids, which suggests a potential for improving grape quality and resistance to Botrytis cinerea. The combined use of eugenol with other EOs and fungicides, as indicated by the treatments OF and OSF, not only displayed a synergistic effect in elevating the concentration of key metabolites but also appeared to be more effective in combating fungal infection compared to individual EO applications. The PCA analysis and subsequent heatmap visualization revealed distinct metabolic clustering among the treatments, with combined EO treatments, especially those including eugenol, markedly influencing the amino acid profile of the berries. Our investigation's results suggest that EOs may offer a viable, eco-friendly alternative to traditional fungicides. Our study also adds to the body of knowledge supporting the advancement of integrated pest management strategies that are efficacious yet environmentally considerate, aligning with the global shift towards more sustainable practices in agriculture and food security.

Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.

Ageing and Polypharmacy in Mesenchymal Stromal Cells: Metabolic Impact Assessed by Hyperspectral Imaging of Autofluorescence.

The impact of age on mesenchymal stromal cell (MSC) characteristics has been well researched. However, increased age is concomitant with increased prevalence of polypharmacy. This adjustable factor may have further implications for the functionality of MSCs and the effectiveness of autologous MSC procedures. We applied hyperspectral microscopy of cell autofluorescence-a non-invasive imaging technique used to characterise cytometabolic heterogeneity-to identify changes in the autofluorescence signals of MSCs from (1) young mice, (2) old mice, (3) young mice randomised to receive polypharmacy (9-10 weeks of oral therapeutic doses of simvastatin, metoprolol, oxycodone, oxybutynin and citalopram), and (4) old mice randomised to receive polypharmacy. Principal Component Analysis and Logistic Regression Analysis were used to assess alterations in spectral and associated metabolic characteristics. Modelling demonstrated that cells from young mice receiving polypharmacy had less NAD(P)H and increased porphyrin relative to cells from old control mice, allowing for effective separation of the two groups (AUC of ROC curve > 0.94). Similarly, cells from old polypharmacy mice were accurately separated from those from young controls due to lower levels of NAD(P)H (p < 0.001) and higher porphyrin (p < 0.001), allowing for an extremely accurate logistic regression (AUC of ROC curve = 0.99). This polypharmacy regimen may have a more profound impact on MSCs than ageing, and can simultaneously reduce optical redox ratio (ORR) and increase porphyrin levels. This has implications for the use of autologous MSCs for older patients with chronic disease.

UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.

Comprehensively studying metabolism requires the measurement of metabolite levels. However, in contrast to the broad availability of gene expression data, metabolites are rarely measured in large molecularly-defined cohorts of tissue samples. To address this basic barrier to metabolic discovery, we propose a Bayesian framework ("UnitedMet") which leverages the empirical strength of RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. We demonstrate that UnitedMet is equally capable of imputing whole pool sizes as well as the outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying a novel association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to combination therapy, and that kidney cancer metastases themselves demonstrate elevated oxidative phosphorylation relative to primary tumors. UnitedMet therefore enables the assessment of metabolic phenotypes in contexts where metabolite measurements were not taken or are otherwise infeasible, opening new avenues for the generation and evaluation of metabolite-centered hypotheses. UnitedMet is open source and publicly available (https://github.com/reznik-lab/UnitedMet).

#2071 The metabolic syndrome impact in the onco-nephrological scenario of renal cancer: when comorbidities beat surgery

Abstract Background and Aims Metabolic syndrome (MS) represents a pathological state in which many risk factors for CKD including obesity, hyperglycemia, hypertension and dyslipidemia co-occur within individuals. In the past decade different lines of evidence underlined the relationship between MS and CKD, two increasing worldwide serious threat to life. With the rise of onco-nephrology, there is a strong need to define the role of MS in the nephrological management of oncological patients. Our study aimed to assess the impact of metabolic syndrome on renal function in patients undergoing partial nephrectomy (PN) for renal cancer (RC). Method We retrospectively analyzed data from 1,112 patients undergoing PN at a tertiary referral center between 2000 and 2023. Patients with metastatic disease, hereditary cancer or a solitary kidney were excluded. Renal function was evaluated with eGFR values using CKD-EPI 2021 formula. AKI and CKD onset were defined using K-DIGO 2012 criteria. MS was defined as at least 3 of the following conditions: obesity, insulin resistance, dyslipidemia and hypertension. Multivariable analyses (MA) were used to determine the impact of MS on preoperative eGFR impairment and post-operative AKI. Covariates were intraoperative blood loss, surgical experience, pT stage, type of surgery (open vs minimally invasive), pre-existing CKD, age, and comorbidities (defined as Charlson Comorbidity Index&amp;gt;3). Results Overall, the rate of MS was 9% (n = 100). The median follow-up was 60 months (IQR 28-68). Patients with MS had lower preoperative eGFR (78 ml/min vs. 87 ml/min), higher estimated blood loss (500 ml vs. 300 ml) and higher rate of complications (38% vs. 29%) relative to non-MS counterparts (all p &amp;lt; 0.001). Additionally, the rate of AKI was 25% (n = 25) vs 18% (n = 182) for metabolic vs non-MS patients (p = 0.01), respectively. At MVA, MS was an independent predictor for both lower preoperative eGFR (OR 1.07, 95% CI 1.01-1.14, p = 0.01) and higher risk of AKI (OR 2.1, 95% CI 1.3-4.1, p = 0.01). MS patients had a worse kidney function at baseline, had higher risk of AKI immediately after surgery and a higher risk of CKD onset over time, with a steep reduction of eGFR even at long term follow-up (Fig. 1). Conclusion Renal cancer patients diagnosed with MS harbored an increased risk of both AKI and CKD even with a partial nephrectomy. Therefore, the role of onco-nephrologists and nutritionists remains a cornerstone in the management of such cohort of patients, before and after surgery.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis

Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype onparoxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P=0.03 and P=0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Carbon substrates promotes stress resistance and drug tolerance in clinical isolates of Candida tropicalis.

Candida tropicalis is a human pathogen and one of the most prevalent non-Candida albicans Candida (NCAC) species causing invasive infections. Azole antifungal resistance in C. tropicalis is also gradually increasing with the increasing incidence of infections. The pathogenic success of C. tropicalis depends on its effective response in the host microenvironment. To become a successful pathogen, cellular metabolism, and physiological status determine the ability of the pathogen to counter diverse stresses inside the host. However, to date, limited knowledge is available on the impact of carbon substrate metabolism on stress adaptation and azole resistance in C. tropicalis. In this study, we determined the impact of glucose, fructose, and sucrose as the sole carbon source on the fluconazole resistance and osmotic (NaCl), oxidative (H2O2) stress adaptation in C. tropicalis clinical isolates. We confirmed that the abundance of carbon substrates influences or increases drug resistance and osmotic and oxidative stress tolerance in C. tropicalis. Additionally, both azole-resistant and susceptible isolates showed similar stress adaptation phenotypes, confirming the equal efficiency of becoming successful pathogens irrespective of drug susceptibility profile. To the best of our knowledge, our study is the first on C. tropicalis to demonstrate the direct relation between carbon substrate metabolism and stress tolerance or drug resistance.

Targeted metabolomics-based understanding of the sleep disturbances in drug-naïve patients with schizophrenia

BackgroundSleep disturbances are a common occurrence in patients with schizophrenia, yet the underlying pathogenesis remain poorly understood. Here, we performed a targeted metabolomics-based approach to explore the potential biological mechanisms contributing to sleep disturbances in schizophrenia.MethodsPlasma samples from 59 drug-naïve patients with schizophrenia and 36 healthy controls were subjected to liquid chromatography-mass spectrometry (LC-MS) targeted metabolomics analysis, allowing for the quantification and profiling of 271 metabolites. Sleep quality and clinical symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Positive and Negative Symptom Scale (PANSS), respectively. Partial correlation analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) model were used to identify metabolites specifically associated with sleep disturbances in drug-naïve schizophrenia.Results16 characteristic metabolites were observed significantly associated with sleep disturbances in drug-naïve patients with schizophrenia. Furthermore, the glycerophospholipid metabolism (Impact: 0.138, p<0.001), the butanoate metabolism (Impact: 0.032, p=0.008), and the sphingolipid metabolism (Impact: 0.270, p=0.104) were identified as metabolic pathways associated with sleep disturbances in drug-naïve patients with schizophrenia.ConclusionsOur study identified 16 characteristic metabolites (mainly lipids) and 3 metabolic pathways related to sleep disturbances in drug-naïve schizophrenia. The detection of these distinct metabolites provide valuable insights into the underlying biological mechanisms associated with sleep disturbances in schizophrenia.

In Vitro and In Vivo Evaluating Bioaccessibility, Bioavailability, and Antioxidant Activities of Butterfly Pea Flower Containing Bioactive Constitutes.

The antioxidant properties of butterfly pea flower (BF), which is rich in natural anthocyanins, have garnered significant attention. The impact of digestion and metabolism on BF extracts and evaluate their subsequent antioxidant activities in vivo were explored in the present study. After in vitro digestion, 42.03 ± 2.74% of total anthocyanins from BF extracts remained, indicating a negative influence of the digestion process on the bioaccessibility of phenolic compounds derived from BF. Furthermore, UPLC-LTQ-Orbitrap-MS2 analysis identified a total of four prototypes and twenty-seven metabolites in rat plasma or urine samples following the intake of BF extracts. The kinetics of key metabolites including delphinidin 3-glucoside (D3G), cyanidin-3-glucoside (C3G), and 4-hydroxybenzoic acid were subsequently determined in blood, and the Cmax values were 69.034 ± 8.05 nM and 51.65 ± 3.205 nM. These key metabolites derived from BF anthocyanins, including C3G and D3G, and flavonoid quercetin exhibited main antioxidant attributes that improved the plasmic and hepatic activities of various antioxidant enzymes and the total antioxidant capacity (T-AOC) and malondialdehyde (MDA) in a D-galactose-induced rat model. These findings provide insights into the bioaccessibility and bioavailability of bioactive constitutes derived from BF extracts, which are crucial for determining the actual efficacy of BF as well as developing functional foods based on BF.

Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder

Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, V°\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\dot{{{\\boldsymbol{V}}}}\\!$$\\end{document}net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.

Age-dependent impact of streptozotocin on metabolic endpoints and Alzheimer's disease pathologies in 3xTg-AD mice

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is widely used in rodent models to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology.STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-β (Aβ) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might have facilitated a direct neurotoxic effect of STZ in older mice.Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.

Serum iron level is independently associated with sarcopenia: a retrospective study

Sarcopenia greatly reduces the quality of life of the elderly, and iron metabolism plays an important role in muscle loss. This study aimed to investigate the association between iron status and sarcopenia. A total of 286 adult patients hospitalized between 2019 and 2021 were included in this study, of which 117 were diagnosed with sarcopenia. Serum iron, total iron binding capacity (TIBC), transferrin, and transferrin saturation levels were compared between groups with and without sarcopenia and were included in the logistic analyses, with significant variables further included in the logistic regression model for the prediction of sarcopenia. Serum iron, TIBC, and transferrin levels decreased significantly in the sarcopenia group (p < 0.05), and were negatively associated with handgrip strength, relative skeletal muscle index, and multiple test performances (p < 0.05). Multivariate logistic analysis showed that sex, age, body mass index (BMI), and serum iron level were independent risk factors for sarcopenia. In the final logistic regression model, male sex (odds ratio [OR] 3.65, 95% confidence interval [CI] 1.67–7.98), age > 65 years (OR 5.40, 95% CI 2.25–12.95), BMI < 24 kg/m2 (OR 0.17, 95% CI 0.08–0.36), and serum iron < 10.95 μmol/L (OR 0.39, 95% CI 0.16–0.93) were included. Our study supported the impact of iron metabolism on muscle strength and performance.