Metabolic Profile Research Articles

Metabolic profiling of the synthetic cannabinoid APP-CHMINACA (PX-3) as studied by in vitro and in vivo models.

The metabolic pathways of APP-CHMINACA were characterized to select the markers of intake for implementation into analytical assays used by the clinical and forensic communities. We have combined the evidences obtained by both in vitro experiments and administration studies on mice. APP-CHMINACA was incubated with either human or mouse liver microsomes. Urine and blood samples were collected at different time points from mice after injection of a 3mg/kg dose of the test compound. Samples were analyzed using liquid chromatography-tandem mass spectrometry. The in vitro studies allowed to isolate eight different metabolic reactions, formed by two metabolic routes, with no differences between human and mouse liver microsomes. The main biotransformation route involved the hydrolysis of the distal amide group and the subsequent hydroxylation on the cyclohexyl-methyl ring. The second route involved multiple hydroxylation of the parent compound, followed by reduction to generate minor metabolites. In blood samples, the most abundant substances identified were APP-CHMINACA unchanged and the metabolites formed by the hydrolysis of the distal amide together with its hydroxylated products. In urine samples, four metabolites formed following the hydroxylation of the distal amide hydrolysis metabolite were detected as the most abundant and long-term metabolites. The outcomes of our study showed that the most suitable markers to detect the intake of APP-CHMINACA in blood and urine samples in the framework of toxicological, clinical and forensic investigations were the metabolite formed by the hydrolysis of the distal amide and its hydroxylated products.

Development of a metabolome-based respiratory infection prognostic during COVID-19 arrival.

In a new respiratory virus pandemic, optimizing allocation of scarce medical resources becomes an urgent challenge. Infection prognosis takes on particular importance when allocating scarce antiviral antibodies and drugs, which are most effective when administered before the onset of severe disease. During arrival of the COVID-19 pandemic to the United States in 2020, we conducted a prognostic biomarker discovery and validation effort based upon metabolomic profiling with a liquid-chromatography-mass spectrometer (LC-MS) type used clinically for rapid toxicology. We obtained urine specimens from 163 patients presenting for evaluation. We obtained LC-MS profiles in the initial cohort and used machine learning methods to define a simplified urine metabolomic signature associated with respiratory failure or death by 90 days. This signature was composed of three metabotypes linked to intestinal microbiome metabolism and anticonvulsant use, with a receiver-operator characteristic area under the curve (ROC AUC) of 89.4%. Blinded application of this signature to the subsequent validation cohort yielded a ROC AUC of 81.2%. A model trained on the two baseline metabotypes present before intubation exhibited similar performance in the validation cohort. This study demonstrates the plausibility and promise of rapid metabolome-based prognostic discovery and validation in the opening wave of a pandemic. The approach used here could be used to inform therapeutic and resource allocation decisions early in a future epidemic.IMPORTANCEIn a new respiratory virus pandemic, the ability to identify patients at greatest risk for severe disease is essential to direct scarce medical resources to those most likely to benefit from them. Tools to predict disease severity are best developed early in a pandemic, but laboratory-based resources to develop these may be limited by available technology and by infection precautions. Here, we show that an accessible metabolic profiling approach could identify a prognostic signature of severe disease in the initial wave of COVID-19, when patients presenting for care often exceeded the available doses of convalescent plasma and remdesivir. In a future pandemic, this approach, alongside efforts to identify clinical disease severity predictors, could improve patient outcomes and facilitate therapeutic trials by identifying individuals at high risk for severe disease.

Metabolic Profile of Histomonas meleagridis in Dwyer’s Media with and Without Rice Starch

Metabolic Profile of Histomonas meleagridis in Dwyer’s Media with and Without Rice Starch

Decoding Glioblastoma Heterogeneity: Neuroimaging Meets Machine Learning.

Recent advancements in neuroimaging and machine learning have significantly improved our ability to diagnose and categorize isocitrate dehydrogenase (IDH)-wildtype glioblastoma, a disease characterized by notable tumoral heterogeneity, which is crucial for effective treatment. Neuroimaging techniques, such as diffusion tensor imaging and magnetic resonance radiomics, provide noninvasive insights into tumor infiltration patterns and metabolic profiles, aiding in accurate diagnosis and prognostication. Machine learning algorithms further enhance glioblastoma characterization by identifying distinct imaging patterns and features, facilitating precise diagnoses and treatment planning. Integration of these technologies allows for the development of image-based biomarkers, potentially reducing the need for invasive biopsy procedures and enabling personalized therapy targeting specific pro-tumoral signaling pathways and resistance mechanisms. Although significant progress has been made, ongoing innovation is essential to address remaining challenges and further improve these methodologies. Future directions should focus on refining machine learning models, integrating emerging imaging techniques, and elucidating the complex interplay between imaging features and underlying molecular processes. This review highlights the pivotal role of neuroimaging and machine learning in glioblastoma research, offering invaluable noninvasive tools for diagnosis, prognosis prediction, and treatment planning, ultimately improving patient outcomes. These advances in the field promise to usher in a new era in the understanding and classification of IDH-wildtype glioblastoma.

Brain metabolic profiling of schizophrenia: a path towards a better understanding of the neuropathogenesis of psychosis.

Schizophrenia (SCZ) is a complex psychotic syndrome whose pathogenesis involves countless protagonists, none of which, to date, can fully explain how this disorder develops. In this narrative review, an overview of the biochemical impairment is offered according to several perspectives. Indeed, the metabolic framework behind SCZ dopaminergic hypotheses, glutamate - gamma-amynobutyric acid dysregulation, norepinephrine and serotonin, calcium channel dysfunction is addressed together with the energetic impairment, involving glucose and lipids in SCZ etiopathogenesis, in order to highlight the multilevel pathways affected in this neuropsychiatric disorder. Furthermore, neuroinflammation is analyzed, by virtue of its important role, widely investigated in recent years, in neurodegeneration. Tracing the neurotransmitter activity at the brain level by assessing the metabolic network behind the abovementioned molecules puts into light as unavoidable the need for future studies to adopt an integrate approach to address SCZ pathological and clinical picture. The combination of all these factors, essential in acquiring an overview on the complexity of SCZ pathophysiology represents a crucial step in the development of a more targeted management of SCZ patients.

Respiratory bioenergetics is enhanced in human, but not bovine macrophages after exposure to M. bovis PPD: Exploratory insights into overall similar Cellular Metabolic Profiles.

The role of macrophage (MØ) cellular metabolism and reprogramming during TB infection is of great interest due to the influence of Mycobacterium spp. on MØ bioenergetics. Recent studies have shown that M. tuberculosis induces a TLR2-dependent shift towards aerobic glycolysis, comparable to the established LPS induced pro-inflammatory M1 MØ polarisation. Distinct differences in the metabolic profile of murine and human MØ indicates species-specific differences in bioenergetics. So far, studies examining the metabolic potential of bovine MØ are lacking, thus the basic bioenergetics of bovine and human MØ were explored in response to a variety of innate immune stimuli. Cellular energy metabolism kinetics were measured concurrently for both species on a Seahorse XFe96 platform to generate bioenergetic profiles for the response to the bona-fide TLR2 and TLR4 ligands, FSL-1 and LPS respectively. Despite previous reports of species-specific differences in TLR signalling and cytokine production between human and bovine MØ, we observed similar respiratory profiles for both species. Basal respiration remained constant between stimulated MØ and controls, whereas addition of TLR ligands induced increased glycolysis, as measured by the surrogate parameter ECAR. In contrast to MØ stimulation with M. tuberculosis PPD, another TLR2 ligand, M. bovis PPD treatment significantly enhanced basal respiration rates and glycolysis only in human MØ. Respiratory profiling further revealed significant elevation of ATP-linked OCR and maximal respiration suggesting a strong OXPHOS activation upon M. bovis PPD stimulation in human MØ. Our results provide an exploratory set of data elucidating the basic respiratory profile of bovine vs. human MØ that will not only lay the foundation for future studies to investigate host-tropism of the M. tuberculosis complex but may explain inflammatory differences observed for other zoonotic diseases.

Production of the antimalarial drug precursor amorphadiene by microbial terpene synthase-like from the moss Sanionia uncinata

Main conclusionThe microbial terpene synthase-like of the moss Sanionia uncinata displays the convergent evolution of a rare plant metabolite amorpha-4,11-diene synthesis.Despite increasing demand for the exploration of biological resources, the diversity of natural compounds synthesized by organisms inhabiting various climates remains largely unexplored. This study focuses on the moss Sanionia uncinata, known as a predominant species within the polar climates of the Antarctic Peninsula, to systematically explore its metabolic profile both in-field and in controlled environments. We here report a diverse array of moss-derived terpene volatiles, including the identification of amorpha-4,11-diene, a rare sesquiterpene compound that is a precursor for antimalarial drugs. Phylogenetic reconstruction and functional validation in planta and in vitro identified a moss terpene synthase, S. uncinata microbial terpene synthase-like 2 (SuMTPSL2), which is associated with amorpha-4,11-diene production. We demonstrate that expressing SuMTPSL2 in various heterologous systems is sufficient to produce amorpha-4,11-diene. These results highlight the metabolic diversity in Antarctica, but also provide insights into the convergent evolution leading to the synthesis of a rare plant metabolite.

The influence of endothelial metabolic reprogramming on the tumor microenvironment.

Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.

Transcriptome profiling of maize transcription factor mutants to probe gene regulatory network predictions.

Transcription factors (TFs) play important roles in regulation of gene expression and phenotype. A variety of approaches have been utilized to develop gene-regulatory networks (GRNs) to predict the regulatory targets for each TF, such as yeast-one-hybrid (Y1H) screens and gene co-expression network (GCN) analysis. Here we identified potential TF targets and used a reverse genetics approach to test the predictions of several GRNs in maize. Loss-of-function mutant alleles were isolated for 22 maize TFs. These mutants did not exhibit obvious morphological phenotypes. However, transcriptomic profiling identified differentially expressed genes in each of the mutant genotypes, and targeted metabolic profiling indicated variable phenolic accumulation in some mutants. An analysis of expression levels for predicted target genes based on Y1H screens identified a small subset of predicted targets that exhibit altered expression levels. The analysis of predicted targets from GCN-based methods found significant enrichments for prediction sets of some TFs, but most predicted targets did not exhibit altered expression. This could result from false-positive GCN predictions, a TF with a secondary regulatory role resulting in minor effects on gene regulation, or redundant gene regulation by other TFs. Collectively, these findings suggest that loss-of-function for single uncharacterized TFs might have limited phenotypic impacts but can reveal subsets of GRN predicted targets with altered expression.

Metabolites and Metabolic Functional Changes-Potential Markers for Endothelial Cell Senescence.

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD+, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets.

Identification of Spatial Specific Lipid Metabolic Signatures in Long-Standing Diabetic Kidney Disease.

Background: Diabetic kidney disease (DKD) is a major complication of diabetes leading to kidney failure. Methods: This study investigates lipid metabolism profiles of long-standing DKD (LDKD, diabetes duration > 10 years) by integrative analysis of available single-cell RNA sequencing and spatial multi-omics data (focusing on spatial continuity samples) from the Kidney Precision Medicine Project. Results: Two injured cell types, an injured thick ascending limb (iTAL) and an injured proximal tubule (iPT), were identified and significantly elevated in LDKD samples. Both iTAL and iPT exhibit increased lipid metabolic and biosynthetic activities and decreased lipid and fatty acid oxidative processes compared to TAL/PT cells. Notably, compared to PT, iPT shows significant upregulation of specific injury and fibrosis-related genes, including FSHR and BMP7. Meanwhile, comparing iTAL to TAL, inflammatory-related genes such as ANXA3 and IGFBP2 are significantly upregulated. Furthermore, spatial metabolomics analysis reveals regionally distributed clusters in the kidney and notably differentially expressed lipid metabolites, such as triglycerides, glycerophospholipids, and sphingolipids, particularly pronounced in the inner medullary regions. Conclusions: These findings provide an integrative description of the lipid metabolism landscape in LDKD, highlighting injury-associated cellular processes and potential molecular mechanisms.

Effectiveness, safety, and patient-reported outcomes of treatment with bictegravir/emtricitabine/tenofovir alafenamide fixed dose combination in people living with HIV in Argentina: the BICTARG cohort.

Real-world data on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) fixed-dose combination from resource-constrained settings like Latin America are limited. We conducted an observational retrospective cohort study of treatment-naive (TN, n=315) and treatment-experienced (TE, n= 2356) people living with HIV prescribed BIC/FTC/TAF in Argentina from 10/2019 to 12/2021, with 24 and 48-week follow-up data analyzed for virological suppression, persistence, safety, and metabolic parameters. Patient-reported outcomes were assessed via across-sectional online survey. Baseline characteristics: median age 45 years, 72.2% male, 99.6% Hispanic/Latino ethnicity. Treatment per sistence at 48 weeks was 99.3% (TN) and 99.5% (TE). Virological suppression rates (<200/<50 copies/mL) at 24 weeks were 97.4/88% (TN) and 99/97% (TE). At 48 weeks were 100/92% (TN) and 99/97% (TE). In the TE group, triglycerides decreased with no other lipid changes. In TN, mild total/LDL/HDL cholesterol increases occurred. eGFR mildly decreased in both groups. The online survey (n=536) showed 91.5% reported no medication concerns. Median quality of life scores were 90 (TN) and 88 (TE). Most reported no self-care, activity, mobility, pain/discomfort, or anxiety/depression issues. BIC/FTC/TAF demonstrated high persistence, safety, virological efficacy, and favorable metabolic profile over 48 weeks. The cross-sectional survey indicated high treatment satisfaction and good quality of life in this cohort from Argentina.

Statin-associated regulation of hepatic PNPLA3 in patients without known liver disease.

Statins are used for metabolic dysfunction-associated steatotic liver disease (MASLD) (NAFLD) treatment, but their role in this context is unclear. Genetic variants of patatin-like phospholipase domain containing 3 (PNPLA3) are associated with MASLD susceptibility and statin treatment efficacy. Access to liver biopsies before established MASLD is limited, and statins and PNPLA3 in early liver steatosis are thus difficult to study. Liver biopsies were collected from 261 patients without known liver disease at surgery and stratified based on statin use and criteria for the metabolic syndrome (MS). Genotypes and transcript levels were measured using Illumina and Affymetrix arrays, and metabolic and lipoprotein profiles by clinical assays. Statin effects on PNPLA3, de novo lipogenesis (DNL), and lipid accumulation were further studied in vitro. The PNPLA3I148M genetic variant was associated with significantly lower hepatic levels of cholesterol synthesis-associated transcripts. Patients with MS had significantly higher hepatic levels of MASLD and lipogenesis-associated transcripts than non-MS patients. Patients with MS on statin therapy had significantly higher hepatic levels of PNPLA3, acetyl-CoA carboxylase alpha, and ATP citrate lyase, and statin use was associated with higher plasma fasting glucose, insulin, and HbA1c. Exposure of hepatocyte-like HepG2 cells to atorvastatin promoted intracellular accumulation of triglycerides and lipogenesis-associated transcripts. Atorvastatin-exposure of HepG2, sterol O-acyltransferase (SOAT) 2-only-HepG2, primary human hepatic stellate, and hepatic stellate cell-like LX2 cells significantly increased levels of PNPLA3 and SREBF2-target genes, whereas knockdown of SREBF2 attenuated this effect. Collectively, these observations suggest statin-associated regulation of PNPLA3 and DNL in liver. The potential interaction between PNPLA3 genotype and metabolic status should be considered in future studies in the context of statin therapy for MASLD.

Metabolomic analysis of rice cultivars from diverse production areas.

Rice grown in Yunnan Province is known for its excellent taste and consumer preference. However, the metabolite composition of this unique rice remains unclear. In this study, the metabolic profile of different rice planted in various producing regions was evaluated. A total of 1,005 metabolites were identified, including nucleotides and their derivatives, amino acids and their derivatives, alkaloids, organic acids, phenolic acids, lignans and coumarins, lipids, terpenoids, quinones, flavones, tannins, and others. Procucing region and varieties can be clearly distinguished on the PCA diagram. Differential metabolites accumulated in the MSD502 vs. MSR88 (138)/LHHG (234)/LHR88 (188) comparison groups. The results in this study provide scientific information for the origin tracing and variety differentiation of raw rice materials.

Multilevel Mechanisms of Cancer Drug Resistance.

Cancer drug resistance represents one of the most significant challenges in oncology and manifests through multiple interconnected molecular and cellular mechanisms. Objective: To provide a comprehensive analysis of multilevel processes driving treatment resistance by integrating recent advances in understanding genetic, epigenetic, and microenvironmental factors. This is a systematic review of the recent literature focusing on the mechanisms of cancer drug resistance, including genomic studies, clinical trials, and experimental research. Key findings include the following: (1) Up to 63% of somatic mutations can be heterogeneous within individual tumors, contributing to resistance development; (2) cancer stem cells demonstrate enhanced DNA repair capacity and altered metabolic profiles; (3) the tumor microenvironment, including cancer-associated fibroblasts and immune cell populations, plays a crucial role in promoting resistance; and (4) selective pressure from radiotherapy drives the emergence of radioresistant phenotypes through multiple adaptive mechanisms. Understanding the complex interplay between various resistance mechanisms is essential for developing effective treatment strategies. Future therapeutic approaches should focus on combination strategies that target multiple resistance pathways simultaneously, guided by specific biomarkers.

Bacterial Diversity, Metabolic Profiling, and Application Potential of Antarctic Soil Metagenomes.

Antarctica has attracted increasing interest in understanding its microbial communities, metabolic potential, and as a source of microbial hydrolytic enzymes with industrial applications, for which advances in next-generation sequencing technologies have greatly facilitated the study of unculturable microorganisms. In this work, soils from seven sub-Antarctic islands and Union Glacier were studied using a whole-genome shotgun metagenomic approach. The main findings were that the microbial community at all sites was predominantly composed of the bacterial phyla Actinobacteria and Cyanobacteria, and the families Streptomycetaceae and Pseudonocardiaceae. Regarding the xenobiotic biodegradation and metabolism pathway, genes associated with benzoate, chloroalkane, chloroalkene, and styrene degradation were predominant. In addition, putative genes encoding industrial enzymes with predicted structural properties associated with improved activity at low temperatures were found, with catalases and malto-oligosyltrehalose trehalohydrolase being the most abundant. Overall, our results show similarities between soils from different Antarctic sites with respect to more abundant bacteria and metabolic pathways, especially at higher classification levels, regardless of their geographic location. Furthermore, our results strengthen the potential of Antarctic soils as a source of industrially relevant enzymes.

Unveils the metabolic changes in groundnut CO 7 kernels stored under modified atmospheric conditions

Storing groundnut kernels is more challenging than storing pods due to increased oxidative damage. Pod storage requires more space and is not cost-effective for long-term storage. Therefore, an attempt was made to store kernels under modified conditions for six months to address these storage issues. An experiment was performed to evaluate the effects of different modified atmospheric storage conditions on the groundnut cultivar CO 7, in both shelled and unshelled forms. Changes in seed quality parameters and metabolic profiles were analyzed during storage at intervals of 30 days and up to 180 days. The kernels stored under nitrogen and vacuum conditions maintained their seed quality traits, including physical, physiological, and biochemical characteristics. GC-MS analysis was performed at the beginning of storage (fresh seeds) and after 180 days (aged seeds). Sixteen metabolic compounds were identified as responsible for seed viability and deterioration, with sucrose being the predominant compound. The sucrose area percentage in fresh seeds was 52.52%, which decreased during aging. At the end of the storage period, the highest sucrose area percentages were found in kernels stored under nitrogen (28.9%) and vacuum (26.95%) conditions. This study concludes that groundnut kernels stored under nitrogen conditions have good storage potential and excel at maintaining seed longevity.

Characteristic alterations of gut microbiota and serum metabolites in patients with chronic tinnitus: a multi-omics analysis.

Chronic tinnitus is a central nervous system disorder. Currently, the effects of gut microbiota on tinnitus remain unexplored. To explore the connection between gut microbiota and tinnitus, we conducted 16S rRNA sequencing of fecal microbiota and serum metabolomic analysis in a cohort of 70 patients with tinnitus and 30 healthy volunteers. We used the weighted gene co-expression network method to analyze the relationship between the gut microbiota and the serum metabolites. The random forest technique was utilized to select metabolites and gut taxa to construct predictive models. A pronounced gut dysbiosis in the tinnitus group, characterized by reduced bacterial diversity, an increased Firmicutes/Bacteroidetes ratio, and some opportunistic bacteria including Aeromonas and Acinetobacter were enriched. In contrast, some beneficial gut probiotics decreased, including Lactobacillales and Lactobacillaceae. In serum metabolomic analysis, serum metabolic disturbances in tinnitus patients and these differential metabolites were enriched in pathways of neuroinflammation, neurotransmitter activity, and synaptic function. The predictive models exhibited great diagnostic performance, achieving 0.94 (95% CI: 0.85-0.98) and 0.96 (95% CI: 0.86-0.99) in the test set. Our study suggests that changes in gut microbiota could potentially influence the occurrence and chronicity of tinnitus, and exert regulatory effects through changes in serum metabolites. Overall, this research provides new perceptions into the potential role of gut microbiota and serum metabolite in the pathogenesis of tinnitus, and proposes the "gut-brain-ear" concept as a pathomechanism underlying tinnitus, with significant clinical diagnostic implications and therapeutic potential.IMPORTANCETinnitus affects millions of people worldwide. Severe cases may lead to sleep disorders, anxiety, and depression, subsequently impacting patients' lives and increasing societal healthcare expenditures. However, tinnitus mechanisms are poorly understood, and effective therapeutic interventions are currently lacking. We discovered the gut microbiota and serum metabolomics changes in patients with tinnitus, and provided the potential pathological mechanisms of dysregulated gut flora in chronic tinnitus. We proposed the innovative concept of the "gut-brain-ear axis," which underscores the exploration of gut microbiota impact on susceptibility to chronic tinnitus through serum metabolic profile modulation. We also reveal novel biomarkers associated with chronic tinnitus, offering a new conceptual framework for further investigations into the susceptibility of patients, potential treatment targets for tinnitus, and assessing patient prognosis. Subsequently, gut microbiota and serum metabolites can be used as molecular markers to assess the susceptibility and prognosis of tinnitus.Furthermore, fecal transplantation may be used to treat tinnitus.

Metabolic Evaluation of the Combined Effect of Acute Cadmium Chloride and Restraint Stress Exposure in Female Wistar Rats

Cadmium is a heavy metal that has been shown to induce metabolic changes while restraint stress is a model of psychological stress used to induce behavioural and physiological changes. This study investigated the combined effect of cadmium chloride administration and restraint stress exposure on metabolic profile of female Wistar rats. Twenty four female Wistar rats were randomly divided into four groups containing six rats per group; Control (CTL) was given only feed and water. Cadmium alone (CCC) and Restraint stress alone(RSS), respectively, were orally administered 100 mg/kg b.w of cadmium chloride and subjected to restraint stress using wire mesh for 30 minutes daily while Cadmium+Restraint stress (RSC) was administered 100 mg/kg b.w of cadmium chloride and restrained for 30 minutes daily. Body weights of the animals were recorded daily throughout the experiment. Twenty-four hours after the last cadmium administration and restraint stress exposure, all animal were anesthetized and sacrificed. Blood was collected via cardiac puncture for biochemical analysis. Results showed significant (p&lt;0.05) increase in serum glucose and cortisol levels but not significant in insulin level of CCC group when compared to control. Serum glucose, insulin, cortisol showed significant (p&lt;0.05) increase in RSS group when compared to control. In RSC group, glucose and insulin was significantly (p&lt;0.05) increased when compared to CCC but not significant when compared with RSS. Cortisol was significantly (p&lt;0.05) increased in RSC group when compared with other groups. Result showed significant (p&lt;0.05) increase in CHO, LDL and TAG of CCC and RSS groups when compared with control. RSC showed significant (p&lt;0.05) increase in CHO, LDL and TAG when compared with CCC and RSS groups. Serum HDL levels showed no significant difference across all groups. Conclusively, cadmium chloride and restraint stress exposure individually lead to metabolic dysfunction and dyslipidemia while the combined exposure exacerbated these effects in female rats.

TET3 regulates terminal cell differentiation at the metabolic level

TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.