PubMed

Am J Physiol Cell Physiol. 2024 Aug 26. doi: 10.1152/ajpcell.00367.2024. Online ahead of print.ABSTRACTBACKGROUND: The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose co-transporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in obese individuals and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear.METHODS: We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with Empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples.RESULTS: ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared to NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multi-tissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05).CONCLUSION: The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG.PMID:39183639 | DOI:10.1152/ajpcell.00367.2024

FASEB J. 2024 Aug 31;38(16):e70014. doi: 10.1096/fj.202400773R.ABSTRACTEnd-ischemic normothermic mechanical perfusion (NMP) could provide a curative treatment to reduce cholestatic liver injury from donation after circulatory death (DCD) in donors. However, the underlying mechanism remains elusive. Our previous study demonstrated that air-ventilated NMP could improve functional recovery of DCD in a preclinical NMP rat model. Here, metabolomics analysis revealed that air-ventilated NMP alleviated DCD- and cold preservation-induced cholestatic liver injury, as shown by the elevated release of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and γ-glutamyl transferase (GGT) in the perfusate (p < .05) and the reduction in the levels of bile acid metabolites, including ω-muricholic acid, glycohyodeoxycholic acid, glycocholic acid, and glycochenodeoxycholate (GCDC) in the perfused livers (p < .05). In addition, the expression of the key bile acid metabolism enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is predominantly expressed in hepatocytes, was substantially elevated in the DCD rat liver, followed by air-ventilated NMP (p < .05), and in vitro, this increase was induced by decreased GCDC and hypoxia-reoxygenation in the hepatic cells HepG2 and L02 (p < .05). Knockdown of UGT1A1 in hepatic cells by siRNA aggravated hepatic injury caused by GCDC and hypoxia-reoxygenation, as indicated by the ALT and AST levels in the supernatant. Mechanistically, UGT1A1 is transcriptionally regulated by peroxisome proliferator-activator receptor-γ (PPAR-γ) under hypoxia-physoxia. Taken together, our data revealed that air-ventilated NMP could alleviate DCD- and cold preservation-induced cholestatic liver injury through PPAR-γ/UGT1A1 axis. Based on the results from this study, air-ventilated NMP confers a promising approach for predicting and alleviating cholestatic liver injury through PPAR-γ/UGT1A1 axis.PMID:39183544 | DOI:10.1096/fj.202400773R

Stem Cell Res Ther. 2024 Aug 26;15(1):268. doi: 10.1186/s13287-024-03881-3.ABSTRACTBACKGROUND: The KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid-base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions.METHODS: We used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16+/- and KCNJ16-/-) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air-liquid interface.RESULTS: KCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16-/- organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16-/- kidney organoids.CONCLUSIONS: Mature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney.PMID:39183338 | DOI:10.1186/s13287-024-03881-3

Mol Neurodegener. 2024 Aug 26;19(1):62. doi: 10.1186/s13024-024-00746-4.ABSTRACTBACKGROUND: Although WD repeat domain 45 (WDR45) mutations have been linked to β -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.METHODS: To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.RESULTS: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.CONCLUSIONS: In this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases.PMID:39183331 | DOI:10.1186/s13024-024-00746-4

BMC Biol. 2024 Aug 26;22(1):184. doi: 10.1186/s12915-024-01985-z.ABSTRACTBACKGROUND: Grafting with dwarf rootstock is an efficient method to control plant height in fruit production. However, the molecular mechanism remains unclear. Our previous study showed that plants with Prunus mume (mume) rootstock exhibited a considerable reduction in plant height, internode length, and number of nodes compared with Prunus persica (peach) rootstock. The present study aimed to investigate the mechanism behind the regulation of plant height by mume rootstocks through transcriptomic and metabolomic analyses with two grafting combinations, 'Longyan/Mume' and 'Longyan/Peach'.RESULTS: There was a significant decrease in brassinolide levels in plants that were grafted onto mume rootstocks. Plant hormone signal transduction and brassinolide production metabolism gene expression also changed significantly. Flavonoid levels, amino acid and fatty acid metabolites, and energy metabolism in dwarf plants decreased. There was a notable upregulation of PmLBD3 gene expression in plant specimens that were subjected to grafting onto mume rootstocks. Auxin signalling cues promoted PmARF3 transcription, which directly controlled this upregulation. Through its binding to PmBAS1 and PmSAUR36a gene promoters, PmLBD3 promoted endogenous brassinolide inactivation and inhibited cell proliferation.CONCLUSIONS: Auxin signalling and brassinolide levels are linked by PmLBD3. Our findings showed that PmLBD3 is a key transcription factor that regulates the balance of hormones through the auxin and brassinolide signalling pathways and causes dwarf plants in stone fruits.PMID:39183294 | DOI:10.1186/s12915-024-01985-z

Chin Med. 2024 Aug 25;19(1):114. doi: 10.1186/s13020-024-00983-1.ABSTRACTBACKGROUND: Prediabetes mellitus (PreDM) is a high-risk state for developing type 2 diabetes mellitus (T2DM) and often goes undiagnosed, which is closely associated with obesity and characterized by insulin resistance that urgently needs to be treated.PURPOSE: To obtain a better understanding of the biological processes associated with both "spleen-dampness" syndrome individuals and those with dysglycaemic control at its earliest stages, we performed a detailed metabolomic analysis of individuals with various early impairments in glycaemic control, the results can facilitate clinicians' decision making and benefit individuals at risk.METHODS: According to the diagnostic criteria of TCM patterns and PreDM, patients were divided into 4 groups with 20 cases, patients with syndrome of spleen deficiency with dampness encumbrance and PreDM (PDMPXSK group), patients with syndrome of dampness-heat in the spleen and PreDM (PDMSRYP group), patients with syndrome of spleen deficiency with dampness encumbrance and normal blood glucose (NDMPXSK group), and patients with syndrome of dampness-heat in the spleen and normal blood glucose (NDMSRYP group). Plasma samples from patients were collected for clinical index assessment and untargeted metabolomics using liquid chromatography-mass spectrometry.RESULTS: Among patients with the syndrome of spleen deficiency with dampness encumbrance (PXSK), those with PreDM (PDMPXSK group) had elevated levels of 2-hour post-load blood glucose (2-h PG), glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (SBP) than those in the normal blood glucose group (NDMPXSK group, P < 0.01). Among patients with the syndrome of dampness-heat in the spleen (SRYP), the levels of body mass index (BMI), fasting blood glucose (FBG), 2-h PG, HbA1c, and fasting insulin (FINS) were higher in the PreDM group (PDMSRYP group) than those in the normal blood glucose group (NDMSRYP group, P < 0.05). In both TCM syndromes, the plasma metabolomic profiles of PreDM patients were mainly discriminatory from the normal blood glucose controls of the same syndrome in the levels of lipid species, with the PXSK syndrome showing a more pronounced and broader spectrum of alterations than the SRYP syndrome. Changes associated with PreDM common to both syndromes included elevations in the levels of 27 metabolites which were mainly lipid species encompassing glycerophospholipids (GPs), diglycerides (DGs) and triglycerides (TGs), cholesterol and derivatives, and decreases in 5 metabolites consisting 1 DG, 1 TG, 2 N,N-dimethyl phosphatidylethanolamine (PE-NMe2) and iminoacetic acid. Correlation analysis identified significant positive correlations of 3α,7α,12α,25-Tetrahydroxy-5β-cholestane-24-one with more than one glycaemia-related indicators, whereas DG (20:4/20:5) and PC (20:3/14:0) were positively and PC (18:1/14:0) was inversely correlated with more than one lipid profile-related indicators. Based on the value of correlation coefficient, the top three correlative pairs were TG with PC (18:1/14:0) (r = - 0.528), TG with TG (14:0/22:4/22:5) (r = 0.521) and FINS with PE-NMe (15:0/22:4) (r = 0.52).CONCLUSION: Our results revealed PreDM patients with different TCM syndromes were characterized by different clinical profiles. Common metabolite markers associated with PreDM shared by the two TCM syndromes were mainly lipid species encompassing GP, GL, cholesterol and derivatives. Our findings were in line with the current view that altered lipid metabolism is a conserved and early event of dysglycaemia. Our study also implied the possible involvement of perturbed bile acid homeostasis and dysregulated PE methylation during development of dysglycaemia.PMID:39183283 | DOI:10.1186/s13020-024-00983-1

Brain. 2024 Aug 26:awae272. doi: 10.1093/brain/awae272. Online ahead of print.ABSTRACTMonogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.PMID:39183150 | DOI:10.1093/brain/awae272

Anal Chim Acta. 2024 Sep 15;1322:343065. doi: 10.1016/j.aca.2024.343065. Epub 2024 Aug 6.ABSTRACTHydroxyl compounds are widely present in plants and play essential roles in plant growth and development. High-coverage detection of hydroxyl compounds is crucial for understanding the physiological processes of plants. Despite the prevalence of chemical derivatization-assisted liquid chromatography-high resolution mass spectrometry (CD-LC-HRMS) in high-coverage detection of compounds with diverse functional groups, the confident identification of these compounds after derivatization remains a significant challenge. Herein, a novel method was developed for the identification of pyridine (PY)-derivatized hydroxyl compounds by comparing the MS/MS similarity of derivatized and corresponding underivatized compounds. Fragmentation rules of standards were summarized, and theoretical calculations have demonstrated the MS/MS similarity of PY-derivatized hydroxyl compounds with their underivatized counterparts. The effectiveness of the developed method was demonstrated by identifying PY-derivatized authentic standards. A total of 90 hydroxyl compounds were putatively identified in maize using the proposed method. This method can significantly enhance ionization efficiency with minimal impact on the quality of the MS/MS spectra, enabling the effective utilization of mass spectra databases for the identification of hydroxyl compounds.PMID:39182991 | DOI:10.1016/j.aca.2024.343065

Anal Chim Acta. 2024 Sep 22;1323:343062. doi: 10.1016/j.aca.2024.343062. Epub 2024 Aug 5.ABSTRACTBACKGROUND: Metabolomics is a scientific field that relies on the comprehensive analysis of metabolites to provide direct insights into functional processes in biological systems. Metabolomic data provides valuable insights into the functional processes of biological systems, often analyzed through univariate and multivariate approaches, and well as with functional or pathway analysis using different methods such as mummichog. Yet, the integration of results from these sources to aid the interpretation of their biological significance remains challenging. This represents a significant bottleneck limiting the applicability of multivariate analysis of metabolomic data, despite its potential for providing deep biological insights.RESULTS: In this work we propose two straightforward methods to facilitate the interpretation of results from multivariate analysis and functional metabolic analysis using: i) p-values from multivariate tests as input in functional analysis, and ii) cluster-CV to assess the impact on the predictive performance of a multivariate model at the pathway level. Four simulated data sets were analyzed including a data set with no class separation, and three data sets with a statistically significant discrimination between classes by including either univariate, multivariate, or both types of discriminant effects. The data sets were analyzed using univariate tests and OPLS-DA. Furthermore, p-values for each feature estimated by univariate analysis and OPLS-DA were used as input for functional analysis in mummichog. Cluster-CV was then used to assess the effect of detected metabolic pathways on the class separation observed by OPLS-DA.SIGNIFICANCE: Through simulated data, we show how these approaches enhance the interpretation of biological effects driving multivariate models and support the identification of altered pathways not detected by univariate analysis. By providing a deeper understanding of metabolic phenotypes, these methods might improve the biological insights derived from statistical and functional analysis of future or previous studies.PMID:39182979 | DOI:10.1016/j.aca.2024.343062

Ann Pharm Fr. 2024 Aug 23:S0003-4509(24)00130-5. doi: 10.1016/j.pharma.2024.08.008. Online ahead of print.ABSTRACTOBJECTIVES: This study aimed to assess the individual and combined effects of SAE and Met on the expression of genes related to insulin signaling, oxidative stress, hormonal imbalance, insulin resistance, and dyslipidemia in rats with induced PCOS.METHODS: The estrous cycle of 50 adult Wistar female rats was monitored through vaginal smears. Subsequently, the rats were randomly assigned into five groups of 10, including control (receiving 1 ml of carboxymethyl cellulose for 49 days), induction (letrozole at 1 mg/kg/d for 21 days), SAE, Met, and SAE/Met. SAE and Met were orally administered at doses of 400 mg/kg/d and 250 mg/kg/d on day 22 and continued for an additional 28 days. Vaginal smears were analyzed, and gene expression levels of GLUT4, SIRT1, TNF-α, and INSR were evaluated using RT-qPCR. Antioxidant parameters were assessed using detection kits.RESULTS: Treatment with SAE and Met restored a regular estrous cycle pattern in PCOS rats. Furthermore, SAE and Met treatment improved hormonal balance, dyslipidemia, and hyperglycemia in the rats. Administration of SAE and Met significantly elevated levels of antioxidant enzymes SOD and GPx in ovarian tissue (P<0.001). Additionally, mRNA levels of GLUT4, SIRT1, and INSR were significantly increased in ovarian tissue following SAE and Met treatment, while TNF-α gene expression decreased significantly (P<0.0001).CONCLUSION: The findings suggest that SAE and Met aqueous extract exert protective effects on letrozole-induced PCOS in rats by modulating gene expression associated with insulin signaling and oxidative stress.PMID:39182906 | DOI:10.1016/j.pharma.2024.08.008

Sci Total Environ. 2024 Aug 23:175732. doi: 10.1016/j.scitotenv.2024.175732. Online ahead of print.ABSTRACTMethane emissions from enteric fermentation present a dual challenge globally: they not only contribute significantly to atmospheric greenhouse gases but also represent a considerable energy loss for ruminant animals. Utilizing high-throughput omics technologies to analyze rumen microbiome samples (meta-omics, i.e., metagenomics, metatranscriptomics, metaproteomics, metabolomics) holds vast potential for uncovering the intricate interplay between diet, microbiota, and methane emissions in these animals. The primary obstacle is the effective integration of diverse meta-omic approaches and their broader application across different ruminant species. Genetic variability significantly impacts methane production in ruminants, suggesting that genomic selection could be a viable strategy to reduce emissions. While substantial research has been conducted on the microbiological aspects of methane production, there remains a critical need to delineate the specific genetic interactions between the host and its microbiome. Advancements in meta-omics technologies are poised to shed light on these interactions, enhancing our understanding of the genetic factors that govern methane output. This review explores the potential of meta-omics to accelerate genetic advancements that could lead to reduced methane emissions in ruminants. By employing a systems biology approach, the integration of various omics technologies allows for the identification of key genomic regions and genetic markers linked to methane production. These markers can then be leveraged in selective breeding programs to cultivate traits associated with lower emissions. Moreover, the review addresses current challenges in applying genomic selection for this purpose and discusses how omics technologies can overcome these obstacles. The systematic integration and analysis of diverse biological data provide deeper insights into the genetic underpinnings and overall biology of methane production traits in ruminants. Ultimately, this comprehensive approach not only aids in reducing the environmental impact of agriculture but also contributes to the sustainability and efficiency of livestock management.PMID:39182764 | DOI:10.1016/j.scitotenv.2024.175732

Food Chem Toxicol. 2024 Aug 23:114952. doi: 10.1016/j.fct.2024.114952. Online ahead of print.ABSTRACTIn recent decades, the toxicity of chiral pesticides to non-target organisms has attracted increasing attention. Cellular metabolic disorders are essential sensitive molecular initiating event for toxicological effects. BF is a typical chiral pesticide, and the liver is the main organ for BF accumulation. This study aimed to investigate the potential molecular mechanism of BF enantiomers' different toxic effects on L02 by a non-targeted metabolomic approach. Results revealed that the BF enantiomers exhibited different metabolic responses. In total, 51 and 36 differential metabolites were perturbed by 1S-cis-BF and 1R-cis-BF at the value of variable importance, respectively. When L02 were exposed to 1R-cis-BF, the significantly disturbed metabolic pathways were nicotinate and nicotinamide metabolism and pyrimidine metabolism. By comparison, more significantly perturbed metabolic pathways were received when the L02 were exposed to 1S-cis-BF, including glycine, serine and threonine metabolism, nicotinate and nicotinamide metabolism, arginine and proline metabolism, cysteine and methionine metabolism, glycerolipid metabolism, histidine metabolism, pyrimidine metabolism, amino sugar and nucleotide sugar metabolism and arginine biosynthesis. The results offer a new perspective in understanding the role of selective cytotoxicity of BF enantiomers, and help to evaluate the risk to human health at the enantiomeric level.PMID:39182637 | DOI:10.1016/j.fct.2024.114952

Food Chem Toxicol. 2024 Aug 23:114949. doi: 10.1016/j.fct.2024.114949. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is a worldwide public health problem with high morbidity and mortality. Cisplatin is a widely used chemotherapeutic agent for treating solid tumors, but the induction of AKI restricts its clinical application. In this study, the effect of cisplatin on the expression of organic ion transporters was investigated through in vivo and in vitro experiments. Targeted metabolomics techniques were used to measure the levels of selected endogenous substances in serum. Transmission electron microscopy was used to observe the microstructure of renal tubular epithelial cells. Our results show that the toxicity of cisplatin on HK-2 cells or HEK-293 cells was time- and dose-dependent. Administration of cisplatin decreased the expression of OAT1/3 and OCT2 and increased the expression of MRP2/4. Mitochondrial damage induced by cisplatin lead to renal tubular epithelial cell injury. In addition, administration of cisplatin resulted in significant changes in endogenous substance levels in serum, including amino acids, carnitine, and fatty acids. These serum amino acids and metabolites (α-aminobutyric acid, proline, and alanine), carnitines (tradecanoylcarnitine, hexanylcarnitine, octanoylcarnitine, 2-methylbutyroylcarnitine, palmitoylcarnitine, and linoleylcarnitine) and fatty acids (9E-tetradecenoic acid) represent endogenous substances with diagnostic potential for cisplatin-induced AKI.PMID:39182635 | DOI:10.1016/j.fct.2024.114949

J Lipid Res. 2024 Aug 23:100633. doi: 10.1016/j.jlr.2024.100633. Online ahead of print.ABSTRACTDRP1 plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with an HFD. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and ER-lipid droplet cross-talk in normal mice. Loss-of-function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays a pivotal role in energy homeostasis in adipose tissue during obesity.PMID:39182608 | DOI:10.1016/j.jlr.2024.100633

J Hazard Mater. 2024 Aug 13;478:135507. doi: 10.1016/j.jhazmat.2024.135507. Online ahead of print.ABSTRACTAir pollution exposure has been linked with coagulation function. However, evidence is limited for the relationships between air pollution, coagulation function and metabolomics in humans. We recruited a panel of 130 rural elderly from the Chayashan township in China, all of whom were free of pre-existing cardiovascular diseases and had provided residential address information. We conducted clinical examinations and collected blood samples from these rural elderly for the detection of coagulation biomarkers (e.g, activated partial thromboplastin time, fibrinogen, thrombin time, and prothrombin time) and untargeted metabolites in both December 2021 and August 2022. We used mini ambient air quality monitor to measure the mean levels of five air pollutants (e.g., PM2.5, SO2, NO2, CO and O3) during 1 to 2 weeks before blood sample collection. The Mummichog pathway analysis was used to identified potential metabolic features and pathways. In this study, we identified 5 pathways associated with both air pollution and coagulation function, and further pinpointed eight metabolic features within these pathways. The majority of these features were lipids, including arachidonic acid and linoleic acid. Overall, the findings of this study offer insights into potential mechanisms, particularly lipid metabolism, that may underlie the association between air pollution and coagulation function.PMID:39182293 | DOI:10.1016/j.jhazmat.2024.135507

Ecotoxicol Environ Saf. 2024 Aug 24;284:116921. doi: 10.1016/j.ecoenv.2024.116921. Online ahead of print.ABSTRACTCalcium ions (Ca2+), essential as second messengers in all cells, play a pivotal role as micronutrients in insects. However, few studies have explored the effects of both insufficient and excessive Ca2+ intake on life history performance and population parameters. This study examines the impact of varying Ca2+ intake levels-insufficient (0 mg/kg), appropriate (100 mg/kg), and excessive (250 mg/kg)-on the life history performance and population parameters of Spodoptera litura using two-sex life tables. Insufficient and excessive Ca2+ intakes significantly extended the preadult development period and decreased the preadult survival rates of S. litura, compared to those on an appropriate Ca2+ intake. The population parameters (Intrinsic rate of increase (r), Finite rate of increase (λ), and Net reproductive rate (R0)) of S. litura on a 100 mg/kg diet (r = 0.1364, λ = 1.1462, R0 = 390) were significantly higher than those on a 0 mg/kg diet (r = 0.1091, λ = 1.1153, R0 = 130.52). Additionally, untargeted metabolomics analysis revealed that inappropriate Ca2+ levels (either insufficient or excessive) triggered significant up-regulation of 71.1 % and 92.8 % of the metabolites in the hemolymph, respectively, compared to the appropriate Ca2+ intake. Notably, disruptions in metabolite balance affected critical components such as melatonin and melanin within the tryptophan and tyrosine metabolism pathways. These findings underscore that both insufficient and excessive Ca2+ intakes adversely affect the life history performance and disrupt hemolymph metabolic balance in S. litura.PMID:39182284 | DOI:10.1016/j.ecoenv.2024.116921

Int Immunopharmacol. 2024 Aug 23;141:112998. doi: 10.1016/j.intimp.2024.112998. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1β, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5.PMID:39182265 | DOI:10.1016/j.intimp.2024.112998

Gut Microbes. 2024 Jan-Dec;16(1):2391535. doi: 10.1080/19490976.2024.2391535. Epub 2024 Aug 25.ABSTRACTBACKGROUND: Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear.METHODS: C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated.RESULTS: Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection.CONCLUSIONS: The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.PMID:39182245 | DOI:10.1080/19490976.2024.2391535

Plant Physiol Biochem. 2024 Aug 10;215:109032. doi: 10.1016/j.plaphy.2024.109032. Online ahead of print.ABSTRACTThere are limited molecular data and few biomarkers available for studies of field-grown plants, especially for plants grown during extremely long days. In this study we present quantitative proteomics data from 3 years of field trials on potato, conducted in northern and southern Sweden and analyze over 3000 proteins per year of the study and complement the proteomic analysis with metabolomic and transcriptomic analyses. Small but consistent differences linked to the longer days (an average of four more hours of light per day) in northern Sweden (20 h light/day) compared to southern Sweden can be observed, with a high correlation between the mRNA determined by RNA-seq and protein abundances. The majority of the proteins with differential abundances between northern and southern Sweden could be divided into three groups: metabolic enzymes (especially GABA metabolism), proteins involved in redox metabolism, and hydrolytic enzymes. The observed differences in metabolic enzyme abundances corresponded well with untargeted metabolite data determined by GC and LC mass-spectrometry. We also analyzed differences in protein abundance between potato varieties that performed relatively well in northern Sweden in terms of yield with those that performed relatively less well. This comparison indicates that the proteins with higher abundance in the high-yield quotient group are more anabolic in their character, whereas the proteins with lower abundance are more catabolic. Our results create a base of information about potato "field-omics" for improved understanding of physiological and molecular processes in field-grown plants, and our data indicate that the potato plant is not generally stressed by extremely long days.PMID:39181085 | DOI:10.1016/j.plaphy.2024.109032

J Pharm Biomed Anal. 2024 Aug 15;251:116424. doi: 10.1016/j.jpba.2024.116424. Online ahead of print.ABSTRACTTo characterize the microbiome and metabolic profile in Crohn's disease (CD) patients with different outcome after infliximab (IFX) treatment. The clinical data of a cohort of 35 patients with moderate-to-severe CD admitted at Jinling hospital between Oct 2022 and Dec 2023 were collected. Stool samples at baseline were collected to perform 16SrRNA and ITS2 sequencing and LC-MS untargeted metabolomics. Of these, seven discontinued IFX and underwent surgery during the induction period, and 28 received IFX at weeks 0, 2, and 6, each administered intravenously. Clinical remission was assessed based on the clinical symptoms and HBI at baseline and week 14. Baseline microbial richness and evenness was not significantly different between remission and non-remission group. The taxonomic community analysis identified decrease of Ruminococcus, Lachnoclostridium, Akkermansia in bacterial community and decrease of Asterotremella and Wallemia in fungal community in the non-remission group. LC-MS analysis showed that histamine, creatinine and L-proline significantly increased in remission group, while androsterone, berberine and episterol significantly decreased. The combined prediction model of histamine, androsterone, and episterol demonstrated a high predictive value of remission in patients after IFX treatment (AUC=0.898, p<0.001). Together, these data might facilitate a priori determination of optimal therapeutics for CD patients.PMID:39180897 | DOI:10.1016/j.jpba.2024.116424