PubMed

BMJ Open. 2024 Dec 9;14(12):e085682. doi: 10.1136/bmjopen-2024-085682.ABSTRACTPURPOSE: Epidemiological studies have reported that environmental factors from fetal period to early childhood can influence the risk of non-communicable diseases in adulthood. This concept has been termed the developmental origins of health and disease (DOHaD). The Chiba study of Mother and Child Health (C-MACH) is a DOHaD concept-based birth cohort study which started in 2014. This study aims to investigate the effects of genetic and environmental factors, particularly fetal and postnatal living environment, on children's health. We also aim to identify candidate biomarkers for their health status. Moreover, the second phase study of C-MACH which was initiated in 2021 aimed at expanding the sample size, especially for gut microbiota and epigenomic analysis; it also aimed at clarifying the impact of the coronavirus disease 2019 (COVID-19) pandemic on children's health.PARTICIPANTS: This study consists of four hospital-based cohorts. Women who were <13 weeks pregnant and their partners were enrolled in the study. All data and biological samples will be stored in the Chiba University Centre for Preventive Medical Sciences.FINDINGS TO DATE: A total of 561 women and their partners provided their consent to participate in this study. Of these women, 505 completed the questionnaire during the early gestational period. The mean age of the 505 women at enrolment was 33.0 (SD, 4.5) years. The mean prepregnancy body mass index (BMI) was 21.7 (SD, 3.6) kg/m2, with 74.5% of the women having a BMI of 18.5-24.9 kg/m2. About 5.2% of the women smoked cigarettes during the early stages of pregnancy.FUTURE PLANS: The primary study outcomes are allergies, obesity, endocrine and metabolic disorders and developmental difficulties in children. Variables related to genome, metabolome, epigenome, gut microbiota and exposome will be evaluated as health-related factors. The relationships between these outcomes and the health-related factors will be analysed.PMID:39653579 | DOI:10.1136/bmjopen-2024-085682

Zhonghua Yi Xue Za Zhi. 2024 Dec 10;104(46):4204-4211. doi: 10.3760/cma.j.cn112137-20240626-01428.ABSTRACTObjective: To explore the associations of plasma acylcarnitine and bile acid levels with the risk of incident coronary heart disease (CHD) in Chinese adults. Methods: The baseline survey of China Kadoorie Biobank (CKB) took place in 10 areas across China during 2004-2008, and the first resurvey took place from July to October 2008, with collection of data via questionnaire, physical examination and blood samples. The current study was based on 2 159 individuals with targeted mass spectrometry metabolomic measurements from the first resurvey of CKB. The associations of acylcarnitines and bile acids with incident CHD were assessed using Cox proportional hazards regression models. Unweighted metabolites scores were constructed to assess the overall effect of acylcarnitines and bile acids on incident CHD. The impact of metabolites on the performance of CHD prediction model was evaluated with the receiver operating characteristic (ROC) area under the curve (AUC). Follow-up for CHD incidence was censored on December 31, 2018. Results: The mean age of the participants was (53.1±9.8) years and 754 were males (34.9%). During (10.5±0.1) years of follow-up, 140 cases of CHD were recorded. Four metabolites including acylcarnitines C3-OH, C5:1, C5:1-DC, and deoxycholic acid (DCA) showed associations with CHD incidence and the HR (95%CI) were 1.474 (1.230-1.767), 0.761 (0.637-0.909), 0.773 (0.650-0.918), and 1.309 (1.113-1.539), respectively [false discovery rate (FDR)0.05]. All metabolite scores, including short-chain, medium-chain, long-chain acylcarnitines, primary and secondary bile acids scores were associated with the risk of CHD (FDR0.05). Compared to the traditional models, the addition of DCA or 4 key metabolites increased the AUC of the predictive model from 0.803 (0.761-0.845) to 0.812 (0.772-0.852) and 0.817 (0.778-0.857), respectively (all P0.05). Conclusions: Acylcarnitine and bile acid levels are associated with the risk of CHD, and DCA or 4 key metabolites can improve the predictive ability for CHD incidence.PMID:39653525 | DOI:10.3760/cma.j.cn112137-20240626-01428

Fungal Biol. 2024 Dec;128(8 Pt B):2372-2380. doi: 10.1016/j.funbio.2023.12.008. Epub 2024 Jan 1.ABSTRACTPlant metabolites have a great potential for limiting the spread of harmful fungi. However, a better understanding of the mode-of-action of these molecules and the defense systems developed by fungi to resist them, is needed to assess the benefits/risks of using them as antifungal treatment. White-rot fungi are excellent models in this respect, as they have adapted to the hostile habitat that is wood. In fact, wood is a source of putative antifungal compounds that can be derived using extraction techniques. In this study, we demonstrated that esculin and esculetin, which are coumarins found in plants and wood, reduce the growth of the wood-rotting fungi Fomitiporia mediterranea, Phanerochaete chrysosporium, Pycnoporus cinnabarinus and Trametes versicolor. We have shown that extracellular strategies are developed by the fungi to deal with esculin, through the involvement of laccases, peroxidases and glycoside hydrolases, and intracellular strategies, mainly via upregulated protein translation. Comparative proteomic and metabolomic approaches revealed that, despite the fact that the species analysed are closely related (they all belong to the Agaricomycetes, and have the same trophic mode), their defense responses to esculin differ.PMID:39653484 | DOI:10.1016/j.funbio.2023.12.008

Gut. 2024 Dec 9:gutjnl-2024-333530. doi: 10.1136/gutjnl-2024-333530. Online ahead of print.ABSTRACTBACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.OBJECTIVE: To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL.DESIGN: This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms.RESULTS: We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in Faecalibacterium prausnitzii which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of F. prausnitzii in NKTCL mouse models. Furthermore, F. prausnitzii culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1.CONCLUSION: These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of F. prausnitzii to ameliorate this malignancy.PMID:39653411 | DOI:10.1136/gutjnl-2024-333530

Int J Biol Macromol. 2024 Dec 7:138427. doi: 10.1016/j.ijbiomac.2024.138427. Online ahead of print.ABSTRACTTriple negative breast cancer (TNBC) seriously endangers women's life and health due to its high invasion and mortality. Reactive oxygen species (ROS) mediated tumor cells apoptosis is considered an effective anticancer approach. Herein, we designed a natural active triple helix β-Glucan (BFP) wrapped single walled carbon nanotubes (SWNTs)-loaded doxorubicin (DOX) self-assembly (BSD) via generating excess ROS to induce oxidative stress damage for TNBC therapy. BSD could directly consume glutathione (GSH) to promote ROS. In vitro results demonstrated that BSD exhibited obvious antitumor effects to breast cancer cells by promoting apoptosis. Un-targeted metabolomics under molecular level identified the specific metabolic targets and unveiled that BSD markedly disturbed multiple metabolic pathways, including purine metabolism, pentose phosphate pathway, glutathione metabolism pathways, amino sugar and nucleotide sugar metabolism and energy metabolism, led to the inhibition of DNA and RNA synthesis, the generation of ROS, the exacerbation of DNA damage, the disruption of cell membrane integrity and the decrease of ATP. In vitro and in vivo oxidative stress assays further verified that BSD significantly promoted intracellular oxidative stress and resulted in cell damage. This study provides theoretical basis for the development and screening of new drugs based on ROS therapy for TNBC.PMID:39653201 | DOI:10.1016/j.ijbiomac.2024.138427

Int J Biol Macromol. 2024 Dec 7:138528. doi: 10.1016/j.ijbiomac.2024.138528. Online ahead of print.ABSTRACTArsenic, a known environmental pollutant with a carcinogenic risk, is associated with chronic liver toxicity. Prebiotic regulation represents an emerging dietary strategy to alleviate arsenic-induced hepatotoxicity; however, research in this area remains limited. This study employed sulfated swim bladder glycosaminoglycan (SBSG), a potential prebiotic, to assess its efficacy in mitigating arsenic-induced liver injury. In basic indicators, SBSG resisted oxidative stress by down-regulating AST, ALT, MDA, and MPO, up-regulating antioxidants (T-SOD, GSH, and GSH-px), and ameliorating histopathological damage. RT-qPCR analysis revealed that SBSG could regulate the Nrf2 signaling pathway and affect the expression of o genes related to ferroptosis and detoxification. The expression of protein further verified that SBSG could play an antioxidant and detoxifying role as an Nrf2 activator. Non-targeted metabolomics results demonstrated that SBSG primarily addresses metabolic disorders by up-regulating D-amino acid metabolism, ABC transporter, and alanine, aspartate and glutamate metabolism. Correlation analysis suggests that SBSG alleviates arsenic-induced liver oxidative damage through mechanisms linked to the Nrf2 pathway and amino acid metabolism. This study provided a research basis for expanding the dietary strategy to reduce arsenic induced toxicity.PMID:39653196 | DOI:10.1016/j.ijbiomac.2024.138528

J Nutr Biochem. 2024 Dec 7:109831. doi: 10.1016/j.jnutbio.2024.109831. Online ahead of print.ABSTRACTThe prevalence of hyperlipidemia is gradually increasing globally, posing a serious threat to public health. Previous studies have shown that paeoniflorin (PF) effectively improved abnormal lipid metabolism in atherosclerotic mice. However, the anti-hyperlipidemia effect and potential mechanism of paeoniflorin remain unclear. The gut microbiota (GM) is closely related to hyperlipidemia. This study was aimed to investigate effects of PF on improving the health of high-fat diet (HFD)-induced hyperlipidemic mice by modulating GM. A hyperlipidemic mouse model was established using an HFD, and the hypolipidemic effect of PF was detected in vivo. Besides16S ribosomal RNA sequencing and SCFAs metabolic analysis were performed to explore the lipid-lowering mechanism of PF. Importantly, fecal microbiota transplantation (FMT) experiments were conducted to verify the lipid-lowering mechanism of PF. The results showed that PF significantly inhibited the development of hyperlipidemia, reduced serum lipid and inflammatory cytokine levels, and improved liver steatosis. In addition, 16S rRNA sequencing revealed that PF treatment significantly increased the relative abundance of Lactobacillus, Coprococcus, Blautia, Roseburia, and Bacteroides while reducing the relative abundance of Prevotella. Meanwhile, the results of targeted metabolomics indicate that PF therapy can effectively restore butyric acid and propionic acid levels in the intestine. The FMT experiments further demonstrated that PF improved hyperlipidemia by regulating GM and its metabolites. The above results provide a valuable theoretical basis for the development and application of PF as a functional food for hyperlipidemia.PMID:39653155 | DOI:10.1016/j.jnutbio.2024.109831

Free Radic Biol Med. 2024 Dec 7:S0891-5849(24)01132-8. doi: 10.1016/j.freeradbiomed.2024.12.028. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is a gradually progressive neurodegenerative disease with a serious impact on patients' quality of life. However, single-targeted therapies are not currently effective, and there is a need to find pluripotent drugs with multiple properties. This study aimed to characterize the metabolism of neurotransmitters using a targeted metabolomics approach and to identify the major metabolic pathways mainly affected by 6‴-feruloylspinosin (6-FS). The mechanism of action of 6-FS in the treatment of AD was elucidated based on experimental validation. The metabolomics analysis revealed changes in 13 metabolic profiles by the LC-MS/MS, with significant changes in five amino acid-related neurotransmitters identified primarily. Based on the correlations, we found an effect of mTOR inhibition on the above neurotransmitter metabolism. Furthermore, pretreatment with 6-FS activated the AMPK/mTOR signaling pathway, promoting cellular autophagy, regulating oxidative stress homeostasis and inhibiting mitochondrial dysfunction. In short, these comprehensive analysis methods help clarify the preventive mechanism of 6-FS and potential targets in AD and provide the necessary support for developing natural products to prevent AD.PMID:39653128 | DOI:10.1016/j.freeradbiomed.2024.12.028

Comp Biochem Physiol C Toxicol Pharmacol. 2024 Dec 7:110102. doi: 10.1016/j.cbpc.2024.110102. Online ahead of print.ABSTRACTNanopolystyrene (NP) and phoxim (PHO) are pervasive environmental contaminants that pose a significant threat to the health of aquatic organisms, prompting widespread concern among researchers and the public alike. The hepatopancreas play important roles in the Chinese mitten crab (Eriocheir sinensis), such as digestion, absorption and detoxification. This study assessed the hepatopancreatic toxicity caused by the exposure of Eriocheir sinensis to environmentally relevant concentrations of NP and/or PHO. After a 21-day exposure period, NP (1.0 × 1010 particles/L) and PHO (24 μg/L) exposure resulted in reduced number of blister-like, resorptive, and fibrillar cells and an elevation in lipid droplets within the hepatopancreas compared to the control group. Furthermore, trypsin and lipase activity decreased, amylase activity increased, and a significantly decrease in the expression of digestion-related genes, including CHT, CarL, and CarB, suggested impairment in both digestive and metabolic functions. The marked upregulation of key genes, including PPARγ, GYK, PEPCK, and SCD, as well as key metabolites such as 4-methylzymosterol-carboxylate, zymosterone, lathosterol, 7-dehydro-desmosterol, vitamin D2, 24-methylene-cycloartanol, 5-dehydroepisterol, and sitosterol in the lipid metabolic pathway, showed that the peroxisome proliferator-activated receptor (PPAR) and steroid biosynthesis signaling pathways were highly affected by exposure to NP and/or PHO. These findings indicated that exposure to NP and/or PHO might adversely affect the hepatopancreatic physiological homeostasis in E. sinensis by causing tissue damage and interfering with digestive and metabolic functions. Our results provide ecotoxicological insights into the effects of nanopolystyrene and/or phoxim exposure on the digestive function of Eriocheir sinensis.PMID:39653099 | DOI:10.1016/j.cbpc.2024.110102

Glia. 2024 Dec 9. doi: 10.1002/glia.24652. Online ahead of print.ABSTRACTAlzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.PMID:39652363 | DOI:10.1002/glia.24652

Arch Microbiol. 2024 Dec 9;207(1):12. doi: 10.1007/s00203-024-04210-1.ABSTRACTCultured milk products including yogurt, buttermilk, and lassi have made their way into South Asian cuisine for hundreds of years and are extraordinarily beneficial to human health. With a study background on lactic acid bacteria (LAB), these products are scientifically proved to aid in strengthening the immune system, for their anti-mutagenic effects, suitability for those who are lactose intolerant, and for protection against cancer, osteoporosis, and gut disorders. As of now, no scientific attention has been given to the microbial diversity of cultured milk products despite its prominent production and importance in the culture. New emerging approaches for studying the genetic composition and metabolic features of microbial communities, such as metagenomics and metabolomics, will open up important sources of knowledge and be a significant tool for informing conservation. These products are highly valued worldwide in the management of cardiometabolic diseases (CMDs), which encompass hypertension, type 2 diabetes, and obesity. The aim of this article will therefore advocate for the health benefits as well as cultural importance of cultured milk products. Indian fermented milk products, along with their historical development, cultural, and research aspects, thereby, highlighting the potential of this kind of product in promoting global health through functional food application, with a focus on recent advancements in their therapeutic potential and applications.PMID:39652203 | DOI:10.1007/s00203-024-04210-1

Eur J Immunol. 2024 Dec 9:e202451440. doi: 10.1002/eji.202451440. Online ahead of print.ABSTRACTPotassium ions (K+) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K+ concentration to 50 mM (high-[K+]e). Here, we demonstrate that high-[K+]e decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K+]e also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and iTreg subsets that promote tumour growth while restricting antitumour Th1 and Th17 subsets. Similar phenotypes were noted in T-cells present within the necrosis-prone core versus the outer zones of hepatocellular carcinoma (HCC)/colorectal carcinoma (CRC) tumours as analysed by GeoMx digital spatial profiling and flow-cytometry. Our results thus expand the understanding of the contribution of high-[K+]e to the immunosuppressive milieu in the TME.PMID:39651799 | DOI:10.1002/eji.202451440

Neuroreport. 2025 Jan 8;36(1):22-30. doi: 10.1097/WNR.0000000000002115. Epub 2024 Dec 4.ABSTRACTThis study aimed to investigate the potential of electroacupuncture as an intervention for inducing 'Awakening and Opening of the Brain' in rats with stroke models induced by middle cerebral artery occlusion/reperfusion (MCAO/R). The efficacy of electroacupuncture in alleviating cerebral ischemic injury was evaluated using Longa scores, triphenyl tetrazolium chloride staining, and hematoxylin and eosin staining. Non-targeted metabolomics analysis was conducted to identify differential metabolite changes before and after electroacupuncture treatment in MCAO/R rats. Network pharmacology analysis was then performed to correlate these differential metabolites with ischemic stroke. The PI3K/AKT/NF-κB signaling pathway was identified as a key target. In vivo experiments further validated the mechanism by which electroacupuncture promotes M2 microglial polarization through inhibition of the PI3K/AKT/NF-κB signaling in MCAO/R rats. This study demonstrated that electroacupuncture reduces brain damage and inhibits inflammation in MCAO/R rats by modulating the PI3K/AKT/NF-κB signaling pathway and promoting the polarization of microglia from M1 to M2.PMID:39651717 | DOI:10.1097/WNR.0000000000002115

bioRxiv [Preprint]. 2024 Nov 27:2024.11.26.624872. doi: 10.1101/2024.11.26.624872.ABSTRACTThe mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins ( Pf MPC1 and Pf MPC2) for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or both Pf MPCs with only minor growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters - DTC (di/tricarboxylic acid carrier) and YHM2 (a putative citrate/α-ketoglutarate carrier protein) - only mildly affected asexual blood-stage replication, even in the context of Pf MPC deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results expose redundant routes used to fuel the blood-stage malaria parasite mitochondrion with imported carbon from two major sources - glucose and glutamine.SIGNIFICANCE: The mitochondrion of malaria parasites generates key molecules, such as acetyl-CoA, that are required for numerous cellular processes. To support mitochondrial biosynthetic pathways, the parasites must transport carbon sources into this organelle. By studying how the mitochondrion obtains pyruvate, a molecule derived from glucose, we have uncovered redundant carbon transport systems that ensure parasite survival in red blood cells. This metabolic redundancy poses a challenge for drug development, as it enables the parasite to adapt and survive by relying on alternative pathways when one is disrupted.PMID:39651245 | PMC:PMC11623635 | DOI:10.1101/2024.11.26.624872

bioRxiv [Preprint]. 2024 Nov 25:2024.11.25.625231. doi: 10.1101/2024.11.25.625231.ABSTRACTHere, we present M2D2, a two-stage machine learning (ML) pipeline that identifies promising antimicrobial drug combinations, which are crucial for combating drug resistance. M2D2 addresses key challenges in drug combination discovery by predicting drug synergies using computationally generated drug-protein interaction data, thereby circumventing the need for expensive omics data. The model improves the accuracy of drug target identification using high-throughput experimental and computational methods via feedback between ML stages. M2D2's transparent framework provides mechanistic insights into drug interactions and was benchmarked against chemogenomics, transcriptomics, and metabolomics datasets. We experimentally validated M2D2 using high-throughput screening of 946 combinations of Food and Drug Administration (FDA)- approved drugs and antibiotics against Escherichia coli . We discovered synergy between a cerebrovascular drug and a widely used penicillin antibiotic and validated predicted mechanisms of action using genome-wide CRISPR inhibition screens. M2D2 offers a transparent ML tool for rapidly designing combination therapies and guides repurposing efforts while providing mechanistic insights.PMID:39651242 | PMC:PMC11623614 | DOI:10.1101/2024.11.25.625231

bioRxiv [Preprint]. 2024 Nov 25:2024.11.24.622516. doi: 10.1101/2024.11.24.622516.ABSTRACTThe metabolic health of the kidney is a primary determinant of the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel kidney functions is limited by the kidney's structural and functional heterogeneity. As the kidney contains many different cell types, we hypothesize that intra-renal mitochondrial heterogeneity contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique to isolate kidney cell-type specific mitochondria. Here, we investigate mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag allele was combined with Slc34a1-CreERT2 , Ggt1-Cre , or Pvalb-Cre alleles to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. Changes with mitochondrial metabolomes induced by fasting suggest that the late PT significantly increases FAO during fasting. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.TRANSLATIONAL STATEMENT: While the renal cortex is often considered a single metabolic compartment, we discovered significant diversity of mitochondrial metabolomes and functional capacities across the proximal tubule and the distal convoluted tubule. As mitochondrial dysfunction is a major biochemical pathway related to kidney disease progression, understanding the differences in mitochondrial metabolism across distinct kidney cell populations is thus critical in the development of effective and targeted therapeutic therapies for acute and chronic kidney disease.PMID:39651228 | PMC:PMC11623503 | DOI:10.1101/2024.11.24.622516

bioRxiv [Preprint]. 2024 Nov 27:2024.11.27.625683. doi: 10.1101/2024.11.27.625683.ABSTRACTThe obligate intracellular parasite Toxoplasma gondii replicates within a specialized compartment called the parasitophorous vacuole (PV). Recent work showed that despite living within a PV, Toxoplasma endocytoses proteins from the cytosol of infected host cells via a so-called ingestion pathway. The ingestion pathway is initiated by dense granule protein GRA14, which binds host ESCRT machinery to bud vesicles into the lumen of the PV. The protein-containing vesicles are internalized by the parasite and trafficked to the Plant Vacuole-like compartment (PLVAC), where cathepsin protease L (CPL) degrades the cargo and the chloroquine resistance transporter (CRT) exports the resulting peptides and amino acids to the parasite cytosol. However, although the ingestion pathway was proposed to be a conduit for nutrients, there is limited evidence for this hypothesis. We reasoned that if Toxoplasma uses the ingestion pathway to acquire nutrients, then parasites lacking GRA14, CPL, or CRT should rely more on biosynthetic pathways or alternative scavenging pathways. To explore this, we conducted a genome-wide CRISPR screen in wild-type (WT) parasites and Δ gra14 , Δ cpl , and Δ crt mutants to identify genes that become more fitness conferring in ingestion-deficient parasites. Our screen revealed a significant overlap of genes that become more fitness conferring in the ingestion mutants compared to WT. Pathway analysis indicated that Δ cpl and Δ crt mutants relied more on pyrimidine biosynthesis, fatty acid biosynthesis, TCA cycle, and lysine degradation. Bulk metabolomic analysis showed reduced levels of glycolytic intermediates and amino acids in the ingestion mutants compared to WT, highlighting the pathway's potential role in host resource scavenging. Interestingly, ingestion mutants showed an exacerbated growth defect when grown in amino acid-depleted media, suggesting a role for the Toxoplasma ingestion pathway during nutrient scarcity.IMPORTANCE: Toxoplasma gondii is an obligate intracellular pathogen that infects virtually any nucleated cell in most warm-blooded animals. Infections are asymptomatic in most cases but people with weakened immunity can experience severe disease. For the parasite to replicate within the host, it must efficiently acquire essential nutrients, especially as it is unable to make several key metabolites. Understanding the mechanisms by which Toxoplasma scavenges nutrients from the host is crucial for identifying potential therapeutic targets. Our study highlights the function of the ingestion pathway in sustaining parasite metabolites and contributes to parasite replication under amino acid limiting conditions. This work advances our understanding of the metabolic adaptability of Toxoplasma .PMID:39651188 | PMC:PMC11623567 | DOI:10.1101/2024.11.27.625683

Front Nutr. 2024 Nov 22;11:1428938. doi: 10.3389/fnut.2024.1428938. eCollection 2024.ABSTRACTINTRODUCTION: The diversity of dairy products and the increasing consumption levels have led to a growing interest in goat and sheep milk, which are rich in essential nutrients and functional components. The study aims to explore the nutritional composition, growth performance, digestibility, and serum metabolic differences of milk powders from cow, goat, and sheep using LC-MS/MS-based metabolomics in rat models.METHODS: Sixty male Sprague-Dawley rats were fed with whole cow, goat, and sheep milk powder samples , and their feces and urine were analyzed for fat and protein content. LC/MS analysis was conducted using a Dionex UltiMate 3000 UHPLC system coupled with a Thermo Q EXACTIVE mass spectrometer, with data processed using Wekemo Bioincloud for quality control, normalization, comparisons with the KEGG database, statistical analyses, and selection of differential metabolites.RESULTS: The sheep milk powder showed highest protein and fat content level, while cow and goat milk powders separately demonstrated higher lactose and carbohydrate levels. Each milk powder had a unique mineral profile, with sheep milk powder containing the highest calcium content. All groups exhibited consistent growth in body weight and high rates of protein and fat digestibility. Metabolomics analysis revealed distinct metabolic profiles, with goat milk powder linked to steroid hormone biosynthesis and sheep milk powder associated with hormone regulation and bile acid pathways.CONCLUSION: This study offers valuable insights into the metabolic implications of different milk powder sources, informing dietary choices and facilitating the development of targeted public health strategies to optimize nutritional intake and promote overall well-being.PMID:39650706 | PMC:PMC11622695 | DOI:10.3389/fnut.2024.1428938

Food Chem (Oxf). 2024 Nov 20;9:100230. doi: 10.1016/j.fochms.2024.100230. eCollection 2024 Dec 30.ABSTRACTRice consumption and demand for premium rice are increasing worldwide. However, the characterizations and how to identify the premium rice are still unclear. Small molecular metabolites have a great advantage in distinguishing subtle differences among similar agricultural products. So, we hypothesized that the metabolites would be the key to identifying the tiny differences in premium rice among similar varieties. In this study, we performed metabolomic and transcriptomic profiles to comprehensively elucidate key metabolites, genes, and formation mechanisms of premium rice. As a result, eight compounds belong to four categories, and 49 different expressional genes were identified in premium rice varieties after comparing with the second-best varieties. Moreover, the integrated analysis confirmed that the amino acid pathway, including 42 expression genes and 11 metabolites, was critical for the premium rice formation. Six genes and two metabolites had significant regulatory effects on the pathways. Furthermore, amino acid quantification confirmed the content of 12 kinds of hydrolytic amino acids, such as aspartic acid and arginine were different between premium and other varieties. These amino acids may serve as potential biomarkers for differentiating premium rice in Northeast China. Our results strongly support the possibility of differentiating premium rice and would provide essential data for premium rice identification and metabolomics-assisted breeding.PMID:39650206 | PMC:PMC11621605 | DOI:10.1016/j.fochms.2024.100230

Front Pharmacol. 2024 Nov 21;15:1503648. doi: 10.3389/fphar.2024.1503648. eCollection 2024.ABSTRACTBACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are important causes of morbidity and mortality in critically ill patients. Gastric contents aspiration is one of the most common causes of ALI/ARDS. To date, there are still no specific and effective pharmacological treatments for ALI/ARDS. Polyvinylalcohol-carbazate (PVAC), a polymer that can bind endogenous aldehydes, neutralize oxidative stress and inhibit inflammatory factors, may be a potential treatment for ALI/ARDS.METHODS: A hydrochloric acid (HCl) induced mouse model was employed to assess the effect of PVAC. The changes of lung mechanics, pulmonary edema, histology and immune cells, cytokines, and lipid mediators in bronchioalveolar lavage fluid (BALF) were investigated in HCl-challenged mice.RESULTS: In the HCl model, PVAC administration alleviated airway hyperresponsiveness and improved pulmonary edema and damage. In addition, it decreased the recruitment of neutrophils to the lung, and inhibited the increase of IL-6, TNF-α and leukotriene B4.CONCLUSION: These data indicates that PVAC is a potential candidate for the treatment of ALI/ARDS induced by aspiration of gastric acid or for the control of "asthma-like" symptoms in patients with gastroesophageal reflux.PMID:39650159 | PMC:PMC11622038 | DOI:10.3389/fphar.2024.1503648