PubMed

Function (Oxf). 2023 Jun 22;4(5):zqad031. doi: 10.1093/function/zqad031. eCollection 2023.ABSTRACTIn this study, novel methods were developed, which allowed continuous (24/7) measurement of arterial blood pressure and renal blood flow in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O2 and metabolites. Specifically, the study determined the effects of a high salt (HS; 4.0% NaCl) diet upon whole kidney O2 consumption and arterial and renal venous plasma metabolomic profiles of normal Sprague-Dawley rats. A separate group of rats was studied to determine changes in the cortex and outer medulla tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to 4.0% NaCl diet. In addition, targeted mRNA expression analysis of cortical segments was performed. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O2 consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. A novel finding was the increased expression of glycolysis-related genes in Cx and isolated proximal tubular segments in response to an HS diet, consistent with increased release of pyruvate and lactate from the kidney to the renal venous blood. Data suggests that aerobic glycolysis (eg, Warburg effect) may contribute to energy production under these circumstances. The study provides evidence that kidney metabolism responds to an HS diet enabling enhanced energy production while protecting from oxidative stress and injury. Metabolomic and transcriptomic analysis of kidneys of Sprague-Dawley rats fed a high salt diet.PMID:37575482 | PMC:PMC10413938 | DOI:10.1093/function/zqad031

Function (Oxf). 2023 Jul 28;4(5):zqad040. doi: 10.1093/function/zqad040. eCollection 2023.ABSTRACTSporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a bona fide biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies.PMID:37575479 | PMC:PMC10413929 | DOI:10.1093/function/zqad040

Bio Protoc. 2023 Aug 5;13(15):e4733. doi: 10.21769/BioProtoc.4733. eCollection 2023 Aug 5.ABSTRACTThe study of genes and their products is an essential prerequisite for fundamental research. Characterization can be achieved by analyzing mutants or overexpression lines or by studying the localization and substrate specificities of the resulting proteins. However, functional analysis of specific proteins in complex eukaryotic organisms can be challenging. To overcome this, the use of heterologous systems to express genes and analyze the resulting proteins can save time and effort. Yeast is a preferred heterologous model organism: it is easy to transform, and tools for genomics, engineering, and metabolomics are already available. Here, we describe a well-established and simple method to analyze the activity of plant monosaccharide transporters in the baker's yeast, Saccharomyces cerevisiae, using a simple growth complementation assay. We used the famous hexose-transport-deficient yeast strain EBY.VW4000 to express candidate plant monosaccharide transporters and analyzed their transport activity. This assay does not require any radioactive labeling of substrates and can be easily extended for quantitative analysis using growth curves or by analyzing the transport rates of fluorescent substrates like the glucose analog 2-NBDG. Finally, to further simplify the cloning of potential candidate transporters, we provide level 0 modular cloning (MoClo) modules for efficient and simple Golden Gate cloning. This approach provides a convenient tool for the functional analysis of plant monosaccharide transporters in yeast. Key features Comprehensive, simple protocol for analysis of plant monosaccharide transporters in yeast Includes optional MoClo parts for cloning with Golden Gate method Includes protocol for the production and transformation of competent yeast cells Does not require hazardous solutions, radiolabeled substrates, or specialized equipment.PMID:37575400 | PMC:PMC10415198 | DOI:10.21769/BioProtoc.4733

Mol Ther Oncolytics. 2023 Jul 19;30:27-38. doi: 10.1016/j.omto.2023.07.004. eCollection 2023 Sep 21.ABSTRACTProstate cancer (PCa) incidence is increasing and endangers men's lives. Early detection of PCa could improve overall survival (OS) by preventing metastasis. The prostate-specific antigen (PSA) test is a popular screening method. Several advisory groups, however, warn against using the PSA test due to its high false positive rate, unsupported outcome, and limited benefit. The number of disease-related biopsies performed annually far outweighs the number of diagnoses. Thus, there is an urgent need to develop accurate diagnostic biomarkers to detect PCa and distinguish between aggressive and indolent cancers. Recently, non-coding RNA (ncRNA), circulating tumor DNA (ctDNA)/ctRNA, exosomes, and metabolomic biomarkers in the liquid biopsies (LBs) of patients with PCa showed significant differences and clinical benefits in diagnosis, prognosis, and monitoring response to therapy. The analysis of urinary exosomal ncRNA presented a substantial correlation among Exos-miR-375 downregulation, clinical T stage, and bone metastases of PCa. Furthermore, the expression of miR-532-5p in urine samples was a vital predictive biomarker of PCa progression. Thus, this review focuses on promising molecular and metabolomic biomarkers in LBs from patients with PCa. We thoroughly addressed the most recent clinical findings of LB biomarker use in diagnosing and monitoring PCa in early and advanced stages.PMID:37575217 | PMC:PMC10415624 | DOI:10.1016/j.omto.2023.07.004

iScience. 2023 Jul 20;26(8):107424. doi: 10.1016/j.isci.2023.107424. eCollection 2023 Aug 18.ABSTRACTMonochorionic-diamniotic twin pregnancies are susceptible to unique complications arising from a single placenta shared by two fetuses. Twin-twin transfusion syndrome (TTTS) is a constellation of disturbances caused by unequal blood flow within the shared placenta giving rise to a major hemodynamic imbalance between the twins. Here, we applied TTTS as a model to uncover fetal metabolic adaptations to cardiovascular stress. We compared untargeted metabolomic analyses of amniotic fluid samples from severe TTTS cases vs. singleton controls. Amniotic fluid metabolites demonstrated alterations in fatty acid, glucose, and steroid hormone metabolism in TTTS. Among TTTS cases, unsupervised principal component analysis revealed two distinct clusters of disease defined by levels of glucose metabolites, amino acids, urea, and redox status. Our results suggest that the human fetal heart can adapt to hemodynamic stress by modulating its glucose metabolism and identify potential differences in the ability of individual fetuses to respond to cardiovascular stress.PMID:37575192 | PMC:PMC10415929 | DOI:10.1016/j.isci.2023.107424

Am J Physiol Cell Physiol. 2023 Aug 14. doi: 10.1152/ajpcell.00153.2023. Online ahead of print.ABSTRACTInducible nitric oxide synthase (iNOS) and vascular endothelial dysfunction have been implicated in the development and progression of atherosclerosis. This study aimed to elucidate the role of iNOS in vascular endothelial dysfunction. Ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS) combined with multivariate data analysis was used to characterize the metabolic changes in human umbilical vein endothelial cells (HUVECs) in response to different treatment conditions. In addition, molecular biology techniques were employed to explain the molecular mechanisms underlying the role of iNOS in vascular endothelial dysfunction. Tumor necrosis factor-alpha (TNF-α) enhances the expression of iNOS, TXNIP, and the level of reactive oxygen species (ROS), facilitates the entry of nuclear factor-kappa B (NF-κB) into the nucleus; and promotes injury in HUVECs. iNOS deficiency reversed the TNF-α-mediated pathological changes in HUVECs. Moreover, TNF-α increased the expression of TNFR-2, and the levels of p-IκBα and IL-6 proteins, and CD31, ICAM-1, and VCAM-1 proteins expression which were significantly reduced in HUVECs with iNOS deficiency. In addition, treating HUVECs in the absence or presence of TNF-α or iNOS, respectively, enabled the identification of putative endogenous biomarkers associated with endothelial dysfunction. These biomarkers were involved in critical metabolic pathways, including glycosylphosphatidylinositol-anchor biosynthesis, amino acid metabolism, sphingolipid metabolism, and fatty acid metabolism. iNOS deficiency during vascular endothelial dysfunction may affect the expression of TNFR-2, vascular adhesion factors and the level of ROS via cellular metabolic changes, thereby attenuating vascular endothelial dysfunction.PMID:37575057 | DOI:10.1152/ajpcell.00153.2023

Anal Chem. 2023 Aug 13. doi: 10.1021/acs.analchem.3c02833. Online ahead of print.ABSTRACTStable isotope-assisted metabolomics (SIAM) is a powerful tool for discovering transformation products (TPs) of contaminants. Nevertheless, the high cost or lack of isotope-labeled analytes limits its application. In-house H/D (hydrogen/deuterium) exchange reactions enable direct 2H labeling to target analytes with favorable reaction conditions, providing intuitive and easy-to-handle approaches for environmentally relevant laboratories to obtain cost-effective 2H-labeled contaminants of emerging concern (CECs). We first combined the use of in-house H/D exchange and 2H-SIAM to discover potential TPs of 6PPD (N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine), providing a new strategy for finding TPs of CECs. 6PPD-d9 was obtained by in-house H/D exchange with favorable reaction conditions, and the impurities were carefully studied. Incomplete deuteride, for instance, 6PPD-d8 in this study, constitutes a major part of the impurities. Nevertheless, it has few adverse effects on the 2H-SIAM pipeline in discovering TPs of 6PPD. The 2H-SIAM pipeline annotated 9 TPs of 6PPD, and commercial standards further confirmed the annotated 6PPDQ (2-anilino-5-(4-methylpentan-2-ylamino)cyclohexa-2,5-diene-1,4-dione) and PPPD (N-phenyl-p-phenylenediamine). Additionally, a possible new formation mechanism for 6PPDQ was proposed, highlighting the performance of the strategy. In summary, this study highlighted a new strategy for discovering the TPs of CECs and broadening the application of SIAM in environmental studies.PMID:37574906 | DOI:10.1021/acs.analchem.3c02833

Colloids Surf B Biointerfaces. 2023 Aug 1;230:113488. doi: 10.1016/j.colsurfb.2023.113488. Online ahead of print.ABSTRACTUnderstanding biomolecular coronas that spontaneously occur around nanocarriers (NCs) in biological fluids is critical to nanomedicine as the coronas influence the behaviors of NCs in biological systems. In contrast to extensive investigations of protein coronas over the past decades, understanding of the coronas of biomolecules beyond proteins, e.g., metabolites, has been rather limited despite such biochemicals being ubiquitously involved in the coronas, which may influence the bio-nano interactions and thus exert certain biological impacts. In this study, serum biomolecular coronas, in particular the coronas of metabolites including lipids, around PEGylated doxorubicin-loaded liposomes with different surface property were investigated. The surface properties of liposomal drugs varied in terms of surface charge and PEGylation density by employing different ionic lipids such as DOTAP and DOPS and different concentrations of PEGylation lipids in liposome formulation. Using the liposomal drugs, the influence of the surface property on the serum metabolite profiles in the coronas was traced for target molecules of 220 lipids and 88 hydrophilic metabolites. From the results, it was found that metabolites rather than proteins mainly constitute the serum coronas on the liposomal drugs. Most of the serum metabolites were found to be retained in the coronas but with altered abundances. Depending on their class, lipids exhibited a different dependence on the surface property. However, overall, lipids appeared to favor corona formation on more negatively charged and PEGylated surfaces. Hydrophilic metabolites also exhibited a similar propensity for corona formation. This study on the surface dependence of metabolite corona formation provides a fundamental contribution toward attaining a comprehensive understanding of biomolecular coronas, which will be critical to the development of efficient nanomedicine.PMID:37574616 | DOI:10.1016/j.colsurfb.2023.113488

Food Chem. 2023 Aug 3;431:137079. doi: 10.1016/j.foodchem.2023.137079. Online ahead of print.ABSTRACTFresh sweet corn has a limited shelf-life due to its high moisture and high sugar content. Low temperature storage is an effective technique employed to extend the shelf-life. However, changes in the chemical composition of sweet corn kernels at low temperatures are not fully understood. In this study, kernels stored at low temperature exhibited higher levels of soluble sugars and lower starch content. In total, 1365 metabolites were characterized in sweet corn kernels. 593 and 308 differentially accumulated metabolites (DAMs) were identified in sweet corn kernels stored at normal and low temperature, respectively. 607 DAMs were identified at low temperature compare to normal temperature. DAMs were consistently enriched in flavonoid biosynthesis, linoleic acid metabolism and sphingolipid metabolism. Moreover, dozens of metabolites were identified as potential biomarkers for post-harvest storage effects in sweet corn. These results extend our knowledge of the dynamic changes in sweet corn kernels stored at low temperatures.PMID:37573745 | DOI:10.1016/j.foodchem.2023.137079

Talanta. 2023 Aug 9;266(Pt 2):125069. doi: 10.1016/j.talanta.2023.125069. Online ahead of print.ABSTRACTGrowth hormone, as a proteohormone, is primarily known of its dramatic effect on longitudinal growth. Recombinant DNA technology has provided a safe, abundant and comparatively cheap supply of human GH for growth hormone-deficient individuals. However, many healthy subjects, especially athletics, administrate GH for enhanced athletic performance or strength. A better and more comprehensive understanding of rhGH effect in healthy individuals is urgent and essential. In this study, we recruited 14 healthy young male and injected rhGH once. Untargeted LC-MS metabolomics profiling of serum and urine was performed before and after the rhGH injection. The GH-induced dysregulation of energy related pathways, such as amino acid metabolism, nucleotide metabolism, glycolysis and TCA cycle, was revealed. Moreover, individuals supplemented with micro-doses of rhGH exhibited significantly changed urinary steroidal profiles, suggesting a role of rhGH in both energy metabolism and steroidogenesis. We expect that our results will be helpful to provide new evidence on the effects of rhGH injection and provide potential biomarkers for rhGH administration.PMID:37574608 | DOI:10.1016/j.talanta.2023.125069

Crit Rev Food Sci Nutr. 2023 Aug 13:1-15. doi: 10.1080/10408398.2023.2245040. Online ahead of print.ABSTRACTFunctional foods and their by-products contain a wide range of bioactive components with an array of health benefits and were proposed to improve public health, well-being, and others. To achieve a circular economy, the processing and extraction of flavonoids, phenolic compounds, and others from functional food and agri-food wastes will require the use of environmentally friendly, sustainable, and a low-cost solution. Extraction methods that can eliminate the use of organic solvents, suitable for use in the laboratory and production of extracts will be covered. This will include subcritical water extraction (SBE), pressurized hot water extraction (PHWE), supercritical fluid extraction (SFE), and others. Based on the selected analytical methods, the determination of the marker or bioactive compounds and chemical fingerprints will provide the control measures to identify the batch-to-batch variation of the composition of the functional food products obtained. The combination of chemical standardization with antioxidant assay, such as DPPH and ABTS+ will provide further information on the quality of the extracts. Lastly, to ascertain the biological and physiological relevance of the antioxidant properties of the target sample, treatment of the antioxidant compounds or extracts was carried out using cellular models, and validated using other experimental endpoints, such as metabolomics.PMID:37574586 | DOI:10.1080/10408398.2023.2245040

Funct Integr Genomics. 2023 Aug 14;23(3):274. doi: 10.1007/s10142-023-01199-6.ABSTRACTThe main aim of the current work was to explore the differential metabolites and differentially expressed genes of longissimus dorsi muscle (LDM) between castrated and uncastrated fattening male South Sichuan black goats (Capra hircus). Then, the key genes regulating important differential metabolites (DMs) in castrated male goats were observed by integrated metabolomics and transcriptomics analyses. In addition, we evaluated the effects of castration on blood constituents, dressing percentage, and water holding capacity of LDM in male black goats. The results showed that the concentrations of alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were significantly increased and testosterone was significantly decreased in castrated male goats compared with the uncastrated male goats, while dressing percentage of black goats and water holding capacity of longissimus dorsi muscle were not significant differences. Through metabolomics and transcriptomics analyses, 23 important KEGG pathways, 13 important DMs, 32 important differentially expressed genes (DEGs), and 13 key genes related to the "Metabolism" and "Organismal systems" pathways were screened. Lipid accumulation may be elevated in the blood of fattening South Sichuan black goats after castration. Castration might play a positive role in energy provision, intercellular signaling, muscle function, softening of meat, disease reduction, and anti-oxidation of LDM. P4HA2, AKR1B1, GPT2, L2HGDH, ENSCHIG00000021660, ENSCHIG00000023861, DGAT2, ULK1, SLC38A3, PLA2G4A, SLC6A1, ENSCHIG00000026624, and ND2 might be the key genes regulating important DMs in the KEGG pathways related to "Metabolism" and "Organismal systems" of castrated male goats compared with the uncastrated male goats.PMID:37574510 | DOI:10.1007/s10142-023-01199-6

Transfus Med Rev. 2023 Aug 2:150750. doi: 10.1016/j.tmrv.2023.150750. Online ahead of print.ABSTRACTOver the last decade, the introduction of omics technologies-especially high-throughput genomics and metabolomics-has contributed significantly to our understanding of the role of donor genetics and nongenetic determinants of red blood cell storage biology. Here we briefly review the main advances in these areas, to the extent these contributed to the appreciation of the impact of donor sex, age, ethnicity, but also processing strategies and donor environmental, dietary or other exposures - the so-called exposome-to the onset and severity of the storage lesion. We review recent advances on the role of genetically encoded polymorphisms on red cell storage biology, and relate these findings with parameters of storage quality and post-transfusion efficacy, such as hemolysis, post-transfusion intra- and extravascular hemolysis and hemoglobin increments. Finally, we suggest that the combination of these novel technologies have the potential to drive further developments towards personalized (or precision) transfusion medicine approaches.PMID:37574398 | DOI:10.1016/j.tmrv.2023.150750

Genet Epidemiol. 2023 Aug 13. doi: 10.1002/gepi.22535. Online ahead of print.ABSTRACTWe propose structural equation models (SEMs) as a general framework to infer causal networks for metabolites and other complex traits. Traditionally SEMs are used only for individual-level data under the assumption that all instrumental variables (IVs) are valid. To overcome these limitations, we propose both one- and two-sample approaches for causal network inference based on SEMs that can: (1) perform causal analysis and discover causal relationships among multiple traits; (2) account for the possible presence of some invalid IVs; (3) allow for data analysis using only genome-wide association studies (GWAS) summary statistics when individual-level data are not available; (4) consider the possibility of bidirectional relationships between traits. Our method employs a simple stepwise selection to identify invalid IVs, thus avoiding false positives while possibly increasing true discoveries based on two-stage least squares (2SLS). We use both real GWAS data and simulated data to demonstrate the superior performance of our method over the standard 2SLS/SEMs. For real data analysis, our proposed approach is applied to a human blood metabolite GWAS summary data set to uncover putative causal relationships among the metabolites; we also identify some metabolites (putative) causal to Alzheimer's disease (AD), which, along with the inferred causal metabolite network, suggest some possible pathways of metabolites involved in AD.PMID:37573486 | DOI:10.1002/gepi.22535

Mol Cancer. 2023 Aug 12;22(1):133. doi: 10.1186/s12943-023-01825-8.ABSTRACTProstate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.PMID:37573301 | DOI:10.1186/s12943-023-01825-8

Med Mycol. 2023 Aug 12:myad085. doi: 10.1093/mmy/myad085. Online ahead of print.ABSTRACTVulvovaginal candidiasis (VVC) is an inflammatory disease primarily infected by Candida albicans. The condition has good short-term treatment effects, high recurrence, and seriously affects the quality of life of women. Metabolomics has been applied to research a variety of inflammatory diseases. In the present study, the vaginal metabolic profiles of VVC patients and healthy populations (CTL) were explored by a non-targeted metabolomics approach. In total, 211 differential metabolites were identified, with the VVC group having 128 over-expressed and 83 under-expressed metabolites compared with healthy individuals. Functional analysis showed that these metabolites were mainly involved in amino acid metabolism and lipid metabolism. In addition, network software analysis indicated that the differential metabolites were associated with MAPK signaling and NF-κB signaling. Further molecular docking suggested that linoleic acid can bind to the ACSL1 protein, which has been shown to be associated with multiple inflammatory diseases and is an upstream regulator of the MAPK and NF-κB signaling pathways that mediate inflammation. Therefore, our preliminary analysis results suggest that VVC has a unique metabolic profile. Linoleic acid, a significantly elevated unsaturated fatty acid in the VVC group, may promote VVC development through the ACSL1/MAPK and ACSL1/NF-κB signaling pathways. This study's findings contribute to further exploring the mechanism of VVC infection and providing new perspectives for the treatment of Candida albicans vaginal infection.PMID:37573133 | DOI:10.1093/mmy/myad085

Environ Toxicol Pharmacol. 2023 Aug 10:104245. doi: 10.1016/j.etap.2023.104245. Online ahead of print.ABSTRACTThe disposition and toxicity of lower chlorinated PCBs (LC-PCBs) with less than five chlorine substituents have received little attention. This study characterizes the distribution and metabolomic effects of PCB 52, an LC-PCB found in indoor and outdoor air, three weeks after intraperitoneal exposure of female Sprague Dawley rats to 0, 1, 10, or 100mg/kg BW. PCB 52 exposure did not affect overall body weight. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis identified PCB 52 in all tissues investigated. Hydroxylated, sulfated, and methylated PCB metabolites, identified using GC-MS/MS and nontarget liquid chromatography-high resolution mass spectrometry (Nt-LCMS), were primarily found in the serum and liver of rats exposed to 100mg/kg BW. Metabolomic analysis revealed minor effects on L-cysteine, glycine, cytosine, sphingosine, thymine, linoleic acid, orotic acid, L-histidine, and erythrose serum levels. Thus, the metabolism of PCB 52 and its effects on the metabolome must be considered in toxicity studies.PMID:37572994 | DOI:10.1016/j.etap.2023.104245

J Ethnopharmacol. 2023 Aug 10:117015. doi: 10.1016/j.jep.2023.117015. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ardisia elliptica Thunb. (AE) (Primulaceae) is a medicinal plant found in the Malay Peninsula and has been traditionally used to treat diabetes. However, limited studies to date in providing scientific evidence to support the antidiabetic efficacy of this plant by in-vitro and in-vivo models.AIM OF THE STUDY: To investigate the anti-hyperglycemic potential of AE through in-vitro enzymatic activities and streptozotocin-nicotinamide (STZ-NA) induced diabetic rat models using proton-nuclear magnetic resonance (1H-NMR)-based metabolomics approach.MATERIALS AND METHODS: Anti-α-amylase and anti-α-glucosidase activities of the hydroethanolic extracts of AE were evaluated. The absolute quantification of bioactive constituents, using ultra-high performance liquid chromatography (UHPLC) was performed for the most active extract. Three different dosage levels of the AE extract were orally administered for 4 weeks consecutively in STZ-NA induced diabetic rats. Physical assessments, biochemical analysis, and an untargeted 1H-NMR-based metabolomics analysis of the urine and serum were carried out on the animal model.RESULTS: Type 2 diabetes mellitus (T2DM) rat model was successfully developed based on the clear separation observed between the STZ-NA induced diabetic and normal non-diabetic groups. Discriminating biomarkers included glucose, citrate, succinate, allantoin, hippurate, 2-oxoglutarate, and 3-hydroxybutyrate, as determined through an orthogonal partial least squares-discriminant analysis (OPLS-DA) model. A treatment dosage of 250 mg/kg body weight (BW) of standardized 70% ethanolic AE extract mitigated increase in serum glucose, creatinine, and urea levels, providing treatment levels comparable to that obtained using metformin, with flavonoids primarily contribute to the anti-hyperglycemic activities. Urinary metabolomics disclosed that the following disturbed metabolism pathways: the citrate cycle (TCA cycle), butanoate metabolism, glycolysis and gluconeogenesis, pyruvate metabolism, and synthesis and degradation of ketone bodies, were ameliorated after treatment with the standardized AE extract.CONCLUSIONS: This study demonstrated the first attempt at revealing the therapeutic effect of oral treatment with 250 mg/kg BW of standardized AE extract on chemically induced T2DM rats. The present study provides scientific evidence supporting the ethnomedicinal use of Ardisia elliptica and further advances the understanding of the fundamental molecular mechanisms affected by this herbal antidote.PMID:37572932 | DOI:10.1016/j.jep.2023.117015

Int J Biol Macromol. 2023 Aug 10:126215. doi: 10.1016/j.ijbiomac.2023.126215. Online ahead of print.ABSTRACTHereunder, for the first time, we reported phytocompounds in the methanolic extract of Acacia modesta (AM) gum through Gas chromatography-mass spectrometry (GS-MS). Further, the AM gum aqueous solution was used for gold nanoparticles (AuNPs) synthesis through a simple, swift, eco-friendly, and less costly green synthesis approach. A total of 108 phytocompounds (63 with nonpolar, 45 with polar column) were identified in the gum extract, which includes fatty acids, alcohols, sterols, aldehyde/ketones, furans, aromatic compounds, esters, phenols, terpenes, sugar derivatives, alkaloids, and flavones. From three used concentrations (5, 10, and 15 mg/mL) of the AM gum aqueous solution, the 15 mg/mL gum solution resulted in more successful AuNP synthesis with a smaller size, which was visualized by a rusty red color appearance. UV-Visible absorption spectroscopy revealed the characteristic surface plasmon resonance (SPR) of AuNPs in aqueous solution at 540 nm. Dynamic light scattering (DLS) measurement of NPs solution revealed a hydrodynamic diameter of 162 ± 02 nm with the highest gum concentration where core AuNPs diameter was 22 ± 03 nm, recorded by Transmission electron microscopy. Zeta potential revealed fair stability of AuNPs that was not decreased with time. Catalytic activity experiments revealed that AM gum-based AuNPs can increase the rate of the reduction of methylene blue 10 times in comparison with AM gum extract alone. Results from this study showed that a diverse array of phytocompounds in AM gum can successfully reduce gold ions into gold nanoparticles, which can be used further in different pharmaceutical and industrial applications.PMID:37572806 | DOI:10.1016/j.ijbiomac.2023.126215

Immunity. 2023 Aug 3:S1074-7613(23)00327-8. doi: 10.1016/j.immuni.2023.07.014. Online ahead of print.ABSTRACTArginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.PMID:37572656 | DOI:10.1016/j.immuni.2023.07.014