PubMed

Funct Integr Genomics. 2023 Feb 8;23(1):57. doi: 10.1007/s10142-023-00982-9.ABSTRACTThe agricultural sector and environmental safety both work hand in hand to promote sustainability in important issues like soil health, plant nutrition, food safety, and security. The conventional methods have greatly harmed the environment and people's health and caused soil fertility and quality to decline as well as deteriorate. Keeping in view the excessive exploitation and cascade of degradation events due to unsustainable farming practices, the need of the hour demands choosing an appropriate, eco-friendly strategy to restore soil health, plant nutrition, and environmental aspects. The priority highlights a need for a sustainable and environment-friendly upgradation of the present agricultural systems to utilize the beneficial aspects related to harnessing the gene-microbiome strategies which would help in the restoration and replenishment of the microbial pool. Thus, exploring the microbiome is the utmost priority which gives a deep insight into the different aspects related to soil and plant and stands out as an important contributor to plant health and productivity. "Microbes" are important drivers for the biogeochemical cycles and targets like sustainability and safety. This essential microbial bulk (soil microbiome) is greatly influenced by agricultural/farming practices. Therefore, with the help of microbiome engineering technologies like meta-transcriptomics, meta-proteomics, metabolomics, and novel gene-altering techniques, we can easily screen out the highly diverse and balanced microbial population in the bulk of soil, enhancing the soil's health and productivity. Importantly, we need to change our cultivation strategies to attain such sustainability. There is an urgent need to revert to natural/organic systems of cultivation patterns where the microbiome hub can be properly utilized to strengthen soil health, decrease insect pest and disease incidence, reduce greenhouse gas emissions, and ultimately prevent environmental degradation. Through this article, we wish to propose a shift in the cultivation pattern from chemical to the novel, upgraded gene-assisted designed eco-friendly methodologies which can help in incorporating, exploring, and harnessing the right microbiome consortium and can further help in the progression of environmentally friendly microbiome technologies for agricultural safety and productivity.PMID:36752963 | DOI:10.1007/s10142-023-00982-9

Mol Omics. 2023 Feb 8. doi: 10.1039/d2mo00320a. Online ahead of print.ABSTRACTType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by increased blood glucose levels. Patients with T2DM have a high risk of developing atherosclerotic coronary artery disease (CAD). CAD with T2DM has a complex etiology and the understanding of the pathophysiology of coronary artery disease (CAD) in the presence of diabetes is poor. Here, we have used LC-MS/MS-based untargeted metabolomics to unveil the alterations of metabolites in the serum of South-Indian patients diagnosed with T2DM, CAD and T2DM along with CAD (T2DM-CAD) compared with the healthy subjects (CT). Using untargeted metabolomics and network-based approaches, a set of metabolites highly co-expressed with T2DM-CAD pathogenesis were identified. Our results revealed that these metabolites belong to essential pathways such as amino acid metabolism, fatty acid metabolism and carbohydrate metabolism. The candidate metabolites identified by metabolomics study are branch chain amino acids, L-arginine, linoleic acid, L-serine, L-cysteine, fructose-6-phosphate, glycerol, creatine and 3-phosphoglyceric acid, and explain the pathogenesis of T2DM-assisted CAD. The identified metabolites could be used as potential prognostic markers to predict CAD in patients diagnosed with T2DM.PMID:36752683 | DOI:10.1039/d2mo00320a

Rheumatology (Oxford). 2023 Feb 8:kead068. doi: 10.1093/rheumatology/kead068. Online ahead of print.ABSTRACTOBJECTIVE: We describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A gene (TNFRSF1A) causing tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with renal AA-amyloidosis.METHODS: Case series of affected family members. We further investigated the plasma metabolome of these patients in comparison to healthy controls using mass spectrometry.RESULTS: In all symptomatic family members, we detected the previously undescribed variant c.332A>G (p.Q111R) in the TNFRSF1A gene. Canakinumab proved an effective treatment option leading to remission in all treated patients. One patient with suspected renal amyloidosis showed near normalisation of proteinuria under treatment. Analysis of the metabolome revealed 31 metabolic compounds to be upregulated and 35 compounds to be downregulated compared with healthy controls. The most dysregulated metabolites belonged to pathways identified as arginine biosynthesis, phenylalanine, tyrosine & tryptophan biosynthesis and cysteine & methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission.CONCLUSION: We present a novel mutation in the TNFRSF1A gene associated with amyloidosis. Canakinumab is an effective treatment for individuals with this new likely pathogenic variant. Alterations in the metabolome were most prominent in the pathways related to arginine biosynthesis, tryptophan metabolism and metabolism of cysteine & methionine and seemed to be unaffected by treatment with canakinumab. Further investigation is needed to determine the role of these metabolomic changes in the pathophysiology of TRAPS.PMID:36752501 | DOI:10.1093/rheumatology/kead068

Plant Biotechnol J. 2023 Feb 8. doi: 10.1111/pbi.14024. Online ahead of print.ABSTRACTFlavonoids have a major contribution to the fruit quality in cultivated strawberries and are regulated by MYB, bHLH, and WD40 transcriptional factors. We reported here the identification of the FaMYB5, an R2R3-MYB transcription factor, which positively regulated the accumulation of anthocyanins and proanthocyanidins through the trans-activation of the F3'H and LAR. The strawberry FaEGL3 and FaLWD1/FaLWD1-like interact with the R2R3-FaMYB5 to form an MYB-bHLH-WD40 complex (MBW), enhancing the regulatory efficiency. The R2R3-FaMYB5 was constitutively expressed in various tissues and in fruits of different developmental stages, which was strikingly contrasting to the fruit-specific expression patterns of FaMYB10. Meanwhile, R2R3-FaMYB5 failed to promote a stable accumulation of anthocyanin glycosides in the mature fruits of the myb10 mutant, mainly due to the suppressed expression of TT19. The R2R3-FaMYB5 was regulated by an antisense long non-coding RNA lncRNA-myb5. Additionally, the R2R3-FaMYB5 protein could interact with FaBT2 and was degraded through the ubiquitin/26S proteasome pathway. Transcriptome and metabolome data showed that R2R3-FaMYB5 enhanced the gene expression and the metabolites accumulation involved in the flavonoid, phenylpropanoid, and lignin biosynthesis pathways. Collectively, we conclude that the FaMYB5 is an R2R3-MYB activator involved in the composition of MBW, which positively regulates the biosynthesis of anthocyanin and proanthocyanidin. These findings provided new insights into the molecular mechanisms that regulate flavonoids in strawberry fruits.PMID:36752420 | DOI:10.1111/pbi.14024

Am J Med Genet A. 2023 Feb 7. doi: 10.1002/ajmg.a.63131. Online ahead of print.ABSTRACTTMEM70 deficiency causing mitochondrial complex V deficiency, nuclear type 2 (MIM: 614052) is the most common nuclear encoded defect affecting ATP synthase and has been well described in the literature as being characterized by neonatal or infantile onset of poor feeding, hypotonia, lethargy, respiratory compromise, heart failure, lactic acidosis, hyperammonemia, and 3-methylglutaconic aciduria progressing to a phenotype of developmental delay, failure to thrive, short stature, nonprogressive cardiomyopathy, microcephaly, facial dysmorphisms, hypospadias, persistent pulmonary hypertension of the newborn, and Wolff-Parkinson-White syndrome, as well as metabolic crises followed by developmental regression. The patient with TMEM70 deficiency herein reported has the unique presentation of aortic root dilatation, differing facial dysmorphisms, and no history of neonatal metabolic decompensation or developmental delay, as well as a plasma metabolomics signature, including elevated 3-methylglutaconic acid, 3-methylglutarylcarnitine, alanine, and lactate, in addition to the commonly described increased 3-methylglutaconic acid on urine organic acid analysis that helped aid in the diagnostic interpretation of variants of uncertain significance in TMEM70.PMID:36751706 | DOI:10.1002/ajmg.a.63131

J Zhejiang Univ Sci B. 2023 Feb 15;24(2):157-171. doi: 10.1631/jzus.B2200213.ABSTRACTThe development of acute liver injury can result in liver cirrhosis, liver failure, and even liver cancer, yet there is currently no effective therapy for it. The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lyciumbarbarum polysaccharides (LBPs) on acute liver injury induced by carbon tetrachloride (CCl4). To create a model of acute liver injury, experimental canines received an intraperitoneal injection of 1 mL/kg of CCl4 solution. The experimental canines in the therapy group were then fed LBPs (20 mg/kg). CCl4-induced liver structural damage, excessive fibrosis, and reduced mitochondrial density were all improved by LBPs, according to microstructure data. By suppressing Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1), promoting the production of sequestosome 1 (SQSTM1)/p62, nuclear factor erythroid 2-related factor 2 (Nrf2), and phase II detoxification genes and proteins downstream of Nrf2, and restoring the activity of anti-oxidant enzymes like catalase (CAT), LBPs can restore and increase the antioxidant capacity of liver. To lessen mitochondrial damage, LBPs can also enhance mitochondrial respiration, raise tissue adenosine triphosphate (ATP) levels, and reactivate the respiratory chain complexes I‒V. According to serum metabolomics, the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism. 9-Hydroxyoctadecadienoic acid (9-HODE), lysophosphatidylcholine (LysoPC/LPC), and phosphatidylethanolamine (PE) may be potential indicators of acute liver injury. This study confirmed that LBPs, an effective hepatoprotective drug, may cure acute liver injury by lowering oxidative stress, repairing mitochondrial damage, and regulating metabolic pathways.PMID:36751701 | DOI:10.1631/jzus.B2200213

Clin Kidney J. 2022 Sep 21;16(2):272-284. doi: 10.1093/ckj/sfac215. eCollection 2023 Feb.ABSTRACTBACKGROUND: Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin-angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19).METHODS: In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score-matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19.RESULTS: uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2.CONCLUSIONS: Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.PMID:36751625 | PMC:PMC9494506 | DOI:10.1093/ckj/sfac215

J Exp Clin Cancer Res. 2023 Feb 7;42(1):42. doi: 10.1186/s13046-023-02607-2.ABSTRACTBACKGROUND: Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained.METHODS: Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8's involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement.RESULTS: GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content.CONCLUSIONS: Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes.PMID:36750850 | DOI:10.1186/s13046-023-02607-2

Metabolomics. 2023 Feb 7;19(2):12. doi: 10.1007/s11306-023-01975-2.ABSTRACTINTRODUCTION: Our untargeted metabolic data unveiled that Acyl-CoAs undergo dephosphorylation, however little is known about these novel metabolites and their physiology/pathology relevance.OBJECTIVES: To understand the relationship between acyl-CoAs dephosphorylation and energy status as implied in our previous work, we seek to investigate how ischemia (energy depletion) triggers metabolic changes, specifically acyl-CoAs dephosphorylation in this work.METHODS: Rat hearts were isolated and perfused in Langendorff mode for 15 min followed by 0, 5, 15, and 30 minutes of global ischemia. The heart tissues were harvested for metabolic analysis.RESULTS: As expected, ATP and phosphocreatine were significantly decreased during ischemia. Most short- and medium-chain acyl-CoAs progressively increased with ischemic time from 0 to 15 min, whereas a 30-minute ischemia did not lead to further change. Unlike other acyl-CoAs, propionyl-CoA accumulated progressively in the hearts that underwent ischemia from 0 to 30 min. Progressive dephosphorylation occurred to all assayed acyl-CoAs and free CoA regardless their level changes during the ischemia.CONCLUSION: The present work further confirms that dephosphorylation of acyl-CoAs is an energy-dependent process and how this dephosphorylation is mediated warrants further investigations. It is plausible that dephosphorylation of acyl-CoAs and limited anaplerosis are involved in ischemic injuries to heart. Further investigations are warranted to examine the mechanisms of acyl-CoA dephosphorylation and how the dephosphorylation is possibly involved in ischemic injuries.PMID:36750484 | DOI:10.1007/s11306-023-01975-2

Wei Sheng Yan Jiu. 2023 Jan;52(1):123-128. doi: 10.19813/j.cnki.weishengyanjiu.2023.01.021.ABSTRACTOBJECTIVE: To explore the differential metabolites in the serum of infants with iron deficiency anemia(IDA) and non iron deficiency anemia, and to explore the potential biomarkers.METHODS: Non-targeted metabolomics of 30 infants with iron deficiency anemia aged 6-11 months and 30 infants with non iron deficiency anemia aged 6-11 months were analyzed by ultra-high performance liquid chromatography with time of flight mass spectrometry using Acquity UPLC BEH C_(18) column(100 mm×2.1 mm, 1.8 μm). The differences of metabolites between the two groups were analyzed by principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA). Differential metabolites were screened according to OPLS-DA variable importance projection(VIP) >1. The related metabolic pathways involved in the markers were analyzed based on the KEGG database.RESULTS: Differences in serum metabolic profiles between iron deficiency anemia group and non iron deficiency anemia group were observed. The 44 potential biomarkers were mainly lipids. Combined with pathway analysis, the metabolic pathways related to different metabolites included glycerophosphingolipid metabolism and sphingolipid metabolism.CONCLUSION: There are differences in lipid metabolites between infants with non iron deficiency anemia and iron deficiency anemia, suggesting that the occurrence and progress of iron deficiency anemia are related to lipid metabolism.PMID:36750340 | DOI:10.19813/j.cnki.weishengyanjiu.2023.01.021

Proc Biol Sci. 2023 Feb 8;290(1992):20221877. doi: 10.1098/rspb.2022.1877. Epub 2023 Feb 8.ABSTRACTAnthropogenic stressors continue to escalate worldwide, driving unprecedented declines in reef environmental conditions and coral health. One approach to better understand how corals can function in the future is to examine coral populations that thrive within present day naturally extreme habitats. We applied untargeted metabolomics (gas chromatography-mass spectrometry (GC-MS)) to contrast metabolite profiles of Pocillopora acuta colonies from hot, acidic and deoxygenated mangrove environments versus those from adjacent reefs. Under ambient temperatures, P. acuta predominantly associated with endosymbionts of the genera Cladocopium (reef) or Durusdinium (mangrove), exhibiting elevated metabolism in mangrove through energy-generating and biosynthesis pathways compared to reef populations. Under transient heat stress, P. acuta endosymbiont associations were unchanged. Reef corals bleached and exhibited extensive shifts in symbiont metabolic profiles (whereas host metabolite profiles were unchanged). By contrast, mangrove populations did not bleach and solely the host metabolite profiles were altered, including cellular responses in inter-partner signalling, antioxidant capacity and energy storage. Thus mangrove P. acuta populations resist periodically high-temperature exposure via association with thermally tolerant endosymbionts coupled with host metabolic plasticity. Our findings highlight specific metabolites that may be biomarkers of heat tolerance, providing novel insight into adaptive coral resilience to elevated temperatures.PMID:36750192 | DOI:10.1098/rspb.2022.1877

Expert Opin Ther Targets. 2023 Feb 7. doi: 10.1080/14728222.2023.2178420. Online ahead of print.NO ABSTRACTPMID:36749698 | DOI:10.1080/14728222.2023.2178420

Int J Syst Evol Microbiol. 2023 Feb;73(2). doi: 10.1099/ijsem.0.005691.ABSTRACTA novel sulphur-reducing bacterium was isolated from a pyrite-forming enrichment culture inoculated with sewage sludge from a wastewater treatment plant. Based on phylogenetic data, strain J.5.4.2-T.3.5.2T could be affiliated with the phylum Synergistota. Among type strains of species with validly published names, the highest 16S rRNA gene sequence identity value was found with Aminiphilus circumscriptus ILE-2T (89.2 %). Cells of the new isolate were Gram-negative, non-spore-forming, straight to slightly curved rods with tapered ends. Motility was conferred by lateral flagella. True branching of cells was frequently observed. The strain had a strictly anaerobic, asaccharolytic, fermentative metabolism with peptides and amino acids as preferred substrates. Sulphur was required as an external electron acceptor during fermentative growth and was reduced to sulphide, whereas it was dispensable during syntrophic growth with a Methanospirillum species. Major fermentation products were acetate and propionate. The cellular fatty acid composition was dominated by unsaturated and branched fatty acids, especially iso-C15 : 0. Its major polar lipids were phosphatidylglycerol, phosphatidylethanolamine and distinct unidentified polar lipids. Respiratory lipoquinones were not detected. Based on the obtained data we propose the novel species and genus Aminithiophilus ramosus, represented by the type strain J.5.4.2-T.3.5.2T (=DSM 107166T=NBRC 114655T) and the novel family Aminithiophilaceae fam. nov. to accommodate the genus Aminithiophilus. In addition, we suggest reclassifying certain members of the Synergistaceae into new families to comply with current standards for the classification of higher taxa. Based on phylogenomic data, the novel families Acetomicrobiaceae fam. nov., Aminiphilaceae fam. nov., Aminobacteriaceae fam. nov., Dethiosulfovibrionaceae fam. nov. and Thermovirgaceae fam. nov. are proposed.PMID:36749697 | DOI:10.1099/ijsem.0.005691

Mol Plant Microbe Interact. 2023 Feb 7. doi: 10.1094/MPMI-09-22-0178-R. Online ahead of print.ABSTRACTBroad-spectrum biocontrol by Pseudomonas protegens CHA0 and other fluorescent pseudomonads is achieved through the generation of various secondary metabolites with antibiotic activities against not only other microbes, but also nematodes and insects present in the rhizosphere. A previous metabolomic study demonstrated that intracellular low-molecular weight effectors, such as guanosine tetraphosphate and γ-aminobutyrate, function as important signals in niche adaptation by strain CHA0 to plant roots. We herein investigated the role of amino acids in the biocontrol trait of P. protegens Cab57 towards Pythium damping off and root rot in cucumber. Among the 11 amino acids tested, only glutamate markedly enhanced the efficacy of biocontrol. A RNA seq analysis revealed that glutamate up-regulated the expression of a chitinase gene cluster (c21370-c21380, where the c21370 gene was annotated as a gene encoding the chitin-binding protein cbp and the c21380 gene encoded chitinase chiC) in strain CHA0. Glutamate up-regulated the expression of the regulatory small RNA rsmZ, but reduced the production levels of other Gac/Rsm-regulated biocontrol factors, such as DAPG and pyoluteorin. The promoter activity of cbp and chitinase activity were characterized in detail; their activities were up-regulated in response to glutamate and their expression was under the control of GacA. Therefore, glutamate appears to be essential for biocontrol activity where chitinase production is regulated in response to glutamate.PMID:36749296 | DOI:10.1094/MPMI-09-22-0178-R

Microb Genom. 2023 Jan;9(1). doi: 10.1099/mgen.0.000918.ABSTRACTMesorhizobia are soil bacteria that establish nitrogen-fixing symbioses with various legumes. Novel symbiotic mesorhizobia frequently evolve following horizontal transfer of symbiosis-gene-carrying integrative and conjugative elements (ICESyms) to indigenous mesorhizobia in soils. Evolved symbionts exhibit a wide range in symbiotic effectiveness, with some fixing nitrogen poorly or not at all. Little is known about the genetic diversity and symbiotic potential of indigenous soil mesorhizobia prior to ICESym acquisition. Here we sequenced genomes of 144 Mesorhizobium spp. strains cultured directly from cultivated and uncultivated Australian soils. Of these, 126 lacked symbiosis genes. The only isolated symbiotic strains were either exotic strains used previously as legume inoculants, or indigenous mesorhizobia that had acquired exotic ICESyms. No native symbiotic strains were identified. Indigenous nonsymbiotic strains formed 22 genospecies with phylogenomic diversity overlapping the diversity of internationally isolated symbiotic Mesorhizobium spp. The genomes of indigenous mesorhizobia exhibited no evidence of prior involvement in nitrogen-fixing symbiosis, yet their core genomes were similar to symbiotic strains and they generally lacked genes for synthesis of biotin, nicotinate and thiamine. Genomes of nonsymbiotic mesorhizobia harboured similar mobile elements to those of symbiotic mesorhizobia, including ICESym-like elements carrying aforementioned vitamin-synthesis genes but lacking symbiosis genes. Diverse indigenous isolates receiving ICESyms through horizontal gene transfer formed effective symbioses with Lotus and Biserrula legumes, indicating most nonsymbiotic mesorhizobia have an innate capacity for nitrogen-fixing symbiosis following ICESym acquisition. Non-fixing ICESym-harbouring strains were isolated sporadically within species alongside effective symbionts, indicating chromosomal lineage does not predict symbiotic potential. Our observations suggest previously observed genomic diversity amongst symbiotic Mesorhizobium spp. represents a fraction of the extant diversity of nonsymbiotic strains. The overlapping phylogeny of symbiotic and nonsymbiotic clades suggests major clades of Mesorhizobium diverged prior to introduction of symbiosis genes and therefore chromosomal genes involved in symbiosis have evolved largely independent of nitrogen-fixing symbiosis.PMID:36748564 | DOI:10.1099/mgen.0.000918

Heliyon. 2023 Jan 21;9(2):e13066. doi: 10.1016/j.heliyon.2023.e13066. eCollection 2023 Feb.ABSTRACTTryptophan and its derived metabolites have been assumed to play important roles in the development and survival of organisms. However, the links of tryptophan and its derived metabolites to temperature change remained largely cryptic. Here we presented that a class of prenyl indole alkaloids biosynthesized from tryptophan dramatically accumulated in thermophilic fungus Thermomyces dupontii under cold stress, in which lipid droplets were also highly accumulated and whose conidiophores were highly build-up. Concurrently, disruption of the key NRPS gene involved in the biosynthesis of prenyl indole alkaloids, resulted in decreased lipid and shrunken mitochondria but enlarged vacuoles. Moreover, the Fe3+ and superoxide levels in ΔNRPS were significantly increased but the reactive oxygen species lipid peroxidation and autophagy levels decreased. Metabolomics study revealed that most enriched metabolites in ΔNRPS were mainly composed of tryptophan degraded metabolites including well known ROS scavenger kynurenamines, and lipid-inhibitors, anthranilic acid and indoleacetic acid, and free radical reaction suppressor free fatty acids. Transcriptomic analysis suggested that the key gene involved in tryptophan metabolism, coinciding with the lipid metabolic processes and ion transports were most up-regulated in ΔNRPS under stress. Our results confirmed a lipid-mediated fungal response to cold stress and unveiled a link of tryptophan-based metabolic reprogramming to the fungal cold adaption.PMID:36747564 | PMC:PMC9898655 | DOI:10.1016/j.heliyon.2023.e13066

Database (Oxford). 2023 Feb 7;2023:baad002. doi: 10.1093/database/baad002.ABSTRACTSaliva as a non-invasive diagnostic fluid has immense potential as a tool for early diagnosis and prognosis of patients. The information about salivary biomarkers is broadly scattered across various resources and research papers. It is important to bring together all the information on salivary biomarkers to a single platform. This will accelerate research and development in non-invasive diagnosis and prognosis of complex diseases. We collected widespread information on five types of salivary biomarkers-proteins, metabolites, microbes, micro-ribonucleic acid (miRNA) and genes found in humans. This information was collected from different resources that include PubMed, the Human Metabolome Database and SalivaTecDB. Our database SalivaDB contains a total of 15 821 entries for 201 different diseases and 48 disease categories. These entries can be classified into five categories based on the type of biomolecules; 6067, 3987, 2909, 2272 and 586 entries belong to proteins, metabolites, microbes, miRNAs and genes, respectively. The information maintained in this database includes analysis methods, associated diseases, biomarker type, regulation status, exosomal origin, fold change and sequence. The entries are linked to relevant biological databases to provide users with comprehensive information. We developed a web-based interface that provides a wide range of options like browse, keyword search and advanced search. In addition, a similarity search module has been integrated which allows users to perform a similarity search using Basic Local Alignment Search Tool and Smith-Waterman algorithm against biomarker sequences in SalivaDB. We created a web-based database-SalivaDB, which provides information about salivary biomarkers found in humans. A wide range of web-based facilities have been integrated to provide services to the scientific community. https://webs.iiitd.edu.in/raghava/salivadb/.PMID:36747479 | DOI:10.1093/database/baad002

Nutr Metab (Lond). 2023 Feb 6;20(1):6. doi: 10.1186/s12986-023-00726-3.ABSTRACTThe use of non-drug intervention for calcium deficiency has attracted attention in recent years. Although calcium carbonate is the preferred raw material for calcium supplementation, there are few reports on the mechanism of the combined action of chondroitin sulfate and calcium to alleviate osteoporosis from the perspective of gut microbiota and metabolomics. In this study, a rat model of osteoporosis was established by feeding a low-calcium diet. The intestinal microbiota abundance, fecal and plasma metabolite expression levels of rats fed a basal diet, a low-calcium diet, a low-calcium diet plus calcium carbonate, and a low-calcium diet plus chondroitin sulfate were compared. The results showed that compared with the low calcium group, the calcium content and bone mineral density of femur were significantly increased in the calcium carbonate and chondroitin sulfate groups. 16 S rRNA sequencing and metabolomics analysis showed that chondroitin sulfate intervention could reduce short-chain fatty acid synthesis of intestinal flora, slow down inflammatory response, inhibit osteoclast differentiation, promote calcium absorption and antioxidant mechanism, and alleviate osteoporosis in low-calcium feeding rats. Correlation analysis showed that the selected intestinal flora was significantly correlated with metabolites enriched in feces and plasma. This study provides scientific evidence of the potential impact of chondroitin sulfate as a dietary supplement for patients with osteoporosis.PMID:36747190 | DOI:10.1186/s12986-023-00726-3

BMC Cancer. 2023 Feb 6;23(1):122. doi: 10.1186/s12885-023-10589-9.ABSTRACTBACKGROUND: Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression.METHODS: The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model.RESULTS: We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells.CONCLUSIONS: Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.PMID:36747147 | DOI:10.1186/s12885-023-10589-9

Nat Metab. 2023 Feb 6. doi: 10.1038/s42255-023-00735-9. Online ahead of print.ABSTRACTMetabolism is a fundamental cellular process that is coordinated with cell cycle progression. Despite this association, a mechanistic understanding of cell cycle phase-dependent metabolic pathway regulation remains elusive. Here we report the mechanism by which human de novo pyrimidine biosynthesis is allosterically regulated during the cell cycle. Combining traditional synchronization methods and metabolomics, we characterize metabolites by their accumulation pattern during cell cycle phases and identify cell cycle phase-dependent regulation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD), the first, rate-limiting enzyme in de novo pyrimidine biosynthesis. Through systematic mutational scanning and structural modelling, we find allostery as a major regulatory mechanism that controls the activity change of CAD during the cell cycle. Specifically, we report evidence of two Animalia-specific loops in the CAD allosteric domain that involve sensing and binding of uridine 5'-triphosphate, a CAD allosteric inhibitor. Based on homology with a mitochondrial carbamoyl-phosphate synthetase homologue, we identify a critical role for a signal transmission loop in regulating the formation of a substrate channel, thereby controlling CAD activity.PMID:36747088 | DOI:10.1038/s42255-023-00735-9