Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Regulation of denitrification performance and microbial topology by lights: Insight into wavelength effects towards microbiota

Mon, 06/02/2023 - 12:00
Water Res. 2022 Nov 28;232:119434. doi: 10.1016/j.watres.2022.119434. Online ahead of print.ABSTRACTThe low efficiency of conventional complete denitrification, as well as the unstable nitrite supply for partial-denitrification coupled anammox (PD/A) restrict the efficient removal of nitrogen from industrial wastewaters. Herein, we proposed an optical strategy to bidirectionally regulate denitrification by introducing lights at different wavelengths, and the underlying mechanisms were elucidated accordingly. It turned out that yellow light at wavelength of 590 nm accelerated denitrification by 35.4%, while blue light delayed denitrification with stable nitrite accumulation above 86.9% and high nitrate removal (99.8%). Microbial physiology and viability further supported the positive effects of yellow light on microbial activity. Additionally, despite the sluggish denitrification aroused by blue light, negligible cellular damage was observed. Antioxidant capability divergence, microbial community shifting and metabolic flux redirection contributed to the wavelength-dependent effects. Halomonas and Pseudomonas were identified as high-credit taxonomic biomarkers of yellow and blue light. As revealed by metabolomics, pantothenate and CoA biosynthesis, glutamate metabolism and alkaloid biosynthesis presented high impact values. Co-analysis of metabolomics and metagenomics based on microbial topology further distinguished pivotal metabolic pathways and genes. Oxidative phosphorylation contributed to the divergent denitrification performance through electron transfer chains, whereas glutamate and glutathione metabolism contributed to oxidative stress alleviation and mediated the metabolic flux between peroxisome and nitrogen metabolism. This study shed a light on the application of optical strategy to regulate denitrification performance and achieve either complete denitrification or PD/A.PMID:36746030 | DOI:10.1016/j.watres.2022.119434

A unified classification approach rating clinical utility of protein biomarkers across neurologic diseases

Mon, 06/02/2023 - 12:00
EBioMedicine. 2023 Feb 4;89:104456. doi: 10.1016/j.ebiom.2023.104456. Online ahead of print.ABSTRACTA major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology.PMID:36745974 | DOI:10.1016/j.ebiom.2023.104456

Cohort profile: The Clinical and Multi-omic (CAMO) cohort, part of the Norwegian Women and Cancer (NOWAC) study

Mon, 06/02/2023 - 12:00
PLoS One. 2023 Feb 6;18(2):e0281218. doi: 10.1371/journal.pone.0281218. eCollection 2023.ABSTRACTINTRODUCTION: Breast cancer is the most common cancer worldwide and the leading cause of cancer related deaths among women. The high incidence and mortality of breast cancer calls for improved prevention, diagnostics, and treatment, including identification of new prognostic and predictive biomarkers for use in precision medicine.MATERIAL AND METHODS: With the aim of compiling a cohort amenable to integrative study designs, we collected detailed epidemiological and clinical data, blood samples, and tumor tissue from a subset of participants from the prospective, population-based Norwegian Women and Cancer (NOWAC) study. These study participants were diagnosed with invasive breast cancer in North Norway before 2013 according to the Cancer Registry of Norway and constitute the Clinical and Multi-omic (CAMO) cohort. Prospectively collected questionnaire data on lifestyle and reproductive factors and blood samples were extracted from the NOWAC study, clinical and histopathological data were manually curated from medical records, and archived tumor tissue collected.RESULTS: The lifestyle and reproductive characteristics of the study participants in the CAMO cohort (n = 388) were largely similar to those of the breast cancer patients in NOWAC (n = 10 356). The majority of the cancers in the CAMO cohort were tumor grade 2 and of the luminal A subtype. Approx. 80% were estrogen receptor positive, 13% were HER2 positive, and 12% were triple negative breast cancers. Lymph node metastases were present in 31% at diagnosis. The epidemiological dataset in the CAMO cohort is complemented by mRNA, miRNA, and metabolomics analyses in plasma, as well as miRNA profiling in tumor tissue. Additionally, histological analyses at the level of proteins and miRNAs in tumor tissue are currently ongoing.CONCLUSION: The CAMO cohort provides data suitable for epidemiological, clinical, molecular, and multi-omics investigations, thereby enabling a systems epidemiology approach to translational breast cancer research.PMID:36745618 | DOI:10.1371/journal.pone.0281218

Toxicity of tributyltin to the European flat oyster Ostrea edulis: Metabolomic responses indicate impacts to energy metabolism, biochemical composition and reproductive maturation

Mon, 06/02/2023 - 12:00
PLoS One. 2023 Feb 6;18(2):e0280777. doi: 10.1371/journal.pone.0280777. eCollection 2023.ABSTRACTTri-Butyl Tin (TBT) remains as a legacy pollutant in the benthic environments. Although the toxic impacts and endocrine disruption caused by TBT to gastropod molluscs have been established, the changes in energy reserves allocated to maintenance, growth, reproduction and survival of European oysters Ostrea edulis, a target species of concerted benthic habitat restoration projects, have not been explored. This study was designed to evaluate the effect of TBT chloride (TBTCl) on potential ions and relevant metabolomic pathways and its association with changes in physiological, biochemical and reproductive parameters in O. edulis exposed to environmental relevant concentrations of TBTCl. Oysters were exposed to TBTCl 20 ng/L (n = 30), 200 ng/L (n = 30) and 2000 ng/L (n = 30) for nine weeks. At the end of the exposure, gametogenic stage, sex, energy reserve content and metabolomic profiling analysis were conducted to elucidate the metabolic alterations that occur in individuals exposed to those compounds. Metabolite analysis showed significant changes in the digestive gland biochemistry in oysters exposed to TBTCl, decreasing tissue ATP concentrations through a combination of the disruption of the TCA cycle and other important molecular pathways involved in homeostasis, mitochondrial metabolism and antioxidant response. TBTCl exposure increased mortality and caused changes in the gametogenesis with cycle arrest in stages G0 and G1. Sex determination was affected by TBTCl exposure, increasing the proportion of oysters identified as males in O. edulis treated at 20ng/l TBTCl, and with an increased proportion of inactive stages in oysters treated with 2000 ng/l TBTCl. The presence and persistence of environmental pollutants, such as TBT, could represent an additional threat to the declining O. edulis populations and related taxa around the world, by increasing mortality, changing reproductive maturation, and disrupting metabolism. Our findings identify the need to consider additional factors (e.g. legacy pollution) when identifying coastal locations for shellfish restoration.PMID:36745593 | DOI:10.1371/journal.pone.0280777

Application of pre-adaptation strategies to improve the growth of probiotic lactobacilli under food-relevant stressful conditions

Mon, 06/02/2023 - 12:00
Food Funct. 2023 Feb 6. doi: 10.1039/d2fo03215e. Online ahead of print.ABSTRACTWhile formulating a probiotic food, it is mandatory to make sure that the viability of probiotics is adequate at the point of consumption, which can be strongly compromised by stressful conditions due to low pH and high osmolarity. In this study, three probiotic lactobacilli were subjected to different pre-adaptation conditions, and the turbidimetric growth kinetics in challenging conditions (pH 4.0-6.5, NaCl 1-7%, sucrose 0.1-0.7 M) were evaluated. Different effects were observed for Lactobacillus acidophilus, Lacticaseibacillus casei, and Lactiplantibacillus plantarum. Indeed, pre-exposition to sub-optimal conditions in terms of pH and % NaCl significantly improved the ability of L. acidophilus and L. casei to overcome the osmotic stress due to salt or sucrose, and similar effects were observed for acidic stress. L. plantarum showed to be more tolerant to the challenging conditions applied in this study. Anyway, the pre-adaptation at conditions SUB_1 (pH 4.5 and NaCl 4%) and SUB_2 (pH 5 and NaCl 2%) speeded-up its growth kinetics by reducing the length of the lag phase under sucrose stress and enhancing the maximum growth rate at the highest pH tested. Moreover, an improvement in biomass amount was observed under sucrose stress. The whole data evidenced that the application of the appropriate pre-adaptation condition could contribute to making probiotics more robust towards challenging conditions due to food matrix, processing, and storage as well as gastrointestinal transit. Further studies will be necessary to gain insight into the proteomics and metabolomics responsible for increased tolerance to stressful conditions.PMID:36745384 | DOI:10.1039/d2fo03215e

Evaluating LC-HRMS metabolomics data processing software using FAIR principles for research software

Mon, 06/02/2023 - 12:00
Metabolomics. 2023 Feb 6;19(2):11. doi: 10.1007/s11306-023-01974-3.ABSTRACTBACKGROUND: Liquid chromatography-high resolution mass spectrometry (LC-HRMS) is a popular approach for metabolomics data acquisition and requires many data processing software tools. The FAIR Principles - Findability, Accessibility, Interoperability, and Reusability - were proposed to promote open science and reusable data management, and to maximize the benefit obtained from contemporary and formal scholarly digital publishing. More recently, the FAIR principles were extended to include Research Software (FAIR4RS).AIM OF REVIEW: This study facilitates open science in metabolomics by providing an implementation solution for adopting FAIR4RS in the LC-HRMS metabolomics data processing software. We believe our evaluation guidelines and results can help improve the FAIRness of research software.KEY SCIENTIFIC CONCEPTS OF REVIEW: We evaluated 124 LC-HRMS metabolomics data processing software obtained from a systematic review and selected 61 software for detailed evaluation using FAIR4RS-related criteria, which were extracted from the literature along with internal discussions. We assigned each criterion one or more FAIR4RS categories through discussion. The minimum, median, and maximum percentages of criteria fulfillment of software were 21.6%, 47.7%, and 71.8%. Statistical analysis revealed no significant improvement in FAIRness over time. We identified four criteria covering multiple FAIR4RS categories but had a low %fulfillment: (1) No software had semantic annotation of key information; (2) only 6.3% of evaluated software were registered to Zenodo and received DOIs; (3) only 14.5% of selected software had official software containerization or virtual machine; (4) only 16.7% of evaluated software had a fully documented functions in code. According to the results, we discussed improvement strategies and future directions.PMID:36745241 | DOI:10.1007/s11306-023-01974-3

Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders

Mon, 06/02/2023 - 12:00
Metabolomics. 2023 Feb 6;19(2):10. doi: 10.1007/s11306-022-01969-6.ABSTRACTINTRODUCTION: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula.OBJECTIVES: To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina.METHODS: We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina.RESULTS: Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific.CONCLUSIONS: The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity.PMID:36745234 | DOI:10.1007/s11306-022-01969-6

Integrated Proteomics and Metabolomics Analysis to Explore the Amelioration Mechanisms of <em>Rosa roxburghii</em> Tratt Fruit Polyphenols on Lipopolysaccharide-Induced Acute Lung Injury Mice

Mon, 06/02/2023 - 12:00
J Agric Food Chem. 2023 Feb 6. doi: 10.1021/acs.jafc.2c04344. Online ahead of print.ABSTRACTAcute lung injury (ALI) is the main cause of death for the elderly and children due to its high morbidity and mortality rates. Plant-derived functional foods are becoming increasingly important to the healthcare and food industries for adjunctive and alternative treatments of ALI. Polyphenols have been regarded to be beneficial to the prevention and amelioration of ALI. Rosa roxburghii Tratt fruit polyphenols (RRTP) has potential to prevent ALI, but mechanism remains unclear. This study was set up to systematically analyze the RRTP extract active ingredients, comprehensively evaluate its protective effects via lung histopathological examination, protein concentration, and cytokines production in ALI mice induced by lipopolysaccharide (LPS), and finally revealed alleviation mechanisms of the regulatory effects of RRTP by proteomics and metabolomics approach. The results demonstrated RRTP could synergistically exert significant preventive effects against ALI by notably ameliorating lung histopathological damage and pulmonary capillary permeability in ALI mice, inhibiting lung tissue inflammatory response and acute phase proteins and S-100 calcium binding proteins, suppressing excessive activation of complement and coagulation cascades, and regulating disordered lipids metabolism and amino acid metabolism. This study illustrated that RRTP has obvious advantages in ALI adjunctive therapy and revealed the complicated amelioration mechanisms, which provides a breakthrough for the development and demonstration of RRTP as a nutritional compound additive for complementary therapy of ALI.PMID:36745194 | DOI:10.1021/acs.jafc.2c04344

Can spatially resolved metabolomics uncover weak points in tumors?

Mon, 06/02/2023 - 12:00
Expert Rev Proteomics. 2023 Feb 6. doi: 10.1080/14789450.2023.2176754. Online ahead of print.NO ABSTRACTPMID:36744392 | DOI:10.1080/14789450.2023.2176754

Oncogenic IDH1 Mutation Imparts Therapeutically Targetable Metabolic Dysfunction in Multiple Tumor Types

Mon, 06/02/2023 - 12:00
Cancer Discov. 2023 Feb 6;13(2):266-268. doi: 10.1158/2159-8290.CD-22-1325.ABSTRACTIn this issue of Cancer Discovery, Thomas and colleagues leverage mass spectrometry metabolomics, stable isotope labeling, and functional studies to explore metabolic vulnerabilities in cancers harboring mutations in isocitrate dehydrogenase (IDH). The authors present compelling data to support the claim that dysregulated lipid synthesis underpins a synthetic lethal target in cancers with IDH1, but not IDH2, mutations. See related article by Thomas et al., p. 496 (9).PMID:36744320 | DOI:10.1158/2159-8290.CD-22-1325

Multiomics integration reveals the effect of Orexin A on glioblastoma

Mon, 06/02/2023 - 12:00
Front Pharmacol. 2023 Jan 20;14:1096159. doi: 10.3389/fphar.2023.1096159. eCollection 2023.ABSTRACTObjectives: This study involved a multi-omics analysis of glioblastoma (GBM) samples to elaborate the potential mechanism of drug treatment. Methods: The GBM cells treated with or without orexin A were acquired from sequencing analysis. Differentially expressed genes/proteins/metabolites (DEGs/ DEPs/ DEMs) were screened. Next, combination analyses were conducted to investigate the common pathways and correlations between the two groups. Lastly, transcriptome-proteome-metabolome association analysis was carried out to determine the common pathways, and the genes in these pathways were analyzed through Kaplan-Meier (K-M) survival analysis in public databases. Cell and animal experiments were performed to investigate the anti-glioma activity of orexin A. Results: A total of 1,527 DEGs, 52 DEPs, and 153 DEMs were found. Moreover, the combination analyses revealed that 6, 4, and 1 common pathways were present in the transcriptome-proteome, proteome-metabolome, and transcriptome-metabolome, respectively. Certain correlations were observed between the two data sets. Finally, 11 common pathways were discovered in association analysis, and 138 common genes were screened out in these common pathways. Six genes showed significant differences in terms of survival in both TCGA and CGGA. In addition, orexin A inhibited the proliferation, migration, and invasion of glioma in vitro and in vivo. Conclusion: Eleven common KEGG pathways with six common genes were found among different omics participations, revealing the underlying mechanisms in different omics and providing theoretical basis and reference for multi-omics research on drug treatment.PMID:36744263 | PMC:PMC9894894 | DOI:10.3389/fphar.2023.1096159

Adding a polyphenol-rich fiber bundle to food impacts the gastrointestinal microbiome and metabolome in dogs

Mon, 06/02/2023 - 12:00
Front Vet Sci. 2023 Jan 20;9:1039032. doi: 10.3389/fvets.2022.1039032. eCollection 2022.ABSTRACTINTRODUCTION: Pet foods fortified with fermentable fibers are often indicated for dogs with gastrointestinal conditions to improve gut health through the production of beneficial post-biotics by the pet's microbiome.METHODS: To evaluate the therapeutic underpinnings of pre-biotic fiber enrichment, we compared the fecal microbiome, the fecal metabolome, and the serum metabolome of 39 adult dogs with well-managed chronic gastroenteritis/enteritis (CGE) and healthy matched controls. The foods tested included a test food (TF1) containing a novel pre-biotic fiber bundle, a control food (CF) lacking the fiber bundle, and a commercially available therapeutic food (TF2) indicated for managing fiber-responsive conditions. In this crossover study, all dogs consumed CF for a 4-week wash-in period, were randomized to either TF1 or TF2 and fed for 4 weeks, were fed CF for a 4-week washout period, and then received the other test food for 4 weeks.RESULTS: Meaningful differences were not observed between the healthy and CGE dogs in response to the pre-biotic fiber bundle relative to CF. Both TF1 and TF2 improved stool scores compared to CF. TF1-fed dogs showed reduced body weight and fecal ash content compared to either CF or TF2, while stools of TF2-fed dogs showed higher pH and lower moisture content vs. TF1. TF1 consumption also resulted in unique fecal and systemic metabolic signatures compared to CF and TF2. TF1-fed dogs showed suppressed signals of fecal bacterial putrefactive metabolism compared to either CF or TF2 and increased saccharolytic signatures compared to TF2. A functional analysis of fecal tryptophan metabolism indicated reductions in fecal kynurenine and indole pathway metabolites with TF1. Among the three foods, TF1 uniquely increased fecal polyphenols and the resulting post-biotics. Compared to CF, consumption of TF1 largely reduced fecal levels of endocannabinoid-like metabolites and sphingolipids while increasing both fecal and circulating polyunsaturated fatty acid profiles, suggesting that TF1 may have modulated gastrointestinal inflammation and motility. Stools of TF1-fed dogs showed reductions in phospholipid profiles, suggesting fiber-dependent changes to colonic mucosal structure.DISCUSSION: These findings indicate that the use of a specific pre-biotic fiber bundle may be beneficial in healthy dogs and in dogs with CGE.PMID:36744230 | PMC:PMC9896628 | DOI:10.3389/fvets.2022.1039032

Mechanism of crocin I on ANIT-induced intrahepatic cholestasis by combined metabolomics and transcriptomics

Mon, 06/02/2023 - 12:00
Front Pharmacol. 2023 Jan 18;13:1088750. doi: 10.3389/fphar.2022.1088750. eCollection 2022.ABSTRACTBackground: Intrahepatic cholestasis (IC) is a disorder of bile production, secretion, and excretion with various causes. Crocin I (CR) is effective in the treatment of IC, but its underlying mechanisms need to be further explored. We aimed to reveal the therapeutic mechanism of crocin I for IC by combining an integrated strategy of metabolomics and transcriptomics. Methods: The hepatoprotective effect of CR against cholestasis liver injury induced by α-naphthylisothiocyanate (ANIT) was evaluated in rats. The serum biochemical indices, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), total bilirubin (TBIL), direct bilirubin (DBIL), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the liver oxidative stress indexes and the pathological characteristics of the liver were analyzed. In addition, we also performed a serum metabolomics study using UPLC-Q Exactive HF-X technology to investigate the effect of CR on the serum of rats with ANIT-induced IC and screened potential biomarkers. The enrichment analysis of differential expressed genes (DEGs) was performed by transcriptomics. Finally, the regulatory targets of CR on potential biomarkers were obtained by combined analysis, and the relevant key targets were verified by western blotting. Results: CR improved serum and liver homogenate indexes and alleviated liver histological injury. Compared with ANIT group, the CR group had 76 differential metabolites, and 10 metabolic pathways were enriched. There were 473 DEGs significantly changed after CR treatment, most of which were enriched in the retinol metabolism, calcium signaling pathway, PPAR signaling pathway, circadian rhythm, chemokine signaling pathway, arachidonic acid metabolism, bile secretion, primary bile acid biosynthesis, and other pathways. By constructing the "compound-reaction-enzyme-gene" interaction network, three potential key-target regulation biomarkers were obtained, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), ATP-binding cassette transporter G5 (ABCG5), and sulfotransferase2A1(SULT2A1), which were further verified by western blotting. Compared with the ANIT group, the CR group significantly increased the expression of ABCG5 and SULT2A1, and the expression of HMGCR significantly decreased. Conclusion: Combined metabolomic and transcriptomic analyses show that CR has a therapeutic effect on IC through regulation of the biosynthesis of bile acids and bilirubin in the bile secretion pathway and regulation of the expression of HMGCR, ABCG5, and SULT2A1.PMID:36744213 | PMC:PMC9890161 | DOI:10.3389/fphar.2022.1088750

Metabolomic Alterations in Mammary Glands from Pubertal Mice Fed a High-Fat Diet

Mon, 06/02/2023 - 12:00
Nutr Metab Insights. 2023 Jan 31;16:11786388221148858. doi: 10.1177/11786388221148858. eCollection 2023.ABSTRACTDietary malpractice is a risk factor for obesity. This study tested the hypothesis that consumption of a high-fat diet alters mammary metabolome in pubertal mice. We performed untargeted metabolomic analysis of primary metabolism on mammary glands from pubertal mice fed the AIN93G standard diet or a high-fat diet (HFD) for 3 weeks. We identified 97 metabolites for statistical comparisons. The HFD altered the amino acid metabolism considerably. This included elevated expression of branched-chain amino acids, non-essential amino acids (aspartic acid and glutamic acid), and methionine sulfoxide (oxidized methionine) and an alteration in the aminoacyl-tRNA biosynthesis pathway. Furthermore, elevations of fumaric acid and malic acid (both are citrate cycle intermediates) and glyceric acid (its phosphate derivatives are intermediates of glycolysis) in HFD-fed mice suggest an acceleration of both citrate cycle and glycolysis. Lower expression of glycerol, oleic acid, and palmitoleic acid, as well as decreased mammary expression of genes encoding lipid metabolism (Acaca, Fads1, Fasn, Scd1, and Srebf1) in HFD-fed mice indicate an attenuated lipid metabolism in the presence of adequate dietary fat. In conclusion, consumption of the HFD for 3 weeks alters metabolic profile of pubertal mammary glands. This alteration may affect mammary development and growth in pubertal mice.PMID:36744049 | PMC:PMC9893363 | DOI:10.1177/11786388221148858

Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition

Mon, 06/02/2023 - 12:00
PNAS Nexus. 2023 Jan 27;2(1):pgac309. doi: 10.1093/pnasnexus/pgac309. eCollection 2023 Jan.ABSTRACTRapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.PMID:36744021 | PMC:PMC9896899 | DOI:10.1093/pnasnexus/pgac309

Poly(ADP-ribose) polymerase-1 and its ambiguous role in cellular life and death

Mon, 06/02/2023 - 12:00
Cell Stress. 2023 Jan 23;7(1):1-6. doi: 10.15698/cst2023.01.275. eCollection 2023 Jan.ABSTRACTThe deletion of the gene coding for poly(ADP-ribose) polymerase-1 (PARP1) or its pharmacological inhibition protects mice against cerebral ischemia and Parkinson's disease. In sharp contrast, PARP1 inhibitors are in clinical use for the eradication of vulnerable cancer cells. It appears that excessive PARP1 activation is involved in a specific cell death pathway called parthanatos, while inhibition of PARP1 in cancer cells amplifies DNA damage to a lethal level. Hence, PARP1 plays a context-dependent role in cell fate decisions. In addition, it appears that PARP1 plays an ambiguous role in organismal aging.PMID:36743979 | PMC:PMC9877585 | DOI:10.15698/cst2023.01.275

Relationship between serum thyroid hormones and their associated metabolites, and gene expression bioindicators in the back skin of <em>Rana [Lithobates] catesbeiana</em> tadpoles and frogs during metamorphosis

Mon, 06/02/2023 - 12:00
Front Endocrinol (Lausanne). 2023 Jan 18;13:1103051. doi: 10.3389/fendo.2022.1103051. eCollection 2022.ABSTRACTAnuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3',5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28 ± 10 and 2.3 ± 0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.PMID:36743912 | PMC:PMC9889540 | DOI:10.3389/fendo.2022.1103051

Editorial: Plant chemoecology: Integrating micro- and macrolevel approaches in regulating secondary metabolism

Mon, 06/02/2023 - 12:00
Front Plant Sci. 2023 Jan 20;13:1119152. doi: 10.3389/fpls.2022.1119152. eCollection 2022.NO ABSTRACTPMID:36743584 | PMC:PMC9897056 | DOI:10.3389/fpls.2022.1119152

Combatting insects mediated biotic stress through plant associated endophytic entomopathogenic fungi in horticultural crops

Mon, 06/02/2023 - 12:00
Front Plant Sci. 2023 Jan 19;13:1098673. doi: 10.3389/fpls.2022.1098673. eCollection 2022.ABSTRACTHorticultural production is a vital catalyst for economic growth, yet insect infestations reduce horticultural crop yield and quality. Pesticides and other pest control methods are used during planting to eliminate pests that cause direct and indirect losses. In such situations, endophytic entomo-pathogenic fungi (EEPF) can act as a potential tools for biological control. They protect plants by boosting growth, nutrition, morpho-physiology and salt or iron tolerance. Antixenosis, antibiosis and plant tolerance change insect performance and preferences. EEPF- plant colonisation slows herbivore development, food consumption, oviposition and larval survival. EEPF changes plant physio-chemical properties like volatile emission profile and secondary metabolite production to regulate insect pest defences. EEPF produces chitinases, laccases, amylases, and cellulases for plant defence. Recent studies focused on EEPF species' significance, isolation, identification and field application. Realizing their full potential is difficult due to insufficient mass production, storage stability and formulation. Genetic-molecular and bioinformatics can help to build EEPF-based biological control systems. Metagenomics helps study microbial EEPF taxonomy and function. Multi-omics and system biology can decode EEPF interactions with host plants and microorganisms. NGS (Next Generation Sequencing), comparative genomics, proteomics, transcriptomics, metabolomics, metatranscriptomics and microarrays are used to evaluate plant-EEPF relationships. IPM requires understanding the abiotic and biotic elements that influence plant-EEPF interaction and the physiological mechanisms of EEPF colonisation. Due to restricted research, there are hundreds of unexplored EEPFs, providing an urgent need to uncover and analyse them.PMID:36743574 | PMC:PMC9894630 | DOI:10.3389/fpls.2022.1098673

Transcriptomic and metabolic regulatory network characterization of drought responses in tobacco

Mon, 06/02/2023 - 12:00
Front Plant Sci. 2023 Jan 18;13:1067076. doi: 10.3389/fpls.2022.1067076. eCollection 2022.ABSTRACTDrought stress usually causes huge economic losses for tobacco industries. Drought stress exhibits multifaceted impacts on tobacco systems through inducing changes at different levels, such as physiological and chemical changes, changes of gene transcription and metabolic changes. Understanding how plants respond and adapt to drought stress helps generate engineered plants with enhanced drought resistance. In this study, we conducted multiple time point-related physiological, biochemical,transcriptomic and metabolic assays using K326 and its derived mutant 28 (M28) with contrasting drought tolerance. Through integrative analyses of transcriptome and metabolome,we observed dramatic changes of gene expression and metabolic profiles between M28 and K326 before and after drought treatment. we found that some of DEGs function as key enzymes responsible for ABA biosynthesis and metabolic pathway, thereby mitigating impairment of drought stress through ABA signaling dependent pathways. Four DEGs were involved in nitrogen metabolism, leading to synthesis of glutamate (Glu) starting from NO-3 /NO-2 that serves as an indicator for stress responses. Importantly, through regulatory network analyses, we detected several drought induced TFs that regulate expression of genes responsible for ABA biosynthesis through network, indicating direct and indirect involvement of TFs in drought responses in tobacco. Thus, our study sheds some mechanistic insights into how plant responding to drought stress through transcriptomic and metabolic changes in tobacco. It also provides some key TF or non-TF gene candidates for engineering manipulation for breeding new tobacco varieties with enhanced drought tolerance.PMID:36743571 | PMC:PMC9891310 | DOI:10.3389/fpls.2022.1067076

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