PubMed

Cell Prolif. 2023 Apr 13:e13479. doi: 10.1111/cpr.13479. Online ahead of print.ABSTRACTAlteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue-1 (LRH-1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH-1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH-1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle-treated db/db mice. Our study indicates the essential role of LRH-1 in governing the Gln metabolism of podocytes, targeting LRH-1 could restore podocytes from diabetes-induced disturbed glutaminolysis in mitochondria.PMID:37057309 | DOI:10.1111/cpr.13479

ERJ Open Res. 2023 Apr 11;9(2):00485-2022. doi: 10.1183/23120541.00485-2022. eCollection 2023 Mar.ABSTRACTSevere asthma represents an important clinical unmet need despite the introduction of biologic agents. Although advanced omics technologies have aided researchers in identifying clinically relevant molecular pathways, there is a lack of an integrated omics approach in severe asthma particularly in terms of its evolution over time. The collaborative Korea-UK research project Precision Medicine Intervention in Severe Asthma (PRISM) was launched in 2020 with the aim of identifying molecular phenotypes of severe asthma by analysing multi-omics data encompassing genomics, epigenomics, transcriptomics, proteomics, metagenomics and metabolomics. PRISM is a prospective, observational, multicentre study involving patients with severe asthma attending severe asthma clinics in Korea and the UK. Data including patient demographics, inflammatory phenotype, medication, lung function and control status of asthma will be collected along with biological samples (blood, sputum, urine, nasal epithelial cells and exhaled breath condensate) for omics analyses. Follow-up evaluations will be performed at baseline, 1 month, 4-6 months and 10-12 months to assess the stability of phenotype and treatment responses for those patients who have newly begun biologic therapy. Standalone and integrated omics data will be generated from the patient samples at each visit, paired with clinical information. By analysing these data, we will identify the molecular pathways that drive lung function, asthma control status, acute exacerbations and the requirement for daily oral corticosteroids, and that are involved in the therapeutic response to biological therapy. PRISM will establish a large multi-omics dataset of severe asthma to identify potential key pathophysiological pathways of severe asthma.PMID:37057090 | PMC:PMC10086686 | DOI:10.1183/23120541.00485-2022

Front Nutr. 2023 Mar 28;10:1040993. doi: 10.3389/fnut.2023.1040993. eCollection 2023.ABSTRACTBACKGROUND: Oxylipins are inflammatory biomarkers derived from omega-3 and-6 fatty acids implicated in inflammatory diseases but have not been studied in a genome-wide association study (GWAS). The aim of this study was to identify genetic loci associated with oxylipins and oxylipin profiles to identify biologic pathways and therapeutic targets for oxylipins.METHODS: We conducted a GWAS of plasma oxylipins in 316 participants in the Diabetes Autoimmunity Study in the Young (DAISY). DNA samples were genotyped using the TEDDY-T1D Exome array, and additional variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) multi-ancestry reference panel. Principal components analysis of 36 plasma oxylipins was used to capture oxylipin profiles. PC1 represented linoleic acid (LA)- and alpha-linolenic acid (ALA)-related oxylipins, and PC2 represented arachidonic acid (ARA)-related oxylipins. Oxylipin PC1, PC2, and the top five loading oxylipins from each PC were used as outcomes in the GWAS (genome-wide significance: p < 5×10-8).RESULTS: The SNP rs143070873 was associated with (p < 5×10-8) the LA-related oxylipin 9-HODE, and rs6444933 (downstream of CLDN11) was associated with the LA-related oxylipin 13 S-HODE. A locus between MIR1302-7 and LOC100131146, rs10118380 and an intronic variant in TRPM3 were associated with the ARA-related oxylipin 11-HETE. These loci are involved in inflammatory signaling cascades and interact with PLA2, an initial step to oxylipin biosynthesis.CONCLUSION: Genetic loci involved in inflammation and oxylipin metabolism are associated with oxylipin levels.PMID:37057071 | PMC:PMC10086335 | DOI:10.3389/fnut.2023.1040993

Front Cell Infect Microbiol. 2023 Mar 28;13:1122450. doi: 10.3389/fcimb.2023.1122450. eCollection 2023.ABSTRACTDespite being considered fragile and fastidious, Campylobacter jejuni is the most prevalent cause of foodborne bacterial gastroenteritis, and chicken meat is considered the main vehicle of transmission to humans. This agent can survive adverse conditions in the form of biofilms, but extreme stress (nutritional, oxidative and thermal) promotes the acquisition of a state called viable but not culturable (VBNC). The emergence of this pathogen worldwide and the recent international requirements in its control instigated us to qualitatively and quantitatively estimate the time required for the acquisition of the VBNC form in 27 strains of C. jejuni, characterize morphological aspects, determine its adaptive and invasive potential and perform comparative metabolomic evaluation. Extreme stress promoted the complete acquisition of the VBNC form in a mean time of 26 days. Starting from an average initial count of 7.8 log CFU/mL, the first four days determined the greatest average reduction of the culturable form of 3.2 log CFU/mL. The scanning and transmission image analyses showed a transition from the typical viable form (VT) to the VBNC form, with initial acquisition of the straight rod shape, followed by loss of the flagella and subdivision into two to 11 imperfect cocci arranged in a chain and rich in cellular content, until their individual release. RT-PCR identified the presence of ciaB and p19 transcripts in the 27 cultivable C. jejuni strains, a character maintained in the VBNC form only for p19 and in 59.3% (16/27) of the VBNC strains for the ciaB gene. The average inoculation of 1.8 log CFU/mL of C. jejuni VBNC into primary chicken embryo hepatocyte cells promoted the occurrence of apoptosis processes significantly after 24 hours of contact by one of the strains tested. In C. jejuni VBNC, we detected higher expression of metabolites linked to protective and adaptation mechanisms and of volatile organic precursor compounds indicative of metabolism interruption. The oscillations in the time of acquisition of the VBNC form together with the presence of transcripts for ciaB and p19, the identification of cell lysis and metabolites that ensure the maintenance of the pathogen alert to the fact that C. jejuni VBNC remains virulent and adapted to stress, which makes evident the potential danger of this latent form, which is not detectable by official methodologies.PMID:37056707 | PMC:PMC10086134 | DOI:10.3389/fcimb.2023.1122450

Nanoscale Adv. 2023 Mar 15;5(8):2251-2260. doi: 10.1039/d3na00014a. eCollection 2023 Apr 11.ABSTRACTExploitation of the biotin-streptavidin interaction for advanced protein engineering is used in many bio-nanotechnology applications. As such, researchers have used diverse techniques involving chemical and enzyme reactions to conjugate biotin to biomolecules of interest for subsequent docking onto streptavidin-associated molecules. Unfortunately, the biotin-streptavidin interaction is susceptible to steric hindrance and conformational malformation, leading to random orientations that ultimately impair the function of the displayed biomolecule. To minimize steric conflicts, we employ sortase A transpeptidation to produce quantitative, seamless, and unbranched nanobody-biotin conjugates for efficient display on streptavidin-associated nanoparticles. We further characterize the protein-nanoparticle complex and demonstrate its usefulness in optical microscopy and multivalent severe acute respiratory syndrome coronavirus (SARS-CoV-2) antigen interaction. The approach reported here provides a template for making novel multivalent and multifunctional protein complexes for avidity-inspired technologies.PMID:37056610 | PMC:PMC10089078 | DOI:10.1039/d3na00014a

Front Plant Sci. 2023 Mar 17;14:1153710. doi: 10.3389/fpls.2023.1153710. eCollection 2023.ABSTRACTThe selection of medicinal plants' chemical markers focuses on bioactivity as the primary goal, followed by the nature of secondary metabolites, their stability, and availability. However, herbal medicines are valued for their complex and holistic pharmacological effects. A correct chemical marker can be carefully selected by a systematic clarification of their chemical-biological relationships. In the current study, the multi-informative molecular networking (MIMN) approach was employed to construct the anti-inflammatory metabolomic pattern of a heat-clearing herb, Scrophularia ningpoensis Hemsl. (S. ningpoensis). The MIMN molecular families characterized by cinnamic acid glycosides showed a higher bioactivity score compared with the other two major chemical classes (iridoid glycosides and iridoid-cinnamic acid glycosides). The Global Natural Product Social Molecular Networking (GNPS) and Reaxys database were used to assist in the putative annotation of eighteen metabolites from the bioactive and non-bioactive molecular families. The anti-inflammatory validation step was based on the detection of reactive oxygen species (ROS) generation by activated human neutrophils. All compounds from the bioactive MIMN molecular families dose-dependently inhibited the total ROS generation promoted by fMLF (IC50: 0.04-0.42 μM), while the compounds from non-bioactive MIMN clusters did not show any significant anti-inflammatory effect. The ROS-dependent anti-inflammatory activity of these cinnamic acid glycosides was attributed to their oxygen radical scavenging ability. The most abundant cinnamic acid glycoside, angoroside C (IC50: 0.34 μM) was suggested to be selected as a chemical marker for S. ningpoensis. In this study, the MIMN platform was applied to assist in the chemical marker selection of S. ningpoensis. The correct selection of markers will aid in the compilation and revision of herbal monographs and pharmacopeias resulting in the precise analysis and classification of medicinal plants on a scientific basis.PMID:37056509 | PMC:PMC10088908 | DOI:10.3389/fpls.2023.1153710

Front Plant Sci. 2023 Mar 28;14:1165384. doi: 10.3389/fpls.2023.1165384. eCollection 2023.ABSTRACTSoybean production is severely hampered by saline-alkaline stress caused by saline-alkalization. Plants have aldehydrogenase (ALDH) family members that convert reactive aldehydes to carboxylic acids to remove active aldehyde molecules. However, little is known about the increased saline-alkali tolerance caused by the ALDH function in soybean. Here, we introduced a previously identified ALDH coding gene AhALDH3H1 from Arachis hypogaea into the soybean genome to investigate its critical role in response to saline-alkali stress. Transgenic soybean with increased aldehyde dehydrogenase activity showed significant tolerance to saline-alkali stress. It reduced malondialdehyde (MDA) content compared to its receptor, suggesting that over-expression of AhALDH3H1 accelerated soybean tolerance to saline-alkali stress by increasing aldehyde dehydrogenase activity, which is responsible for scavenging toxic MDA. To further analyze the inner mechanisms that allow transgenic plants to tolerate saline-alkali stress, we sequenced the transcriptome and metabolome of P3 (wild type, WT) and transgenic lines which were separately treated with water and a saline-alkali solution. When subjected to saline-alkali stress, the integrated analysis of the transcriptome and metabolome suggested that several genes related to cell wall structure crucial for preserving cell wall extensibility and plasticity were largely responsible for restoring homeostasis within the transgenic cells compared to WT. Metabolites, including both necessary ingredients for cell wall genesis and harmful production produced during the saline-alkali stress response, could be transported efficiently with the help of the ABC transporter, reducing the negative effects of saline-alkali stress. These findings suggest that introducing AhALDH3H1 increases transgenic soybean tolerance to saline-alkali stress may through cell wall structure maintenance and metabolites transport.PMID:37056489 | PMC:PMC10086354 | DOI:10.3389/fpls.2023.1165384

J Cancer. 2023 Mar 27;14(5):809-820. doi: 10.7150/jca.81623. eCollection 2023.ABSTRACTAnti-angiogenesis therapy has shown significant anti-tumor effects against a variety of cancers. But resistance to antiangiogenic drugs, intrinsic and evasive, is frequently found in patients during treatment. Here, we report that dihydroartemisinin (DHA), a derivative of the Chinese medicine artemisinin, enhances antiangiogenic drug-induced cytotoxicity in osteosarcoma (OS) cells. Proteomics analysis revealed that DHA treatment significantly affected the activity of the collagen-modifying enzyme lysyl oxidase-like 2 (LOXL2), a regulatory gene associated with poor prognosis of OS. Furthermore, we found that DHA reduced the expression of vascular endothelial growth factor (VEGFA) by downregulating LOXL2. This mechanism was confirmed by QRT-PCR, western blot, and ELISA assays. Correspondingly, vector-enforced expression of LOXL2 markedly reduced VEGFA secretion. Untargeted metabolomic analysis revealed that the lipid metabolism that confers antiangiogenic drug resistance, was also interfered with by DHA. Thus, DHA not only exerts antitumor effects in OS cells directly but also synergizes with the antiangiogenic drug by regulating vascular endothelial growth factor A (VEGFA) expression and lipid metabolism.PMID:37056396 | PMC:PMC10088882 | DOI:10.7150/jca.81623

Front Oncol. 2023 Mar 28;13:1190120. doi: 10.3389/fonc.2023.1190120. eCollection 2023.ABSTRACT[This corrects the article DOI: 10.3389/fonc.2022.1032336.].PMID:37056334 | PMC:PMC10086418 | DOI:10.3389/fonc.2023.1190120

Front Genet. 2023 Mar 28;14:1108086. doi: 10.3389/fgene.2023.1108086. eCollection 2023.ABSTRACTBackground: Non-alcoholic fatty liver disease (NAFLD) is a liver disease associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. The risk factors for NAFLD have not been identified. Metabolic dysfunction has been found to be an important factor in the pathogenesis and progression of NAFLD. However, the causal impact of blood metabolites on NAFLD is unclear. Methods: We performed a two-sample Mendelian randomization (MR) study. A genome-wide association study (GWAS) with 7824 participants provided data on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of NAFLD, which contained 8,434 cases and 770,180 controls of Europeans. The inverse variance weighted (IVW) model was chosen as the primary two-sample MR analysis approach, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. In addition, we performed replication, meta-analysis, and metabolic pathway analysis. We further conducted colocalization analysis to deeply reflect the causality. Results: After rigorous genetic variant selection, IVW, sensitivity analysis, replication, and meta-analysis, two known metabolites were identified as being associated with the development of NAFLD [biliverdin: OR = 1.45; 95% CI 1.20-1.75; p = 0.0001; myristoleate: OR = 0.57; 95% CI 0.39-0.83; p = 0.0030]. Conclusion: By combining genomics with metabolomics, our findings provide a new perspective on the underlying mechanisms of NAFLD and have important implications for the screening and prevention of NAFLD.PMID:37056283 | PMC:PMC10086196 | DOI:10.3389/fgene.2023.1108086

Neural Regen Res. 2023 Oct;18(10):2184-2185. doi: 10.4103/1673-5374.369104.NO ABSTRACTPMID:37056128 | DOI:10.4103/1673-5374.369104

J Hazard Mater. 2023 Mar 5;445:130585. doi: 10.1016/j.jhazmat.2022.130585. Epub 2022 Dec 9.ABSTRACTExcessive copper pollutes the environment and endangers human health, attracting plenty of global attention. In this study, a novel strain named Bacillus coagulans XY2 was discovered to have a great copper tolerance and adsorption capacity. B. coagulans XY2 might maintain copper homeostasis through multisystem synergies of copper resistance, sulfur metabolism, Fe-S cluster assembly, and siderophore transport. In mice, by promoting the expression of SREBF-1 and SREBF-2 and their downstream genes, B. coagulans XY2 significantly inhibited the copper-induced decrease in weight growth rate, ameliorated dyslipidemia, restored total cholesterol and triglyceride contents both in serum and liver. Furthermore, B. coagulans XY2 recovered the diversity of gut microbiota and suppressed the copper-induced reduction in the ratio of Firmicutes to Bacteroidota. Serum metabolomics analysis showed that the alleviating effect of B. coagulans XY2 on copper toxicity was mainly related to lipid metabolism. For the first time, we demonstrated mechanisms of copper toxicity mitigation by B. coagulans XY2, which was related to self-adsorption, host copper excretion promotion, and lipid metabolism regulation. Moreover, working model of B. coagulans XY2 on copper homeostasis was predicted by whole-genome analysis. Our study provides a new solution for harmfulness caused by copper both in human health and the environment.PMID:37055990 | DOI:10.1016/j.jhazmat.2022.130585

Drug Test Anal. 2023 Apr 13. doi: 10.1002/dta.3480. Online ahead of print.ABSTRACTBeing able to attest when a bloodstain was deposited at a crime scene can be invaluable to a prosecution process, and methods to provide that information have long been desired. Determining the Time since Deposition (TsD) of a trace would allow placing a subject both in space and time to the crime scene - or prove that a trace left by that person was unrelated to it, because it was deposited before or after the time a crime had occurred. To this day, no method for TsD-determination has made its way into routine forensic casework, mainly because of the numerous challenges that await when trying to understand and account for all the influencing and confounding factors that affect the aging process (such as, e.g., temperature, UV-light exposure, or humidity). Here, we present an untargeted metabolomics-based study using liquid-chromatography high-resolution mass-spectrometry (LC-HRMS) and data-dependent acquisition to analyze blood samples aged under two distinctly different storage conditions over 48 weeks. Global differences in age- and storage-dependent changes in blood metabolomes were described, and TsD-classification strategies based on qualitative and quantitative assessment of molecular features (MFs) have been proposed. Based on the selected criteria to best predict the TsD, the dipeptide Phenylalanylalanine (PheAla) can be considered as a promising candidate for TsD prediction. In essence, changes in the blood metabolome dynamics showed a strong association with increasing TsD, but significant differences depending on storage conditioning were observed, facilitating the need to study further the influence of (individual) influencing factors on TsD-determination.PMID:37055932 | DOI:10.1002/dta.3480

Curr Pediatr Rev. 2023 Apr 11. doi: 10.2174/1573396320666230411093122. Online ahead of print.ABSTRACTTo date, the complex picture of atopic dermatitis (AD) has not yet been fully clarified, despite the important prevalence of this disease in the pediatric population (20%) and the possibility of persistence into adulthood, with important implications for the quality of life of those affected, as well as significant social and financial costs. The most recent scientific evidence suggests a new interpretation of AD, highlighting the important role of the environment, particularly that of nutrition in the early stages of development. In fact, the new indications seem to point out the harmful effect of elimination diets, except in rare cases, the uselessness of chrono-insertions during complementary feeding and some benefits, albeit weak, of breastfeeding in those at greater risk. In this context, metabolomics and lipidomics can be necessary for a more in-depth knowledge of the complex metabolic network underlying this pathology. In fact, an alteration of the metabolic contents in children with AD has been highlighted, especially in correlation to the intestinal microbiota. While preliminary lipidomic studies showed the usefulness of a more in-depth knowledge of the alterations of the skin barrier to improve the development of baby skin care products. Therefore, investigating the response of different allergic phenotypes could be useful for better patient management and understanding, thus providing an early intervention on dysbiosis necessary to regulate the immune response from the earliest stages of development.PMID:37055903 | DOI:10.2174/1573396320666230411093122

Oxid Med Cell Longev. 2023 Apr 13;2023:5509913. doi: 10.1155/2023/5509913. eCollection 2023.ABSTRACTBACKGROUND: In high-altitude areas, hypoxic stress can elicit a series of physiological responses in humans. Exosomes play important roles in both local and distal cellular communications.METHODS: We used ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) studies to analyze the differentially expressed metabolomics and proteomics in serum exosome of hypoxic preconditioning participants and control subjects in the hypoxic conditions.RESULTS: Fifty-seven military personnel were divided into hypoxic preconditioning group (n = 27) and control group (n = 30). One hundred thirty-six differentially expressed serum exosomal metabolites were found between the hypoxic preconditioning and control groups in the hypoxic conditions, and these differentially expressed metabolites were enriched in pathways related to lysine degradation, butanoate metabolism, GABAergic synapse, histidine metabolism, and linoleic acid metabolism. In addition, hypoxic preconditioning participants showed 102 excellent differential expressions of proteomics compared to controls, which involved actin cytoskeleton organization, hemostasis, complement and coagulation cascades, vesicle-medicated transport, wound healing, etc.CONCLUSIONS: We revealed that the expression of exosomal metabolites and proteomics in hypoxic preconditioning participants was significantly different compared to controls in hypoxic conditions.PMID:37089582 | PMC:PMC10118903 | DOI:10.1155/2023/5509913

Food Chem. 2023 Apr 13;420:136156. doi: 10.1016/j.foodchem.2023.136156. Online ahead of print.ABSTRACTThyme is a culinary herb highly susceptible to increasing mislabeling occurring in the spice industry. In this study, proton nuclear magnetic resonance spectroscopy (1H NMR) combined with multivariate statistics was successfully applied with two authenticity purposes: (1) tracing thyme metabolic differences among three relevant geographical regions (Morocco, Spain, and Poland), and (2) assessing the influence of sterilization processing on the metabolic fingerprint. Multivariate data analysis provided six and seven key geographical and processing markers, respectively, including thymol, organic acids, chlorogenic acid, and some carbohydrates (e.g., sucrose). Additionally, for the first time, a mid-level data fusion approach was tested for thyme authenticity combining three complementary and synergic analytical platforms: gas and liquid chromatography coupled with high-resolution mass spectrometry, and 1H NMR spectroscopy, providing a comprehensive metabolomics insight into the origin and processing effects on thyme fingerprinting, and opening the path to new metabolomics approaches for quality control in the spice industry.PMID:37075575 | DOI:10.1016/j.foodchem.2023.136156

Molecules. 2023 Mar 27;28(7):2991. doi: 10.3390/molecules28072991.ABSTRACTThe Tibetan pig is a characteristic breed of the Qinghai-Tibet Plateau with distinct physiological and meat quality attributes. The liver lipid profile can offer an important perspective to explore the uniqueness of Tibetan pigs. A quantitative comparison of liver lipidomes revealed significant differences in the lipid profiles between Tibetan and Yorkshire pigs raised at different altitudes. The abundance of lipids in the livers of pigs raised at a high altitude was higher than that of pigs raised at a lower altitude, whereas the abundance of lipids in the livers of Yorkshire pigs was higher than that of Tibetan pigs raised at the same altitude. Of the 1101 lipids identified, 323 and 193 differentially abundant lipids (DALs) were identified in the pairwise comparisons of Tibetan and Yorkshire pigs raised at different altitudes, respectively. The DALs of Tibetan pigs consisted mainly of 161 triglycerides, along with several acylcarnitines, represented by carnitine C2:0, and significant changes in the abundance of some phospholipids. The DALs of Yorkshire pigs were more complex, with significant increases in the abundance of triglycerides, cholesteryl esters, and free fatty acids, and decreases in the abundance of some phospholipids. This research provides strong theoretical and data support for the high-quality development of the highland livestock industry.PMID:37049754 | DOI:10.3390/molecules28072991

Nat Methods. 2023 Apr 13. doi: 10.1038/s41592-023-01850-x. Online ahead of print.ABSTRACTA substantial fraction of metabolic features remains undetermined in mass spectrometry (MS)-based metabolomics, and molecular formula annotation is the starting point for unraveling their chemical identities. Here we present bottom-up tandem MS (MS/MS) interrogation, a method for de novo formula annotation. Our approach prioritizes MS/MS-explainable formula candidates, implements machine-learned ranking and offers false discovery rate estimation. Compared with the mathematically exhaustive formula enumeration, our approach shrinks the formula candidate space by 42.8% on average. Method benchmarking on annotation accuracy was systematically carried out on reference MS/MS libraries and real metabolomics datasets. Applied on 155,321 recurrent unidentified spectra, our approach confidently annotated >5,000 novel molecular formulae absent from chemical databases. Beyond the level of individual metabolic features, we combined bottom-up MS/MS interrogation with global optimization to refine formula annotations while revealing peak interrelationships. This approach allowed the systematic annotation of 37 fatty acid amide molecules in human fecal data. All bioinformatics pipelines are available in a standalone software, BUDDY ( https://github.com/HuanLab/BUDDY ).PMID:37055660 | DOI:10.1038/s41592-023-01850-x

Pediatr Surg Int. 2023 Apr 13;39(1):180. doi: 10.1007/s00383-023-05452-8.ABSTRACTPURPOSE: Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development.METHODS: To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1.RESULTS: The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase.CONCLUSION: Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.PMID:37055635 | DOI:10.1007/s00383-023-05452-8

Geroscience. 2023 Apr 13. doi: 10.1007/s11357-023-00793-7. Online ahead of print.ABSTRACTDyslipidemia is an independent and modifiable risk factor for aging and age-related disorders. Routine lipid panel cannot capture all individual lipid species in blood (i.e., blood lipidome). To date, a comprehensive assessment of the blood lipidome associated with mortality is lacking in large-scale community-dwelling individuals, especially in a longitudinal setting. Using liquid chromatograph-mass spectrometry, we repeatedly measured individual lipid species in 3,821 plasma samples collected at two visits (~ 5.5 years apart) from 1,930 unique American Indians in the Strong Heart Family Study. We first identified baseline lipids associated with risks for all-cause mortality and CVD mortality (mean follow-up period: 17.8 years) in American Indians, followed by replication of top hits in European Caucasians in the Malmö Diet and Cancer-Cardiovascular Cohort (n = 3,943, mean follow-up period: 23.7 years). The model adjusted age, sex, BMI, smoking, hypertension, diabetes, and LDL-c at baseline. We then examined the associations between changes in lipid species and risk of mortality. Multiple testing was controlled by false discovery rate (FDR). We found that baseline levels and longitudinal changes of multiple lipid species, e.g., cholesterol esters, glycerophospholipids, sphingomyelins, and triacylglycerols, were significantly associated with risks of all-cause or CVD mortality. Many lipids identified in American Indians could be replicated in European Caucasians. Network analysis identified differential lipid networks associated with risk of mortality. Our findings provide novel insight into the role of dyslipidemia in disease mortality and offer potential biomarkers for early prediction and risk reduction in American Indians and other ethnic groups.PMID:37055600 | DOI:10.1007/s11357-023-00793-7