PubMed

Am J Physiol Lung Cell Mol Physiol. 2023 Jun 13. doi: 10.1152/ajplung.00303.2022. Online ahead of print.ABSTRACTVanadium is available as a dietary supplement and also is known to be toxic if inhaled, yet little information is available concerning effects of vanadium on mammalian metabolism when at concentrations found in food and water. Vanadium pentoxide (V+5) is representative of the most common dietary and environmental exposures, and prior research shows low-dose V+5 exposure causes oxidative stress measured by glutathione oxidation and protein S-glutathionylation. We examined the metabolic impact of V+5 at relevant dietary and environmental doses (0.01, 0.1, 1 ppm for 24 h) in human lung fibroblasts (HLF) and male C57BL/6J mice (0.02, 0.2, 2 ppm in drinking water for 7 months). Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that V+5 induced significant metabolic perturbations in both HLF cells and mouse lungs. We noted 30% of the significantly altered pathways in HLF cells, including pyrimidines and aminosugars, fatty acids, mitochondrial and redox pathways, showed similar dose-dependent patterns in mouse lung tissues. Alterations in lipid metabolism included leukotrienes and prostaglandins involved in inflammatory signaling, which have been associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other disease processes. Elevated hydroxyproline levels and excessive collagen deposition were also present in lungs from V+5-treated mice. Taken together, these results show that oxidative stress from environmental V+5, ingested at low levels, could alter metabolism to contribute to common human lung diseases.PMID:37310758 | DOI:10.1152/ajplung.00303.2022

J Agric Food Chem. 2023 Jun 13. doi: 10.1021/acs.jafc.3c02415. Online ahead of print.ABSTRACTSour rot, caused by Geotrichum citri-aurantii, is a major postharvest disease in citrus and results in significant economic losses. The genus Beauveria is recognized as a promising source of biocontrol agents for agricultural applications. Herein, we established a targeted strategy by integrating genomics and metabolomics to accelerate the discovery of new cyclopeptides from antagonistic metabolites produced by the marine-derived fungus Beauveria felina SYSU-MS7908. As a result, we isolated and characterized seven cyclopeptides, including six new molecules, isaridins I-N (1-6). Their chemical structures and conformational analysis were extensively elucidated using spectroscopic techniques (NMR, HRMS, and MS'MS data), modified Mosher's and Marfey's methods, and single-crystal X-ray diffraction. Notably, isaridin K (3) contains a peptide backbone with an N-methyl-2-aminobutyric acid residue rarely found in natural cyclopeptides. Bioassays showed that compound 2 could significantly inhibit the mycelial growth of G. citri-aurantii by destroying the cell membrane. These findings provide an effective strategy for searching for new fungal peptides for potential agrochemical fungicides and also pave the way for further exploration of applications in agriculture, food, and medicine.PMID:37310400 | DOI:10.1021/acs.jafc.3c02415

Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2023 Jun 13:1-10. doi: 10.1080/19440049.2023.2220827. Online ahead of print.ABSTRACTIn Korea, Angelica gigas is commonly known as Danggui. However, two other species on the market, Angelica acutiloba and Angelica sinensis, are also commonly called Danggui. Since the three Angelica species have different biologically active components, thus, different pharmacological activities, clear discrimination between them is needed to prevent their misuse. A. gigas is used not only as a cut or powdered product but also in processed foods, where it is mixed with other ingredients. To discriminate between the three Angelica species, reference samples were analysed as non-targeted using liquid chromatography-quadrupole time of flight/mass spectrometry (LC-QTOF/MS) and a metabolomics approach in which a discrimination model was established by partial least squares-discriminant analysis (PLS-DA). Then, the Angelica species in the processed foods were identified. First, 32 peaks were selected as marker compounds and a discrimination model was created using PLS-DA, and its validation was confirmed. Classification of the Angelica species was undertaken using the YPredPS value, and it was confirmed that all 21 foods examined contained the appropriate Angelica species indicated on the product packaging. Likewise, it was confirmed that all three Angelica species were accurately classified in the samples to which they were added.PMID:37310353 | DOI:10.1080/19440049.2023.2220827

Chem Commun (Camb). 2023 Jun 13. doi: 10.1039/d3cc01578e. Online ahead of print.ABSTRACTNonribosomal peptide synthetases produce many important peptide natural products and are centred around carrier proteins (CPs) that deliver intermediates to various catalytic domains. We show that the replacement of CP substrate thioesters by stabilised ester analogues leads to active condensation domain complexes, whereas amide stabilisation generates non-functional complexes.PMID:37310188 | DOI:10.1039/d3cc01578e

J Cereb Blood Flow Metab. 2023 Jun 13:271678X231182244. doi: 10.1177/0271678X231182244. Online ahead of print.ABSTRACTVascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease, and pathological changes in cerebral vascular structure and function are pivotal causes of VCI. Cognitive impairment caused by arterial ischemia has been extensively studied the whole time; the influence of cerebral venous congestion on cognitive impairment draws doctors' attention in recent clinical practice, but the underlying neuropathophysiological alterations are not completely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in cognitive-behavioral deterioration and possible electrophysiological mechanisms. Using cerebral venous congestion rat models, we found these rats exhibited decreased long-term potentiation (LTP) in the hippocampal dentate gyrus and impaired spatial learning and memory. Based on untargeted metabolomics, N-acetyl-L-cysteine (NAC) deficiency was detected in cerebral venous congestion rats; supplementation with NAC appeared to ameliorate synaptic deficits, rescue impaired LTP, and mitigate cognitive impairment. In a cohort of cerebral venous congestion patients, NAC levels were decreased; NAC concentration was negatively correlated with subjective cognitive decline (SCD) score but positively correlated with mini-mental state examination (MMSE) score. These findings provide a new perspective on cognitive impairment and support further exploration of NAC as a therapeutic target for the prevention and treatment of VCI.PMID:37309740 | DOI:10.1177/0271678X231182244

J Inherit Metab Dis. 2023 Jun 12. doi: 10.1002/jimd.12642. Online ahead of print.ABSTRACTToxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA) and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further. This article is protected by copyright. All rights reserved.PMID:37309295 | DOI:10.1002/jimd.12642

Thorac Cancer. 2023 Jun 12. doi: 10.1111/1759-7714.14988. Online ahead of print.ABSTRACTBACKGROUND: Lung cancer is the most common cancer-related death worldwide. In 2022, the number of daily deaths of lung cancer was estimated to reach around 350 in the United States. Lung adenocarcinoma is the main subtype of lung cancer and patients with malignant pleural effusion (MPE) suffer from poor prognosis. Microbiota and its metabolites are associated with cancer progression. However, the effect of pleural microbiota on pleural metabolic profile of MPE in lung adenocarcinoma patients remains largely unknown.METHODS: Pleural effusion samples collected from lung adenocarcinoma patients with MPE (n = 14) and tuberculosis pleurisy patients with benign pleural effusion (BPE group, n = 10) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (liquid chromatography tandem mass spectrometry [LC-MS/MS]) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatic approaches.RESULTS: The metabolic profile of MPE in lung adenocarcinoma patients were clearly distinguished from BPE with 121 differential metabolites across six significantly enriched pathways identified. Glycerophospholipids, fatty and carboxylic acids, and derivatives were the most common differential metabolites. Sequencing of microbial data revealed nine significantly enriched genera (i.e., Staphylococcus, Streptococcus, Lactobacillus) and 26 enriched ASVs (i.e., species Lactobacillus_delbrueckii) in MPE. Integrated analysis correlated MPE-associated microbes with metabolites, such as phosphatidylcholine and metabolites involved in the citrate cycle pathway.CONCLUSION: Our results provide substantial evidence of a novel interplay between the pleural microbiota and metabolome, which was drastically perturbed in MPE in lung adenocarcinoma patients. Microbe-associated metabolites can be used for further therapeutic explorations.PMID:37309281 | DOI:10.1111/1759-7714.14988

J Invest Dermatol. 2023 May;143(5):864-867.e9. doi: 10.1016/j.jid.2022.10.010. Epub 2022 Oct 29.NO ABSTRACTPMID:37306380 | DOI:10.1016/j.jid.2022.10.010

Mol Metab. 2023 Jun 10:101752. doi: 10.1016/j.molmet.2023.101752. Online ahead of print.ABSTRACTBACKGROUND: Insulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin results in insulin resistance and to several metabolic and organ alterations. We have previously demonstrated that BAG3 regulates insulin secretion. Herein we explored the consequences of beta-cells specific BAG3 deficiency in an animal model.METHODS: We generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo.RESULTS: Beta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease.CONCLUSION: Altogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance.PMID:37308077 | DOI:10.1016/j.molmet.2023.101752

Exp Eye Res. 2023 Jun 10:109538. doi: 10.1016/j.exer.2023.109538. Online ahead of print.ABSTRACTDiabetic retinopathy (DR) is an important complication of diabetes mellitus and a prevalent blind-causing ophthalmic disease. Despite years of efforts, rapid and accurate diagnosis of DR remains a challenging task. Metabolomics has been used as a diagnostic tool for disease progression and therapy monitoring. In this study, retinal tissues were collected from diabetic mice and age-matched non-diabetic mice. An unbiased metabolic profiling was performed to identify altered metabolites and metabolic pathways in DR. 311 differential metabolites were identified between diabetic retinas and non-diabetic retinas under the criteria of variable importance in projection (VIP) > 1 and P < 0.05. These differential metabolites were highly enriched in purine metabolism, amino acid metabolism, glycerophospholipid metabolism, and pantaothenate and CoA biosynthesis. We then evaluated the sensitivity and specificity of purine metabolites as the candidate biomarkers for DR through the area under the receiver-operating characteristic curves (AUC-ROCs). Compared with other purine metabolites, adenosine, guanine, and inosine had higher sensitivity, specificity, and accuracy for DR prediction. In conclusion, this study sheds new light on the metabolic mechanism of DR, which can facilitate clinical diagnosis, therapy, and prognosis of DR in the future.PMID:37308049 | DOI:10.1016/j.exer.2023.109538

J Ethnopharmacol. 2023 Jun 10:116773. doi: 10.1016/j.jep.2023.116773. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with limited therapy. Renshen Pingfei Formula (RPFF), a classic Chinese medicine derivative formula, has been shown to exert therapeutic effects on IPF.AIM OF THE STUDY: The study aimed to explore the anti-pulmonary fibrosis mechanism of RPFF through network pharmacology, clinical plasma metabolomics, and in vitro experiment.METHODS: Network pharmacology was used to study the holistic pharmacological mechanism of RPFF in the treatment of IPF. The differential plasma metabolites for RPFF in the treatment of IPF were identified by untargeted metabolomics analysis. By integrated analysis of metabolomics and network pharmacology, the therapeutic target of RPFF for IPF and the corresponding herbal ingredients were identified. In addition, the effects of the main components of the formula, kaempferol and luteolin, which regulate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway were observed in vitro according to the orthogonal design.RESULTS: A total of 92 potential targets for RPFF in the treatment of IPF were obtained. The Drug-Ingredients-Disease Target network showed that PTGS2, ESR1, SCN5A, PPAR-γ, and PRSS1 were associated with more herbal ingredients. The protein-protein interaction (PPI) network identified the key targets of RPFF in IPF treatment, including IL6, VEGFA, PTGS2, PPAR-γ, and STAT3. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis acquired the main enriched pathways, and PPAR-γ involved in multiple signaling pathways, including the AMPK signaling pathway. Untargeted clinical metabolomics analysis revealed plasma metabolite variations in patients with IPF versus controls and before versus after RPFF treatment for patients with IPF. Six differential metabolites were explored as differential plasma metabolites for RPFF in IPF treatment. Combined with network pharmacology, a therapeutic target PPAR-γ of RPFF in IPF treatment and the corresponding herbal components were identified. Based on the orthogonal experimental design, the experiments showed that kaempferol and luteolin can decrease the mRNA and protein expression of α-smooth muscle actin (α-SMA), and the combination of lower dose can inhibit α-SMA mRNA and protein expression by promoting the AMPK/PPAR-γ pathway in transforming growth factor beta 1 (TGF-β1)-treated MRC-5 cells.CONCLUSIONS: This study revealed that the therapeutic effects of RPFF are due to multiple ingredients and have multiple targets and pathways, and PPAR-γ is one of therapeutic targets for RPPF in IPF and involved in the AMPK signaling pathway. Two ingredients of RPFF, kaempferol and luteolin, can inhibit fibroblast proliferation and the myofibroblast differentiation of TGF-β1, and exert a synergistic effect through AMPK/PPAR-γ pathway activation.PMID:37308028 | DOI:10.1016/j.jep.2023.116773

Sci Total Environ. 2023 Jun 10:164808. doi: 10.1016/j.scitotenv.2023.164808. Online ahead of print.ABSTRACTNanoplastics (NPs) induce nephrotoxicity in mammals, but an understanding of the potential mechanism or amelioration strategies is lacking. Herein, we established the polystyrene nanoplastics (PS-NPs, 100 nm)-induced nephrotoxicity murine model, and investigated the potential molecular mechanism of docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) alleviating effects. Based on the biochemical indices, H&E staining and kidney metabolomics, we found that PS-NPs did cause murine nephrotoxicity, mainly due to inflammation, oxidative stress, and lipid disturbance. DHA-PS administration alleviated these effects, mainly by decreasing renal levels of IL-6, IL-1β, TNF-α and MDA, increasing the level of IL-10, increasing the activities of SOD, GSH-Px, CAT, and alleviating lipid disturbance, mainly by modulating kidney glycerophospholipid metabolism, linoleic acid metabolism and the SIRT1-AMPK pathway. This is the first time that the amelioration effects of DHA-PS on PS-NPs-induced nephrotoxicity have been investigated from multiple perspectives, providing a potential mechanism of nephrotoxicity caused by PS-NPs.PMID:37308008 | DOI:10.1016/j.scitotenv.2023.164808

J Biol Chem. 2023 Jun 10:104909. doi: 10.1016/j.jbc.2023.104909. Online ahead of print.ABSTRACTSustainable TGF-β1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-β1 signaling remains unclear. In this study, we revealed that dietary folate restriction promoted the resolution of liver fibrosis in mice with nonalcoholic steatohepatitis (NASH). In activated hepatic stellate cells (HSCs), folate shifted toward mitochondrial metabolism to sustain TGF-β1 signaling. Mechanistically, nontargeted metabolomics screening identified that α-linolenic acid (ALA) is exhausted by mitochondrial folate metabolism in activated HSCs. Knocking down serine hydroxymethyltransferase 2 (SHMT2) increases the bioconversion of ALA to docosahexaenoic acid (DHA) which inhibits TGF-β1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in NASH mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/TGF-βR1 reproduction is a feedforward signaling to sustain profibrotic TGF-β1 signaling and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.PMID:37307917 | DOI:10.1016/j.jbc.2023.104909

J Transl Med. 2023 Jun 12;21(1):384. doi: 10.1186/s12967-023-04244-x.ABSTRACTBACKGROUND: We aimed to evaluate the impacts of metabolomic body mass index (metBMI) phenotypes on the risks of cardiovascular and ocular diseases outcomes.METHODS: This study included cohorts in UK and Guangzhou, China. By leveraging the serum metabolome and BMI data from UK Biobank, this study developed and validated a metBMI prediction model using a ridge regression model among 89,830 participants based on 249 metabolites. Five obesity phenotypes were obtained by metBMI and actual BMI (actBMI): normal weight (NW, metBMI of 18.5-24.9 kg/m2), overweight (OW, metBMI of 25-29.9 kg/m2), obesity (OB, metBMI ≥ 30 kg/m2), overestimated (OE, metBMI-actBMI > 5 kg/m2), and underestimated (UE, metBMI-actBMI < - 5 kg/m2). Additional participants from the Guangzhou Diabetes Eye Study (GDES) were included for validating the hypothesis. Outcomes included all-cause and cardiovascular (CVD)-cause mortality, as well as incident CVD (coronary heart disease, heart failure, myocardial infarction [MI], and stroke) and age-related eye diseases (age-related macular degeneration [AMD], cataracts, glaucoma, and diabetic retinopathy [DR]).RESULTS: In the UKB, although OE group had lower actBMI than NW group, the OE group had a significantly higher risk of all-cause mortality than those in NW prediction group (HR, 1.68; 95% CI 1.16-2.43). Similarly, the OE group had a 1.7-3.6-fold higher risk than their NW counterparts for cardiovascular mortality, heart failure, myocardial infarction, and coronary heart disease (all P < 0.05). In addition, risk of age-related macular denegation (HR, 1.96; 95% CI 1.02-3.77) was significantly higher in OE group. In the contrast, UE and OB groups showed similar risks of mortality and of cardiovascular and age-related eye diseases (all P > 0.05), though the UE group had significantly higher actBMI than OB group. In the GDES cohort, we further confirmed the potential of metabolic BMI (metBMI) fingerprints for risk stratification of cardiovascular diseases using a different metabolomic approach.CONCLUSIONS: Gaps of metBMI and actBMI identified novel metabolic subtypes, which exhibit distinctive cardiovascular and ocular risk profiles. The groups carrying obesity-related metabolites were at higher risk of mortality and morbidity than those with normal health metabolites. Metabolomics allowed for leveraging the future of diagnosis and management of 'healthily obese' and 'unhealthily lean' individuals.PMID:37308902 | DOI:10.1186/s12967-023-04244-x

BMC Genomics. 2023 Jun 12;24(1):319. doi: 10.1186/s12864-023-09410-5.ABSTRACTBACKGROUND: There is still more to learn about the pathobiology of COVID-19. A multi-omic approach offers a holistic view to better understand the mechanisms of COVID-19. We used state-of-the-art statistical learning methods to integrate genomics, metabolomics, proteomics, and lipidomics data obtained from 123 patients experiencing COVID-19 or COVID-19-like symptoms for the purpose of identifying molecular signatures and corresponding pathways associated with the disease.RESULTS: We constructed and validated molecular scores and evaluated their utility beyond clinical factors known to impact disease status and severity. We identified inflammation- and immune response-related pathways, and other pathways, providing insights into possible consequences of the disease.CONCLUSIONS: The molecular scores we derived were strongly associated with disease status and severity and can be used to identify individuals at a higher risk for developing severe disease. These findings have the potential to provide further, and needed, insights into why certain individuals develop worse outcomes.PMID:37308820 | DOI:10.1186/s12864-023-09410-5

Diabetologia. 2023 Jun 13. doi: 10.1007/s00125-023-05943-2. Online ahead of print.ABSTRACTAIMS/HYPOTHESIS: This study aimed to elucidate the aetiological role of plasma proteins in glucose metabolism and type 2 diabetes development.METHODS: We measured 233 proteins at baseline in 1653 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort study (median follow-up time: 13.5 years). We used logistic regression in the cross-sectional analysis (n=1300), and Cox regression accounting for interval-censored data in the longitudinal analysis (n=1143). We further applied two-level growth models to investigate associations with repeatedly measured traits (fasting glucose, 2 h glucose, fasting insulin, HOMA-B, HOMA-IR, HbA1c), and two-sample Mendelian randomisation analysis to investigate causal associations. Moreover, we built prediction models using priority-Lasso on top of Framingham-Offspring Risk Score components and evaluated the prediction accuracy through AUC.RESULTS: We identified 14, 24 and four proteins associated with prevalent prediabetes (i.e. impaired glucose tolerance and/or impaired fasting glucose), prevalent newly diagnosed type 2 diabetes and incident type 2 diabetes, respectively (28 overlapping proteins). Of these, IL-17D, IL-18 receptor 1, carbonic anhydrase-5A, IL-1 receptor type 2 (IL-1RT2) and matrix extracellular phosphoglycoprotein were novel candidates. IGF binding protein 2 (IGFBP2), lipoprotein lipase (LPL) and paraoxonase 3 (PON3) were inversely associated while fibroblast growth factor 21 was positively associated with incident type 2 diabetes. LPL was longitudinally linked with change in glucose-related traits, while IGFBP2 and PON3 were linked with changes in both insulin- and glucose-related traits. Mendelian randomisation analysis suggested causal effects of LPL on type 2 diabetes and fasting insulin. The simultaneous addition of 12 priority-Lasso-selected biomarkers (IGFBP2, IL-18, IL-17D, complement component C1q receptor, V-set and immunoglobulin domain-containing protein 2, IL-1RT2, LPL, CUB domain-containing protein 1, vascular endothelial growth factor D, PON3, C-C motif chemokine 4 and tartrate-resistant acid phosphatase type 5) significantly improved the predictive performance (ΔAUC 0.0219; 95% CI 0.0052, 0.0624).CONCLUSIONS/INTERPRETATION: We identified new candidates involved in the development of derangements in glucose metabolism and type 2 diabetes and confirmed previously reported proteins. Our findings underscore the importance of proteins in the pathogenesis of type 2 diabetes and the identified putative proteins can function as potential pharmacological targets for diabetes treatment and prevention.PMID:37308750 | DOI:10.1007/s00125-023-05943-2

J Cancer Res Clin Oncol. 2023 Jun 12. doi: 10.1007/s00432-023-04872-2. Online ahead of print.ABSTRACTINTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is among the most common cancers in the world with a low survival rate and common diagnosis at late stages. Deubiquitination of proteins is involved in tumor growth, metastasis, apoptosis, and immunosuppressive pathways. The impact of the ubiquitin-specific protease (USP4) on survival was only scarcely investigated so far. The goal of our research was to analyze the association of USP4 expression with prognosis and clinicopathological features in HNSCC.METHODS: USP4 mRNA levels were derived from The Cancer Genome Atlas (TCGA) for a cohort of 510 patients. Protein expression of USP4 was analyzed by immunohistochemistry in a second cohort of 113 patients. Associations between USP4 levels and overall survival, disease-free survival and clinicopathological data were analyzed.RESULTS: High levels of USP4 mRNA were associated with prolonged overall survival in univariable analysis. There was no more association with survival after correction for the confounders HPV, stage and smoker status. High USP4 mRNA levels were linked to a lower T-stage, the patient's age at diagnosis, and a positive HPV status. USP4 protein levels were not associated with prognosis or other features.CONCLUSION: Since high USP4 mRNA was not an independent prognostic marker, we assume that the association is a result of the correlation of high USP4 mRNA with an HPV-positive status. Therefore, further investigation of USP4 mRNA and its association with the HPV status of HNSCC patients is warranted.PMID:37308746 | DOI:10.1007/s00432-023-04872-2

Sci Rep. 2023 Jun 12;13(1):9500. doi: 10.1038/s41598-023-36261-7.ABSTRACTChinese cordyceps was one of most valuable traditional Chinese medicine fungi. To elucidate the molecular mechanisms related to energy supply mechanism involved in the initiation and formation of primordium in Chinese cordyceps, we performed the integrated metabolomic and transcriptomic analyses of it at pre-primordium period, primordium germination period and after-primordium period, respectively. Transcriptome analysis showed that many genes related to 'starch and sucrose metabolism', 'fructose and mannose metabolism', 'linoleic acid metabolism', 'fatty acids degradation' and 'glycerophospholipid metabolism' were highly up-regulated at primordium germination period. Metabolomic analysis showed many metabolites regulated by these genes in these metabolism pathways were also markedly accumulated at this period. Consequently, we inferred that carbohydrate metabolism and β-oxidation pathway of palmitic acid and linoleic acid worked cooperatively to generate enough acyl-CoA, and then entered TCA cycle to provide energy for fruiting body initiation. Overall, our finding provided important information for further exploring the energy metabolic mechanisms of realizing the industrialization of Chinese cordyceps artificial cultivation.PMID:37308669 | DOI:10.1038/s41598-023-36261-7

Cell Death Discov. 2023 Jun 12;9(1):182. doi: 10.1038/s41420-023-01475-1.ABSTRACTMetabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.PMID:37308557 | DOI:10.1038/s41420-023-01475-1

Sci Rep. 2023 Jun 12;13(1):9529. doi: 10.1038/s41598-023-36618-y.ABSTRACTHeterosis contributes greatly to the worldwide agricultural yield. However, the molecular mechanism underlying heterosis remains unclear. This study took advantage of Arabidopsis intraspecific hybrids to identify heterosis-related metabolites. Forty-six intraspecific hybrids were used to examine parental effects on seed area and germination time. The degree of heterosis was evaluated based on biomass: combinations showing high heterosis of F1 hybrids exhibited a biomass increase from 6.1 to 44% over the better parent value (BPV), whereas that of the low- and no-heterosis hybrids ranged from - 19.8 to 9.8% over the BPV. Metabolomics analyses of F1 hybrids with high heterosis and those with low one suggested that changes in TCA cycle intermediates are key factors that control growth. Notably, higher fumarate/malate ratios were observed in the high heterosis F1 hybrids, suggesting they provide metabolic support associated with the increased biomass. These hybrids may produce more energy-intensive biomass by speeding up the efficiency of TCA fluxes. However, the expression levels of TCA-process-related genes in F1 hybrids were not associated with the intensity of heterosis, suggesting that the post-transcriptional or post-translational regulation of these genes may affect the productivity of the intermediates in the TCA cycle.PMID:37308530 | DOI:10.1038/s41598-023-36618-y