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

Integrating Data Mining with Metabolomics to Analyze the Mechanism of the "Pearl-Borneol" Pair in Promoting Healing of Diabetic Wounds

Fri, 12/07/2024 - 12:00
Endocr Metab Immune Disord Drug Targets. 2024 Jul 11. doi: 10.2174/0118715303295707240614060314. Online ahead of print.ABSTRACTINTRODUCTION: Chronic diabetic wounds pose a significant threat to the health of diabetic patients, representing severe and enduring complications. Globally, an estimated 2.5% to 15% of the annual health budget is associated with diabetes, with diabetic wounds accounting for a substantial share. Exploring new therapeutic agents and approaches to address delayed and impaired wound healing in diabetes becomes imperative. Traditional Chinese medicine (TCM) has a long history and remarkable efficacy in treating chronic wound healing. In this study, all topically applied proprietary Chinese medicines (pCMs) for wound healing officially approved by the National Medical Products Administration (NMPA) were collected from the NMPA TCM database. Data mining was employed to obtain a high-frequency TCM ingredients pair, Pearl-Borneol (1:1).METHOD: This study investigated the effect and molecular mechanism of the Pearl-Borneol pair on the healing of diabetic wounds by animal experiments and metabolomics. The results from animal experiments showed that the Pearl-Borneol pair significantly accelerated diabetic wound healing, exhibiting a more potent effect than the Pearl or Borneol treatment alone. Meanwhile, the metabolomics analysis identified significant differences in metabolic profiles in wounds between the model and normal groups, indicating that diabetic wounds had distinct metabolic characteristics from normal wounds. Moreover, Vaseline-treated wounds exhibited similar metabolic profiles to the wounds from the model group, suggesting that Vaseline might have a negligible impact on diabetic wound metabolism. In addition, wounds treated with Pearl, Borneol, and Pearl-Borneol pair displayed significantly different metabolic profiles from Vaseline-treated wounds, signifying the influence of these treatments on wound metabolism. Subsequent enrichment analysis of the metabolic pathway highlighted the involvement of the arginine metabolic pathway, closely associated with diabetic wounds, in the healing process under Pearl- Borneol pair treatment. Further analysis revealed elevated levels of arginine and citrulline, coupled with reduced nitric oxide (NO) in both the model and Vaseline-treated wounds compared to normal wounds, pointing to impaired arginine utilization in diabetic wounds. Interestingly, treatment with Pearl and Pearl-Borneol pair lowered arginine and citrulline levels while increasing NO content, suggesting that these treatments may promote the catabolism of arginine to generate NO, thereby facilitating faster wound closure. Additionally, borneol alone significantly elevated NO content in wounds, potentially due to its ability to directly reduce nitrates/nitrites to NO. Oxidative stress is a defining characteristic of impaired metabolism in diabetic wounds.RESULTS: The result showed that both Pearl and Pearl-Borneol pair decreased the oxidative stress biomarker methionine sulfoxide level in diabetic wounds compared to those treated with Vaseline, indicating that Pearl alone or combined with Borneol may enhance the oxidative stress microenvironment in diabetic wounds.CONCLUSION: In summary, the findings validate the effectiveness of the Pearl-Borneol pair in accelerating the healing of diabetic wounds, with effects on reducing oxidative stress, enhancing arginine metabolism, and increasing NO generation, providing a mechanistic basis for this therapeutic approach.PMID:38994612 | DOI:10.2174/0118715303295707240614060314

The impact of surgical treatment for deep endometriosis: metabolic profile, quality of life and psychological aspects

Fri, 12/07/2024 - 12:00
Rev Bras Ginecol Obstet. 2024 Jun 27;46:e-rbgo42. doi: 10.61622/rbgo/2024rbgo42. eCollection 2024.ABSTRACTOBJECTIVE: To evaluate the effects of surgical treatment of deep endometriosis on the metabolic profile, quality of life and psychological aspects.METHODS: Prospective observational study, carried out with women of reproductive age diagnosed with deep endometriosis, treated in a specialized outpatient clinic, from October/2020 to September/2022, at a University Hospital in Fortaleza - Brazil. Standardized questionnaires were applied to collect data on quality of life and mental health, in addition to laboratory tests to evaluate dyslipidemia and dysglycemia, at two moments, preoperatively and six months after surgery. The results were presented using tables, averages and percentages.RESULTS: Thirty women with an average age of 38.5 years were evaluated. Seven quality of life domains showed improved scores: pain, control and impotence, well-being, social support, self-image, work life and sexual relations after surgery (ES ≥ 0.80). There was an improvement in mental health status with a significant reduction in anxiety and depression postoperatively. With the metabolic profile, all average levels were lower after surgery: total cholesterol 8.2% lower, LDL 12.8% lower, triglycerides 10.9% lower, and fasting blood glucose 7.3% lower (p < 0.001).CONCLUSION: Surgical treatment of deep endometriosis improved the quality of life and psychological aspects of patients. The lipid profile of patients after laparoscopy was favorable when compared to the preoperative lipid profile.PMID:38994463 | PMC:PMC11239215 | DOI:10.61622/rbgo/2024rbgo42

Metabolome profiling and transcriptome analysis unveiling the crucial role of magnesium transport system for magnesium homeostasis in tea plants

Fri, 12/07/2024 - 12:00
Hortic Res. 2024 Jun 3;11(7):uhae152. doi: 10.1093/hr/uhae152. eCollection 2024 Jul.ABSTRACTMagnesium (Mg2+) is a crucial nutrient for the growth and development of Camellia sinensis and is closely related to the quality of tea. However, the underlying mechanisms responding to low-Mg 2+ stress in tea plants remain largely unknown. In this study, photosynthetic parameters, metabolomics, and transcriptomics were utilized to explore the potential effects of low Mg2+ on the growth and metabolism of C. sinensis. Low-Mg2+ treatment increased the ratio of shoot dry weight to root dry weight but decreased the photosynthesis of C. sinensis. Forty and thirty metabolites were impacted by Mg2+ shortage in C. sinensis shoots and roots, respectively. Integrated transcriptome and metabolome analyses revealed the possible reasons for the decreased contents of chlorophyll and catechins and the increased theanine content in C. sinensis roots. Weighted gene co-expression network analysis indicated that the Mg2+ transport system was essential in the regulation of Mg2+ homeostasis in C. sinensis, in which CsMGT5 was identified to be the key regulator according to CsMGT5-overexpressing and complementary assays in Arabidopsis thaliana. Moreover, silencing of CsMGT5 in vivo reduced the content of chlorophyll in C. sinensis shoots. In addition, CsMGT5 might collaborate with ammonium transporters to keep the amino acid content steady, suggesting its potential application for tea quality improvement. All these findings demonstrate the key roles of CsMGTs for Mg2+ homeostasis in C. sinensis, providing a theoretical basis for Mg2+ efficient utilization in plants.PMID:38994447 | PMC:PMC11237192 | DOI:10.1093/hr/uhae152

The mammosphere-derived epithelial cell secretome modulates neutrophil functions in the bovine model

Fri, 12/07/2024 - 12:00
Front Immunol. 2024 Jun 27;15:1367432. doi: 10.3389/fimmu.2024.1367432. eCollection 2024.ABSTRACTBACKGROUND: Innovative therapies against bacterial infections are needed. One approach is to focus on host-directed immunotherapy (HDT), with treatments that exploit natural processes of the host immune system. The goals of this type of therapy are to stimulate protective immunity while minimizing inflammation-induced tissue damage. We use non-traditional large animal models to explore the potential of the mammosphere-derived epithelial cell (MDEC) secretome, consisting of all bioactive factors released by the cells, to modulate host immune functions. MDEC cultures are enriched for mammary stem and progenitor cells and can be generated from virtually any mammal. We previously demonstrated that the bovine MDEC secretome, collected and delivered as conditioned medium (CM), inhibits the growth of bacteria in vitro and stimulates functions related to tissue repair in cultured endothelial and epithelial cells.METHODS: The immunomodulatory effects of the bovine MDEC secretome on bovine neutrophils, an innate immune cell type critical for resolving bacterial infections, were determined in vitro using functional assays. The effects of MDEC CM on neutrophil molecular pathways were explored by evaluating the production of specific cytokines by neutrophils and examining global gene expression patterns in MDEC CM-treated neutrophils. Enzyme linked immunosorbent assays were used to determine the concentrations of select proteins in MDEC CM and siRNAs were used to reduce the expression of specific MDEC-secreted proteins, allowing for the identification of bioactive factors modulating neutrophil functions.RESULTS: Neutrophils exposed to MDEC secretome exhibited increased chemotaxis and phagocytosis and decreased intracellular reactive oxygen species and extracellular trap formation, when compared to neutrophils exposed to control medium. C-X-C motif chemokine 6, superoxide dismutase, peroxiredoxin-2, and catalase, each present in the bovine MDEC secretome, were found to modulate neutrophil functions.CONCLUSION: The MDEC secretome administered to treat bacterial infections may increase neutrophil recruitment to the site of infection, stimulate pathogen phagocytosis by neutrophils, and reduce neutrophil-produced ROS accumulation. As a result, pathogen clearance might be improved and local inflammation and tissue damage reduced.PMID:38994364 | PMC:PMC11236729 | DOI:10.3389/fimmu.2024.1367432

Analysis of metabolic characteristics of metabolic syndrome in elderly patients with gastric cancer by non-targeted metabolomics

Fri, 12/07/2024 - 12:00
World J Gastrointest Oncol. 2024 Jun 15;16(6):2419-2428. doi: 10.4251/wjgo.v16.i6.2419.ABSTRACTBACKGROUND: The relationship between metabolic syndrome (MetS) and gastric cancer (GC), which is a common metabolic disease, has attracted much attention. However, the specific metabolic characteristics of MetS in elderly patients with GC remain unclear.AIM: To investigate the differentially abundant metabolites and metabolic pathways between preoperative frailty and MetS in elderly patients with GC based on nontargeted metabolomics techniques.METHODS: In this study, 125 patients with nonfrail nonmeal GC were selected as the control group, and 50 patients with GC in the frail group were selected as the frail group. Sixty-five patients with GC combined with MetS alone were included in the MetS group, and 50 patients with GC combined with MetS were included in the MetS group. Nontargeted metabolomics techniques were used to measure plasma metabolite levels by ultrahigh-performance liquid chromatography-mass spectrometry. Multivariate statistical analysis was performed by principal component analysis, orthogonal partial least squares, pattern recognition analysis, cluster analysis, and metabolic pathway annotation.RESULTS: A total of 125 different metabolites, including amino acids, glycerophospholipids, sphingolipids, fatty acids, sugars, nucleosides and nucleotides, and acidic compounds, were identified via nontargeted metabolomics techniques. Compared with those in the control group, there were 41, 32, and 52 different metabolites in the MetS group, the debilitated group, and the combined group, respectively. Lipid metabolites were significantly increased in the MetS group. In the weak group, amino acids and most glycerol phospholipid metabolites decreased significantly, and fatty acids and sphingosine increased significantly. The combined group was characterized by significantly increased levels of nucleotide metabolites and acidic compounds. The alanine, aspartic acid, and glutamate metabolic pathways were obviously enriched in the asthenic group, and the glycerol and phospholipid metabolic pathways were obviously enriched in the combined group.CONCLUSION: Elderly GC patients with simple frailty, simple combined MetS, and frailty combined with MetS have different metabolic characteristics, among which amino acid and glycerophospholipid metabolite levels are significantly lower in frail elderly GC patients, and comprehensive supplementation of fat and protein should be considered. Many kinds of metabolites, such as amino acids, lipids, nucleotides, and acidic compounds, are abnormally abundant in patients with MetS combined with fthenia, which may be related to tumor-related metabolic disorders.PMID:38994147 | PMC:PMC11236236 | DOI:10.4251/wjgo.v16.i6.2419

<em>Fusobacterium</em> species are distinctly associated with patients with Lynch syndrome colorectal cancer

Fri, 12/07/2024 - 12:00
iScience. 2024 Jun 4;27(7):110181. doi: 10.1016/j.isci.2024.110181. eCollection 2024 Jul 19.ABSTRACTAccumulating evidence demonstrates clear correlation between the gut microbiota and sporadic colorectal cancer (CRC). Despite this, there is limited understanding of the association between the gut microbiota and CRC in Lynch Syndrome (LS), a hereditary type of CRC. Here, we analyzed fecal shotgun metagenomic and targeted metabolomic of 71 Japanese LS subjects. A previously published Japanese sporadic CRC cohort, which includes non-LS controls, was utilized as a non-LS cohort (n = 437). LS subjects exhibited reduced microbial diversity and low-Faecalibacterium enterotypes compared to non-LS. Patients with LS-CRC had higher levels of Fusobacterium nucleatum and fap2. Differential fecal metabolites and functional genes suggest heightened degradation of lysine and arginine in LS-CRC. A comparison between LS and non-LS subjects prior to adenoma formation revealed distinct fecal metabolites of LS subjects. These findings suggest that the gut microbiota plays a more responsive role in CRC tumorigenesis in patients with LS than those without LS.PMID:38993678 | PMC:PMC11237946 | DOI:10.1016/j.isci.2024.110181

Branch Chain Amino Acid Metabolism Promotes Brain Metastasis of NSCLC through EMT Occurrence by Regulating ALKBH5 activity

Fri, 12/07/2024 - 12:00
Int J Biol Sci. 2024 Jun 29;20(9):3285-3301. doi: 10.7150/ijbs.85672. eCollection 2024.ABSTRACTMetabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.PMID:38993559 | PMC:PMC11234221 | DOI:10.7150/ijbs.85672

Proteomic and metabolomic profiling of methicillin resistant versus methicillin sensitive Staphylococcus aureus using a simultaneous extraction protocol

Fri, 12/07/2024 - 12:00
Front Microbiol. 2024 Jun 26;15:1402796. doi: 10.3389/fmicb.2024.1402796. eCollection 2024.ABSTRACTBACKGROUND: Understanding the biology of methicillin resistant Staphylococcus aureus (MRSA) is crucial to unlocking insights for new targets in our fight against this antimicrobial resistant priority pathogen. Although proteomics and metabolomic profiling offer the potential to elucidating such biological markers, reports of methodological approaches for carrying this out in S. aureus isolates remain limited. We describe the use of a dual-functionality methanol extraction method for the concurrent extraction of protein and metabolites from S. aureus and report on the comparative analysis of the proteomic and metabolomic profiles of MRSA versus methicillin sensitive S. aureus (MSSA).METHODS: Bacterial reference strains MRSA ATCC43300 and MSSA ATCC25923 were used. The conventional urea methodology was used for protein extraction and a methanol based method was used for concurrent proteins and metabolites extraction. Proteomic and metabolomic profiling was carried out using TimsTOF mass spectrometry. Data processing was carried out using the MaxQuant version 2.1.4.0.RESULTS: This study represents the first report on the utilization of the methanol extraction method for concurrent protein and metabolite extraction in Gram positive bacteria. Our findings demonstrate good performance of the method for the dual extraction of proteins and metabolites from S. aureus with demonstration of reproducibility. Comparison of MRSA and MSSA strains revealed 407 proteins with significantly different expression levels. Enrichment analysis of those proteins revealed distinct pathways involved in fatty acid degradation, metabolism and beta-lactam resistance. Penicillin-binding protein PBP2a, the key determinant of MRSA resistance, exhibited distinct expression patterns in MRSA isolates. Metabolomic analysis identified 146 metabolites with only one exclusive to the MRSA. The enriched pathways identified were related to arginine metabolism and biosynthesis.CONCLUSION: Our findings demonstrate the effectiveness of the methanol-based dual-extraction method, providing simultaneous insights into the proteomic and metabolomic landscapes of S. aureus strains. These findings demonstrate the utility of proteomic and metabolomic profiling for elucidating the biological basis of antimicrobial resistance.PMID:38993491 | PMC:PMC11238212 | DOI:10.3389/fmicb.2024.1402796

Finding the best predictive model for hypertensive depression in older adults based on machine learning and metabolomics research

Fri, 12/07/2024 - 12:00
Front Psychiatry. 2024 Jun 27;15:1370602. doi: 10.3389/fpsyt.2024.1370602. eCollection 2024.ABSTRACTOBJECTIVE: Depression is a common comorbidity in hypertensive older adults, yet depression is more difficult to diagnose correctly. Our goal is to find predictive models of depression in hypertensive patients using a combination of various machine learning (ML) methods and metabolomics.METHODS: Methods We recruited 379 elderly people aged ≥65 years from the Chinese community. Plasma samples were collected and assayed by gas chromatography/liquid chromatography-mass spectrometry (GC/LC-MS). Orthogonal partial least squares discriminant analysis (OPLS-DA), volcano diagrams and thermograms were used to distinguish metabolites. The attribute discriminators CfsSubsetEval combined with search method BestFirst in WEKA software was used to find the best predicted metabolite combinations, and then 24 classification methods with 10-fold cross-validation were used for prediction.RESULTS: 34 individuals were considered hypertensive combined with depression according to our criteria, and 34 subjects with hypertension only were matched according to age and sex. 19 metabolites by GC-MS and 65 metabolites by LC-MS contributed significantly to the differentiation between the depressed and non-depressed cohorts, with a VIP value of more than 1 and a P value of less than 0.05. There were multiple metabolic pathway alterations. The metabolite combinations screened with WEKA for optimal diagnostic value included 12 metabolites. The machine learning methods with AUC values greater than 0.9 were bayesNet and random forests, and their other evaluation measures are also better.CONCLUSION: Altered metabolites and metabolic pathways are present in older adults with hypertension combined with depression. Methods using metabolomics and machine learning performed quite well in predicting depression in hypertensive older adults, contributing to further clinical research.PMID:38993388 | PMC:PMC11236531 | DOI:10.3389/fpsyt.2024.1370602

Association between HLA alleles and haplotypes with age at diagnosis of type 1 diabetes in an admixed Brazilian population: A nationwide study

Fri, 12/07/2024 - 12:00
HLA. 2024 Jul;104(1):e15574. doi: 10.1111/tan.15574.ABSTRACTTo investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.PMID:38993161 | DOI:10.1111/tan.15574

PCMD: A multilevel comparison database of intra- and cross-species metabolic profiling in 530 plant species

Fri, 12/07/2024 - 12:00
Plant Commun. 2024 Jul 11:101038. doi: 10.1016/j.xplc.2024.101038. Online ahead of print.ABSTRACTComparative metabolomics plays a crucial role in investigating gene function, exploring metabolite evolution, and accelerating crop genetic improvement. However, a systematic platform for comparing intra- and cross-species metabolites is currently lacking. Here, we report the Plant Comparative Metabolome Database (PCMD; http://yanglab.hzau.edu.cn/PCMD), a multilevel comparison database based on predicted metabolic profiles in 530 plant species. PCMD serves as a platform for comparing metabolite characteristics at various levels, including species, metabolites, pathways, and biological taxonomy. The database also provides a series of user-friendly online tools, such as Species-comparison, Metabolites-enrichment, and ID conversion, enabling users to perform comparisons and enrichment analyses of metabolites across different species. In addition, PCMD establishes a unified system based on existing metabolite-related databases by standardizing metabolite numbering. PCMD is the most species-rich comparative plant metabolomics database currently available, and a case study demonstrated its capability to provide new insights into understanding plant metabolic diversity.PMID:38993115 | DOI:10.1016/j.xplc.2024.101038

Metabolic Profiling of Cochlear Organoids Identifies α-Ketoglutarate and NAD<sup>+</sup> as Limiting Factors for Hair Cell Reprogramming

Fri, 12/07/2024 - 12:00
Adv Sci (Weinh). 2024 Jul 11:e2308032. doi: 10.1002/advs.202308032. Online ahead of print.ABSTRACTCochlear hair cells are the sensory cells responsible for transduction of acoustic signals. In mammals, damaged hair cells do not regenerate, resulting in permanent hearing loss. Reprogramming of the surrounding supporting cells to functional hair cells represent a novel strategy to hearing restoration. However, cellular processes governing the efficient and functional hair cell reprogramming are not completely understood. Employing the mouse cochlear organoid system, detailed metabolomic characterizations of the expanding and differentiating organoids are performed. It is found that hair cell differentiation is associated with increased mitochondrial electron transport chain (ETC) activity and reactive oxidative species generation. Transcriptome and metabolome analyses indicate reduced expression of oxidoreductases and tricyclic acid (TCA) cycle metabolites. The metabolic decoupling between ETC and TCA cycle limits the availability of the key metabolic cofactors, α-ketoglutarate (α-KG) and nicotinamide adenine dinucleotide (NAD+). Reduced expression of NAD+ in cochlear supporting cells by PGC1α deficiency further impairs hair cell reprogramming, while supplementation of α-KG and NAD+ promotes hair cell reprogramming both in vitro and in vivo. These findings reveal metabolic rewiring as a central cellular process during hair cell differentiation, and highlight the insufficiency of key metabolites as a metabolic barrier for efficient hair cell reprogramming.PMID:38993037 | DOI:10.1002/advs.202308032

Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors

Thu, 11/07/2024 - 12:00
J Immunother Cancer. 2024 Jul 11;12(7):e009399. doi: 10.1136/jitc-2024-009399.ABSTRACTBACKGROUND: Metabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related adverse events (irAEs) occurrence. However, there is a lack of reliable metabolic biomarkers to predict irAEs. This study aims to explore the potential metabolic biomarkers to predict risk of irAEs and to investigate the association of plasma metabolites level with survival in patients with lung cancer receiving PD-1/PD-L1 inhibitor treatment.METHODS: The study collected 170 plasmas of 85 patients with lung cancer who received immune checkpoint inhibitors (ICIs) treatment. 58 plasma samples of 29 patients with irAEs were collected before ICIs treatment and at the onset of irAEs. 112 plasma samples of 56 patients who did not develop irAEs were collected before ICIs treatment and plasma matched by treatment cycles to onset of irAEs patients. Untargeted metabolomics analysis was used to identify the differential metabolites before initiating ICIs treatment and during the process that development of irAEs. Kaplan-Meier curves analysis was used to detect the associations of plasma metabolites level with survival of patients with lung cancer.RESULTS: A total of 24 differential metabolites were identified to predict the occurrence of irAEs. Baseline acylcarnitines and steroids levels are significantly higher in patients with irAEs, and the model of eight acylcarnitine and six steroid metabolites baseline level predicts irAEs occurrence with area under the curve of 0.91. Patients with lower concentration of baseline decenoylcarnitine(AcCa(10:1) 2, decenoylcarnitine(AcCa(10:1) 3 and hexanoylcarnitine(AcCa(6:0) in plasma would have better overall survival (OS). Moreover, 52 differential metabolites were identified related to irAEs during ICIs treatment, dehydroepiandrosterone sulfate, corticoserone, cortisol, thyroxine and sphinganine 1-phaosphate were significantly decreased in irAEs group while oxoglutaric acid and taurocholic acid were significantly increased in irAEs group.CONCLUSIONS: High levels of acylcarnitines and steroid hormone metabolites might be risk factor to development of irAEs, and levels of decenoylcarnitine (AcCa(10:1) 2, decenoylcarnitine (AcCa(10:1) 3 and hexanoylcarnitine (AcCa(6:0) could be used to predict OS for patients with lung cancer received ICIs treatment.PMID:38991728 | DOI:10.1136/jitc-2024-009399

Arbuscular mycorrhizal fungi regulate amino acid metabolism, phytohormones and glycolysis pathway to promote the growth of Suaeda salsa under combined Cd and NaCl stresses

Thu, 11/07/2024 - 12:00
Plant Physiol Biochem. 2024 Jul 8;214:108921. doi: 10.1016/j.plaphy.2024.108921. Online ahead of print.ABSTRACTThe use of halophytes in conjunction with arbuscular mycorrhizal (AM) fungi has been found to enhance the removal efficacy of heavy metals and salts in heavy metals contaminated saline soil. The mechanisms of AM fungi on promoting halophyte growth and regulating metabolism remain unclear. In this study, combinations of 0 g kg-1 NaCl and 3 mg kg-1 Cd (S0Cd3), 6 g kg-1 NaCl and 3 mg kg-1 Cd (S6Cd3), and 12 g kg-1 NaCl and 3 mg kg-1 Cd (S12Cd3) were employed to explore the impact of Funneliformis mosseae on the growth and metabolism of Suaeda salsa. The results showed that AM fungi increased the biomass and the P, K+, Ca2+, and Mg2+ accumulations, reduced the Cd and Na+ concentrations in S0Cd3 and S6Cd3, and increased the Cd concentrations in S12Cd3. AM fungi inoculation reduced the Cd and Na+ transfer factors and increased the Cd and Na+ accumulations in S6Cd3. The metabolomics of S6Cd3 showed that AM fungi upregulated the expression of 5-hydroxy-L-tryptophan and 3-indoleacid acid in tryptophan metabolism, potentially acting as crucial antioxidants enabling plants to actively cope with abiotic stresses. AM fungi upregulated the expression of arbutin in glycolysis process, enhancing the plants' osmoregulation capacity. AM fungi upregulated the expression of 2-hydroxycinnamic acid in phenylalanine metabolism and dopaquinone in tyrosine metabolism. These two metabolites help effectively remove reactive oxygen species. Correspondingly, AM fungi decreased MDA content and increased soluble sugar content. These results indicate that AM fungi improve the stress resistance of S. salsa by increasing nutrient uptake and regulating physiological and metabolic changes.PMID:38991594 | DOI:10.1016/j.plaphy.2024.108921

Melatonin differentially refines the metabolome to improve seed formation during grain developmental stages and enhances yield in two contrasting rice cultivars, grown in arsenic-contaminated soil

Thu, 11/07/2024 - 12:00
Plant Physiol Biochem. 2024 Jun 22;214:108849. doi: 10.1016/j.plaphy.2024.108849. Online ahead of print.ABSTRACTThe manuscript revealed the ameliorative effects of exogenous melatonin in two distinct reproductive stages, i.e., developing grains (20 days after pollination) and matured grains (40 days after pollination) in two contrasting indica rice genotypes, viz., Khitish (arsenic-susceptible) and Muktashri (arsenic-tolerant), irrigated with arsenic-contaminated water throughout their life-cycle. Melatonin administration improved yield-related parameters like rachis length, primary and secondary branch length, number of grains per panicle, number of filled and empty grains per panicle, grain length and breadth and 1000-grain per weight. Expression of GW2, which negatively regulates grain development, was suppressed, along with concomitant induction of positive regulators like GIF1, DEP1 and SPL14 in both Khitish and Muktashri. Melatonin lowered arsenic bioaccumulation in grains and tissue biomass, more effectively in Khitish. Unregulated production of reactive oxygen species, leading to cellular necrosis caused by arsenic, was reversed in presence of melatonin. Endogenous melatonin level was stimulated due to up-regulation of the key biosynthetic genes, SNAT and ASMT. Melatonin enhanced the production of diverse antioxidants like anthocyanins, flavonoids, total phenolics and ascorbic acid and also heightened the production of thiol-metabolites (cysteine, reduced glutathione, non-protein thiols and phytochelatin), ensuring effective chelation and arsenic detoxification. Altogether, our observation, supported by principal component analysis, proved that melatonin re-programs the antioxidative metabolome to enhance plant resilience against arsenic stress to mitigate oxidative damages and reduce arsenic translocation from the soil to tissue biomass and edible grains.PMID:38991592 | DOI:10.1016/j.plaphy.2024.108849

Aspects of quercetin stability and its liposomal enhancement in yellow onion skin extracts

Thu, 11/07/2024 - 12:00
Food Chem. 2024 Jul 5;459:140347. doi: 10.1016/j.foodchem.2024.140347. Online ahead of print.ABSTRACTQuercetin is a flavonoid that occurs in many types of fruit and vegetables and is stable for no longer than 4.5 h in the investigated pH range (6.0-8.0), even at 4 °C in the dark. At higher temperatures, the degradation/oxidation process is much faster. Simple but effective proliposomal encapsulation was used to protect the quercetin from environmental conditions such as pH. With this approach, 65 to 90% of pure quercetin and quercetin-rich onion extract was kept after >60 days under conditions that favoured its oxidation (pH 7.4). In addition, the encapsulated quercetin decreases the lipid peroxidation induced by pulsed UV light by >50%. At a mass ratio of 1:100 quercetin to lipids (w/w), the liposomes remained intact in solutions for six months. Quercetin in lipid bilayers simultaneously protects the unsaturated lipids from peroxidation.PMID:38991436 | DOI:10.1016/j.foodchem.2024.140347

Copper toxicity in the liver of broiler chicken: insights from metabolomics and AMPK-mTOR mediated autophagy perspective

Thu, 11/07/2024 - 12:00
Poult Sci. 2024 Jun 22;103(9):104011. doi: 10.1016/j.psj.2024.104011. Online ahead of print.ABSTRACTExposure to copper (Cu) has been associated with metabolic disorders in animals and humans, but the underlying mechanism remains unclear. One-day-old broiler chickens, numbering a total of 192, were nourished with dietary intakes that contained varying concentrations of Cu, specifically 11, 110, 220, and 330 mg/kg of Cu, for a period extending over a duration of 7 wk. As a result of the study, Cu exposure resulted in vacuolization, fragmentation of mitochondria cristae, and the increase of autophagosomes in hepatocytes. Metabolomics analysis illustrated that Cu caused a total of 59 different metabolites in liver, predominantly associated with the glycerophospholipid metabolic pathway, leading to metabolic disruption. Moreover, high-Cu diet markedly reduced the levels of AMPKα1, p-AMPKα1, mTOR, and p-mTOR and enhanced the expression levels of the autophagy-related factors (Atg5, Dynein, Beclin1, and LC3-II). Overall, Cu exposure caused chicken liver injury and resulted in disturbed metabolic processes and mediated autophagy primarily through the AMPK-mTOR axis.PMID:38991386 | DOI:10.1016/j.psj.2024.104011

Integrative metabolomics and transcriptomics analysis revealed specific genes and metabolites affecting meat quality of chickens under different rearing systems

Thu, 11/07/2024 - 12:00
Poult Sci. 2024 Jun 24;103(9):103994. doi: 10.1016/j.psj.2024.103994. Online ahead of print.ABSTRACTDifferent rearing systems have varying effect on animal welfare and meat quality of poultry. Currently, there are no established standards for the rearing systems of Chinese indigenous chickens. Our study aimed to investigate the effects of different rearing systems on the meat quality, gene profiles, and metabolites of Chinese indigenous chickens (Nanchuan chicken). 10-wk-old Nanchuan chickens (n=360) were randomly divided into 3 groups (cage, net, and free-range groups), with 6 replicates per group (20 chickens per replicate). The experiment lasted for 12 wk. At 154-days-old, 36 healthy chickens (6 males and 6 females per group) were randomly selected, euthanized, and their breast muscles were collected to assess the meat quality parameters and histomorphological characteristics. Additionally, breast muscles from 18 random hens (3 males and 3 females per group) were used for metabolomics and RNA-seq analysis. The results showed that rearing systems significantly affected the meat quality and myofiber characteristics. The meat quality of breast muscles from free-range chickens was superior to that of caged chickens, characterized by more tender meat and smaller myofiber cross-sectional areas. Integrative metabolomics and transcriptomics analysis revealed that the differentially expressed genes of chicken breast muscles were primarily involved in the myofiber differentiation. Mechanically, the improved meat quality of breast muscle in free-range chickens were mainly associated with enhanced skeletal muscle differentiation facilitated by fibromodulin, increased levels of up-regulated Acetyl-L-carnitine and Propionylcarnitine level, and decreased levels of Nonanoic acid and Elaidic acid abundance (Graphical abstract). This provides a comprehensive understanding of the most effective and sustainable breeding, production, and rearing systems for Chinese indigenous chickens. It also contributes to the current knowledge of the molecular mechanisms underlying the effects of rearing systems on growth performance and meat quality of chickens.PMID:38991385 | DOI:10.1016/j.psj.2024.103994

CD39 is induced by nutrient deprivation in colorectal cancer cells and contributes to the tolerance to hypoxia

Thu, 11/07/2024 - 12:00
Biochem Biophys Res Commun. 2024 Jul 6;730:150367. doi: 10.1016/j.bbrc.2024.150367. Online ahead of print.ABSTRACTRapid tumor growth and insufficient blood supply leads to the development of a hypoxic and nutrient deprived microenvironment. To survive, tumor cells need to tolerate these adverse conditions. Here we found the expression of CD39 was enhanced in necrotic regions distant from blood vessels. We speculate that this is a strategy for tumor cells to actively adapt to the hostile environment. Further studies showed that CD39 was induced by nutrient deprivation through the AMPK signalling pathway. We next explored the significance of CD39 for tumor cells. Our results showed that CD39 reduced cellular oxygen consumption, which could be significant for tumor cells if the available oxygen is limited. Metabolomics analysis showed that overexpression of CD39 significantly altered cellular metabolism, and tricarboxylic acid (TCA) cycle was identified as the most impacted metabolic pathway. In order to explore the molecular mechanism, we performed RNA-seq analysis. The results showed that CD39 significantly up-regulated the expression of pyruvate dehydrogenase kinase isozyme 2 (PDK2), thus inhibiting the activity of pyruvate dehydrogenase (PDH) and TCA cycle. Finally, CD39 was shown to protect tumor cells from hypoxia-induced cell death and reduce intratumoral hypoxia levels. CD39 has attracted a great deal of attention as a newly discovered immune checkpoint molecule in recent years. Our results indicate that CD39 not only plays a role in immune regulation, but also enables tumor cells to tolerate hypoxia by inhibiting TCA cycle and reducing cellular oxygen consumption. This study provides evidence that targeting CD39 may be a novel strategy to prevent adaptation of tumor cells in stressed conditions.PMID:38991255 | DOI:10.1016/j.bbrc.2024.150367

Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI

Thu, 11/07/2024 - 12:00
Acta Neuropathol Commun. 2024 Jul 12;12(1):113. doi: 10.1186/s40478-024-01820-0.ABSTRACTBACKGROUND: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD).METHODS: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.RESULTS: We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ1-42 levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB1) and serotonergic 2A (5HT2A) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.CONCLUSIONS: Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.PMID:38992700 | DOI:10.1186/s40478-024-01820-0

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