PubMed

J Ethnopharmacol. 2024 Jul 5:118517. doi: 10.1016/j.jep.2024.118517. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored.AIM OF THE STUDY: To elucidate the specific mechanism by which AS-IV moderates DKD progression.MATERIALS AND METHODS: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods.RESULTS: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells.CONCLUSIONS: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.PMID:38972525 | DOI:10.1016/j.jep.2024.118517

Sci Total Environ. 2024 Jul 5:174532. doi: 10.1016/j.scitotenv.2024.174532. Online ahead of print.ABSTRACTBlack phosphorus quantum dots (BPQDs) have recently emerged as a highly promising contender in biomedical applications ranging from drug delivery systems to cancer therapy modalities. Nevertheless, the potential toxicity and its effects on human health need to be thoroughly investigated. In this study, we utilized multi-omics integrated approaches to explore the complex mechanisms of BPQDs-induced kidney injury. First, histological examination showed severe kidney injury in male mice after subacute exposure to 1 mg/kg BPQDs for 28 days. Subsequently, transcriptomic and metabolomic analyses of kidney tissues exposed to BPQDs identified differentially expressed genes and metabolites associated with ferroptosis, an emerging facet of regulated cell death. Our findings highlight the utility of the multi-omics integrated approach in predicting and elucidating potential toxicological outcomes of nanomaterials. Furthermore, our study provides a comprehensive understanding of the mechanisms driving BPQDs-induced kidney injury, underscoring the importance of recognizing ferroptosis as a potential toxic mechanism associated with BPQDs.PMID:38972417 | DOI:10.1016/j.scitotenv.2024.174532

Ophthalmology. 2024 Jul 5:S0161-6420(24)00415-9. doi: 10.1016/j.ophtha.2024.07.004. Online ahead of print.ABSTRACTPURPOSE: To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and evaluate their utility in predicting DR development and progression.DESIGN: Multicenter, multi-ethnic cohort study.PARTICIPANTS: This study included 17,675 participants with baseline pre-diabetes/diabetes, in accordance with the 2021 American Diabetes Association guideline, and free of baseline DR from the UK Biobank (UKB); and an additional 638 diabetic participants from the Guangzhou Diabetic Eye Study (GDES) for external validation.METHODS: Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort. Model assessments included the C-statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical utility in both cohorts.MAIN OUTCOME MEASURES: DR development, progression, and retinal microvascular damage.RESULTS: Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C-statistic: 0.802, 95% CI, 0.760-0.843 vs. 0.751, 95% CI, 0.706-0.796; P = 5.56×10-4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C-statistic: 0.807, 95% CI, 0.711-0.903 vs. 0.617, 95% CI, 0.494, 0.740; P = 1.68×10-4) and progression (C-statistic: 0.797, 95% CI, 0.712-0.882 vs. 0.665, 95% CI, 0.545-0.784; P = 0.003) in the external cohort. Improvements in NRIs, IDIs, and clinical utility were also evident in both cohorts (all P <0.05). In addition, lactate and citrate were associated to microvascular damage across macular and optic disc regions (all P <0.05).CONCLUSIONS: Metabolomic profiling has proven effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology.PMID:38972358 | DOI:10.1016/j.ophtha.2024.07.004

Caries Res. 2024 Jul 5. doi: 10.1159/000540090. Online ahead of print.ABSTRACTINTRODUCTION: The identification of salivary molecules that can be associated to dental caries could provide insights about caries risk and offer valuable information to develop caries prediction models. However, the search for a universal caries biomarker has proven elusive due to the multifactorial nature of this oral disease. We have therefore performed a systematic effort to identify caries-associated metabolites and proteins in saliva samples from adolescents that had a caries experience and those that were caries-free.METHODS: Quantification of approximately 100 molecules was performed by the use of a wide range of techniques, ranging from NMR metabolomics to ELISA, Luminex or colorimetric assays, as well as clinical features like plaque accumulation and gingival index. In addition, simplified dietary and oral hygiene habits questionnaires were also obtained.RESULTS: The caries-free group had significantly lower consumption of sweetened beverages and higher toothbrushing frequency. Surprisingly, very few compounds were found to individually provide discriminatory power between Caries-experienced and Caries-Free individuals. The data analysis revealed several potential reasons that could underly this lack of association value with caries, including differences in metabolite concentrations throughout the day, a lack of correlation between metabolite concentrations in plaque and saliva, or sex-related differences, among others. However, when multiple compounds were combined by multivariate analysis and random forest modelling, a combination of 3-5 compounds were found to provide good prediction models for morning (with an AUC accuracy of 0.87) and especially afternoon samples (AUC=0.93).CONCLUSION: While few salivary biomarker could differentiate between caries-free and caries-experienced adolescents, a combination of markers proved effective, particularcly in afternoon samples. To predict caries risk, these biomarkers should be validated in larger cohorts and longitudinal settings, considering factors such as gender differences, and variations in oral hygiene and diet.PMID:38972309 | DOI:10.1159/000540090

Poult Sci. 2024 Jun 3;103(9):103931. doi: 10.1016/j.psj.2024.103931. Online ahead of print.ABSTRACTHybrid breeding has proven to enhance meat quality and is extensively utilized in goose breeding. Nevertheless, there is a paucity of research investigating the molecular mechanisms that underlie the meat quality of hybrid geese. In this study, we employed the Sichuan White Goose as the maternal line for hybridization with the Zhedong White Goose and Tianfu Meat Goose P3 line. We assessed the growth and slaughter meat quality performance of 10-wk-old hybrid offspring in comparison to Sichuan white goose purebred offspring. The results indicate that hybrid geese have significantly improved performance in growth and slaughter meat quality. Furthermore, we conducted a comprehensive analysis of the chest muscles of hybrid offspring through transcriptomics and metabolomics to unravel the effects of hybrid breeding on growth and meat quality. A total of 673 differentially expressed genes (DEGs), and 93 differentially expressed metabolites were identified. The joint analysis highlighted the significant enrichment of DEGs AMPD1, AMPD3, RRM2, ENTPD3, and the metabolite UMP in the nucleotide metabolism pathway. These findings underscore the crucial role of these genetic and metabolic factors in regulating muscle growth and meat quality in hybrid populations.PMID:38972281 | DOI:10.1016/j.psj.2024.103931

J Ayurveda Integr Med. 2024 Jul 6;15(4):101009. doi: 10.1016/j.jaim.2024.101009. Online ahead of print.ABSTRACTBACKGROUND: Arthritis is a common clinical condition seen in Ayurveda clinics. Clinical trials have reported Ayurvedic interventions to be of benefits in many arthritic conditions including Rheumatoid Arthritis (RA). No mechanistic details however are available about how such interventions on their own or as a combination of whole system Ayurveda might be working.OBJECTIVE: The study aims to evaluate simultaneously the clinical outcome of Ayurveda whole system (AWS) intervention in RA patients and identifying the serum metabolic signatures which could be useful for diagnosing the disease and monitoring treatment response.MATERIAL AND METHODS: RA patients (n = 37) simultaneously diagnosed as Amavata fulfilling the specific inclusion and exclusion criteria were recruited in the study and were given Ayurveda whole system (AWS) intervention comprised of oral medicines, local therapy and dietary recommendation for 3 months. The clinical and serum metabolic changes were investigated for pre-treatment RA patients (baseline RA group, n = 37) and post-treatment RA patients (following treatment of 6-weeks (RA_F, n = 26) and three months (RA_T, n = 36). For comparative serum metabolomics analysis, 57 normal healthy control (HC) subjects were also involved and the serum metabolic profiles were measured at high-field 800 MHz NMR spectrometer. The serum metabolic profiles were compared using multivariate statistical analysis and discriminatory metabolic features were evaluated for diagnostic potential using receiver operating characteristic (ROC) curve analysis.RESULTS: A significant reduction in DAS-28 ESR, AAM Score, total swollen joints, total tender joints were observed following AWS intervention. The clinical outcomes were concordant with changes in metabolic profiles of RA patients as these were also shifting towards the normal levels following the intervention. Compared to healthy control (HC) subjects, the sera of baseline RA patients were characterised by increased circulatory level of succinate, lysine, mannose, creatine, and 3-Hydroxybutyrate (3-HB) and decreased levels of alanine. The present study also evaluated the serum metabolic ratios for their discriminatory and diagnostic potential and notably, six metabolic ratios (KHR, KThR, KVR, GHR, PTR and SHR) were found significantly altered (elevated) in baseline RA patients. However, in RA patients receiving AWS treatment, these metabolic changes showed marked convergence towards the metabolic signatures of healthy controls.CONCLUSION: This first of its kind study clearly shows the clinical efficacy of Ayurvedic Whole System (AWS) intervention in the management of Rheumatoid Arthritis (RA), as demonstrated by significant improvements in key clinical parameters. The intervention not only alleviated symptoms but also induced a profound metabolic shifting towards normalization; thus, underscoring the potential of AWS intervention to modulate cellular metabolism in a manner that facilitates a return to homeostasis in RA patients. However, future studies are imperative to confirm these preliminary observations and delineate the underlying mechanisms of action of intervention in cases of RA.PMID:38972279 | DOI:10.1016/j.jaim.2024.101009

Plant Physiol Biochem. 2024 Jul 5;214:108915. doi: 10.1016/j.plaphy.2024.108915. Online ahead of print.ABSTRACTCopper (Cu) toxicity in crops is a result of excessive release of Cu into environment. Little is known about mitigation of Cu toxicity through the application of carbon-based nanomaterials including water-soluble fullerene C60 derivatives. Two derivatives of fullerene were examined: polyhydroxylated C60 (fullerenol) and arginine C60 derivative. In order to study the response of Cu-stressed plants (Cucumis sativus L.) to these nanomaterials, metabolomics analysis by gas chromatography-mass spectrometry (GC-MS) was performed. Excess Cu (15 μM) caused substantial increase in xylem sap Cu, retarded dry biomass and leaf chlorosis of hydroponically grown cucumber. In Cu-stressed leaves, metabolomes was disturbed towards suppression metabolism of nitrogen (N) compounds and activation metabolism of hexoses. Also, upregulation of some metabolites involving in antioxidant defense system, such as ascorbic acid, tocopherol and ferulic acid, was occurred in Cu-stressed leaves. Hydroponically added fullerene adducts decreased the xylem sap Cu and alleviated Cu toxicity with effectiveness has been most pronounced for arginine C60 derivative. Metabolic responses of plants subjected to high Cu with fullerene derivatives were opposite to that observed under Cu alone. Fatty acids up-regulation (linolenic acid) and antioxidant molecules (tocopherol) down-regulation might indicate that arginine C60 adduct can alleviate Cu induced oxidative stress. Although fullerenol slightly improved cucumber growth, its effect on metabolic state of Cu-stressed plants was not statistically significant. We suggest that tested fullerene C60 adducts have a potential to prevent Cu toxicity in plants through a mechanism associated with their capability to restrict xylem transport of Cu from roots to shoot, and to maintain antioxidative properties of plants.PMID:38972240 | DOI:10.1016/j.plaphy.2024.108915

Int Immunopharmacol. 2024 Jul 6;138:112617. doi: 10.1016/j.intimp.2024.112617. Online ahead of print.ABSTRACTSevere steatosis in donor livers is contraindicated for transplantation due to the high risk of ischemia-reperfusion injury (IRI). Although Ho-1 gene-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) can mitigate IRI, the role of gut microbiota and metabolites in this protection remains unclear. This study aimed to explore how gut microbiota and metabolites contribute to HO-1/BMMSCs-mediated protection against IRI in severe steatotic livers. Using rat models and cellular models (IAR20 and THLE-2 cells) of steatotic liver IRI, this study revealed that ischemia-reperfusion led to significant liver and intestinal damage, heightened immune responses, impaired liver function, and altered gut microbiota and metabolite profiles in rats with severe steatosis, which were partially reversed by HO-1/BMMSCs transplantation. Integrated microbiome and metabolome analyses identified gut microbial metabolite oleanolic acid as a potential protective agent against IRI. Experimental validation showed that oleanolic acid administration alone alleviated IRI and inhibited ferroptosis in both rat and cellular models. Network pharmacology and molecular docking implicated KEAP1/NRF2 pathway as a potential target of oleanolic acid. Indeed, OA experimentally upregulated NRF2 activity, which underlies its inhibition of ferroptosis and protection against IRI. The gut microbial metabolite OA protects against IRI in severe steatotic liver by promoting NRF2 expression and activity, thereby inhibiting ferroptosis.PMID:38972213 | DOI:10.1016/j.intimp.2024.112617

Biochem Biophys Res Commun. 2024 Jul 2;728:150346. doi: 10.1016/j.bbrc.2024.150346. Online ahead of print.ABSTRACTTissue-specific deficiency of nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD+)-salvage pathway, causes a decrease of NAD+ in the tissue, resulting in functional abnormalities. The NAD+-salvage pathway is drastically activated in the mammary gland during lactation, but the significance of this has not been established. To investigate the impact of NAD+ perturbation in the mammary gland, we generated two new lines of mammary gland epithelial-cell-specific Nampt-knockout mice (MGKO). LC-MS/MS analyses confirmed that the levels of NAD+ and its precursor nicotinamide mononucleotide (NMN) were significantly increased in lactating mammary glands. We found that murine milk contained a remarkably high level of NMN. MGKO exhibited a significant decrease in tissue NAD+ and milk NMN levels in the mammary gland during lactation periods. Despite the decline in NAD+ levels, the mammary glands of MGKO appeared to develop normally. Transcriptome analysis revealed that the gene profiles of MGKO were indistinguishable from those of their wild-type counterparts, except for Nampt. Although the NMN levels in milk from MGKO were decreased, the metabolomic profile of milk was otherwise unaltered. The mammary gland also contains adipocytes, but adipocyte-specific deficiency of Nampt did not affect mammary gland NAD+ metabolism or mammary gland development. These results demonstrate that the NAD+ -salvage pathway is activated in mammary epithelial cells during lactation and suggest that this activation is required for production of milk NMN rather than mammary gland development. Our MGKO mice could be a suitable model for exploring the potential roles of NMN in milk.PMID:38972085 | DOI:10.1016/j.bbrc.2024.150346

BMC Cancer. 2024 Jul 7;24(1):809. doi: 10.1186/s12885-024-12595-x.ABSTRACTBACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry.METHODS: Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations.RESULTS: Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p < 0.001) cell levels increased as the disease progressed, their subsets: NK CD56dimCD16- (p = 0.024) and NKTs CD56+ (p = 0.008) cell levels reduced significantly. Of note is the negative association of NK CD56dimCD16- (p < 0.001) cell levels with survival time. The gene expression analyses showed no statistically significant correlation when comparing the PDAC groups with the controls. The inflammatory status of PDAC was assessed by ROS levels of serum which were elevated in CP (p = 0.025), (RPC (p = 0.003) and LAPC (p = 0.008)) while no significant change was observed in MPC, compared to the HC group. ROS was shown to be positively correlated with GlycA (R = 0.45, p = 0.0096). Single-cell analyses showed a significant difference in the ratio of NKT cells per total cell counts in LAPC (p < 0.001) and MPC (p < 0.001) groups compared with HC, confirming observations in our sample group.CONCLUSION: The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.PMID:38973003 | DOI:10.1186/s12885-024-12595-x

Plant Mol Biol. 2024 Jul 8;114(4):83. doi: 10.1007/s11103-024-01480-7.ABSTRACTConsumer trends towards nutrient-rich foods are contributing to global increasing demand for tropical fruit. However, commercial cultivars in the breeding pipeline that are tailored to meet market demand are at risk of possessing reduced fruit flavour qualities. This stems from recurrent prioritised selection for superior agronomic traits and not fruit flavour, which may in turn reduce consumer satisfaction. There is realisation that fruit quality traits, inclusive of flavour, must be equally selected for; but currently, there are limited tools and resources available to select for fruit flavour traits, particularly in tropical fruit species. Although sugars, acids, and volatile organic compounds are known to define fruit flavour, the specific combinations of these, that result in defined consumer preferences, remain unknown for many tropical fruit species. To define and include fruit flavour preferences in selective breeding, it is vital to determine the metabolites that underpin them. Then, objective quantitative analysis may be implemented instead of solely relying on human sensory panels. This may lead to the development of selective genetic markers through integrated omics approaches that target biosynthetic pathways of flavour active compounds. In this review, we explore progress in the development of tools to be able to strategically define and select for consumer-preferred flavour profiles in the breeding of new cultivars of tropical fruit species.PMID:38972957 | DOI:10.1007/s11103-024-01480-7

Nat Commun. 2024 Jul 7;15(1):5697. doi: 10.1038/s41467-024-49972-w.ABSTRACTClimate and environmental changes threaten human mental health, but the impacts of specific environmental conditions on neuropsychiatric disorders remain largely unclear. Here, we show the impact of a humid heat environment on the brain and the gut microbiota using a conditioned housing male mouse model. We demonstrate that a humid heat environment can cause anxiety-like behaviour in male mice. Microbial 16 S rRNA sequencing analysis reveals that a humid heat environment caused gut microbiota dysbiosis (e.g., decreased abundance of Lactobacillus murinus), and metabolomics reveals an increase in serum levels of secondary bile acids (e.g., lithocholic acid). Moreover, increased neuroinflammation is indicated by the elevated expression of proinflammatory cytokines in the serum and cortex, activated PI3K/AKT/NF-κB signalling and a microglial response in the cortex. Strikingly, transplantation of the microbiota from mice reared in a humid heat environment readily recapitulates these abnormalities in germ-free mice, and these abnormalities are markedly reversed by Lactobacillus murinus administration. Human samples collected during the humid heat season also show a decrease in Lactobacillus murinus abundance and an increase in the serum lithocholic acid concentration. In conclusion, gut microbiota dysbiosis induced by a humid heat environment drives the progression of anxiety disorders by impairing bile acid metabolism and enhancing neuroinflammation, and probiotic administration is a potential therapeutic strategy for these disorders.PMID:38972900 | DOI:10.1038/s41467-024-49972-w

Gut Microbes. 2024 Jan-Dec;16(1):2375483. doi: 10.1080/19490976.2024.2375483. Epub 2024 Jul 7.ABSTRACTPancreatic cancer has a dismal prognosis, as it is often diagnosed at stage IV of the disease and is characterized by metastatic spread. Gut microbiota and its metabolites have been suggested to influence the metastatic spread by modulating the host immune system or by promoting angiogenesis. To date, the gut microbial profiles of metastatic and non-metastatic patients need to be explored. Taking advantage of the 16S metagenomic sequencing and the PEnalized LOgistic Regression Analysis (PELORA) we identified clusters of bacteria with differential abundances between metastatic and non-metastatic patients. An overall increase in Gram-negative bacteria in metastatic patients compared to non-metastatic ones was identified using this method. Furthermore, to gain more insight into how gut microbes can predict metastases, a machine learning approach (iterative Random Forest) was performed. Iterative Random Forest analysis revealed which microorganisms were characterized by a different level of relative abundance between metastatic and non-metastatic patients and established a functional relationship between the relative abundance and the probability of having metastases. At the species level, the following bacteria were found to have the highest discriminatory power: Anaerostipes hadrus, Coprobacter secundus, Clostridium sp. 619, Roseburia inulinivorans, Porphyromonas and Odoribacter at the genus level, and Rhodospirillaceae, Clostridiaceae and Peptococcaceae at the family level. Finally, these data were intertwined with those from a metabolomics analysis on fecal samples of patients with or without metastasis to better understand the role of gut microbiota in the metastatic process. Artificial intelligence has been applied in different areas of the medical field. Translating its application in the field of gut microbiota analysis may help fully exploit the potential information contained in such a large amount of data aiming to open up new supportive areas of intervention in the management of cancer.PMID:38972056 | DOI:10.1080/19490976.2024.2375483

Gut Microbes. 2024 Jan-Dec;16(1):2374608. doi: 10.1080/19490976.2024.2374608. Epub 2024 Jul 7.ABSTRACTWith the increasing of aging population and the consumption of high-fat diets (HFD), the incidence of Alzheimer's disease (AD) has skyrocketed. Natural antioxidants show promising potential in the prevention of AD, as oxidative stress and neuroinflammation are two hallmarks of AD pathogenesis. Here, we showed that quinic acid (QA), a polyphenol derived from millet, significantly decreased HFD-induced brain oxidative stress and neuroinflammation and the levels of Aβ and p-Tau. Examination of gut microbiota suggested the improvement of the composition of gut microbiota in HFD mice after QA treatment. Metabolomic analysis showed significant increase of gut microbial tryptophan metabolites indole-3-acetic acid (IAA) and kynurenic acid (KYNA) by QA. In addition, IAA and KYNA showed negative correlation with pro-inflammatory factors and AD indicators. Further experiments on HFD mice proved that IAA and KYNA could reproduce the effects of QA that suppress brain oxidative stress and inflammation and decrease the levels of of Aβ and p-Tau. Transcriptomics analysis of brain after IAA administration revealed the inhibition of DR3/IKK/NF-κB signaling pathway by IAA. In conclusion, this study demonstrated that QA could counteract HFD-induced brain oxidative stress and neuroinflammation by regulating inflammatory DR3/IKK/NF-κB signaling pathway via gut microbial tryptophan metabolites.PMID:38972055 | DOI:10.1080/19490976.2024.2374608

Clin Nutr ESPEN. 2024 Jul 1;63:283-293. doi: 10.1016/j.clnesp.2024.06.043. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: The challenge posed by diabetes necessitates a paradigm shift from conventional diagnostic approaches focusing on glucose and lipid levels to the transformative realm of precision medicine. This approach, leveraging advancements in genomics and proteomics, acknowledges the individualistic genetic variations, dietary preferences, and environmental exposures in diabetes management. The study comprehensively analyzes the evolving diabetes landscape, emphasizing the pivotal role of genomics, proteomics, microRNAs (miRNAs), metabolomics, and bioinformatics.RESULTS: Precision medicine revolutionizes diabetes research and treatment by diverging from traditional diagnostic methods, recognizing the heterogeneous nature of the condition. MiRNAs, crucial post-transcriptional gene regulators, emerge as promising therapeutic targets, influencing key facets such as insulin signaling and glucose homeostasis. Metabolomics, an integral component of omics sciences, contributes significantly to diabetes research, elucidating metabolic disruptions, and offering potential biomarkers for early diagnosis and personalized therapies. Bioinformatics unveils dynamic connections between natural substances, miRNAs, and cellular pathways, aiding in the exploration of the intricate molecular terrain in diabetes. The study underscores the imperative for experimental validation in natural product-based diabetes therapy, emphasizing the need for in vitro and in vivo studies leading to clinical trials for assessing effectiveness, safety, and tolerability in real-world applications. Global cooperation and ethical considerations play a pivotal role in addressing diabetes challenges worldwide, necessitating a multifaceted approach that integrates traditional knowledge, cultural competence, and environmental awareness.CONCLUSIONS: The key components of diabetes treatment, including precision medicine, metabolomics, bioinformatics, and experimental validation, converge in future strategies, embodying a holistic paradigm for diabetes care anchored in cutting-edge research and global healthcare accessibility.PMID:38972039 | DOI:10.1016/j.clnesp.2024.06.043

Metabolomics. 2024 Jul 7;20(4):71. doi: 10.1007/s11306-024-02141-y.ABSTRACTBACKGROUND AND OBJECTIVE: Blood-based small molecule metabolites offer easy accessibility and hold significant potential for insights into health processes, the impact of lifestyle, and genetic variation on disease, enabling precise risk prevention. In a prospective study with records of heart failure (HF) incidence, we present metabolite profiling data from individuals without HF at baseline.METHODS: We uncovered the interconnectivity of metabolites using data-driven and causal networks augmented with polygenic factors. Exploring the networks, we identified metabolite broadcasters, receivers, mediators, and subnetworks corresponding to functional classes of metabolites, and provided insights into the link between metabolomic architecture and regulation in health. We incorporated the network structure into the identification of metabolites associated with HF to control the effect of confounding metabolites.RESULTS: We identified metabolites associated with higher and lower risk of HF incidence, such as glycine, ureidopropionic and glycocholic acids, and LPC 18:2. These associations were not confounded by the other metabolites due to uncovering the connectivity among metabolites and adjusting each association for the confounding metabolites. Examples of our findings include the direct influence of asparagine on glycine, both of which were inversely associated with HF. These two metabolites were influenced by polygenic factors and only essential amino acids, which are not synthesized in the human body and are obtained directly from the diet.CONCLUSION: Metabolites may play a critical role in linking genetic background and lifestyle factors to HF incidence. Revealing the underlying connectivity of metabolites associated with HF strengthens the findings and facilitates studying complex conditions like HF.PMID:38972029 | DOI:10.1007/s11306-024-02141-y

Int J Gynaecol Obstet. 2024 Jul 7. doi: 10.1002/ijgo.15770. Online ahead of print.ABSTRACTWhile the pathophysiology of pre-eclampsia has been postulated as being secondary to placental dysfunction, a cardiac origin has more recently been proposed. Although an association between fetal congenital cardiovascular disease and pre-eclampsia has been demonstrated, no precise pathophysiologic mechanism for this association has been described. This review highlights the current biophysical (including echocardiography and Doppler indices) and biochemical (including proteomic, metabolomic and genetic/transcriptomic) markers of cardiac dysfunction that have been investigated in maternal and fetal cardiac disease and their overlap with predictors of pre-eclampsia. Common pathways of inflammatory and anti-angiogenesis imbalance, endothelial damage, and oxidative stress have been demonstrated in both cardiovascular disease and pre-eclampsia and further investigation into these pathways could help to elucidate the common pathophysiologic mechanisms linking these disorders.PMID:38972011 | DOI:10.1002/ijgo.15770

BMC Plant Biol. 2024 Jul 6;24(1):637. doi: 10.1186/s12870-024-05364-2.ABSTRACTBACKGROUND: Based on our previous research, a full-length cDNA sequence of HvANS gene was isolated from purple and white Qingke. The open reading frame (ORF) in the purple variety Nierumuzha was 1320 base pairs (bp), encoding 439 amino acids, while the ORF in the white variety Kunlun 10 was 1197 bp, encoding 398 amino acids. A nonsynonymous mutation was found at the position of 1195 bp (T/C) in the coding sequence (CDS) of the HvANS gene. We carried out a series of studies to further clarify the relationship between the HvANS gene and anthocyanin synthesis in Qingke.RESULTS: The conservative structural domain prediction results showed that the encoded protein belonged to the PLN03178 superfamily. Multiple comparisons showed that this protein had the highest homology with Hordeum vulgare, at 88.61%. The approximately 2000 bp promoter sequence of the HvANS gene was identical in both varieties. The real-time fluorescence PCR (qRT-PCR) results revealed that HvANS expression was either absent or very low in the roots, stems, leaves, and awns of Nierumuzha. In contrast, the HvANS expression was high in the seed coats and seeds of Nierumuzha. Likewise, in Kunlun 10, HvANS expression was either absent or very low, indicating a tissue-specific and variety-specific pattern for HvANS expression. The subcellular localization results indicated that HvANS was in the cell membrane. Metabolomic results indicated that the HvANS gene is closely related to the synthesis of three anthocyanin substances (Idaein chloride, Kinetin 9-riboside, and Cyanidin O-syringic acid). Yeast single hybridization experiments showed that the HvANS promoter interacted with HvANT1, which is the key anthocyanin regulatory protein. In a yeast two-hybrid experiment, we obtained two significantly different proteins (ZWY2020 and POMGNT2-like) and verified the results by qRT-PCR.CONCLUSIONS: These results provide a basis for further studies on the regulatory mechanism of HvANS in the synthesis of anthocyanins in Qingke purple grains.PMID:38971739 | DOI:10.1186/s12870-024-05364-2

BMC Plant Biol. 2024 Jul 6;24(1):639. doi: 10.1186/s12870-024-05363-3.ABSTRACTBACKGROUND: Alkaloids, important secondary metabolites produced by plants, play a crucial role in responding to environmental stress. Heuchera micrantha, a well-known plant used in landscaping, has the ability to purify air, and absorb toxic and radioactive substances, showing strong environmental adaptability. However, there is still limited understanding of the accumulation characteristics and metabolic mechanism of alkaloids in H. micrantha.RESULTS: In this study, four distinct varieties of H. micrantha were used to investigate the accumulation and metabolic traits of alkaloids in its leaves. We conducted a combined analysis of the plant's metabolome and transcriptome. Our analysis identified 44 alkaloids metabolites in the leaves of the four H. micrantha varieties, with 26 showing different levels of accumulation among the groups. The HT and JQ varieties exhibited higher accumulation of differential alkaloid metabolites compared to YH and HY. We annotated the differential alkaloid metabolites to 22 metabolic pathways, including several alkaloid metabolism. Transcriptome data revealed 5064 differentially expressed genes involved in these metabolic pathways. Multivariate analysis showed that four key metabolites (N-hydroxytryptamine, L-tyramine, tryptamine, and 2-phenylethylamine) and three candidate genes (Cluster-15488.116815, Cluster-15488.146268, and Cluster-15488.173297) that merit further investigation.CONCLUSIONS: This study provided preliminarily insight into the molecular mechanism of the biosynthesis of alkaloids in H. micrantha. However, further analysis is required to elucidate the specific regulatory mechanisms of the candidate gene involved in the synthesis of key alkaloid metabolites. In summary, our findings provide important information about how alkaloid metabolites build up and the metabolic pathways involved in H. micrantha varieties. This gives us a good starting point for future research on the regulation mechanism, and development, and utilization of alkaloids in H. micrantha.PMID:38971732 | DOI:10.1186/s12870-024-05363-3

Methods Enzymol. 2024;700:77-104. doi: 10.1016/bs.mie.2024.02.015. Epub 2024 Mar 22.ABSTRACTThe biophysical drivers of membrane lateral heterogeneity, often termed lipid rafts, have been largely explored using synthetic liposomes or mammalian plasma membrane-derived giant vesicles. Yeast vacuoles, an organelle comparable to mammalian lysosomes, is the only in vivo system that shows stable micrometer scale phase separation in unperturbed cells. The ease of manipulating lipid metabolism in yeast makes this a powerful system for identifying lipids involved in the onset of vacuole membrane heterogeneity. Vacuole domains are induced by stationary stage growth and nutritional starvation, during which they serve as a docking and internalization site for lipid droplet energy stores. Here we describe methods for characterizing vacuole phase separation, its physiological function, and its lipidic drivers. First, we detail methodologies for robustly inducing vacuole domain formation and quantitatively characterizing during live cell imaging experiments. Second, we detail a new protocol for biochemical isolation of stationary stage vacuoles, which allows for lipidomic dissection of membrane phase separation. Third, we describe biochemical techniques for analyzing lipid droplet internalization in vacuole domains. When combined with genetic or chemical perturbations to lipid metabolism, these methods allow for systematic dissection of lipid composition in the structure and function of ordered membrane domains in living cells.PMID:38971613 | DOI:10.1016/bs.mie.2024.02.015