PubMed

Sci Rep. 2023 May 12;13(1):7706. doi: 10.1038/s41598-023-34813-5.ABSTRACTOver the years, a substantial body of information has accumulated suggesting dietary consumption of grapes may have a positive influence on human health. Here, we investigate the potential of grapes to modulate the human microbiome. Microbiome composition as well as urinary and plasma metabolites were sequentially assessed in 29 healthy free-living male (age 24-55 years) and female subjects (age 29-53 years) following two-weeks of a restricted diet (Day 15), two-weeks of a restricted diet with grape consumption (equivalent to three servings per day) (Day 30), and four-weeks of restricted diet without grape consumption (Day 60). Based on alpha-diversity indices, grape consumption did not alter the overall composition of the microbial community, other than with the female subset based on the Chao index. Similarly, based on beta-diversity analyses, the diversity of species was not significantly altered at the three time points of the study. However, following 2 weeks of grape consumption, taxonomic abundance was altered (e.g., decreased Holdemania spp. and increased Streptococcus thermophiles), as were various enzyme levels and KEGG pathways. Further, taxonomic, enzyme and pathway shifts were observed 30 days following the termination of grape consumption, some of which returned to baseline and some of which suggest a delayed effect of grape consumption. Metabolomic analyses supported the functional significance of these alterations wherein, for example, 2'-deoxyribonic acid, glutaconic acid, and 3-hydroxyphenylacetic acid were elevated following grape consumption and returned to baseline following the washout period. Inter-individual variation was observed and exemplified by analysis of a subgroup of the study population showing unique patterns of taxonomic distribution over the study period. The biological ramifications of these dynamics remain to be defined. However, while it seems clear that grape consumption does not perturb the eubiotic state of the microbiome with normal, healthy human subjects, it is likely that shifts in the intricate interactive networks that result from grape consumption have physiological significance of relevance to grape action.PMID:37173385 | DOI:10.1038/s41598-023-34813-5

Nat Commun. 2023 May 12;14(1):2748. doi: 10.1038/s41467-023-38010-w.ABSTRACTPhosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp-/-) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP- PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP- PPARδ interaction that suppresses PPAR activity.PMID:37173315 | DOI:10.1038/s41467-023-38010-w

J Ethnopharmacol. 2023 May 10:116578. doi: 10.1016/j.jep.2023.116578. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cupressus torulosa (family Cupressaceae), widely distributed in the north western Himalayan region of India, is a coniferous aromatic tree with various traditional uses of its aerial parts. Its needles have been used for anti-inflammatory, anticonvulsant, antimicrobial, and wound-healing properties.AIM OF THE STUDY: The study aimed at investigating the previously unknown anti-inflammatory activity of the hydromethanolic extract of the needles employing in vitro and in vivo assays and scientifically validate traditional claim of their use in treatment of inflammation. Chemical characterization of the extract with the aid of UPLCQTOFMS was also of interest.MATERIALS AND METHODS: C. torulosa needles were first defatted with hexane and sequentially extracted with chloroform and 25% aqueous methanol (AM). Since the presence of phenolics (TPCs, 208.21 ± 0.95 mg GAE/g needles) and flavonoids (TFCs, 84.61 ± 1.21 mg QE/g needles) was observed in the AM extract only, it was chosen for biological and chemical examinations. Acute toxicity of the AM extract on female mice was evaluated following the OECD guideline 423. In vitro anti-inflammatory activity of the AM extract was examined using egg albumin denaturation assay while carrageenan-induced paw edema and formalin-induced paw edema models at doses of 100, 200 and 400 mg/kg po were used to determine the in vivo activity of the AM extract on Wistar rats of either sex. The components of the AM extract were analyzed by UPLC-QTOF-MS method using non-targeted metabolomics approach.RESULTS: AM extract was found to be non-toxic at 2000 mg/kg b.w. with no signs of abnormal locomotion, seizures and writhing. The extract demonstrated promising in vitro anti-inflammatory activity (IC50 160.01 μg/mL) compared to standard diclofenac sodium (IC50 73.94 μg/mL) in egg albumin denaturation assay. In carrageenan-induced paw edema and formalin-induced paw edema tests the extract showed significant anti- inflammatory activity (57.28% and 51.04% inhibition of paw edema, respectively) at the dose of 400 mg/kg p.o. after 4 h in comparison to the standard diclofenac sodium which displayed 61.39% and 52.90% inhibition, respectively, at the dose of 10 mg/kg p.o. after 4 h in these models. A total of 63 chemical constituents, majority of them being phenolics, were found in the AM extract of the needles. Two compounds namely monotropein (iridoid glycoside), (±)12-HETE (eicosanoid) and fraxin (coumarin glycoside) were reported to have anti-inflammatory effect.CONCLUSIONS: For the first time our study demonstrated that hydro-methanolic extract of C. torulosa needles exhibit anti-inflammatory activity thereby supporting their traditional use in the treatment of inflammatory disorders. UPLCQTOFMS assisted chemical profile of the extract was also unveiled.PMID:37172917 | DOI:10.1016/j.jep.2023.116578

J Chromatogr A. 2023 May 3;1700:464047. doi: 10.1016/j.chroma.2023.464047. Online ahead of print.ABSTRACTThe combined use of ethanol and cocaine is frequent among drug-abuse users and leads to further exacerbation of health consequences compared to individual consumption and this is of special concern during the transition to adulthood. Despite its high prevalence, the effect of combined consumption of cocaine and ethanol has been scarcely studied. In this work, we report the first untargeted metabolomic study in brain tissues to contribute to the advancement in the knowledge of the possible neurobiological effects of this polysubstance dependence. Liquid Chromatography coupled to high resolution Mass Spectrometry was employed to analyze three different brain tissues samples, prefrontal cortex, striatum and hippocampus, from male and female young rats exposed intravenously to a self-administration of these drugs. After optimizing the best sample treatment and selecting the chromatographic and detection conditions to find the maximum number of significant features (possible biomarker metabolites), the high resolution of the Orbitrap analyzer used in this work has made it possible to find up to 761 significant features with assigned molecular formula, of which up to 190 were tentatively identified and 44 unequivocally confirmed. The results demonstrated that the altered metabolic pathways are involved in multiple functions: receptor systems, such as the Glutamine-Glutamic acid-GABA axis or the catecholamine pathway, purinergic and pyrimidine pathways, fatty acids or oxidative stress, among others.PMID:37172540 | DOI:10.1016/j.chroma.2023.464047

Talanta. 2023 May 6;260:124647. doi: 10.1016/j.talanta.2023.124647. Online ahead of print.ABSTRACTMānuka honey is a valuable commodity produced by bees foraging the flowers of Leptospermum scoparium, a bush native to New Zealand and Australia. Due to its high value and proven health benefits, authenticity fraud in the sale of this food is a significant risk, as recounted in the literature. Four compulsory natural products must be present at minimum concentrations to authenticate mānuka honey (3-phenyllactic acid, 2'-methoxyacetophenone, 2-methoxybenzoic acid, and 4-hydroxyphenyllactic acid). However, spiking other kinds of honey with these compounds and/or the dilution of mānuka honey with other varieties may result in fraud going undetected. In this work, liquid chromatography coupled with high-resolution mass spectrometry and a metabolomics-based strategy has allowed us to tentatively identify 19 natural products -putative mānuka honey markers-, nine of which are reported for the first time. Chemometric models applied to these markers allowed the detection of both spiking and dilution fraud attempts of mānuka honey, even at 75% mānuka honey purity. Thus, the herein-reported methodology can be employed in the prevention and detection of mānuka honey adulteration even at low levels, and the tentatively identified markers presented in this work proved valuable for mānuka honey authentication procedures.PMID:37172434 | DOI:10.1016/j.talanta.2023.124647

Int Immunopharmacol. 2023 May 10;119:110271. doi: 10.1016/j.intimp.2023.110271. Online ahead of print.ABSTRACTChronic cerebral hypoperfusion (CCH) can cause cognitive impairments. Dl-3-n-butylphthalide (NBP) is widely used in neurological disorders; but, the role of NBP in CCH remains unclear. This study aimed to investigate the potential mechanism of NBP on CCH through untargeted metabolomics. Animals were divided into CCH, Sham, and NBP groups. A rat model of bilateral carotid artery ligation was used to simulate CCH. Cognitive function of the rats was assessed using the Morris water maze test. Additionally, we used LC-MS/MS to detect ionic intensities of metabolites between the three groups for off-target metabolism analysis and to screen for differential metabolites. The analysis showed an improvement in cognitive function in rats after NBP treatment. Moreover, metabolomic studies showed that the serum metabolic profiles of the Sham and CCH groups were significantly altered, and 33 metabolites were identified as potential biomarkers associated with the effects of NBP. These metabolites were enriched in 24 metabolic pathways.And the pathway of differential metabolite enrichment was further verified by immunofluorescence. Thus, the study provides a theoretical basis for the pathogenesis of CCH and the treatment of CCH by NBP, and supports a wider application of NBP drugs.PMID:37172424 | DOI:10.1016/j.intimp.2023.110271

J Hazard Mater. 2023 Apr 29;455:131542. doi: 10.1016/j.jhazmat.2023.131542. Online ahead of print.ABSTRACTAs the main producer of aflatoxins, Aspergillus flavus is also one of the most important causes of invasive and non-invasive aspergillosis. Therefore, it is crucial to unravel the regulatory mechanisms of growth, metabolism, and pathogenicity of A. flavus. SWD1 is highly conserved across species for maintaining COMPASS methyltransferase activity, but the bio-function of SWD1 in A. flavus has not been explored. Through genetic analysis, this study revealed that SWD1 is involved in fungal morphogenesis and AFB1 biosynthesis by regulating the orthodox pathways through H3K4me1-3. Stresses sensitivity and crop models analysis revealed that SWD1 is a key regulator for the resistance of A. flavus to adapt to extreme adverse environments and to colonize crop kernels. It also revealed that the WD40 domain and 25 aa highly conserved sequence are indispensable for SWD1 in the regulation of mycotoxin bio-synthesis and fungal virulence. Metabolomic analysis inferred that SWD1 is crucial for the biosynthesis of numerous primary and secondary metabolites, regulates biological functions by reshaping the whole metabolic process, and may inhibit fungal virulence by inducing the apoptosis of mycelia through the inducer sphingosine. This study elucidates the epigenetic mechanism of SWD1 in regulating fungal pathogenicity and mycotoxin biosynthesis, and provides a potential novel target for controlling the virulence of A. flavus.PMID:37172387 | DOI:10.1016/j.jhazmat.2023.131542

J Agric Food Chem. 2023 May 12. doi: 10.1021/acs.jafc.2c09053. Online ahead of print.ABSTRACTLiquid chromatography/high-resolution mass spectrometry (LC/HRMS) can provide identification of grape metabolites which are variety markers. White grapes are poorer in polyphenolics, and the main secondary metabolites which contribute the sensorial characteristics of wines are the glycosidically bound volatile precursors and their aglycones. The profiles of three white grape juices (Pinot grigio, Garganega, and Trebbiano) were characterized by LC/HRMS, and 70 signals of putative glycosidic terpenols, norisoprenoids, and benzenoids were identified. Four signals found only in Pinot grigio corresponded to a norisoprenoid hexose-hexose, 3-oxo-α-ionol (or 3-hydroxy-β-damascone) rhamnosyl-hexoside, monoterpene-diol hexosyl-pentosyl-hexoside, and hexose-norisoprenoid; three signals were found only in Garganega (putative isopropyl alcohol pentosyl-hexoside, phenylethanol rhamnosyl-hexoside, and norisoprenoid hexose-hexose isomers), and a monoterpenol pentosyl-hexoside isomer only in Trebbiano. These variety markers were then investigated in juice blends of the three varieties. This approach can be used to develop control methods to reveal not-allowed grape varieties and practices in white wines winemaking.PMID:37172217 | DOI:10.1021/acs.jafc.2c09053

Eur J Prev Cardiol. 2023 May 12:zwad160. doi: 10.1093/eurjpc/zwad160. Online ahead of print.ABSTRACTAIMS: To identify a group of metabolites associated with incident CVD in people with type 2 diabetes and assess its predictive performance over-and-above a current CVD risk score (QRISK3).METHODS: A panel of 228 serum metabolites was measured at baseline in 1,066 individuals with type 2 diabetes (Edinburgh Type 2 Diabetes Study) who were then followed up for CVD over the subsequent 10 years. We applied 100 repeats of Cox LASSO (least absolute shrinkage and selection operator) to select metabolites with frequency >90% as components for a metabolites-based risk score (MRS). The predictive performance of the MRS was assessed in relation to a reference model which was based on QRISK3 plus prevalent CVD and statin use at baseline.RESULTS: Of 1,021 available individuals, 255 (25.0%) developed CVD (median follow-up: 10.6 years). Twelve metabolites relating to fluid balance, ketone bodies, amino acids, fatty acids, glycolysis and lipoproteins were selected to construct the MRS which showed positive association with 10-year cardiovascular risk following adjustment for traditional risk factors [HR 2.67 (95%CI 1.96, 3.64)]. C-statistic was 0.709 (95%CI 0.679, 0.739) for the reference model alone, increasing slightly to 0.728 (95%CI 0.700, 0.757) following addition of the MRS. Compared with the reference model, the net reclassification index and integrated discrimination index for the reference model plus the MRS was 0.362 (95%CI 0.179, 0.506) and 0.041 (95%CI 0.020, 0.071), respectively.CONCLUSIONS: Metabolomics data might improve predictive performance of current CVD risk scores based on traditional risk factors in people with type 2 diabetes. External validation is warranted to assess the generalizability of improved CVD risk prediction using the MRS.PMID:37172216 | DOI:10.1093/eurjpc/zwad160

Anal Chem. 2023 May 12. doi: 10.1021/acs.analchem.3c00260. Online ahead of print.ABSTRACTTandem mass spectrometry (MS/MS) shows great promise in the research of metabolomics, providing an abundance of information on compounds. Due to the rapid development of mass spectrometric techniques, a large number of MS/MS spectral data sets have been produced from different experimental environments. The massive data brings great challenges into the spectral analysis including compound identification and spectra clustering. The core challenge in MS/MS spectral analysis is how to describe a spectrum more quantitatively and effectively. Recently, emerging deep-learning-based technologies have brought new opportunities to handle this challenge in which high-quality descriptions of MS/MS spectra can be obtained. In this study, we propose a novel contrastive learning-based method for the representation of MS/MS spectra, called CLERMS, which is based on transformer architecture. Specifically, an optimized model architecture equipped with a sinusoidal embedder and a novel loss function composed of InfoNCE loss and MSE loss has been proposed for the attainment of good embedding from the peak information and the metadata. We evaluate our method using a GNPS data set, and the results demonstrate that the learned embedding can not only distinguish spectra from different compounds but also reveal the structural similarity between them. Additionally, the comparison between our method and other methods on the performance of compound identification and spectra clustering shows that our method can achieve significantly better results.PMID:37172113 | DOI:10.1021/acs.analchem.3c00260

J Clin Immunol. 2023 May 12. doi: 10.1007/s10875-023-01500-z. Online ahead of print.ABSTRACTThe paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.PMID:37171742 | DOI:10.1007/s10875-023-01500-z

Biofactors. 2023 May 12. doi: 10.1002/biof.1954. Online ahead of print.ABSTRACTThe liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR-FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14-3-3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow-up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.PMID:37171157 | DOI:10.1002/biof.1954

Mol Plant Pathol. 2023 May 12. doi: 10.1111/mpp.13349. Online ahead of print.ABSTRACTPlant-pathogenic fungi are causative agents of the majority of plant diseases and can lead to severe crop loss in infected populations. Fungal colonization is achieved by combining different strategies, such as avoiding and counteracting the plant immune system and manipulating the host metabolome. Of major importance are virulence factors secreted by fungi, which fulfil diverse functions to support the infection process. Most of these proteins are highly specialized, with structural and biochemical information often absent. Here, we present the atomic structures of the cerato-platanin-like protein Cpl1 from Ustilago maydis and its homologue Uvi2 from Ustilago hordei. Both proteins adopt a double-Ψβ-barrel architecture reminiscent of cerato-platanin proteins, a class so far not described in smut fungi. Our structure-function analysis shows that Cpl1 binds to soluble chitin fragments via two extended grooves at the dimer interface of the two monomer molecules. This carbohydrate-binding mode has not been observed previously and expands the repertoire of chitin-binding proteins. Cpl1 localizes to the cell wall of U. maydis and might synergize with cell wall-degrading and decorating proteins during maize infection. The architecture of Cpl1 harbouring four surface-exposed loop regions supports the idea that it might play a role in the spatial coordination of these proteins. While deletion of cpl1 has only mild effects on the virulence of U. maydis, a recent study showed that deletion of uvi2 strongly impairs U. hordei virulence. Our structural comparison between Cpl1 and Uvi2 reveals sequence variations in the loop regions that might explain a diverging function.PMID:37171083 | DOI:10.1111/mpp.13349

Curr Pharm Des. 2023 May 11. doi: 10.2174/1381612829666230511161308. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is an increasingly serious disease worldwide that can damage the joints and bones of sufferers. Sanmiao Pill (SMP), a classical traditional Chinese medicine (TCM) prescription, has been used for effective treatments for RA in the clinic. To comprehensively illuminate the therapeutic mechanism of SMP in the treatment of RA, the effects of SMP on biomarkers and metabolic pathways in rats with adjuvant-induced arthritis (AIA) were examined.METHODS: Sprague Dawley rats were randomly divided into two control (CC, Control) groups, two model (MM, Model) groups, a methotrexate group (MTX, 7.6 mg/kg body weight per week), and two SMP groups (San-L, 28.7 mg/kg body weight per day and San-H, 57.4 mg/kg body weight per day). Rats' body weight, paw swelling, arthritis scores, biochemical parameters, histopathology, and so on were used to evaluate the success of the model and the therapeutic effects of SMP. The metabolic techniques were used to characterize the metabolic profile and biomarkers of the serum and urine samples of rats to reveal the metabolic changes that occurred after SMP treatment.RESULTS: After 21 days of treatment, SMP improved weight gain, reduced the severity of paw swelling, lowered the levels of biochemical indicators (CCP-Ab, IL-6, TNF-α, RF), decreased destruction of articular cartilage and bone erosion, and protected the affected joints.Additionally, 17 and 19 potential biomarkers associated with RA were identified in the serum and urine, respectively. SMP significantly reversed 14 potential biomarkers, such as arachidonic acid, lysoPC(20:4(5Z,8Z,11Z,14Z)), L-tryptophan, 9-cis-Retinoic acid, hippuric acid, pyridoxine, and pantothenic acid. These metabolites are associated with arachidonic acid metabolism, glycerophospholipid catabolism, tryptophan metabolism, phenylalanine metabolism, vitamin B6 metabolism, etc. Conclusion: These results indicated that RA-related biomarkers reflected the metabolic profile of AIA rats. Meanwhile, SMP could effectively treat RA mainly by reducing inflammation and regulating abnormal lipid metabolic pathways and amino acid metabolisms. It showed that metabolomics could be used to analyze the metabolic profiles involved in RA and reveal the mechanism of SMP treatment of RA.PMID:37171005 | DOI:10.2174/1381612829666230511161308

Med Sci Sports Exerc. 2023 May 12. doi: 10.1249/MSS.0000000000003205. Online ahead of print.ABSTRACTPURPOSE: The aim of this study was to understand the serum metabolomic signatures of moderate-to-vigorous physical activity (MVPA) and sedentary behavior, and further associate their metabolomic signatures with incident cardiometabolic diseases.METHODS: This analysis included 2711 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 years (2008-11). An untargeted, liquid chromatography-mass spectrometry (LC-MS) was used to profile the serum metabolome. The associations of metabolites with accelerometer-measured MVPA and sedentary time were examined using survey linear regressions adjusting for covariates. The weighted correlation network analysis (WGCNA) identified modules of correlated metabolites in relation to sedentary time, and the modules were associated with incident diabetes, dyslipidemia, and hypertension over the 6-year follow up.RESULTS: Of 624 metabolites, five and 102 were associated with MVPA and sedentary behavior at FDR < 0.05, respectively, after adjusting for socioeconomic and lifestyle factors. The WGCNA analysis identified 8 modules from 102 metabolites associated with sedentary time. Four modules (branched-chain amino acids [BCAA], erythritol, polyunsaturated fatty acid [PUFA], creatine) were positively, and the other four (acyl choline, plasmalogen GPC, plasmalogen GPE, urea cycle) were negatively correlated with sedentary time. Among these modules, a higher BCAA score and a lower plasmalogen GPC score were associated with increased risks of diabetes and dyslipidemia. A higher erythritol score was associated with increased risk of diabetes, and a lower acyl choline score was linked to increased risk of hypertension.CONCLUSIONS: In this study of US Hispanics/Latinos, we identified multiple serum metabolomic signatures of sedentary behavior and their associations with risk of incident diabetes, hypertension, and dyslipidemia. These findings suggest a potential role of circulating metabolites in the links between sedentary behavior and cardiometabolic diseases.PMID:37170952 | DOI:10.1249/MSS.0000000000003205

J Exp Bot. 2023 May 12:erad177. doi: 10.1093/jxb/erad177. Online ahead of print.ABSTRACTModern genetics and biochemistry have revolutionized our understanding of plant biology. However, biochemical genetics can be traced to the foundation of Mendelian genetics indeed one of the milestone discoveries of Mendels seven characteristics of pea plants could later be ascribed to be due to mutation in starch branching enzyme. Here we review both current and historical strategies for the elucidation of plant metabolic pathways and the genes which encode their component enzymes and regulators. We utilize this historical review to discuss a range of classical genetic phenomena including, epistasis, canalization and heterosis as viewed through the lens of contemporary high-throughput data obtained via the array of approaches currently adopted in multi-omics studies.PMID:37170864 | DOI:10.1093/jxb/erad177

Endocrinology. 2023 May 12:bqad073. doi: 10.1210/endocr/bqad073. Online ahead of print.ABSTRACTApproximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30%-40% of patients with ER+ breast cancer still experiences recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified NAMPT, an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with Fulv. We tested whether the blockade of NAD+ production via inhibition of nicotinamide phosphoribosyltransferase (NAMPT) synergizes with standard-of-care therapies for ER+ metastatic breast cancer in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibitor in combination with Fulv reversed the expression of gene sets associated with more aggressive tumor phenotype, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant metastatic breast cancer is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα-NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment.PMID:37170651 | DOI:10.1210/endocr/bqad073

Allergol Immunopathol (Madr). 2023 May 1;51(3):99-107. doi: 10.15586/aei.v51i3.788. eCollection 2023.ABSTRACTBronchiolitis is the most common respiratory infection leading to hospitalization and constitutes a significant healthcare burden. The two main viral agents causing bronchiolitis, respiratory syncytial virus (RSV) and rhinovirus (RV), have distinct cytopathic, immune response, and clinical characteristics. Different approaches have been suggested for subtyping bronchiolitis based on viral etiology, atopic status, transcriptome profiles in blood, airway metabolome, lipidomic data, and airway microbiota. The highest risk of asthma at school age has been in a subgroup of bronchiolitis characterized by older age, high prevalence of RV infection, previous breathing problems, and/or eczema. Regarding solely viral etiology, RV-bronchiolitis in infancy has been linked to a nearly three times higher risk of developing asthma than RSV-bronchiolitis. Although treatment with betamimetics and systemic corticosteroids has been found ineffective in bronchiolitis overall, it can be beneficial for infants with severe RV bronchiolitis. Thus, there is a need to develop a more individualized therapeutic approach for bronchiolitis and follow-up strategies for infants at higher risk of asthma in the future perspective.PMID:37169566 | DOI:10.15586/aei.v51i3.788

Physiol Plant. 2023 May 11:e13933. doi: 10.1111/ppl.13933. Online ahead of print.ABSTRACTSignificant variations in leaf colours, pigment contents, and main taste compounds in young shoots from albino tea plants (Camellia sinensis) influence tea flavour. However, the seasonal metabolic pattern and molecular regulatory mechanism of these metabolites remain largely elusive. Herein, we conducted morphological, biochemical, metabolomic and transcriptomic analyses between an albino tea cultivar 'Zhonghuang 3' ('ZH3') and a green strain 'Tai cha 15' ('TC15') at four time points (Apr 12, May 31, Jul 14, and Aug 17) to elucidate dynamic changes in these compounds and predict the relationships among transcription factors (TFs), target genes (TGs), and metabolite abundance. Generally, leaf colours and pigment contents were significantly lighter and lower, respectively, in 'ZH3' than in 'TC15' from spring to summer, but were subsequently similar. Compared to 'TC15', 'ZH3' had lower and broader phenol/ammonia ratio as well as stable caffeine content and showed more significantly different metabolites and differentially expressed genes. The relationship between pigments, main taste compounds and their biosynthetic genes, as well as TFs and their TGs had genetic specificity. These results suggested that the biosynthesis of these compounds was probably both season- and variety-dependent. In total, 12 models of the TF-TG-metabolite regulatory network were proposed to uncover the biosynthetic and regulatory mechanisms of these metabolites in tea plants. High correlation was observed between some structural genes and TFs with the accumulation of these metabolites. These findings provide novel insights into the regulatory mechanisms underlying accumulation of pigments and main taste compounds in tea plants. This article is protected by copyright. All rights reserved.PMID:37169369 | DOI:10.1111/ppl.13933

J Ethnopharmacol. 2023 May 9:116566. doi: 10.1016/j.jep.2023.116566. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal prescription Yi-Fei San-Jie pill (YFSJ) has been used for adjuvant treatment in patients with lung cancer for a long time.AIM OF THE STUDY: Reports have indicated that the combination of gefitinib (Gef) with YFSJ inhibits the proliferation of EGFR-TKI-resistant cell lines by enhancing cellular apoptosis and autophagy in non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying the effect of YFSJ on EGFR-TKI resistance and related metabolic pathways remain to be explored.MATERIALS AND METHODS: In our report, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), metabolomics, network pharmacology, bioinformatics, and biological analysis methods were used to investigate the mechanism.RESULTS: The UPLC-MS/MS data identified 42 active compounds of YFSJ extracts. YFSJ extracts can enhance the antitumor efficacy of Gef without hepatic and renal toxicity in vivo. The analysis of the metabolomics pathway enrichment revealed that YFSJ mainly affected the tyrosine metabolism pathway in rat models. Moreover, YFSJ has been shown to reverse Gef resistance and improve the effects of Gef on the cellular viability, migration capacity, and cell cycle arrest of NSCLC cell lines with EGFR mutations. The results of network pharmacology and molecular docking analyses revealed that tyrosine metabolism-related active compounds of YFSJ affect EGFR-TKIs resistance in NSCLC by targeting cell cycle and the MET/EGFR signaling pathway; these findings were validated by western blotting and immunohistochemistry.CONCLUSIONS: YFSJ inhibits NSCLC by inducing cell cycle arrest in the G1/S phase to suppress tumor growth, cell viability, and cell migration through synergistic effects with Gef via the tyrosine metabolic pathway and the EGFR/MET signaling pathway. To summarize, the findings of the current study indicate that YFSJ is a prospective complementary treatment for Gef-resistant NSCLC.PMID:37169317 | DOI:10.1016/j.jep.2023.116566