PubMed

Eur J Prev Cardiol. 2023 Sep 1:zwad285. doi: 10.1093/eurjpc/zwad285. Online ahead of print.ABSTRACTAIMS: To investigate the associations between passive tobacco smoke exposure and daily smoking with a comprehensive metabolic profile, measured repeatedly from childhood to adulthood.METHODS: Study cohort was derived from the Special Turku Coronary Risk Factor Intervention Project(STRIP). Smoking status was obtained by questionnaire, while serum cotinine concentrations were measured using gas chromatography. Metabolic measures were quantified by nuclear magnetic resonance metabolomics at 9(n = 539), 11(n = 536), 13(n = 525), 15(n = 488), 17(n = 455), and 19(n = 409) years. Association of passive tobacco smoke exposure with metabolic profile compared participants who reported less-than-weekly smoking and had serum cotinine concentration <1 ng/mL(no exposure) to those whose cotinine concentration was ≥10 ng/mL(passive tobacco smoke exposure). Associations of daily smoking with metabolic profile in adolescence were analysed by comparing participants reporting daily smoking to those reporting no tobacco use and having serum cotinine concentrations <1 ng/mL.RESULTS: Passive tobacco smoke exposure was directly associated with the serum ratio of monounsaturated fatty acids to total fatty acids (β=0.34SD, [0.17-0.51], p < 0.0001) and inversely associated with the serum ratios of polyunsaturated fatty acids. Exposure to passive tobacco smoke was directly associated with VLDL particle size (β=0.28SD, [0.12-0.45], p = 0.001), and inversely associated with HDL particle size (β=-0.21SD, [-0.34-(-0.07)], p = 0.003). Daily smokers exhibited a similar metabolic profile to those exposed to passive tobacco smoke. These results persisted after adjusting for body mass index, STRIP study group allocation, dietary target score, pubertal status, and parental socio-economic status.CONCLUSIONS: Both passive and active tobacco smoke exposure during childhood and adolescence are detrimentally associated with circulating metabolic measures indicative of increased cardiometabolic risk.PMID:37655930 | DOI:10.1093/eurjpc/zwad285

Appl Environ Microbiol. 2023 Sep 1:e0082623. doi: 10.1128/aem.00826-23. Online ahead of print.ABSTRACTComparative proteomics and untargeted metabolomics were combined to study the physiological and metabolic adaptations of Rhodococcus qingshengii IGTS8 under biodesulfurization conditions. After growth in a chemically defined medium with either dibenzothiophene (DBT) or MgSO4 as the sulfur source, many differentially produced proteins and metabolites associated with several metabolic and physiological processes were detected including the metabolism of carbohydrates, amino acids, lipids, nucleotides, vitamins, protein synthesis, transcriptional regulation, cell envelope biogenesis, and cell division. Increased production of the redox cofactor mycofactocin and associated proteins was one of the most striking adaptations under biodesulfurization conditions. While most central metabolic enzymes were less abundant in the presence of DBT, a key enzyme of the glyoxylate shunt, isocitrate lyase, was up to 26-fold more abundant. Several C1 metabolism and oligotrophy-related enzymes were significantly more abundant in the biodesulfurizing culture. R. qingshengii IGTS8 exhibited oligotrophic growth in liquid and solid media under carbon starvation. Moreover, the oligotrophic growth was faster on the solid medium in the presence of DBT compared to MgSO4 cultures. In the DBT culture, the cell envelope and phospholipids were remodeled, with lower levels of phosphatidylethanolamine and unsaturated and short-chain fatty acids being the most prominent changes. Biodesulfurization increased the biosynthesis of osmoprotectants (ectoine and mannosylglycerate) as well as glutamate and induced the stringent response. Our findings reveal highly diverse and overlapping stress responses that could protect the biodesulfurizing culture not only from the associated sulfate limitation but also from chemical, oxidative, and osmotic stress, allowing efficient resource management. IMPORTANCE Despite decades of research, a commercially viable bioprocess for fuel desulfurization has not been developed yet. This is mainly due to lack of knowledge of the physiology and metabolism of fuel-biodesulfurizing bacteria. Being a stressful condition, biodesulfurization could provoke several stress responses that are not understood. This is particularly important because a thorough understanding of the microbial stress response is essential for the development of environmentally friendly and industrially efficient microbial biocatalysts. Our comparative systems biology studies provide a mechanistic understanding of the biology of biodesulfurization, which is crucial for informed developments through the rational design of recombinant biodesulfurizers and optimization of the bioprocess conditions. Our findings enhance the understanding of the physiology, metabolism, and stress response not only in biodesulfurizing bacteria but also in rhodococci, a precious group of biotechnologically important bacteria.PMID:37655899 | DOI:10.1128/aem.00826-23

Microbiol Spectr. 2023 Sep 1:e0018923. doi: 10.1128/spectrum.00189-23. Online ahead of print.ABSTRACTGut microbiota and their secreted metabolites have an influence on the initiation and progression of colon cancer. Probiotics are extensively perceived as a potential microbiota-modulation strategy to promote the health of the host, while the effectiveness of preventing colon cancer based on microbiota therapy has not been confirmed, and antitumor mechanisms influenced by microbiota and their metabolites with the intervention of probiotics remain to be further investigated. In vitro, Lactobacillus (JY300-8 and JMR-01) significantly inhibited the proliferation of CT26, HT29, and HCT116 cells. Moreover, we studied the prevention and therapy efficiency of Lactobacillus and its underlying antitumor mechanism through the alteration of gut microbiota and their metabolites regulated by Lactobacillus in colon cancer models in mice. We demonstrated that the pre-administration of Lactobacillus (JY300-8 and JMR-01) for 20 days before establishing tumor models resulted in an 86.21% reduction in tumor formation rate compared to tumor control group. Subsequently, continuous oral administration of living Lactobacillus significantly suppresses tumor growth, and tumor volumes decrease by 65.2%. Microbiome and metabolome analyses reveal that Lactobacillus suppresses colonic tumorigenesis and progression through the modulation of gut microbiota homeostasis and metabolites, including the down-regulation of secondary bile acids, sphingosine 1-phosphate (S1P), and pyrimidine metabolism, as well as the production of anticarcinogenic compounds in tumor-bearing mice. Additionally, metabolome analyses of Lactobacillus (JY300-8 and JMR-01) indicate that living Lactobacillus could reduce the relative abundance of alanine and L-serine to suppress tumor progression by regulating the tumor microenvironment, including down-regulation of pyrimidine metabolism and S1P signaling in cancer. These findings provide a potential prevention strategy and therapeutic target for colon cancer through the intervention of dietary Lactobacillus. IMPORTANCE The modulation of gut microbiota and metabolites has a significant influence on the progression of colon cancer. Our research indicated that the intervention of probiotics is a potentially feasible strategy for preventing colon cancer. We have also revealed the underlying antitumor mechanism through the alteration of gut microbiota and their metabolites, which could lead to broader biomedical impacts on the prevention and therapy of colon cancer with microbiota-based therapy regulated by probiotics.PMID:37655887 | DOI:10.1128/spectrum.00189-23

J Clin Invest. 2023 Sep 1;133(17):e171117. doi: 10.1172/JCI171117.ABSTRACTBACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.PMID:37655657 | DOI:10.1172/JCI171117

J Am Heart Assoc. 2023 Sep 1:e029817. doi: 10.1161/JAHA.123.029817. Online ahead of print.ABSTRACTBackground Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization-related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood-brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood-brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA-treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand-alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.PMID:37655472 | DOI:10.1161/JAHA.123.029817

Front Microbiol. 2023 Aug 15;14:1187982. doi: 10.3389/fmicb.2023.1187982. eCollection 2023.ABSTRACTIt is of positive significance to explore the mechanism of antioxidant and metabolic response of Canna indica under Cr stress mediated by rhizosphere niche. However, the mechanisms of recruitment and interaction of rhizosphere microorganisms in plants still need to be fully understood. This study combined physiology, microbiology, and metabolomics, revealing the interaction between C. indica and rhizosphere microorganisms under Cr stress. The results showed that Cr stress increased the content of malondialdehyde (MDA) and oxygen-free radicals (ROS) in plants. At the same time, the activities of antioxidant enzymes (SOD, POD, and APX) and the contents of glutathione (GSH) and soluble sugar were increased. In addition, Cr stress decreased the α diversity index of C. indica rhizosphere bacterial community and changed its community structure. The dominant bacteria, namely, Actinobacteriota, Proteobacteria, and Chloroflexi accounted for 75.16% of the total sequence. At the same time, with the extension of stress time, the colonization amount of rhizosphere-dominant bacteria increased significantly, and the metabolites secreted by roots were associated with the formation characteristics of Proteobacteria, Actinobacteria, Bacteroidetes, and other specific bacteria. Five critical metabolic pathways were identified by metabolome analysis, involving 79 differentially expressed metabolites, which were divided into 15 categories, mainly including lipids, terpenoids, and flavonoids. In conclusion, this study revealed the recruitment and interaction response mechanism between C. indica and rhizosphere bacteria under Cr stress through multi-omics methods, providing the theoretical basis for the remediation of Cr-contaminated soil.PMID:37655347 | PMC:PMC10465350 | DOI:10.3389/fmicb.2023.1187982

Acta Pharm Sin B. 2023 Aug;13(8):3561-3574. doi: 10.1016/j.apsb.2023.03.021. Epub 2023 Mar 29.ABSTRACTWS9326A is a peptide antibiotic containing a highly unusual N-methyl-E-2-3-dehydrotyrosine (NMet-Dht) residue that is incorporated during peptide assembly on a non-ribosomal peptide synthetase (NRPS). The cytochrome P450 encoded by sas16 (P450Sas) has been shown to be essential for the formation of the alkene moiety in NMet-Dht, but the timing and mechanism of the P450Sas-mediated α,β-dehydrogenation of Dht remained unclear. Here, we show that the substrate of P450Sas is the NRPS-associated peptidyl carrier protein (PCP)-bound dipeptide intermediate (Z)-2-pent-1'-enyl-cinnamoyl-Thr-N-Me-Tyr. We demonstrate that P450Sas-mediated incorporation of the double bond follows N-methylation of the Tyr by the N-methyl transferase domain found within the NRPS, and further that P450Sas appears to be specific for substrates containing the (Z)-2-pent-1'-enyl-cinnamoyl group. A crystal structure of P450Sas reveals differences between P450Sas and other P450s involved in the modification of NRPS-associated substrates, including the substitution of the canonical active site alcohol residue with a phenylalanine (F250), which in turn is critical to P450Sas activity and WS9326A biosynthesis. Together, our results suggest that P450Sas catalyses the direct dehydrogenation of the NRPS-bound dipeptide substrate, thus expanding the repertoire of P450 enzymes that can be used to produce biologically active peptides.PMID:37655329 | PMC:PMC10465960 | DOI:10.1016/j.apsb.2023.03.021

Acta Pharm Sin B. 2023 Aug;13(8):3238-3251. doi: 10.1016/j.apsb.2023.05.021. Epub 2023 May 23.ABSTRACTEmerging evidence has demonstrated the vital role of metabolism in various diseases or disorders. Metabolomics provides a comprehensive understanding of metabolism in biological systems. With advanced analytical techniques, metabolomics exhibits unprecedented significant value in basic drug research, including understanding disease mechanisms, identifying drug targets, and elucidating the mode of action of drugs. More importantly, metabolomics greatly accelerates the drug development process by predicting pharmacokinetics, pharmacodynamics, and drug response. In addition, metabolomics facilitates the exploration of drug repurposing and drug-drug interactions, as well as the development of personalized treatment strategies. Here, we briefly review the recent advances in technologies in metabolomics and update our knowledge of the applications of metabolomics in drug research and development.PMID:37655318 | PMC:PMC10465962 | DOI:10.1016/j.apsb.2023.05.021

JTO Clin Res Rep. 2023 Jul 27;4(9):100556. doi: 10.1016/j.jtocrr.2023.100556. eCollection 2023 Sep.ABSTRACTINTRODUCTION: Neoadjuvant chemoimmunotherapy has recently been the standard of care for resectable locally advanced NSCLC. Factors affecting the neoadjuvant immunotherapy efficacy, however, remain elusive. Metabolites have been found to modulate immunity and associate with immunotherapeutic efficacy in advanced tumors. Therefore, we aimed to investigate the impact of plasma metabolites on the pathologic response after neoadjuvant chemoimmunotherapy.METHODS: Patients with stage IIIA (N2) NSCLC who underwent neoadjuvant chemoimmunotherapy in a prospective phase 2 clinical trial (NCT04422392) were enrolled. Metabolomic profiling of the plasma before treatment was performed using liquid chromatography-mass spectrometry. A Lewis lung carcinoma mouse model was further used to investigate the underlying mechanisms. Proteomics and multiplexed immunofluorescence of the mice tumor were performed.RESULTS: A total of 39 patients who underwent three cycles of anti-programmed cell death-protein 1 (anti-PD-1) (sintilimab) and chemotherapy were included. The level of acetaminophen (APAP) was found to be significantly elevated in patients who did not achieve major pathologic response. The level of APAP remained an independent predictor for major pathologic response in multivariate logistic analysis. In the Lewis lung carcinoma mouse model, combination of APAP and anti-PD-1 treatment significantly reduced the treatment efficacy compared with anti-PD-1 treatment alone. Proteomics of the tumor revealed that myeloid leukocyte activation and neutrophil activation pathways were enriched after APAP treatment. Tumor microenvironment featuring analysis also revealed that the combination treatment group was characterized with more abundant neutrophil signature. Further multiplexed immunofluorescence confirmed that more neutrophil extracellular trap formation was observed in the combination treatment group.CONCLUSIONS: APAP could impair neoadjuvant chemoimmunotherapy efficacy in patients with NSCLC by promoting neutrophil activation and neutrophil extracellular trap formation.PMID:37654895 | PMC:PMC10466912 | DOI:10.1016/j.jtocrr.2023.100556

Front Physiol. 2023 Aug 15;14:1195441. doi: 10.3389/fphys.2023.1195441. eCollection 2023.ABSTRACTObjective: Diabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is highly associated with devastating outcomes. Hypoxia-inducible factor (HIF), the main transcription factor that regulates cellular responses to hypoxia, plays an important role in regulating erythropoietin (EPO) synthesis. FG-4592 is the HIF stabilizer that is widely used in patients with renal anemia. We investigated the effect of FG-4592 on DKD phenotypes and the pharmacologic mechanism from the perspective of gut microbiota and systemic metabolism. Design: We collected the clinical data of 73 participants, including 40 DKD patients with combined renal anemia treated with FG-4592, and 33 clinical index-matched DKD patients without FG-4592 treatment from The First Affiliated Hospital of Zhengzhou University at the beginning and after a 3-6-month follow-up period. We established DKD mouse models treated by FG-4592 and performed fecal microbiota transplantation from FG-4592-treated DKD mice to investigate the effects of FG-4592 on DKD and to understand this mechanism from a microbial perspective. Untargeted metabolome-microbiome combined analysis was implemented to globally delineate the mechanism of FG-4592 from both microbial and metabolomic aspects. Result: DKD phenotypes significantly improved after 3-6 months of FG-4592 treatment in DKD patients combined with renal anemia, including a decreased level of systolic blood pressure, serum creatinine, and increased estimated glomerular infiltration rate. Such effects were also achieved in the DKD mouse model treated with FG-4592 and can be also induced by FG-4592-influenced gut microbiota. Untargeted plasma metabolomics-gut microbiota analysis showed that FG-4592 dramatically altered both the microbial and metabolic profiles of DKD mice and relieved DKD phenotypes via upregulating beneficial gut microbiota-associated metabolites. Conclusion: FG-4592 can globally relieve the symptoms of DKD patients combined with renal anemia. In the animal experiment, FG-4592 can reconstruct the intestinal microbial profiles of DKD to further upregulate the production of gut-associated beneficial metabolites, subsequently improving DKD phenotypes.PMID:37654676 | PMC:PMC10465800 | DOI:10.3389/fphys.2023.1195441

Front Med (Lausanne). 2023 Aug 16;10:1210170. doi: 10.3389/fmed.2023.1210170. eCollection 2023.ABSTRACTBACKGROUND: Tai Chi (TC) controls pain through mind-body exercise and appears to alter inflammatory mediators. TC actions on lipid biomarkers associated with inflammation and brain neural networks in women with knee osteoarthritic pain were investigated.METHODS: A single-center, pre- and post-TC group (baseline and 8 wk) exercise pilot study in postmenopausal women with knee osteoarthritic pain was performed. 12 eligible women participated in TC group exercise. The primary outcome was liquid chromatography tandem mass spectrometry determination of circulating endocannabinoids (eCB) and oxylipins (OxL). Secondary outcomes were correlations between eCB and OxL levels and clinical pain/limitation assessments, and brain resting-state function magnetic resonance imaging (rs-fMRI).RESULTS: Differences in circulating quantitative levels (nM) of pro-inflammatory OxL after TC were found in women. TC exercise resulted in lower OxL PGE1 and PGE2 and higher 12-HETE, LTB4, and 12-HEPE compared to baseline. Pain assessment and eCB and OxL levels suggest crucial relationships between TC exercise, inflammatory markers, and pain. Higher plasma levels of eCB AEA, and 1, 2-AG were found in subjects with increased pain. Several eCB and OxL levels were positively correlated with left and right brain amygdala-medial prefrontal cortex functional connectivity.CONCLUSION: TC exercise lowers pro-inflammatory OxL in women with knee osteoarthritic pain. Correlations between subject pain, functional limitations, and brain connectivity with levels of OxL and eCB showed significance. Findings indicate potential mechanisms for OxL and eCB and their biosynthetic endogenous PUFA precursors that alter brain connectivity, neuroinflammation, and pain.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT04046003.PMID:37654656 | PMC:PMC10466388 | DOI:10.3389/fmed.2023.1210170

Heliyon. 2023 Aug 19;9(8):e19150. doi: 10.1016/j.heliyon.2023.e19150. eCollection 2023 Aug.ABSTRACTBACKGROUND: Normothermic machine perfusion (NMP) could provide protection to organs from donation after circulatory death (DCD) before transplantation, and its molecular mechanism remains unclear. Our previous study discovered that the air-ventilated NMP confers a better DCD liver recovery than oxygen-ventilated NMP. The purpose in the current study was to investigate the protective mechanism of air-ventilated NMP in a rat model of DCD liver by metabolomics, and to select biomarker to predict liver function recovery.MATERIALS AND METHODS: Peroxisome proliferator activator receptor-α (PPARα) agonist or antagonist was administered via the perfusion circuit in the air-ventilated NMP. Perfusate samples were taken for measurements of aminotransferases using standard biochemical methods, tumor necrosis factor-alpha and interleukin-6. Liver biopsies were allocated for detection of metabolomics, PPARα and cytochrome P450 1A2 (CYP1A2).RESULTS: Metabolomics analysis revealed the significant increased γ-linolenic acid and decreased adrenic acid during the air-ventilated NMP, indicating linoleic acid metabolism pathway was associated with a better DCD liver recovery; as a major enzyme involved in linolenic acid metabolism, CYP1A2 was found correlated with a less inflammation and better liver function with the air-ventilated NMP; PPARα agonist could increase CYP1A2 expression and activity, decrease inflammation response, and improve liver function with the air-ventilated NMP, while PPARα antagonist played the opposite.CONCLUSION: Air-ventilated NMP confers a better liver recovery from DCD rats through the activated linoleic acid metabolism and CYP1A2 upregulation; CYP1A2 expression and activity might function as biomarker to predict DCD liver function recovery with NMP.PMID:37654459 | PMC:PMC10465863 | DOI:10.1016/j.heliyon.2023.e19150

Magn Reson Chem. 2023 Sep 1. doi: 10.1002/mrc.5391. Online ahead of print.ABSTRACTProstate cancer (PCa) is one of the most prevalent cancers in men worldwide. For its detection, serum prostate-specific antigen (PSA) screening is commonly used, despite its lack of specificity, high false positive rate, and inability to discriminate indolent from aggressive PCa. Following increases in serum PSA levels, clinicians often conduct prostate biopsies with or without advanced imaging. Nuclear magnetic resonance (NMR)-based metabolomics has proven to be promising for advancing early-detection and elucidation of disease progression, through the discovery and characterization of novel biomarkers. This retrospective study of urine-NMR samples, from prostate biopsy patients with and without PCa, identified several metabolites involved in energy metabolism, amino acid metabolism, and the hippuric acid pathway. Of note, lactate and hippurate-key metabolites involved in cellular proliferation and microbiome effects, respectively-were significantly altered, unveiling widespread metabolomic modifications associated with PCa development. These findings support urine metabolomics profiling as a promising strategy to identify new clinical biomarkers for PCa detection and diagnosis.PMID:37654196 | DOI:10.1002/mrc.5391

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2023 Aug;45(4):581-590. doi: 10.3881/j.issn.1000-503X.15496.ABSTRACTObjective To investigate the effects of Weidiao-3(WD-3)Mixture on the clinical efficacy of immunotherapy for advanced gastric cancer and the intestinal flora.Methods Fifty-one patients with advanced gastric cancer treated in Wuxi Traditional Chinese Medicine Hospital from January 2020 to December 2021 were randomized into a WD-3 group(immunotherapy + WD-3 Mixture,one dose per day)(n=25)and a gastric cancer(GC) group(only immunotherapy)(n=26)according to the admission time.Ten healthy volunteers were included as the healthy control group.The Karnofsky score and the Quality of Life Questionnare-Core score were evaluated before and after treatment,and the clinical efficacy was compared after treatment.After treatment,the stool samples were collected for 16SrRNA gene high-throughput sequencing and targeted metabolomics.The α and β diversity and structure of the intestinal flora and the content of short-chain fatty acids were compared between groups.Results The quality of life in both groups improved after treatment and was better in the WD-3 group than in the GC group(P=0.035).The dry mouth(P=0.038)and altered taste(P=0.008)were mitigated in the WD-3 group after treatment,and the reflux(P=0.001)and dry mouth(P=0.022)were mitigated in the GC group after treatment.After treatment,the WD-3 group outperformed the GC group in terms of dysphagia(P=0.047)and dry mouth(P=0.045).The WD-3 group was superior to the GC group in terms of objective remission rate and disease control rate,with prolonged median progression-free survival and median overall survival(P=0.039,P=0.043).The α and β diversity indexes of the intestinal flora showed no significant differences between WD-3 and GC groups(all P>0.05).At the phylum level,WD-3 and GC groups had lower relative abundance of Firmicutes(P=0.038,P=0.042)and higher relative abundance of Proteobacteria(P=0.016,P=0.015)than the healthy control group.The relative abundance of Actinomycetes in the GC group was lower than that in the healthy control group(P=0.035)and the WD-3 group(P=0.046).At the genus level,the GC group had lower relative abundance of Bifidobacteria and Coprococcus than the healthy control group and the WD-3 group(all P<0.001).LEfSe revealed the differences in the relative abundance of 6 intestinal bacterial taxa between the WD-3 group and the GC group.At the genus level,Saccharopolyspora had higher relative abundance in the WD-3 group than in the healthy control group and only existed in the WD-3 group.The content of isobutyric acid and isovaleric acid in the WD-3 group was higher than that in the healthy control group(P=0.037,P=0.004).Conclusion WD-3 Mixture may increase the relative abundance of Bifidobacteria and Coprococcus and the content of isobutyric acid and isovaleric acid to alter the intestinal microecology,thereby improving the efficacy of immunotherapy for gastric cancer.PMID:37654138 | DOI:10.3881/j.issn.1000-503X.15496

Plants (Basel). 2023 May 22;12(10):2059. doi: 10.3390/plants12102059.ABSTRACTAlfalfa (Medicago sativa L.) is a widely grown perennial leguminous forage crop with a number of positive attributes. However, despite its moderate ability to tolerate saline soils, which are increasing in prevalence worldwide, it suffers considerable yield declines under these growth conditions. While a general framework of the cascade of events involved in plant salinity response has been unraveled in recent years, many gaps remain in our understanding of the precise molecular mechanisms involved in this process, particularly in non-model yet economically important species such as alfalfa. Therefore, as a means of further elucidating salinity response mechanisms in this species, we carried out in-depth physiological assessments of M. sativa cv. Beaver, as well as transcriptomic and untargeted metabolomic evaluations of leaf tissues, following extended exposure to salinity (grown for 3-4 weeks under saline treatment) and control conditions. In addition to the substantial growth and photosynthetic reductions observed under salinity treatment, we identified 1233 significant differentially expressed genes between growth conditions, as well as 60 annotated differentially accumulated metabolites. Taken together, our results suggest that changes to cell membranes and walls, cuticular and/or epicuticular waxes, osmoprotectant levels, antioxidant-related metabolic pathways, and the expression of genes encoding ion transporters, protective proteins, and transcription factors are likely involved in alfalfa's salinity response process. Although some of these alterations may contribute to alfalfa's modest salinity resilience, it is feasible that several may be disadvantageous in this context and could therefore provide valuable targets for the further improvement of tolerance to this stress in the future.PMID:37653976 | DOI:10.3390/plants12102059

Plants (Basel). 2023 May 22;12(10):2058. doi: 10.3390/plants12102058.ABSTRACTFood-deceptive flowers primarily use visual signals (such as color) to mimic model plants and deceive insects into achieving pollination. Paphiopedilum micranthum is a food-deceptive orchid that has a pink labellum and two purple petals with a yellow base and has been proven to be pollinated by bumblebees. However, the chemical and molecular bases of the floral color are not well understood. We conducted targeted metabolite profiling and transcriptomic analysis to determine the color signal and its genetic basis in P. micranthum. We found that both anthocyanins and carotenoids contribute significantly to the formation of floral color that determines the color signal. Higher concentrations of anthocyanins (cyanidin and peonidin) and carotenoids (primarily lutein and zeaxanthin) were detected in the petal compared to the labellum. The upregulation of structural genes of CHS, F3'H, DFR and ANS on the anthocyanin biosynthesis pathway in petals was identified, as well as three genes of LCYE, BCH, and CCD4 on the carotenoid biosynthesis pathway. Furthermore, we discovered that three R2R3-MYBs and one bHLH transcription factors were co-expressed with the expression of different genes. These genes and transcription factors may be responsible for the spatial color difference of P. micranthum. Our study emphasizes that the color of this food-deceptive orchids is achieved through specific genes and transcription factors associated with the pigment biosynthesis pathway.PMID:37653975 | DOI:10.3390/plants12102058

Plants (Basel). 2023 May 22;12(10):2054. doi: 10.3390/plants12102054.ABSTRACTCold stress impairs plant growth and development, resulting in crop failure. Cultivated potato (Solanum tuberosum L.) is sensitive to freezing, while its wild relative, S. commersonii, has a strong freezing tolerance. To decipher the anti-freezing mechanism of CM, we carried out a transcriptomic and metabolomic analysis of an anti-freezing variety of CM (a type of S. commersonii) and a freeze-sensitive variety of DM (a type of Solanum tuberosum L.). A total of 49,232 high-quality transcripts from 12,811 gene loci, including 46,772 coding sequences and 2018 non-coding RNAs, were identified. KEEG enrichment analysis of differentially expressed genes (DEGs) between the two varieties showed that the flavonoid biosynthesis pathway was strongly induced by freezing stress, which was proven by flavonoid metabolome analysis. Consistent with the accumulation of more flavonoids, nearly all the pathway genes were significantly upregulated in CM than those in DM. The transcript levels of two chalcone synthase (CHS-1) isoforms and four isoforms of flavonoid 3'-hydroxylase (F3'H-1) were confirmed by qRT-PCR. Co-expression analysis identified one Myb-related and three UGTs (UDP-glycosyltransferase) that were significantly upregulated in CM during freezing stress. Our findings support that the flavonoid pathway was significantly enhanced by freezing stress and the greater accumulation ofglycosylatedflavonoids in resistant types than that of sensitive types, maybe accounting for the increased freezing tolerance of freeze-resistant potato varieties.PMID:37653971 | DOI:10.3390/plants12102054

Plants (Basel). 2023 May 22;12(10):2052. doi: 10.3390/plants12102052.ABSTRACTStem nematode disease can seriously reduce the yield of sweet potato (Ipomoea batatas (L.) Lam). To explore resistance mechanism to stem nematode in sweet potato, transcriptomes and metabolomes were sequenced and compared between two sweet potato cultivars, the resistant Zhenghong 22 and susceptible Longshu 9, at different times after stem nematode infection. In the transcriptional regulatory pathway, mitogen-activated protein kinase signaling was initiated in Zhenghong 22 at the early stage of infection to activate genes related to ethylene production. Stem nematode infection in Zhenghong 22 also triggered fatty acid metabolism and the activity of respiratory burst oxidase in the metabolic pathway, which further stimulated the glycolytic and shikimic pathways to provide raw materials for secondary metabolite biosynthesis. An integrated analysis of the secondary metabolic regulation pathway in the resistant cultivar Zhenghong 22 revealed the accumulation of tryptophan, phenylalanine, and tyrosine, leading to increased biosynthesis of phenylpropanoids and salicylic acid and enhanced activity of the alkaloid pathway. Stem nematode infection also activated the biosynthesis of terpenoids, abscisic acid, zeatin, indole, and brassinosteroid, resulting in improved resistance to stem nematode. Finally, analyses of the resistance regulation pathway and a weighted gene co-expression network analysis highlighted the importance of the genes itf14g17940 and itf12g18840, encoding a leucine-rich receptor-like protein and 1-aminocyclopropane-1-carboxylate synthase, respectively. These are candidate target genes for increasing the strength of the defense response. These results provide new ideas and a theoretical basis for understanding the mechanism of resistance to stem nematode in sweet potato.PMID:37653969 | DOI:10.3390/plants12102052

Plants (Basel). 2023 May 19;12(10):2038. doi: 10.3390/plants12102038.ABSTRACTSelenium (Se) plays an important role in the growth of plants. Alfalfa (Medicago sativa L.) is a perennial legume forage crop with high nutritional value and Se-rich functions. Many studies have shown that selenium can promote alfalfa growth, but few have explored the molecular biology mechanisms behind this effect. In this study, alfalfa was divided into two groups. One group was sprayed with sodium selenite (Na2SeO3) and the other group was sprayed with distilled water as a control. This study determined the growth, reproductive traits, physiological changes, transcriptome and metabolome of both groups of alfalfa. We found that foliar spraying of 100 mg/L Na2SeO3 could significantly increase the growth rate, dry weight, total Se content, amount of pollen per flower, pollen viability, pod spirals, and seed number per pod of alfalfa plants. The level of chlorophyll, soluble protein, proline, and glutathione also increased dramatically in Na2SeO3-sprayed alfalfa seedlings. After transcriptome and metabolome analysis, a total of 614 differentially expressed genes (DEGs) and 1500 differentially expressed metabolites (DEMs), including 26 secondary differentially metabolites were identified. The DEGs were mainly enriched in MAPK signaling pathway, phenylpropanoid biosynthesis, isoflavonoid biosynthesis, cutin, suberine, and wax biosynthesis, and glycerolipid metabolism. The DEMs were mainly enriched in flavone and flavonol biosynthesis, carbon metabolism, glyoxylate and dicarboxylate metabolism, nitrogen metabolism, and phenylpropanoid biosynthesis. Integrative analysis of transcriptome and metabolome showed that the foliar spraying of Na2SeO3 mainly affects phenylpropanoid biosynthesis to promote alfalfa growth.PMID:37653955 | DOI:10.3390/plants12102038

Plants (Basel). 2023 May 19;12(10):2032. doi: 10.3390/plants12102032.ABSTRACTCytochrome P450 (CYP74) family members participate in the generation of oxylipins and play essential roles in plant adaptation. However, the metabolic reprogramming mediated by CYP74s under cold stress remains largely unexplored. Herein, we report how cold-triggered OsHPL1, a member of the CYP74 family, modulates rice metabolism. Cold stress significantly induced the expression of OsHPL1 and the accumulation of OPDA (12-oxo-phytodienoic acid) and jasmonates in the wild-type (WT) plants. The absence of OsHPL1 attenuates OPDA accumulation to a low temperature. Then, we performed a widely targeted metabolomics study covering 597 structurally annotated compounds. In the WT and hpl1 plants, cold stress remodeled the metabolism of lipids and amino acids. Although the WT and hpl1 mutants shared over one hundred cold-affected differentially accumulated metabolites (DAMs), some displayed distinct cold-responding patterns. Furthermore, we identified 114 and 56 cold-responding DAMs, specifically in the WT and hpl1 mutants. In conclusion, our work characterized cold-triggered metabolic rewiring and the metabolic role of OsHPL1 in rice.PMID:37653948 | DOI:10.3390/plants12102032