PubMed

bioRxiv. 2023 Jul 4:2023.07.03.547607. doi: 10.1101/2023.07.03.547607. Preprint.ABSTRACTMachine learning (ML) has become a widespread strategy for studying complex microbiome signatures associated with disease. To this end, metagenomics data are often processed into a single "view" of the microbiome, such as its taxonomic (species) or functional (gene) composition, which in turn serves as input to such ML models. When further omics are available, such as metabolomics, these can be analyzed as additional complementary views. Following training and evaluation, the resulting model can be explored to identify informative features, generating hypotheses regarding underlying mechanisms. Importantly, however, using a single view generally offers relatively limited hypotheses, failing to capture simultaneous shifts or dependencies across multiple microbiome layers that likely play a role in microbiome-host interactions. In this work, inspired by the broad domain of multi-view learning , we constructed an integrated ML analysis pipeline using multiple microbiome views. We specifically aimed to investigate the impact of various integration approaches on the ability to predict disease state based on multiple microbiome-related views, and to generate biological insights. Applying this pipeline to data from 25 case-control metagenomics studies, we found that multi-view models typically result in performances that are comparable to the best-performing single view, yet, provide a mixed set of informative features from different views, while accounting for dependencies and links between them. To further enhance such models, we developed a new framework termed MintTea, based on sparse generalized canonical correlation analysis, to identify multi-view modules of features, highlighting shared trends in the data expressed by the different views. We showed that this framework identified multiple modules that were both highly predictive of the disease state, and exhibited strong within-module associations between features from different views. We accordingly advocate for using multi-view models to capture multifaceted microbiome signatures that likely better reflect the complex mechanisms underlying microbiome-disease associations.PMID:37461534 | PMC:PMC10349976 | DOI:10.1101/2023.07.03.547607

Res Sq. 2023 Jul 6:rs.3.rs-3112286. doi: 10.21203/rs.3.rs-3112286/v1. Preprint.ABSTRACTNutrient handling is an essential function of the gastrointestinal tract. Most nutrient absorption occurs in the small intestine and is coordinated by hormone-producing intestinal epithelial cells known as enteroendocrine cells (EECs). In contrast, the colon mostly reclaims water and electrolytes, and handles the influx of microbially-derived metabolites, including short chain fatty acids (SCFA). Hormonal responses of small intestinal EECs have been extensively studied but much less in known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. We found that colonic EEC deficiency leads to hyperphagia and obesity. Surprisingly, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment and transfer to germ free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we found that differential glutamate production by intestinal microbiota corresponds to increase appetite due to EEC loss. Finally, we show that colonic glutamate administration can directly increase food intake and activate appetite centers in the central nervous system. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.PMID:37461519 | PMC:PMC10350199 | DOI:10.21203/rs.3.rs-3112286/v1

Comb Chem High Throughput Screen. 2023 Jul 17. doi: 10.2174/1386207326666230717094936. Online ahead of print.ABSTRACTBACKGROUND: Liver cirrhosis is one of the leading causes of decreased life expectancy worldwide. However, the molecular mechanisms underlying liver cirrhosis remain unclear. In this study, we performed a comprehensive analysis using transcriptome and metabolome sequencing to explore the genes, pathways, and interactions associated with liver cirrhosis.METHODS: We performed transcriptome and metabolome sequencing of blood samples from patients with cirrhosis and healthy controls (1:1 matched for sex and age). We validated the differentially expressed microRNA (miRNA) and mRNAs using real-time quantitative polymerase chain reaction.RESULTS: For transcriptome analysis, we screened for differentially expressed miRNAs and mRNAs, analyzed mRNAs to identify possible core genes and pathways, and performed co-analysis of miRNA and mRNA sequencing results. In terms of the metabolome, we screened five pathways that were substantially enriched in the differential metabolites. Next, we identified the metabolites with the most pronounced differences among these five metabolic pathways. We performed receiver operating characteristic (ROC) curve analysis of these five metabolites to determine their diagnostic efficacy for cirrhosis. Finally, we explored possible links between the transcriptome and metabolome.CONCLUSION: Based on sequencing and bioinformatics, we identified miRNAs and genes that were differentially expressed in the blood of patients with liver cirrhosis. By exploring pathways and disease-specific networks, we identified unique biological mechanisms. In terms of metabolomes, we identified novel biomarkers and explored their diagnostic efficacy. We identified possible common pathways in the transcriptome and metabolome that could serve as candidates for further studies.PMID:37461343 | DOI:10.2174/1386207326666230717094936

J Mass Spectrom. 2023 Jul 17:e4961. doi: 10.1002/jms.4961. Online ahead of print.ABSTRACTA breeding program to produce new grape varieties tolerant to main vine fungal pathogens (Plasmopara viticola and Erysiphe necator) is carrying out by crossing Vitis vinifera cv. "Glera" with resistant genotypes such as "Solaris," "Bronner," and "Kunleany." Firstly, resistance gene-based markers analyses allowed the identification of five genotypes, which have inherited the resistance loci against mildews. To select those that also inherited the phenotype as close as possible to 'Glera' suitable to be introduced in the Prosecco wine production protocols, the grape glycosidic derivatives were studied by UHPLC/QTOF mass spectrometry. Targeted identification of the metabolites was performed using a database expressly constructed by including the glycosidic volatile precursors previously identified in grape and wine. A total of 77 glycosidic derivatives including many aroma precursors and some variety markers, were identified. Original resistant genotypes had distinct metabolomic profiles and different to 'Glera', while the crossings showed varying similarity degrees to V. vinifera parent. Findings demonstrated the Glera × Bronner and Glera × Solaris crossings are more suitable to produce high-sustainable Prosecco wines. Coupling of glycosidic volatile precursors profiling to multivariate statistical analysis was effective for phenotypic characterization of grapes and to evaluate their enological potential.PMID:37461255 | DOI:10.1002/jms.4961

Int J Biol Macromol. 2023 Jul 15:125843. doi: 10.1016/j.ijbiomac.2023.125843. Online ahead of print.ABSTRACTGinseng is widely regarded as a panacea in Oriental medicine mainly due to its immunomodulatory activity. We previously found that sulfur fumigation, a commonly used pesticidal and anti-bacterial processing practice, weakened the immunomodulatory activity of ginseng. However, if and how sulfur fumigation affects the polysaccharides in ginseng, the crucial components contributing to the immunomodulatory function, remain unknown. Here we report that polysaccharides extracted from sulfur-fumigated ginseng (SGP) presented different chemical properties with polysaccharides extracted with non-fumigated ginseng (NGP), particularly increased water extraction yield and decreased branching degree. SGP had weaker immunomodulatory activity than NGP in immunocompromised mice, as evidenced by less improved immunophenotypes involving body weight, immune organ indexes, white blood cells, lymphocyte cell populations and inflammation. The different immunomodulatory activities were accompanied by changes in the interaction between the polysaccharides and gut microbiota, in which SGP stimulated the growth of different bacteria but produced less SCFAs as compared to NGP. Fecal microbiota transplantation experiment suggested that gut microbiota played a central role in causing the weakened immunomodulatory activity in vivo. This study provides definite evidence that sulfur fumigation affects the chemistry and bioactivity of ginseng polysaccharides, thereby contributing to understanding how sulfur fumigation weakens the immunomodulatory activity of ginseng.PMID:37460073 | DOI:10.1016/j.ijbiomac.2023.125843

J Ethnopharmacol. 2023 Jul 15:116892. doi: 10.1016/j.jep.2023.116892. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Carex baccans, known as Shan-Bai-Zi or Ye-Gao-Liang in China, is a traditional medicinal herb used by several ethnic groups in Yunnan Province. It is utilized for the treatment of wound infections, ulcers, and dysentery. However, there is currently a dearth of research reports on its antimicrobial potential.AIM OF THE STUDY: The substance basis of the antimicrobial activity of C. baccans will be unveiled, and the in vitro and in vivo antibacterial activities against multidrug-resistant bacteria of its major active compounds, as well as their preliminary mechanisms of action, will be investigated.MATERIALS AND METHODS: An antibacterial bioactivity-guided isolation method was used to isolate and identify the active compound curcusinol from C. baccans. UPLC-DAD-MS was employed for the quantitative analysis of curcusinol. The antibacterial activity, resistance profile, synergistic effects, anti-biofilm activity, and potential mechanisms of action of curcusinol against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and other multidrug-resistant bacteria (Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii) were investigated using various methods, including the broth microdilution method, scanning electron microscopy, time kill assay, multi-generational resistance induction assay, checkerboard synergy assay, anti-biofilm assay, and metabolomics. Furthermore, the therapeutic efficacy of curcusinol was assessed in vivo by establishing an animal skin wound infection model of MRSA.RESULTS: curcusinol was isolated from the fruit of C. baccans, which accounts for 3.1% of the dry weight of the fruit. Curcusinol exhibited significant bactericidal and anti-biofilm activities against antibiotic-resistant Gram-positive bacteria in vitro. Furthermore, curcusinol acted as an antibiotic adjuvant to enhance the activity of various commonly used antibiotics against both Gram-positive and Gram-negative antibiotic-resistant bacteria without cytotoxicity to mammalian cells (A549 and RAW264.7) at 64 μM. Moreover, curcusinol affected arginine biosynthesis, cysteine and methionine metabolism, and alanine, aspartate, and glutamate metabolism significantly in MRSA cells under stress. Additionally, curcusinol effectively treated MRSA-infected mouse skin wounds and accelerated wound healing in vivo.CONCLUSIONS: The results of this study not only support the traditional uses of C. baccans but also demonstrate that its major active compound, curcusinol, is an effective plant-derived bactericidal agent and antibacterial adjuvant with potential applications in the treatment of skin infections.PMID:37460030 | DOI:10.1016/j.jep.2023.116892

J Ethnopharmacol. 2023 Jul 15:116806. doi: 10.1016/j.jep.2023.116806. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Diarrhea is a frequently encountered gastrointestinal complication in clinical practice, and E. coli is one of the main causative agents. Although Qingjie decoction (QJD) has been shown to be highly effective in treating diarrhea by eliminating heat-toxin, the underlying molecular mechanisms and pathways of QJD remain unclear.AIM OF REVIEW: The aim of this research was to explore the effects and fundamental mechanism of QJD on diarrhea induced by E.coli in rats.MATERIALS AND METHODS: Initially, we used UHPLC-MS/MS analysis to identify the chemical composition of QJD. Then, we constructed a visualization network using network pharmacology. Next, we utilized metabolomics to identify differentially expressed metabolites of QJD that are effective in treating diarrhea.RESULTS: The chemical composition of QJD was analyzed using UHPLC-MS/MS, which identified a total of 292 components. Using a network pharmacology approach, 127 bioactive compounds of QJD were screened, targeting 171 potential diarrhea treatment targets. TNF-α, IL-6, IL-1β, and CAT were identified as important targets through visualizing the PPI network. Enrichment analysis demonstrated significant enrichment in the TNF signaling pathway, IL-17 signaling pathway, and PI3K-Akt signaling pathway. QJD showed beneficial effects, such as increased body weight, decreased fecal water content, and reduced inflammatory cell infiltration in the duodenum and colon, as well as maintaining the structure of the duodenum and colon. Metabolomic analysis revealed 32 differentially expressed metabolites in the control, model and QJD-H groups, including glucose, valine, and cysteine. Functional analysis indicated that differential metabolites were related to energy metabolism, including glucose metabolism, TCA cycle, and amino acid metabolism.CONCLUSION: QJD significantly increased body weight, decreased water content in feces, relieved inflammatory cell infiltration, maintained the structure of duodenum and colon. Combining network analysis and metabolomics, QJD exerted therapeutic effects by inhibiting inflammation and oxidative stress, regulating glucose metabolism, tricarboxylic acid metabolism, and amino acid metabolism.PMID:37460028 | DOI:10.1016/j.jep.2023.116806

Pharmacol Res. 2023 Jul 15:106856. doi: 10.1016/j.phrs.2023.106856. Online ahead of print.ABSTRACTDiverse microbial communities colonize different habitats of the human body, including gut, oral cavity, nasal cavity and tissues. These microbial communities are known as human microbiome, plays a vital role in maintaining the health. However, changes in the composition and functions of human microbiome can result in chronic low-grade inflammation, which can damage the epithelial cells and allows pathogens and their toxic metabolites to translocate into other organs such as the liver, heart, and kidneys, causing metabolic inflammation. This dysbiosis of human microbiome has been directly linked to the onset of several non-communicable diseases. Recent metabolomics studies have revealed that pathogens produce several uraemic toxins. These metabolites can serve as inter-kingdom signals, entering the circulatory system and altering host metabolism, thereby aggravating a variety of diseases. Interestingly, Enterobacteriaceae, a critical member of Proteobacteria, has been commonly associated with several non-communicable diseases, and the abundance of this family has been positively correlated with uraemic toxin production. Hence, this review provides a comprehensive overview of Enterobacterial translocation and their metabolites role in non-communicable diseases. This understanding may lead to the identification of novel biomarkers for each metabolic disease as well as the development of novel therapeutic drugs.PMID:37460001 | DOI:10.1016/j.phrs.2023.106856

Sci Total Environ. 2023 Jul 15:165517. doi: 10.1016/j.scitotenv.2023.165517. Online ahead of print.ABSTRACTThe role played by metabolites in exhaled breath condensate (EBC) in the effect of PM on schoolchildren's pulmonary function has received little attention. Accordingly, we examined whether metabolites in EBC mediated the effect of PM10, PM2.5, and PM1 on the pulmonary function of schoolchildren at a residential primary school who had received an air-cleaner cross-over intervention. Samples of EBC were collected from a total of 60 schoolchildren and subjected to metabolomics analysis. We found that the effect of PM on six pulmonary function indicators was mediated by the following nine lipid peroxidation-related and energy metabolism-related metabolites present in EBC: 4-hydroxynonenal, arachidoyl ethanolamide, dl-pyroglutamic acid, 5-deoxy-d-glucose, myristic acid, lauric acid, linoleic acid, l-proline, and palmitic acid. However, while all nine of these metabolites mediated the effects of PM on boys' pulmonary function, only 4-hydroxynonenal, arachidoyl ethanolamide, and dl-pyroglutamic acid mediated the effects of PM on girls' pulmonary function. Overall, our results show that (1) short-term exposure to PM affected the schoolchildren's pulmonary function by causing an imbalance between lipid peroxidation and glutathione-based antioxidant activity and by perturbing energy metabolism in respiratory system and (2) there was a sex-dependent antioxidant response to PM exposure, with boys being less resistant than girls.PMID:37459994 | DOI:10.1016/j.scitotenv.2023.165517

J Hepatol. 2023 Jul 15:S0168-8278(23)04981-4. doi: 10.1016/j.jhep.2023.07.005. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Recent studies have highlighted the role of gut microbiome and metabolites in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to investigate the specific beneficial bacteria species as novel prophylaxis for NAFLD-HCC.METHODS: The role of Bifidobacterium pseudolongum was assessed in two NAFLD-HCC mice models induced by diethylnitrosamine with high-fat/high-cholesterol diet or with choline-deficient/high-fat diet. Germ-free mice were used for B. pseudolongum metabolic study. Stool, portal vein and liver tissues were collected from mice for non-targeted and targeted metabolomic profiles. B. pseudolongum conditioned medium (B.p CM) or candidate metabolite were co-cultured with two human NAFLD-HCC cell lines (HKCI2 and HKCI10).RESULTS: B. pseudolongum was the top depleted bacterium in NAFLD-HCC in mice. Oral gavage of B. pseudolongum significantly suppressed NAFLD-HCC formation in two mouse models (P<0.01). NAFLD-HCC cells co-incubation with B.p CM significantly suppressed cell proliferation, inhibited the G1/S phase transition and induced apoptosis. Acetate was identified as the critical metabolite generated from B. pseudolongum in B.p CM and confirmed in germ-free mice. Acetate inhibited cell proliferation and induced cell apoptosis in NAFLD-HCC cell lines and suppressed NAFLD-HCC tumor formation in vivo. B. pseudolongum restored heathy gut microbiome composition and improved gut barrier function. Mechanistically, B. pseudolongum-produced acetate entered portal vein to reach to the liver and bind to G coupled-protein receptor 43 (GPR43) on hepatocytes. GPR43 activation suppressed IL-6/JAK1/STAT3 signaling pathway, thereby preventing NAFLD-HCC progression.CONCLUSIONS: B. pseudolongum protected against NAFLD-HCC by secreting anti-tumor metabolite acetate through gut-liver axis. B. pseudolongum is a potential probiotic for NAFLD-HCC prevention.IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an increasing healthcare burden worldwide. There is an urgent need to develop effective agents to prevent NAFLD-HCC progression. Herein, we show probiotic Bifidobacterium pseudolongum significantly suppressed NAFLD-HCC progression by secreting acetate, which bind to hepatic G coupled-protein receptor 43 (GPR43) through gut-liver axis and suppressed hepatic oncogenic IL-6/JAK1/STAT3 signaling pathway. Bifidobacterium pseudolongum is a potential novel probiotic for NAFLD-HCC prevention.PMID:37459922 | DOI:10.1016/j.jhep.2023.07.005

Prostaglandins Other Lipid Mediat. 2023 Jul 15:106764. doi: 10.1016/j.prostaglandins.2023.106764. Online ahead of print.ABSTRACTCaloric restriction (CR) is a dietetic intervention based on the reduction of daily calorie intake by 10-30%. When subjected to CR, the organism adjusts its metabolism to the changing availability of key nutrients. However, fatty acids' content in organisms subjected to long-term CR has not been evaluated. The aim of the research was to analyze the influence of long-term CR on the contents of medium- and long-chain fatty acids, as well as on the contents of fatty acid derivatives in liver. The study was performed on C57BL female (n = 12) and male (n = 12) mice subjected to lifelong 30% calorie restriction. Fatty acids were analyzed using gas chromatography, while fatty acid derivatives were analyzed with liquid chromatography. The dynamics of change of the lipid profile of the labeled fatty acids observed in the liver tissue confirms that lipolysis actively takes place in this organ when hungry. Moreover, it is highly possible that de novo synthesis of acids takes place, with the aim to ensure energy substrates to the body. Moreover, an increase of concentration was observed for fatty acid derivatives, those with anti-inflammatory properties (resolvin, LTX A4). However, there was no increase in the concentration of pro-inflammatory eicosanoids. The results suggest that it is important to take into consideration the introduction of appropriate supplements when using CR.PMID:37459907 | DOI:10.1016/j.prostaglandins.2023.106764

Genome Med. 2023 Jul 17;15(1):52. doi: 10.1186/s13073-023-01209-z.ABSTRACTBACKGROUND: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk.METHODS: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data.RESULTS: By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent.CONCLUSIONS: Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations.PMID:37461045 | DOI:10.1186/s13073-023-01209-z

Anal Bioanal Chem. 2023 Jul 18. doi: 10.1007/s00216-023-04826-0. Online ahead of print.ABSTRACTIn the present study, we developed and validated a fast, simple, and sensitive quantitative method for the simultaneous determination of eleven nucleosides and deoxynucleosides from urine samples. The analyses were performed with the use of liquid chromatography coupled with triple quadrupole mass spectrometry. The sample pretreatment procedure was limited to centrifugation, vortex mixing of urine samples with a methanol/water solution (1:1, v/v), evaporation and dissolution steps. The analysis lasted 20 min and was performed in dynamic multiple reaction monitoring mode (dMRM) in positive polarity. Process validation was conducted to determine the linearity, precision, accuracy, limit of quantification, stability, recovery and matrix effect. All validation procedures were carried out in accordance with current FDA and EMA regulations. The validated method was applied for the analysis of 133 urine samples derived from bladder cancer patients before tumor resection and 24 h, 2 weeks, and 3, 6, 9, and 12 months after the surgery. The obtained data sets were analyzed using a linear mixed-effect model. The analysis revealed that concentration level of 2-methylthioadenosine was decreased, while for inosine, it was increased 24 h after tumor resection in comparison to the preoperative state. The presented quantitative longitudinal study of urine nucleosides and deoxynucleosides before and up to 12 months after bladder tumor resection brings additional prospective insight into the metabolite excretion pattern in bladder cancer disease. Moreover, incurred sample reanalysis was performed proving the robustness and repeatability of the developed targeted method.PMID:37460824 | DOI:10.1007/s00216-023-04826-0

Sci Rep. 2023 Jul 17;13(1):11522. doi: 10.1038/s41598-023-38750-1.ABSTRACTTo understand differences between asymptomatic colonized and infected states of indwelling medical devices, we sought to determine penile prosthesis biofilm composition, microbe-metabolite interaction networks, and association with clinical factors. Patients scheduled for penile prosthesis removal/revision were included. Samples from swabbed devices and controls underwent next-generation sequencing, metabolomics, and culture-based assessments. Biofilm formation from device isolates was reconstituted in a continuous-flow stir tank bioreactor. 93% of 27 analyzed devices harbored demonstrable biofilm. Seven genera including Faecalibaculum and Jeotgalicoccus were more abundant in infected than uninfected device biofilms (p < 0.001). Smokers and those with diabetes mellitus or cardiac disease had lower total normalized microbial counts than those without the conditions (p < 0.001). We identified microbe-metabolite interaction networks enriched in devices explanted for infection and pain. Biofilm formation was recapitulated on medical device materials including silicone, PTFE, polyurethane, and titanium in vitro to facilitate further mechanistic studies. Nearly all penile prosthesis devices harbor biofilms. Staphylococcus and Escherichia, the most common causative organisms of prosthesis infection, had similar abundance irrespective of infection status. A series of other uncommon genera and metabolites were differentially abundant, suggesting a complex microbe-metabolite pattern-rather than a single organism-is responsible for the transition from asymptomatic to infected or painful states.PMID:37460611 | DOI:10.1038/s41598-023-38750-1

Nat Commun. 2023 Jul 17;14(1):4271. doi: 10.1038/s41467-023-39769-8.ABSTRACTMultiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.PMID:37460553 | DOI:10.1038/s41467-023-39769-8

Cell Death Discov. 2023 Jul 17;9(1):251. doi: 10.1038/s41420-023-01549-0.ABSTRACTThe ketogenic diet (KD) is a low carbohydrate and high-fat protein diet. It plays a protective role in neurodegenerative diseases by elevating the levels of ketone bodies in blood, regulating central and peripheral metabolism and mitochondrial functions, inhibiting neuroinflammation and oxidative stress, and altering the gut microbiota. However, studies on ketogenic therapy for Parkinson's disease (PD) are still in their infancy. Therefore, we examined the possible protective effect of KD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, examined the mouse gut microbiota and its metabolites, and performed transcriptomics and metabolomics on the substantia nigra of mice. Our results showed that a long-term medium-chain triglyceride KD (MCT-KD) significantly reduced MPTP-induced damage to dopaminergic (DA) neurons, exerted antioxidant stress through the PI3K/Akt/Nrf2 pathway, and reversed oxidative stress in DA neurons. The MCT-KD also reduced mitochondrial loss, promoted ATP production, and inhibited the activation of microglia to protect DA neurons in MPTP-induced PD mice. MCT-KD altered the gut microbiota and consequently changed the metabolism of substantia nigra neurons through gut microbiota metabolites. Compared to the MPTP group, MCT-KD increased the abundance of gut microbiota, including Blautia and Romboutsia. MCT-KD also affects purine metabolism in the substantia nigra pars compacta (SNpc) by altering fecal metabolites. This study shows that MCT-KD has multiple protective effects against PD.PMID:37460539 | DOI:10.1038/s41420-023-01549-0

Zhonghua Xin Xue Guan Bing Za Zhi. 2023 Jul 24;51(7):722-730. doi: 10.3760/cma.j.cn112148-20230329-00182.ABSTRACTObjective: To reveal the similarities and differences in myocardial metabolic characteristics between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) mice using metabolomics. Methods: The experimental mice were divided into 4 groups, including control, HFpEF, sham and HFrEF groups (10 mice in each group). High fat diet and Nω-nitroarginine methyl ester hydrochloride (L-NAME) were applied to construct a"two-hit"HFpEF mouse model. Transverse aortic constriction (TAC) surgery was used to construct the HFrEF mouse model. The differential expression of metabolites in the myocardium of HFpEF and HFrEF mice was detected by untargeted metabolomics (UHPLC-QE-MS). Variable importance in projection>1 and P<0.05 were used as criteria to screen and classify the differentially expressed metabolites between the mice models. KEGG functional enrichment and pathway impact analysis demonstrated significantly altered metabolic pathways in both HFpEF and HFrEF mice. Results: One hundred and nine differentially expressed metabolites were detected in HFpEF mice, and 270 differentially expressed metabolites were detected in HFrEF mice. Compared with the control group, the most significantly changed metabolite in HFpEF mice was glycerophospholipids, while HFrEF mice presented with the largest proportion of carboxylic acids and their derivatives. KEGG enrichment and pathway impact analysis showed that the differentially expressed metabolites in HFpEF mice were mainly enriched in pathways such as biosynthesis of unsaturated fatty acids, ether lipid metabolism, amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and arginine and proline metabolism. The differentially expressed metabolites in HFrEF mice were mainly enriched in arginine and proline metabolism, glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and arachidonic acid metabolism, etc. Conclusions: HFpEF mice have a significantly different myocardial metabolite expression profile compared with HFrEF mice. In addition, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, glycerophospholipid metabolism and arginine and proline metabolism are significantly altered in both HFpEF and HFrEF mice, suggesting that these metabolic pathways may play an important role in disease progression in both types of heart failure.PMID:37460426 | DOI:10.3760/cma.j.cn112148-20230329-00182

J Pharm Biomed Anal. 2023 Jul 13;234:115573. doi: 10.1016/j.jpba.2023.115573. Online ahead of print.ABSTRACTTripterygium wilfordii (TW), a well-known traditional Chinese medicine, was widely used in the treatment of autoimmune disorders and inflammatory diseases. However, the clinical use of TW was limited by severe toxicities, such as hepatotoxicity and nephrotoxicity. Our previous studies indicated that roasting was an effective approach for reducing TW-induced toxicity. After roasting, celastrol was completely decomposed, partially converted into 1-hydroxy-2,5,8-trimethyl-9-fluorenone and the total alkaloids content were significantly reduced. However, the detoxication mechanisms of roasting on TW were poorly unknown. This study aimed to explore the toxicity and detoxification mechanisms of TW after roasting based on urine metabolomics. Promising biomarkers were evaluated by multiple comparison analyses. Sixteen toxicity biomarkers were identified between control group and total extract group. Twelve toxicity biomarkers were identified between control group and total alkaloids group. Eight toxicity biomarkers were identified between control group and celastrol group. These metabolites were mainly involved in seven metabolic pathways, summarized as pentose and glucuronate interconversions, lipid metabolism (sphingolipid metabolism, glycerophospholipid metabolisms, fatty acid biosynthesis and steroid hormone biosynthesis) and amino acid metabolism (taurine and hypotaurine metabolism, tryptophan metabolism). After roasting, the toxicities of total extract, total alkaloids and celastrol were relieved by ameliorative serum parameters and pathological changes in hepatic and renal tissues which revealed that the reduction of celastrol and total alkaloids played important roles in the detoxification of roasting on TW. Furthermore, roasting regulated the levels of fourteen potential biomarkers in the total extract group, ten potential biomarkers in the total alkaloids group and seven candidate biomarkers in the celastrol group to normal levels. Biological pathway analysis revealed that roasting may ameliorate TW-induced metabolic disorders in pentose and glucuronate interconversions, lipid metabolism and amino acid metabolism. This study provided evidence for the application of roasting in TW.PMID:37459834 | DOI:10.1016/j.jpba.2023.115573

Biomed Pharmacother. 2023 Jul 15;165:115160. doi: 10.1016/j.biopha.2023.115160. Online ahead of print.ABSTRACTEssential hypertension (EH) is a leading cause of cardiovascular morbidity and mortality. Fructus Tribuli (FT), as a traditional medicine, has been frequently used for thousands of years. The crude Fructus Tribuli (CFT), decoction pieces being processed to remove impurities, have been listed as an important medicine for the treatment of hypertension in the elderly. According to the theory of traditional Chinese medicine, the CFT can enhance the EH treatment after being stir-fried into stir-fried Fructus Tribuli (SFT). At present, whether the SFT can enhance the EH treatment and its potential pharmacodynamic substances and mechanism are unknown. In this study, an integrated "spectrum-effect relationship-network pharmacology-metabolomics" strategy was used. Using male spontaneously hypertensive rats as an experimental model, we compared the therapeutic effects of CFT and SFT on EH. Subsequently, to define the pharmacodynamic material basis of SFT in enhancing the EH treatment, the steroidal saponins (main active components of FT) were selected for spectrum-effect relationship analysis. Furthermore, we applied the joint pathway analysis of network pharmacology and metabolomics to explore the underlying mechanism of SFT in enhancing the EH treatment. Results showed that SFT was better than CFT in the EH treatment. The steroidal saponins transformed by stir-frying were the potential pharmacodynamic substances that SFT could enhance the EH treatment. And the mechanism of action might be associated with regulating glycerophospholipid metabolism and arachidonic acid metabolism, especially arachidonic acid metabolism. This study provided a scientific basis for the clinical use of SFT as an important medicine for the EH treatment.PMID:37459662 | DOI:10.1016/j.biopha.2023.115160

Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2301538120. doi: 10.1073/pnas.2301538120. Epub 2023 Jul 17.ABSTRACTPseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.PMID:37459522 | DOI:10.1073/pnas.2301538120