PubMed

Front Mol Neurosci. 2023 Jan 27;15:972297. doi: 10.3389/fnmol.2022.972297. eCollection 2022.ABSTRACTPrecocious puberty (PP) is a common condition among children. According to the pathogenesis and clinical manifestations, PP can be divided into central precocious puberty (CPP, gonadotropin dependent), peripheral precocious puberty (PPP, gonadotropin independent), and incomplete precocious puberty (IPP). Identification of the variations in key metabolites involved in CPP and their underlying biological mechanisms has increased the understanding of the pathological processes of this condition. However, little is known about the role of metabolite variations in the drug treatment of CPP. Moreover, it remains unclear whether the understanding of the crucial metabolites and pathways can help predict disease progression after pharmacological therapy of CPP. In this study, systematic metabolomic analysis was used to examine three groups, namely, healthy control (group N, 30 healthy female children), CPP (group S, 31 female children with CPP), and treatment (group R, 29 female children) groups. A total of 14 pathways (the top two pathways were aminoacyl-tRNA biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis) were significantly enriched in children with CPP. In addition, two short peptides (His-Arg-Lys-Glu and Lys-Met-His) were found to play a significant role in CPP. Various metabolites associated with different pathways including amino acids, PE [19:1(9Z)0:0], tumonoic acid I, palmitic amide, and linoleic acid-biotin were investigated in the serum of children in all groups. A total of 45 metabolites were found to interact with a chemical drug [a gonadotropin-releasing hormone (GnRH) analog] and a traditional Chinese medicinal formula (DBYW). This study helps to understand metabolic variations in CPP after drug therapy, and further investigation may help develop individualized treatment approaches for CPP in clinical practice.PMID:36776772 | PMC:PMC9912178 | DOI:10.3389/fnmol.2022.972297

Expo Health. 2022 Dec;14(4):941-949. doi: 10.1007/s12403-022-00468-2. Epub 2022 Feb 3.ABSTRACTIn utero and early life exposure to inorganic arsenic (iAs) alters immune response in experimental animals and is associated with an increased risk of infant infections. iAs exposure is related to differences in the gut microbiota diversity, community structure, and the relative abundance of individual microbial taxa both in laboratory and human studies. Metabolomics permits a direct measure of molecular products of microbial and host metabolic processes. We conducted NMR metabolomics analysis on infant stool samples and quantified the relative concentrations of 34 known microbial-related metabolites. We examined these metabolites in relation to both in utero and infant log2 urinary total arsenic concentrations (utAs, the sum of iAs and iAs metabolites) collected at approximately 6 weeks of age using linear regression models, adjusted for infant sex, age at sample collection, type of delivery (vaginal vs. cesarean section), feeding mode (breast milk vs. any formula), and specific gravity. Increased fecal butyrate (b = 214.24), propionate (b = 518.33), cholate (b = 8.79), tryptophan (b= 14.23), asparagine (b = 28.80), isoleucine (b = 65.58), leucine (b = 95.91), malonate (b = 50.43), and uracil (b = 36.13), concentrations were associated with a doubling of infant utAs concentrations (p< 0.05). These associations were largely among infants who were formula fed. No clear associations were observed with maternal utAs and infant fecal metabolites. Metabolomic analyses of infant stool samples lend further evidence that the infant gut microbiota is sensitive to As exposure, and these effects may have functional consequences.PMID:36776720 | PMC:PMC9918239 | DOI:10.1007/s12403-022-00468-2

Nat Cardiovasc Res. 2022 Sep;1(9):817-829. doi: 10.1038/s44161-022-00117-6. Epub 2022 Aug 29.ABSTRACTHeart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors. We confirm bioenergetic defects in human HF and reveal selective depletion of adenylate purines required for maintaining ATP levels. We observe substantial reductions in fatty acids and acylcarnitines in failing tissue, despite plasma elevations, suggesting defective import of fatty acids into cardiomyocytes. Glucose levels, in contrast, are elevated. Pyruvate dehydrogenase, which gates carbohydrate oxidation, is de-repressed, allowing increased lactate and pyruvate burning. Tricarboxylic acid cycle intermediates are significantly reduced. Finally, bioactive lipids are profoundly reprogrammed, with marked reductions in ceramides and elevations in lysoglycerophospholipids. These data unveil profound metabolic abnormalities in human failing hearts.PMID:36776621 | PMC:PMC9910091 | DOI:10.1038/s44161-022-00117-6

Front Nutr. 2023 Jan 26;10:1093761. doi: 10.3389/fnut.2023.1093761. eCollection 2023.ABSTRACTINTRODUCTION: Polygonati Rhizoma is a multi-purpose food with medicinal uses. Fermentation of Polygonati Rhizoma by lactic acid bacteria could provide new insights into the development of Polygonati Rhizoma products.METHODS: In this study, Lactiplantibacillus plantarum was fermented with Polygonati Rhizoma extracts in a bioreactor under aerobic and anaerobic conditions with pH and DO real-time detection. Metabolic profiling was determined by UHPLC-QE-MS/MS system. Principal component analysis and orthogonal partial least-squares discriminant analysis were used to perform multivariate analysis.RESULTS: A total of 98 differential metabolites were identified in broth after fermentation, and 36 were identified between fermentation under aerobic and anaerobic conditions. The main metabolic pathways in the fermentation process are ABC transport and amino acid biosynthesis. Most of the compounds such as L-arginine, L-aspartic acid, leucine, L-lysine, citrate, inosine, carnitine, betaine, and thiamine were significantly increased during fermentation, playing a role in enhancing food flavor. Compared with anaerobic fermentation, aerobic conditions led to a significant rise in the levels of some compounds such as valine, isoleucine, and glutamate; this increase was mainly related to branched-chain amino acid transaminase, isocitrate dehydrogenase, and glutamate dehydrogenase.DISCUSSION: Aerobic fermentation is more beneficial for the fermentation of Polygonati Rhizoma by L. plantarum to produce flavor and functional substances. This study is the first report on the fermentation of Polygonati Rhizoma by L. plantarum and provides insights that would be applicable in the development of Polygonati Rhizoma fermented products.PMID:36776612 | PMC:PMC9908587 | DOI:10.3389/fnut.2023.1093761

Oncoimmunology. 2023 Feb 6;12(1):2174723. doi: 10.1080/2162402X.2023.2174723. eCollection 2023.NO ABSTRACTPMID:36776523 | PMC:PMC9908291 | DOI:10.1080/2162402X.2023.2174723

Oncoimmunology. 2023 Feb 7;12(1):2175506. doi: 10.1080/2162402X.2023.2175506. eCollection 2023.NO ABSTRACTPMID:36776522 | PMC:PMC9908292 | DOI:10.1080/2162402X.2023.2175506

Adv Drug Alcohol Res. 2022;2:10550. doi: 10.3389/adar.2022.10550. Epub 2022 Jul 14.ABSTRACTCannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.PMID:36776218 | PMC:PMC9910956 | DOI:10.3389/adar.2022.10550

Adv Biol (Weinh). 2023 Feb 12:e2200265. doi: 10.1002/adbi.202200265. Online ahead of print.ABSTRACTThe outbreak of coronavirus disease 2019 (COVID-19) has caused a worldwide pandemic since 2019. A metabolic disorder is a contributing factor to deaths from COVID-19. However, the underlying mechanism of metabolic dysfunction in COVID-19 patients and the potential interventions are not elucidated. Here targeted plasma metabolomic is performed, and the metabolite profiles among healthy controls, and asymptomatic, moderate, and severe COVID-19 patients are compared. Among the altered metabolites, arachidonic acid and linolenic acid pathway metabolites are profoundly up-regulated in COVID-19 patients. Arginine biosynthesis, alanine, aspartate, and glutamate metabolism pathways are significantly disturbed in asymptomatic patients. In the comparison of metabolite variances among the groups, higher levels of l-citrulline and l-glutamine are found in asymptomatic carriers and moderate or severe patients at the remission stage. Furthermore, l-citrulline and l-glutamine combination therapy is demonstrated to effectively protect mice from coronavirus infection and endotoxin-induced sepsis, and is observed to efficiently prevent the occurrence of pulmonary fibrosis and central nervous system damage. Collectively, the data reveal the metabolite profile of asymptomatic COVID-19 patients and propose a potential strategy for COVID-19 treatment.PMID:36775870 | DOI:10.1002/adbi.202200265

Epilepsia. 2023 Feb 12. doi: 10.1111/epi.17540. Online ahead of print.ABSTRACTOBJECTIVE: High fat and low carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible Modified Atkins Diet (MAD) that is more palatable, mimicking fasting and inducing high ketone body levels. Low carbohydrate diets may shift brain energy production, particularly impacting neuron and astrocyte linked metabolism.METHODS: We evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to Control participants consuming a non-modified higher carbohydrate diet (n = 6 MAD, mean age 43.7 years, range 21-53, diet average 10 days; n = 10 Control, mean age 41.9 years, range 28-64).RESULTS: By metabolomics, there were 13 increased metabolites in plasma (n = 15 participants with available specimens) that included 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex (n = 16), and 11 decreased metabolites in hippocampus (n = 6) that had top associations with mitochondrial functions. Cortex and plasma 3-hydroxybutyric acid levels had a positive correlation (p = 0.0088, R2 = 0.48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p < 0.01, FDR > 5%) in hippocampal NADH related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling).SIGNIFICANCE: Short-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to Control participants, in combination with trending expression changes observed in hippocampal NADH related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables.PMID:36775798 | DOI:10.1111/epi.17540

J Gastroenterol Hepatol. 2023 Feb 12. doi: 10.1111/jgh.16142. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: The role of the microbiota in diverticulosis and diverticular disease is underexplored. This systematic review aimed to assess all literature pertaining to the microbiota and metabolome associations in asymptomatic diverticulosis, symptomatic uncomplicated diverticular disease (SUDD), and diverticulitis pathophysiology.METHODS: Seven databases were searched for relevant studies published up to September 28th , 2022. Data were screened in Covidence and extracted to Excel. Critical appraisal was undertaken using the Newcastle Ottawa Scale for case/control studies.RESULTS: Of the 413 papers screened by title and abstract, 48 full-text papers were reviewed in detail with 12 studies meeting the inclusion criteria. Overall, alpha and beta diversity were unchanged in diverticulosis; however, significant changes in alpha diversity were evident in diverticulitis. A similar Bacteroidetes to Firmicutes ratio compared to controls was reported across studies. The genus-level comparisons showed no relationship with diverticular disease. Butyrate-producing microbial species were decreased in abundance suggesting a possible contribution to the pathogenesis of diverticular disease. Comamonas species was significantly increased in asymptomatic diverticulosis patients who later developed diverticulitis. Metabolome analysis reported significant differences in diverticulosis and SUDD, with upregulated uracil being the most consistent outcome in both. No significant differences were reported in the mycobiome.CONCLUSION: Overall, there is no convincing evidence of microbial dysbiosis in colonic diverticula to suggest that the microbiota contributes to the pathogenesis of asymptomatic diverticulosis, SUDD, or diverticular disease. Future research investigating microbiota involvement in colonic diverticula should consider an investigation of mucosa-associated microbial changes within the colonic diverticulum itself.PMID:36775316 | DOI:10.1111/jgh.16142

Exp Eye Res. 2023 Feb 10:109409. doi: 10.1016/j.exer.2023.109409. Online ahead of print.ABSTRACTOBJECTIVE: The study aimed to profile and quantify tear metabolites associated with bacterial keratitis using both untargeted and targeted metabolomic platforms.METHODS: Untargeted metabolomic analysis using liquid-chromatography-Q Exactive-HF mass-spectrometry explored tear metabolites significantly associated with bacterial keratitis (n = 6) compared to healthy participants (n = 6). Differential statistics and principal component analysis determined meaningful metabolite differences between cases and controls. Purines and nucleosides were further quantified and compared between 15 cases and 15 controls in the targeted metabolomic platform using TSQ quantum access triple quadrupole mass spectrometry. Compound quantification was done by plotting the calibration curves and the difference in the compound levels was evaluated using the Wilcoxon rank-sum test.RESULTS: In the untargeted analysis, 49 tear metabolites (27 upregulated and 22 downregulated) were differentially expressed between cases and controls. The untargeted analysis indicated that the purine metabolism pathway was the most affected by bacterial keratitis. Metabolite quantification in the targeted analysis further confirmed the upregulation of xanthine (P = 0.02) and downregulation of adenine (P < 0.0001), adenosine (P < 0.0001) and cytidine (P < 0.0001) in the tears of participants with bacterial keratitis compared to that of healthy participants.CONCLUSIONS: Bacterial keratitis significantly changes the tear metabolite profile, including five major compound classes such as indoles, amino acids, nucleosides, carbohydrates, and steroids. This study also indicates that tear fluids can be used to map the metabolic pathways and uncover metabolic markers associated with bacterial keratitis. Conceivably, the inhibition of nucleoside synthesis may contribute to the pathophysiology of bacterial keratitis because nucleosides are required for maintaining cellular energy homeostasis and immune adaptability.PMID:36775205 | DOI:10.1016/j.exer.2023.109409

Sci Total Environ. 2023 Feb 10:162109. doi: 10.1016/j.scitotenv.2023.162109. Online ahead of print.ABSTRACTSaline-alkali water resources are abundant and widely distributed in China. The effective utilization of saline-alkali water resources by fishery is of great significance to enhance the aquatic product economy and restore the ecology of saline-alkali environments. Eriocheir sinensis is a saline-alkali water-suitable species. To explore its physiological response to saline-alkali stress, the hepatopancreas tissue structure, antioxidation, immunocompetence and metabolomics were investigated after 96 h of gradient saline-alkali treatment. The results confirmed the hepatopancreas damage through tissue sectioning, abnormal enzyme activity (aspartate transaminase (AST), alanine aminotransferase (ALT)) and aberrant malondialdehyde (MDA) content. The activity of superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) was significantly upregulated (p < 0.05), which was followed by a decrease trend, indicating the enhancement of antioxidant capacity in response to the stress. Strengthened immunocompetence in response to saline-alkali toxicity was shown in the gradual increase of immune enzyme activity (acid phosphatase (ACP) and alkaline phosphatase (AKP)) and the upregulated expression of immune genes (hsp 70, hsp 90, proPO and toll). Among the differential metabolites quantified by metabolomics, small peptides were significantly downregulated (p < 0.05), and acylcarnitines were obviously upregulated (p < 0.05), indicating that saline-alkali toxicity inhibited protein catabolism and stimulated the mobilization of energy reserves. Metabolic pathways enriched through the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that Eriocheir sinensis activated different mechanisms in response to various degrees of stress, such as "ABC transporters" and "purine metabolism" in response to low saline-alkali stress, while "pyrimidine metabolism" and "beta-alanine metabolism" to high saline-alkali stress.PMID:36775159 | DOI:10.1016/j.scitotenv.2023.162109

Clin Chim Acta. 2023 Feb 10:117251. doi: 10.1016/j.cca.2023.117251. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Chronic pancreatitis (CP) is an inflammatory disease characterized by irreversible changes. However, acute CP attacks can lead to various complications and affect patient prognosis. Therefore, this study aimed to identify reliable candidate metabolic biomarkers for diagnosing acute CP attacks and complement candidate diagnostic markers for CP.METHODS: A total of 139 serum specimens were prospectively included in three consecutive exploratory, identification, and validation studies. All samples were analyzed for candidate diagnostic biomarkers and metabolic pathways using a liquid chromatography-mass spectrometer.RESULTS: Serum metabolic profiles differed between patients with CP and non-pancreatic disease controls, and 239 potential metabolic biomarkers for diagnosing CP were identified. Based on identification and validation studies, Diacylglycerol(16:0/18:4), 16-F1-PhytoP, N-(hexacosanoyl)-tetradecasphing-4-enine, carnosic acid, and Auxin b were identified as biomarkers for distinguishing acute attacks from non-acute attacks in patients with CP. The area under the curve of the Diacylglycerol(16:0/18:4) was 0.969 (95% confidence interval, 0.869-1) in the validation study.CONCLUSIONS: To the best of our knowledge, this is the first prospective cohort study to identify and validate a metabolomic signature in serum for diagnosing acute attacks of CP. In addition, our study identified 239 potential biomarkers for CP diagnosis.PMID:36775008 | DOI:10.1016/j.cca.2023.117251

Transl Oncol. 2023 Feb 10;30:101632. doi: 10.1016/j.tranon.2023.101632. Online ahead of print.ABSTRACTBACKGROUND: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment.MATERIALS AND METHODS: A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6).RESULTS: Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway.CONCLUSIONS: Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours.PMID:36774883 | DOI:10.1016/j.tranon.2023.101632

Int Immunopharmacol. 2023 Feb 10;116:109810. doi: 10.1016/j.intimp.2023.109810. Online ahead of print.ABSTRACTAnkylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that mainly affects the axial skeleton, whose typical features are inflammatory back pain, bone structural damage and pathological new bone formation. The pathology of ectopic new bone formation is still little known. In this study, we found increased purine metabolites in plasma of patients with AS. Similarly, metabolome analysis indicated increased purine metabolites in both serum of CD4-Cre; Ptpn11fl/fl and SHP2-deficient chondrocytes. SHP2-deficient chondrocytes promoted the growth of wild type chondrocytes and differentiation of osteoblasts in CD4-Cre; Ptpn11fl/fl mice, which spontaneously developed AS-like bone disease. Purine metabolites, along with PTHrP derived from SHP2-deficient chondrocytes, accelerated the growth of chondrocytes and ectopic new bone formation through PKA/CREB signaling. Moreover, Suramin, a purinergic receptor antagonist, suppressed pathological new bone formation in AS-like bone disease. Overall, these results highlight the potential role of targeting purinergic signaling in retarding ectopic new bone formation in AS.PMID:36774858 | DOI:10.1016/j.intimp.2023.109810

Int Immunopharmacol. 2023 Feb 10;116:109847. doi: 10.1016/j.intimp.2023.109847. Online ahead of print.ABSTRACTSeptic cardiomyopathy is a lethal symptom of sepsis. Discovery of effective therapy that prevents cardiac injury in sepsis is critical in the clinical management of sepsis. NSC228155 is a novel compound with therapeutic potential on acute kidney injury by preventing apoptosis and protecting mitochondria. Whether NSC228155 protects against septic cardiomyopathy is unclear. In the present study, adult C57BL/6J mice were i.p injected with 5 mg/kg/day NSC228155 for 2 days before 10 mg/kg lipopolysaccharide (LPS) injection. Cardiac functional testing and sampling for serum and tissue were performed 12 and 24 h post LPS injection, respectively. NSC228155 significantly improved cardiac function examined by echocardiography, decreased the serum lactate dehydrogenase (LDH) and creatine kinase-MB, and pathologically alleviated cardiac injury in LPS mice. Accordingly, NSC228155 attenuated cardiomyocytes' mitochondrial damage as shown by decreased damaged mitochondrial ratio and activated signals for mitochondrial biogenesis, dynamics and mitophagy in LPS mice model. Metabolomics analysis demonstrated that NSC228155 corrected the metabolic disturbance involved in oxidative stress and energy metabolism, and decreased tissue injury metabolites in LPS-stimulated cardiac tissue. In the LPS-stimulated cardiac cell culture derived from human induced pluripotent stem cells, NSC228155 effectively restored the beating frequency, decreased LDH release, and protected mitochondria. NSC228155 also inhibited inflammation shown by decreased pro-inflammatory mediators in both serum and cardiac tissue in LPS model. Taken together, NSC228155 significantly improved cardiac function by directly preventing against cardiac cell injury and inhibiting inflammation in LPS model, hence may be a potential novel therapy against septic cardiomyopathy.PMID:36774857 | DOI:10.1016/j.intimp.2023.109847

Phytomedicine. 2023 Feb 8;112:154712. doi: 10.1016/j.phymed.2023.154712. Online ahead of print.ABSTRACTBACKGROUND: Hydroxytyrosol (HT), as the main compound in olive leaves with its potential ability to cross blood-brain barrier (BBB), has exhibited the advantaged antidepressant effect. However, no information is available regarding the brain regional uptake of HT, as well the underlying antidepressant mechanism remains unclear.PURPOSE: To comprehensively reveal the brain uptake of HT and its specific mechanism on the accompanying antidepressant activity.STUDY DESIGN AND METHODS: The BBB penetration and brain regional distribution of HT in the normal and chronic unpredictable mild stress (CUMS)-induced depressive mice in consideration with the BBB integrality were analyzed. Then, the hippocampal region-specific responses of biomolecules and concurrent alterations in the therapeutic effect of HT on depression were explored using untargeted metabolomics, spatial-resolved metabolomics and tissue proteomics, which were confirmed by LPS-induced BV-2 microglia and CUMS mice.RESULTS: BBB permeability analysis in normal and CUMS mice confirmed that increased BBB permeability of CUMS mice was induced by the deficiency of tight junction-related proteins. Consistently, according to the established LC-MS/MS method, it was found that HT could not be largely detected in the cerebrospinal fluids and brains of normal mice after oral administration, while it could excessively penetrate the BBB (200-fold higher), and mostly distributed in the hippocampus of CUMS mice. Meanwhile, multi-omics analysis combined with targeted analysis discovered that HT could mainly improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway in CUMS mice. Besides, in vitro experiments further confirmed the anti-complement ability of HT, which could inhibit C3-CD11b pathway for alleviating the LPS-induced BV-2 microglia activation.CONCLUSION: HT can excessively penetrate the BBB and be mostly distributed in the hippocampus of depressive mice, which contribute to improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway for microglia activation. These findings give the clearer understanding of brain regional pharmacokinetics of HT and its accompanying molecular mechanism against depression.PMID:36774845 | DOI:10.1016/j.phymed.2023.154712

Phytomedicine. 2023 Feb 8;112:154709. doi: 10.1016/j.phymed.2023.154709. Online ahead of print.ABSTRACTBACKGROUND: Mailuo Shutong Pills (MLST) have displayed pharmacological activity against thromboangiitis obliterans (TAO). However, the active ingredients and therapeutic mechanism of MLST against TAO remained to be further clarified.PURPOSE: The aim of this study was to explore the active components of MLST and their synergistic mechanism against TAO by integrating pharmacokinetics (PK) and pharmacometabolomics (PM).METHODS: TAO model rats were established by sodium laurate solution. Firstly, the efficacy of MLST was evaluated by gangrene score, blood flow velocity, and hematoxylin-eosin (H&E) staining. Secondly, PK research was conducted on bioavailable components to characterize their dynamic behaviors under TAO. Thirdly, multiple plasma and urine metabolic biomarkers for sodium laurate-induced TAO rats were found by untargeted metabolomics, and then variations in TAO-altered metabolites following MLST treatment were analyzed utilizing multivariate and bioinformatic analysis. Additionally, metabolic pathway analysis was performed using MetaboAnalyst. Finally, the dynamic link between absorbed MLST-compounds and TAO-associated endogenous metabolites was established by correlation analysis.RESULTS: MLST significantly alleviated gangrene symptoms by improving the infiltration of inflammatory cells and blood supply in TAO rats. Significant differences in metabolic profiles were found in 17 differential metabolites in plasma and 24 in urine between Sham and TAO rats. The 10 bioavailable MLST-compounds, such as chlorogenic acid and paeoniflorin, showed positive or negative correlations with various TAO-altered metabolites related to glutamate metabolism, histidine metabolism, arachidonic acid metabolism and so on.CONCLUSION: This study originally investigated the dynamic interaction between MLST and the biosystem, providing unique insight for disclosing the active components of MLST and their synergistic mechanisms against TAO, which also shed light on new therapeutic targets for TAO and treatment.PMID:36774843 | DOI:10.1016/j.phymed.2023.154709

Food Chem. 2023 Jan 3;413:135385. doi: 10.1016/j.foodchem.2023.135385. Online ahead of print.ABSTRACTIrradiation increases the security and storage period of preserved Chinese bacon; nevertheless, the biological mechanisms underlying the changes in fat quality caused by irradiation are unknown. We investigated the influence of irradiation on Chinese bacon by proteomic and metabolomic. We identified 24 proteins that participated in metabolism and 40 common differential metabolites enriched in 16 signalling pathways. Correlation analysis revealed that irradiation altered 11 pathways shared between the proteome and metabolome, including two lipid metabolism pathways. Acetyl-CoA carboxylase, ACSL, octanoic acid, decanoic acid, palmitic acid, and oleic acid participated in fatty acid biosynthesis. Acyl-CoA thioesterase 1/2/4, enoyl-CoA reductase, acetyl-CoA acyltransferase 1, enoyl-CoA hydratase 2, palmitic acid, and oleic acid participated in unsaturated fatty acid biosynthesis. These findings lay the groundwork for multi-omics research on the effects of irradiation on Chinese bacon quality, assisting in assessing irradiated Chinese bacon quality, and developing effective strategies to standardise quality parameters.PMID:36774839 | DOI:10.1016/j.foodchem.2023.135385

Ecotoxicol Environ Saf. 2023 Feb 10;252:114628. doi: 10.1016/j.ecoenv.2023.114628. Online ahead of print.ABSTRACTOngoing and extensive use of pesticides negatively impact the environment and human health. Microbe-based remediation bears importance as it is an eco-friendly and cost-effective technique. The present study investigated chlorpyrifos (CHL) and glyphosate (GLY) degrading potential of Bacillus cereus AKAD 3-1, isolated from the soybean rhizosphere. Optimization and validation of different process variables were carried out by response surface methodology (RSM) and artificial neural network (ANN). Critical parameters which affect the degradation process are initial pesticide concentration, pH, and inoculum size. At optimum conditions, the bacterial strain demonstrated 94.52% and 83.58% removal of chlorpyrifos and glyphosate, respectively. Both Central-composite design (CCD-RSM) and ANN approaches proved to perform well in modeling and optimizing the growth conditions. The optimum ANN-GA model resulted in R2 ≥ 0.99 for chlorpyrifos and glyphosate, while in the case of RSM, the obtained R2 value was 0.96 and 0.95, respectively. Results indicated that the process variables significantly (p < 0.05) impact chlorpyrifos and glyphosate biodegradation. Moreover, the predicted RSM model had a "lack of fit p-value" of "0.8849" and "0.2502" for chlorpyrifos and glyphosate, respectively. GC-MS analysis revealed that the strain first converted chlorpyrifos into 3,5,6-trichloro pyridin-2-ol & O, O-diethyl O-hydrogen phosphorothiate. Later, these intermediate metabolites were broken and completely mineralized into non-toxic by-products. Similarly, glyphosate was first converted into 2-(methylamino) acetic acid and amino-oxyphosphonic acid, which were further mineralized without any toxic by-products. Taken together, the results of this study clarify the biodegradation pathways and highlights the promising potential of B. cereus AKAD 3-1 in the bioremediation of chlorpyrifos and glyphosate-polluted environments.PMID:36774796 | DOI:10.1016/j.ecoenv.2023.114628