PubMed

Plant Environ Interact. 2023 Sep 15;4(5):229-257. doi: 10.1002/pei3.10121. eCollection 2023 Oct.ABSTRACTRice is more vulnerable to drought than maize, wheat, and sorghum because its water requirements remain high throughout the rice life cycle. The effects of drought vary depending on the timing, intensity, and duration of the events, as well as on the rice genotype and developmental stage. It can affect all levels of organization, from genes to the cells, tissues, and/or organs. In this study, a moderate water deficit was applied to two contrasting rice genotypes, IAC 25 and CIRAD 409, during their reproductive stage. Multi-level transcriptomic, metabolomic, physiological, and morphological analyses were performed to investigate the complex traits involved in their response to drought. Weighted gene network correlation analysis was used to identify the specific molecular mechanisms regulated by each genotype, and the correlations between gene networks and phenotypic traits. A holistic analysis of all the data provided a deeper understanding of the specific mechanisms regulated by each genotype, and enabled the identification of gene markers. Under non-limiting water conditions, CIRAD 409 had a denser shoot, but shoot growth was slower despite better photosynthetic performance. Under water deficit, CIRAD 409 was weakly affected regardless of the plant level analyzed. In contrast, IAC 25 had reduced growth and reproductive development. It regulated transcriptomic and metabolic activities at a high level, and activated a complex gene regulatory network involved in growth-limiting processes. By comparing two contrasting genotypes, the present study identified the regulation of some fundamental processes and gene markers, that drive rice development, and influence its response to water deficit, in particular, the importance of the biosynthetic and regulatory pathways for cell wall metabolism. These key processes determine the biological and mechanical properties of the cell wall and thus influence plant development, organ expansion, and turgor maintenance under water deficit. Our results also question the genericity of the antagonism between morphogenesis and organogenesis observed in the two genotypes.PMID:37822730 | PMC:PMC10564380 | DOI:10.1002/pei3.10121

Plant Environ Interact. 2023 Sep 11;4(5):275-290. doi: 10.1002/pei3.10122. eCollection 2023 Oct.ABSTRACTPlant growth-promoting bacterias (PGPBs) can increase crop output under normal and abiotic conditions. However, the mechanisms underlying the plant salt tolerance-promoting role of PGPBs still remain largely unknown. In this study, we demonstrated that Halomonas ventosae JPT10 promoted the salt tolerance of both dicots and monocots. Physiological analysis revealed that JPT10 reduced reactive oxygen species accumulation by improving the antioxidant capability of foxtail millet seedlings. The metabolomic analysis of JPT10-inoculated foxtail millet seedlings led to the identification of 438 diversely accumulated metabolites, including flavonoids, phenolic acids, lignans, coumarins, sugar, alkaloids, organic acids, and lipids, under salt stress. Exogenous apigenin and chlorogenic acid increased the salt tolerance of foxtail millet seedlings. Simultaneously, JPT10 led to greater amounts of abscisic acid (ABA), indole-3-acetic acid (IAA), salicylic acid (SA), and their derivatives but lower levels of 12-oxo-phytodienoic acid (OPDA), jasmonate (JA), and JA-isoleucine (JA-Ile) under salt stress. Exogenous JA, methyl-JA, and OPDA intensified, whereas ibuprofen or phenitone, two inhibitors of JA and OPDA biosynthesis, partially reversed, the growth inhibition of foxtail millet seedlings caused by salt stress. Our results shed light on the response of foxtail millet seedlings to H. ventosae under salt stress and provide potential compounds to increase salt tolerance in foxtail millet and other crops.PMID:37822729 | PMC:PMC10564379 | DOI:10.1002/pei3.10122

iScience. 2023 Sep 9;26(10):107839. doi: 10.1016/j.isci.2023.107839. eCollection 2023 Oct 20.ABSTRACTIn various cancer models, dietary interventions have been shown to inhibit tumor growth, improve anticancer drug efficacy, and enhance immunity, but no such evidence exists for epithelial ovarian cancer (EOC), the most lethal gynecologic cancer. The anticancer immune responses induced by 16-h intermittent fasting (IF) were studied in mice with EOC. IF consistently reduced metabolic growth factors and cytokines that stimulate tumor growth, creating a tumor-hostile environment. Immune profiling showed that IF dramatically alters anti-cancer immunity by increasing CD4+ and CD8+ cells, Th1 and cytotoxic responses, and metabolic fitness. β-hydroxy butyrate (BHB), a bioactive metabolite produced by IF, partially imitates its anticancer effects by inducing CD8+ effector function. In a direct comparison, IF outperformed exogenous BHB treatment in survival and anti-tumor immune response, probably due to increased ketogenesis. Thus, IF and one of its metabolic mediators BHB suppress EOC growth and sustain a potent anti-tumor T cell response.PMID:37822507 | PMC:PMC10562806 | DOI:10.1016/j.isci.2023.107839

Front Plant Sci. 2023 Sep 26;14:1263354. doi: 10.3389/fpls.2023.1263354. eCollection 2023.ABSTRACTCitrus fruit's appearance is the primary criterion used to assess its quality for the fresh market, hence the rind's condition is a crucial quality trait. Pre-harvest rind disorder is one of the major physiological problems in mandarins. The disorder occurs right before harvest following rain events in some Mandarin varieties. Despite the economic damage caused by this kind of disorder, very limited information is available about the molecular mechanisms underlying the occurrence of this disorder. In the present study, we evaluated the primary metabolites, antioxidants, and hormones associated with the pre-harvest rind disorder in Mandarins. The study was carried out using ten-year-old 'Owari' Satsuma mandarin trees grafted on 'Carrizo' rootstock and grown in a commercial orchard in San Joaquin Valley, California, USA. Samples were collected from healthy tissue of healthy fruit (HF_HT), healthy tissue of damaged fruit (DF_HT), and damaged tissue of damaged fruit (DF_DT). Damaged fruit (DF_HT and DF_DT) showed lower cellulose concentrations than healthy fruit tissues (HF_HT), however, had similar contents of pectin and hemicellulose. The antioxidant activities showed no significant difference in all paired comparisons between samples as expressed in the malondialdehyde (MDA) content. However, DF_DT had a higher H2O2 content compared to HF_HT, but DF_HT had a similar content to that of HF_HT. Furthermore, peroxidase (POD) and polyphenol oxidase (PPO) activities were increased in DF_DT compared to HF_HT (P = 0.0294) and DF_HT (P = 0.0044), respectively. Targeted metabolomics analysis revealed that a total of 76 metabolites were identified in Satsuma rind tissues, and the relative concentrations of 43 metabolites were significantly different across studied samples. The hormonal analysis showed the involvement of jasmonate O-methyltransferase, jasmonic acid-amido synthetase JAR1-like, and JA-isoleucine may key role in causing the rind disorder in mandarins. In addition, the damaged fruit tissues have a higher level of jasmonic acid (JA), 12-oxo-phytodienoic acid, and JA-isoleucine than undamaged tissue.PMID:37822340 | PMC:PMC10562707 | DOI:10.3389/fpls.2023.1263354

Aging Cell. 2023 Oct 12:e13946. doi: 10.1111/acel.13946. Online ahead of print.ABSTRACTAgeing is characterised at the molecular level by six transcriptional 'hallmarks of ageing', that are commonly described as progressively affected as time passes. By contrast, the 'Smurf' assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.PMID:37822253 | DOI:10.1111/acel.13946

J Dev Orig Health Dis. 2023 Oct 12:1-12. doi: 10.1017/S2040174423000260. Online ahead of print.ABSTRACTThe maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.PMID:37822211 | DOI:10.1017/S2040174423000260

J Agric Food Chem. 2023 Oct 11. doi: 10.1021/acs.jafc.3c05501. Online ahead of print.ABSTRACTFumonisin B1 (FB1) is a representative form of fumonisin and is widely present in food and feed. Hydrolyzed fumonisin B1 (HFB1) emerges as a breakdown product of FB1, which is accompanied by FB1 alterations. While previous studies have primarily focused on the liver or kidney toxicity of FB1, with limited studies existing on its neurotoxicity and even fewer on the toxicity of HFB1, this study focuses on the neurotoxicity of FB1 and HFB1 exposure in mice investigated by the open field test, Morris water maze test, histopathological analysis, and nontargeted metabolomics. Further, the levels of oxidative stress-related indices, neurotransmitters, and sphingolipids in the brain were measured to analyze their correlation with behavioral outcomes. The results showed that both FB1 (5 mg/kg) and HFB1 (2.8 mg/kg) reduced autonomous exploratory behavior in mice, impaired spatial learning and memory, and caused mild abnormalities in the brain structure. Quantitative analysis further indicated that exposure to FB1 and HFB1 disrupted neurotransmitter homeostasis, exacerbated oxidative stress, and significantly increased the sphinganine/sphingosine (Sa/So) ratio. Moreover, HFB1 exhibited neurotoxic effects similar to those of FB1, emphasizing the need to pay attention to the neurotoxicity effect of HFB1. These findings underscore the importance of understanding the risks and potential neurological damage associated with FB1 and HFB1 exposure, highlighting the necessity for further research in this crucial field.PMID:37822021 | DOI:10.1021/acs.jafc.3c05501

J Orthop Surg Res. 2023 Oct 11;18(1):769. doi: 10.1186/s13018-023-04240-3.ABSTRACTBACKGROUND: Gout is the most common inflammatory arthritis and closely related to metabolic syndrome, leading to excruciating pain and the decline in quality of patients' life. However, the pathogenesis of gout is still unclear, and novel biomarkers are demanded for the early prediction and diagnosis of gout.OBJECTIVE: This study aimed at profiling the dysregulated metabolic pathways in asymptomatic hyperuricemia (AHU) and gout and elucidating the associations between AHU, gout and metabolomics, which may aid in performing gout screening.METHODS: A total of 300 participants, including 114 healthy controls, 92 patients with AHU, and 94 patients with gout, were analyzed by using a combination of dried blood spot (DBS) sampling and mass spectrometry (MS) technology. Multiple algorithms were applied to characterize altered metabolic profiles in AHU and gout. The mainly altered metabolites were identified by random forest analysis.RESULTS: There were significant differences in AHU and gout compared with control group. The altered metabolites were involved in oxidation of fatty acids, carnitine synthesis, urea cycle, and amino acid metabolism in AHU and gout. Random forest classification of 16 metabolites yielded 3 important features to distinguish gout from AHU.CONCLUSIONS: Distinct metabolomic signatures were observed in AHU and gout. The selected metabolites may have the potential to improve the early detection of gout.PMID:37821971 | DOI:10.1186/s13018-023-04240-3

Cancer Metab. 2023 Oct 11;11(1):16. doi: 10.1186/s40170-023-00317-z.ABSTRACTBACKGROUND: Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC.METHODS: In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry.RESULTS: The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression.CONCLUSIONS: Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients.PMID:37821929 | DOI:10.1186/s40170-023-00317-z

J Transl Med. 2023 Oct 11;21(1):714. doi: 10.1186/s12967-023-04424-9.ABSTRACTPURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk.METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC).RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS.CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.PMID:37821919 | DOI:10.1186/s12967-023-04424-9

BMC Genomics. 2023 Oct 11;24(1):607. doi: 10.1186/s12864-023-09628-3.ABSTRACTSchisandra sphenanthera is an extremely important medicinal plant, and its main medicinal component is bioactive lignans. The S. sphenanthera fruit is preferred by the majority of consumers, and the root, stem, and leaf are not fully used. To better understand the lignan metabolic pathway, transcriptome and metabolome analyses were performed on the four major tissues of S. sphenanthera. A total of 167,972,229 transcripts and 91,215,760 unigenes with an average length of 752 bp were identified. Tissue-specific gene analysis revealed that the root had the highest abundance of unique unigenes (9703), and the leaves had the lowest (189). Transcription factor analysis showed that MYB-, bHLH- and ERF-transcription factors, which played important roles in the regulation of secondary metabolism, showed rich expression patterns and may be involved in the regulation of processes involved in lignan metabolism. In different tissues, lignans were preferentially enriched in fruit and roots by gene expression profiles related to lignan metabolism and relative lignan compound content. Furthermore, schisandrin B is an important compound in S. sphenanthera. According to weighted gene co-expression network analysis, PAL1, C4H-2, CAD1, CYB8, OMT27, OMT57, MYB18, bHLH3, and bHLH5 can be related to the accumulation of lignans in S. sphenanthera fruit, CCR5, SDH4, CYP8, CYP20, and ERF7 can be related to the accumulation of lignans in S. sphenanthera roots. In this study, transcriptome sequencing and targeted metabolic analysis of lignans will lay a foundation for the further study of their biosynthetic genes.PMID:37821824 | DOI:10.1186/s12864-023-09628-3

Cancer Gene Ther. 2023 Oct 11. doi: 10.1038/s41417-023-00675-2. Online ahead of print.ABSTRACTOmipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.PMID:37821641 | DOI:10.1038/s41417-023-00675-2

Proteomics. 2023 Oct 11:e2300052. doi: 10.1002/pmic.202300052. Online ahead of print.ABSTRACTSelenium is a well-known health-relevant element related with cancer chemoprevention, neuroprotective roles, beneficial in diabetes, and in several infectious diseases, among others. It is naturally present in some foods, but deficiency in people led to the production of nutraceuticals, supplements, and functional food enriched in this element. There is a U-shaped link between selenium levels and health and a narrow range between toxic and essential levels, and thus, supplementation should be performed carefully. Omics methodologies have become valuable approaches to delve into the responses of dietary selenium in mammals that allowed a deeper knowledge about the metabolism of this element as well as its biological role. In this review, we discuss omics approaches from the workflows to their applications that has been previously used to deep insight into the metabolism of dietary selenium. There is a special focus on selenoproteins, metabolomics responses in blood and tissues (e.g., brain, reproductive organs, etc.) as well as the impact on gut microbiota and its metabolites profile. Thus, we mainly reviewed heteroatom-tagged proteomics, metallomics, metabolomics, and metataxonomics, usually combined with transcriptomics, genomics, and other molecular methods.PMID:37821362 | DOI:10.1002/pmic.202300052

J Proteome Res. 2023 Oct 11. doi: 10.1021/acs.jproteome.3c00436. Online ahead of print.ABSTRACTSorghum (Sorghum bicolor), a grass native to Africa, is a popular alternative to barley for brewing beer. The importance of sorghum to beer brewing is increasing because it is a naturally gluten-free cereal, and climate change is expected to cause a reduction in the production of barley over the coming decades. However, there are challenges associated with the use of sorghum instead of barley in beer brewing. Here, we used proteomics and metabolomics to gain insights into the sorghum brewing process to advise processes for efficient beer production from sorghum. We found that during malting, sorghum synthesizes the amylases and proteases necessary for brewing. Proteomics revealed that mashing with sorghum malt required higher temperatures than barley malt for efficient protein solubilization. Both α- and β-amylase were considerably less abundant in sorghum wort than in barley wort, correlating with lower maltose concentrations in sorghum wort. However, metabolomics revealed higher glucose concentrations in sorghum wort than in barley wort, consistent with the presence of an abundant α-glucosidase detected by proteomics in sorghum malt. Our results indicate that sorghum can be a viable grain for industrial fermented beverage production, but that its use requires careful process optimization for efficient production of fermentable wort and high-quality beer.PMID:37821127 | DOI:10.1021/acs.jproteome.3c00436

Clin Chim Acta. 2023 Oct 9:117589. doi: 10.1016/j.cca.2023.117589. Online ahead of print.ABSTRACTOBJECTIVES: The present study was conducted to evaluate the performance of serum bile acids in the prediction of cirrhosis in chronic hepatitis B (CHB) population.METHODS: Dysregulated metabolites were explored using untargeted and targeted metabolomic analyses. A machine learning model based on platelet (PLT) and several bile acids was constructed using light gradient boosting machine (LightGBM), to differentiate HBV-associated cirrhosis (BAC) from CHB patients.RESULTS: Serum bile acids were dysregulated in BAC compared to CHB patients. The LightGBM model consisted of PLT, TUDCA, UDCA, TLCA, LCA and CA. The model demonstrated a strong discrimination ability in the internal test subset of the training cohort to diagnose BAC from CHB patients (AUC = 0.97). The high diagnostic accuracy of the model was further validated in an independent validation cohort. In addition, the model had high predictive efficacy in discriminating compensated BAC from CHB patients (AUC = 0.89). The performance of the model was better than AST/ALT ratio and the gradient boosting (GB)-based model reported in previous studies.CONCLUSIONS: Our study showed that this LightGBM model based on PLT and 5 bile acids has potential in clinical assessments of CHB progression and will be useful for early detection of cirrhosis in CHB patients.PMID:37821059 | DOI:10.1016/j.cca.2023.117589

J Ethnopharmacol. 2023 Oct 9:117220. doi: 10.1016/j.jep.2023.117220. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICALRELEVANCE: Codonopsis pilosula (DS), a traditional Chinese medicine, had been used to regulate the immune, digestive and circulatory systems of the human, as well as protect the gastrointestinal tract, improve lung function.AIM OF THE STUDY: The aim of study was to explore the effects and mechanism of Codonopsis pilosula aqueous extract (DS) intervention in improving ulcerative colitis (UC).MATERIALS AND METHODS: UC model rats were established using combination of TNBS and ethanol. Tissue samples were collected for transcriptome and metabolomics analysis. Network pharmacology was performed on DS to identify bioactive compounds. Western blot was used to detect the key proteins involved in UC pathogenesis and PI3K/AKT pathways.RESULTS: DS exerted the preventive and therapeutic effects in improving UC via inhibiting abnormal inflammatory responses and promoting antioxidant capacity. Levels of intestinal barrier, oxidative stress and inflammatory mediators were improved to nearly normal level in vivo by DS. Metabolome profiles showed that DS could restore the metabolic disorders associated with the UC pathogenesis. Further transcriptome results showed that DS mainly alleviate UC through inhibiting PI3K/Akt signaling pathway, and various related genes that dramatically expressed in UC Model rats were downregulated by DS. Typically, network pharmacology analysis identified that Glycitein was the hub compounds that involved in the mechanism of DS in improving UC.CONCLUSIONS: The results show that Codonopsis pilosula (DS) was an potential excellent material in treating of UC depending on its suitable concentration. Possible therapeutic mechanisms of the DS involved in mitigating colonal inflammation, restoring metabolic disorders, promoting antioxidant capacity, and especially blocking the activation of PI3K/Akt pathway.PMID:37820998 | DOI:10.1016/j.jep.2023.117220

J Ethnopharmacol. 2023 Oct 9:117301. doi: 10.1016/j.jep.2023.117301. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu Decoction (HGWD) is a classic traditional Chinese herbal formula from "Synopsis of Golden Chamber," which is used to treat blood stagnation and has been used for alleviating diabetic peripheral neuropathy (DPN) in the clinic. However, the mechanisms of HGWD intervention DPN are still to be discovered.AIM OF THE STUDY: This study aims to explore the mechanism of HGWD intervention DPN by integrating plasma metabolomics and gut microbiome.MATERIALS AND METHODS: BKS Cg-m+/+Leprdb/J (db/db) mice with DPN were at 16 weeks of age. The indices of DPN phenotypes in db/db mice, pathomorphology of the sciatic nerve, intraepithelial nerve fibers (IENF) of the foot pad, levels of blood lipids and oxidative stress, and inflammatory reaction were used to appraise the HGWD efficacy. Finally, the pharmacological mechanisms of HGWD intervening DPN were explored by metabolomics and 16S rRNA gene sequencing.RESULTS: HGWD reversed DPN phenotypes in db/db mice, improved peripheral nerve structure, ameliorated the level of blood lipids and nerve growth factor in plasma, enhanced antioxidant capacity, and alleviated inflammatory responses. Plasma metabolomics disclosed that HGWD remarkably regulated the unusual levels of thirty-seven metabolites involved in sphingolipid metabolism, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and amino acid biosynthesis pathways. The gut microbiome showed that nine bacteria were highly correlated with the efficacy of HGWD in DPN. Integrating analysis of microbiome and metabolomics demonstrated that the interaction of four bacteria with four metabolic pathways might be the significant mechanism of HGWD intervention in DPN.CONCLUSIONS: The mediation of gut microbiota and plasma metabolism may be the potential mechanism of HGWD ameliorating DPN in db/db mice. The interaction of Lactobacillus, Alloprevotella, Bacteroides, and Desulfovibio with four metabolic pathways might be the critical mechanism for HGWD treating DPN.PMID:37820997 | DOI:10.1016/j.jep.2023.117301

J Ethnopharmacol. 2023 Oct 9:117296. doi: 10.1016/j.jep.2023.117296. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tinospora crispa (L.) Hook. f. & Thomson stem (TCS) has long been used as folk medicine for the treatment of diabetes mellitus. Previous study revealed that TCS possesses multi-ingredients and multi-targets characteristic potential as insulin sensitizer activity. However, its mechanisms of action and molecular targets are still obscure.AIM OF THE STUDY: In the present study, we investigated the effects of TCS against insulin resistance in muscle cells through integrating in vitro experiment and identifying its active biomarker using metabolomics and in molecular docking validation.MATERIALS AND METHODS: We used centrifugal partition chromatography (CPC) to isolate 33 fractions from methanolic extract of TCS, and then used UHPLC-Orbitrap-HRMS to identify the detectable metabolites in each fraction. We assessed the insulin sensitization activity of each fraction using enzyme-linked immunosorbent assay (ELISA), and then used confocal immunocytochemistry microscopy to measure the translocation of glucose transporter 4 (GLUT4) to the cell membrane. The identified active metabolites were further simulated for its molecular docking interaction using Autodock Tools.RESULTS: The polar fractions of TCS significantly increased insulin sensitivity, as measured by the inhibition of phosphorylated insulin receptor substrate-1 (pIRS1) at serine-312 residue (ser312) also the increasing number of translocated GLUT4 and glycogen content. We identified 58 metabolites of TCS, including glycosides, flavonoids, alkaloids, coumarins, and nucleotides groups. The metabolomics and molecular docking simulations showed the presence of minor metabolites consisting of tinoscorside D, higenamine, and tinoscorside A as the active compounds.CONCLUSIONS: Our findings suggest that TCS is a promising new treatment for insulin resistance and the identification of the active metabolites in TCS could lead to the development of new drugs therapies for diabetes that target these pathways.PMID:37820996 | DOI:10.1016/j.jep.2023.117296

J Ethnopharmacol. 2023 Oct 9:117272. doi: 10.1016/j.jep.2023.117272. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla var. Yunnanensis (Franch.) Hand.-Mazz., a perennial medicinal herb commonly known as "Chonglou" in Chinese, is mainly effective against innominate toxin swelling, insect sting, snake bite, traumatic injuries and various inflammatory. It is also recorded with mild toxicity. The rare species Paris luquanensis H. Li has been also used as folk medicine in Yunnan province for the same effects. Compared with P. polyphylla var. Yunnanensis (35-100 cm in height), this species has variegated leaves, and grows slower and is therefore shorter (6-23 cm in height). There are a number of different cultivars based on the shape of the petal and the height of Paris plant. However, currently, investigations into the differences of the chemical profiling of these cultivars are lacking.AIM OF THE STUDY: This study aims to: (1) examine metabolites variations in Paris polyphylla var. Yunnanensis cultivars and Paris luquanensis; (2) investigate the different metabolite accumulation patterns between rhizomes and leaves and provide more useful information for the application of P. polyphylla var. Yunnanensis leaves; (3) compare in vivo effects on the recruitment of reactive oxygen species (ROS) and Neutrophils and toxic effects in zebrafish model between leaves and rhizomes of P. polyphylla var. Yunnanensis and P. luquanensis.MATERIALS AND METHODS: The change patterns of metabolites in the leaves and rhizomes of four P. polyphylla var. Yunnanensis cultivars and one P. luquanensis cultivar were analyzed using an UPLC-ESI-MS/MS system. The total phenolic acid, total flavonoid, total saponin components and in vitro antioxidant activities were determined by spectrophotometric methods. The in vivo toxicity and their effects on the recruitment of ROS and neutrophils in zebrafish model were performed.RESULTS: The widely targeted metabolomics method detected 695 metabolites in tested samples and classified as 15 known classes according to structures of the metabolites. By overall-comparing the SDMs discerned between leaves and rhizomes of each samples, 161 metabolites were substantially altered in all the cultivars. There are 62 and 64 SDMs showing constitutive differential accumulation between leaves and rhizomes of P. polyphylla var. Yunnanensis (samples A-D) and P. luquanensis (sample E), respectively. The levels of TSC, TPC and TFC decreased significantly in leaves as compared to rhizomes for all cultivars, with the exception of TPC in cultivar A, which is almost the same in leave and rhizome. The DPPH scavenging property and FRAP values of rhizomes are higher than those of leaves for all cultivars. However, there is no distinct different between leaves and rhizomes of different sample extracts for in vivo effects on the recruitment of ROS and neutrophils in zebrafish model. BL extracts showed high toxicity to the developing embryos.CONCLUSION: As far as we are concerned, this study analyzes the P. polyphylla var. Yunnanensis and P. luquanensis variegation from the perspective of the metabolites pattern for the first time. The results give a valuable insight into the specie metabolic profiling and in vivo anti-oxidant, anti-inflammatory and toxic effects of these Paris plants.PMID:37820995 | DOI:10.1016/j.jep.2023.117272

Int J Biol Macromol. 2023 Oct 9:127335. doi: 10.1016/j.ijbiomac.2023.127335. Online ahead of print.ABSTRACTThis study aimed to explore the efficacy of polysaccharides from bergamot (BP) in alleviating DSS-induced colitis. Results showed that BP was primarily composed of two components, BP-1 and BP-2, with similar monosaccharide compositions to BP (mainly glucose and xylose) and molecular weights (Mw) of 4.50 × 105 and 2.35 × 105 Da. This study found BP relieved disease symptoms such as weight loss and colon shortening in mice with colitis. Gut microbiota and metabolomics analysis revealed that the BP could also promote the proliferation of beneficial bacteria such as Bifidobacteria, Butyrivibrio, and Blautia, resulting in increased levels of SCFAs and L-phenylalanine, which were associated with phenylalanine, tyrosine, and tryptophan metabolism pathways. Further analysis validated the inflammatory activity of L-phenylalanine. Hence, BP may relieve colitis symptoms by regulating the gut microbiota and metabolism, which reduced inflammation and enhanced the expression of tight junctional proteins (TJ proteins) and mucin in the intestine.PMID:37820919 | DOI:10.1016/j.ijbiomac.2023.127335