PubMed

Food Sci Anim Resour. 2023 Nov;43(6):1044-1054. doi: 10.5851/kosfa.2023.e54. Epub 2023 Nov 1.ABSTRACTGrowing evidence indicates a crucial role of the gut microbiota in physiological functions. Gut-brain axis imbalance has also been associated with neuropsychiatric and neurodegenerative disorders. Studies have suggested that probiotics regulate the stress response and alleviate mood-related symptoms. In this study, we investigated the effects of the probiotic Lacticaseibacillus rhamnosus IDCC3201 (L3201) on the behavioral response and fecal metabolite content in an unpredictable chronic mild stress (UCMS) mouse model. Our study shows that chronic stress in mice for three weeks resulted in significant changes in behavior, including lower locomotor activity, higher levels of anxiety, and depressive-like symptoms, compared to the control group. Metabolomic analysis demonstrated that disrupted fecal metabolites associated with aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis by UCMS were restored with the administration of L3201. Oral administration of the L3201 ameliorated the observed changes and improved the behavioral alterations along with fecal metabolites, suggesting that probiotics play a neuroprotective role.PMID:37969325 | PMC:PMC10636227 | DOI:10.5851/kosfa.2023.e54

Food Sci Anim Resour. 2023 Nov;43(6):1067-1086. doi: 10.5851/kosfa.2023.e63. Epub 2023 Nov 1.ABSTRACTWith rapid advances in meat science in recent decades, changes in meat quality during the pre-slaughter phase of muscle growth and the post-slaughter process from muscle to meat have been investigated. Commonly used techniques have evolved from early physicochemical indicators such as meat color, tenderness, water holding capacity, flavor, and pH to various omic tools such as genomics, transcriptomics, proteomics, and metabolomics to explore fundamental molecular mechanisms and screen biomarkers related to meat quality and taste characteristics. This review highlights the application of omics and integrated multi-omics in meat quality and taste characteristics studies. It also discusses challenges and future perspectives of multi-omics technology to improve meat quality and taste. Consequently, multi-omics techniques can elucidate the molecular mechanisms responsible for changes of meat quality at transcriptome, proteome, and metabolome levels. In addition, the application of multi-omics technology has great potential for exploring and identifying biomarkers for meat quality and quality control that can make it easier to optimize production processes in the meat industry.PMID:37969318 | PMC:PMC10636221 | DOI:10.5851/kosfa.2023.e63

Acta Neuropsychiatr. 2023 Nov 16:1-50. doi: 10.1017/neu.2023.52. Online ahead of print.ABSTRACTOBJECTIVE: We aimed to answer the questions of whether early-life (perinatal and/or juvenile) exercise can induce antidepressant-like effects in a validated rodent model of depression, and whether such early-life intervention could prevent or reverse the adverse effects of early-life stress in their offspring.METHODS: Male and female FSL rats born to a dam that exercised during gestation, or not, were either maternally separated between PND02 and 16 and weaned on PND17, or not. Half of these animals then underwent a fourteen-day low intensity exercise regimen from PND22. Baseline depressive-like behaviour was assessed on PND21 and then reassessed on PND36, whereafter hippocampal monoamine levels, redox state markers and metabolic markers, relevant to mitochondrial function were measured.RESULTS: Prepubertal exercise was identified as the largest contributing factor to the observed effects, where it decreased immobility time in the FST by 6%, increased time spent in the open arms of the EPM by 9%. Hippocampal serotonin and norepinephrine levels were also increased by 35 and 26%, respectively, whilst nicotinic acid was significantly decreased.CONCLUSION: These findings suggests that prepubertal low intensity exercise induces beneficial biological alterations that could translate into antidepressant behaviour in genetically susceptible individuals.PMID:37969008 | DOI:10.1017/neu.2023.52

Probl Endokrinol (Mosk). 2023 Nov 11;69(5):45-54. doi: 10.14341/probl13278.ABSTRACTAgeing (as known as eldering, senescence) is a genetically and epigenetically programmed pathophysiological process. Velocity of biological ageing is defined as balance between alteration and reparation of body structures. According to last World Health Organization (WHO) highlights ageing still stays an extremely actual scientific, social and demographic problem: in 2020 total number of people older than 60 years and older was 1 billion people; in 2030 future number may be 1,4 billion people, in 2050 - 2,1 billion people. Absence of single universal theory of aging nowadays is reason for scientifical and clinical collaboration between biologists and doctors, including endocrinologists. Designing of potentially effective newest anti-ageing strategies (such as natural/synthetic telomerase regulators, mesenchymal stem cells etc.) is of interest to scientific community. The aim of present article is a review of modern omics (genomic, proteomic, metabolomic) ageing mechanisms, potential ways of targeted prevention and treatment of age-related disease according to conception of personalized medicine. Present review is narrative, it does not lead to systematic review, meta-analysis and does not aim to commercial advertisement. Review has been provided via PubMed article that have been published since 1979 until 2022.PMID:37968951 | DOI:10.14341/probl13278

J Dent Res. 2023 Nov 15:220345231203562. doi: 10.1177/00220345231203562. Online ahead of print.ABSTRACTSystemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 (n = 6,229) and Parogene (n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants (n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.PMID:37968796 | DOI:10.1177/00220345231203562

BMC Plant Biol. 2023 Nov 16;23(1):567. doi: 10.1186/s12870-023-04585-1.ABSTRACTBACKGROUND: Edgeworthia chrysantha, a deciduous shrub endemic to China, is known for its high ornamental value, extensive cultivation history, and wide-ranging applications. However, theoretical research on this plant is severely lacking. While its flowering process displays striking color transitions from green (S1) to yellow (S2) and then to white (S3), the scientific exploration of this phenomenon is limited, and the underlying regulatory mechanisms are yet to be elucidated.RESULTS: Correlation analysis between phenotypic measurements and pigment content revealed that carotenoids and chlorophyll are the key pigments responsible for the color changes. Metabolomic analysis of carotenoids demonstrated that lutein and β-carotene were present at higher levels in S1, while S2 exhibited increased diversity and quantity of carotenoids compared to other stages. Notably, antheraxanthin, zeaxanthin, lycopene, and α-cryptoxanthin showed significant increases. In S3, apart from the colorless phytoene, other carotenoid metabolites were significantly reduced to extremely low levels. Transcriptomic data indicated that PSY, Z-ISO, crtZ, ZEP, PDS and ZDS are key genes involved in carotenoid biosynthesis and accumulation, while NCED plays a crucial role in carotenoid degradation. SGR was identified as a key gene contributing to the progressive decline in chlorophyll content. Additionally, three transcription factors potentially regulating carotenoid metabolism were also identified.CONCLUSIONS: This study represents the first systematic investigation, spanning from phenotypic to molecular levels, of the color-changing phenomenon in E. chrysantha. The study elucidates the crucial pigments, metabolites, genes, and transcription factors responsible for flower color changes during the flowering process, thereby providing preliminary understanding of the intrinsic regulatory mechanisms. These findings establish a theoretical foundation for the genetic improvement of flower color in E. chrysantha.PMID:37968605 | DOI:10.1186/s12870-023-04585-1

Adv Biol (Weinh). 2023 Nov 15:e2300404. doi: 10.1002/adbi.202300404. Online ahead of print.ABSTRACTTrehalose is synthesized in insects through the trehalose 6-phosphate synthase and phosphatase (TPS/TPP) pathway. TPP dephosphorylates trehalose 6-phosphate to release trehalose. Trehalose is involved in metamorphosis, but its relation with body weight, size, and developmental timing is unexplored. The expression and activity of TPS/TPP fluctuate depending on trehalose demand. Thus, TPS/TPP inhibition can highlight the significance of trehalose in insect physiology. TPS/TPP transcript levels are elevated in the pre-pupal and pupal stages in Helicoverpa armigera. The inhibition of recombinantly expressed TPP by N-(phenylthio)phthalimide (NPP), is validated by in vitro assays. In vivo inhibition of trehalose synthesis reduces larval weight and size, hampers metamorphosis, and reduces its overall fitness. Insufficient trehalose leads to a shift in glucose flux, reduced energy, and dysregulated fatty acid oxidation. Metabolomics reaffirms the depletion of trehalose, glucose, glucose 6-phosphate, and suppressed tricarboxylic acid cycle. Reduced trehalose hampers the energy level affecting larval vitality. Through trehalose synthesis inhibition, the importance of trehalose in insect physiology and development is investigated. Also, in two other lepidopterans, TPP inhibition impedes physiology and survival. NPP is also found to be effective as an insecticidal formulation. Overall, trehalose levels affect the larval size, weight, and metabolic homeostasis for larval-pupal transition in lepidoptera.PMID:37968550 | DOI:10.1002/adbi.202300404

Stem Cell Res Ther. 2023 Nov 14;14(1):329. doi: 10.1186/s13287-023-03516-z.ABSTRACTBACKGROUND: Mesenchymal stem cells (MSCs) have immunomodulatory properties and therapeutic effects on autoimmune diseases through their secreted factors, referred to as the secretome. However, the specific key factors of the MSC secretome and their mechanisms of action in immune cells have not been fully determined. Most in vitro experiments are being performed using immune cells, but experiments using natural killer (NK) cells have been neglected, and a few studies using NK cells have shown discrepancies in results. NK cells are crucial elements of the immune system, and adjustment of their activity is essential for controlling various pathological conditions. The aim of this study was to elucidate the role of the adipose tissue-derived stem cell (ADSC) secretome on NK cell activity.METHODS: To obtain the ADSC secretome, we cultured ADSCs in medium and concentrated the culture medium using tangential flow filtration (TFF) capsules. We assessed NK cell viability and proliferation using CCK-8 and CFSE assays, respectively. We analyzed the effects of the ADSC secretome on NK cell activity and pathway-related proteins using a combination of flow cytometry, ELISA, cytotoxicity assay, CD107a assay, western blotting, and quantitative real-time PCR. To identify the composition of the ADSC secretome, we performed LC-MS/MS profiling and bioinformatics analysis. To elucidate the molecular mechanisms involved, we used mRNA sequencing to profile the transcriptional expression of human blood NK cells.RESULTS: The ADSC secretome was found to restrict IL-2-mediated effector function of NK cells while maintaining proliferative potency. This effect was achieved through the upregulation of the inhibitory receptor CD96, as well as downregulation of activating receptors and IL-2 receptor subunits IL-2Rα and IL-2Rγ. These changes were associated with attenuated JAK-STAT and AKT pathways in NK cells, which were achieved through the upregulation of cytokine-inducible SH2-containing protein (CIS, encoded by Cish) and dual specificity protein phosphatase 4 (DUSP4). Furthermore, proteomic analysis revealed twelve novel candidates associated with the immunomodulatory effects of MSCs.CONCLUSIONS: Our findings reveal a detailed cellular outcome and regulatory mechanism of NK cell activity by the ADSC secretome and suggest a therapeutic tool for treating NK-mediated inflammatory and autoimmune diseases using the MSC secretome.PMID:37964351 | PMC:PMC10648656 | DOI:10.1186/s13287-023-03516-z

J Appl Genet. 2023 Nov 16. doi: 10.1007/s13353-023-00799-z. Online ahead of print.ABSTRACTLambdoid bacteriophages are excellent models in studies on molecular aspects of virus-host interactions. However, some of them carry genes encoding toxins which are responsible for virulence of pathogenic strains of bacteria. Shiga toxin-converting bacteriophages (Stx phages) encode Shiga toxins that cause virulence of enterohemorrhagic Escherichia coli (EHEC), and their effective production depends on Stx prophage induction. The exo-xis region of the lambdoid phage genome consists of genes which are dispensable for the phage multiplication under laboratory conditions; however, they might modulate the virus development. Nevertheless, their exact effects on the phage and host physiology remained unclear. Here, we present results of complex studies on the role of the exo-xis region of bacteriophage Φ24B, one of Stx2b phages. Transcriptomic analyses, together with proteomic and metabolomic studies, provided the basis for understanding the functions of the exo-xis region. Genes from this region promoted lytic development of the phage over lysogenization. Moreover, expression of the host genes coding for DnaK, DnaJ, GrpE, and GroELS chaperones was impaired in the cells infected with the Δexo-xis phage mutant, relative to the wild-type virus, corroborating the conclusion about lytic development promotion by the exo-xis region. Proteomic and metabolomic analyses indicated also modulation of gad and nrf operons, and levels of amino acids and acylcarnitines, respectively. In conclusion, the exo-xis region controls phage propagation and host metabolism by influencing expression of different phage and bacterial genes, directing the virus to the lytic rather than lysogenic developmental mode.PMID:37968427 | DOI:10.1007/s13353-023-00799-z

Geroscience. 2023 Nov 16. doi: 10.1007/s11357-023-01005-y. Online ahead of print.ABSTRACTOlder women and Black individuals are more likely to experience frailty. A metabolomic characterization of frailty may help inform more effective interventions aimed at improving health, reducing disparities, and preventing frailty with aging. We sought to identify metabolites and pathways associated with vigor to frailty and determine whether associations differed by sex and/or race among n = 2189 older Black and White men and women from the Health, Aging, and Body Composition (Health ABC) study. Fasting plasma metabolites were measured using liquid chromatography-mass spectrometry. Vigor to frailty was based on weight change, physical activity, gait speed, grip strength, and usual energy. We used linear regression of a single metabolite on vigor to frailty, adjusting for age, sex, race, study site, and multiple comparisons using a Bonferroni correction. Among 500 metabolites, 113 were associated with vigor to frailty (p < 0.0001). Associations between metabolites and vigor to frailty did not differ significantly by race and/or sex. Lower amino acids, glycerophospholipids, sphingolipids, and dehydroepiandrosterone sulfate and higher acylcarnitines, fatty acids, amino acid derivatives, organic acids, carbohydrates, citric acid cycle metabolites, and trimethylamine oxide were associated with frailer scores. Pathway analyses identified the citric acid cycle as containing more frailty-associated metabolites than expected by chance (p = 0.00005). Calories and protein intake did not differ by vigor to frailty. Frailer Health ABC participants may have lower utilization of energy pathways, potentially as a result of less demand and less efficient utilization of similar amounts of nutrients when compared to more vigorous participants.PMID:37968423 | DOI:10.1007/s11357-023-01005-y

Nat Commun. 2023 Nov 15;14(1):7385. doi: 10.1038/s41467-023-43315-x.ABSTRACTInfections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.PMID:37968313 | DOI:10.1038/s41467-023-43315-x

Sci Rep. 2023 Nov 15;13(1):19979. doi: 10.1038/s41598-023-47334-y.ABSTRACTHydrolyzed protein diets are extensively used to treat chronic enteropathy (CE) in cats. However, the biochemical effects of such a diet on feline CE have not been characterized. In this study an untargeted 1H nuclear magnetic resonance spectroscopy-based metabolomic approach was used to compare the urinary, plasma, and fecal metabolic phenotypes of cats with CE to control cats with no gastrointestinal signs recruited at the Royal Veterinary College (RVC). In addition, the biomolecular consequences of a hydrolyzed protein diet in cats with CE was also separately determined in cats recruited from the RVC (n = 16) and the University of Bristol (n = 24) and whether these responses differed between dietary responders and non-responders. Here, plasma metabolites related to energy and amino acid metabolism significantly varied between CE and control cats in the RVC cohort. The hydrolyzed protein diet modulated the urinary metabolome of cats with CE (p = 0.005) in both the RVC and Bristol cohort. In the RVC cohort, the urinary excretion of phenylacetylglutamine, p-cresyl-sulfate, creatinine and taurine at diagnosis was predictive of dietary response (p = 0.025) although this was not observed in the Bristol cohort. Conversely, in the Bristol cohort plasma betaine, glycerol, glutamine and alanine at diagnosis was predictive of outcome (p = 0.001), but these same results were not observed in the RVC cohort. The biochemical signature of feline CE in the RVC cohort was consistent with that identified in human and animal models of inflammatory bowel disease. The hydrolyzed protein diet had the same effect on the urinary metabolome of cats with CE at both sites. However, biomarkers that were predictive of dietary response at diagnosis differed between the 2 sites. This may be due to differences in disease severity, disease heterogeneity, factors unrelated to the disease or small sample size at both sites. As such, further studies utilizing larger number of cats are needed to corroborate these findings.PMID:37968311 | DOI:10.1038/s41598-023-47334-y

J Appl Toxicol. 2023 Nov 15. doi: 10.1002/jat.4562. Online ahead of print.ABSTRACTCholestasis is a pathological condition characterized by disruptions in bile flow, leading to the accumulation of bile acids (BAs) in hepatocytes. Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by α-naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC-MS/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and β-muricholic acid (β-MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase Cyp8b1, while enhancing the expression of hepatic efflux transporter Mrp4, as well as the renal efflux transporters Mdr1 and Mrp2. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT-induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.PMID:37968239 | DOI:10.1002/jat.4562

J Biosci Bioeng. 2023 Nov 13:S1389-1723(23)00322-5. doi: 10.1016/j.jbiosc.2023.10.004. Online ahead of print.ABSTRACTGeotrichum candidum is a dimorphic yeast used in cheese processing. To our knowledge, no major metabolites have been identified to date in G. candidum except for some amino acid and fatty acid metabolites. This has limited research on the commercial use of G. candidum. In this study, we aimed to analyze temporal changes in the intra- and extra-cellular metabolites of G. candidum and Saccharomyces cerevisiae cultured in YM medium as reference. As a result of metabolite analysis, it was observed that G. candidum tends to accumulate pentose phosphate pathway compounds, which are involved in nucleic acid synthesis, after 48 h of cultivation when compared to S. cerevisiae. In addition, G. candidum accumulated higher amounts of the antioxidant glutathione in the medium than did S. cerevisiae. In addition, G. candidum accumulated large amounts of B vitamins such as pantothenic acid and nicotinic acid in the medium. Finally, we examined the potential of G. candidum as a host for the production of useful compounds such as pantothenic acid. When cultured in medium supplemented with the pantothenic acid precursor β-alanine, G. candidum produced 12-fold higher amounts of pantothenic acid (30 μM) than that by S. cerevisiae. This study indicates that G. candidum accumulates various useful compounds that are dissimilar to those produced by S. cerevisiae. Furthermore, G. candidum has the potential to produce useful chemicals under appropriate culture conditions.PMID:37968228 | DOI:10.1016/j.jbiosc.2023.10.004

J Ethnopharmacol. 2023 Nov 13:117402. doi: 10.1016/j.jep.2023.117402. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: DHZCP is a traditional Chinese medicinal formula in "The Synopsis of Prescriptions of the Golden Chamber" that has been often used in the treatment of hepatic disorders, gynecopathy and atherosclerosis. However, its underlying mechanisms in preventing hepatic fibrosis remain incompletely understood.AIM OF THE STUDY: This study aims to explore the therapeutic efficacy and potential mechanism of DHZCP in a CCL4-induced experimental hepatic fibrosis rat model.MATERIALS AND METHODS: DHZCP was orally administered at doses of 0.168, 0.084 and 0.042 g⋅kg-1⋅d-1 in a CCL4-induced hepatic fibrosis model using SD rats. Histopathology, immunohistochemistry and biochemical analysis, ELISA, Flow cytometry, WB, RT-PCR, 16 S rRNA, and untargeted metabolomic analysis were used to determine the therapeutic effects and mechanisms of DHZCP in the treatment of CCL4-induced hepatic fibrosis.RESULTS: Pharmacodynamically, DHZCP inhibited ALT and AST, improved liver function, decreased NF-κB, TNF-α and IL-6 in liver tissue, indicating its role in inhibiting CCL4-induced liver inflammation. Most importantly, it reduces the level of fibrosis in serum and liver tissue. Histological analysis also showed that DHZCP could effectively inhibit inflammatory cytokine infiltration and excessive collagen deposition. Mechanistically, DHZCP regulates gut microbiota, improves the proportion of firmicutes and bacteroidota at the phylum level, and increases the abundance of beneficial bacteria at the genus level, such as muribagulaceae unclassified, prevotella, alloprevotella, closteriales unclassified, lachnospiraceae unclassified and phascolarctobacterium. Instead, it reduced the abundance of two harmful bacteria, desulfovibrio and colidextribacter. Four types of metabolites such as hydrocarbons, organic nitrogen compounds, organic oxygen compounds, and organosulfur compounds were added. Furthermore, DHZCP was found to reduce the damage of intestinal barrier caused by changes in gut microbiota and metabolites.CONCLUSION: DHZCP is an effective inhibitor of hepatic fibrosis by regulating gut microbiota and metabolites, improving the integrity of the intestinal barrier.PMID:37967779 | DOI:10.1016/j.jep.2023.117402

J Ethnopharmacol. 2023 Nov 13:117420. doi: 10.1016/j.jep.2023.117420. Online ahead of print.ABSTRACTHEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Functional constipation (FC), characterized by chronic constipation, significantly impacts physiological function and induces psychological stress in patients. However, current clinical treatment options for FC are currently limited. Cistanche deserticola, a traditional Chinese medicine that promotes intestinal moisture and bowel relaxation, contains cistanche total alditol extract (CTAE) as its primary active extract. However, the production of CTAE, its overall efficacy, and potential mechanisms for treating FC have yet to been investigated.AIM OF THE STUDY: This study aimed to reveal the overall efficacy and potential mechanism of action of CTAE in rats with FC using a combination of stable preparation, pharmacodynamics, non-targeted metabolomics, bile acid metabolomics, and western blotting.MATERIALS AND METHODS: Fourteen batches of CTAE underwent quality testing. A rat model of FC was developed using diphenoxylate tablets. The comprehensive pharmacodynamic effects of CTAE on FC were evaluated using fecal characteristics (wet weight, dry weight, and water content), intestinal transmission (colonic EMG amplitude, colonic EMG frequency, propulsion length, and propulsion rate), serum and colon biochemical indicators, distribution of interstitial cells of Cajal (ICC), and pathological examination. Non-targeted metabolomics was performed to assess the changes in endogenous metabolite profiles induced by CTAE. Bile acid metabolomics and western blotting analyses were employed to validate the potential mechanisms of action of CTAE.RESULTS: CTAE, with a total content of betaine, mannitol, D-fructose, glucose, and sucrose of (75.94 ± 3.82) %, significantly enhanced intestinal transit, regulated neurotransmitters, increased the expression of c-kit in ICC, and alleviated intestinal inflammation in rats with FC. Non-targeted metabolomics revealed that CTAE significantly alleviated FC-induced metabolic disorders, mainly the biosynthesis of primary bile acids. Targeted metabolomic analysis confirmed that CTAE regulated FC-induced bile acid disorders. Western-blotting results confirmed that CTAE increased the expression of CYP8B1, FGF15, TGR5, and FXR, thereby modulating bile acid synthesis and enterohepatic circulation.CONCLUSION: CTAE demonstrates significant therapeutic effects on FC, primarily through the regulation of bile acid synthesis and enterohepatic circulation. These findings provide a promising foundation for the development and clinical application of novel CATE-based drugs.PMID:37967778 | DOI:10.1016/j.jep.2023.117420

Metabolism. 2023 Nov 13:155736. doi: 10.1016/j.metabol.2023.155736. Online ahead of print.ABSTRACTBACKGROUND: Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7.METHODS: We biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7-/- mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7.RESULTS: Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing lipid accumulation in hepatocytes. Non-alcoholic fatty liver disease (NAFLD) was induced by a 12-week high fat/fructose/cholesterol diet in wild type (WT) and Pcsk7-/- mice that were then allowed to recover on a 4-week control diet. Pcsk7-/- mice recovered more effectively than WT mice from all NAFLD-related liver phenotypes. Finally, subcutaneous administration of GalNAc-ASOs targeting hepatic Pcsk7 to WT mice validated the above results.CONCLUSIONS: Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome. This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD.PMID:37967646 | DOI:10.1016/j.metabol.2023.155736

Paediatr Perinat Epidemiol. 2023 Nov 15. doi: 10.1111/ppe.13021. Online ahead of print.ABSTRACTBACKGROUND: Systematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates.OBJECTIVE: To develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard.METHODS: We designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample.RESULTS: Out of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets.CONCLUSIONS: This easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.PMID:37967567 | DOI:10.1111/ppe.13021

Environ Pollut. 2023 Nov 13;341:122870. doi: 10.1016/j.envpol.2023.122870. Online ahead of print.NO ABSTRACTPMID:37967506 | DOI:10.1016/j.envpol.2023.122870

J Clin Endocrinol Metab. 2023 Nov 15:dgad668. doi: 10.1210/clinem/dgad668. Online ahead of print.ABSTRACTBACKGROUND AND AIM: The endocannabinoid system is a signalling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the ECS are linked to the development of cardiometabolic diseases. Here, we investigated the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors.METHODS: The study included 133 young adults (age 22.1 ± 2.2 years, 67% women). Fasting plasma levels of eCBs and their analogues were measured using liquid chromatography-tandem mass spectrometry. Body composition, brown adipose tissue (BAT) volume, glucose uptake, and traditional cardiometabolic risk factors were measured.RESULTS: Plasma levels of eCBs and several eCB analogues were positively correlated with adiposity and traditional cardiometabolic risk factors (e.g., serum insulin and triacylglycerides levels, all r ≥ 0.17 and p ≤ 0.045). Plasma levels of 2-AG and PDEA were negatively correlated with BAT volume and glucose uptake (all r ≤ -0.17 and P ≤ 0.047). We observed that the plasma levels of eCBs and their analogues were higher in metabolically unhealthy overweight-obese participants than in metabolically healthy overweight-obese participants.CONCLUSION: Our findings show that the plasma levels of eCBs and their analogues are related to higher levels of adiposity and worse cardiometabolic profile.PMID:37967236 | DOI:10.1210/clinem/dgad668