PubMed

Mar Drugs. 2023 Apr 26;21(5):271. doi: 10.3390/md21050271.ABSTRACTBACKGROUND: Terrein (Terr) is a bioactive marine secondary metabolite that possesses antiproliferative/cytotoxic properties by interrupting various molecular pathways. Gemcitabine (GCB) is an anticancer drug used to treat several types of tumors such as colorectal cancer; however, it suffers from tumor cell resistance, and therefore, treatment failure.METHODS: The potential anticancer properties of terrein, its antiproliferative effects, and its chemomodulatory effects on GCB were assessed against various colorectal cancer cell lines (HCT-116, HT-29, and SW620) under normoxic and hypoxic (pO2 ≤ 1%) conditions. Further analysis via flow cytometry was carried out in addition to quantitative gene expression and 1HNMR metabolomic analysis.RESULTS: In normoxia, the effect of the combination treatment (GCB + Terr) was synergistic in HCT-116 and SW620 cell lines. In HT-29, the effect was antagonistic when the cells were treated with (GCB + Terr) under both normoxic and hypoxic conditions. The combination treatment was found to induce apoptosis in HCT-116 and SW620. Metabolomic analysis revealed that the change in oxygen levels significantly affected extracellular amino acid metabolite profiling.CONCLUSIONS: Terrein influenced GCB's anti-colorectal cancer properties which are reflected in different aspects such as cytotoxicity, cell cycle progression, apoptosis, autophagy, and intra-tumoral metabolism under normoxic and hypoxic conditions.PMID:37233465 | DOI:10.3390/md21050271

J Fungi (Basel). 2023 Apr 30;9(5):536. doi: 10.3390/jof9050536.ABSTRACTFomitiporia mediterranea M. Fischer (Fmed) is a white-rot wood-decaying fungus associated with one of the most important and challenging diseases in vineyards: Esca. To relieve microbial degradation, woody plants, including Vitis vinifera, use structural and chemical weapons. Lignin is the most recalcitrant of the wood cell wall structural compounds and contributes to wood durability. Extractives are constitutive or de novo synthesized specialized metabolites that are not covalently bound to wood cell walls and are often associated with antimicrobial properties. Fmed is able to mineralize lignin and detoxify toxic wood extractives, thanks to enzymes such as laccases and peroxidases. Grapevine wood's chemical composition could be involved in Fmed's adaptation to its substrate. This study aimed at deciphering if Fmed uses specific mechanisms to degrade grapevine wood structure and extractives. Three different wood species, grapevine, beech, and oak. were exposed to fungal degradation by two Fmed strains. The well-studied white-rot fungus Trametes versicolor (Tver) was used as a comparison model. A simultaneous degradation pattern was shown for Fmed in the three degraded wood species. Wood mass loss after 7 months for the two fungal species was the highest with low-density oak wood. For the latter wood species, radical differences in initial wood density were observed. No differences between grapevine or beech wood degradation rates were observed after degradation by Fmed or by Tver. Contrary to the Tver secretome, one manganese peroxidase isoform (MnP2l, jgi protein ID 145801) was the most abundant in the Fmed secretome on grapevine wood only. Non-targeted metabolomic analysis was conducted on wood and mycelium samples, using metabolomic networking and public databases (GNPS, MS-DIAL) for metabolite annotations. Chemical differences between non-degraded and degraded woods, and between mycelia grown on different wood species, are discussed. This study highlights Fmed physiological, proteomic and metabolomic traits during wood degradation and thus contributes to a better understanding of its wood degradation mechanisms.PMID:37233247 | DOI:10.3390/jof9050536

J Fungi (Basel). 2023 Apr 24;9(5):507. doi: 10.3390/jof9050507.ABSTRACTFusarium graminearum (F. graminearum) is a filamentous fungus that infects cereals such as corn, wheat, and barley, with serious impact on yield as well as quality when the grain is contaminated with mycotoxins. Despite the huge impact of F. graminearum on food security and mammalian health, the mechanisms used by F. graminearum to export virulence factors during infection are not fully understood and may involve non-classical secretory pathways. Extracellular vesicles (EVs) are lipid-bound compartments produced by cells of all kingdoms that transport several classes of macromolecules and are implicated in cell-cell communication. EVs produced by human fungal pathogens carry cargo that facilitate infection, leading us to ask whether plant fungal pathogens also deliver molecules that increase virulence via EVs. We examined the metabolome of the EVs produced by F. graminearum to determine whether they carry small molecules that could modulate plant-pathogen interactions. We discovered that EVs from F. graminearum were produced in liquid medium-containing inducers of trichothecene production, but in lower quantities compared to other media. Nanoparticle tracking analysis and cryo-electron microscopy revealed that the EVs were morphologically similar to EVs from other organisms; hence, the EVs were metabolically profiled using LC-ESI-MS/MS. This analysis revealed that EVs carry 2,4-dihydroxybenzophenone (BP-1) and metabolites that have been suggested by others to have a role in host-pathogen interactions. BP-1 reduced the growth of F. graminearum in an in vitro assay, suggesting that F. graminearum might use EVs to limit metabolite self-toxicity.PMID:37233218 | DOI:10.3390/jof9050507

Curr Issues Mol Biol. 2023 May 4;45(5):4017-4034. doi: 10.3390/cimb45050256.ABSTRACT1α,25-Dihydroxyvitamin D3 (VitD3) is the active form of vitamin D, and it regulates gene expression and protein synthesis in mammalian follicle development. However, the function of VitD3 in the follicular development of layers remains unclear. This study investigated, through in vivo and in vitro experiments, the effects of VitD3 on follicle development and steroid hormone biosynthesis in young layers. In vivo, ninety 18-week-old Hy-Line Brown laying hens were randomly divided into three groups for different treatments of VitD3 (0, 10, and 100 μg/kg). VitD3 supplementation promoted follicle development, increasing the number of small yellow follicles (SYFs) and large yellow follicles (LYFs) and the thickness of the granulosa layer (GL) of SYFs. Transcriptome analysis revealed that VitD3 supplementation altered gene expression in the ovarian steroidogenesis, cholesterol metabolism, and glycerolipid metabolism signaling pathways. Steroid hormone-targeted metabolomics profiling identified 20 steroid hormones altered by VitD3 treatment, with 5 being significantly different among the groups. In vitro, it was found that VitD3 increased cell proliferation, promoted cell-cycle progression, regulated the expression of cell-cycle-related genes, and inhibited the apoptosis of granulosa cells from pre-hierarchical follicles (phGCs) and theca cells from prehierarchical follicles (phTCs). In addition, the steroid hormone biosynthesis-related genes, estradiol (E2) and progesterone (P4) concentrations, and vitamin D receptor (VDR) expression level was significantly altered by VitD3. Our findings identified that VitD3 altered the gene expression related to steroid metabolism and the production of testosterone, estradiol, and progesterone in the pre-hierarchical follicles (PHFs), resulting in positive effects on poultry follicular development.PMID:37232725 | DOI:10.3390/cimb45050256

J Proteome Res. 2023 May 26. doi: 10.1021/acs.jproteome.3c00093. Online ahead of print.ABSTRACTIncidence and mortality rates of alcoholic liver disease (ALD) is one of the highest in the world. In the present study, we found that the genetic knockout nuclear receptor the peroxisome proliferator-activated receptor α (PPARα) exacerbated ALD. Lipidomics of the liver revealed changed levels of lipid species encompassing phospholipids, ceramides (CM), and long-chain fatty acids in Ppara-null mice induced by ethanol. Moreover, 4-hydroxyphenylacetic acid (4-HPA) was changed as induced by ethanol in the metabolome of urine. Moreover, the phylum level analysis showed a decrease in the level of Bacteroidetes and an increase in the level of Firmicutes after alcohol feeding in Ppara-null mice, while there was no change in wild-type mice. In Ppara-null mice, the level of Clostridium_sensu_stricto_1 and Romboutsia were upregulated after alcohol feeding. These data revealed that PPARα deficiency potentiated alcohol-induced liver injury through promotion of lipid accumulation, changing the metabolome of urine, and increasing the level of Clostridium_sensu_stricto_1 and Romboutsia. 4-HPA could improve ALD in mice by regulating inflammation and lipid metabolism. Therefore, our findings suggest a novel approach to the treatment of ALD: focusing on the gut microbiota and its metabolites. Data are available via ProteomeXchange (PXD 041465).PMID:37232578 | DOI:10.1021/acs.jproteome.3c00093

Stat Med. 2023 May 26. doi: 10.1002/sim.9806. Online ahead of print.ABSTRACTResearchers in biology and medicine have increasingly focused on characterizing circadian rhythms and their potential impact on disease. Understanding circadian variation in metabolomics, the study of chemical processes involving metabolites may provide insight into important aspects of biological mechanism. Of scientific importance is developing a statistical rigorous approach for characterizing different types of 24-hour patterns among high dimensional longitudinal metabolites. We develop a latent class approach to incorporate variation in 24-hour patterns across metabolites where profiles are modeled with finite mixtures of distinct shape-invariant circadian curves that themselves incorporate variation in amplitude and phase across metabolites. An efficient Markov chain Monte Carlo sampling is used to carry out Bayesian posterior computation. When the model was fit separately by individual to the data from a small group of participants, two distinct 24-hour rhythms were identified, with one being sinusoidal and the other being more complex with multiple peaks. Interestingly, the latent pattern associated with circadian variation (simple sinusoidal curve) had a similar phase across the three participants, while the more complex latent pattern reflecting diurnal variation differed across individual. The results suggested that this modeling framework can be used to separate 24-hour rhythms into an endogenous circadian and one or more exogenous diurnal patterns in describing human metabolism.PMID:37232457 | DOI:10.1002/sim.9806

Genome Biol Evol. 2023 May 26:evad098. doi: 10.1093/gbe/evad098. Online ahead of print.ABSTRACTMost organismal phenotypes have a polygenic basis, which enables adaptive phenotypic responses on ecological time scales. While adaptive phenotypic changes are highly parallel in replicate populations, this does not apply to the contributing loci. In particular for small populations, the same phenotypic shift can be fueled by different sets of alleles at alternative loci (genetic redundancy). Although this phenomenon is empirically well supported, the molecular basis of the genetic redundancy is not yet understood. To fill this gap, we compared the heterogeneity of the evolutionary transcriptomic and metabolomic response in 10 Drosophila simulans populations which evolved parallel high level phenotypic changes in a novel temperature environment but used different allelic combinations of alternative loci. We showed that the metabolome evolved more parallel than the transcriptome, confirming a hierarchical organization of molecular phenotypes. Different sets of genes responded in each evolved population but led to the enrichment of similar biological functions and a consistent metabolic profile. Since even the metabolomic response was still highly heterogeneous across evolved populations, we propose that selection may operate on pathways/networks.PMID:37232360 | DOI:10.1093/gbe/evad098

Food Funct. 2023 May 26. doi: 10.1039/d3fo00997a. Online ahead of print.ABSTRACTDiabetes has become a significant disease threatening human health and social development. Food intervention is considered an essential strategy to prevent early diabetes development sustainably. The natural product, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), commonly found in fruits and diets, has many potential antihypoglycemic, antibacterial, and antitumor activities. We found that PGG can promote glucose uptake in whole-organism zebrafish screening, which help in downregulating the glucose levels. We investigated the metabolome and transcriptome changes in zebrafish exposed to high glucose and PGG intervention. The differential genes and metabolites were screened out based on the comparisons of blank, hyperglycemic, and the PGG-exposed groups of zebrafish larvae. Combined with RT-qPCR validation, we found that PGG mainly restored four genes (fthl27, LOC110438965, plat, and aacs) and six metabolites abnormally invoked by high glucose. These validated genes are related with the key metabolites sphingosine and (R)-3-hydroxybutanoate involving the pathways of apelin, apoptosis, necroptosis, and butanoate metabolism. Our findings provided a new mechanistic basis for understanding the hypoglycaemic function of the commonly present dietary molecule (PGG) and offered a new perspective for the rational utilization of PGG to regulate metabolic disorders.PMID:37232296 | DOI:10.1039/d3fo00997a

Nephron. 2023 May 15:1. doi: 10.1159/000530918. Online ahead of print.ABSTRACTBACKGROUND: Progression of chronic kidney disease (CKD) in childhood is associated with multiple long-term adverse outcomes including an increased risk of death. The early diagnosis and recognition of CKD progression allows for enrollment in clinical trials and timely interventions. Early recognition of CKD progression would be enabled by further developing clinically relevant kidney biomarkers which identify those children at highest risk of kidney function decline.SUMMARY: Glomerular filtration rate and proteinuria are traditional markers to classify and prognosticate CKD progression in clinical practice but have several limitations. Over the recent decades, novel biomarkers have been identified from blood or urine with metabolomic screening studies, proteomic screening studies, and improved knowledge of CKD pathophysiology. This review will highlight promising biomarkers associated with the progression of CKD which will potentially serve as future diagnostic and prognostic markers in children with CKD.KEY MESSAGES: Further studies are needed in children with CKD to validate putative biomarkers, particularly candidate proteins and metabolites, for improving clinical management in pediatric CKD.PMID:37232009 | DOI:10.1159/000530918

J Cosmet Dermatol. 2023 May 25. doi: 10.1111/jocd.15812. Online ahead of print.ABSTRACTOBJECTIVE: This study aims to compare the plasma metabolic profiles of patients with herpes labialis with healthy controls and identify the biomarkers of herpes labialis.SUBJECTS AND METHODS: We collected 18 patients with herpes labialis and 20 healthy individuals. Plasma samples from both groups were analyzed using gas chromatography-mass spectrometry (GC-MS).RESULTS: According to the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), we found that metabolic profiles had changed in patients with herpes labialis compared to the controls. By further selecting the different metabolites according to the variable importance in the projection (VIP) and p valve of t-tests, we found that acetic acid, pyroglutamic acid, alanine, ethanedioic acid, cyclohexaneacetic acid, pyruvic acid, d-mannose, phosphoric acid, l-amphetamine, and citric acid were decreased in patients with herpes labialis, while sedoheptulose and ethylamine were increased. Pathway analysis showed that herpes labialis may affect the amino acid and energy metabolism.CONCLUSIONS: Our findings may contribute to elucidating the metabolic basis of herpes labialis and provide a new perspective for further research on the "Shang-Huo" state in traditional Chinese medicine (TCM).PMID:37231973 | DOI:10.1111/jocd.15812

Plant Signal Behav. 2023 Dec 31;18(1):2213934. doi: 10.1080/15592324.2023.2213934.ABSTRACTPiriformospora indica, a plant root-colonizing basidiomycete fungus, exhibits strong growth-promoting activity in symbiosis with a broad range of plants. Here, we report the potential of P. indica to improve growth, yield, and disease resistance in wheat in the field. In the present study, P. indica successfully colonized wheat through chlamydospores and formed dense mycelial networks that covered roots. Plants subjected to the seed soaking (SS) treatment with P. indica chlamydospore suspensions enhanced tillering 2.28-fold compared to the non-inoculated wheat in the tillering stage. In addition, P. indica colonization promoted vegetative growth significantly during the three-leaf, tillering, and jointing stages. Moreover, the P. indica-SS-treatment enhanced wheat yield by 16.37 ± 1.63%, by increasing grains per ear and panicle weight and decreased damage to wheat shoot and root architecture markedly, with high field control effects against Fusarium pseudograminearum (81.59 ± 1.32%), Bipolaris sorokiniana (82.19 ± 1.59%), and Rhizoctonia cerealis (75.98 ± 1.36%). Most of the primary metabolites, such as amino acids, nucleotides, and lipids, involved in vegetative reproduction were increased in P. indica-SS-treatment plants, whereas secondary metabolites, such as terpenoids, polyketides, and alkaloids, decreased following P. indica inoculation. The up-regulated processes of protein, carbohydrate, and lipid metabolism indicated that P. indica colonization increased growth, yield, and disease resistance via the acceleration of plant primary metabolism. In conclusion, P. indica improved morphological, physiological, and metabolic substance levels, and further promoted its growth, yield, and disease resistance in wheat.PMID:37231769 | DOI:10.1080/15592324.2023.2213934

J Nutr. 2022 Dec;152(12):2956-2965. doi: 10.1093/jn/nxac195. Epub 2023 Feb 10.ABSTRACTBACKGROUND: The fecal metabolome is affected by diet and includes metabolites generated by human and microbial metabolism. Advances in -omics technologies and analytic approaches have allowed researchers to identify metabolites and better utilize large data sets to generate usable information. One promising aspect of these advancements is the ability to determine objective biomarkers of food intake.OBJECTIVES: We aimed to utilize a multivariate, machine learning approach to identify metabolite biomarkers that accurately predict food intake.METHODS: Data were aggregated from 5 controlled feeding studies in adults that tested the impact of specific foods (almonds, avocados, broccoli, walnuts, barley, and oats) on the gastrointestinal microbiota. Fecal samples underwent GC-MS metabolomic analysis; 344 metabolites were detected in preintervention samples, whereas 307 metabolites were detected postintervention. After removing metabolites that were only detected in either pre- or postintervention and those undetectable in ≥80% of samples in all study groups, changes in 96 metabolites relative concentrations (treatment postintervention minus preintervention) were utilized in random forest models to 1) examine the relation between food consumption and fecal metabolome changes and 2) rank the fecal metabolites by their predictive power (i.e., feature importance score).RESULTS: Using the change in relative concentration of 96 fecal metabolites, 6 single-food random forest models for almond, avocado, broccoli, walnuts, whole-grain barley, and whole-grain oats revealed prediction accuracies between 47% and 89%. When comparing foods with one another, almond intake was differentiated from walnut intake with 91% classification accuracy.CONCLUSIONS: Our findings reveal promise in utilizing fecal metabolites as objective complements to certain self-reported food intake estimates. Future research on other foods at different doses and dietary patterns is needed to identify biomarkers that can be applied in feeding study compliance and clinical settings.PMID:37230693 | DOI:10.1093/jn/nxac195

J Nutr. 2022 Dec;152(12):2778-2788. doi: 10.1093/jn/nxac228. Epub 2023 Feb 10.ABSTRACTBACKGROUND: Beneficial effects of nut supplementation on cognitive function have previously been demonstrated in young and older adults. Alterations to gut microbiota have also been shown following tree nut consumption. However, no data exists on the effects of nuts on cognition and intestinal microbial communities assessed within the same study.OBJECTIVES: The study aimed to examine the effects of daily consumption of tree nuts for 4 wk on cognitive function (primary outcome), mood, metabolomics, and gut microbial species (secondary outcomes) in healthy, nonelderly adults.METHODS: This randomized, placebo-controlled, double-blind, counterbalanced crossover study assessed the effects of 4 wk of supplementation with 30 g/d mixed tree nuts versus placebo on cognition and mood in 79 healthy adults aged 18-49 y. Metabolic responses, gut bacterial community structure, and the potential for these to impact cognition were explored using a multi-omic approach. Bacterial community analysis was conducted in Quantitative Insights Into Microbial Ecology 2 (QIIME2).RESULTS: Mixed model analysis indicated that nut consumption led to significant improvements to accuracy (placebo M = 92.2% compared with NUTS M = 94.5%; P = 0.019) and speed of response (placebo M = 788 ms compared with NUTS M = 757 ms; P = 0.004) on a picture recognition task. No significant changes to bacterial community α or β diversity were observed when comparing nut consumption to the placebo arm. However, an unclassified Lachnospiraceae amplicon sequence variant (ASV) was significantly enriched in participants when supplemented with nuts (P = 0.015). No correlations were observed between the changes to picture recognition and the changes to the unclassified Lachnospiraceae ASV. There were no significant changes to the urinary metabolome.CONCLUSIONS: These findings indicate a positive effect of nut on cognition following only 4 wk of consumption in a healthy nonelderly sample, as well as upregulation of a microbial taxa associated with gut health. The effects appear to be independent of one another, but further exploration is required in those experiencing cognitive decline and/or gut dysbiosis.PMID:37230675 | DOI:10.1093/jn/nxac228

J Nutr. 2022 Dec;152(12):2643-2644. doi: 10.1093/jn/nxac233. Epub 2023 Feb 10.NO ABSTRACTPMID:37230659 | DOI:10.1093/jn/nxac233

Anal Chim Acta. 2023 Jul 18;1265:341274. doi: 10.1016/j.aca.2023.341274. Epub 2023 May 3.ABSTRACTLipidomics studies strive for a comprehensive identification and quantification of lipids. While reversed phase (RP) liquid chromatography (LC) coupled to high resolution mass spectrometry (MS) offers unrivalled selectivity and thus is the preferred method for lipid identification, accurate lipid quantification remains challenging. The widely adopted one-point lipid class specific quantification (one internal standard per lipid class) suffers from the fact that ionization of internal standard and target lipid occurs under different solvent composition as a consequence of chromatographic separation. To address this issue, we established a dual flow injection and chromatography setup that allows to control solvent conditions during ionization enabling isocratic ionization while running a RP gradient through the use of a counter-gradient. Using this dual LC pump platform, we investigated the impact of solvent conditions within a RP gradient on ionization response and arising quantification biases. Our results confirmed that changing solvent composition significantly influences ionization response. Quantification of human plasma (SRM 1950) lipids under gradient and isocratic ionization conditions further confirmed these findings as significant differences between the two conditions were found for the majority of lipids. While the quantity of sphingomyelins with >40 C atoms was consistently overestimated under gradient ionization, isocratic ionization improved their recovery compared to consensus values. However, the limitation of consensus values was demonstrated as overall only small changes in z-score were observed because of high uncertainties of the consensus values. Furthermore, we observed a trueness bias between gradient and isocratic ionization when quantifying a panel of lipid species standards which is highly dependent on lipid class and ionization mode. Uncertainty calculations under consideration of the trueness bias as RP gradient uncertainty revealed that especially ceramides with >40 C atoms had a high bias leading to total combined uncertainties of up to 54%. The assumption of isocratic ionization significantly decreases total measurement uncertainty and highlights the importance of studying the trueness bias introduced by a RP gradient to reduce quantification uncertainty.PMID:37230568 | DOI:10.1016/j.aca.2023.341274

Anal Chim Acta. 2023 Jul 18;1265:341271. doi: 10.1016/j.aca.2023.341271. Epub 2023 May 4.ABSTRACTProteins carry a plethora of post-translational modifications (PTMs), such as glycosylation or phosphorylation, which may affect stability and activity. Analytical strategies are needed to investigate these PTMs in their native state to determine the link between structure and function. The coupling of native separation techniques with mass spectrometry (MS) has emerged as a powerful tool for in-depth protein characterization. Yet obtaining high ionization efficiency still can be challenging. Here, we explored the potential of dopant-enriched nitrogen (DEN) gas to improve nano-electrospray ionization (nano-ESI)-MS of native proteins after anion exchange chromatography. The dopant gas was enriched with different dopants (acetonitrile, methanol, and isopropanol) and the effects were compared with the use of solely nitrogen gas for six proteins covering a wide range of physicochemical properties. The use of DEN gas resulted generally in lower charge states, independent of the selected dopant. Moreover, less adduct formation was observed, particularly for the acetonitrile-enriched nitrogen gas. Importantly, striking differences in MS signal intensity and spectral quality were observed for extensively glycosylated proteins, where isopropanol- and methanol-enriched nitrogen appeared to be most beneficial. Altogether, the use of DEN gas improved nano-ESI of native glycoproteins and increased spectral quality for highly glycosylated proteins that normally suffer from low ionization efficiency.PMID:37230565 | DOI:10.1016/j.aca.2023.341271

J Adv Res. 2023 May 23:S2090-1232(23)00144-3. doi: 10.1016/j.jare.2023.05.006. Online ahead of print.ABSTRACTINTRODUCTION: Zearalenone-14-glucoside (Z14G) is a modified mycotoxin that widely contaminates food across the world. Our preliminary experiment showed that Z14G degrades to zearalenone (ZEN) in the intestine exerting toxicity. Notably, oral administration of Z14G in rats induces intestinal nodular lymphatic hyperplasia.OBJECTIVES: To investigate the mechanism of Z14G intestinal toxicity and how it differs from ZEN toxicity. We conducted a precise toxicology study on the intestine of rats exposed to Z14G and ZEN using multi-omics technology.METHODS: Rats were exposed to ZEN (5 mg/kg), Z14G-L (5 mg/kg), Z14G-H (10 mg/kg), and pseudo germ free (PGF)-Z14G-H (10 mg/kg) for 14 days. Histopathological studies were performed on intestines from each group and compared. Metagenomic, metabolomic, and proteomic analyses were performed on rat feces, serum, and intestines, respectively.RESULTS: Histopathological studies showed that Z14G exposure resulted in dysplasia of gut-associated lymphoid tissue (GALT) compared to ZEN exposure. The elimination of gut microbes in the PGF-Z14G-H group alleviated or eliminated Z14G-induced intestinal toxicity and GALT dysplasia. Metagenomic analysis revealed that Z14G exposure significantly promoted the proliferation of Bifidobacterium and Bacteroides compared to ZEN. Metabolomic analysis showed that Z14G exposure significantly reduced bile acid, while proteomic analysis found that Z14G exposure significantly reduced the expression of C-type lectins compared to ZEN.CONCLUSIONS: Our experimental results and previous research suggest that Z14G is hydrolyzed to ZEN by Bifidobacterium and Bacteroides promoting their co-trophic proliferation. This leads to inactivation of lectins by hyperproliferative Bacteroides when ZEN caused intestinal involvement, resulting in abnormal lymphocyte homing and ultimately GALT dysplasia. It is noteworthy that Z14G is a promising model drug to establish rat models of intestinal nodular lymphatic hyperplasia (INLH), which is of great significance for studying the pathogenesis, drug screening and clinical application of INLH.PMID:37230382 | DOI:10.1016/j.jare.2023.05.006

Life Sci. 2023 May 23:121788. doi: 10.1016/j.lfs.2023.121788. Online ahead of print.ABSTRACTAIM: Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective.MAIN METHOD: We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis.KEY FINDING: We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets.SIGNIFICANCE: Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.PMID:37230377 | DOI:10.1016/j.lfs.2023.121788

J Hepatol. 2023 May 23:S0168-8278(23)00341-0. doi: 10.1016/j.jhep.2023.05.012. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most weight-loss effective surgical procedure, decreases obesity and comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear.METHODS: We studied the hepatic transcriptome of 26 non-diabetic obese patients undergoing RYGB before and one-year post-surgery. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BA).RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the down-regulation of a module of genes implicated in inflammation and the up-regulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with post-surgery liver disease status improvement.CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis.IMPACTS AND IMPLICATION: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of RYGB patients, studied before and one year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.PMID:37230231 | DOI:10.1016/j.jhep.2023.05.012

J Hepatol. 2023 May 23:S0168-8278(23)00339-2. doi: 10.1016/j.jhep.2023.04.040. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that intestine clock has major impact on shaping peripheral rhythms via diurnal nutritional signals. Here we investigate the role of intestine clock in controlling liver rhythmicity and metabolism.METHODS: Transcriptomic analysis, metabolomics, metabolic assays, histology, qPCR, and immunoblotting were performed with Bmal1-iKO (intestine-specific knockout of Bmal1), Rev-erbα-iKO and control mice.RESULTS: Bmal1-iKO causes a large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, liver clock is resistant to the entrainment by inverted feeding and high-fat diet. Importantly, Bmal1-iKO remodels diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis in the dark phase, leading to elevated glucose production (hyperglycemia) and insulin insensitivity. Conversely, Rev-erbα-iKO causes a diversion to lipogenesis from gluconeogenesis in the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcoholic liver injury. These temporal diversions are attributed to a disruption of hepatic SREBP-1c rhythmicity, which is maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of local clock.CONCLUSION: Our findings establish a pivotal role of intestine clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health.IMPACT AND IMPLICATIONS: Our findings establish the centrality of the intestine clock amongst peripheral tissue clocks, and associate liver-related pathologies with malfunction of intestine clock. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. The knowledge will help the clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors.PMID:37230230 | DOI:10.1016/j.jhep.2023.04.040