PubMed

J Adv Res. 2024 Aug 13:S2090-1232(24)00361-8. doi: 10.1016/j.jare.2024.08.018. Online ahead of print.ABSTRACTINTRODUCTION: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown.OBJECTIVES: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD.METHODS: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vitro and in vivo experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury.RESULTS: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense.CONCLUSION: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.PMID:39147198 | DOI:10.1016/j.jare.2024.08.018

Free Radic Biol Med. 2024 Aug 13:S0891-5849(24)00596-3. doi: 10.1016/j.freeradbiomed.2024.08.009. Online ahead of print.ABSTRACTHydrogen-rich water (HRW) is a beverage containing a high concentration of hydrogen that has been researched for its antioxidant, anti-apoptotic, and anti-inflammatory properties in asthma. This study investigates the potential therapeutic impact of HRW on the gut-lung axis. Using 16S rRNA and serum metabolomics, we examined changes in gut microbiota and serum metabolites in asthmatic mice after HRW intervention, followed by validation experiments. The findings revealed that HRW influenced gut microbiota by increasing Ligilactobacillus and Bifidobacterium abundance and enhancing the presence of indole-3-acetic acid (IAA), a microbially derived serum metabolite. Both in vivo and in vitro experiments showed that HRW's protective effects against airway inflammation in asthmatic mice may be linked to the gut microbiota, with IAA potentially playing a role in reducing asthmatic airway inflammation through the aryl hydrocarbon receptors (AhR) signaling pathway. In summary, HRW can modify gut microbiota, increase Bifidobacterium abundance, elevate microbial-derived IAA levels, and activate AhR, which could potentially alleviate inflammation in asthma.PMID:39147072 | DOI:10.1016/j.freeradbiomed.2024.08.009

Sci Total Environ. 2024 Aug 13:175468. doi: 10.1016/j.scitotenv.2024.175468. Online ahead of print.ABSTRACTAlthough there are studies in the literature on the effects of different coloured light-emitting diodes (LEDs) on different organisms, there is limited information on how these effects change with temperature increase. In this study, the effects of blue, green, red and white LED lights on the early development process of zebrafish (Danio rerio (Hamilton, 1822)) were comprehensively investigated. In addition, to simulate global warming, it was examined how a one-degree temperature increase affects this process. For this purpose, zebrafish embryos, which were placed at 4 hpf (hours post fertilization) in an incubator whose interior was divided into four areas, were kept at three different temperatures (28, 29 and 30 °C) for 120 h. The group kept in a dark environment was chosen as the control. The temperature of the control group was also increased at the same rate as the other groups. The results showed that at the end of the exposure period, temperature and light colour caused an increase in body malformations. Histopathological damage and immunopositive signals of HSP 70 and 8-OHdG biomarkers in larval brains, increase in free oxygen radicals, apoptotic cells and lipid accumulation throughout the body, increase in locomotor activity, decrease in heart rate and blood flow, and significant changes in more than thirty metabolite levels were detected. In addition, it has been determined that many metabolic pathways are affected, especially glutathione, vitamin B6 and pyrimidine metabolism. Moreover, it has been observed that a one-degree temperature increase worsens this negative effect. It was concluded that blue light was the closest light to the control group and was less harmful than other light colours. The study revealed that blue light produced results that were most similar to those seen in the control group.PMID:39147052 | DOI:10.1016/j.scitotenv.2024.175468

Poult Sci. 2024 Jul 29;103(10):104138. doi: 10.1016/j.psj.2024.104138. Online ahead of print.ABSTRACTIntestinal microbial metabolism has an important impact on the health of laying hens, and microbes are also important hosts for ARGs. However, the relationship between intestinal microbes and antibiotic resistance in laying hens is unclear. In this study, a slaughtering experiment, an in vitro fermentation experiment and a single-bacteria culture experiment were carried out, and metagenomic and metabolomic analyses were used to investigate the relationships between microbial metabolism and the antibiotic resistome in the cecum of laying hens. The results showed that there were different types of ARGs in the intestines of laying hens, and the risk scores of the ARGs tended to decrease with growth stage. A total of 1142 metagenome-assembled genomes (MAGs) were obtained, and Escherichia coli was found to be the dominant ARG host, carrying 62 ARGs. Metabolomics revealed that indole and its derivatives, such as indole-3-lactic acid, were negatively correlated with a variety of ARGs. Moreover, in vitro fermentation experiment and single-bacteria culture experiment demonstrated that indole-3-lactic acid reduced the abundance and risk of multiple ARGs in the intestine and inhibited the growth of the ARG host Escherichia coli. In the context of high concern about intestinal microbial metabolism and antibiotic resistance, this is the first study to focus on the relationship between intestinal microbial metabolism and antibiotic resistance in laying hens. These findings have important implications for healthy farming and antibiotic resistance control.PMID:39146922 | DOI:10.1016/j.psj.2024.104138

Cell Host Microbe. 2024 Aug 14;32(8):1207-1209. doi: 10.1016/j.chom.2024.07.009.ABSTRACTDue to its enormous incidence and mortality, sepsis is a huge health priority. In the latest issue of Cell, an innovative approach is provided that addresses the major sepsis hurdles of today, i.e., early recognition, prompt treatment, translation from experimental animals to human patients, and urgent need for novel therapeutics.PMID:39146788 | DOI:10.1016/j.chom.2024.07.009

J Hazard Mater. 2024 Aug 5;478:135434. doi: 10.1016/j.jhazmat.2024.135434. Online ahead of print.ABSTRACTAntibiotic resistome has emerged as a global threat to public health. However, gestational antibiotic resistome and potential link with adverse pregnancy outcomes remains poorly understood. Our study reports for the first time an association between gut antibiotic resistome during early pregnancy and the risk of gestational diabetes mellitus (GDM) based on a prospective nested case-control cohort including 120 cases and 120 matched controls. A total of 214 antibiotic resistance gene (ARG) subtypes belonging to 17 ARG types were identified in > 10 % fecal samples collected during each trimester. The data revealed dynamic profiles of gut antibiotic resistome through pregnancy, and significant positive associations between selected features (i.e., ARG abundances and a GDM-ARG score which is a new feature characterizing the association between ARGs and GDM) of gut antibiotic resistome during early pregnancy and GDM risk as well as selected endogenous metabolites. The findings demonstrate ubiquitous presence of ARGs in pregnant women and suggest it could constitute an important risk factor for the development of GDM.PMID:39146585 | DOI:10.1016/j.jhazmat.2024.135434

Circ Res. 2024 Aug 16;135(5):629-631. doi: 10.1161/CIRCRESAHA.124.325130. Epub 2024 Aug 15.NO ABSTRACTPMID:39146397 | DOI:10.1161/CIRCRESAHA.124.325130

Int Microbiol. 2024 Aug 15. doi: 10.1007/s10123-024-00574-y. Online ahead of print.ABSTRACTMetarhizium spp. have emerged as an alternative to chemical pesticides for protecting crops from insect pest. Here, we investigated midgut microbial community and metabolites of Spodoptera litura at three different timepoints after infection with Metarhizium flavoviride. The innate immune system of S. litura was activated with levels of polyphenol oxidase, carboxylesterase, multifunctional oxidase, and glutathione S-transferase activity significantly increasing. Exposure to the fungal pathogen also altered bacterial abundance and diversity in host's midgut, and these changes varied depending on the time elapsed since exposure. We identified more operational taxonomic units in the treated samples as compared to the control samples at all tested time points. A total of 372 metabolites were identified, and 88, 149, and 142 differentially accumulated metabolites (DAMs) were identified between the treatment and control groups at 3 timepoints after treatment, respectively. Based on the changes of DAMs in response to M. flavoviride infection at different timepoints and significantly enriched KEGG pathways, we speculated that "tyrosine metabolism," "galactose metabolism," "ATP-binding cassette transporters," "neuroactive ligand-receptor interaction," "purine metabolism," "arginine and proline metabolism," "beta-alanine metabolism," "lysosome," and "carbon metabolism" may participate in the metabolic-level defense response. An integrated pathway-level analysis of the 16S-rDNA and metabolomic data illustrated the connections and interdependencies between the metabolic responses of S. litura and the midgut microorganisms to M. flavoviride infection. This work emphasizes the value of integrated analyses of insect-pathogen interactions, provides a framework for future studies of critical microorganisms and metabolic determinants of these interactions, establishes a theoretical basis for the sustainable use of M. flavoviride.PMID:39145832 | DOI:10.1007/s10123-024-00574-y

Nanoscale. 2024 Aug 15. doi: 10.1039/d4nr02328e. Online ahead of print.ABSTRACTIn the last two decades, the development of nanotechnology has resulted in inorganic nanoparticles playing crucial roles in key industries, ranging from healthcare to energy technologies. For instance, gold and silver nanoparticles are widely used in rapid COVID-19 and flu tests, titania and zinc oxide nanoparticles are commonly found in cosmetic products, and superparamagnetic iron oxide nanoparticles have been clinically exploited as contrast agents and anti-anemia medicines. As a result, human exposure to nanomaterials is continuously increasing, raising concerns about their potential adverse health effects. Historically, the study of nanoparticle toxicity has largely relied on macroscopic observations obtained in different in vitro and in vivo models, resulting in readouts such as median lethal dose, biodistribution profile, and/or histopathological assessment. In recent years, omics methodologies, including transcriptomics, epigenomics, proteomics, metabolomics, and lipidomics, are increasingly used to characterize the biological interactions of nanomaterials, providing a better and broader understanding of their impact and mechanisms of toxicity. These approaches have been able to identify important genes and gene products that mediate toxicological effects, as well as endogenous functions and pathways dysregulated by nanoparticles. Omics methods improve our understanding of nanoparticle biology, and unravel mechanistic insights into nanomedicine-based therapies. This review aims to provide a deeper understanding and new perspectives of omics approaches to characterize the toxicity and biological interactions of inorganic nanoparticles, and improve the safety of nanoparticle applications.PMID:39145718 | DOI:10.1039/d4nr02328e

Environ Sci Technol. 2024 Aug 15. doi: 10.1021/acs.est.4c06035. Online ahead of print.ABSTRACTPoor air quality is increasingly linked to gastrointestinal diseases, suggesting a potential correlation with human intestine health. However, this relationship remains largely unexplored due to limited research. This study used a controlled mouse model exposed to cooking oil fumes (COFs) and metagenomics, transcriptomics, and metabolomics to elucidate interactions between intestine microbiota and host metabolism under environmental stress. Our findings reveal that short-term COF inhalation induces pulmonary inflammation within 3 days and leads to gastrointestinal disturbances, elucidating a pathway connecting respiratory exposure to intestinal dysfunction. The exposure intensity significantly correlates with changes in intestinal tissue integrity, microbial composition, and metabolic function. Extended exposure of 7 days disrupts intestine microbiota and alters tryptophan metabolism, with further changes observed after 14 days, highlighting an adaptive response. These results highlight the vulnerability of intestinal health to airborne pollutants and suggest a pathway through which inhaled pollutants may affect distant organ systems.PMID:39145585 | DOI:10.1021/acs.est.4c06035

Pharmacoepidemiol Drug Saf. 2024 Aug;33(8):e5855. doi: 10.1002/pds.5855.ABSTRACTPURPOSE: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined.METHODS: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression.RESULTS: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications.CONCLUSION: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.PMID:39145400 | DOI:10.1002/pds.5855

Clin Kidney J. 2024 Jul 16;17(8):sfae221. doi: 10.1093/ckj/sfae221. eCollection 2024 Aug.ABSTRACTBACKGROUND: Acute kidney injury (AKI) is a serious complication in patients undergoing cardiac surgery, with the underlying mechanism remaining elusive and a lack of specific biomarkers for cardiac surgery-associated AKI (CS-AKI).METHODS: We performed an untargeted metabolomics analysis of urine samples procured from a cohort of patients with or without AKI at 6 and 24 h following cardiac surgery. Based on the differential urinary metabolites discovered, we further examined the expressions of the key metabolic enzymes that regulate these metabolites in kidney during AKI using a mouse model of ischemia-reperfusion injury (IRI) and in hypoxia-treated tubular epithelial cells (TECs).RESULTS: The urine metabolomic profiles in AKI patients were significantly different from those in non-AKI patients, including upregulation of tryptophan metabolism- and aerobic glycolysis-related metabolites, such as l-tryptophan and d-glucose-1-phosphate, and downregulation of fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycle-related metabolites. Spearman correlation analysis showed that serum creatinine was positively correlated with urinary l-tryptophan and indole, which had high accuracy for predicting AKI. In animal experiments, we demonstrated that the expression of rate-limiting enzymes in glycolysis, such as hexokinase II (HK2), was significantly upregulated during renal IRI. However, the TCA cycle-related key enzyme citrate synthase was significantly downregulated after IRI. In vitro, hypoxia induced downregulation of citrate synthase in TECs. In addition, FAO-related gene peroxisome proliferator-activated receptor alpha (PPARα) was remarkably downregulated in kidney during renal IRI.CONCLUSION: This study presents urinary metabolites related to CS-AKI, indicating the rewiring of the metabolism in kidney during AKI, identifying potential AKI biomarkers.PMID:39145145 | PMC:PMC11322674 | DOI:10.1093/ckj/sfae221

J Endocr Soc. 2024 Jul 31;8(9):bvae140. doi: 10.1210/jendso/bvae140. eCollection 2024 Jul 26.ABSTRACTCONTEXT: Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear.PURPOSE: To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles.METHODS: Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization.RESULTS: Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate = .002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r = .507) and hemoglobin A1c (HbA1c) (r = .553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = -.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men.MAIN CONCLUSION: Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol.PMID:39145114 | PMC:PMC11322837 | DOI:10.1210/jendso/bvae140

Heliyon. 2024 Jul 19;10(15):e34760. doi: 10.1016/j.heliyon.2024.e34760. eCollection 2024 Aug 15.ABSTRACTWe used gas chromatography-mass spectrometry (GC-MS) with an untargeted metabolomics approach to look at the metabolite profiles of traditional Iranian yogurts made from cow, goat, buffalo, and sheep milk. Results showed that different animal milks significantly influenced physicochemical properties and fatty acid (FA) composition, resulting in diverse metabolites. Over 80 % of all the fatty acids in the yogurt samples were saturated. The main fatty acids found were myristic acid (C14:0), palmitic acid (C16:0), and oleic acid + petroselenic acid (cis-9 C18:1 + cis-6 C18:1). In total, 36 metabolites, including esters, aldehydes, alcohols, and acids, were detected. Some important metabolites that changed yogurt profiles were 2-heptanone, methyl acetate, 2-propanone, butyl formate, and 4-methyl benzal. Associations between metabolite profiles and milk compositional traits were also observed, with statistical models showing a strong correlation between metabolite profiles and FA content. This study is the first to explore the impact of different animal sources and regions in Iran on the metabolome profiles of traditional yogurts. These results give us useful information about how metabolites differ between species and can be used to make new dairy products based on milk compositions and metabolites, which will help with future formulations of autochthonous starters.PMID:39145000 | PMC:PMC11320151 | DOI:10.1016/j.heliyon.2024.e34760

Front Microbiol. 2024 Jul 31;15:1393422. doi: 10.3389/fmicb.2024.1393422. eCollection 2024.ABSTRACTBACKGROUND: Breast cancer is the most prevalent cancer globally and is associated with significant mortality. Recent research has provided crucial insights into the role of gut microbiota in the onset and progression of breast cancer, confirming its impact on the disease's management. Despite numerous studies exploring this relationship, there is a lack of comprehensive bibliometric analyses to outline the field's current state and emerging trends. This study aims to fill that gap by analyzing key research directions and identifying emerging hotspots.METHOD: Publications from 2013 to 2023 were retrieved from the Web of Science Core Collection database. The VOSviewer, R language and SCImago Graphica software were utilized to analyze and visualize the volume of publications, countries/regions, institutions, authors, and keywords in this field.RESULTS: A total of 515 publications were included in this study. The journal Cancers was identified as the most prolific, contributing 21 papers. The United States and China were the leading contributors to this field. The University of Alabama at Birmingham was the most productive institution. Peter Bai published the most papers, while James J. Goedert was the most cited author. Analysis of highly cited literature and keyword clustering confirmed a close relationship between gut microbiota and breast cancer. Keywords such as "metabolomics" and "probiotics" have been prominently highlighted in the keyword analysis, indicating future research hotspots in exploring the interaction between metabolites in the breast cancer microenvironment and gut microbiota. Additionally, these keywords suggest significant interest in the therapeutic potential of probiotics for breast cancer treatment.CONCLUSION: Research on the relationship between gut microbiota and breast cancer is expanding. Attention should be focused on understanding the mechanisms of their interaction, particularly the metabolite-microbiota-breast cancer crosstalk. These insights have the potential to advance prevention, diagnosis, and treatment strategies for breast cancer. This bibliometric study provides a comprehensive assessment of the current state and future trends of research in this field, offering valuable perspectives for future studies on gut microbiota and breast cancer.PMID:39144230 | PMC:PMC11322113 | DOI:10.3389/fmicb.2024.1393422

Front Microbiol. 2024 Jul 31;15:1436382. doi: 10.3389/fmicb.2024.1436382. eCollection 2024.ABSTRACTThe quality of fermented plant leaves is closely related to the interleaf microorganisms and their metabolic activities. In this experiment, a multi-omics analysis was applied to investigate the link between the structural composition of the phyllosphere microbial community and the main metabolites during the fermentation process. It was found that the whole fermentation process of cigar leaves could be divided into three stages, in which the Mid-Stage was the most active period of microbial metabolic activities and occupied an important position. Staphylococcus, Brevundimonas, Acinetobacter, Brevibacterium, Pantoea, Aspergillus, Wallemia, Meyerozyma, Sampaiozyma, Adosporium and Trichomonascus played important roles in this fermentation. Staphylococcus and Aspergillus are the microorganisms that play an important role in the fermentation process. Staphylococcus were strongly correlated with lipids and amino acids, despite its low abundance, Stenotrophomonas is importantly associated with terpene and plays a significant role throughout the process. It is worth noting that Wapper exists more characteristic fungal genera than Filler and is more rapid in fermentation progress, which implies that the details of the fermentation process should be adjusted appropriately to ensure stable quality when faced with plant leaves of different genotypes. This experiment explored the relationship between metabolites and microorganisms, and provided a theoretical basis for further optimizing the fermentation process of plant leaves and developing techniques to improve product quality. Biomarker is mostly present in the pre-fermentation phase, but the mid-fermentation phase is the most important part of the process.PMID:39144227 | PMC:PMC11322134 | DOI:10.3389/fmicb.2024.1436382

3 Biotech. 2024 Sep;14(9):199. doi: 10.1007/s13205-024-04035-1. Epub 2024 Aug 12.ABSTRACTThe present work deals with the establishment of hairy root cultures from different explants of C. procera using Agrobacterium rhizogenes strain A4. A high transformation frequency (95%) was obtained from leaves followed by cotyledons (81.6%) and hypocotyls (38.3%). Genetic transformation of hairy roots was confirmed through PCR by amplifying a 400 bp fragment of the rolB gene. Hairy roots were highly branched, possessed plagiotropic and rapid growth on hormone-free ½ B5 medium. Ten cardiac glycosides, including calotropagenin, calotoxin, frugoside, coroglaucigenin, calotropin, calactin, uzarigenin, asclepin, uscharidin, and uscharin, based on their specific masses and fragmentation properties were identified in ethanolic extracts of hairy roots by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry UHPLC/QTOF-MS. This protocol could be used as a powerful tool for large-scale in vitro production of highly valued cardiac glycosides and for further transcriptomics or metabolomics studies.PMID:39144068 | PMC:PMC11319682 | DOI:10.1007/s13205-024-04035-1

Biofactors. 2024 Aug 14. doi: 10.1002/biof.2106. Online ahead of print.ABSTRACTLimonene, a dietary monocyclic monoterpene commonly found in citrus fruits and various aromatic plants, has garnered increasing interest as a gastrointestinal protectant. This study aimed to assess the effects of limonene on intestinal epithelial barrier function and investigate the involvement of cannabinoid receptor type-1 (CB1R) in vitro. Additionally, the study focused on examining the metabolomic changes induced by limonene in the intestinal epithelial cells (Caco-2). Initial analysis of transepithelial electrical resistance (TEER) revealed that both l-limonene and d-limonene, isomers of limonene, led to a dose- and time-dependent increase in TEER in normal cells and those inflamed by pro-inflammatory cytokines mixture (CytoMix). Furthermore, both types of limonene reduced CytoMix-induced paracellular permeability, as demonstrated by a decrease in Lucifer yellow flux. Moreover, d-limonene and l-limonene treatment increased the expression of tight junction molecules (TJs) such as occludin, claudin-1, and ZO-1, at both the transcriptional and translational levels. d-Limonene upregulates E-cadherin, a molecule involved in adherens junctions (AJs). Mechanistic investigations demonstrated that d-limonene and l-limonene treatment significantly inhibited CB1R at the protein, while the mRNA level remained unchanged. Notably, the inhibitory effect of d-limonene on CB1R was remarkably similar to that of pharmacological CB1R antagonists, such as rimonabant and ORG27569. d-limonene also alters Caco-2 cell metabolites. A substantial reduction in β-glucose and 2-succinamate was detected, suggesting limonene may impact intestinal epithelial cells' glucose uptake and glutamate metabolism. These findings suggest that d-limonene's CB1R antagonistic property could effectively aid in the recovery of intestinal barrier damage, marking it a promising gastrointestinal protectant.PMID:39143845 | DOI:10.1002/biof.2106

Aging Cell. 2024 Aug 14:e14302. doi: 10.1111/acel.14302. Online ahead of print.ABSTRACTHuntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.PMID:39143698 | DOI:10.1111/acel.14302

Alzheimers Res Ther. 2024 Aug 14;16(1):183. doi: 10.1186/s13195-024-01549-x.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated.METHODS: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases.RESULTS: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase.CONCLUSIONS: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.PMID:39143583 | DOI:10.1186/s13195-024-01549-x