PubMed

J Nucl Med. 2023 Sep 21:jnumed.123.265980. doi: 10.2967/jnumed.123.265980. Online ahead of print.ABSTRACTAndrogen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: β = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: β = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: β = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: β = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.PMID:37734840 | DOI:10.2967/jnumed.123.265980

Osteoarthritis Cartilage. 2023 Sep 19:S1063-4584(23)00920-2. doi: 10.1016/j.joca.2023.09.007. Online ahead of print.ABSTRACTOBJECTIVE: To better understand the pathogenesis of knee osteoarthritis (OA) through identification of serum diagnostics.DESIGN: We conducted multiple reaction monitoring mass spectrometry analysis of 107 peptides in baseline sera of two cohorts: the Foundation for NIH (n=596 Kellgren-Lawrence (KL) grade 1-3 knee OA participants); and the Johnston County Osteoarthritis Project (n=127 multi-joint controls free of radiographic OA of the hands, hips, knees (bilateral KL=0), and spine). Data were split into (70%) training and (30%) testing sets. Diagnostic peptide and clinical data predictors were selected by random forest (RF); selection was based on association (p<0.05) with OA status in multivariable logistic regression models. Model performance was based on area under the curve (AUC) of receiver operating characteristic and precision-recall (PR) curves.RESULTS: RF selected 23 peptides (19 proteins) and BMI as diagnostic of OA. BMI weakly diagnosed OA (ROC-AUC 0.57, PR-AUC 0.812) and only symptomatic OA cases. ACTG was the strongest univariable predictor (ROC-AUC 0.705, PR-AUC 0.897). The final model (8 serum peptides) was highly diagnostic (ROC-AUC 0.833, 95% CI 0.751, 0.905; PR-AUC 0.929, 95% CI 0.876, 0.973) in the testing set and equally diagnostic of non-symptomatic and symptomatic cases (AUCs 0.830-0.835), and not significantly improved with addition of BMI. The STRING database predicted multiple high confidence interactions of the 19 diagnostic OA proteins.CONCLUSIONS: No more than 8 serum protein biomarkers were required to discriminate knee OA from non-OA. These biomarkers lend strong support to the involvement and cross-talk of complement and coagulation pathways in the development of OA.DATA AND MATERIALS AVAILABILITY: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. All proteomic data for this study are available at ftp://massive.ucsd.edu/ or massive.ucsd.edu.PMID:37734705 | DOI:10.1016/j.joca.2023.09.007

J Hepatol. 2023 Sep 19:S0168-8278(23)05105-X. doi: 10.1016/j.jhep.2023.09.012. Online ahead of print.NO ABSTRACTPMID:37734684 | DOI:10.1016/j.jhep.2023.09.012

Sci Total Environ. 2023 Sep 19;905:167050. doi: 10.1016/j.scitotenv.2023.167050. Online ahead of print.NO ABSTRACTPMID:37734230 | DOI:10.1016/j.scitotenv.2023.167050

EBioMedicine. 2023 Sep 19;96:104791. doi: 10.1016/j.ebiom.2023.104791. Online ahead of print.ABSTRACTBACKGROUND: As new infectious diseases (ID) emerge and others continue to mutate, there remains an imminent threat, especially for vulnerable individuals. Yet no generalizable framework exists to identify the at-risk group prior to infection. Metabolomics has the advantage of capturing the existing physiologic state, unobserved via current clinical measures. Furthermore, metabolomics profiling during acute disease can be influenced by confounding factors such as indications, medical treatments, and lifestyles.METHODS: We employed metabolomic profiling to cluster infection-free individuals and assessed their relationship with COVID severity and influenza incidence/recurrence.FINDINGS: We identified a metabolomic susceptibility endotype that was strongly associated with both severe COVID (ORICUadmission = 6.7, p-value = 1.2 × 10-08, ORmortality = 4.7, p-value = 1.6 × 10-04) and influenza (ORincidence = 2.9; p-values = 2.2 × 10-4, βrecurrence = 1.03; p-value = 5.1 × 10-3). We observed similar severity associations when recapitulating this susceptibility endotype using metabolomics from individuals during and after acute COVID infection. We demonstrate the value of using metabolomic endotyping to identify a metabolically susceptible group for two-and potentially more-IDs that are driven by increases in specific amino acids, including microbial-related metabolites such as tryptophan, bile acids, histidine, polyamine, phenylalanine, and tyrosine metabolism, as well as carbohydrates involved in glycolysis.INTERPRETATIONS: These metabolites may be identified prior to infection to enable protective measures for these individuals.FUNDING: The Longitudinal EMR and Omics COVID-19 Cohort (LEOCC) and metabolomic profiling were supported by the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health.PMID:37734204 | DOI:10.1016/j.ebiom.2023.104791

Food Chem. 2023 Sep 11;434:137424. doi: 10.1016/j.foodchem.2023.137424. Online ahead of print.ABSTRACTThis study investigated the main volatile components in ten Thai colored rice varieties cultivated in two agricultural locations of Thailand (Central and Northern region) using a static headspace GC-MS metabolomics approach. The results indicated that volatolomics could successfully differentiate between the geographical origins of the same rice variety grown in regions within the same country. The volatile profiles of the colored rice obtained from the two locations were clearly different, with three volatile compounds isolated as key aroma producers in each area. Primary volatile compounds upregulated in colored rice varieties grown in Northern Thailand included undecanoic acid, 10-methyl-methyl ester; methyl 8-methyl-nonanoate; and pyrimidine, 4-methyl. Hexadecanoic acid, methyl ester; methyl 9-cis,11-trans-octadecadienoate; and 10-octadecenoic acid methyl ester were upregulated in the rice samples grown in Central Thailand. The environmental factors that could affect colored rice aroma at the agricultural sites included temperature, downward surface shortwave radiation, and vapor pressure deficit.PMID:37734150 | DOI:10.1016/j.foodchem.2023.137424

Environ Int. 2023 Sep 14;180:108206. doi: 10.1016/j.envint.2023.108206. Online ahead of print.ABSTRACTBACKGROUND: Agricultural workers are consistently exposed to elevated heat exposures and vulnerable to acute kidney injury. The underlying pathophysiology and detailed molecular mechanisms of AKI among agricultural workers, and the disproportionate burden of HRI and heat stress exposure are not well understood, especially at the level of cellular metabolism.OBJECTIVE: The aim of this study was to examine the impact of heat exposures on renal biomarkers and on the human metabolome via untargeted high-resolution metabolomics among agricultural and non-agricultural workers.METHODS: Blood and urine samples were collected pre- and post-work shift from 63 agricultural workers and 27 non- agricultural workers. We evaluated pre- and post-work shift renal biomarkers and completed untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Metabolome-wide association studies (MWAS) models identified the metabolic features differentially expressed between agricultural workers and non-agricultural workers.RESULTS: Median values of pre-shift creatinine and osteopontin (p < 0.05) were higher for agricultural workers than non-agricultural workers. Metabolic pathway enrichment analyses revealed 27 diverse pathways differed between agricultural workers and non-agricultural workers (p < 0.05) including TCA cycle and urea cycle, carbohydrate metabolism, histidine metabolism and evidence for altered microbiome shikimate pathway.CONCLUSION: This is the first investigation on the metabolic pathways that are affected among agricultural workers who are exposed to heat compared to non-heat exposed workers. This study shows extensive responses of central metabolic systems to heat exposures that impact human health.PMID:37734144 | DOI:10.1016/j.envint.2023.108206

Science. 2023 Sep 22;381(6664):1316-1323. doi: 10.1126/science.abq1053. Epub 2023 Sep 21.ABSTRACTAlthough tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.PMID:37733872 | DOI:10.1126/science.abq1053

J Cell Physiol. 2023 Sep 21. doi: 10.1002/jcp.31123. Online ahead of print.ABSTRACTHibernating mammals are natural models of resistance to ischemia, hypoxia-reperfusion injury, and hypothermia. Daurian ground squirrels (spermophilus dauricus) can adapt to endure multiple torpor-arousal cycles without sustaining cardiac damage. However, the molecular regulatory mechanisms that underlie this adaptive response are not yet fully understood. This study investigates morphological, functional, genetic, and metabolic changes that occur in the heart of ground squirrels in three groups: summer active (SA), late torpor (LT), and interbout arousal (IBA). Morphological and functional changes in the heart were measured using hematoxylin-eosin (HE) staining, Masson staining, echocardiography, and enzyme-linked immunosorbent assay (ELISA). Results showed significant changes in cardiac function in the LT group as compared with SA or IBA groups, but no irreversible damage occurred. To understand the molecular mechanisms underlying these phenotypic changes, transcriptomic and metabolomic analyses were conducted to assess differential changes in gene expression and metabolite levels in the three groups of ground squirrels, with a focus on GO and KEGG pathway analysis. Transcriptomic analysis showed that differentially expressed genes were involved in the remodeling of cytoskeletal proteins, reduction in protein synthesis, and downregulation of the ubiquitin-proteasome pathway during hibernation (including LT and IBA groups), as compared with the SA group. Metabolomic analysis revealed increased free amino acids, activation of the glutathione antioxidant system, altered cardiac fatty acid metabolic preferences, and enhanced pentose phosphate pathway activity during hibernation as compared with the SA group. Combining the transcriptomic and metabolomic data, active mitochondrial oxidative phosphorylation and creatine-phosphocreatine energy shuttle systems were observed, as well as inhibition of ferroptosis signaling pathways during hibernation as compared with the SA group. In conclusion, these results provide new insights into cardio-protection in hibernators from the perspective of gene and metabolite changes and deepen our understanding of adaptive cardio-protection mechanisms in mammalian hibernators.PMID:37733616 | DOI:10.1002/jcp.31123

Acta Med Litu. 2022;29(2):311-319. doi: 10.15388/Amed.2022.29.2.16. Epub 2022 Jun 29.ABSTRACTBACKGROUND: Simulation as a proxy tool for conditional clinical training became a powerful technique for introducing trainees to the ultrasound imaging world, allowing them to become a trained sonographer taking into consideration different rates of progress in completing a specific task against the time and ensuring the long-lasting maintenance of the obtained practical skills. Adding a costly, but effective high-fidelity simulator to the residency program justified the expense, demonstrating efficiency of training for improving the clinical performance and confidence of trainees.MATERIALS AND METHODS: A pilot study in Riga Maternity Hospital within the framework of the study "Role of metabolome, biomarkers and ultrasound parameters in successful labor induction" (Fundamental and Applied Research Programme lzp-2021/1-0300) was performed between March 1st 2022 and 31st April 2022. A virtual-reality simulator (ScanTrainer, MedaphorTM, Cardiff, UK) was used with the teaching module for assessment of the uterine cervix. Five trainees in obstetrics and two young specialists included in the study. None of them had Fetal Medicine Foundation certificate of competence in the assessment of the uterine cervical lenght before. The time used on the simulator, the number of simulations and a mean confidence in cervical length assessment before and after simulation were recorded.RESULTS: The study on assesment of uterine cervical lenght demonstrated statistically significant increase in confidence (p=0.008) and statistically significant decrease in time needed to complete correctly the same tasks for the trainees (p=0.008) that shows a positive learning curve over the time of training on ScanTrainer, Medaphor.CONCLUSIONS: The simple task allows to become a certified specialist in uterine cervical assessment in the short period of time. That support the productiveness of the simulation-based education. The training program should be updated taking into consideration simulation curriculum.PMID:37733389 | PMC:PMC9799008 | DOI:10.15388/Amed.2022.29.2.16

Pest Manag Sci. 2023 Sep 21. doi: 10.1002/ps.7784. Online ahead of print.ABSTRACTBotrytis cinerea is the primary disease affecting cucumber production. It can be managed by applying pesticides and cultivating disease-resistant cucumber strains. However, challenges, such as drug resistance in pathogenic bacteria and changes in physiological strains, are obstacles in the effective management of B. cinerea. Nano-selenium (Nano-Se) has potential in enhancing crop resistance to biological stress, but the exact mechanism for boosting disease resistance remains unclear. Here, we used metabolomics and transcriptomics to examine how Nano-Se, as an immune activator, induces plant resistance. Compared with the control group, the application of 10.0 mg/L Nano-Se on the cucumber plant's leaf surface resulted in increased levels of chlorophyll, catalase (10.2%), glutathione (326.6%), glutathione peroxidase (52.2%), cucurbitacin (41.40%), and metabolites associated with the phenylpropane synthesis pathway, as well as the total antioxidant capacity (21.3%). Additionally, the expression levels of jasmonic acid (14.8 times) and related synthetic genes, namely LOX (264.1%), LOX4 (224.1%), and AOC2 (309.2%), were up-regulated. A transcription analysis revealed that the CsaV3_4G002860 gene was up-regulated in the KEGG enrichment pathway in response to B. cinerea infection following the 10.0 mg/L Nano-Se treatment. In conclusion, the activation of the phenylpropane biosynthesis and branched-chain fatty acid pathways by Nano-Se promotes the accumulation of jasmonic acid and cucurbitacin in cucumber plants. This enhancement enables the plants to exhibit resistance against B. cinerea infections. Additionally, this study identified a potential candidate gene for cucumber resistance to B. cinerea induced by Nano-Se, thereby laying a theoretical foundation for further research in this area. This article is protected by copyright. All rights reserved.PMID:37733166 | DOI:10.1002/ps.7784

Biomed Chromatogr. 2023 Sep 21:e5732. doi: 10.1002/bmc.5732. Online ahead of print.ABSTRACTThe current study utilizes a comprehensive network pharmacology and metabolomics analysis to investigate the mechanism of action of Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) for the treatment of ulcerative colitis (UC). In this study, we established a mouse model of UC using dextran sulfate sodium. Colonic tissues were collected from mice and then subjected to hematoxylin and eosin staining, as well as histopathological analysis, to assess the therapeutic effect of MMRAC. Furthermore, we assessed the mechanisms through which MMRAC combats UC by employing integrated metabolomics and network pharmacology strategies. Lastly, we validated the key targets identified through western blot and molecular docking. An integrated network of metabolomics and network pharmacology was constructed using Cytoscape to identify eight endogenous metabolites involved in the therapeutic action of MMRAC on UC. Further comprehensive analyses were focused on four key targets and their associated core metabolites and pathways. The results of western blot and molecular docking demonstrated that MMRAC could modulate key targets and their expression levels. The cumulative results indicated that MMRAC restored intestinal function in UC, reduced inflammatory responses, and alleviated oxidative stress by influencing the methionine and cysteine metabolic pathways, as well as the urea cycle. In addition, it had an impact on arginine, proline, glutamate, aspartate, and asparagine metabolic pathways and their associated targets.PMID:37732359 | DOI:10.1002/bmc.5732

J Biomol Struct Dyn. 2023 Sep 21:1-18. doi: 10.1080/07391102.2023.2257322. Online ahead of print.ABSTRACTHuntington's disease is associated with increased CAG repeat resulting in an expanded polyglutamine tract in the protein Huntingtin (HTT) leading to its aggregation resulting in neurodegeneration. Previous studies have shown that N-terminal HTT with 46Q aggregated in the stationary phase but not the logarithmic phase in the yeast model of HD. We carried out a metabolomic analysis of logarithmic and stationary phase yeast model of HD expressing different polyQ lengths attached to N-terminal HTT tagged with enhanced green fluorescent protein (EGFP). The results show significant changes in the metabolic profile and deregulated pathways in stationary phase cells compared to logarithmic phase cells. Comparison of metabolic pathways obtained from logarithmic phase 46Q versus 25Q with those obtained for presymptomatic HD patients from our previous study and drosophila model of HD showed considerable overlap. The arginine biosynthesis pathway emerged as one of the key pathways that is common in stationary phase yeast compared to logarithmic phase and HD patients. Treatment of yeast with arginine led to a significant decrease, while transfer to arginine drop-out media led to a significant increase in the size of protein aggregates in both logarithmic and stationary phase yeast model of HD. Knockout of arginine transporters in the endoplasmic reticulum and vacuole led to a significant decrease in mutant HTT aggregation. Overall our results highlight arginine as a critical metabolite that modulates the aggregation of mutant HTT and disease progression in HD.Communicated by Ramaswamy H. Sarma.PMID:37732342 | DOI:10.1080/07391102.2023.2257322

Front Vet Sci. 2023 Sep 5;10:1228360. doi: 10.3389/fvets.2023.1228360. eCollection 2023.ABSTRACTINTRODUCTION: Ochratoxin A (OTA) is a widely distributed mycotoxin. Nano-selenium (Nano-Se) is an emerging form of selenium known for its superior bioavailability, remarkable catalytic efficiency, and robust adsorbing capacity. Despite these characteristics, its impact on the microbial community and metabolomics in the cecum of chickens exposed to OTA has been infrequently investigated. This research examined the microbiota and metabolomic alterations linked to OTA in chickens, with or without Nano-Se present.METHODS: A cohort of 80 healthy chickens at the age of 1 day was randomly distributed into four groups of equal numbers, namely the Se cohort (1 mg/kg Nano-Se), the OTA cohort (50 μg/kg OTA), the OTA-Se cohort (50 μg/kg OTA + 1 mg/kg Nano-Se), and the control group. Each chicken group's caecal microbiome and metabolome were characterized using 16S rRNA sequencing and Liquid chromatography coupled with mass spectrometry (LC-MS) analyses.RESULTS AND DISCUSSION: Our results showed that the on day 21, the final body weight was significantly reduced in response to OTA treatments (p < 0.05), the average daily gain in the OTA group was found to be inferior to the other groups (p < 0.01). In addition, Nano-Se supplementation could reduce the jejunum and liver pathological injuries caused by OTA exposure. The 16S rRNA sequencing suggest that Nano-Se supplementation in OTA-exposed chickens mitigated gut microbiota imbalances by promoting beneficial microbiota and suppressing detrimental bacteria. Moreover, untargeted metabolomics revealed a significant difference in caecal metabolites by Nano-Se pretreatment. Collectively, the dataset outcomes highlighted that Nano-Se augmentation regulates intestinal microbiota and associated metabolite profiles, thus influencing critical metabolic pathways, and points to a possible food-additive product.PMID:37732141 | PMC:PMC10507861 | DOI:10.3389/fvets.2023.1228360

Research (Wash D C). 2023 Sep 19;6:0216. doi: 10.34133/research.0216. eCollection 2023.ABSTRACTInsufficient sleep can produce a multitude of deleterious repercussions on various domains of human well-being. Concomitantly, the walnut (Juglans mandshurica) confers numerous salutary biological activities pertaining to sleep. Nevertheless, the sedative and hypnotic capacities of walnut's functional constituents remain obscure. In this investigation, we analyzed the sedative and hypnotic components of the walnut Diaphragma juglandis fructus and innovatively discovered a compound, defined as 3-hydroxy-4-iminobutyric acid (HIBA), which disrupts motor activity and enhances sleep duration by regulating the neurotransmitters (GABA, DA, etc.) within the brain and serum of mice. Subsequently, a metabolomics approach of the serum, basal ganglia, hypothalamus, and hippocampus as well as the gut microbiota was undertaken to unravel the underlying molecular mechanisms of sleep promotion. Our data reveal that HIBA can regulate the metabolism of basal ganglia (sphingolipids, acylcarnitines, etc.), possibly in relation to HIBA's influence on the gut microbiome (Muribaculum, Bacteroides, Lactobacillus, etc.). Therefore, we introduce a novel natural product, HIBA, and explicate the modulation of sleep promotion in mice based on the microbiota-gut-brain axis. This study contributes fresh insights toward natural product-based sleep research.PMID:37732131 | PMC:PMC10508226 | DOI:10.34133/research.0216

Front Endocrinol (Lausanne). 2023 Sep 5;14:1159707. doi: 10.3389/fendo.2023.1159707. eCollection 2023.ABSTRACTINTRODUCTION: Yu-Ye Tang (YYT) is a classical formula widely used in treatment of type 2 diabetes mellitus (T2DM). However, the specific mechanism of YYT in treating T2DM is not clear.METHODS: The aim of this study was to investigate the therapeutic effect of YYT on T2DM by establishing a rat model of T2DM. The mechanism of action of YYT was also explored through investigating gut microbiota and serum metabolites.RESULTS: The results indicated YYT had significant therapeutic effects on T2DM. Moreover, YYT could increase the abundance of Lactobacillus, Candidatus_Saccharimonas, UCG-005, Bacteroides and Blautia while decrease the abundance of and Allobaculum and Desulfovibrio in gut microbiota of T2DM rats. Nontargeted metabolomics analysis showed YYT treatment could regulate arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, glycerophospholipid metabolism, pentose and glucuronate interconversions, phenylalanine metabolism, steroid hormone biosynthesis, terpenoid backbone biosynthesis, tryptophan metabolism, and tyrosine metabolism in T2DM rats.DISCUSSION: In conclusion, our research showed that YYT has a wide range of therapeutic effects on T2DM rats, including antioxidative and anti-inflammatory effects. Furthermore, YYT corrected the altered gut microbiota and serum metabolites in T2DM rats. This study suggests that YYT may have a therapeutic impact on T2DM by regulating gut microbiota and modulating tryptophan and glycerophospholipid metabolism, which are potential key pathways in treating T2DM.PMID:37732114 | PMC:PMC10507721 | DOI:10.3389/fendo.2023.1159707

Front Psychiatry. 2023 Sep 5;14:1182535. doi: 10.3389/fpsyt.2023.1182535. eCollection 2023.ABSTRACTMuch recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration.PMID:37732074 | PMC:PMC10507876 | DOI:10.3389/fpsyt.2023.1182535

Hortic Res. 2023 Aug 16;10(9):uhad164. doi: 10.1093/hr/uhad164. eCollection 2023 Sep.ABSTRACTArtemisia annua is the only known plant source of the potent antimalarial artemisinin, which occurs as the low- and high-artemisinin producing (LAP and HAP) chemotypes. Nevertheless, the different mechanisms of artemisinin producing between these two chemotypes were still not fully understood. Here, we performed a comprehensive analysis of genome resequencing, metabolome, and transcriptome data to systematically compare the difference in the LAP chemotype JL and HAP chemotype HAN. Metabolites analysis revealed that 72.18% of sesquiterpenes was highly accumulated in HAN compared to JL. Integrated omics analysis found a DBR2-Like (DBR2L) gene may be involved in artemisinin biosynthesis. DBR2L was highly homologous with DBR2, belonged to ORR3 family, and had the DBR2 activity of catalyzing artemisinic aldehyde to dihydroartemisinic aldehyde. Genome resequencing and promoter cloning revealed that complicated variations existed in DBR2L promoters among different varieties of A. annua and were clustered into three variation types. The promoter activity of diverse variant types showed obvious differences. Furthermore, the core region (-625 to 0) of the DBR2L promoter was identified and candidate transcription factors involved in DBR2L regulation were screened. Thus, the result indicates that DBR2L is another key enzyme involved in artemisinin biosynthesis. The promoter variation in DBR2L affects its expression level, and thereby may result in the different yield of artemisinin in varieties of A. annua. It provides a novel insight into the mechanism of artemisinin-producing difference in LAP and HAP chemotypes of A. annua, and will assist in a high yield of artemisinin in A. annua.PMID:37731862 | PMC:PMC10508037 | DOI:10.1093/hr/uhad164

iScience. 2023 Aug 29;26(10):107754. doi: 10.1016/j.isci.2023.107754. eCollection 2023 Oct 20.ABSTRACTHepatic fibrosis is a classic pathological manifestation of metabolic chronic hepatopathy. The pathological process might either gradually deteriorate into cirrhosis and ultimately liver cancer with inappropriate nutrition supply, or be slowed down by several multifunctional nutrients, alternatively. Herein, we found diet with excessive phenylalanine (Phe) and tyrosine (Tyr) exacerbated hepatic fibrosis symptoms of liver dysfunction and gut microflora dysbiosis in mice. Chitooligosaccharides (COS) could ameliorate hepatic fibrosis with the regulation of amino acid metabolism by downregulating the mTORC1 pathway, especially that of Phe and Tyr, and also with the alleviation of the dysbiosis of gut microbiota, simultaneously. Conclusively, this work presents new insight into the role of Phe and Tyr in the pathologic process of hepatic fibrosis, while revealing the effectiveness and molecular mechanism of COS in improving hepatic fibrosis from the perspective of metabolites.PMID:37731617 | PMC:PMC10507131 | DOI:10.1016/j.isci.2023.107754

iScience. 2023 Sep 1;26(10):107790. doi: 10.1016/j.isci.2023.107790. eCollection 2023 Oct 20.ABSTRACTDoxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.PMID:37731615 | PMC:PMC10507231 | DOI:10.1016/j.isci.2023.107790