PubMed

Mutat Res Genet Toxicol Environ Mutagen. 2023 Oct;891:503681. doi: 10.1016/j.mrgentox.2023.503681. Epub 2023 Aug 18.ABSTRACTGenotoxicity is an important information that should be included in human biomonitoring programmes. However, the usually applied cytogenetic assays are laborious and time-consuming, reason why it is critical to develop rapid and economic new methods. The aim of this study was to evaluate if the molecular profile of frozen whole blood, acquired by Fourier Transform Infrared (FTIR) spectroscopy, allows to assess genotoxicity in occupational exposure to antineoplastic drugs, as obtained by the cytokinesis-block micronucleus assay. For that purpose, 92 samples of peripheral blood were studied: 46 samples from hospital professionals occupationally exposed to antineoplastic drugs and 46 samples from workers in academia without exposure (controls). It was first evaluated the metabolome from frozen whole blood by methanol precipitation of macromolecules as haemoglobin, followed by centrifugation. The metabolome molecular profile resulted in 3 ratios of spectral bands, significantly different between the exposed and non-exposed group (p < 0.01) and a spectral principal component-linear discriminant analysis (PCA-LDA) model enabling to predict genotoxicity from exposure with 73 % accuracy. After optimization of the dilution degree and solution used, it was possible to obtain a higher number of significant ratios of spectral bands, i.e., 10 ratios significantly different (p < 0.001), highlighting the high sensitivity and specificity of the method. Indeed, the PCA-LDA model, based on the molecular profile of whole blood, enabled to predict genotoxicity from the exposure with an accuracy, sensitivity, and specificity of 92 %, 93 % and 91 %, respectively. All these parameters were achieved based on 1 μL of frozen whole blood, in a high-throughput mode, i.e., based on the simultaneous analysis of 92 samples, in a simple and economic mode. In summary, it can be conclude that this method presents a very promising potential for high-dimension screening of exposure to genotoxic substances.PMID:37770138 | DOI:10.1016/j.mrgentox.2023.503681

Plant Physiol. 2023 Sep 28:kiad515. doi: 10.1093/plphys/kiad515. Online ahead of print.ABSTRACTTandem direct repeat (TDR)-containing proteins, present across all domains of life, play crucial roles in plant development and defense mechanisms. Previously, we identified that disruption of a bryophyte-specific protein family, SHORT-LEAF (SHLF), possessing the longest reported TDRs, is the cause of the shlf mutant phenotype in Physcomitrium patens. shlf exhibits reduced apical dominance, altered auxin distribution, and two-fold shorter leaves. However, the molecular role of SHLF was unclear due to the absence of known conserved domains. Through a series of protein domain deletion analyses, here, we demonstrate the importance of the signal peptide and the conserved TDRs and report a minimal functional protein (miniSHLF) containing the N-terminal signal peptide and first two TDRs (N-TDR1-2). We also demonstrate that SHLF behaves as a secretory protein and that the TDRs contribute to a pool of secreted peptides essential for SHLF function. Further, we identified that the mutant secretome lacks SHLF peptides, which are abundant in WT and miniSHLF secretomes. Interestingly, shlf mutants supplemented with the secretome or peptidome from WT or miniSHLF showed complete or partial phenotypic recovery. Transcriptomic and metabolomic analyses revealed that shlf displays an elevated stress response, including high ROS activity and differential accumulation of genes and metabolites involved in the phenylpropanoid pathway, which may affect auxin distribution. The TDR-specific synthetic peptide SHLFpep3 (INIINAPLQGFKIA) also rescued the mutant phenotypes, including the altered auxin distribution, in a dosage-dependent manner and restored the mutant's stress levels. Our study shows that secretory SHLF peptides derived from conserved TDRs regulate moss gametophore development.PMID:37770073 | DOI:10.1093/plphys/kiad515

Life Sci. 2023 Sep 26:122125. doi: 10.1016/j.lfs.2023.122125. Online ahead of print.ABSTRACTSarcopenia remains one of the major pathological features of type 2 diabetes (T2D), especially in older individuals. This condition describes gradual loss of muscle mass, strength, and function that reduces the overall vitality and fitness, leading to increased hospitalizations and even fatalities to those affected. Preclinical evidence indicates that dysregulated mitochondrial dynamics, together with impaired activity of the NADPH oxidase system, are the major sources of oxidative stress that drive skeletal muscle damage in T2D. While patients with T2D also display relatively higher levels of circulating inflammatory markers in the serum, including high sensitivity-C-reactive protein, interleukin-6, and tumor necrosis factor-α that are independently linked with the deterioration of muscle function and sarcopenia in T2D. In fact, beyond reporting on the pathological consequences of both oxidative stress and inflammation, the current review highlights the importance of strengthening intracellular antioxidant systems to preserve muscle mass, strength, and function in individuals with T2D.PMID:37769808 | DOI:10.1016/j.lfs.2023.122125

Neurobiol Dis. 2023 Sep 26:106312. doi: 10.1016/j.nbd.2023.106312. Online ahead of print.ABSTRACTAlzheimer's disease is the most common type of dementia in the elderly. It is a progressive degenerative disorder that may begin to develop up to 15 years before clinical symptoms appear. The identification of early biomarkers is crucial to enable a prompt diagnosis and to start effective interventions. In this work, we conducted a metabolomic study using proton Nuclear Magnetic Resonance (1H NMR) spectroscopy in serum samples from patients with neuropathologically confirmed Alzheimer's disease (AD, n = 51), mild cognitive impairment (MCI, n = 27), and cognitively healthy controls (HC, n = 50) to search for metabolites that could be used as biomarkers. Patients and controls underwent yearly clinical follow-ups for up to six years. MCI group included samples from three subgroups of subjects with different disease progression rates. The first subgroup included subjects that remained clinically stable at the MCI stage during the period of study (stable MCI, S-MCI, n = 9). The second subgroup accounted for subjects which were diagnosed with MCI at the moment of blood extraction, but progressed to clinical dementia in subsequent years (MCI-to-dementia, MCI-D, n = 14). The last subgroup was composed of subjects that had been diagnosed as dementia for the first time at the moment of sample collection (incipient dementia, Incp-D, n = 4). Partial Least Square Discriminant Analysis (PLS-DA) models were developed. Three models were obtained, one to discriminate between AD and HC samples with high sensitivity (93.75%) and specificity (94.75%), another model to discriminate between AD and MCI samples (100% sensitivity and 82.35% specificity), and a last model to discriminate HC and MCI with lower sensitivity and specificity (67% and 50%). Differences within the MCI group were further studied in an attempt to determine those MCI subjects that could develop AD-type dementia in the future. The relative concentration of metabolites, and metabolic pathways were studied. Alterations in the pathways of alanine, aspartate and glutamate metabolism, pantothenate and CoA biosynthesis, and beta-alanine metabolism, were found when HC and MCI- D patients were compared. In contrast, no pathway was found disturbed in the comparison of S-MCI with HC groups. These results highlight the potential of 1H NMR metabolomics to support the diagnosis of dementia in a less invasive way, and set a starting point for the study of potential biomarkers to identify MCI or HC subjects at risk of developing AD in the future.PMID:37769747 | DOI:10.1016/j.nbd.2023.106312

Sci Total Environ. 2023 Sep 26:167352. doi: 10.1016/j.scitotenv.2023.167352. Online ahead of print.ABSTRACTWide usage of plastic coupled with mismanagement has created a humongous environmental hazard threatening entire ecosystems. To date, the potential effects of plastic debris-induced soil nutrition substance changes and the relevant microbial metabolic behavior remain unclear. Here, we studied the effect of plastic films polyethylene and polylactic acid in differential soil environments (farmland, woodland, and wetland) for 120 days. Soil enzyme activities (urease, neutral phosphatase, and catalase) and nutrition substance (NH4+-N, available P, available K, and soil organic matter) present obvious variations in polylactic acid groups compared to polyethylene-treated samples. 16S rRNA gene sequencing indicates that several bacteria abundance such as Bacteroidales, Actinobacteriota, Nitrososphaeraceae, Pyrinomonadalcs, Muribaculaceae, exhibited obvious up-regulation or down-regulation, and simultaneously, the carbon, nitrogen, and phosphorus cycling relevant species Bryobacter, Bradyrhizobium, and Sphingomonas, expressed wider margin of down-regulation in abundance in plastic treatment soil samples. As a result, the abundance of metabolites including sugar, amino acid, and fatty acids, which may associated with nutrition substance metabolic pathways, were significantly altered in the stress of plastic. These findings provide valuable information on the environmental effects of plastics, and the relationships of subsequent nutrition substance changes and microbial metabolic behavior.PMID:37769723 | DOI:10.1016/j.scitotenv.2023.167352

Sci Total Environ. 2023 Sep 26:167359. doi: 10.1016/j.scitotenv.2023.167359. Online ahead of print.ABSTRACTThe co-existence of microplastics (MPs) and antibiotics in the coastal environment poses a combined ecological risk. Single toxic effects of MPs or antibiotics on aquatic organisms have been verified, however, the exploration of their combined toxic effects remains limited. Here, foodborne polystyrene microplastics (PS-MPs, 10 μm, 0.1 % w/w in food) and waterborne tetracyclines (TC, 50 μg/L) were used to expose an estuarine fish Oryzias melastigma for four weeks. We found that the aqueous availability of TC was not significantly altered coexisting with MPs. The fish body weight gain was significantly slower in TC alone or combined groups than the control group, consistent with the lower lipid content in livers. The body length gain was significantly inhibited by the combined presence compared to the single exposure. Both exposures led to a shift of gut microbiota composition and diversity. TC and the combined group possessed similar gut microbiota which is distinct from PS-MPs and the control group. The Firmicutes/Bacteroidetes (F/B) ratio in the TC and combined groups were significantly lower compared to the control, while the PS-MPs group showed no significant impact. Metabolomic analysis of the fish liver confirmed the shift of metabolites in specific pathways after different exposures. More, a number of gut microbiota-related metabolites on lipid metabolism was perturbed, which were annotated in arachidonic acid metabolism and linoleic acid metabolism. In all, TC modulates bacterial composition in the fish gut and disturbs their liver metabolites via the gut-liver axis, which led to the slower growth of O. melastigma. More, the adverse impact was aggravated by the co-exposure to foodborne PS-MPs.PMID:37769716 | DOI:10.1016/j.scitotenv.2023.167359

J Clin Endocrinol Metab. 2023 Sep 28:dgad559. doi: 10.1210/clinem/dgad559. Online ahead of print.ABSTRACTOBJECTIVES: To describe cerebrospinal fluid (CSF) metabolomic pattern of pituitary stalk lesions.METHODS: CSF was collected from patients with different pituitary stalk lesions (germ cell tumor (GCT), n = 27; hypophysitis, n = 10; Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD), n = 10) treated at Peking Union Medical College Hospital. CSF metabolome profiling was characterized through Liquid Chromatography-Mass Spectrometer (LC-MS).RESULTS: 44 metabolites were significantly different between GCT and hypophysitis patients (P < 0.05). When comparing GCT (CSF beta subunit of human chorionic gonadotrophin (β-hCG) < 5 mIU/ml) with hypophysitis patients, there were 15 differential metabolites (P < 0.05, fold change > 1.5 or < 1/1.5). All the metabolites had the AUC (area under the curve) above 0.7. Besides, 9 metabolites were significantly different between GCT and LCH + ECD patients (P < 0.05) and 7 metabolites had significant differences between GCT (CSF β-hCG < 5 mIU/ml) and LCH + ECD patients (P < 0.05, fold change > 1.5 or < 1/1.5). 6 metabolites were significantly different between hypophysitis and LCH + ECD patients (P < 0.05) and 5 of them had fold change more than 1.5 or less than 1/1.5. Three metabolites, 5-deoxydiplosporin, cloversaponin I and phytosphingosine, showed excellent capabilities to differentiate three diseases. Furthermore, we determined 67 metabolites associated with clinical test results (ρ > 0.2, P < 0.05) and 29 metabolites showed strong correlation (ρ > 0.4, P < 0.05).CONCLUSIONS: Our study is the first to systematically investigate the metabolomics of CSF in different pituitary stalk lesions. CSF metabolomics is a useful strategy for biomarker discovery.PMID:37769631 | DOI:10.1210/clinem/dgad559

Food Chem. 2023 Sep 22;435:137529. doi: 10.1016/j.foodchem.2023.137529. Online ahead of print.ABSTRACTThe production of fine-flavor cocoa represents a promising avenue to enhance socioeconomic development in Colombia and Latin America. Premium chocolate is obtained through a post-harvesting process, which relies on semi-standardized techniques. The change in the metabolic profile during cocoa processing considerably impacts flavor and nutraceutical properties of the final product. Understanding this impact considering both volatiles and non-volatile compounds is crucial for process and product re-engineering of cocoa post-harvesting. Consequently, this work studied the metabolic composition of cocoa liquor by untargeted metabolomics and lipidomics. This approach offered a comprehensive view of cocoa biochemistry, considering compounds associated with bioactivity and flavor in cocoa liquor. Their variations were traced back over the cocoa processing (i.e., drying, and roasting), highlighting their impact on flavor development and the nutraceutical properties. These results represent the basis for future studies aimed to re-engineer cocoa post-harvesting considering the variation of key flavor and bioactive compounds over processing.PMID:37769563 | DOI:10.1016/j.foodchem.2023.137529

Food Chem. 2023 Sep 23;435:137573. doi: 10.1016/j.foodchem.2023.137573. Online ahead of print.ABSTRACTCitrus fruits are one of the most important fruits in the global food industry due to their unique taste and nutritional benefits. Herein, we characterize the physicochemical and bioactive attributes of twenty-nine Greek citrus accessions, including oranges, mandarins/clementines, lemons, bergamot, citrons and lime along with twenty-seven highly commercial international cultivars. The assessed genotypes differ in various quality traits including color, ripening, and textural attributes. Several indigenous cultivars displayed desirable organoleptic traits, such as the oranges 'Valencia Oval Porou' (e.g., juice content and ascorbic acid) and 'Sanguine Gouritis' (eg., soluble solids (SSC) and acidity (TA) ratio), the mandarin 'Clementine Porou' (e.g., SSC/TA) and the lemon 'Vakalou' (e.g., firmness, acidity). Differences in primary metabolites, mainly in sugars, organic acids and amino acids were recorded among the tested species and cultivars. In addition, the autochthonous orange cultivars 'Sanguine Gouritsis' and 'Valencia Oval Porou' contained high sucrose levels whereas 'Lainato Chanion' had high hesperidin content. This large-scale analysis supports the ample availability of genetic resources for the development of citrus cultivars with improved nutritional quality traits.PMID:37769559 | DOI:10.1016/j.foodchem.2023.137573

Clin Nutr. 2023 Sep 20;42(11):2124-2137. doi: 10.1016/j.clnu.2023.09.006. Online ahead of print.ABSTRACTBACKGROUND: McArdle disease is caused by myophosphorylase deficiency leading to blocked glycogenolysis in skeletal muscle. Consequently, individuals with McArdle disease have intolerance to physical activity, muscle fatigue, and pain. These symptoms vary according to the availability of alternative fuels for muscle contraction. In theory, a modified ketogenic diet (mKD) can provide alternative fuels in the form of ketone bodies and potentially boost fat oxidation.METHODS: This randomized, single-blind, placebo-controlled, cross-over study aimed to investigate if a mKD improves exercise capacity in individuals with McArdle disease. Participants were randomized to follow a mKD (75-80% fat, 15% protein, 5-10% carbohydrates) or placebo diet (PD) first for three weeks, followed by a wash-out period, and then the opposite diet. The primary outcome was change in heart rate during constant-load cycling. Secondary outcomes included change in plasma metabolites, perceived exertion, indirect calorimetry measures, maximal exercise capacity, and patient-reported outcomes.RESULTS: Fifteen out of 20 patients with genetically verified McArdle disease completed all study visits, and 14 were included in the data analyses. We found that the mKD induced a metabolic shift towards increased fat oxidation (∼60% increase), and a 19-fold increase in plasma β-hydroxybutyrate (p < 0.05). The mKD did not improve heart rate responses during constant-load cycling but did improve patient-reported outcomes and maximal exercise capacity (∼20% increase) compared to the PD.CONCLUSION: The mKD did not alleviate all McArdle disease-related symptoms but did induce some positive changes. To date, no satisfactory treatment options exist other than exercise training. To that end, a mKD can be a possible nutritional strategy for some individuals with McArdle disease who are motivated to undertake a restrictive diet.CLINICAL TRIAL REGISTRATION: clinical trials.gov: NCT04044508.PMID:37769369 | DOI:10.1016/j.clnu.2023.09.006

Drug Dev Res. 2023 Sep 28. doi: 10.1002/ddr.22119. Online ahead of print.ABSTRACTGlioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV-TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM-derived astrocytes and OECs-TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC-TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs-TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase-3 in the coculture of OECs-TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC-TK/GCV gene therapy on GBM cells.PMID:37769152 | DOI:10.1002/ddr.22119

J Nanobiotechnology. 2023 Sep 28;21(1):352. doi: 10.1186/s12951-023-02105-9.ABSTRACTBACKGROUND: Macrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs.RESULTS: Naïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis.CONCLUSION: This study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.PMID:37770932 | DOI:10.1186/s12951-023-02105-9

BMC Plant Biol. 2023 Sep 29;23(1):455. doi: 10.1186/s12870-023-04470-x.ABSTRACTBACKGROUND: Salt stress is one of the key factors limiting rice production. Alginate oligosaccharides (AOS) enhance plant stress resistance. However, the molecular mechanism underlying salt tolerance in rice induced by AOS remains unclear. FL478, which is a salt-tolerant indica recombinant inbred line and IR29, a salt-sensitive rice cultivar, were used to comprehensively analyze the effects of AOS sprayed on leaves in terms of transcriptomic and metabolite profiles of rice seedlings under salt stress.RESULTS: In this experiment, exogenous application of AOS increased SOD, CAT and APX activities, as well as GSH and ASA levels to reduce the damage to leaf membrane, increased rice stem diameter, the number of root tips, aboveground and subterranean biomass, and improved rice salt tolerance. Comparative transcriptomic analyses showed that the regulation of AOS combined with salt treatment induced the differential expression of 305 and 1030 genes in FL478 and IR29. The expressed genes enriched in KEGG pathway analysis were associated with antioxidant levels, photosynthesis, cell wall synthesis, and signal transduction. The genes associated with light-trapping proteins and RLCK receptor cytoplasmic kinases, including CBA, LHCB, and Lhcp genes, were fregulated in response to salt stress. Treatment with AOS combined with salt induced the differential expression of 22 and 50 metabolites in FL478 and IR29. These metabolites were mainly related to the metabolism of amino and nucleotide sugars, tryptophan, histidine, and β -alanine. The abundance of metabolites associated with antioxidant activity, such as 6-hydroxymelatonin, wedelolactone and L-histidine increased significantly. Combined transcriptomic and metabolomic analyses revealed that dehydroascorbic acid in the glutathione and ascorbic acid cycles plays a vital role in salt tolerance mediated by AOS.CONCLUSION: AOS activate signal transduction, regulate photosynthesis, cell wall formation, and multiple antioxidant pathways in response to salt stress. This study provides a molecular basis for the alleviation of salt stress-induced damage by AOS in rice.PMID:37770835 | DOI:10.1186/s12870-023-04470-x

Trop Anim Health Prod. 2023 Sep 28;55(5):340. doi: 10.1007/s11250-023-03733-x.ABSTRACTThe neonate with low birth weight (LBW) resulted from intrauterine growth retardation (IUGR) exists a substantial risk of postpartum death. Placental insufficiency is responsible for inadequate fetal growth; however, the pathological mechanisms of placental dysfunction-induced IUGR in pigs remain unclear. In this study, the characteristics of placental morphology, placental transcriptome, and cord serum metabolome were explored between the Kele piglets with LBW and the ones with normal birth weight (NBW). Results showed that LBW was a common occurrence in Kele piglets. The LBW placentas showed inferior villus development and lower villi density compared to NBW placentas. There were 1024 differentially expressed genes (DEGs) identified by transcriptome analysis between the LBW and NBW placentas, of which 218 and 806 genes were up- and down-regulated in the LBW placentas, respectively. PPI network analysis showed that ITGB2, CD4, IL6, ITGB3, LCK, RAC2, CD8A, JAK3, TYROBP, and CXCR4 were hub genes in all DEGs. From GO and KEGG enrichment analysis, DEGs were primarily enriched in immunological response, cell adhesion, immune response, cytokine-cytokine receptor interaction, and PI3K-Akt signaling pathway. By using metabolomic analysis, a total of 115 differential metabolites in the cord serum of LBW and NBW piglets were found, mostly linked to amino acid metabolism and sphingolipid metabolism. In comparison to NBW piglets, LBW piglets had lower levels of arginine, isoleucine, and aspartic acid in the cord. Taken together, these data revealed dysplasia of the placental villus, insufficient supply of nutrients, and abnormal immune function of the placenta may be associated with the occurrence and development of LBW in Kele pigs.PMID:37770796 | DOI:10.1007/s11250-023-03733-x

Cell Mol Life Sci. 2023 Sep 28;80(10):309. doi: 10.1007/s00018-023-04963-w.ABSTRACTBacterial endophthalmitis is a severe complication of eye surgeries that can lead to vision loss. Current treatment involves intravitreal antibiotic injections that control bacterial growth but not inflammation. To identify newer therapeutic targets to promote inflammation resolution in endophthalmitis, we recently employed an untargeted metabolomics approach. This led to the discovery that the levels of S-nitroso-L-glutathione (GSNO) were significantly reduced in an experimental murine Staphylococcus aureus (SA) endophthalmitis model. In this study, we tested the hypothesis whether GSNO supplementation via different routes (oral, intravitreal) provides protection during bacterial endophthalmitis. Our results show that prophylactic administration of GSNO via intravitreal injections ameliorated SA endophthalmitis. Therapeutically, oral administration of GSNO was found to be most effective in reducing intraocular inflammation and bacterial burden. Moreover, oral GSNO treatment synergized with intravitreal antibiotic injections in reducing the severity of endophthalmitis. Furthermore, in vitro experiments using cultured human retinal Muller glia and retinal pigment epithelial (RPE) cells showed that GSNO treatment reduced SA-induced inflammatory mediators and cell death. Notably, both in-vivo and ex-vivo data showed that GSNO strengthened the outer blood-retinal barrier during endophthalmitis. Collectively, our study demonstrates GSNO as a potential therapeutic agent for the treatment of intraocular infections due to its dual anti-inflammatory and cytoprotective properties.PMID:37770649 | DOI:10.1007/s00018-023-04963-w

Arch Pharm (Weinheim). 2023 Sep 28:e2300382. doi: 10.1002/ardp.202300382. Online ahead of print.ABSTRACTIn recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques. The synthesized boron-containing drug candidates were found to significantly inhibit cell proliferation and induce apoptosis-mediated cell death in HT-29 (colorectal cells), SaOs-2 (osteosarcoma cells), and U87-MG (glioblastoma cells). Moreover, we revealed that the anticancer effects of boron-containing fingolimod compounds were found to be significantly enhanced over boron-free control groups and, strikingly, over the widely used anticancer drug 5-fluorouracil. The metabolomic analysis confirmed that administration of the boron-containing drug candidates induces significant changes in the metabolite profiles in HT-29, SaOs-2, and U87-MG cells. Altogether, our results showed that boron-containing fingolimod compounds can be further examined to reveal their potential as anticancer drug candidates.PMID:37768844 | DOI:10.1002/ardp.202300382

Environ Sci Technol. 2023 Sep 28. doi: 10.1021/acs.est.3c04549. Online ahead of print.ABSTRACTNumerous studies have emphasized the toxicity of graphene-based nanomaterials to algae, however, the fundamental behavior and processes of graphene in biological hosts, including its transportation, metabolization, and bioavailability, are still not well understood. As photosynthetic organisms, algae are key contributors to carbon fixation and may play an important role in the fate of graphene. This study investigated the biological fate of 14C-labeled few-layer graphene (14C-FLG) in Chlamydomonas reinhardtii (C. reinhardtii). The results showed that 14C-FLG was taken up by C. reinhardtii and then translocated into its chloroplast. Metabolomic analysis revealed that 14C-FLG altered the metabolic profiles (including sugar metabolism, fatty acid, and tricarboxylic acid cycle) of C. reinhardtii, which promoted the photosynthesis of C. reinhardtii and then enhanced their growth. More importantly, the internalized 14C-FLG was metabolized into 14CO2, which was then used to participate in the metabolic processes required for life. Approximately 61.63%, 25.31%, and 13.06% of the total radioactivity (from 14CO2) was detected in carbohydrates, lipids, and proteins of algae, respectively. Overall, these results reveal the role of algae in the fate of graphene and highlight the potential of available graphene in bringing biological effects to algae, which helps to better assess the environmental risks of graphene.PMID:37768274 | DOI:10.1021/acs.est.3c04549

J Cachexia Sarcopenia Muscle. 2023 Sep 28. doi: 10.1002/jcsm.13342. Online ahead of print.ABSTRACTBACKGROUND: Sarcopenia in liver cirrhosis is associated with low quality of life and high mortality risk. The pathogenesis has yet to be fully understood. We hypothesized that gut microbiome, bile acid (BA) composition and metabolites differ between cirrhotic patients with and without sarcopenia and contribute to pathogenesis.METHODS: Cirrhotic patients with (n = 78) and without (n = 38) sarcopenia and non-cirrhotic controls with (n = 39) and without (n = 20) sarcopenia were included in this study. Faecal microbiome composition was studied by 16S rDNA sequencing, serum and faecal BA composition by ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolite composition in serum, faeces and urine by nuclear magnetic resonance.RESULTS: Bacteroides fragilis, Blautia marseille, Sutterella spp. and Veillonella parvula were associated with cirrhotic patients with sarcopenia, whereas Bacteroides ovatus was more abundant in cirrhotic patients without sarcopenia. We observed significantly elevated secondary BAs, deoxycholic acid (DCA; P = 0.01) and lithocholic acid (LCA; P = 0.02), and the ratios of deoxycholic acid to cholic acid (DCA:CA; P = 0.04), lithocholic acid to chenodeoxycholic acid (LCA:CDCA; P = 0.03) and 12 alpha-hydroxylated to non-12 alpha-hydroxylated BAs (12-α-OH:non-12-α-OH BAs; P = 0.04) in serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia, indicating an enhanced transformation of primary to secondary BAs by the gut microbiome. CA (P = 0.02) and the ratios of CA:CDCA (P = 0.03) and total ursodeoxycholic acid to total secondary BAs (T-UDCA:total-sec-BAs, P = 0.03) were significantly reduced in the stool of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia. Also, valine and acetate were significantly reduced in the serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia (P = 0.01 and P = 0.03, respectively). Multivariate logistic regression further confirmed the association of B. ovatus (P = 0.01, odds ratio [OR]: 12.8, 95% confidence interval [CI]: 168.1; 2.2), the ratios of 12-α-OH:non-12-α-OH BAs (P = 0.03, OR: 2.54, 95% CI: 0.99; 6.55) and T-UDCA:total-sec-BAs (P = 0.04, OR: 0.25, 95% CI: 0.06; 0.98) in serum and stool CA:CDCA (P = 0.04, OR: 0.79, 95% CI: 0.62; 0.99), and serum valine (P = 0.04, OR: 1.00, 95% CI: 1.02; 1.00) with sarcopenia in cirrhosis after correcting for the severity of liver disease and sex.CONCLUSIONS: Our study suggests a potential functional gut microbiome-host interaction linking sarcopenia with the altered gut microbiomes, BA profiles and amino acids pointing towards a potential mechanistic interplay in understanding sarcopenia pathogenesis.PMID:37767786 | DOI:10.1002/jcsm.13342

Arterioscler Thromb Vasc Biol. 2023 Sep 28. doi: 10.1161/ATVBAHA.123.319181. Online ahead of print.ABSTRACTBACKGROUND: Thrombosis is a major complication after cardiac surgery in children with congenital heart disease. The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with thrombosis after surgery in children with congenital heart disease.METHODS: In this prospective cohort study, all blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range, 0 days-18 years) with congenital heart disease undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model.RESULTS: Out of 1115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 25 children (12.3%) developed thrombosis. Among the 776 metabolites, 175 were significantly associated with thrombosis (false discovery rate Q<0.05). The top 3 metabolites showing the strongest associations with thrombosis were eicosapentaenoate, stearidonate, and andro steroid monosulfate C19H28O6S (false discovery rate, 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism and glycerophospholipid metabolism were enriched (false discovery rate, 0.003 for both) and had significant impact on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.969 in the training sample (70% of the total sample) and 0.833 in the testing sample (the remaining 30%).CONCLUSIONS: We have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm these findings and examine the mechanistic pathways to thrombosis.PMID:37767707 | DOI:10.1161/ATVBAHA.123.319181

Expert Rev Proteomics. 2023 Sep 28:1-19. doi: 10.1080/14789450.2023.2258282. Online ahead of print.ABSTRACTINTRODUCTION: Cystic fibrosis (CF) is a genetic disease characterized by thick and sticky mucus accumulation, which may harm numerous internal organs. Various variables such as gene modifiers, environmental factors, age of diagnosis, and CF transmembrane conductance regulator (CFTR) gene mutations influence phenotypic disease diversity. Biomarkers that are based on genomic information may not accurately represent the underlying mechanism of the disease as well as its lethal complications. Therefore, recent advancements in mass spectrometry (MS)-based proteomics may provide deep insights into CF mechanisms and cellular functions by examining alterations in the protein expression patterns from various samples of individuals with CF.AREAS COVERED: We present current developments in MS-based proteomics, its application, and findings in CF. In addition, the future roles of proteomics in finding diagnostic and prognostic novel biomarkers.EXPERT OPINION: Despite significant advances in MS-based proteomics, extensive research in a large cohort for identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers for CF disease is highly needed.PMID:37766616 | DOI:10.1080/14789450.2023.2258282