PubMed

J Microbiol Methods. 2023 Oct 18:106846. doi: 10.1016/j.mimet.2023.106846. Online ahead of print.ABSTRACTAcute ischaemic stroke (AIS) is a complex, systemic, pathological, and physiological process. Systemic inflammatory responses and disorders of the gut microbiome contribute to increased mortality and disability following AIS. We conducted 16S high-throughput sequencing and ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry-based non-targeted metabolomic analyses of the plasma from a Tibetan miniature pig middle cerebral artery occlusion (MCAO) model. A significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Actinobacteria were observed after the onset of AIS. Among the plasma metabolites, the levels of phospholipids and amino acids were considerably altered. Loading values and differential metabolite-bacterial group association analyses of the metabolome and microbiome indicated a correlation between the microbiome and metabolome of Tibetan miniature pigs after MCAO. Furthermore, significant changes were observed in the ABC transporter pathway and purine metabolism in the gut microbiome-plasma metabolome during the early stage of AIS. Kyoto Encyclopaedia of Genes and Genomes enrichment analysis showed that arginine, proline, and cyanoamino acid metabolism was upregulated while ABC transporter metabolism pathway and carbohydrate digestion and absorption were substantially downregulated. The results of this study suggest that AIS affects the gut microbiota and plasma metabolites in Tibetan miniature pigs and that faecal microbiota transplantation could be a potential therapeutic approach for AIS.PMID:37863204 | DOI:10.1016/j.mimet.2023.106846

Poult Sci. 2023 Sep 23;102(12):103118. doi: 10.1016/j.psj.2023.103118. Online ahead of print.ABSTRACTInosine monophosphate (IMP) plays a significant role in meat taste, yet the molecular mechanisms controlling IMP deposition in muscle tissues still require elucidation. The present study systematically and comprehensively explores the molecular network governing IMP deposition in different regions of Jingyuan chicken muscle. Two muscle groups, the breast and leg, were examined as test materials. Using nontargeted metabolomic sequencing, we screened and identified 20 metabolites that regulate IMP-specific deposition. We maintained regular author and institution formatting, used clear, objective, and value-neutral language, and avoided biased or emotional language. We followed a consistent footnote style and formatting features and used precise word choice with technical terms where appropriate. Out of these, 5 were identified as significant contributors to the regulation of IMP deposition. We explained technical term abbreviations when first used and ensured a logical flow of information with causal connections between statements. The results indicate that PGM1, a key enzyme involved in synthesis, is higher in the breast muscle compared to the leg muscle, which may provide an explanation for the increased deposition of IMP in the breast muscle. We aimed for a clear structure with logical progression, avoided filler words, and ensured grammatical correctness. The activity of key enzymes (PKM2, AK1, AMPD1) involved in this process was higher in the breast muscle than in the leg muscle. In the case of IMP degradation metabolism, the activity of its participating enzyme (PurH) was lower in the breast muscle than in the leg muscle. These findings suggest that the increased deposition of IMP in Jingyuan chickens' breast muscle may result from elevated metabolism and reduced catabolism of key metabolites. In summary, a metaomic strategy was utilized to assess the molecular network regulation mechanism of IMP-specific deposition in various segments of Jingyuan chicken. These findings provide insight into genetic improvement and molecular breeding of meat quality traits for top-notch broilers.PMID:37862870 | DOI:10.1016/j.psj.2023.103118

Nature. 2023 Oct 20. doi: 10.1038/s41586-023-06755-5. Online ahead of print.NO ABSTRACTPMID:37863963 | DOI:10.1038/s41586-023-06755-5

Nat Commun. 2023 Oct 20;14(1):6627. doi: 10.1038/s41467-023-42210-9.ABSTRACTToll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.PMID:37863913 | DOI:10.1038/s41467-023-42210-9

Environ Pollut. 2023 Oct 18:122777. doi: 10.1016/j.envpol.2023.122777. Online ahead of print.ABSTRACTThe aim of this study was to conduct transcriptomic, proteomic, and metabolomic analysis to provide a comprehensive view of plant response to tetracycline stress. Pumpkin seeds were cultured for 7 days without or with tetracycline at 10 mg/L. Pumpkin roots showed excessive growth inhibition, but not yet strong growth restraining in cotylendons. Tetracycline affected the abundance of metabolites related to flavonoid biosynthesis and amino acid metabolism. Main changes of metabolites in flavonoid biosynthesis were consistent with mRNA changes. Amino acid changes are mainly mediated by proteins or mRNAs. To be specific, tetracycline treatment increased the levels of rutin, caffeate, cinnamaldehyde, 4-hydroxycinnamic acid, ferulic acid, naringenin, apigenin, luteolin, (-)-epigallocatechin, astragalin, L-serine, and glutathione and the transcript levels related to these compounds; and decreased the levels of indole pyruvate, indole acetaldehyde, L-arginine, S-adenosylhomocysteine, L-glutamine, and gamma-glutamylcysteine and the transcript levels related to these compounds. Tetracycline treatment also increased the levels of oxoglutaric acid, L-glutamic acid, gamma-aminobutyric acid, and gamma-glutamylalanine and enzymes involved in their production; and decreased the levels of L-isoleucine, L-valine, and L-leucine and enzymes involved in their production. We elucidated several biological processes (e.g. phenylpropanoid/flavonoid biosynthesis pathways, amino acid metabolic pathways) that were altered by tetracycline, and provided a multi-omic perspective on the mechanisms underlying the response to tetracycline stress in pumpkin roots. We provide a useful reference for the development of environmental quality management methods.PMID:37863256 | DOI:10.1016/j.envpol.2023.122777

Cancer Cell. 2023 Oct 16:S1535-6108(23)00328-8. doi: 10.1016/j.ccell.2023.09.012. Online ahead of print.ABSTRACTTumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.PMID:37863066 | DOI:10.1016/j.ccell.2023.09.012

Phytomedicine. 2023 Oct 6;122:155122. doi: 10.1016/j.phymed.2023.155122. Online ahead of print.ABSTRACTBACKGROUND: Colchicine (COL) is a well-known plant-derived mitogenic toxin that has been widely applied for the treatment of immune system diseases and various cancers. However, its clinical use is severely limited by frequent occurrence of poisoning accidents, and the mechanism of COL poisoning is not clear yet.PURPOSE: The present study aimed to unveil how COL works as a toxin based on untargeted metabolomics analysis of animal models and clinical human case.METHODS: KM mice orally administered COL were used to establish poisoning models, and plasma samples were collected for untargeted metabolomics analysis. The data mining was performed to screen dose-dependent differences and disturbed metabolic pathways. The blood samples collected from clinical COL poisoning human case at various time points during treatment period were further analyzed to investigate the temporal changes in the metabolic disposition of COL in vivo and also verify the findings from mice. Finally, the expression of key pathways was evaluated by ELISA and Western blotting analysis.RESULTS: Histological examination demonstrated systemic toxicity of COL poisoning in mice. Metabolite profiling analysis of plasma samples from model mice and clinical case both revealed that COL poisoning could significantly disturb in vivo metabolism of amino acid and lipid metabolism by the FXR/AMPK signal pathway. Quantitative monitoring of the metabolic process of COL further demonstrated that it could be greatly ameliorated with the rapid metabolic transformation of COL in vivo, which thus may be an effective detoxification pathway for COL poisoning.CONCLUSION: The findings of the present study provided new insight into the molecular mechanism of COL poisoning, thus helpful for guiding reasonable application of this phytotoxin.PMID:37863002 | DOI:10.1016/j.phymed.2023.155122

Food Chem. 2023 Oct 14;436:137768. doi: 10.1016/j.foodchem.2023.137768. Online ahead of print.ABSTRACTThe accurate identification of tea grade is crucial to the quality control of tea. However, existing methods lack sufficient generalization ability in identifying tea grades due to the effect of temporal and spatial factors. In this study, we analyzed the effect of cultivar and altitude on EnshiYulu (ESYL) tea grades and established a robust model to evaluate their quality. Principal component analysis (PCA) revealed that differences in variety and elevation can mask grade differences. Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) was used for grade identification of samples from different altitudes. For ESYL tea samples above and below 800 m altitude, 75 and 35 grade differentiated metabolites were discovered, with 14 common differentiated metabolites. Based on reconstructed OPLS-DA models, the grades of multi-altitude sources ESYL were discriminated with a rate > 85%. These results demonstrate the potential of a grade discrimination model based on common differential metabolites, which exhibits generalization ability.PMID:37862999 | DOI:10.1016/j.foodchem.2023.137768

Mar Environ Res. 2023 Oct 16;192:106231. doi: 10.1016/j.marenvres.2023.106231. Online ahead of print.ABSTRACTLife on tidal coasts presents physiological major challenges for sessile species. Fluctuations in oxygen and temperature can affect bioenergetics and modulate metabolism and redox balance, but their combined effects are not well understood. We investigated the effects of intermittent hypoxia (12h/12h) in combination with different temperature regimes (normal (15 °C), elevated (30 °C) and fluctuating (15 °C water/30 °C air)) on the Pacific oyster Crassostrea (Magallana) gigas. Fluctuating temperature led to energetic costly metabolic rearrangements and accumulation of proteins in oyster tissues. Elevated temperature led to high (60%) mortality and oxidative damage in survivors. Normal temperature had no major negative effects but caused metabolic shifts. Our study shows high plasticity of oyster metabolism in response to oxygen and temperature fluctuations and indicates that metabolic adjustments to oxygen deficiency are strongly modulated by the ambient temperature. Co-exposure to constant elevated temperature and intermittent hypoxia demonstrates the limits of this adaptive metabolic plasticity.PMID:37862760 | DOI:10.1016/j.marenvres.2023.106231

Ecotoxicol Environ Saf. 2023 Oct 18;266:115607. doi: 10.1016/j.ecoenv.2023.115607. Online ahead of print.ABSTRACTTsinling lenok trout (Brachymystax lenok tsinlingensis Li) is a species of cold-water salmon that faces serious challenges due to global warming. High temperature stress has been found to damage the gut integrity of cold-water fish, impacting their growth and immunity. However, limited research exists on the causal relationship between gut microbial disturbance and metabolic dysfunction in cold-water fish induced by high temperature stress. To address this gap, we conducted a study to investigate the effects of high temperature stress (24 °C) on the gut tissue structure, antioxidant capacity, gut microorganisms, and metabolome reactions of tsinling lenok trout. Our analysis using 16 S rDNA gene sequencing revealed significant changes in the gut microbial composition and metabolic profile. Specifically, the abundance of Firmicutes and Gemmatimonadetes decreased significantly with increasing temperature, while the abundance of Bacteroidetes increased significantly. Metabolic analysis revealed a significant decrease in the abundance of glutathione, which is synthesized from glutamate and glycine, under high temperature stress. Additionally, there was a notable reduction in the levels of adenosine, inosine, xanthine, guanosine, and deoxyguanosine, which are essential for DNA/RNA synthesis. Conversely, there was a significant increase in the abundance of D-glucose 6 P. Furthermore, high temperature stress adversely affects intestinal structure and barrier function. Our findings provide valuable insights into the mechanism of high temperature stress in cold-water fish and serve as a foundation for future research aimed at mitigating the decline in production performance caused by such stress.PMID:37862746 | DOI:10.1016/j.ecoenv.2023.115607

Diabetes. 2023 Oct 20:db230142. doi: 10.2337/db23-0142. Online ahead of print.ABSTRACTWe investigated the link between enhancement of insulin sensitivity (SI) (by hyperinsulinemiceuglycemic clamp) and muscle metabolites following 12-weeks of aerobic (high-intensity interval training, HIIT), resistance (RT), or combined (CT) exercise training in 52 lean healthy people. Muscle RNA-sequencing revealed a significant association between SI following both HIIT and RT and the branched chain amino acid (BCAA) metabolic pathway. Concurrent to increased expression and activity of branched chain ketoacid dehydrogenase enzyme, many muscle amino metabolites including BCAAs, glutamate, phenylalanine, aspartate, asparagine, methionine, and GABA increased by HIIT, supporting substantial impact of HIIT on amino acid metabolism. Short-chain C3 and C5 acylcarnitines were reduced in muscle by all three training modes, but unlike RT, both HIIT and CT increased TCA metabolites and cardiolipins, supporting greater mitochondrial activity by aerobic training. Conversely, RT and CT increased more plasma membrane phospholipids than HIIT, suggesting a resistance exercise effect on cellular membrane protection against environmental damage. Sex and age contributed modestly to the exerciseinduced changes in metabolites and their association to cardiometabolic parameters. Integrated transcriptomic and metabolomic analyses suggest various clusters of genes and metabolites are involved in distinct effects of HIIT, RT, and CT. These distinct metabolic signatures of different exercise modes independently link each type of exercise training to improved SI and cardiometabolic risk.PMID:37862464 | DOI:10.2337/db23-0142

Proc Natl Acad Sci U S A. 2023 Oct 24;120(43):e2301733120. doi: 10.1073/pnas.2301733120. Epub 2023 Oct 20.ABSTRACTRetinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms involved in the digestion and recycling of POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play an essential role, this was never investigated. Here, we show that global as well as RPE-selective loss of peroxisomal β-oxidation in multifunctional protein 2 (MFP2) knockout mice impairs the digestive function of lysosomes in the RPE at a very early age, followed by RPE degeneration. This was accompanied by prolonged mammalian target of rapamycin activation, lipid deregulation, and mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The RPE degeneration caused secondary photoreceptor death. Notably, the deterioration of the RPE did not occur in an Mfp2/rd1 mutant mouse line, characterized by absent POS shedding. Our findings prove that peroxisomal β-oxidation in the RPE is essential for handling the polyunsaturated fatty acids present in ingested POS and shed light on retinopathy in patients with peroxisomal disorders. Our data also have implications for gene therapy development as they highlight the importance of targeting the RPE in addition to the photoreceptor cells.PMID:37862382 | DOI:10.1073/pnas.2301733120

Chem Res Toxicol. 2023 Oct 20. doi: 10.1021/acs.chemrestox.3c00209. Online ahead of print.ABSTRACTExogenous compounds and metabolites derived from therapeutics, microbiota, or environmental exposures directly interact with endogenous metabolic pathways, influencing disease pathogenesis and modulating outcomes of clinical interventions. With few spectral library references, the identification of covalently modified biomolecules, secondary metabolites, and xenobiotics is a challenging task using global metabolomics profiling approaches. Numerous liquid chromatography-coupled mass spectrometry (LC-MS) small molecule analytical workflows have been developed to curate global profiling experiments for specific compound groups of interest. These workflows exploit shared structural moiety, functional groups, or elemental composition to discover novel and undescribed compounds through nontargeted small molecule discovery pipelines. This Review introduces the concept of structure-oriented LC-MS discovery methodology and aims to highlight common approaches employed for the detection and characterization of covalently modified biomolecules, secondary metabolites, and xenobiotics. These approaches represent a combination of instrument-dependent and computational techniques to rapidly curate global profiling experiments to detect putative ions of interest based on fragmentation patterns, predictable phase I or phase II metabolic transformations, or rare elemental composition. Application of these methods is explored for the detection and identification of novel and undescribed biomolecules relevant to the fields of toxicology, pharmacology, and drug discovery. Continued advances in these methods expand the capacity for selective compound discovery and characterization that promise remarkable insights into the molecular interactions of exogenous chemicals with host biochemical pathways.PMID:37862059 | DOI:10.1021/acs.chemrestox.3c00209

Chembiochem. 2023 Oct 20:e202300572. doi: 10.1002/cbic.202300572. Online ahead of print.ABSTRACTBiomanufacturing via microorganisms relies on carbon substrates for molecular feedstocks and a source of energy to carry out enzymatic reactions. This creates metabolic bottlenecks and lowers the efficiency for substrate conversion. Nanoparticle biohybridization with proteins and whole cell surfaces can bypass the need for redox cofactor regeneration for improved secondary metabolite production in a non-specific manner. Here we propose using nanobiohybrid organisms (Nanorgs), intracellular protein-nanoparticle hybrids formed through the spontaneous coupling of core-shell quantum dots (QDs) with histidine-tagged enzymes in non-photosynthetic bacteria, for light-mediated control of bacterial metabolism. This proved to eliminate metabolic constrictions and replace glucose with light as the source of energy in Escherichia coli, with an increase of growth by 1.7-fold in 75 % reduced nutrient media. Metabolomic tracking through carbon isotope labeling confirmed flux shunting through targeted pathways, with accumulation of metabolites downstream of respective targets. Finally, application of Nanorgs with the Ehrlich pathway improved isobutanol titers/yield by 3.9-fold in 75 % less carbon source from E. coli strains with no genetic alterations. These results demonstrate the promise of Nanorgs for metabolic engineering and low-cost biomanufacturing.PMID:37861981 | DOI:10.1002/cbic.202300572

Chin J Integr Med. 2023 Oct 20. doi: 10.1007/s11655-023-3706-0. Online ahead of print.ABSTRACTOBJECTIVE: To investigate the anti-liver cancer effects and aspartic acid (Asp)-related action mechanism of Euphorbia fischeriana Steud. (Lang Du, LD).METHODS: The mice model of liver cancer was established by injection of H22 cells. After 5 days, mice were randomly divided into model group, sorafenib group (20 mg/kg), LD high-dose (LDH, 1.36 g/kg) group, LD medium-dose (LDM, 0.68 g/kg) group, and LD low-dose (LDL, 0.34 g/kg) group, 10 mice each group. Drugs were intragastrically administered to the mice once daily for 10 days, respectively. Body weight, tumor size and tumor weight were recorded. Hepatic index was calculated. Pathological changes of liver cancer tissues were evaluated by hematoxylin and eosin staining and TUNEL staining. Liquid chromatography-mass spectrometer was used to analyze different metabolites between the model and LDH groups.RESULTS: After LD treatment, tumor weight, tumor size and hepatic index were reduced compared with the model group. Necrocytosis and karyorrhexis of tumor cells were found. Moreover, 61 differential metabolites (18 up-regulated, 43 down-regulated) were affirmed and 20 pathways of KEGG (P<0.05) were gotten. In addition, Bel-7402, HepG2 and H22 cell viabilities were significantly increased after adding Asp into the medium. And then, the cell proliferation effect induced by Asp was ameliorated by LD.CONCLUSION: The anti-liver cancer efficacy of LD extract was validated in H22 mice model, and inhibition of Asp level might be the underlying mechanism.PMID:37861961 | DOI:10.1007/s11655-023-3706-0

J Agric Food Chem. 2023 Oct 20. doi: 10.1021/acs.jafc.3c02337. Online ahead of print.ABSTRACTGreen pea hull is a processing byproduct of green pea and rich in polyphenols. Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by accumulation of lipids in the liver for which there are no effective treatment strategies. Here, a mouse model of NAFLD induced by a DSS+high-fat diet (HFD) was established to investigate the effect of green pea hull polyphenol extract (EGPH). The results show that EGPH relief of NAFLD was a combined effect, including reducing hepatic fat accumulation, improving antioxidant activity and blood lipid metabolism, and maintaining glucose homeostasis. Increased intestinal permeability aggravated NAFLD. Combined metabolomics and transcriptomic analysis showed that vitamin B6 is the key target substance for EGPH to alleviate NAFLD, and it may be the intestinal flora metabolite. After EGPH intervention, the level of vitamin B6 in mice was significantly increased, and more than 60% in the blood enters the liver, which activated or inhibited PPAR and TLR4/NF-κB signaling pathways to relieve NAFLD. Our research could be a win-win for expanding the use of green pea hull and the search for NAFLD prophylactic drugs.PMID:37861789 | DOI:10.1021/acs.jafc.3c02337

J Agric Food Chem. 2023 Oct 20. doi: 10.1021/acs.jafc.3c00897. Online ahead of print.ABSTRACTAlpha-glycosyl isoquercitrin (AGIQ), composed of isoquercitrin and glycosylated quercetin, has multiple biological effects. Here, we further examined the influence of AGIQ on brain function and provided its potential mechanism. Male C57BL/6 mice were treated with 0, 0.005, and 0.05% AGIQ in drinking water for 4 weeks prior to behavioral testing. Behavior tests showed that 0.05% AGIQ treatment significantly improved learning and memory function without affecting emotion. In the hippocampus, the gene expression of antioxidative defense enzymes was upregulated after 0.05% AGIQ treatment. In contrast, AGIQ caused significant alterations in the microbial abundance of genera Akkermansia, Bifidobacterium, and Alistipes associated with memory function. Metabolomics analysis identified that taurine concentration was significantly increased in serum and hippocampus from AGIQ-treated mice. The correlation analysis suggested that elevated serum taurine levels were closely related to the abundance of Akkermansia, indicating the underlying crosstalk of gut microbiota and serum metabolites. In vitro fecal culture further demonstrated that AGIQ could increase the level of Akkermansia. Taurine could exert antioxidant activity in SH-SY5Y neuroblastoma cell lines in vitro. Finally, vancomycin-induced alterations of gut microbiota attenuated the taurine increases in the serum and the antioxidant gene level in the hippocampus by AGIQ. Taken together, it is likely that AGIQ could increase genus Akkermansia abundance and ultimately increase taurine levels in serum and hippocampus to improve learning and memory function, relying on the gut microbiota-blood-brain axis. Our results supply a new view for understanding effects of AGIQ on brain function.PMID:37861708 | DOI:10.1021/acs.jafc.3c00897

Medicine (Baltimore). 2023 Oct 20;102(42):e35675. doi: 10.1097/MD.0000000000035675.ABSTRACTBACKGROUND: Clinacanthus nutans (for abbreviation thereafter) is often used as medicine in the form of fresh juice in the folk to treat many kinds of cancers, including renal cell carcinoma (RCC). It is speculated that its active ingredient may have heat sensitivity, but there are currently no reports on this aspect. Therefore, based on the folk application for fresh juice of C nutans, this study used metabonomics and network pharmacology to explore the material basis and mechanism of action of C nutans against RCC.METHODS: Firstly, untargeted metabolomics profiling was performed by Liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry to screen the metabolites down-regulated by heat in the extract of C nutans. Secondly, we collected the targets of metabolites in the Swiss Target Prediction platform. In addition, the targets of RCC were obtained in the GeneCards database. The "component-target-disease" network was established by Cytoscape3.9.0 software. Then we constructed a protein-protein interaction network in the STRING network platform to screen core targets. The gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis of core targets were carried out to predict the relevant pathway of C nutans in the treatment of RCC. Finally, the molecular docking verification of the core targets were carried out.RESULTS: In this study, 35 potential active ingredients and 125 potential targets were obtained. And the core targets were Cellular tumor antigen p53, Signal transducer and activator of transcription 3, and so on. Then, 48 biological processes, 30 cell components, and 36 molecular functions were obtained by gene ontology enrichment analysis. Besides, 44 pathways were obtained by Kyoto encyclopedia of genes and genomes enrichment analysis, including Pathway in cancer, PI3K-Akt signal pathway, P53 signal pathway, and so on. The docking model between the core target and its corresponding components was stable.CONCLUSION: This research is based on the folk application of C nutans, showed its potential active ingredients by metabonomics, and predicted the potential mechanism of C nutans in the treatment of RCC by network pharmacology. It provides new references for follow-up research and new drug development.PMID:37861516 | DOI:10.1097/MD.0000000000035675

Environ Toxicol Chem. 2023 Oct 20. doi: 10.1002/etc.5774. Online ahead of print.ABSTRACTHigh levels of 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), which is a substitute for perfluorooctane sulfonate (PFOS), are detected in various environmental matrices, wildlife and humans. F-53B has received increased attention due to its potential risk to ecosystems. However, its toxicity in the soil organisms remains unclear. In this study, a comparative investigation was conducted on the toxicities of F-53B and PFOS to the earthworm Eisenia. fetida. F-53B was significantly more acutely toxic to earthworms than PFOS with LC50s of 1.43 and 1.83 mmol/kg dry soil (~816 and 984 mg/kg dry soil), respectively. Although both F-53B and PFOS, at 0.4 mmol/kg dry soil (= 228 and 215 mg/kg dry soil) caused oxidative stress in earthworms, as evidenced by increased superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities as well as malondialdehyde (MDA) level, the stress caused by F-53B was higher than that by PFOS. In the transcriptomic and metabolomic studies, negative effects of PFOS and F-53B were observed on several metabolic processes in earthworms, including protein digestion and amino acid absorption, lipid metabolism, and the immune response. Compared to PFOS, F-53B exhibited a weaker disruption of lipid metabolism, comparable potency for toxicity to the immune response, and a stronger potency in the extracellular matrix (ECM) destruction along with apoptosis and ferroptosis induction. Hence, our data suggest that F-53B is more toxic than PFOS to earthworms. The findings provide some new insights into the potential toxicity of F-53B to soil organisms.PMID:37861387 | DOI:10.1002/etc.5774

J Virol. 2023 Oct 20:e0119423. doi: 10.1128/jvi.01194-23. Online ahead of print.ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to fatal outcomes for subgroups of patients with pre-existing co-morbidities. We previously reported a significant association between high expression levels of a cancer stem cell protein, doublecortin-like kinase 1 (DCLK1), in the lungs and macrophages of SARS-CoV-2-infected patients and the severity of coronavirus disease 2019 (COVID-19). Herein, we demonstrate a pivotal role of DCLK1 in the viral replication cycle and the dysregulation of cell signaling that contributes to SARS-CoV-2 pathology. Through CRISPR/Cas9-mediated DCLK1 knockout and inhibition of its kinase using a small molecule kinase inhibitor of DCLK1 (DCLK1-IN-1), we effectively blocked the viral replication-transcription processes. Furthermore, DCLK1 inhibition reversed the virus-induced positive and/or negative modulation of the cellular interactome and signaling pathways. We observed a decrease in the phosphorylation of a serine/arginine-rich region in the nucleocapsid protein, which regulates viral replication and packaging, upon treatment with DCLK1-IN-1. In a murine model of COVID-19, intranasal inoculation of SARS-CoV-2 induced severe lung pathology accompanied by increased DCLK1 expression, high titers of viral genomic and subgenomic RNAs, and elevated levels of inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha). Remarkably, treatment of infected mice with DCLK1-IN-1 reduced viral RNAs, downregulated inflammatory cytokines, restored normal cell signaling pathways, and improved lung pathology. In conclusion, our findings underscore the crucial role of DCLK1 in SARS-CoV-2 pathology and suggest it as a promising target for therapeutic intervention. IMPORTANCE Severe COVID-19 and post-acute sequelae often afflict patients with underlying co-morbidities. There is a pressing need for highly effective treatment, particularly in light of the emergence of SARS-CoV-2 variants. In a previous study, we demonstrated that DCLK1, a protein associated with cancer stem cells, is highly expressed in the lungs of COVID-19 patients and enhances viral production and hyperinflammatory responses. In this study, we report the pivotal role of DCLK1-regulated mechanisms in driving SARS-CoV-2 replication-transcription processes and pathogenic signaling. Notably, pharmacological inhibition of DCLK1 kinase during SARS-CoV-2 effectively impedes these processes and counteracts virus-induced alternations in global cell signaling. These findings hold significant potential for immediate application in treating COVID-19.PMID:37861336 | DOI:10.1128/jvi.01194-23