PubMed

Zhongguo Zhong Yao Za Zhi. 2024 Apr;49(7):1774-1784. doi: 10.19540/j.cnki.cjcmm.20240115.701.ABSTRACTThe study aims to investigate the effects and potential mechanism of raw and processed Aconitum pendulum Busch on rheumatoid arthritis(RA) and analyze their toxicity attenuating and efficacy retaining effects. The bovine type Ⅱ collagen-induced arthritis(CIA) rat model was established. The weight, cardiac index, immune organ index, and arthritis index of the rats were recorded and calculated after administration. ELISA was used to measure the expressions of creatine kinase(CK), cardiac troponin T(cTnT), and multiple factors. The pathological morphological changes in heart tissue and ankle joint tissue were observed by hematoxylin-eosin staining. Connexin 43(Cx43) expression in the hearts of CIA rats was detected via immunohistochemical method. The levels of endogenous metabolites in the serum of CIA rats were detected by UPLC-Q-TOF-MS. Potential biomarkers were screened, and related metabolic pathways were analyzed. The results showed that raw A. pendulum could induce local myocardial fiber degeneration and necrosis, increase the cardiac index, decrease the average positive area of Cx43 expression significantly, and increase the expressions of CK and cTnT in cardiac tissue of rats. Meanwhile, raw A. pendulum could decrease the immune organ index, interleukin-6(IL-6), and other inflammatory cytokine contents in the serum and improve the damaged synovium and joint surface of CIA rats, with toxicity and efficacy coexisting. The Zanba stir-fired A. pendulum could reduce the index of arthritis, immune organ index, and content of IL-6 and inflammatory cytokines in serum and improve damaged synovium and joint surface of CIA rats with no obvious cardiac toxicity, showing significant toxicity attenuating and efficacy retaining effects. A total of 19 potential biomarkers of raw A. pendulum and Zanba stir-fired A. pendulum against RA were screened by serum metabolomics, including glycerophospholipid metabolism, glycine, serine, and threonine metabolism, arginine and proline metabolism, and steroid hormone synthesis. In conclusion, Xizang medicine A. pendulum is preventive and curative for RA. Raw A. pendulum has certain cardiotoxicity, and Zanba stir-fired A. pendulum has significant toxicity attenuating and efficacy retaining effects. The anti-RA mechanism may be related to the regulation of glycerophospholipid and amino acid metabolism.PMID:38812189 | DOI:10.19540/j.cnki.cjcmm.20240115.701

Zhongguo Zhong Yao Za Zhi. 2024 Apr;49(7):1749-1761. doi: 10.19540/j.cnki.cjcmm.20231212.702.ABSTRACTShenling Baizhu San(SLBZS) is a commonly used medicine for the treatment of ulcerative colitis(UC). This study aims to explore the mechanism of SLBZS in treating UC by using colonic metabolomics and network pharmacology. BALB/c mice were randomly divided into four groups: a blank group, a model group, an SLBZS group, and a sulfasalazine group. UPLC-Q-TOF-MS/MS technology was utilized to analyze the metabolic profiles of colonic tissue in mice, and differential metabolites and related metabolic pathways were screened. Based on the online database, active ingredients, action targets, and UC disease targets of SLBZS were screened. The protein-protein interaction(PPI) network of core targets of SLBZS in treating UC was constructed using STRING and Cytoscape 3.9.1. Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed using the DAVID database. A "metabolite-reaction-enzyme-gene" network was constructed to conduct a combined analysis of metabolomics and network pharmacology. SLBZS reversed the levels of 25 metabolites involved in various pathways such as D-glutamine and D-glutamate metabolism, caffeine metabolism, sphingolipid metabolism, arginine biosynthesis, lysine degradation, alanine, aspartate, and glutamate metabolism, glycerophospholipid metabolism, and pyrimidine metabolism in UC colonic tissue. 47 core targets of SLBZS in treating UC were involved in pathways including the MAPK signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, lipid and atherosclerosis, inflammatory bowel disease, and Th17 cell differentiation. Integrated analysis showed that glycerophospholipid metabolism and pyrimidine metabolism were key metabolic pathways in the treatment of UC with SLBZS. The results suggested that SLBZS improved colonic mucosal morphology by regulating colonic metabolites, down-regulated the expression of inflammation-related core target genes to reduce inflammation levels, and alleviated lipid metabolism disorders, thereby exerting a therapeutic effect on UC.PMID:38812187 | DOI:10.19540/j.cnki.cjcmm.20231212.702

Zhongguo Zhong Yao Za Zhi. 2024 May;49(10):2818-2827. doi: 10.19540/j.cnki.cjcmm.20240206.501.ABSTRACTThis study aims to explore the potential metabolic pathways and targets of Puerariae Thomsonii Radix in the clinical treatment of mild dyslipidemia. UPLC-Q-TOF-MS and EASY-nLC-timsTOF-Pro2 were employed to perform metabolomic and proteomic analyses of the plasma samples collected from the patients with mild dyslipidemia at baseline and after 12 weeks of treatment with Puerariae Thomsonii Radix. The multivariate statistical analysis was carried out for comparison between groups, and the correlation analysis was performed for the metabolites and proteins closely related to mild dyslipidemia with the blood lipid indexes. The possible pathways and targets for mitigating mild dyslipidemia were screened out by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. The results showed that 56 differential metabolites and 78 differential proteins in the plasma of patients were associated with Puerariae Thomsonii Radix treatment. In addition, changes were detected for the proteins or metabolites(ApoB-100, 9,10-DHOME, GAPDH, PGK1, PGAM1, ENO1, etc.) involved in lipoprotein, lipid, and glucose metabolism and the proteins or metabolites(oxidized phospholipid, PLA2G7, LTA4H, etc.) related to inflammation and oxidative stress. Puerariae Thomsonii Radix may down-regulate the overexpression of ApoB-100, activate the peroxisome proliferator-activated receptor α/γ(PPARα/γ), promote the catabolism of fat and glycerol, and alleviate the oxidative stress mediated by oxidized phospholipids and leukotriene B4(LTB4) in the treatment of mild dyslipidemia.PMID:38812181 | DOI:10.19540/j.cnki.cjcmm.20240206.501

Zhongguo Zhong Yao Za Zhi. 2024 May;49(10):2734-2744. doi: 10.19540/j.cnki.cjcmm.20240219.303.ABSTRACTPrunella vulgaris, aptly named for its withering at the summer solstice, displays significant variation in quality arising from differing harvest time. However, research on the chemical composition changes of its spikes at various stages is limited, and the specific metabolites remain unclear. In order to elucidate the metabolites and metabolic pathways of the spikes of P. vulgaris, the current study deployed ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) and targeted metabolomics to characterize the compound variability in the spikes of P. vulgaris across different periods. Multivariate statistical techniques such as principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were used to identify the differences in metabolites, and relevant metabolic pathways were analyzed. A total of 602 metabolites were identified by metabolomics, of which organic acids and their derivatives were the most abundant, followed by flavonoids. Multiple differential metabolites, including p-hydroxybenzoic acids and gallic acids were identified based on variable importance in projection(VIP)>1 and P<0.05. The results of enrichment analysis suggested that isoflavonoids biosynthesis, aminobenzoate degradation, benzoate degradation, anthocyanins biosynthesis, metabolic pathways, microbial metabolism in different environments, secondary plant metabolite biosynthesis, tryptophan metabolism, and phenylpropanoid synthesis were the main metabolic pathways. These results intend to elucidate the dynamic changes of differential metabolites of P. vulgaris and provide a theoretical basis for further study of the harvesting mechanism of spikes of P. vulgaris.PMID:38812174 | DOI:10.19540/j.cnki.cjcmm.20240219.303

Zhongguo Zhong Yao Za Zhi. 2024 May;49(10):2666-2679. doi: 10.19540/j.cnki.cjcmm.20240211.101.ABSTRACTThis study aims to explore the molecular regulatory mechanism of the differential accumulation of flavonoids between 'Xianglei' and the wild type of Lonicera macranthoides. The flowers, stems, and leaves of the two varieties of L. macranthoides were collected. Ultra-performance liquid chromatography-mass spectrometry(UPLC-MS) and high-throughput sequencing(RNA-seq) were employed to screen out the differential flavonoids, key differentially expressed genes(DEGs) and transcription factors(TFs). Fourteen DEGs were randomly selected for verification by qRT-PCR. The results showed that a total of 17 differential flavonoids were obtained, including naringin chalcone, apigenin, and quercetin. The transcriptomic analysis predicted 19 DEGs associated with flavonoids, including 2 genes encoding chitin synthase(CHS) and 3 genes encoding chalcone isomerase(CHI). The regulatory network analysis and weighted gene co-expression network analysis(WGCNA) screen out the key enzyme genes CHS1, FLS1, and HCT regulating the accumulation of flavonoids. MYB12 and LBD4 may be involved in the biosynthesis of flavonoids by regulating the expression of key enzyme genes CHS1, FLS1, and HCT. The qRT-PCR and RNA-seq results were similar regarding the expression patterns of the 14 randomly selected DEGs. This study preliminarily analyzed the transcriptional regulatory mechanism for the differential accumulation of flavonoids in the two varieties of L. macranthoides and laid a foundation for further elucidating the regulatory effects of key enzyme genes and TFs on the accumulation of flavonoids.PMID:38812167 | DOI:10.19540/j.cnki.cjcmm.20240211.101

Zhongguo Zhong Yao Za Zhi. 2024 May;49(10):2575-2584. doi: 10.19540/j.cnki.cjcmm.20231107.401.ABSTRACTAsari Radix et Rhizoma is a common drug for relieving exterior syndrome in clinics, but its toxicity limits its use. In this study, the mechanism of hepatic damage of Asari Radix et Rhizoma was studied by network pharmacology and metabolomics. The hepatic damage-related dataset, namely GSE54257 was downloaded from the GEO database. The Limma package was used to analyze the differentially expressed genes in the dataset GSE54257. Toxic components and target genes of Asari Radix et Rhizoma were screened by TCMSP, ECTM, and TOXNET. The hepatic damage target genes of Asari Radix et Rhizoma were obtained by mapping with the differentially expressed gene of GSE54257, and a PPI network was constructed. GO and KEGG enrichment analysis of target genes were performed, and a "miRNA-target gene-signal pathway" network was drawn with upstream miRNA information. Thirty rats were divided into a blank group, a high-dose Asari Radix et Rhizoma group, and a low-dose Asari Radix et Rhizoma group, which were administered once a day. After continuous administration for 28 days, liver function indexes and liver pathological changes were detected. Five liver tissue samples were randomly collected from the blank group and high-dose Asari Radix et Rhizoma group, and small molecule metabolites were analyzed by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS). The orthogonal partial least squares-discriminant analysis(OPLS-DA) method was used to screen differential metabolites, and enrichment analysis, correlation analysis, and cluster analysis were conducted for differential metabolites. Finally, the MetaboAnalyst platform was used to conduct pathway enrichment analysis for differential metabolites. It was found that there were 14 toxic components in Asari Radix et Rhizoma, corresponding to 37 target genes, and 12 genes related to liver toxicity of Asari Radix et Rhizoma were obtained by mapping to differentially expressed genes of GSE54257. The animal test results showed that Asari Radix et Rhizoma could significantly increase the liver function index, reduce the activity of the free radical scavenging enzyme, change the liver oxidative stress level, and induce lipid peroxidation damage in rats. The results of untargeted metabolomics analysis showed that compared with the blank group, nine metabolites were up-regulated, and 16 metabolites were down-regulated in the liver tissue of the Asari Radix et Rhizoma group. These 25 metabolites had strong correlations and good clustering. Pathway enrichment analysis showed that these differential metabolites and the 12 hepatotoxic target genes of Asari Radix et Rhizoma were mainly involved in purine metabolism, as well as the biosynthesis and metabolism of valine, leucine, glycine, serine, and threonine. The study confirmed that the hepatica damage effect of Asari Radix et Rhizoma was the result of multi-component, multi-target, and multi-signaling pathways, and its mechanism may be related to inhibiting nucleotide synthesis and affecting protein metabolism.PMID:38812158 | DOI:10.19540/j.cnki.cjcmm.20231107.401

Zhongguo Zhong Yao Za Zhi. 2024 May;49(10):2557-2565. doi: 10.19540/j.cnki.cjcmm.20231213.402.ABSTRACTThis study aims to explore the potential mechanism of Biejiajian Pills in the treatment of non-alcoholic steatohepatitis(NASH) based on lipidomics. A mouse model of NASH was induced by high-fat/high cholesterol diet, and the mice of the normal group were fed with a normal diet. The therapeutic efficacy of Biejiajian Pills against NASH was evaluated through biochemical indexes in both of serum and liver, as well as the hepatic histopathology. Lipid metabolites in the liver were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS)-based lipidomics. Then the partial least-squares discriminant analysis, t-test and receiver operating characteristic curve analysis were performed to screen the differential lipid metabolites and the main biomarkers. The proteins and genes involved in the lipid metabolism and inflammatory response were detected by Western blot and qPCR. The results demonstrated that Biejiajian Pills notably lowered the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) in the serum and the levels of triglyceride(TG) and total cholesterol(TC) in the liver tissue. In addition, Biejiajian Pills alleviated the lipid accumulation, hepatocyte ballooning, and liver fibrosis. Lipidomics revealed that Biejiajian Pills regulated the content of 11 biomarkers including phosphatidyl choline(PC), phosphatidyl ethanolamine(PE), sphingomyelin(SM), and ceramide(Cer). The results of Western blot and qPCR demonstrated that Biejiajian Pills regulated the expression of sterol regulatory element-binding protein 1(SREBP1), peroxisome proliferator-activated receptor gamma(PPARγ) and phospho-AMP-activated protein kinase(p-AMPK), and the mRNA level of fatty acid translocase 36 gene(Cd36), Pparγ, cardiolipin synthase 1 gene(Crls1), and phospholipase Cβ2 gene(Plcβ2). Furthermore, Biejiajian Pills displayed inhibitory effects on phospho-p38 MAPK(p-p38 MAPK) and phospho-ERK1/2(p-ERK1/2) and the mRNA levels of interleukin-6 gene(Il-6), interleukin-1β gene(Il-1β) and tumor necrosis factor-α gene(Tnf-α). In conclusion, Biejiajian Pills could alleviate the lipid metabolism disorders and regulate the expression of SREBP1, PPARγ, and p-AMPK and the mRNA levels of pro-inflammatory cytokines.PMID:38812156 | DOI:10.19540/j.cnki.cjcmm.20231213.402

Zhongguo Zhong Yao Za Zhi. 2024 May;49(9):2393-2401. doi: 10.19540/j.cnki.cjcmm.20240207.101.ABSTRACTRhei Radix et Rhizoma is common traditional Chinese medicine with multiple original plants. The content and proportion of the active components in Rhei Radix et Rhizoma from different plant species were compared to accurately evaluate the medicine qua-lity and provide a theoretical basis for precise use of this medicine in clinical practice. In this study, fresh Rhei Radix et Rhizoma samples were collected from the four-year-old plants of Rheum palmatum, R. tanguticum, and R. officinale. The relative content of 220 anthraquinones, anthrones, and tannins in the samples were determined by pseudo-targeted metabolomics, and the differential components were screened by multivariate statistical methods. The principal component analysis classified the samples into three clusters according to the original plants. The orthogonal partial least squares-discriminant analysis(OPLS-DA) screened out 117 differential components, including 8 free anthraquinones, 18 anthraquinone glycosides, 80 anthrones, and 11 tannins. Twenty-eight components had the highest content in R. tanguticum, mainly including sennosides, anthraquinone glycosides, and procyanidins. Thirty-five components showed the highest content in R. officinale, mainly including free anthraquinones and catechines. Fifty-four components showed the highest content in R. palmatum, mainly including dianthrones, while the structures of most of them cannot be determined temporarily. The content distribution of differential components in the three original plants indicates that R. tanguticum has the strongest effect of purging, while R. officinale has the strongest effect of clearing heat and purging fire, and both have stronger effects of resolvong stasis and dredging meridians than R. palmatum.PMID:38812140 | DOI:10.19540/j.cnki.cjcmm.20240207.101

Clin Transl Med. 2024 Jun;14(6):e1696. doi: 10.1002/ctm2.1696.ABSTRACTThe spatiotemporal heterogeneity of neurons, circuits and regulators is being uncovered at a single-cell level, from single-cell gene expression to functional regulations. The classifications, architectonics and functional communications amongst neural cells and circuits within the brain can be clearly delineated using single-cell multiomics and transomics. This Editorial highlights the spatiotemporal heterogeneity of neurons and circuits as well as regulators, initiates the translation of neuronal diversity and spatial organisation at single-cell levels into clinical considerations, and enables the discovery and development of new therapies for neurological diseases. It is predicted that single-cell and spatial multiomics will be integrated with metabolomic profiles and corresponding gene epigenetic modifications. The interactions amongst DNAs, RNAs and proteins in a cell provide details of intracellular functional regulations and new opportunities for the translation of temporospatial diversity of neural cell subtypes/states into clinical practice. The application of single-cell multiomics with four-dimensional genome to the human pathological brain will lead us to a new milestone of the diagnosis and treatment.PMID:38812092 | DOI:10.1002/ctm2.1696

Mol Cancer. 2024 May 29;23(1):114. doi: 10.1186/s12943-024-02022-x.ABSTRACTBACKGROUND: Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood.METHODS: We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment.RESULTS: Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth.CONCLUSIONS: Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.PMID:38811984 | DOI:10.1186/s12943-024-02022-x

BMC Plant Biol. 2024 May 29;24(1):470. doi: 10.1186/s12870-024-05187-1.ABSTRACTRing rot, caused by Botryosphaeria dothidea, is an important fungal disease of pear fruit during postharvest storage. Melatonin, as a plant growth regulator, plays an important role in enhancing the stress resistance of pear fruits. It enhances the resistance of pear fruits to ring rot by enhancing their antioxidant capacity. However, the underlying mechanism remains unclear. In this study, we examined the effect of melatonin on the growth of B. dothidea. Results showed that melatonin did not limit the growth of B. dothidea during in vitro culture. However, metabolomics and transcriptomics analyses of 'Whangkeumbae' pear (Pyrus pyrifolia) revealed that melatonin increased the activity of antioxidant enzymes, including peroxidase (POD), superoxide dismutase (SOD), and polyphenol oxidase (PPO), in the fruit and activated the phenylpropanoid metabolic pathway to improve fruit resistance. Furthermore, melatonin treatment significantly increased the contents of jasmonic acid and phlorizin in pear fruit, both of which could improve disease resistance. Jasmonic acid regulates melatonin synthesis and can also promote phlorizin synthesis, ultimately improving the resistance of pear fruit to ring rot. In summary, the interaction between melatonin and jasmonic acid and phlorizin enhances the antioxidant defense response and phenylpropanoid metabolism pathway of pear fruit, thereby enhancing the resistance of pear fruit to ring rot disease. Our results provide new insights into the application of melatonin in the resistance to pear fruit ring rot.PMID:38811892 | DOI:10.1186/s12870-024-05187-1

BMC Plant Biol. 2024 May 30;24(1):473. doi: 10.1186/s12870-024-05195-1.ABSTRACTBACKGROUND: Carbon nano sol (CNS) can markedly affect the plant growth and development. However, few systematic analyses have been conducted on the underlying regulatory mechanisms in plants, including tobacco (Nicotiana tabacum L.).RESULTS: Integrated analyses of phenome, ionome, transcriptome, and metabolome were performed in this study to elucidate the physiological and molecular mechanisms underlying the CNS-promoting growth of tobacco plants. We found that 0.3% CNS, facilitating the shoot and root growth of tobacco plants, significantly increased shoot potassium concentrations. Antioxidant, metabolite, and phytohormone profiles showed that 0.3% CNS obviously reduced reactive oxygen species production and increased antioxidant enzyme activity and auxin accumulation. Comparative transcriptomics revealed that the GO and KEGG terms involving responses to oxidative stress, DNA binding, and photosynthesis were highly enriched in response to exogenous CNS application. Differential expression profiling showed that NtNPF7.3/NtNRT1.5, potentially involved in potassium/auxin transport, was significantly upregulated under the 0.3% CNS treatment. High-resolution metabolic fingerprints showed that 141 and 163 metabolites, some of which were proposed as growth regulators, were differentially accumulated in the roots and shoots under the 0.3% CNS treatment, respectively.CONCLUSIONS: Taken together, this study revealed the physiological and molecular mechanism underlying CNS-mediated growth promotion in tobacco plants, and these findings provide potential support for improving plant growth through the use of CNS.PMID:38811869 | DOI:10.1186/s12870-024-05195-1

Sci Rep. 2024 May 29;14(1):12376. doi: 10.1038/s41598-024-63173-x.ABSTRACTArachidonic acid (C20: 4n-6, AA) plays a fundamental role in fish physiology, influencing growth, survival and stress resistance. However, imbalances in dietary AA can have detrimental effects on fish health and performance. Optimal AA requirements for rainbow trout have not been established. This study aimed to elucidate the effects of varying dietary AA levels on survival, growth, long-chain polyunsaturated fatty acid (LC-PUFA) biosynthetic capacity, oxylipin profiles, lipid peroxidation, and stress resistance of rainbow trout fry. Over a period of eight weeks, 4000 female rainbow trout fry at the resorptive stage (0.12 g) from their first feeding were fed diets with varying levels of AA (0.6%, 1.1% or 2.5% of total fatty acids) while survival and growth metrics were closely monitored. The dietary trial was followed by an acute confinement stress test. Notably, while the fatty acid profiles of the fish reflected dietary intake, those fed an AA-0.6% diet showed increased expression of elongase5, highlighting their inherent ability to produce LC-PUFAs from C18 PUFAs and suggesting potential AA or docosapentaenoic acidn-6 (DPAn-6) biosynthesis. However, even with this biosynthetic capacity, the trout fed reduced dietary AA had higher mortality rates. The diet had no effect on final weight (3.38 g on average for the three diets). Conversely, increased dietary AA enhanced eicosanoid production from AA, suggesting potential inflammatory and oxidative consequences. This was further evidenced by an increase in non-enzymatic lipid oxidation metabolites, particularly in the AA-2.5% diet group, which had higher levels of phytoprostanes and isoprostanes, markers of cellular oxidative damage. Importantly, the AA-1.1% diet proved to be particularly beneficial for stress resilience. This was evidenced by higher post-stress turnover rates of serotonin and dopamine, neurotransmitters central to the fish's stress response. In conclusion, a dietary AA intake of 1.1% of total fatty acids appears to promote overall resilience in rainbow trout fry.PMID:38811794 | DOI:10.1038/s41598-024-63173-x

Sci Rep. 2024 May 29;14(1):12377. doi: 10.1038/s41598-024-62472-7.ABSTRACTSacubitril/valsartan has been highly recognized as a treatment for Chronic heart failure (CHF). Its potential cardioprotective benefits and mechanisms, however, remain to be explored. Metabolomics can be used to identify the metabolic characteristics and related markers, as well as the influence of drugs, thereby opening up the new mechanism for sacubitril/valsartan therapy in CHF disease. In this study, the ligation of left anterior descending and exhaustive swimming were used to induce a rat model of CHF after myocardial infarction. The efficacy was appraised with echocardiography, serum NT-proBNP, and histopathologica. UPLC-Q/TOF-MS combined with multivariate statistical analysis approach were used to analyze the effect of sacubitril/valsartan on CHF rats. RT-qPCR and western blot were performed to investigate the tryptophan/kynurenine metabolism pathway. Accordingly, the basal cardiac function were increased, while the serum NT-proBNP and collagen volume fraction decreased in CHF rats with sacubitril/valsartan. Sacubitril/valsartan regulated the expression of kynurenine et.al 8 metabolomic biomarkers in CHF rats serum, and it contributed to the cardioprotective effects through tryptophan metabolism pathway. In addition, the mRNA and protein expression of the indoleamine 2,3-dioxygenase (IDO) in the myocardial tissue of CHF rats, were down-regulated by sacubitril/valsartan, which was the same with the IL-1β, IFN-γ, TNF-α, COX-2, and IL-6 mRNA expression, and IL-1β, IFN-γ, and TNF-α expression in serum. In conclusion, sacubitril/valsartan can ameliorate cardiac function and ventricular remodeling in CHF rats, at least in part through inhibition of tryptophan/kynurenine metabolism.PMID:38811632 | DOI:10.1038/s41598-024-62472-7

Nat Commun. 2024 May 29;15(1):4582. doi: 10.1038/s41467-024-48770-8.ABSTRACTThe intestinal anaerobic bacterium Akkermansia muciniphila is specialized in the degradation of mucins, which are heavily O-glycosylated proteins that constitute the major components of the mucus lining the intestine. Despite that adhesion to mucins is considered critical for the persistence of A. muciniphila in the human intestinal tract, our knowledge of how this intestinal symbiont recognizes and binds to mucins is still limited. Here, we first show that the mucin-binding properties of A. muciniphila are independent of environmental oxygen concentrations and not abolished by pasteurization. We then dissected the mucin-binding properties of pasteurized A. muciniphila by use of a recently developed cell-based mucin array that enables display of the tandem repeats of human mucins with distinct O-glycan patterns and structures. We found that A. muciniphila recognizes the unsialylated LacNAc (Galβ1-4GlcNAcβ1-R) disaccharide selectively on core2 and core3 O-glycans. This disaccharide epitope is abundantly found on human colonic mucins capped by sialic acids, and we demonstrated that endogenous A. muciniphila neuraminidase activity can uncover the epitope and promote binding. In summary, our study provides insights into the mucin-binding properties important for colonization of a key mucin-foraging bacterium.PMID:38811534 | DOI:10.1038/s41467-024-48770-8

Cell Death Dis. 2024 May 29;15(5):376. doi: 10.1038/s41419-024-06759-7.ABSTRACTThe tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca2+ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.PMID:38811531 | DOI:10.1038/s41419-024-06759-7

Anal Chim Acta. 2024 Jun 29;1310:342694. doi: 10.1016/j.aca.2024.342694. Epub 2024 May 10.ABSTRACTBACKGROUND: Metabolomics is an emerging and powerful technology that offers a comprehensive view of an organism's physiological status. Although widely applied in human medicine, it is only recently making its introduction in veterinary medicine. As a result, validated metabolomics protocols in feline medicine are lacking at the moment. Since biological interpretation of metabolomics data can be misled by the extraction method used, species and matrix-specific optimized and validated metabolomic protocols are sorely needed.RESULTS: Systematic optimization was performed using fractional factorial experiments for both serum (n = 57) and urine (n = 24), evaluating dilution for both matrices, and aliquot and solvent volume, protein precipitation time and temperature for serum. For the targeted (n = 76) and untargeted (n = 1949) validation of serum respectively, excellent instrumental, intra-assay and inter-day precision were observed (CV ≤ 15% or 30%, respectively). Linearity deemed sufficient both targeted and untargeted (R2 ≥ 0.99 or 0.90, respectively). An appropriate targeted recovery between 70 and 130% was achieved. For the targeted (n = 69) and untargeted (n = 2348) validation of the urinary protocol, excellent instrumental and intra-assay precision were obtained (CV ≤ 15% or 30%, respectively). Subsequently, the discriminative ability of our metabolomics methods was confirmed for feline chronic kidney disease (CKD) by univariate statistics (n = 41 significant metabolites for serum, and n = 55 for urine, p-value<0.05) and validated OPLS-DA models (R2(Y) > 0.95, Q2(Y) > 0.65, p-value<0.001 for both matrices).SIGNIFICANCE: This study is the first to present an optimized and validated wholistic metabolomics methods for feline serum and urine using ultra-high performance liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry. This robust methodology opens avenues for biomarker panel selection and a deeper understanding of feline CKD pathophysiology and other feline applications.PMID:38811133 | DOI:10.1016/j.aca.2024.342694

Int J Biol Macromol. 2024 May 27:132705. doi: 10.1016/j.ijbiomac.2024.132705. Online ahead of print.ABSTRACTTrypanosoma cruzi is the causative agent of Chagas disease, as well as a trypanosomatid parasite with a complex biological cycle that requires precise mechanisms for regulating gene expression. In Trypanosomatidae, gene regulation occurs mainly at the mRNA level through the recognition of cis elements by RNA-binding proteins (RBPs). Alba family members are ubiquitous DNA/RNA-binding proteins with representatives in trypanosomatid parasites functionally related to gene expression regulation. Although T. cruzi possesses two groups of Alba proteins (Alba1/2 and Alba30/40), their functional role remains poorly understood. Thus, herein, a characterization of T. cruzi Alba (TcAlba) proteins was undertaken. Physicochemical, structural, and phylogenetic analysis of TcAlba showed features compatible with RBPs, such as hydrophilicity, RBP domains/motifs, and evolutionary conservation of the Alba-domain, mainly regarding other trypanosomatid Alba. However, in silico RNA interaction analysis of T. cruzi Alba proteins showed that TcAlba30/40 proteins, but not TcAlba1/2, would directly interact with the assayed RNA molecules, suggesting that these two groups of TcAlba proteins have different targets. Given the marked differences existing between both T. cruzi Alba groups (TcAlba1/2 and TcAlba30/40), regarding sequence divergence, RNA binding potential, and life-cycle expression patterns, we suggest that they would be involved in different biological processes.PMID:38810850 | DOI:10.1016/j.ijbiomac.2024.132705

Sci Total Environ. 2024 May 27:173576. doi: 10.1016/j.scitotenv.2024.173576. Online ahead of print.ABSTRACTSurface modification of graphene-based nanomaterials (GBNs) may occur in aquatic environment and during intentional preparation. However, the influence of the surface groups on the developmental toxicity of GBNs has not been determined. In this study, we evaluated the developmental toxicity of three GBNs including GO (graphene oxide), RGO (reduced GO) and RGO-N (aminated RGO) by employing zebrafish embryos at environmentally relevant concentrations (1-100 μg/L), and the underlying metabolic mechanisms were explored. The results showed that both GO and RGO-N disturbed the development of zebrafish embryos, and the adverse effect of GO was greater than that of RGO-N. Furthermore, the oxygen-containing groups of GBNs play a more important role in inducing developmental toxicity compared to size, defects and nitrogen-containing groups. Specifically, the epoxide and hydroxyl groups of GBNs increased their intrinsic oxidative potential, promoted the generation of ROS, and caused lipid peroxidation. Moreover, a significant decrease in guanosine and abnormal metabolism of multiple glycerophospholipids were observed in all three GBN-treated groups. Nevertheless, GO exposure triggered more metabolic activities related to lipid peroxidation than RGO or RGO-N exposure, and the disturbance intensity of the same metabolite was greater than that of the other two agents. These findings reveal underlying metabolic mechanisms of GBN-induced developmental toxicity.PMID:38810761 | DOI:10.1016/j.scitotenv.2024.173576

Sci Total Environ. 2024 May 27:173494. doi: 10.1016/j.scitotenv.2024.173494. Online ahead of print.ABSTRACTThe soil is a vital resource that hosts many microorganisms crucial in biogeochemical cycles and ecosystem health. However, human activities such as the use of metal nanoparticles (MNPs), pesticides and the impacts of global climate change (GCCh) can significantly affect soil microbial communities (SMC). For many years, pesticides and, more recently, nanoparticles have contributed to sustainable agriculture to ensure continuous food production to sustain the significant growth of the world population and, therefore, the demand for food. Pesticides have a recognized pest control capacity. On the other hand, nanoparticles have demonstrated a high ability to improve water and nutrient retention, promote plant growth, and control pests. However, it has been reported that their accumulation in agricultural soils can also adversely affect the environment and soil microbial health. In addition, climate change, with its variations in temperature and extreme water conditions, can lead to drought and increased soil salinity, modifying both soil conditions and the composition and function of microbial communities. Abiotic stressors can interact and synergistically or additively affect soil microorganisms, significantly impacting soil functioning and the capacity to provide ecosystem services. Therefore, this work reviewed the current scientific literature to understand how multiple stressors interact and affect the SMC. In addition, the importance of molecular tools such as metagenomics, metatranscriptomics, proteomics, or metabolomics in the study of the responses of SMC to exposure to multiple abiotic stressors was examined. Future research directions were also proposed, focusing on exploring the complex interactions between stressors and their long-term effects and developing strategies for sustainable soil management. These efforts will contribute to the preservation of soil health and the promotion of sustainable agricultural practices.PMID:38810746 | DOI:10.1016/j.scitotenv.2024.173494