PubMed

Br J Cancer. 2023 Apr 19. doi: 10.1038/s41416-023-02256-4. Online ahead of print.ABSTRACTBACKGROUND: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity.METHODS: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39-77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability.RESULTS: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of 'Val Leu Ile degradation pathway'. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival.CONCLUSIONS: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.PMID:37076565 | DOI:10.1038/s41416-023-02256-4

Cell Death Dis. 2023 Apr 19;14(4):278. doi: 10.1038/s41419-023-05800-5.ABSTRACTNeuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.PMID:37076499 | DOI:10.1038/s41419-023-05800-5

Cell Death Dis. 2023 Apr 19;14(4):276. doi: 10.1038/s41419-023-05791-3.ABSTRACTOmicron variants of SARS-CoV-2 have spread rapidly worldwide; however, most infected patients have mild or no symptoms. This study aimed to understand the host response to Omicron infections by performing metabolomic profiling of plasma. We observed that Omicron infections triggered an inflammatory response and innate immune, and adaptive immunity was suppressed, including reduced T-cell response and immunoglobulin antibody production. Similar to the original SARS-CoV-2 strain circulating in 2019, the host developed an anti-inflammatory response and accelerated energy metabolism in response to Omicron infection. However, differential regulation of macrophage polarization and reduced neutrophil function has been observed in Omicron infections. Interferon-induced antiviral immunity was not as strong in Omicron infections as in the original SARS-CoV-2 infections. The host response to Omicron infections increased antioxidant capacity and liver detoxification more than in the original strain. Hence, these findings suggest that Omicron infections cause weaker inflammatory alterations and immune responses than the original SARS-CoV-2 strain.PMID:37076483 | DOI:10.1038/s41419-023-05791-3

Nat Commun. 2023 Apr 19;14(1):2236. doi: 10.1038/s41467-023-37729-w.ABSTRACTBiological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.PMID:37076473 | DOI:10.1038/s41467-023-37729-w

J Agric Food Chem. 2023 Apr 19. doi: 10.1021/acs.jafc.3c00234. Online ahead of print.ABSTRACTThe marine-derived Streptomyces sp. FIMYZ-003 strain was found to produce novel siderophores with yields negatively correlated with the iron concentration in the medium. Mass spectrometry (MS)-based metabolomics coupled with metallophore assays identified two novel α-hydroxycarboxylate-type siderophores, fradiamines C and D (3 and 4), together with two related known siderophores, fradiamines A and B (1 and 2). Their chemical structures were elucidated by nuclear magnetic resonance (NMR) and MS experiments. The annotation of a putative fra biosynthetic gene cluster enabled us to propose the biosynthetic pathway of fradiamines A-D. Furthermore, the solution-phase iron-binding activity of fradiamines was evaluated using metabolomics, confirming them as general iron scavengers. Fradiamines A-D exhibited Fe(III) binding activity equivalent to that of deferoxamine B mesylate. Growth analysis of pathogenic microbes demonstrated that fradiamine C promoted the growth of Escherichia coli and Staphylococcus aureus, but fradiamines A, B, and D did not. The results indicate that fradiamine C may serve as a novel iron carrier applicable to antibiotic delivery strategies to treat and prevent foodborne pathogens.PMID:37076425 | DOI:10.1021/acs.jafc.3c00234

PLoS One. 2023 Apr 19;18(4):e0284138. doi: 10.1371/journal.pone.0284138. eCollection 2023.ABSTRACTBACKGROUND: Plenty of studies have focused on the bile acids profile in gallstones. The objective of our systematic review is to provide a comprehensive summary about bile acids profiles in gallstones and analyzes the difference between gallstones and control group in diverse samples, determining the characteristic bile acids as the metabolite biomarkers for predicting gallstone.METHODS: EMBASE, the Cochrane Library, PubMed, Web of Science, Wanfang databases, China National Knowledge Infrastructure (CNKI), VIP Information Resource Integration Service Platform (CQVIP), and China Biology Medicine Disc (SinoMed) will be searched with the keywords of gallstones and metabolomics. The screening process will be performed strictly according to inclusion and exclusion criteria. The CONSORT checklist and the Newcastle-Ottawa Scale (NOS) will assess the risk of bias for randomized controlled trials and observational studies, respectively. The qualitative review will be conducted to summarize the bile acids profile in gallstones. The concentrations of bile acids in both case group and control group will be the primary outcomes to perform the meta-analyses.EXPECTED RESULTS: Our systematic review will find the characteristic bile acids as the candidate metabolite biomarkers which equipped potential value to predict gallstones.CONCLUSION: Expanding the current knowledge on the physiopathology of gallstones and identifying novel predictive biomarkers can help to facilitate the detection and management of gallstones. Consequently, we expect this protocol to be a reasonable method to filtrate candidate differential bile acids which have potential value to predict gallstones.PROSPERO REGISTRATION NUMBER: CRD42022339649.PMID:37075059 | DOI:10.1371/journal.pone.0284138

JAMA Psychiatry. 2023 Apr 19. doi: 10.1001/jamapsychiatry.2023.0685. Online ahead of print.ABSTRACTIMPORTANCE: Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression.OBJECTIVE: To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD.DESIGN, SETTING AND PARTICIPANTS: This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021.MAIN OUTCOMES AND MEASURES: Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform.RESULTS: The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β [SE], -0.07 [0.02]; FDR = 4 × 10-04) and pyruvate was significantly increased (β [SE], 0.04 [0.02]; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not.CONCLUSIONS AND RELEVANCE: The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.PMID:37074710 | DOI:10.1001/jamapsychiatry.2023.0685

Mol Biol Rep. 2023 Apr 19. doi: 10.1007/s11033-023-08421-5. Online ahead of print.ABSTRACTThe self-renew ability of cancer stem cells (CSCs) continues to challenge our determination for accomplishing cancer therapy breakthrough. Ineffectiveness of current cancer therapies to eradicate CSCs has contributed to chemoresistance and tumor recurrence. Yet, the discoveries of highly effective therapies have not been thoroughly developed. Further insights into cancer metabolomics and gene-regulated mechanisms of mitochondria in CSCs can expedite the development of novel anticancer drugs. In cancer cells, the metabolism is reprogrammed from oxidative phosphorylation (OXPHOS) to glycolysis. This alteration allows the cancer cell to receive continuous energy supplies and avoid apoptosis. The pyruvate obtained from glycolysis produces acetyl-coenzyme A (Acetyl-CoA) via oxidative decarboxylation and enters the tricarboxylic acid cycle for adenosine triphosphate generation. Mitochondrial calcium ion (Ca2+) uptake is responsible for mitochondrial physiology regulation, and reduced uptake of Ca2+ inhibits apoptosis and enhances cell survival in cancer. There have been many discoveries of mitochondria-associated microRNAs (miRNAs) stimulating the metabolic alterations in mitochondria via gene regulation which promote cancer cell survival. These miRNAs are also found in CSCs where they regulate genes and activate different mechanisms to destroy the mitochondria and enhance CSCs survival. By targeting the miRNAs that induced mitochondrial destruction, the mitochondrial functions can be restored; thus, it triggers CSCs apoptosis and completely eliminates the CSCs. In general, this review article aims to address the associations between miRNAs with mitochondrial activities in cancer cells and cancer stem cells that support cancer cell survival and self-renewal.PMID:37074612 | DOI:10.1007/s11033-023-08421-5

Food Chem Toxicol. 2023 Apr 18:113777. doi: 10.1016/j.fct.2023.113777. Online ahead of print.ABSTRACTP: radix is a perennial herb, and its extracts have various biological properties that make it a potential candidate for the treatment of tumors, edema, and lymphatic stasis. However, the main factor contributing to its toxicity are not clear. Here, we used a zebrafish toxicological model to study the main toxicity factor of P. radix and explore the potential mechanisms involved. The results revealed that Esculentoside B was the major toxic factor of P. radix. Exposure of zebrafish larvae to Esculentoside B caused developmental abnormalities, neurotoxicity and altered locomotor behavior. The combination of AChE activity and the expression levels of genes relevant to CNS development demonstrated that Esculentoside B is neurotoxic to zebrafish larvae, impairs their CNS development, and that AChE may be a toxic target of Esculentoside B. Metabolomic analysis has revealed that Esculentoside B exposure can disrupt D-Amino acid metabolism, protein export, autophagy, and mTOR signaling pathways in zebrafish larvae. These findings provide insights into the molecular mechanisms underlying EsB-induced neurotoxicity in zebrafish, which can facilitate further research and development of P. radix for safe consumption.PMID:37080526 | DOI:10.1016/j.fct.2023.113777

J Affect Disord. 2023 Apr 18:S0165-0327(23)00492-5. doi: 10.1016/j.jad.2023.04.031. Online ahead of print.ABSTRACTBACKGROUND: The gut-brain axis has been shown to play an important role in depression. However, few studies have examined proteomic changes in the intestine of the nonhuman primate model of depression.METHODS: We investigated the intestinal proteome of macaques (Macaca fascicularis) with depression-like (DL) behaviors by data-independent acquisition techniques. We also performed integration analyses of proteomic changes, previous metabolomic and microbiotic data. Moreover, we confirmed the gene expressions of key proteins.RESULTS: Sixty-five differentially expressed proteins (DEPs) were identified, of which fifty-four DEPs were down-regulated and the others were altered conversely in DL macaques compared with the control group. Pathway analysis indicated that mitochondrial function and energy metabolism were representative functions of DEPs. The key DEPs were significantly associated with glycerophospholipid metabolism and imbalances of gut microbe. We confirmed that key molecules (NDUFB4, UQCR10, PISD) were significantly inhibited, which may disturb the energy transformation of the electron respiratory chain and the homeostasis of the mitochondrial membrane.LIMITATIONS: Further research is warranted to determine the effects of depression on other peripheral organs.CONCLUSIONS: These findings suggest the functional disorder of intestinal mitochondria in DL macaques. The disturbances of glycerophospholipid metabolism and gut microbiota may exacerbate disruptions of energy metabolism. Taking together, our study provides new clues to the relationship between depression and intestinal proteome.PMID:37080496 | DOI:10.1016/j.jad.2023.04.031

Int J Biol Macromol. 2023 Apr 18:124419. doi: 10.1016/j.ijbiomac.2023.124419. Online ahead of print.ABSTRACTThe intestinal mucosal barrier is one of the important barriers to prevent harmful substances and pathogens from entering the body environment and to maintain intestinal homeostasis. This study investigated the reparative effect and possible mechanism of Tetrastigma hemsleyanum polysaccharides (THP) on ceftriaxone-induced intestinal mucosal damage. Our results suggested that THP repaired the mechanical barrier damage of intestinal mucosa by enhancing the expression of intestinal tight junction proteins, reducing intestinal mucosal permeability and improving the pathological state of intestinal epithelial cells. Intestinal immune and chemical barrier was further restored by THP via the increment of the body's cytokine levels, intestinal SIgA levels, intestinal goblet cell number, intestinal mucin-2 levels, and short-chain fatty acid levels. In addition, THP increased the abundance of probiotic bacteria (such as Lactobacillus), reduced the abundance of harmful bacteria (such as Enterococcus) to repair the intestinal biological barrier, restored intestinal mucosal barrier function, and maintains intestinal homeostasis. The possible mechanisms were related to sphingolipid metabolism, linoleic acid metabolism, and d-glutamine and D-glutamate metabolism. Our results demonstrated the potential therapeutic effect of THP against intestinal flora disorders and intestinal barrier function impairment caused by antibiotics.PMID:37080409 | DOI:10.1016/j.ijbiomac.2023.124419

J Ethnopharmacol. 2023 Apr 18:116505. doi: 10.1016/j.jep.2023.116505. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Dachaihu decoction (DCH), a classic formula for Yangming and Shaoyang Syndrome Complex recorded in "Treatise on Cold Damage", has been widely used in treating intestinal disorders and inflammatory diseases with few side effects in China. However, the mechanism of DCH on septic intestinal injury (SII) remain to be explored.AIM OF THE STUDY: This study aimed to clarify the mechanism of DCH on SII.MATERIALS AND METHODS: SII model of rat, established by cecal ligation and puncture (CLP), was used to study the effect of DCH on SII. 24 h mortality was recorded. Histological changes were observed by H&E staining. The expression of tight junction protein ZO-1 (ZO-1) and mucin2 (MUC2) was determined by immunohistochemical analysis. Secretory IgA (sIgA), diamine oxidase (DAO) and intestinal fatty acid binding protein (iFABP) were determined by enzyme-linked immunosorbent assay (ELISA). IL-1β, IL-6 and TNF-α were measured by ELISA and quantitative Real-time PCR (RT-qPCR). The gut microbiota was analyzed by 16 S rRNA sequencing. The potential targets and pathways of DCH in treating SII were analyzed by integrative analysis of transcriptomic and metabolomic methods. Total glutathione (T-GSH), GSH, GSSG (reduced form of GSH), GSH peroxidase (GPX), superoxide dismutase (SOD), malonaldehyde (MDA) and indicators of hepatic and renal function were measured by biochemical kits.RESULTS: Medium dose of DCH improved 24 h mortality of SII rats, reduced the pathological changes of ileum, and increased the expression levels of ZO-1, MUC2 and sIgA. DCH decreased DAO, iFABP of serum and IL-1β, IL-6, TNF-α of ileum. DCH improved α- and β-diversity and modulated the structure of gut microbiota, with Escherichia_Shigella decreased and Bacteroides and Ruminococcus increased. GSH metabolism was identified as the key pathway of DCH on SII by integrative analysis of transcriptome and metabolome. GSH/GSSG and the most common indicators of oxidative stress, were validated. Antioxidative T-GSH, GSH, GPX and SOD were increased, while MDA, the mark of lipid peroxidation was downregulated by DCH. Eventually, DCH was proved to be safe and hepato- and nephro-protective.CONCLUSION: DCH ameliorated septic intestinal injury possibly by modulating the gut microbiota and enhancing glutathione metabolism of SII rats, without hepatotoxicity and nephrotoxicity.PMID:37080366 | DOI:10.1016/j.jep.2023.116505

Crit Care. 2023 Apr 18;27(1):147. doi: 10.1186/s13054-023-04435-4.NO ABSTRACTPMID:37072785 | PMC:PMC10114463 | DOI:10.1186/s13054-023-04435-4

Gut. 2023 Apr 18:gutjnl-2022-329213. doi: 10.1136/gutjnl-2022-329213. Online ahead of print.ABSTRACTOBJECTIVE: Bile acid diarrhoea (BAD) is debilitating yet treatable, but it remains underdiagnosed due to challenging diagnostics. We developed a blood test-based method to guide BAD diagnosis.DESIGN: We included serum from 50 treatment-naive patients with BAD diagnosed by gold standard 75selenium homotaurocholic acid test, 56 feature-matched controls and 37 patients with non-alcoholic fatty liver disease (NAFLD). Metabolomes were generated using mass spectrometry covering 1295 metabolites and compared between groups. Machine learning was used to develop a BAD Diagnostic Score (BDS).RESULTS: Metabolomes of patients with BAD significantly differed from controls and NAFLD. We detected 70 metabolites with a discriminatory performance in the discovery set with an area under receiver-operating curve metric above 0.80. Logistic regression modelling using concentrations of decanoylcarnitine, cholesterol ester (22:5), eicosatrienoic acid, L-alpha-lysophosphatidylinositol (18:0) and phosphatidylethanolamine (O-16:0/18:1) distinguished BAD from controls with a sensitivity of 0.78 (95% CI 0.64 to 0.89) and a specificity of 0.93 (95% CI 0.83 to 0.98). The model was independent of covariates (age, sex, body mass index) and distinguished BAD from NAFLD irrespective of fibrosis stage. BDS outperformed other blood test-based tests (7-alpha-hydroxy-4-cholesten-3-one and fibroblast growth factor 19) currently under development.CONCLUSIONS: BDS derived from serum metabolites in a single-blood sample showed robust identification of patients with BAD with superior specificity and sensitivity compared with current blood test-based diagnostics.PMID:37072179 | DOI:10.1136/gutjnl-2022-329213

J Ethnopharmacol. 2023 Apr 16:116481. doi: 10.1016/j.jep.2023.116481. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The combined prescription of two classical decoctions (Ma-Xing-Shi-Gan decoction with Xiao-Chai-Hu decoction), named as San-Yang-He-Zhi (SYHZ) decoction, has been widely used for the treatment of influenza virus (IFV) infections for decades.AIM OF THE STUDY: This study aimed to evaluate the anti-influenza effect of SYHZ decoction and explore the underlying mechanism.MATERIALS AND METHODS: The ingredients of SYHZ decoction were analyzed by mass spectrometry. An animal model of IFV infection was established by challenging C57BL/6J mice with PR8 virus. Three groups of mice were infected with lethal or non-lethal doses of IFV, then followed by oral administration of phosphate-buffered saline (PBS), or SYHZ, or oseltamir; blank control mice (without IFV infection) were treated with PBS. Survival rate, Lung index, colon length, body weight loss and IFV viral load were measured 7 days post infection; histology and electron-microscopy examinations of lung tissue were performed; cytokine and chemokine levels in lung and serum were measured; and the intestinal metagenome, the cecum metabolome, and the lung transcriptome were analyzed.RESULTS: SYHZ treatment significantly improved survival rate compared with PBS (40% vs 0%); improved lung index, colon length, and body weight loss; and alleviated lung histological damage and viral load. SYHZ-treated mice had significantly lower levels of IL-1β, TNF-α, IL-6, CCL2, CXCL10 in lung and serum, and increased levels of multiple bioactive components in cecum. Pro-inflammatory cytokines, Toll- and NOD-like receptors, pro-apoptosis molecules, and lung-injury-related proteins were downregulated in SYHZ mice, whereas surfactant protein and mucin were upregulated. The NOD-like receptor pathway, Toll-like receptor pathway, and NF-κB pathway were downregulated by SYHZ treatment.CONCLUSIONS: SYHZ decoction alleviated IFV infection in a mouse model. Multiple bioactive ingredients of SYHZ may inhibit replication of IFV and suppress excessive immune response.PMID:37072090 | DOI:10.1016/j.jep.2023.116481

Int J Biol Macromol. 2023 Apr 16:124479. doi: 10.1016/j.ijbiomac.2023.124479. Online ahead of print.ABSTRACTAmmopiptanthus mongolicus, an evergreen broad-leaved plant, can tolerate severe freezing stress (temperatures as low as -20 °C in winter). The apoplast is the space outside the plasma membrane that plays an important role in plant responses to environmental stress. Here, we investigated, using a multi-omics approach, the dynamic alterations in the levels of proteins and metabolites in the apoplast and related gene expression changes involved in the adaptation of A. mongolicus to winter freezing stress. Of the 962 proteins identified in the apoplast, the abundance of several PR proteins, including PR3 and PR5, increased significantly in winter, which may contribute to winter freezing-stress tolerance by functioning as antifreeze proteins. The increased abundance of the cell-wall polysaccharides and cell wall-modifying proteins, including PMEI, XTH32, and EXLA1, may enhance the mechanical properties of the cell wall in A. mongolicus. Accumulation of flavonoids and free amino acids in the apoplast may be beneficial for ROS scavenging and the maintenance of osmotic homeostasis. Integrated analyses revealed gene expression changes associated with alterations in the levels of apoplast proteins and metabolites. Our study improved the current understanding of the roles of apoplast proteins and metabolites in plant adaptation to winter freezing stress.PMID:37072058 | DOI:10.1016/j.ijbiomac.2023.124479

Physiol Plant. 2023 Apr 18:e13914. doi: 10.1111/ppl.13914. Online ahead of print.ABSTRACTHydrangea (Hydrangea arborescens var. 'Annabelle') flowers are composed of sweet aroma sepals rather than true petals and can change color. Floral volatiles play important roles in plants, such as attracting pollinators, defending against herbivores, and signaling. However, the biosynthesis and regulatory mechanisms underlying fragrance formation in H. arborescens during flower development remain unknown. In this study, a combination of metabolite profiling and RNA sequencing (RNA-seq) was employed to identify genes associated with floral scent biosynthesis mechanisms in 'Annabelle' flowers at three developmental stages (F1, F2, and F3). The floral volatile data revealed that the 'Annabelle' volatile profile includes a total of 33 volatile organic compounds (VOCs), and VOCs were abundant during the F2 stage of flower development, followed by the F1 and F3 stages, respectively. Terpenoids and benzenoids/phenylpropanoids were abundant during the F2 and F1 stages, with the latter being the most abundant, whereas fatty acid derivatives and other compounds were found in large amount during the F3 stage. According to ultra performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS) analysis, benzene and substituted derivatives, carboxylic acids and derivatives, and fatty acyls play a significant role in the floral metabolite profile. The transcriptome data revealed a total of 17,461 differentially expressed genes (DEGs), with 7,585, 12,795, and 9,044 DEGs discovered between the F2 and F1, F3 and F1, and F2 and F3 stages, respectively. Several terpenoids and benzenoids/phenylpropanoids biosynthesis-related DEGs were identified, and GRAS/bHLH/MYB/AP2/WRKY were more abundant among transcription factors (TFs). Finally, DEGs interlinked with VOCs compounds were determined using cytoscape and k-means analysis. Our results paves the way for the discovery of new genes, critical data for future genetic studies, and a platform for the metabolic engineering of genes involved in the production of Hydrangea's signature floral fragrance.PMID:37072650 | DOI:10.1111/ppl.13914

Nat Commun. 2023 Apr 18;14(1):2210. doi: 10.1038/s41467-023-37843-9.ABSTRACTThe number of tRNA isodecoders has increased dramatically in mammals, but the specific molecular and physiological reasons for this expansion remain elusive. To address this fundamental question we used CRISPR editing to knockout the seven-membered phenylalanine tRNA gene family in mice, both individually and combinatorially. Using ATAC-Seq, RNA-seq, ribo-profiling and proteomics we observed distinct molecular consequences of single tRNA deletions. We show that tRNA-Phe-1-1 is required for neuronal function and its loss is partially compensated by increased expression of other tRNAs but results in mistranslation. In contrast, the other tRNA-Phe isodecoder genes buffer the loss of each of the remaining six tRNA-Phe genes. In the tRNA-Phe gene family, the expression of at least six tRNA-Phe alleles is required for embryonic viability and tRNA-Phe-1-1 is most important for development and survival. Our results reveal that the multi-copy configuration of tRNA genes is required to buffer translation and viability in mammals.PMID:37072429 | DOI:10.1038/s41467-023-37843-9

Chem Biodivers. 2023 Apr 18:e202201047. doi: 10.1002/cbdv.202201047. Online ahead of print.ABSTRACTPhenylpropionamides in the seed of Cannabis sativa L. (PHS) have a protective effect on neuroinflammation and antioxidant activity. In this study, the UHPLC-Orbitrap-fusion-TMS-based metabolomics approach was used to analyze the serum samples and identify potential biomarkers in Streptozotocin (STZ) induced Alzheimer's disease (AD) rats. The results revealed that ptimary bile acid biosynthesis and taurine and hypotaurine metabolism were significantly correlated with STZ-induced AD rats. In addition, the key enzymes in these two pathways were verified at the protein level. The levels of cysteine dioxygenase type I (CDO1), cysteine sulfinic acid decarboxylase (CSAD), cysteamine (2-aminoethanethiol) dioxygenase (ADO), 7α-hydroxylase (CYP7A1), and sterol 12α-hydroxylase (CYP8B1) were the key enzymes affecting the two pathways in AD rats compared with the control group (CON). Furthermore, after a high-dose group of phenylpropionamides in the seed of Cannabis sativa L. (PHS-H) was administrated, the levels of CDO1, CSAD, CYP7A1, and CYP8B1 were all callback. These findings demonstrate for the first time that the anti-AD effect of PHS is associated with the regulation of primary bile acid biosynthesis and taurine and hypotaurine metabolism in STZ-induced AD rats.PMID:37072341 | DOI:10.1002/cbdv.202201047

Bioinformatics. 2023 Apr 18:btad195. doi: 10.1093/bioinformatics/btad195. Online ahead of print.ABSTRACTMOTIVATION: Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is widely used in composition profiling in untargeted metabolomics research. While retaining complete sample information, mass spectrometry (MS) data naturally have the characteristics of high dimensionality, high complexity, and huge data volume. In mainstream quantification methods, none of the existing methods can perform direct three-dimensional analysis on lossless profile MS signals. All software simplifies calculations by dimensionality reduction or lossy grid transformation, ignoring the full three-dimensional signal distribution of mass spectrometry data and resulting in inaccurate feature detection and quantification.RESULTS: On the basis that the neural network is effective for high-dimensional data analysis and can discover implicit features from large amounts of complex data, in this work, we propose 3D-MSNet, a novel deep-learning-based model for untargeted feature extraction. 3D-MSNet performs direct feature detection on three-dimensional MS point clouds as an instance segmentation task. After training on a self-annotated 3D feature dataset, we compared our model with 9 popular software (MS-DIAL, MZmine 2, XCMS Online, MarkerView, Compound Discoverer, MaxQuant, Dinosaur, DeepIso, PointIso) on two metabolomics and one proteomics public benchmark datasets. Our 3D-MSNet model outperformed other software with significant improvement in feature detection and quantification accuracy on all evaluation datasets. Furthermore, 3D-MSNet has high feature extraction robustness and can be widely applied to profile MS data acquired with various high-resolution mass spectrometers with various resolutions.AVAILABILITY: 3D-MSNet is open-source and freely available at https://github.com/CSi-Studio/3D-MSNet under a permissive license. Benchmark datasets, training dataset, evaluation methods and results are available at https://doi.org/10.5281/zenodo.6582912.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.PMID:37071700 | DOI:10.1093/bioinformatics/btad195