PubMed

Nutrients. 2022 Oct 22;14(21):4442. doi: 10.3390/nu14214442.ABSTRACTSarcopenia is a multifactorial disease that limits autonomy for the growing elderly population. An optimal amount of dietary protein has shown to be important to maintain muscle mass during aging. Yet, the optimal distribution of that dietary protein has not been fully clarified. The aim of the present study was to examine whether an even, compared to a skewed, distribution of daily dietary protein leads to higher muscle protein synthesis and amino acid utilization. Twelve healthy males and twelve healthy females aged between 65 and 80 years were block randomized to either an even (EVEN, n = 12) or skewed (SKEWED, n = 12) dietary protein distribution for three daily main meals. Seven days of habituation were followed by three trial days, which were initiated by oral intake of deuterium oxide (D2O). The dietary protein throughout all trial meals was intrinsically labelled with 2H5-phenylalanine. Blood samples were drawn daily, and muscle biopsies were taken before and at the end of the trial to measure muscle protein synthesis (FSR) and muscle protein incorporation of the dietary-protein-derived tracer. Muscle protein FSR was no different between the two groups (EVEN 2.16 ± 0.13%/day and SKEWED 2.23 ± 0.09%/day, p = 0.647), and the muscle protein incorporation of the intrinsically labeled 2H5-phenylalanine tracer was not different between the two groups (EVEN 0.0049 ± 0.0004 MPE% and SKEWED 0.0054 ± 0.0003 MPE%, p = 0.306). In conclusion, the daily distribution pattern of the dietary protein did not affect muscle protein synthesis or the utilization of dietary protein.PMID:36364705 | DOI:10.3390/nu14214442

Molecules. 2022 Nov 6;27(21):7613. doi: 10.3390/molecules27217613.ABSTRACTSideritis clandestina (Bory & Chaub.) Hayek subsp. peloponnesiaca (Boiss. & Heldr.) Baden (SCP) is endemic to the mountains of the Northern Peloponnese (Greece). This and other Sideritis taxa, collectively known as mountain tea, are widely ingested as beverages for refreshment or medicinal purposes. We describe a methodology for the characterization of SCP. Four iridoid glycosides (monomelittoside, melittoside, ajugoside, and 7-O-acetyl-8-epiloganic acid), two phenolic acid glycosides (vanillic and salicylic acid glycosides), and three caffeoyl ester glycosides (chlorogenic acid, verbascoside, and isoverbascoside) were isolated from SCP for the first time. We used ultrasound-assisted extraction of 3 g of plant material to produce petroleum ether and aqueous extracts, which we then analyzed using GC/MS and LC/MS. This was applied to eight samples from four different taxa. In total, 70 volatile and 27 polar metabolites were determined. The S. clandestina samples had a lower phenolic content and weaker antioxidant properties than S. raeseri and S. scardica. However, S. clandestina ssp. clandestina seemed to be the most aromatic taxon, with almost double the number of volatiles as the others. Τhis study could contribute to authentication and chemotaxonomic studies of Sideritis taxa.PMID:36364439 | DOI:10.3390/molecules27217613

Molecules. 2022 Nov 4;27(21):7573. doi: 10.3390/molecules27217573.ABSTRACTMore than one hundred cannabinoids have been found in cannabis. Δ9-Tetrahydrocannabinol (THC) is the recognized addictive constituent in cannabis; however, the mechanisms underlying THC-induced toxicity remain elusive. To better understand cannabis-induced toxicity, the present study compared the metabolic pathways of THC and its isomer cannabidiol (CBD) in human and mouse liver microsomes using the metabolomic approach. Thirty-two metabolites of THC were identified, including nine undescribed metabolites. Of note, two glutathione (GSH) and two cysteine (Cys) adducts were found in THC's metabolism. Molecular docking revealed that THC conjugates have a higher affinity with GSH and Cys than with the parent compound, THC. Human recombinant cytochrome P450 enzymes, and their corresponding chemical inhibitors, demonstrated that CYP3A4 and CYP1B1 were the primary enzymes responsible for the formation of THC-GSH and THC-Cys, thus enabling conjugation to occur. Collectively, this study systematically compared the metabolism of THC with the metabolism of CBD using the metabolomic approach, which thus highlights the critical role of metabolomics in identifying novel drug metabolites. Moreover, this study also facilitates mechanistic speculation in order to expand the knowledge of drug metabolism and safety.PMID:36364400 | DOI:10.3390/molecules27217573

Molecules. 2022 Nov 4;27(21):7571. doi: 10.3390/molecules27217571.ABSTRACTThe halal status of meat products is an important factor being considered by many parties, especially Muslims. Analytical methods that have good specificity for the authentication of halal meat products are important as quality assurance to consumers. Metabolomic and lipidomic are two useful strategies in distinguishing halal and non-halal meat. Metabolomic and lipidomic analysis produce a large amount of data, thus chemometrics are needed to interpret and simplify the analytical data to ease understanding. This review explored the published literature indexed in PubMed, Scopus, and Google Scholar on the application of chemometrics as a tool in handling the large amount of data generated from metabolomic and lipidomic studies specifically in the halal authentication of meat products. The type of chemometric methods used is described and the efficiency of time in distinguishing the halal and non-halal meat products using chemometrics methods such as PCA, HCA, PLS-DA, and OPLS-DA is discussed.PMID:36364396 | DOI:10.3390/molecules27217571

Molecules. 2022 Nov 3;27(21):7548. doi: 10.3390/molecules27217548.ABSTRACTGinkgolide is a unique terpenoid natural compound in Ginkgo biloba, and it has an important medicinal value. Proper selenium has been reported to promote plant growth and development, and improve plant quality, stress resistance, and disease resistance. In order to study the effects of exogenous selenium (Se) on the physiological growth and the content of terpene triolactones (TTLs) in G. biloba seedlings, the seedlings in this work were treated with Na2SeO3. Then, the physiological indexes, the content of the TTLs, and the expression of the related genes were determined. The results showed that a low dose of Na2SeO3 was beneficial to plant photosynthesis as it promoted the growth of ginkgo seedlings and increased the root to shoot ratio. Foliar Se application significantly increased the content of soluble sugar and protein and promoted the content of TTLs in ginkgo leaves; indeed, it reached the maximum value of 7.95 mg/g in the ninth week, whereas the application of Se to the roots inhibited the synthesis of TTLs. Transcriptome analysis showed that foliar Se application promoted the expression levels of GbMECPs, GbMECT, GbHMGR, and GbMVD genes, whereas its application to the roots promoted the expression of GbDXS and GbDXR genes. The combined analysis results of metabolome and transcriptome showed that genes such as GbDXS, GbDXR, GbHMGR, GbMECPs, and GbCYP450 were significantly positively correlated with transcription factors (TFs) GbWRKY and GbAP2/ERF, and they were also positively correlated with the contents of terpene lactones (ginkgolide A, ginkgolide B, ginkgolide M, and bilobalide). Endogenous hormones (MeJA-ILE, ETH, and GA7) were also involved in this process. The results suggested that Na2SeO3 treatment affected the transcription factors related to the regulation of endogenous hormones in G. biloba, and further regulated the expression of genes related to the terpene synthesis structure, thus promoting the synthesis of ginkgo TTLs.PMID:36364373 | DOI:10.3390/molecules27217548

Molecules. 2022 Nov 3;27(21):7509. doi: 10.3390/molecules27217509.ABSTRACTIndonesia has high biodiversity of algae that are under-utilised due to limitations in the processing techniques. Here, we observed the effect of two different extraction methods (cold maceration and ultrasonic-assisted extraction (UAE)) on multiple variables of Indonesian brown algae ethanol extracts (Sargassum polycystum, Sargassum cristaefolium, Sargassum aquifolium and Turbinaria ornata). The variables observed included metabolites screening by untargeted metabolomics liquid chromatography-high-resolution mass spectrometry (LC-HRMS), observation of total phenolic content (TPC), total flavonoid content (TFC), anti-oxidant and B16-F10 melanoma cells cytotoxicity. UAE extracts had higher extraction yield and TPC, but no TFC difference was observed. UAE extract had more lipophilic compounds, such as fatty acids (Palmitic acid, Oleamide, Palmitoleic acid, Eicosapentaenoic acid, α-Linolenic acid, Arachidonic acid), lipid-derived mediators (11,12-Epoxyeicosatrienoic acid ((±)11(12)-EET)), steroid derivatives (Ergosterol peroxide), lipophilic metabolite (Fucoxanthin), and lipid-soluble vitamins (all-trans-retinol). Principle component analysis (PCA) revealed that TPC, not TFC, in the UAE extracts was correlated with the anti-oxidant activities and cytotoxicity of the extracts towards B16-F10 melanoma cells. This means other non-flavonoid phenolic and lipophilic compounds may have contributed to its bioactivity. These results suggest that out of the two methods investigated, UAE could be a chosen method to extract natural anti-melanogenic agents from brown algae.PMID:36364336 | DOI:10.3390/molecules27217509

Molecules. 2022 Nov 2;27(21):7471. doi: 10.3390/molecules27217471.ABSTRACTThe recovery of industrial by-products is part of the zero-waste circular economy. Lentil seed coats are generally considered to be a waste by-product. However, this low-value by-product is rich in bioactive compounds and may be considered an eco-friendly source of health-promoting phytochemicals. For the first time, a sustainable microwave-assisted extraction technique was applied, and a solvent screening was carried out to enhance the bioactive compound content and the antioxidant activity of green and red lentil hull extracts. With respect to green lentil hull extracts that were obtained with different solvents, the aqueous extract of the red lentil seed coats showed the highest total phenolic and total flavonoid content (TPC = 28.3 ± 0.1 mg GAE/g dry weight, TFC = 1.89 ± 0.01 mg CE/100 mg dry weight, respectively), as well as the highest antioxidant activity, both in terms of the free radical scavenging activity (ABTS, 39.06 ± 0.73 mg TE/g dry weight; DPPH, IC50 = 0.39 μg/mL) and the protection of the neuroblastoma cell line (SH-SY5Y, IC50 = 10.1 ± 0.6 μg/mL), the latter of which has never been investigated so far. Furthermore, a metabolite discovery analysis was for the first time performed on the aqueous extracts of both cultivars using an HPLC separation which was coupled with an Orbitrap-based high-Resolution Mass Spectrometry technique.PMID:36364300 | DOI:10.3390/molecules27217471

Molecules. 2022 Oct 29;27(21):7365. doi: 10.3390/molecules27217365.ABSTRACTMetabolomics is an essential method to study the dynamic changes of metabolic networks and products using modern analytical techniques, as well as reveal the life phenomena and their inherent laws. Currently, more and more attention has been paid to the development of metabolic histochemistry in the fungus field. This paper reviews the application of metabolomics in fungal research from five aspects: identification, response to stress, metabolite discovery, metabolism engineering, and fungal interactions with plants.PMID:36364192 | DOI:10.3390/molecules27217365

Molecules. 2022 Oct 29;27(21):7357. doi: 10.3390/molecules27217357.ABSTRACTDysbiosis is a crucial manifestation of dyslipidemia; however, oral supplementation of probiotic modulates the intestinal commensal composition. The protective mechanism of probiotics against hyperlipidemia is still under investigation. To elucidate the hypolipidemic effect of Lactobacillus rhamnosus TR08 through the analysis of gut microbiota and lipid metabolomics, we investigated changes in gut microbiota and lipid metabolomic phenotypes in mice by real time quantitative PCR and untargeted metabolomics analysis. High fat diet-induced dyslipidemia mice were orally administered with TR08 for 8 weeks. The proinflammatory cytokines (interleukin-2 and interferon-γ) levels in spleen and aortic wall injury in the mice fed with a high-fat diet were inhibited after treatment with TR08 at 1 × 108 CFU per day per mouse. TR08 also reshaped the gut microbiota with increases of the relative abundances of Bifidobacterium and Bacteroides, reduced the abundance of the pro-pathogen bacterial Enterococcus, increased the serum level of short chain fatty acids (SCFAs) contents, and promoted sphingomholipid metabolic pathway. The results indicated that TR08 could improve the intestinal microbiota of mice to increase the production of SCFAs, and then play the anti-inflammation induced by hyperlipidemia and reduce the inflammatory injury of blood vessel wall. Therefore, TR08 can potentially be used as a hypolipidemic effect probiotic in further interventions.PMID:36364184 | DOI:10.3390/molecules27217357

Molecules. 2022 Oct 28;27(21):7343. doi: 10.3390/molecules27217343.ABSTRACTIn the current study, the total content from two Apocynum species leaves (Apocynum venetum and Apocynum hendersonii) collected from the Ili River Valley Region were extracted, and their bioactivities were investigated. The results showed a significant variation in the total flavonoid contents in the leaf samples collected at different periods (June, July, August, and September), with the highest content in August (60.11 ± 0.38 mg RE/g DW for A. venetum and 56.56 ± 0.24 mg RE/g DW for A. hendersonii), and the lowest in June (22.36 ± 0.05 mg RE/g DW for A. venetum and 20.79 ± 0.02 mg RE/g DW for A. hendersonii). The total flavonoid content was comparably higher in A. venetum than in A. hendersonii. Leaves extracts from the two species demonstrated strong bioactivity, which positively correlated with the total flavonoid contents. The anti-oxidative activity of A. venetum was higher than that of A. hendersonii in tandem with its higher flavonoid contents; the antibacterial activity, however, was conversely opposite. Furthermore, a total of 83 flavonoid metabolites were identified in the two species based on UPLC-ESI-MS/MS, out of which 24 metabolites were differentially accumulated. The variability in these metabolites might be the reason for the different bioactivities displayed by the two species. The present study provides insight into the optimal harvest time for Apocynum species planted in the major distribution area of the Ili River Valley and the specific utilization of A. venetum and A. hendersonii.PMID:36364168 | DOI:10.3390/molecules27217343

Molecules. 2022 Oct 26;27(21):7275. doi: 10.3390/molecules27217275.ABSTRACTIn general, food processing and its conditions affect nutrients, bioactive compounds, and sensory characteristics of food products. This research aims to use a non-targeted metabolomics approach based on UPLC-ESI-QTOF-MS to determine how fruit processing can affect the metabolic profile of fruits and, through a comprehensive metabolic analysis, identify possible markers to assess their degree of processing. The present study uses a real case from the food industry to evaluate markers of the processing of strawberry and apple purees industrially elaborated with different processing techniques and conditions. The results from the multivariate analysis revealed that samples were grouped according to the type of processing, evidencing changes in their metabolic profiles and an apparent temperature-dependent effect. These metabolic profiles showed changes according to the relevance of thermal conditions but also according to the exclusively cold treatment, in the case of strawberry puree, and the pressure treatment, in the case of apple puree. After data analysis, seven metabolites were identified and proposed as processing markers: pyroglutamic acid, pteroyl-D-glutamic acid, 2-hydroxy-5-methoxy benzoic acid, and 2-hydroxybenzoic acid β-d-glucoside in strawberry and di-hydroxycinnamic acid glucuronide, caffeic acid and lysoPE(18:3(9Z,12Z,15Z)/0:0) in apple purees. The use of these markers may potentially help to objectively measure the degree of food processing and help to clarify the controversial narrative on ultra-processed foods.PMID:36364102 | DOI:10.3390/molecules27217275

Molecules. 2022 Oct 25;27(21):7208. doi: 10.3390/molecules27217208.ABSTRACTBiochemical investigations were carried out on the embalmed head of Nebiri (Museo Egizio, Turin; S-5109)-an 18th Dynasty Ancient Egyptian dignitary-and on the canopic jar containing his lungs (Museo Egizio, Turin; S. 5111/02) with the aim of characterizing the organ's (lung) specific paleo-proteins and of identifying the compounds used in his embalming "recipe". The application of a functionalized film method allowed us to perform a non-invasive sampling. Paleo-proteomics confirmed the presence of lung tissue-specific proteins (organ specific) as well as the presence of proteins linked to severe inflammation. Paleoproteomics and paleometabolomics further allowed the identification of the main components of Nebiri's embalming recipe: animal fats and glue, balms, essential oils, aromatic plants, heated Pistacia, and coniferous resins. Both the use of Pistacia and coniferous resins in an early 18th Dynasty individual confirm Nebiri's high social status. The technique applied offers a targeted approach to the chemical characterization of human tissues, embalming compounds, and organic materials layering in pottery. The ability of the functionalized film method to harvest all types of compounds, from macromolecules (i.e., proteins) to small molecules (i.e., organic acids) opens a new path in the study of ancient material culture; furthermore, it allows to perform untargeted analysis, which is necessary when no a priori information is available.PMID:36364034 | DOI:10.3390/molecules27217208

Molecules. 2022 Oct 24;27(21):7199. doi: 10.3390/molecules27217199.ABSTRACTSpecies in the fungal genus Rhizopus are able to convert simple sugars into primary metabolites such as fumaric acid, lactic acid, citric acid, and, to a lesser extent, malic acid in the presence of specific carbon and nitrogen sources. This ability has been linked to plant pathogenicity. Rhizopus stolonifer causes hull rot disease in almonds, symptoms of which have been previously associated with the fungus's production of fumaric acid. Six isolates of R. stolonifer taken from infected almond hulls were grown in artificial media amended with one of four carbon sources (glucose, fructose, sucrose, and xylose) and two nitrogen sources (asparagine and ammonium sulphate) chosen based on almond hull composition and used in industry. Proton nuclear magnetic resonance (1H NMR)-based metabolomics identified that R. stolonifer could metabolise glucose, fructose, sucrose, and to a lesser extent xylose, and both nitrogen sources, to produce three metabolites, i.e., fumaric acid, lactic acid, and ethanol, under in vitro conditions. Sugar metabolisation and acid production were significantly influenced by sugar source and isolates, with five isolates depleting glucose most rapidly, followed by fructose, sucrose, and then xylose. The maximum amounts of metabolites were produced when glucose was the carbon source, with fumaric acid produced in higher amounts than lactic acid. Isolate 19A-0069, however, preferred sucrose as the carbon source, and Isolate 19A-0030 produced higher amounts of lactic acid than fumaric acid. This is the first report, to our knowledge, of R. stolonifer producing lactic acid in preference to fumaric acid. Additionally, R. stolonifer isolate 19-0030 was inoculated into Nonpareil almond fruit on trees grown under high- and low-nitrogen and water treatments, and hull compositions of infected and uninfected fruit were analysed using 1H NMR-based metabolomics. Glucose and asparagine content of uninfected hulls was influenced by the nitrogen and water treatments provided to the trees, being higher in the high-nitrogen and water treatments. In infected hulls, glucose and fructose were significantly reduced but not sucrose or xylose. Large amounts of both fumaric and lactic acid were produced, particularly under high-nitrogen treatments. Moreover, almond shoots placed in dilute solutions of fumaric acid or lactic acid developed leaf symptoms very similar to the 'strike' symptoms seen in hull rot disease in the field, suggesting both acids are involved in causing disease.PMID:36364023 | DOI:10.3390/molecules27217199

Molecules. 2022 Oct 22;27(21):7157. doi: 10.3390/molecules27217157.ABSTRACTValorisation of food by-products has recently attracted considerable attention due to the opportunities to improve the economic and environmental sustainability of the food production chain. Large quantities of non-edible parts of the artichoke plant (Cynara cardunculus L.) comprising leaves, stems, roots, bracts, and seeds are discarded annually during industrial processing. These by-products contain many phytochemicals such as dietary fibres, phenolic acids, and flavonoids, whereby the most challenging issue concerns about the recovery of high-added value components from these by-products. The aim of this work is to develop a novel valorisation strategy for the sustainable utilisation of artichoke leaves' waste, combining green pressurised-liquid extraction (PLE), spectrophotometric assays and UPLC-HRMS phytochemical characterization, to obtain bioactive-rich extract with high antioxidant capacity. Multivariate analysis of the major selected metabolites was used to compare different solvent extraction used in PLE.PMID:36363983 | DOI:10.3390/molecules27217157

Microorganisms. 2022 Nov 8;10(11):2205. doi: 10.3390/microorganisms10112205.ABSTRACTRapamycin is a polyketide macrocyclic antibiotic with exceptional pharmacological potential. To explore the potential mechanism of rapamycin overproduction, the intracellular metabolic differences of three chemical elicitor treatments were first investigated by combining them with dynamic metabolomics and network analysis. The metabolic response characteristics of each chemical elicitor treatment were identified by a weighted gene co-expression network analysis (WGCNA) model. According to the analysis of the identified metabolic modules, the changes in the cell membrane permeability might play a key role in rapamycin overproduction for dimethyl sulfoxide (DMSO) treatment. The enhancement of the starter unit of 4,5-dihydroxycyclohex-1-ene carboxylic acid (DHCHC) and the nicotinamide adenine dinucleotide phosphate (NADPH) availability were the main functions in the LaCl3 treatment. However, for sodium butyrate (SB), the improvement of the methylmalonyl-CoA and NADPH availability was a potential reason for the rapamycin overproduction. Further, the responsive metabolic pathways after chemical elicitor treatments were selected to predict the potential key limiting steps in rapamycin accumulation using a genome-scale metabolic network model (GSMM). Based on the prediction results, the targets within the reinforcement of the DHCHC and NADPH supply were selected to verify their effects on rapamycin production. The highest rapamycin yield improved 1.62 fold in the HT-aroA/zwf2 strain compared to the control.PMID:36363797 | DOI:10.3390/microorganisms10112205

J Clin Med. 2022 Nov 1;11(21):6493. doi: 10.3390/jcm11216493.ABSTRACTWe recently described a unique plasma metabolite profile in subjects with pediatric acute-onset neuropsychiatric syndrome (PANS), suggesting pathogenic models involving specific patterns of neurotransmission, neuroinflammation, and oxidative stress. Here, we extend the analysis to a group of patients with autism spectrum disorder (ASD), as a consensus has recently emerged around its immune-mediated pathophysiology with a widespread involvement of brain networks. This observational case-control study enrolled patients referred for PANS and ASD from June 2019 to May 2020, as well as neurotypical age and gender-matched control subjects. Thirty-four PANS outpatients, fifteen ASD outpatients, and twenty-five neurotypical subjects underwent physical and neuropsychiatric evaluations, alongside serum metabolomic analysis with 1H-NMR. In supervised models, the metabolomic profile of ASD was significantly different from controls (p = 0.0001), with skewed concentrations of asparagine, aspartate, betaine, glycine, lactate, glucose, and pyruvate. Metabolomic separation was also observed between PANS and ASD subjects (p = 0.02), with differences in the concentrations of arginine, aspartate, betaine, choline, creatine phosphate, glycine, pyruvate, and tryptophan. We confirmed a unique serum metabolomic profile of PANS compared with both ASD and neurotypical subjects, distinguishing PANS as a pathophysiological entity per se. Tryptophan and glycine appear as neuroinflammatory fingerprints of PANS and ASD, respectively. In particular, a reduction in glycine would primarily affect NMDA-R excitatory tone, overall impairing downstream glutamatergic, dopaminergic, and GABAergic transmissions. Nonetheless, we found metabolomic similarities between PANS and ASD that suggest a putative role of N-methyl-D-aspartate receptor (NMDA-R) dysfunction in both disorders. Metabolomics-based approaches could contribute to the identification of novel ASD and PANS biomarkers.PMID:36362721 | DOI:10.3390/jcm11216493

Int J Mol Sci. 2022 Nov 5;23(21):13569. doi: 10.3390/ijms232113569.ABSTRACTNanmu (Phoebe zhennan) is an extremely valuable tree plant that is the main source of famous "golden-thread nanmu" wood. The potential metabolites and gene regulation mechanisms involved in golden thread formation are poorly understood, even though the color change from sapwood to heartwood has been investigated in several tree plants. Here, five radial tissues from sapwood to heartwood were compared via integrative metabolomic and transcriptomic analysis to reveal the secondary metabolites and molecular mechanisms involved in golden thread formation. During heartwood formation, gradual starch grain loss is accompanied by the cell lumen deposition of lipids and color-related extractives. Extractives of 20 phenylpropanoids accumulated in heartwood, including cinnamic acids and derivatives, coumarin acid derivatives, and flavonoids, which were identified as being closely related to the golden thread. Phenylpropanoids co-occurring with abundant accumulated metabolites of prenol lipids, fatty acyls, steroids, and steroid derivatives may greatly contribute to the characteristics of golden thread formation. Additionally, the expression of nine genes whose products catalyze phenylpropanoid and flavonoids biosynthesis was upregulated in the transition zone, then accumulated and used to color the heartwood. The expression levels of transcription factors (e.g., MYB, bHLH, and WRKY) that act as the major regulatory factors in the synthesis and deposition of phenylpropanoid and flavonoids responsible for golden thread formation were also higher than in sapwood. Our results not only explain golden thread formation in nanmu, but also broaden current knowledge of special wood color formation mechanisms. This work provides a framework for future research focused on improving wood color.PMID:36362363 | DOI:10.3390/ijms232113569

Int J Mol Sci. 2022 Nov 5;23(21):13561. doi: 10.3390/ijms232113561.ABSTRACTCases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and signaling pathway mediated by MK2 in PNETs has not been investigated. To characterize the impact of MK2 on PNET growth, we used the RipTag2 transgenic murine model of PNETs, and we developed a primary PNET cell line for both in vitro and in vivo studies. In the transgenic murine model of PNETs, we found that MK2 inhibition improves survival of mice and prevents PNET progression. MK2 blockade abolished cytokine/chemokine production, which was related to macrophage function. A role for MK2 in the regulation of metabolic factor secretion in PNETs was identified, making this the first study to identify a potential role for the MK2 pathway in regulation of tumor metabolism. Moreover, using an in vitro approach and allograft model of PNETs, we were able to show that macrophages with MK2 depletion exhibit increased cytotoxicity against PNET cells and substantially decreased production of pro-inflammatory cytokines and chemokines, as well as metabolic factors. Taken together, our work identifies MK2 as a potent driver of immune response and metabolic effectors in PNETs, suggesting it is a potential therapeutic target for patients with PNETs.PMID:36362348 | DOI:10.3390/ijms232113561

Int J Mol Sci. 2022 Nov 4;23(21):13546. doi: 10.3390/ijms232113546.ABSTRACTLow temperature is a major environmental factor, which limits rapeseed (Brassica napus L.) growth, development, and productivity. So far, the physiological and molecular mechanisms of rapeseed responses to cold stress are not fully understood. Here, we explored the transcriptome and metabolome profiles of two rapeseed genotypes with contrasting cold responses, i.e., XY15 (cold-sensitive) and GX74 (cold-tolerant). The global metabolome profiling detected 545 metabolites in siliques of both genotypes before (CK) and after cold-stress treatment (LW). The contents of several sugar metabolites were affected by cold stress with the most accumulated saccharides being 3-dehydro-L-threonic acid, D-xylonic acid, inositol, D-mannose, D-fructose, D-glucose, and L-glucose. A total of 1943 and 5239 differentially expressed genes were identified from the transcriptome sequencing in XY15CK_vs_XY15LW and GX74CK_vs_GX74LW, respectively. We observed that genes enriched in sugar metabolism and biosynthesis-related pathways, photosynthesis, reactive oxygen species scavenging, phytohormone, and MAPK signaling were highly expressed in GX74LW. In addition, several genes associated with cold-tolerance-related pathways, e.g., the CBF-COR pathway and MAPK signaling, were specifically expressed in GX74LW. Contrarily, genes in the above-mentioned pathways were mostly downregulated in XY15LW. Thus, our results indicate the involvement of these pathways in the differential cold-stress responses in XY15 and GX74.PMID:36362332 | DOI:10.3390/ijms232113546

Int J Mol Sci. 2022 Nov 4;23(21):13533. doi: 10.3390/ijms232113533.ABSTRACTPod size is one of the important factors affecting peanut yield. However, the metabolites relating to pod size and their biosynthesis regulatory mechanisms are still unclear. In the present study, two peanut varieties (Tif and Lps) with contrasting pod sizes were used for a comparative metabolome and transcriptome analysis. Developing peanut pods were sampled at 10, 20 and 30 days after pegging (DAP). A total of 720 metabolites were detected, most of which were lipids (20.3%), followed by phenolic acids (17.8%). There were 43, 64 and 99 metabolites identified as differentially accumulated metabolites (DAMs) at 10, 20 and 30 DAP, respectively, and flavonoids were the major DAMs between Tif and Lps at all three growth stages. Multi-omics analysis revealed that DAMs and DEGs (differentially expressed genes) were significantly enriched in the phenylpropanoid biosynthesis (ko00940) pathway, the main pathway of lignin biosynthesis, in each comparison group. The comparisons of the metabolites in the phenylpropanoid biosynthesis pathway accumulating in Tif and Lps at different growth stages revealed that the accumulation of p-coumaryl alcohol (H-monolignol) in Tif was significantly greater than that in Lps at 30 DAP. The differential expression of gene-LOC112771695, which is highly correlated with p-coumaryl alcohol and involved in the biosynthesis of monolignols, between Tif and Lps might explain the differential accumulation of p-coumaryl alcohol. The content of H-lignin in genetically diverse peanut varieties demonstrated that H-lignin content affected peanut pod size. Our findings would provide insights into the metabolic factors influencing peanut pod size and guidance for the genetic improvement of the peanut.PMID:36362327 | DOI:10.3390/ijms232113533