PubMed

Genomics. 2023 Jun 28:110675. doi: 10.1016/j.ygeno.2023.110675. Online ahead of print.ABSTRACTMango (Mangifera indica L.) is a widely appreciated tropical fruit for its rich color and nutrition. However, knowledge on the molecular basis of color variation is limited. Here, we studied HY3 (yellowish-white pulp) and YX4 (yellow pulp), reaped with 24 h gap from the standard harvesting time. The carotenoids and total flavonoids increased with the advance of harvest time (YX4 > HY34). Transcriptome sequencing showed that higher expressions of the core carotenoid biosynthesis genes and flavonoid biosynthesis genes are correlated to their respective contents. The endogenous indole-3-acetic acid and jasmonic acid contents decreased but abscisic acid and ethylene contents increased with an increase in harvesting time (YX4 > HY34). Similar trends were observed for the corresponding genes. Our results indicate that the color differences are related to carotenoid and flavonoid contents, which in turn are influenced by phytohormone accumulation and signaling.PMID:37390936 | DOI:10.1016/j.ygeno.2023.110675

J Ethnopharmacol. 2023 Jun 28:116855. doi: 10.1016/j.jep.2023.116855. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Sargentodoxa cuneata and Patrinia villosa (S&P) are two natural herbal medicine widely used for treatment of various inflammatory diseases in Traditional Chinese Medicine, whereas the mode of action needs to be further investigated.AIM OF THE STUDY: This study aimed to explore the anti-inflammatory effects and unravel the involved mechanism of S&P extract.MATERIALS AND METHODS: The components of S&P extract were first detected using the liquid chromatography-tandem mass spectrometry (LC-MS/MS). The effects of S&P extract on the viability and migration ability of macrophages were detected using CCK8, LDH, adhesion and transwell assays. Cytokine release and macrophage phenotype transition were measured using a cytometric bead array and flow cytometry. The potential mechanism was uncovered using an integrative approach combining RNA sequencing and LC-MS/MS-based metabolic analysis. The expression of related proteins was further validated using western blotting.RESULTS: S&P extract inhibited the proliferation and migration of LPS-induced macrophages, changed the morphology of macrophages, and inhibited the production of NO and the expression of iNOS. Furthermore, the extract inhibited tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production and the expression of the M1 phenotype markers CD11c and CD16/32, whereas it promoted interleukin-10 (IL-10) production and the expression of the M2 phenotype markers CD206 and arginase 1 (Arg1). RNA sequencing analysis demonstrated that the upregulated genes by S&P extract treatment were involved in M2 macrophages: Il10, Ccl17, Ccl22, Cd68. The downregulated genes were involved in M1 macrophages and glycolysis processes: Stat1, Il18, Cd80, Cd86, Nos2, Il6, Pik3ap1, Raf1, Pdhb, etc. Metabolomics results showed that the S&P extract strongly ameliorated lipopolysaccharide (LPS)-induced metabolic disturbances. KEGG analysis indicated that most of these metabolites were involved in glucose metabolism, which is involved in the tumor necrosis factor (TNF), phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt), Glycolysis, and mitogen-activated protein kinase (MAPK) pathways. In vitro experiments further confirmed that the extract significantly inhibited the phosphorylation of focal adhesion kinase (FAK), PI3K and Akt, and the expression of glucose metabolism-related proteins. Adding a FAK inhibitor (defactinib) further inhibited the expression of M1/M2 phenotypic markers and the phosphorylation of FAK, PI3K, and Akt.CONCLUSIONS: S&P extract can induce M2 polarization and shift macrophages from M1 to M2 tissue repair in LPS-induced inflammation by regulating glucose metabolism and the FAK/PI3K/Akt pathway.PMID:37390878 | DOI:10.1016/j.jep.2023.116855

Food Chem. 2023 Jun 25;427:136711. doi: 10.1016/j.foodchem.2023.136711. Online ahead of print.ABSTRACTRoasting is essential for processing large-leaf yellow tea (LYT). However, the effect of the roasting on the metabolic and sensory profiles of LYT remains unknown. Herein, the metabolomics and sensory quality of LYT at five roasting degrees were evaluated by liquid/gas chromatography mass spectrometry and quantitative descriptive analysis. A higher degree of roasting resulted in a significantly stronger crispy rice, fried rice, and smoky-burnt aroma (p < 0.05), which is closely associated with heterocyclic compound accumulation (concentrations: 6.47 ± 0.27 - 1065.00 ± 5.58 µg/g). Amino acids, catechins, flavonoid glycosides and N-ethyl-2-pyrrolidone-substituted flavan-3-ol varied with roasting degree. The enhancement of crispy-rice and burnt flavor coupled with the reduction of bitterness and astringency. Correlations analysis revealed the essential compounds responsible for roasting degree, including 2,3-diethyl-5-methylpyrazine, hexanal, isoleucine, N-ethyl-2-pyrrolidone-substituted flavan-3-ol (EPSF), and others. These findings provide a theoretical basis for improving the specific flavors of LYT.PMID:37390734 | DOI:10.1016/j.foodchem.2023.136711

J Pharm Biomed Anal. 2023 Jun 26;234:115548. doi: 10.1016/j.jpba.2023.115548. Online ahead of print.ABSTRACTColorectal cancer is a highly prevalent malignancy that threatens human health worldwide. Despite the availability of chemotherapy as a primary treatment option, individuals with CRC undergoing frequent chemotherapy are susceptible to developing drug resistance, which can result in poor treatment outcomes. Consequently, there is an urgent need to discover new bioactive compounds for the treatment of CRC. Capilliposide A is a triterpenoid saponin that is extracted from Lysimachia capillipes Hemsl. Although it has been reported that LC-A exhibits good bioactivity, its metabolic profile and potential mechanism underlying its anti-CRC effects remain unknown. In this study, the metabolic products of LC-A in rat plasma, feces, and urine were identified using an LC-MS platform. In addition, LC-MS-based metabolomics was employed to investigate the mechanism of LC-A against CRC. The results showed that LC-A significantly inhibited CRC cell proliferation, attenuated tumor growth, and alleviated metabolic abnormalities in CRC-bearing mice. Furthermore, the levels of p-cresol sulfate and phenylacetylglycine in CRC model plasma decreased, with an increment in sphingosine 1-phosphate, D-tryptophan, and L-2-aminoadipic acid. These metabolite levels can be reversed by LC-A treatment. These metabolite alterations were related to the sphingolipid and amino acid metabolic pathways, demonstrating that LC-A anti-CRC effects were regulated through the modulation of underlying metabolism. Additionally, seven metabolites of LC-A were characterized in rat feces, plasma, and urine. This study offers a scientific foundation for elucidating the metabolism of LC-A and its treatment of colorectal cancer.PMID:37390605 | DOI:10.1016/j.jpba.2023.115548

Poult Sci. 2023 Jun 14;102(9):102856. doi: 10.1016/j.psj.2023.102856. Online ahead of print.ABSTRACTThe gut microbiota is known to have significant involvement in the regulation of lipogenesis and adipogenesis, yet the mechanisms responsible for this relationship remain poorly understood. The current study aims to provide insight into the potential mechanisms by which the gut microbiota modulates lipogenesis in chickens. Using chickens fed with a normal-fat diet (NFD, n = 5) and high-fat diet (HFD, n = 5), we analyzed the correlation between gut microbiota, cecal metabolomics, and lipogenesis by 16s rRNA sequencing, miRNA and mRNA sequencing as well as targeted metabolomics analysis. The potential metabolite/miRNA/mRNA axis regulated by gut microbiota was identified using chickens treated with antibiotics (ABX, n = 5). The possible mechanism of gut microbiota regulating chicken lipogenesis was confirmed by fecal microbiota transplantation (FMT) from chickens fed with NFD to chickens fed with HFD (n = 5). The results showed that HFD significantly altered gut microbiota composition and enhanced chicken lipogenesis, with a significant correlation between 3. Furthermore, HFD significantly altered the hepatic miRNA expression profiles and reduced the abundance of hepatic butyric acid. Procrustes analysis indicated that the HFD-induced dysbiosis of the gut microbiota might affect the expression profiles of hepatic miRNA. Specifically, HFD-induced gut microbiota dysbiosis may reduce the abundance of butyric acid and downregulate the expression of miR-204 in the liver. Multiomics analysis identified ACSS2 as a target gene of miR-204. Gut microbiota depletion by an antibiotic cocktail (ABX) showed a gut microbiota-dependent manner in the abundance of butyric acid and the expression of miR-204/ACSS2, which have been observed to be significantly correlated. Fecal microbiota transplantation from NFD chickens into HFD chickens effectively attenuated the HFD-induced excessive lipogenesis, elevated the abundance of butyric acid and the relative expression of miR-204, and reduced the expression of ACSS2 in the liver. Mechanistically, our results showed that the gut microbiota plays an antiobesity role by regulating the butyric acid/miR-204/ACSS2 axis in chickens. This work contributed to a better understanding of the functions of gut microbiota in regulating chicken lipogenesis.PMID:37390560 | DOI:10.1016/j.psj.2023.102856

Anal Chem. 2023 Jun 30. doi: 10.1021/acs.analchem.3c00957. Online ahead of print.ABSTRACTGlycosylation of metabolites serves multiple purposes. Adding sugars makes metabolites more water soluble and improves their biodistribution, stability, and detoxification. In plants, the increase in melting points enables storing otherwise volatile compounds that are released by hydrolysis when needed. Classically, glycosylated metabolites were identified by mass spectrometry (MS/MS) using [M-sugar] neutral losses. Herein, we studied 71 pairs of glycosides with their respective aglycones, including hexose, pentose, and glucuronide moieties. Using liquid chromatography (LC) coupled to electrospray ionization high-resolution mass spectrometry, we detected the classic [M-sugar] product ions for only 68% of glycosides. Instead, we found that most aglycone MS/MS product ions were conserved in the MS/MS spectra of their corresponding glycosides, even when no [M-sugar] neutral losses were observed. We added pentose and hexose units to the precursor masses of an MS/MS library of 3057 aglycones to enable rapid identification of glycosylated natural products with standard MS/MS search algorithms. When searching unknown compounds in untargeted LC-MS/MS metabolomics data of chocolate and tea, we structurally annotated 108 novel glycosides in standard MS-DIAL data processing. We uploaded this new in silico-glycosylated product MS/MS library to GitHub to enable users to detect natural product glycosides without authentic chemical standards.PMID:37390485 | DOI:10.1021/acs.analchem.3c00957

Arthritis Rheumatol. 2023 Jun 30. doi: 10.1002/art.42635. Online ahead of print.ABSTRACTOBJECTIVES: To discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and establish a predictive model by machine learning (ML) algorithms.METHODS: Serum samples from a discovery cohort with 163 InGF and 239 FrGF patients were analyzed by mass spectrometry-based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation-based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF.RESULTS: 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross-talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML-based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively.CONCLUSIONS: Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.PMID:37390372 | DOI:10.1002/art.42635

Front Med. 2023 Jun 30. doi: 10.1007/s11684-023-0989-7. Online ahead of print.ABSTRACTMigraine is one of the most prevalent and disabling neurological disease, but the current pharmacotherapies show limited efficacy and often accompanied by adverse effects. Acupuncture is a promising complementary therapy, but further clinical evidence is needed. The influence of acupuncture on migraine is not an immediate effect, and its mechanism remains unclear. This study aims to provide further clinical evidence for the anti-migraine effects of acupuncture and explore the mechanism involved. A randomized controlled trial was performed among 10 normal controls and 38 migraineurs. The migraineurs were divided into blank control, sham acupuncture, and acupuncture groups. Patients were subjected to two courses of treatment, and each treatment lasted for 5 days, with an interval of 1 day between the two courses. The effectiveness of treatment was evaluated using pain questionnaire. The functional magnetic resonance imaging (fMRI) data were analyzed for investigating brain changes induced by treatments. Blood plasma was collected for metabolomics and proteomics studies. Correlation and mediation analyses were performed to investigate the interaction between clinical, fMRI and omics changes. Results showed that acupuncture effectively relieved migraine symptoms in a way different from sham acupuncture in terms of curative effect, affected brain regions, and signaling pathways. The anti-migraine mechanism involves a complex network related to the regulation of the response to hypoxic stress, reversal of brain energy imbalance, and regulation of inflammation. The brain regions of migraineurs affected by acupuncture include the lingual gyrus, default mode network, and cerebellum. The effect of acupuncture on patients' metabolites/proteins may precede that of the brain.PMID:37389804 | DOI:10.1007/s11684-023-0989-7

Ann Surg. 2023 Jun 30. doi: 10.1097/SLA.0000000000005973. Online ahead of print.ABSTRACTOBJECTIVE AND SUMMARY BACKGROUND DATA: Propranolol, a non-selective beta receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta blockade are well characterized, the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves outcomes after burn injury by profoundly modulating metabolic pathways.METHODS: In this phase II randomized controlled trial, patients with burns ≥20% of total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, inflammatory and lipidomic profiles, untargeted metabolomics, and molecular pathways.RESULTS: Fifty-two severely burned patients were enrolled in this trial (propranolol n=23 and controls n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism, as well as catecholamine degradation (P<0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of pro-inflammatory palmitic acid (P<0.05) and saturated fatty acids (P<0.05) with an increased ratio of polyunsaturated fatty acids (P<0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn (P<0.05). These metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 (P<0.05) and significantly reduced ER stress by decreasing p-JNK (P<0.05).CONCLUSIONS: Propranolol's ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses.PMID:37389480 | DOI:10.1097/SLA.0000000000005973

Front Microbiol. 2023 Jun 14;14:1188455. doi: 10.3389/fmicb.2023.1188455. eCollection 2023.ABSTRACTPharmacological treatment of inflammatory bowel disease (IBD) is inefficient and difficult to discontinue appropriately, and enterobacterial interactions are expected to provide a new target for the treatment of IBD. We collected recent studies on the enterobacterial interactions among the host, enterobacteria, and their metabolite products and discuss potential therapeutic options. Intestinal flora interactions in IBD are affected in the reduced bacterial diversity, impact the immune system and are influenced by multiple factors such as host genetics and diet. Enterobacterial metabolites such as SCFAs, bile acids, and tryptophan also play important roles in enterobacterial interactions, especially in the progression of IBD. Therapeutically, a wide range of sources of probiotics and prebiotics exhibit potential therapeutic benefit in IBD through enterobacterial interactions, and some have gained wide recognition as adjuvant drugs. Different dietary patterns and foods, especially functional foods, are novel therapeutic modalities that distinguish pro-and prebiotics from traditional medications. Combined studies with food science may significantly improve the therapeutic experience of patients with IBD. In this review, we provide a brief overview of the role of enterobacteria and their metabolites in enterobacterial interactions, discuss the advantages and disadvantages of the potential therapeutic options derived from such metabolites, and postulate directions for further research.PMID:37389342 | PMC:PMC10303177 | DOI:10.3389/fmicb.2023.1188455

Front Plant Sci. 2023 Jun 14;14:1175012. doi: 10.3389/fpls.2023.1175012. eCollection 2023.ABSTRACTINTRODUCTION: Titanium dioxide nanoparticles (TiO2 NPs) are among the most widely used inorganic nanomaterials in industry, medicine and food additives. There are increasing concerns regarding their potential risks to plants and the environment. Mulberry trees are widely grown in China due to their high survival rate and ability to aid ecological recovery.METHODS: Herein, the effects of TiO2 NPs with different concentrations (100, 200, 400 and 800 mg/L) on the growth and physiology of the mulberry tree were systematically evaluated in aspects of physiology, transcriptomics and metabolomics.RESULTS: Results showed that TiO2 NPs could be absorbed by the mulberry sapling root system and be transferred to the plant shoot. This results in the destruction of mulberry sapling root and leaf tissue. Furthermore, the number of chloroplasts and their pigment contents were reduced and the homeostasis of metal ions was disrupted. The toxic effects of TiO2 NPs attenuated the mulberry sapling's stress resistance, the contents of malondialdehyde in 100 mg/L, 200 mg/L 400 mg/L and 800 mg/L treatment groups increased by 87.70%, 91.36%, 96.57% and 192.19% respectively compared with the control group. The transcriptomic data showed that TiO2 NPs treatment mainly affected the expression of genes related to energy synthesis and transport, protein metabolism, and response to stress. Meanwhile, the results of metabolomics showed that 42 metabolites produced significant differences in mulberry, of which 26 differential metabolites were up-regulated in expression and 16 differential metabolites were down-regulated, mainly including metabolic pathways such as secondary metabolite biosynthesis, citric acid cycle, and tricarboxylic acid cycle, and was not conducive to the seed germination and or growth of the mulberry sapling.DISCUSSION: This study enriches the understanding of the effects of TiO2 NPs on plants and provides a reference for the comprehensive scientific assessment of the potential risks of nanomaterials on plants.PMID:37389295 | PMC:PMC10301732 | DOI:10.3389/fpls.2023.1175012

Front Plant Sci. 2023 Jun 14;14:1187551. doi: 10.3389/fpls.2023.1187551. eCollection 2023.ABSTRACTINTRODUCTION: Apricot fruits are edible and serve as a source of medicinal compounds. Flavonols are important plant secondary metabolites that have antioxidant and antitumor effects and may promote cardiovascular health.METHODS: The flavonoid content in three stages of the 'Kuijin' and the 'Katy' was observed, followed by the combination of metabolome and transcriptome analysis to explore the metabolic basis of flavonol synthesis.RESULTS: The differences in the metabolite contents between stages (of the same cultivar) and between cultivars (at the same stage) revealed decreases in the flavonoid content as fruits developed (i.e., from 0.28 mg/g to 0.12 mg/g in 'Kuijin' and from 0.23 mg/g to 0.05 mg/g in 'Katy'). To decipher the regulation of flavonol synthesis in apricot (Prunus armeniaca L.), the metabolomes and transcriptomes of fruit pulp at three developmental stages of 'Kuijin' and the 'Katy' were analyzed. A total of 572 metabolites were detected in 'Kuijin' and the 'Katy' pulp, including 111 flavonoids. The higher flavonol content young 'Kuijin' fruits at 42 days after full bloom is mainly due to 10 types of flavonols. Three pairs of significant differences in flavonol content were identified. From these three comparison groups, three structural genes were strongly correlated with the levels of 10 types of flavonols (Pearson correlation coefficients > 0.8, p value < 0.05), including PARG09190, PARG15135, and PARG17939. The weighted gene co-expression network analysis showed that the turquoise module genes were highly correlated with flavonol contents (P < 0.01). There were 4897 genes in this module. Out of 4897 genes, 28 transcription factors are associated with 3 structural genes based on weight value. Two of the transcription factors are not only associated with PARG09190 but also with PARG15135, indicating their critical importance in the flavonols biosynthesis. The two TFs are PARG27864 and PARG10875.DISCUSSION: These findings provide new insights into the biosynthesis of flavonols and may explain the significant differences in flavonoid content between the 'Kuijin' and the 'Katy' cultivars. Moreover, it will aid in genetic improvement to enhance the nutritional and health value of apricots.PMID:37389287 | PMC:PMC10303810 | DOI:10.3389/fpls.2023.1187551

World J Gastroenterol. 2023 Jun 14;29(22):3534-3547. doi: 10.3748/wjg.v29.i22.3534.ABSTRACTBACKGROUND: Alterations in plasma and intestinal metabolites contribute to the pathogenesis and progression of alcohol-related liver cirrhosis (ALC).AIM: To explore the common and different metabolites in the plasma and feces of patients with ALC and evaluate their clinical implications.METHODS: According to the inclusion and exclusion criteria, 27 patients with ALC and 24 healthy controls (HCs) were selected, and plasma and feces samples were collected. Liver function, blood routine, and other indicators were detected with automatic biochemical and blood routine analyzers. Liquid chromatography-mass spectrometry was used to detect the plasma and feces metabolites of the two groups and the metabolomics of plasma and feces. Also, the correlation between metabolites and clinical features was analyzed.RESULTS: More than 300 common metabolites were identified in the plasma and feces of patients with ALC. Pathway analysis showed that these metabolites are enriched in bile acid and amino acid metabolic pathways. Compared to HCs, patients with ALC had a higher level of glycocholic acid (GCA) and taurocholic acid (TCA) in plasma and a lower level of deoxycholic acid (DCA) in the feces, while L-threonine, L-phenylalanine, and L-tyrosine increased simultaneously in plasma and feces. GCA, TCA, L-methionine, L-phenylalanine, and L-tyrosine in plasma were positively correlated with total bilirubin (TBil), prothrombin time (PT), and maddrey discriminant function score (MDF) and negatively correlated with cholinesterase (CHE) and albumin (ALB). The DCA in feces was negatively correlated with TBil, MDF, and PT and positively correlated with CHE and ALB. Moreover, we established a P/S BA ratio of plasma primary bile acid (GCA and TCA) to fecal secondary bile acid (DCA), which was relevant to TBil, PT, and MDF score.CONCLUSION: The enrichment of GCA, TCA, L-phenylalanine, L-tyrosine, and L-methionine in the plasma of patients with ALC and the reduction of DCA in feces were related to the severity of ALC. These metabolites may be used as indicators to evaluate the progression of alcohol-related liver cirrhosis.PMID:37389241 | PMC:PMC10303510 | DOI:10.3748/wjg.v29.i22.3534

iScience. 2023 Jun 7;26(7):107046. doi: 10.1016/j.isci.2023.107046. eCollection 2023 Jul 21.ABSTRACTWeight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to ad-libitum (AL)-fed controls. Analysis of liver and blood metabolome and transcriptome revealed distinct and sometimes contrasting metabolic effects between the two interventions. SG primarily influenced one-carbon metabolic pathways, whereas IF-CR increased de novo lipogenesis and glycogen storage. These findings suggest that the unique metabolic pathways affected by SG and IF-CR contribute to their distinct clinical benefits, with bariatric surgery potentially influencing long-lasting changes through its effect on one-carbon metabolism.PMID:37389181 | PMC:PMC10300224 | DOI:10.1016/j.isci.2023.107046

Oncoimmunology. 2023 Jun 27;12(1):2227510. doi: 10.1080/2162402X.2023.2227510. eCollection 2023.ABSTRACTToll-like receptor 3 (TLR3) agonists such as polyinosinic:polycytidylic acid (poly(I:C)) have immunostimulatory effects that can be taken advantage of to induce anticancer immune responses in preclinical models. In addition, poly(I:C) has been introduced into clinical trials to demonstrate its efficacy as an adjuvant and to enhance the immunogenicity of locally injected tumors, thus reverting resistance to PD-L1 blockade in melanoma patients. Here, we report the pharmacokinetic, pharmacodynamic, mechanistic and toxicological profile of a novel TLR3 agonist, TL-532, a chemically synthesized double-stranded RNA that is composed by blocks of poly(I:C) and poly(A:U) (polyadenylic - polyuridylic acid). In preclinical models, we show that TL-532 is bioavailable after parenteral injection, has an acceptable toxicological profile, and stimulates the production of multiple chemokines and interleukins that constitute pharmacodynamic markers of its immunostimulatory action. When given at a high dose, TL-532 monotherapy reduced the growth of bladder cancers growing on mice. In addition, in immunodeficient mice lacking formylpeptide receptor-1 (FPR1), TL-532 was able to restore the response of orthotopic subcutaneous fibrosarcoma to immunogenic chemotherapy. Altogether, these findings may encourage further development of TL-532 as an immunotherapeutic anticancer agent.PMID:37389102 | PMC:PMC10305499 | DOI:10.1080/2162402X.2023.2227510

Trends Analyt Chem. 2023 Aug;165:117117. doi: 10.1016/j.trac.2023.117117. Epub 2023 Jun 1.ABSTRACTTissues and other cell populations are highly heterogeneous at the cellular level, owing to differences in expression and modifications of proteins, polynucleotides, metabolites, and lipids. The ability to assess this heterogeneity is crucial in understanding numerous biological phenomena, including various pathologies. Traditional analyses apply bulk-cell sampling, which masks the potentially subtle differences between cells that can be important in understanding of biological processes. These limitations due to cell heterogeneity inspired significant efforts and interest toward the analysis of smaller sample sizes, down to the level of individual cells. Among the emerging techniques, the unique capabilities of capillary electrophoresis coupled with mass spectrometry (CE-MS) made it a prominent technique for proteomics and metabolomics analysis at the single-cell level. In this review, we focus on the application of CE-MS in the proteomic and metabolomic profiling of single cells and highlight the recent advances in sample preparation, separation, MS acquisition, and data analysis.PMID:37388554 | PMC:PMC10306258 | DOI:10.1016/j.trac.2023.117117

Front Pharmacol. 2023 Jun 14;14:1235626. doi: 10.3389/fphar.2023.1235626. eCollection 2023.ABSTRACT[This corrects the article DOI: 10.3389/fphar.2022.961087.].PMID:37388450 | PMC:PMC10303910 | DOI:10.3389/fphar.2023.1235626

Cardiovasc Ther. 2023 Jun 21;2023:8774971. doi: 10.1155/2023/8774971. eCollection 2023.ABSTRACTBACKGROUND: To date, immunotherapy for patients with malignant tumors has shown a significant association with myocarditis. However, the mechanism of metabolic reprogramming changes for immunotherapy-related cardiotoxicity is still not well understood.METHODS: The CD45+ single-cell RNA sequencing (scRNA-seq) of the Pdcd1-/-Ctla4+/- and wild-type mouse heart in GSE213486 was downloaded to demonstrate the heterogeneity of immunocyte atlas in immunotherapy-related myocarditis. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrum metabolomics analysis detects the metabolic network differences. The drug prediction, organelle level interaction, mitochondrial level regulatory network, and phosphorylation site prediction for key regulators have also been screened via multibioinformatics analysis methods.RESULTS: The scRNA analysis shows that the T cell is the main regulatory cell subpopulation in the pathological progress of immunotherapy-related myocarditis. Mitochondrial regulation pathway significantly participated in pseudotime trajectory- (PTT-) related differential expressed genes (DEGs) in the T cell subpopulation. Additionally, both the gene set enrichment analysis (GSEA) of PTT-related DEGs and LC-MS/MS metabolomics analysis showed that mitochondrial-regulated glycerolipid metabolism plays a central role in metabolic reprogramming changes for immunotherapy-related cardiotoxicity. Finally, the hub-regulated protease of diacylglycerol kinase zeta (Dgkz) was significantly identified and widely played various roles in glycerolipid metabolism, oxidative phosphorylation, and lipid kinase activation.CONCLUSION: Mitochondrial-regulated glycerolipid metabolism, especially the DGKZ protein, plays a key role in the metabolic reprogramming of immunotherapy-related myocarditis.PMID:37388276 | PMC:PMC10307211 | DOI:10.1155/2023/8774971

Plant Biotechnol J. 2023 Jun 30. doi: 10.1111/pbi.14112. Online ahead of print.ABSTRACTLow temperature is the main environmental factor affecting the yield, quality and geographical distribution of crops, which significantly restricts development of the fruit industry. The NAC (NAM, ATAF1/2 and CUC2) transcription factor (TF) family is involved in regulating plant cold tolerance, but the mechanisms underlying these regulatory processes remain unclear. Here, the NAC TF MdNAC104 played a positive role in modulating apple cold tolerance. Under cold stress, MdNAC104-overexpressing transgenic plants exhibited less ion leakage and lower ROS (reactive oxygen species) accumulation, but higher contents of osmoregulatory substances and activities of antioxidant enzymes. Transcriptional regulation analysis showed that MdNAC104 directly bound to the MdCBF1 and MdCBF3 promoters to promote expression. In addition, based on combined transcriptomic and metabolomic analyses, as well as promoter binding and transcriptional regulation analyses, we found that MdNAC104 stimulated the accumulation of anthocyanin under cold conditions by upregulating the expression of anthocyanin synthesis-related genes, including MdCHS-b, MdCHI-a, MdF3H-a and MdANS-b, and increased the activities of the antioxidant enzymes by promoting the expression of the antioxidant enzyme-encoding genes MdFSD2 and MdPRXR1.1. In conclusion, this study revealed the MdNAC104 regulatory mechanism of cold tolerance in apple via CBF-dependent and CBF-independent pathways.PMID:37387580 | DOI:10.1111/pbi.14112

Expert Rev Anti Infect Ther. 2023 Jun 30. doi: 10.1080/14787210.2023.2232112. Online ahead of print.ABSTRACTOBJECTIVES: Evaluation of the antifungal properties of Tamarix nilotica fractions against Candida albicans clinical isolates.METHODS: The in vitro antifungal potential was evaluated by agar well diffusion and broth microdilution methods. The antibiofilm potential was assessed by crystal violet, scanning electron microscopy (SEM), and qRT-PCR. The in vivo antifungal activity was evaluated by determining the burden in the lung tissues of infected mice, histopathological, immunohistochemical studies, and ELISA.RESULTS: Both the dichloromethane (DCM) and ethyl acetate (EtOAc) fractions had minimum inhibitory concentration (MIC) values of 64-256 and 128-1024 μg/mL, respectively. SEM examination showed that the DCM fraction decreased the biofilm formation capacity of the treated isolates. A significant decline in biofilm gene expression was observed in 33.33% of the DCM-treated isolates. A considerable decline in the CFU/g lung count in infected mice was observed, and histopathological examinations revealed that the DCM fraction maintained the lung tissue architecture. Immunohistochemical investigations indicated that the DCM fraction significantly (p < 0.05) decreased the expression of pro-inflammatory and inflammatory cytokines (TNF-α, NF-kB, COX-2, IL-6, and IL-1β) in the immunostained lung sections. The phytochemical profiling of DCM and EtOAc fractions was performed using Liquid chromatography-mass spectrometry (LC-ESI-MS/MS).CONCLUSION: T. nilotica DCM fraction could be a significant source of natural products with antifungal activity against C. albicans infections.PMID:37387417 | DOI:10.1080/14787210.2023.2232112