PubMed

Drug Dev Res. 2023 Sep 28. doi: 10.1002/ddr.22119. Online ahead of print.ABSTRACTGlioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV-TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM-derived astrocytes and OECs-TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC-TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs-TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase-3 in the coculture of OECs-TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC-TK/GCV gene therapy on GBM cells.PMID:37769152 | DOI:10.1002/ddr.22119

J Nanobiotechnology. 2023 Sep 28;21(1):352. doi: 10.1186/s12951-023-02105-9.ABSTRACTBACKGROUND: Macrophages are highly plastic innate immune cells that play key roles in host defense, tissue repair, and homeostasis maintenance. In response to divergent stimuli, macrophages rapidly alter their functions and manifest a wide polarization spectrum with two extremes: M1 or classical activation and M2 or alternative activation. Extracellular vesicles (EVs) secreted from differentially activated macrophages have been shown to have diverse functions, which are primarily attributed to their microRNA cargos. The role of protein cargos in these EVs remains largely unexplored. Therefore, in this study, we focused on the protein cargos in macrophage-derived EVs.RESULTS: Naïve murine bone marrow-derived macrophages were treated with lipopolysaccharide or interlukin-4 to induce M1 or M2 macrophages, respectively. The proteins of EVs and their parental macrophages were subjected to quantitative proteomics analyses, followed by bioinformatic analyses. The enriched proteins of M1-EVs were involved in proinflammatory pathways and those of M2-EVs were associated with immunomodulation and tissue remodeling. The signature proteins of EVs shared a limited subset of the proteins of their respective progenitor macrophages, but they covered many of the typical pathways and functions of their parental cells, suggesting their respective M1-like and M2-like phenotypes and functions. Experimental examination validated that protein cargos in M1- or M2-EVs induced M1 or M2 polarization, respectively. More importantly, proteins in M1-EVs promoted viability, proliferation, and activation of T lymphocytes, whereas proteins in M2-EVs potently protected the tight junction structure and barrier integrity of epithelial cells from disruption. Intravenous administration of M2-EVs in colitis mice led to their accumulation in the colon, alleviation of colonic inflammation, promotion of M2 macrophage polarization, and improvement of gut barrier functions. Protein cargos in M2-EVs played a key role in their protective function in colitis.CONCLUSION: This study has yielded a comprehensive unbiased dataset of protein cargos in macrophage-derived EVs, provided a systemic view of their potential functions, and highlighted the important engagement of protein cargos in the pathophysiological functions of these EVs.PMID:37770932 | DOI:10.1186/s12951-023-02105-9

BMC Plant Biol. 2023 Sep 29;23(1):455. doi: 10.1186/s12870-023-04470-x.ABSTRACTBACKGROUND: Salt stress is one of the key factors limiting rice production. Alginate oligosaccharides (AOS) enhance plant stress resistance. However, the molecular mechanism underlying salt tolerance in rice induced by AOS remains unclear. FL478, which is a salt-tolerant indica recombinant inbred line and IR29, a salt-sensitive rice cultivar, were used to comprehensively analyze the effects of AOS sprayed on leaves in terms of transcriptomic and metabolite profiles of rice seedlings under salt stress.RESULTS: In this experiment, exogenous application of AOS increased SOD, CAT and APX activities, as well as GSH and ASA levels to reduce the damage to leaf membrane, increased rice stem diameter, the number of root tips, aboveground and subterranean biomass, and improved rice salt tolerance. Comparative transcriptomic analyses showed that the regulation of AOS combined with salt treatment induced the differential expression of 305 and 1030 genes in FL478 and IR29. The expressed genes enriched in KEGG pathway analysis were associated with antioxidant levels, photosynthesis, cell wall synthesis, and signal transduction. The genes associated with light-trapping proteins and RLCK receptor cytoplasmic kinases, including CBA, LHCB, and Lhcp genes, were fregulated in response to salt stress. Treatment with AOS combined with salt induced the differential expression of 22 and 50 metabolites in FL478 and IR29. These metabolites were mainly related to the metabolism of amino and nucleotide sugars, tryptophan, histidine, and β -alanine. The abundance of metabolites associated with antioxidant activity, such as 6-hydroxymelatonin, wedelolactone and L-histidine increased significantly. Combined transcriptomic and metabolomic analyses revealed that dehydroascorbic acid in the glutathione and ascorbic acid cycles plays a vital role in salt tolerance mediated by AOS.CONCLUSION: AOS activate signal transduction, regulate photosynthesis, cell wall formation, and multiple antioxidant pathways in response to salt stress. This study provides a molecular basis for the alleviation of salt stress-induced damage by AOS in rice.PMID:37770835 | DOI:10.1186/s12870-023-04470-x

Trop Anim Health Prod. 2023 Sep 28;55(5):340. doi: 10.1007/s11250-023-03733-x.ABSTRACTThe neonate with low birth weight (LBW) resulted from intrauterine growth retardation (IUGR) exists a substantial risk of postpartum death. Placental insufficiency is responsible for inadequate fetal growth; however, the pathological mechanisms of placental dysfunction-induced IUGR in pigs remain unclear. In this study, the characteristics of placental morphology, placental transcriptome, and cord serum metabolome were explored between the Kele piglets with LBW and the ones with normal birth weight (NBW). Results showed that LBW was a common occurrence in Kele piglets. The LBW placentas showed inferior villus development and lower villi density compared to NBW placentas. There were 1024 differentially expressed genes (DEGs) identified by transcriptome analysis between the LBW and NBW placentas, of which 218 and 806 genes were up- and down-regulated in the LBW placentas, respectively. PPI network analysis showed that ITGB2, CD4, IL6, ITGB3, LCK, RAC2, CD8A, JAK3, TYROBP, and CXCR4 were hub genes in all DEGs. From GO and KEGG enrichment analysis, DEGs were primarily enriched in immunological response, cell adhesion, immune response, cytokine-cytokine receptor interaction, and PI3K-Akt signaling pathway. By using metabolomic analysis, a total of 115 differential metabolites in the cord serum of LBW and NBW piglets were found, mostly linked to amino acid metabolism and sphingolipid metabolism. In comparison to NBW piglets, LBW piglets had lower levels of arginine, isoleucine, and aspartic acid in the cord. Taken together, these data revealed dysplasia of the placental villus, insufficient supply of nutrients, and abnormal immune function of the placenta may be associated with the occurrence and development of LBW in Kele pigs.PMID:37770796 | DOI:10.1007/s11250-023-03733-x

Cell Mol Life Sci. 2023 Sep 28;80(10):309. doi: 10.1007/s00018-023-04963-w.ABSTRACTBacterial endophthalmitis is a severe complication of eye surgeries that can lead to vision loss. Current treatment involves intravitreal antibiotic injections that control bacterial growth but not inflammation. To identify newer therapeutic targets to promote inflammation resolution in endophthalmitis, we recently employed an untargeted metabolomics approach. This led to the discovery that the levels of S-nitroso-L-glutathione (GSNO) were significantly reduced in an experimental murine Staphylococcus aureus (SA) endophthalmitis model. In this study, we tested the hypothesis whether GSNO supplementation via different routes (oral, intravitreal) provides protection during bacterial endophthalmitis. Our results show that prophylactic administration of GSNO via intravitreal injections ameliorated SA endophthalmitis. Therapeutically, oral administration of GSNO was found to be most effective in reducing intraocular inflammation and bacterial burden. Moreover, oral GSNO treatment synergized with intravitreal antibiotic injections in reducing the severity of endophthalmitis. Furthermore, in vitro experiments using cultured human retinal Muller glia and retinal pigment epithelial (RPE) cells showed that GSNO treatment reduced SA-induced inflammatory mediators and cell death. Notably, both in-vivo and ex-vivo data showed that GSNO strengthened the outer blood-retinal barrier during endophthalmitis. Collectively, our study demonstrates GSNO as a potential therapeutic agent for the treatment of intraocular infections due to its dual anti-inflammatory and cytoprotective properties.PMID:37770649 | DOI:10.1007/s00018-023-04963-w

Arch Pharm (Weinheim). 2023 Sep 28:e2300382. doi: 10.1002/ardp.202300382. Online ahead of print.ABSTRACTIn recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques. The synthesized boron-containing drug candidates were found to significantly inhibit cell proliferation and induce apoptosis-mediated cell death in HT-29 (colorectal cells), SaOs-2 (osteosarcoma cells), and U87-MG (glioblastoma cells). Moreover, we revealed that the anticancer effects of boron-containing fingolimod compounds were found to be significantly enhanced over boron-free control groups and, strikingly, over the widely used anticancer drug 5-fluorouracil. The metabolomic analysis confirmed that administration of the boron-containing drug candidates induces significant changes in the metabolite profiles in HT-29, SaOs-2, and U87-MG cells. Altogether, our results showed that boron-containing fingolimod compounds can be further examined to reveal their potential as anticancer drug candidates.PMID:37768844 | DOI:10.1002/ardp.202300382

Environ Sci Technol. 2023 Sep 28. doi: 10.1021/acs.est.3c04549. Online ahead of print.ABSTRACTNumerous studies have emphasized the toxicity of graphene-based nanomaterials to algae, however, the fundamental behavior and processes of graphene in biological hosts, including its transportation, metabolization, and bioavailability, are still not well understood. As photosynthetic organisms, algae are key contributors to carbon fixation and may play an important role in the fate of graphene. This study investigated the biological fate of 14C-labeled few-layer graphene (14C-FLG) in Chlamydomonas reinhardtii (C. reinhardtii). The results showed that 14C-FLG was taken up by C. reinhardtii and then translocated into its chloroplast. Metabolomic analysis revealed that 14C-FLG altered the metabolic profiles (including sugar metabolism, fatty acid, and tricarboxylic acid cycle) of C. reinhardtii, which promoted the photosynthesis of C. reinhardtii and then enhanced their growth. More importantly, the internalized 14C-FLG was metabolized into 14CO2, which was then used to participate in the metabolic processes required for life. Approximately 61.63%, 25.31%, and 13.06% of the total radioactivity (from 14CO2) was detected in carbohydrates, lipids, and proteins of algae, respectively. Overall, these results reveal the role of algae in the fate of graphene and highlight the potential of available graphene in bringing biological effects to algae, which helps to better assess the environmental risks of graphene.PMID:37768274 | DOI:10.1021/acs.est.3c04549

J Cachexia Sarcopenia Muscle. 2023 Sep 28. doi: 10.1002/jcsm.13342. Online ahead of print.ABSTRACTBACKGROUND: Sarcopenia in liver cirrhosis is associated with low quality of life and high mortality risk. The pathogenesis has yet to be fully understood. We hypothesized that gut microbiome, bile acid (BA) composition and metabolites differ between cirrhotic patients with and without sarcopenia and contribute to pathogenesis.METHODS: Cirrhotic patients with (n = 78) and without (n = 38) sarcopenia and non-cirrhotic controls with (n = 39) and without (n = 20) sarcopenia were included in this study. Faecal microbiome composition was studied by 16S rDNA sequencing, serum and faecal BA composition by ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolite composition in serum, faeces and urine by nuclear magnetic resonance.RESULTS: Bacteroides fragilis, Blautia marseille, Sutterella spp. and Veillonella parvula were associated with cirrhotic patients with sarcopenia, whereas Bacteroides ovatus was more abundant in cirrhotic patients without sarcopenia. We observed significantly elevated secondary BAs, deoxycholic acid (DCA; P = 0.01) and lithocholic acid (LCA; P = 0.02), and the ratios of deoxycholic acid to cholic acid (DCA:CA; P = 0.04), lithocholic acid to chenodeoxycholic acid (LCA:CDCA; P = 0.03) and 12 alpha-hydroxylated to non-12 alpha-hydroxylated BAs (12-α-OH:non-12-α-OH BAs; P = 0.04) in serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia, indicating an enhanced transformation of primary to secondary BAs by the gut microbiome. CA (P = 0.02) and the ratios of CA:CDCA (P = 0.03) and total ursodeoxycholic acid to total secondary BAs (T-UDCA:total-sec-BAs, P = 0.03) were significantly reduced in the stool of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia. Also, valine and acetate were significantly reduced in the serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia (P = 0.01 and P = 0.03, respectively). Multivariate logistic regression further confirmed the association of B. ovatus (P = 0.01, odds ratio [OR]: 12.8, 95% confidence interval [CI]: 168.1; 2.2), the ratios of 12-α-OH:non-12-α-OH BAs (P = 0.03, OR: 2.54, 95% CI: 0.99; 6.55) and T-UDCA:total-sec-BAs (P = 0.04, OR: 0.25, 95% CI: 0.06; 0.98) in serum and stool CA:CDCA (P = 0.04, OR: 0.79, 95% CI: 0.62; 0.99), and serum valine (P = 0.04, OR: 1.00, 95% CI: 1.02; 1.00) with sarcopenia in cirrhosis after correcting for the severity of liver disease and sex.CONCLUSIONS: Our study suggests a potential functional gut microbiome-host interaction linking sarcopenia with the altered gut microbiomes, BA profiles and amino acids pointing towards a potential mechanistic interplay in understanding sarcopenia pathogenesis.PMID:37767786 | DOI:10.1002/jcsm.13342

Arterioscler Thromb Vasc Biol. 2023 Sep 28. doi: 10.1161/ATVBAHA.123.319181. Online ahead of print.ABSTRACTBACKGROUND: Thrombosis is a major complication after cardiac surgery in children with congenital heart disease. The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with thrombosis after surgery in children with congenital heart disease.METHODS: In this prospective cohort study, all blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range, 0 days-18 years) with congenital heart disease undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model.RESULTS: Out of 1115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 25 children (12.3%) developed thrombosis. Among the 776 metabolites, 175 were significantly associated with thrombosis (false discovery rate Q<0.05). The top 3 metabolites showing the strongest associations with thrombosis were eicosapentaenoate, stearidonate, and andro steroid monosulfate C19H28O6S (false discovery rate, 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism and glycerophospholipid metabolism were enriched (false discovery rate, 0.003 for both) and had significant impact on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.969 in the training sample (70% of the total sample) and 0.833 in the testing sample (the remaining 30%).CONCLUSIONS: We have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm these findings and examine the mechanistic pathways to thrombosis.PMID:37767707 | DOI:10.1161/ATVBAHA.123.319181

Expert Rev Proteomics. 2023 Sep 28:1-19. doi: 10.1080/14789450.2023.2258282. Online ahead of print.ABSTRACTINTRODUCTION: Cystic fibrosis (CF) is a genetic disease characterized by thick and sticky mucus accumulation, which may harm numerous internal organs. Various variables such as gene modifiers, environmental factors, age of diagnosis, and CF transmembrane conductance regulator (CFTR) gene mutations influence phenotypic disease diversity. Biomarkers that are based on genomic information may not accurately represent the underlying mechanism of the disease as well as its lethal complications. Therefore, recent advancements in mass spectrometry (MS)-based proteomics may provide deep insights into CF mechanisms and cellular functions by examining alterations in the protein expression patterns from various samples of individuals with CF.AREAS COVERED: We present current developments in MS-based proteomics, its application, and findings in CF. In addition, the future roles of proteomics in finding diagnostic and prognostic novel biomarkers.EXPERT OPINION: Despite significant advances in MS-based proteomics, extensive research in a large cohort for identifying and validating diagnostic, prognostic, predictive, and therapeutic biomarkers for CF disease is highly needed.PMID:37766616 | DOI:10.1080/14789450.2023.2258282

Am J Reprod Immunol. 2023 Oct;90(4):e13781. doi: 10.1111/aji.13781.ABSTRACTBACKGROUND: The vaginal microbiome (VMB) is a critical determinant of reproductive health, where a microbial shift towards a dysbiotic environment has implications for susceptibility to, and clinical presentation of sexually transmitted infections (STIs). Metabolomic profiling of the vaginal microenvironment has led to the identification of metabolic responses to clinical conditions of dysbiosis. However, no studies have examined metabolic markers that are common across conditions and can serve as a signature for vaginal dysbiosis.METHOD OF STUDY: We have conducted a comprehensive systematic review and meta-analysis to identify consistently deregulated metabolites along with their impact on host and microbial metabolism during dysbiosis. We employed two complementary approaches including a vote counting analysis for all eligible studies identified in the systematic review, in addition to a meta-analysis for a subset of studies with sufficient available data. Significantly deregulated metabolites were then selected for pathway enrichment analysis.RESULTS: Our results revealed a total of 502 altered metabolites reported across 10 dysbiotic conditions from 16 studies. Following a rigorous, collective analysis, six metabolites which were consistently downregulated and could be generalized to all dysbiotic conditions were identified. In addition, five downregulated and one upregulated metabolite was identified from a bacterial vaginosis (BV) focused sub-analysis. These metabolites have the potential to serve as a metabolic signature for vaginal dysbiosis. Their role in eight altered metabolic pathways indicates a disruption of amino acid, carbohydrate, and energy metabolism during dysbiosis.CONCLUSION: Based on this analysis, we propose a schematic model outlining the common metabolic perturbations associated with vaginal dysbiosis, which can be potential targets for therapeutics and prophylaxis.PMID:37766408 | DOI:10.1111/aji.13781

Sensors (Basel). 2023 Sep 14;23(18):7885. doi: 10.3390/s23187885.ABSTRACTThis Editorial provides summaries and an overview of research and review articles published in the Sensors journal, volumes 21 (2021), 22 (2022), and 23 (2023), within the biomedical Special Issue "Portable Electronic-Nose Devices for Noninvasive Early Disease Detection", which focused on recent sensors, biosensors, and clinical instruments developed for noninvasive early detection and diagnosis of human and animal diseases. The ten articles published in this Special Issue provide new information associated with recent electronic-nose (e-nose) and related volatile organic compound (VOC)-detection technologies developed to improve the effectiveness and efficiency of diagnostic methodologies for early disease detection prior to symptom development. For review purposes, the summarized articles were placed into three broad groupings or topic areas, including veterinary-wildlife pathology, human clinical pathology, and the detection of dietary effects on VOC emissions. These specified categories were used to define sectional headings devoted to related research studies with a commonality based on a particular disease being investigated or type of analytical instrument used in analyses.PMID:37765943 | DOI:10.3390/s23187885

Plants (Basel). 2023 Sep 21;12(18):3333. doi: 10.3390/plants12183333.ABSTRACTPrunus mume is a famous ornamental woody tree with colorful flowers. P. mume with yellow flowers is one of the most precious varieties. Regretfully, metabolites and regulatory mechanisms of yellow flowers in P. mume are still unclear. This hinders innovation of flower color breeding in P. mume. To elucidate the metabolic components and molecular mechanisms of yellow flowers, we analyzed transcriptome and metabolome between 'HJH' with yellow flowers and 'ZLE' with white flowers. Comparing the metabolome of the two varieties, we determined that carotenoids made contributions to the yellow flowers rather than flavonoids. Lutein was the key differential metabolite to cause yellow coloration of 'HJH'. Transcriptome analysis revealed significant differences in the expression of carotenoid cleavage dioxygenase (CCD) between the two varieties. Specifically, the expression level of PmCCD4 was higher in 'ZLE' than that in 'HJH'. Moreover, we identified six major transcription factors that probably regulated PmCCD4 to affect lutein accumulation. We speculated that carotenoid cleavage genes might be closely related to the yellow flower phenotype in P. mume. Further, the coding sequence of PmCCD4 has been cloned from the 'HJH' petals, and bioinformatics analysis revealed that PmCCD4 possessed conserved histidine residues, ensuring its enzymatic activity. PmCCD4 was closely related to PpCCD4, with a homology of 98.16%. Instantaneous transformation analysis in petal protoplasts of P. mume revealed PmCCD4 localization in the plastid. The overexpression of PmCCD4 significantly reduced the carotenoid content in tobacco plants, especially the lutein content, indicating that lutein might be the primary substrate for PmCCD4. We speculated that PmCCD4 might be involved in the cleavage of lutein in plastids, thereby affecting the formation of yellow flowers in P. mume. This work could establish a material and molecular basis of molecular breeding in P. mume for improving the flower color.PMID:37765497 | DOI:10.3390/plants12183333

Plants (Basel). 2023 Sep 16;12(18):3284. doi: 10.3390/plants12183284.ABSTRACTSalicylic acid (SA) is produced by plants in response to pathogen infection. SA binds the NONEXPRESSOR OF PATHOGENESIS-RELATED GENES (NPR) family of receptors to regulate both positive (NPR1) and negative (NPR3/4) plant immune responses by interacting with the clade II TGACG (TGA) motif-binding transcription factors (TGA2, TGA5, and TGA6). Here, we report that the principal metabolome-level response to SA treatment in Arabidopsis is a reduction in sucrose and other free sugars. We observed nearly identical effects in the tga256 triple mutant, which lacks all clade II TGA transcription factors. The tga256 mutant presents reduced leaf blade development and elongated hypocotyls, roots, and petioles consistent with sucrose starvation. No changes were detected in auxin levels, and mutant seedling growth could be restored to that of wild-type by sucrose supplementation. Although the retrograde signal 2-C-methyl-D-erythritol-2,4-cyclodiphosphate is known to stimulate SA biosynthesis and defense signaling, we detected no negative feedback by SA on this or any other intermediate of the 2-C-methyl-D-erythritol-4-phosphate pathway. Trehalose, a proxy for the sucrose regulator trehalose-6-phosphate (T6P), was highly reduced in tga256, suggesting that defense-related reductions in sugar availability may be controlled by changes in T6P levels. We conclude that the negative regulatory roles of TGA2/5/6 include maintaining sucrose levels in healthy plants. Disruption of TGA2/5/6-NPR3/4 inhibitory complexes by mutation or SA triggers sucrose reductions in Arabidopsis leaves, consistent with the 'pathogen starvation' hypothesis. These findings highlight sucrose availability as a mechanism by which TGA2/5/6 balance defense and development.PMID:37765448 | DOI:10.3390/plants12183284

Plants (Basel). 2023 Sep 14;12(18):3265. doi: 10.3390/plants12183265.ABSTRACTMorus alba is used as a traditional Chinese medicine due to its various biological activities. Phenylpropanoid metabolism is one of the most important pathways in Morus alba to produce secondary metabolites and response to stress. From the general phenylpropanoid pathway, there are two metabolic branches in M. alba, including flavonoid and lignin biosynthesis, which also play roles in response to stress. However, the dynamic changes between flavonoid and lignin biosynthesis under Botrytis cinerea infection and UV-B stress in M. alba were unclear. To explore the different regulation mode of flavonoid and lignin biosynthesis in M. alba leaves' response to biotic and abiotic stress, a combined proteomic and metabolomic study of M. alba leaves under UV-B stress and B. cinerea infection was performed. The results showed that most of the proteins involved in the lignin and flavonoid biosynthesis pathway were increased under either UV-B stress or B. cinerea infection in M. alba. This was also confirmed by enzyme assays and metabolomics analysis. Additionally, the abundance of proteins involved in the biosynthesis of jasmonic acid was increased after B. cinerea infection. This suggests that both flavonoid and lignin biosynthesis participate in the responses to abiotic and biotic stress in M. alba, but they might be regulated by different hormone signaling.PMID:37765429 | DOI:10.3390/plants12183265

Plants (Basel). 2023 Sep 7;12(18):3197. doi: 10.3390/plants12183197.ABSTRACTE. rutaecarpa var. officinalis is a traditional Chinese medicinal plant known for its therapeutic effects, which encompass the promotion of digestion, the dispelling of cold, the alleviation of pain, and the exhibition of anti-inflammatory and antibacterial properties. The principal active component of this plant, limonin, is a potent triterpene compound with notable pharmacological activities. Despite its significance, the complete biosynthesis pathway of limonin in E. rutaecarpa var. officinalis remains incompletely understood, and the underlying molecular mechanisms remain unexplored. The main purpose of this study was to screen the reference genes suitable for expression analysis in E. rutaecarpa var. officinalis, calculate the expression patterns of the genes in the limonin biosynthesis pathway, and identify the relevant enzyme genes related to limonin biosynthesis. The reference genes play a pivotal role in establishing reliable reference standards for normalizing the gene expression data, thereby ensuring precision and credibility in the biological research outcomes. In order to identify the optimal reference genes and gene expression patterns across the diverse tissues (e.g., roots, stems, leaves, and flower buds) and developmental stages (i.e., 17 July, 24 August, 1 September, and 24 October) of E. rutaecarpa var. officinalis, LC-MS was used to analyze the limonin contents in distinct tissue samples and developmental stages, and qRT-PCR technology was employed to investigate the expression patterns of the ten reference genes and eighteen genes involved in limonin biosynthesis. Utilizing a comprehensive analysis that integrated three software tools (GeNorm ver. 3.5, NormFinder ver. 0.953 and BestKeeper ver. 1.0) and Delta Ct method alongside the RefFinder website, the best reference genes were selected. Through the research, we determined that Act1 and UBQ served as the preferred reference genes for normalizing gene expression during various fruit developmental stages, while Act1 and His3 were optimal for different tissues. Using Act1 and UBQ as the reference genes, and based on the different fruit developmental stages, qRT-PCR analysis was performed on the pathway genes selected from the "full-length transcriptome + expression profile + metabolome" data in the limonin biosynthesis pathway of E. rutaecarpa var. officinalis. The findings indicated that there were consistent expression patterns of HMGCR, SQE, and CYP450 with fluctuations in the limonin contents, suggesting their potential involvement in the limonin biosynthesis of E. rutaecarpa var. officinalis. This study lays the foundation for further research on the metabolic pathway of limonin in E. rutaecarpa var. officinalis and provides reliable reference genes for other researchers to use for conducting expression analyses.PMID:37765365 | DOI:10.3390/plants12183197

Plants (Basel). 2023 Sep 7;12(18):3200. doi: 10.3390/plants12183200.ABSTRACTBlueberry is a nutrient-rich berry, and its taste and flavor directly determine the consumer preference. Until now, few studies have focused on the comparison of fresh food quality and the key metabolites in superior fresh-eating blueberry cultivars. Herein, fruit quality indicators of 10 highbush blueberry cultivars were evaluated using 'Bluerain' as the control. Appearance quality analysis of fruits showed that 'Brigitta' had a larger fruit size and 'Anna' was the smallest. 'Anna' fruits, followed by 'O'Neal', had the highest ratio of soluble solids to acidity because of their lowest titratable acidity content. Despite the high soluble sugar content, the antioxidants in 'Anna' fruits such as total flavonoids, anthocyanins and vitamin C were lowest among all cultivars, while 'Duke' seemed to have opposite patterns. Furthermore, a total of 553 and 557 metabolites were identified by non-targeted metabolomics liquid chromatography-tandem mass spectrometry (LC-MS/MS) in positive and negative ion mode, respectively. Particularly, the numbers of differentially accumulated metabolites (DAMs) were the most between the 'O'Neal' vs. 'Bluerain' group. The DAMs involved in the metabolic pathways, sesquiterpenoid and triterpenoid biosynthesis, monoterpenoid biosynthesis, galactose metabolism, starch and sucrose metabolism, may be mainly related to the synthesis of flavor and carbohydrate substances. Moreover, the expression patterns of genes involved in sugar metabolism were verified by quantitative real-time PCR (qRT-PCR) analysis in different cultivars. Therefore, the systematical comparison of the quality characteristics, metabolites and expression profiles of related genes in highbush blueberries with good flavor could provide some basis for further research on fresh fruit breeding of blueberries.PMID:37765362 | DOI:10.3390/plants12183200

Pharmaceutics. 2023 Sep 2;15(9):2269. doi: 10.3390/pharmaceutics15092269.ABSTRACTAgathis species are widely distributed around Southeast Asia, Australasia, South Pacific islands, and etc. Traditionally, Agathis species have been used as the folk medicines, the common ethnopharmacological uses of Agathis genus are the treatments of headache and myalgia. This study aims to investigate the chemical composition of Agathis dammara (Lamb.) Rich. leaf essential oil and to explore its antimelanogenesis effect. The chemical constituents of leaf essential oil are analyzed using gas chromatography-mass spectrometry (GC-MS), the major constituents of leaf essential oil are sesquiterpenoids. The major constituents are δ-cadinene (16.12%), followed by γ-gurjunene (15.57%), 16-kaurene (12.43%), β-caryophyllene (8.58%), germacrene D (8.53%), and γ-cadinene (5.33%). As for the in vitro antityrosinase activity, leaf essential oil inhibit the tyrosinase activity of mushroom when the substrate is 3,4-dihydroxyphenylalanine (L-DOPA). Leaf essential oil prevents tyrosinase from acting as diphenolase and catalyzing L-DOPA to dopaquinone, and converting into dark melanin pigments. A. dammara leaf essential oil also exhibits the in vivo antimelanogenesis effect, leaf essential oil reduces 43.48% of melanin formation in zebrafish embryos at the concentration of 50 μg/mL. Results reveal A. dammara leaf essential oil has the potential for developing the skin whitening drug and depigmentation ingredient for hyperpigmentary disorders.PMID:37765238 | DOI:10.3390/pharmaceutics15092269

Pharmaceutics. 2023 Aug 29;15(9):2225. doi: 10.3390/pharmaceutics15092225.ABSTRACTOpioid utilization for pain management is prevalent among cancer patients. There is significant evidence describing the many effects of opioids on cancer development. Despite the pivotal role of metabolic reprogramming in facilitating cancer growth and metastasis, the specific impact of opioids on crucial oncogenic metabolic pathways remains inadequately investigated. This review provides an understanding of the current research on opioid-mediated changes to cellular metabolic pathways crucial for oncogenesis, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS). The existing literature suggests that opioids affect energy production pathways via increasing intracellular glucose levels, increasing the production of lactic acid, and reducing ATP levels through impediment of OXPHOS. Opioids modulate pathways involved in redox balance which may allow cancer cells to overcome ROS-mediated apoptotic signaling. The majority of studies have been conducted in healthy tissue with a predominant focus on neuronal cells. To comprehensively understand the impact of opioids on metabolic pathways critical to cancer progression, research must extend beyond healthy tissue and encompass patient-derived cancer tissue, allowing for a better understanding in the context of the metabolic reprogramming already undergone by cancer cells. The current literature is limited by a lack of direct experimentation exploring opioid-induced changes to cancer metabolism as they relate to tumor growth and patient outcome.PMID:37765194 | DOI:10.3390/pharmaceutics15092225

Pharmaceuticals (Basel). 2023 Sep 13;16(9):1290. doi: 10.3390/ph16091290.ABSTRACTSystemic arterial hypertension (SAH) is one of the most prevalent chronic diseases worldwide and is related to serious health complications. It has been pointed out as a major risk factor for COVID-19. This study aimed to determine the impact of COVID-19 on the metabolomic profile, the correlation with the plasmatic levels of losartan and its active metabolite (EXP3174), biochemical markers, and blood pressure (BP) control in hypertensive patients. 1H NMR metabolomic profiles of hypertensive and normotensive patients with and without previous COVID-19 diagnosis were identified. Plasmatic levels of LOS and EXP3174 were correlated with BP, biochemical markers, and the metabolomic fingerprint of the groups. Biomarkers linked to important aspects of SAH and COVID-19 were identified, such as glucose, glutamine, arginine, creatinine, alanine, choline, erythritol, homogentisate, 0-tyrosine, and 2-hydroxybutyrate. Those metabolites are indicative of metabolic alterations, kidney damage, pulmonary dysfunction, and persistent inflammation, which can be found in both diseases. Some hypertensive patients did not reach the therapeutic levels of LOS and EXP3174, while the BP control was also limited among the normotensive patients with previous COVID-19 diagnoses. Metabolomics proved to be an important tool for assessing the effectiveness of losartan pharmacotherapy and the damage caused by SAH and COVID-19 in hypertensive patients.PMID:37765098 | DOI:10.3390/ph16091290