PubMed

Int J Radiat Oncol Biol Phys. 2024 Aug 8:S0360-3016(24)03176-6. doi: 10.1016/j.ijrobp.2024.07.2327. Online ahead of print.ABSTRACTPURPOSE: radiotherapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiotherapy resistance, which mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiotherapy and the associated underlying mechanisms.MATERIALS AND METHODS: Male C3H mice bearing syngeneic SCC-VII tumor were received irradiation (2 × 8Gy). The impact of irradiation on tumor-infiltrating macrophages were assessed. Bone marrow derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium (irCM) and irradiated tumor derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, while key metabolites were investigated the mechanism in macrophage in vitro and in vivo.RESULTS: Radiotherapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in tumor microenvironment and drove infiltrated macrophages towards an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of nicotinamide (NAM) to macrophages. NAM directly bound to the NF-κB transcriptional activity regulator USP7, through which NAM reduced translocation of NF-κB into the nucleus, thereby decreasing the release of cytokines IL6 and IL8. Increased enzyme activity of nicotinamide phosphoribosyl transferase (NAMPT) which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAMPT decreased NAM levels in irTEVs and increased radiotherapy sensitivity through alleviating immunosuppressive function of macrophages.CONCLUSIONS: Radiotherapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophage towards an immunosuppressive phenotype. Pharmacological targeting NAD+ metabolism might be a promising strategy for radiotherapy sensitization of HNSCC.PMID:39127084 | DOI:10.1016/j.ijrobp.2024.07.2327

Transl Oncol. 2024 Aug 8;49:102082. doi: 10.1016/j.tranon.2024.102082. Online ahead of print.ABSTRACTBACKGROUND: The mechanisms by which SLC2A1 enhances chemo-resistance of taxanes to non-small cell lung cancer (NSCLC) remains enigmatic.METHODS: An investigation into the SLC2A1 expression pattern and prognosis across diverse datasets, as well as our internally collected samples, was undertaken. Additionally, the biological function of SLC2A1 was further delved into through in vitro experiments. The study also examined the chemo-resistance of NSCLC to taxanes using CCK-8, Annexin-V, and caspase-3 assays. Furthermore, the impact of taxanes on SLC2A1 expression was determined via western blot analysis. The effects of SLC2A1 on the formation of CSCs was examined via flow cytometry and metabolomics techniques. Finally, the impact of SLC2A1 on the tumor microenvironment was analyzed using single-cell sequencing and cellchat.RESULTS: In the present investigation, it was observed that there was an elevated expression of SLC2A1 in NSCLC tumor tissues, which exhibited a significant association with a poorer prognosis. SLC2A1 overexpression in vitro promoted NSCLC cell proliferation, invasion, migration, chemo-resistance, and the formation of CD90+ and EpCAM+ CSCs. NSCLC cells were categorized based on SLC2A1 and EpCAM expression. SLC2A1highEpCAM+ CSCs were more chemo-resistance to taxanes. NSCLC patients with high SLC2A1 and EpCAM expression had poorer prognosis. Mechanically, SLC2A1 promoted the formation of CD90+ and EpCAM+ CSCs via activating glycolysis. Finally, SLC2A1low tumor cells promoted CD8+T cell function via HLA-A, B, C, and suppressed NK cell function via HLA-E.CONCLUSION: Together, SLC2A1 plays an important role in enhancing chemo-resistance of taxanes to NSCLC.PMID:39126936 | DOI:10.1016/j.tranon.2024.102082

Phytomedicine. 2024 Aug 3;133:155922. doi: 10.1016/j.phymed.2024.155922. Online ahead of print.ABSTRACTBACKGROUND: Cartilage metabolism dysregulation is a crucial driver in knee osteoarthritis (KOA). Modulating the homeostasis can mitigate the cartilage degeneration in KOA. Curcumenol, derived from traditional Chinese medicine Curcuma Longa L., has demonstrated potential in enhancing chondrocyte proliferation and reducing apoptosis. However, the specific mechanism of Curcumenol in treating KOA remains unclear. This study aimed to demonstrate the molecular mechanism of Curcumenol in treating KOA based on the transcriptomics and metabolomics, and both in vivo and in vitro experimental validations.MATERIALS AND METHODS: In this study, a destabilization medial meniscus (DMM)-induced KOA mouse model was established. And the mice were intraperitoneally injected with Curcumenol at 4 and 8 mg/kg concentrations. The effects of Curcumenol on KOA cartilage and subchondral was evaluated using micro-CT, histopathology, and immunohistochemistry (IHC). In vitro, OA chondrocytes were induced with 10 μg/mL lipopolysaccharide (LPS) and treated with Curcumenol to evaluate the proliferation, apoptosis, and extracellular matrix (ECM) metabolism through CCK8 assay, flow cytometry, and chondrocyte staining. Furthermore, transcriptomics and metabolomics were utilized to identify differentially expressed genes (DEGs) and metabolites. Finally, integrating multi-omics analysis, virtual molecular docking (VMD), and molecular dynamics simulation (MDS), IHC, immunofluorescence (IF), PCR, and Western blot (WB) validation were conducted to elucidate the mechanism by which Curcumenol ameliorates KOA cartilage degeneration.RESULTS: Curcumenol ameliorated cartilage destruction and subchondral bone loss in KOA mice, promoted cartilage repair, upregulated the expression of COL2 while downregulated MMP3, and improved ECM synthesis metabolism. Additionally, Curcumenol also alleviated the damage of LPS on the proliferation activity and suppressed apoptosis, promoted ECM synthesis. Transcriptomic analysis combined with weighted gene co-expression network analysis (WGCNA) identified a significant downregulation of 19 key genes in KOA. Metabolomic profiling showed that Curcumenol downregulates the expression of d-Alanyl-d-alanine, 17a-Estradiol, Glutathione, and Succinic acid, while upregulating Sterculic acid and Azelaic acid. The integrated multi-omics analysis suggested that Curcumenol targeted KDM6B to regulate downstream protein H3K27me3 expression, which inhibited methylation at the histone H3K27, consequently reducing Succinic acid levels and improving KOA cartilage metabolism homeostasis. Finally, both in vivo and in vitro findings indicated that Curcumenol upregulated KDM6B, suppressed H3K27me3 expression, and stimulated collagen II expression and ECM synthesis, thus maintaining cartilage metabolism homeostasis and alleviating KOA cartilage degeneration.CONCLUSION: Curcumenol promotes cartilage repair and ameliorates cartilage degeneration in KOA by upregulating KDM6B expression, thereby reducing H3K27 methylation and downregulating Succinic Acid, restoring metabolic stability and ECM synthesis.PMID:39126921 | DOI:10.1016/j.phymed.2024.155922

J Hazard Mater. 2024 Aug 3;478:135354. doi: 10.1016/j.jhazmat.2024.135354. Online ahead of print.ABSTRACTCo-culturing fungi and microalgae may effectively remediate wastewater containing Cd and harvest microalgae. Nevertheless, a detailed study of the mechanisms underlying the synergistic interactions between fungi and microalgae under Cd(II) exposure is lacking. In this study, Cd(II) exposure resulted in a significant enhancement of antioxidants, such as glutathione (GSH), malondialdehyde (MDA), hydrogen peroxide (H2O2) and superoxide dismutase (SOD) compared to the control group, suggesting that the cellular antioxidant defense response was activated. Extracellular proteins and extracellular polysaccharides of the symbiotic system were increased by 60.61 % and ,24.29 %, respectively, after Cd(II) exposure for 72 h. The adsorption behavior of Cd(II) was investigated using three-dimensional fluorescence excitation-emission matrix (3D-EEM), fourier transform infrared spectroscopy (FTIR), and scanning electron microscope (SEM). Metabolomics results showed that the TCA cycle provided effective material and energy supply for the symbiotic system to resist the toxicity of Cd(II); Proline, histidine, and glutamine strengthened the synergistic adsorption capacity of the fungus and microalgae. Overall, the theoretical foundation for a deep comprehension of the beneficial interactions between fungi and microalgae under Cd(II) exposure and the role of the fungal-algal symbiotic system in the management of heavy metal pollution is provided by this combined physiological and metabolomic investigation.PMID:39126852 | DOI:10.1016/j.jhazmat.2024.135354

J Food Sci. 2024 Aug 10. doi: 10.1111/1750-3841.17229. Online ahead of print.ABSTRACTGerminated brown rice has recently garnered widespread attention due to its high nutritional value. Previous research demonstrated that the bioactive components and functional properties of germinated brown rice varieties exhibit significant differences. Three germinated rice cultivars weedy rice WR04-6 (WR) and two cultivated rice cultivars with superior eating quality, Koshihikari (YG) and Daohuaxiang (DHX), were analyzed using metabolites and transcriptome profiling. Widely targeted metabolomics results showed that 85.9% and 71.2% of differential metabolites for WR vs. YG and WR vs. DHX were enriched in WR, respectively. The substances mainly included amino acids and derivatives, carbohydrates and its derivatives, organic acids and its derivatives, and flavonoids. Higher antioxidant activity was detected in WR compared to cultivated rice in metabolome analysis. Transcriptome analyses indicated that 18 responsive genes played pivotal roles in the conversion of key metabolites. These findings will provide theoretical underpinnings for the development of rice germplasm resources and the formulation of functional germinated grain foods.PMID:39126703 | DOI:10.1111/1750-3841.17229

Clin Rheumatol. 2024 Aug 10. doi: 10.1007/s10067-024-07094-0. Online ahead of print.ABSTRACTSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a significant health burden. There is an essential need for novel biomarkers and therapeutic targets to improve diagnosis and management. Mendelian randomization (MR) was applied to explore causal links between SLE and various biomarkers like immune cells, metabolites, and inflammatory cytokines using multiple databases. Initially, biomarkers significantly associated with SLE were identified. Bidirectional MR helped clarify these relationships, and a two-step mediation MR examined their effects on SLE risk. Intersection analysis was used to identify biomarkers with consistent effects across datasets. Four biomarkers were identified as having significant associations with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI levels [odds ratio (OR), 1.379; 95% confidence interval (CI), 1.180 to 1.613; FDR, 0.046], IL-17A levels (OR, 2.197; 95% CI, 1.412 to 3.418; FDR, 0.044), N-acetyl-aspartyl-glutamate (NAAG) levels (OR, 0.882; 95% CI, 0.831 to 0.936; FDR, 0.030), and ribitol levels (OR, 0.743; 95% CI, 0.644 to 0.857; FDR, 0.012). Bidirectional MR showed an inverse effect of NAAG on IL-17A levels (OR, 0.978; 95% CI, 0.962 to 0.994; p = 0.006). Mediation analysis indicated that NAAG influenced SLE risk both directly (beta = - 0.108) and indirectly through IL-17A (beta = - 0.018), highlighting the potential mediating role of IL-17A. After expanding the significance criteria to p < 0.05, intersection analysis across multiple datasets revealed 29 biomarkers with consistent beta directions, including 19 potential risk factors (beta > 0) and 10 protective factors (beta < 0) for SLE. This research has revealed significant genetic associations with SLE and demonstrated that IL-17A mediates the relationship between NAAG levels and SLE risk, highlighting potential new targets for personalized therapeutic interventions. Key Points • This study employs MR to identify significant genetic associations between various biomarkers and SLE, providing novel insights into potential biomarkers and therapeutic targets. • Four key biomarkers were identified as significantly associated with SLE risk: 1-palmitoyl-2-arachidonoyl-GPI, IL-17A, N-acetyl-aspartyl-glutamate (NAAG), and ribitol. • The findings suggest that NAAG levels have a protective effect against SLE, partly mediated through IL-17A, indicating a complex interplay between these biomarkers in the pathogenesis of SLE. • Intersectional analysis across multiple datasets revealed 29 biomarkers with consistent effects on SLE risk, highlighting new directions for future research and potential personalized therapeutic strategies.PMID:39126578 | DOI:10.1007/s10067-024-07094-0

World J Microbiol Biotechnol. 2024 Aug 10;40(10):297. doi: 10.1007/s11274-024-04105-9.ABSTRACTVancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.PMID:39126539 | DOI:10.1007/s11274-024-04105-9

J Bone Miner Res. 2024 Aug 10:zjae121. doi: 10.1093/jbmr/zjae121. Online ahead of print.ABSTRACTThe skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine (DMOG) rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.PMID:39126376 | DOI:10.1093/jbmr/zjae121

Biomed Chromatogr. 2024 Aug 10:e5969. doi: 10.1002/bmc.5969. Online ahead of print.ABSTRACTThis study aimed to explore the pharmacodynamics and mechanisms of different processing methods of Ligustrum lucidum Ait. (LLA) in addressing kidney-yin deficiency (KYD). Forty-eight Sprague-Dawley rats were divided into eight groups based on their weight. The KYD model was established by intragastric administration of levothyroxine sodium. Each group was administered the corresponding treatment for 15 consecutive days. The general condition of the rats during the treatment period was observed. In addition, the levels of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and the ratio of cAMP to cGMP in the serum of rats from different groups were measured. Serum samples were analyzed using the ultra-performance liquid chromatography (UPLC)-Orbitrap Fusion MS technique for metabolomics analysis. Compared with the model group, the general condition of the rats in the wine-steamed L. lucidum group (WL) and salt-steamed L. lucidum group (SSL) groups showed significant improvement. The serum levels of cAMP, cGMP, and the cAMP-to-cGMP ratio tended to return to normal. Metabolic analysis identified 38 relevant biomarkers and revealed 3 major metabolic pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; and sphingolipid metabolism. The different processing methods of LLA demonstrated therapeutic effects on KYD in rats, likely related to the restoration of disturbed metabolism by adjusting the levels of endogenous metabolites in the kidney. The SSL demonstrated significantly superior effects compared with the other four types of LLA processed products.PMID:39126348 | DOI:10.1002/bmc.5969

Physiol Plant. 2024 Jul-Aug;176(4):e14465. doi: 10.1111/ppl.14465.ABSTRACTSugar is vital for plant growth and determines fruit quality via its content and composition. This study explores the differential sugar accumulation in two plum varieties, 'Fengtangli (FTL)' and 'Siyueli (SYL)'. The result showed that 'FTL' fruit displayed higher soluble solids and sugar content at various development stages. Metabolomic analysis indicated increased sorbitol in 'FTL', linked to elevated sorbitol-6-phosphate-dehydrogenase (S6PDH) activity. Transcriptome analysis identified a key gene for sorbitol synthesis, PsS6PDH4, which was significantly higher expressed in 'FTL' than in 'SYL'. The function of the PsS6PDH4 gene was verified in strawberry, apple, and plum fruits using transient overexpression and virus-induced gene silencing techniques. The results showed that overexpression of the PsS6PDH4 gene in strawberry, apple, and plum fruits promoted the accumulation of soluble solids content and sorbitol, while inhibition of the gene reduced soluble solids content and sorbitol content. Meanwhile, analysis of the relationship between PsS6PDH4 gene expression, sorbitol, and soluble solids content in four different plum varieties revealed a significant correlation between PsS6PDH4 gene expression and soluble solids content as well as sorbitol content. This research discovered PsS6PDH4 as a crucial regulator of sugar metabolism in plum, with potential applications in improving fruit sweetness and nutritional value in various fruit species. Understanding these molecular pathways can lead to innovative approaches for enhancing fruit quality, benefiting sustainable agriculture and consumer preferences in the global fruit industry.PMID:39126176 | DOI:10.1111/ppl.14465

Proteomics. 2024 Aug 9:e2300591. doi: 10.1002/pmic.202300591. Online ahead of print.ABSTRACTINSC94Y transgenic pigs represent a model for mutant insulin gene-induced diabetes of youth, with impaired insulin secretion and beta cell loss, leading to elevated fasting blood glucose levels. A key complication of diabetes mellitus is diabetic retinopathy (DR), characterized by hyperglycemia-induced abnormalities in the retina. Adjacent to the retina lies the vitreous, a gelatinous matrix vital for ocular function. It harbors proteins and signaling molecules, offering insights into vitreous biology and ocular health. Moreover, as a reservoir for secreted molecules, the vitreous illuminates molecular processes within intraocular structures, especially under pathological conditions. To uncover the proteomic profile of porcine vitreous and explore its relevance to DR, we employed discovery proteomics to compare vitreous samples from INSC94Y transgenic pigs and wild-type controls. Our analysis identified 1404 proteins, with 266 showing differential abundance in INSC94Y vitreous. Notably, the abundances of ITGB1, COX2, and GRIFIN were significantly elevated in INSC94Y vitreous. Gene Set Enrichment Analysis unveiled heightened MYC and mTORC1 signaling in INSC94Y vitreous, shedding light on its biological significance in diabetes-associated ocular pathophysiology. These findings deepen our understanding of vitreous involvement in DR and provide valuable insights into potential therapeutic targets. Raw data are accessible via ProteomeXchange (PXD038198).PMID:39126128 | DOI:10.1002/pmic.202300591

Int J Mol Sci. 2024 Aug 5;25(15):8538. doi: 10.3390/ijms25158538.ABSTRACTThe senescence of bone marrow mesenchymal stromal cells (MSCs) leads to the impairment of stemness and osteogenic differentiation capacity. In a previous study, we screened out stearoyl-CoA desaturase 2 (SCD2), the most evidently changed differential gene in lipid metabolism, using combined transcriptomic and metabolomic analyses, and verified that SCD2 could mitigate MSC senescence. However, the underlying molecular mechanism by which the rate-limiting enzyme of lipogenesis SCD2 manipulates MSC senescence has not been completely understood. In this study, we demonstrate that SCD2 over-expression alleviates MSC replicative senescence and ameliorates their osteogenic differentiation through the regulation of lipogenesis. Furthermore, SCD2 expression is reduced, whereas miR-200c-3p expression is elevated in replicative senescent MSCs. SCD2 is the direct target gene of miR-200c-3p, which can bind to the 3'-UTR of SCD2. MiR-200c-3p replenishment in young MSCs is able to diminish SCD2 expression levels due to epigenetic modulation. In addition, SCD2-rescued MSC senescence and enhanced osteogenic differentiation can be attenuated by miR-200c-3p repletion via suppressing lipogenesis. Taken together, we reveal the potential mechanism of SCD2 influencing MSC senescence from the perspective of lipid metabolism and epigenetics, which provides both an experimental basis for elucidating the mechanism of stem cell senescence and a novel target for delaying stem cell senescence.PMID:39126105 | DOI:10.3390/ijms25158538

Int J Mol Sci. 2024 Aug 2;25(15):8448. doi: 10.3390/ijms25158448.ABSTRACTTherapy-induced senescence (TIS) represents a major cellular response to anticancer treatments. Both malignant and non-malignant cells in the tumor microenvironment undergo TIS and may be harmful for cancer patients since TIS cells develop a senescence-associated secretory phenotype (SASP) that can sustain tumor growth. The SASP also modulates anti-tumor immunity, although the immune populations involved and the final results appear to be context-dependent. In addition, senescent cancer cells are able to evade senescence growth arrest and to resume proliferation, likely contributing to relapse. So, research data suggest that TIS induction negatively affects therapy outcomes in cancer patients. In line with this, new interventions aimed at the removal of senescent cells or the reprogramming of their SASP, called senotherapy, have become attractive therapeutic options. To date, the lack of reliable, cost-effective, and easy-to-use TIS biomarkers hinders the application of recent anti-senescence therapeutic approaches in the clinic. Hence, the identification of biomarkers for the detection of TIS tumor cells and TIS non-neoplastic cells is a high priority in cancer research. In this review article, we describe the current knowledge about TIS, outline critical gaps in our knowledge, and address recent advances and novel approaches for the discovery of TIS biomarkers.PMID:39126015 | DOI:10.3390/ijms25158448

Int J Mol Sci. 2024 Aug 1;25(15):8430. doi: 10.3390/ijms25158430.ABSTRACTElastin, a key structural protein essential for the elasticity of the skin and elastogenic tissues, degrades with age. Replenishing elastin holds promise for anti-aging cosmetics and the supplementation of elastic activities of the cardiovascular system. We employed RiboScreenTM, a technology for identifying molecules that enhance the production of specific proteins, to target the production of tropoelastin. We make use of RiboScreenTM in two crucial steps: first, to pinpoint a target ribosomal protein (TRP), which acts as a switch to increase the production of the protein of interest (POI), and second, to identify small molecules that activate this ribosomal protein switch. Using RiboScreenTM, we identified ribosomal protein L40, henceforth eL40, as a TRP switch to boost tropoelastin production. Drug discovery identified a small-molecule hit that binds to eL40. In-cell treatment demonstrated activity of the eL40 ligand and delivered increased tropoelastin production levels in a dose-dependent manner. Thus, we demonstrate that RiboScreenTM can successfully identify a small-molecule hit capable of selectively enhancing tropoelastin production. This compound has the potential to be developed for topical or systemic applications to promote skin rejuvenation and to supplement elastic functionality within the cardiovascular system.PMID:39125999 | DOI:10.3390/ijms25158430

Int J Mol Sci. 2024 Aug 1;25(15):8420. doi: 10.3390/ijms25158420.ABSTRACTInflammatory bowel disease (IBD) represents heterogeneous and relapsing intestinal conditions with a severe impact on the quality of life of individuals and a continuously increasing prevalence. In recent years, the development of sequencing technology has provided new means of exploring the complex pathogenesis of IBD. An ideal solution is represented by the approach of precision medicine that investigates multiple cellular and molecular interactions, which are tools that perform a holistic, systematic, and impartial analysis of the genomic, transcriptomic, proteomic, metabolomic, and microbiomics sets. Hence, it has led to the orientation of current research towards the identification of new biomarkers that could be successfully used in the management of IBD patients. Multi-omics explores the dimension of variation in the characteristics of these diseases, offering the advantage of understanding the cellular and molecular mechanisms that affect intestinal homeostasis for a much better prediction of disease development and choice of treatment. This review focuses on the progress made in the field of prognostic and predictive biomarkers, highlighting the limitations, challenges, and also the opportunities associated with the application of genomics and epigenomics technologies in clinical practice.PMID:39125988 | DOI:10.3390/ijms25158420

Int J Mol Sci. 2024 Aug 1;25(15):8400. doi: 10.3390/ijms25158400.ABSTRACTTo date, not many studies have presented evidence of SARS-CoV-2 infecting the female reproductive system. Furthermore, so far, no effect of the administration of anti-COVID 19 vaccines has been reported to affect the quality of oocytes retrieved from women who resorted to assisted reproduction technology (ART). The FF metabolic profiles of women who had been infected by SARS-CoV-2 before IVF treatments or after COVID-19 vaccination were examined by 1H NMR. Immunochemical characterization of proteins and cytokines involved in the redox and inflammatory pathways was performed. The increased expression of SOD2 and NQO1, the lack of alteration of IL-6 and CXCL10 levels, as well as the increased expression of CD39, suggested that, both sharing similar molecular mechanisms or proceeding along different routes, the redox balance is controlled in the FF of both vaccinated and recovered women compared to controls. The lower amount of metabolites known to have proinflammatory activity, i.e., TMAO and lipids, further supported the biochemical results, suggesting that the FF microenvironment is controlled so as to guarantee oocyte quality and does not compromise the outcome of ART. In terms of the number of blastocysts obtained after ICSI and the pregnancy rate, the results are also comforting.PMID:39125969 | DOI:10.3390/ijms25158400

Int J Mol Sci. 2024 Jul 29;25(15):8285. doi: 10.3390/ijms25158285.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by the build-up of fat in the liver of individuals in the absence of alcohol consumption. This condition has become a burden in modern societies aggravated by the lack of appropriate predictive biomarkers (other than liver biopsy). To better understand this disease and to find appropriate biomarkers, a new technology has emerged in the last two decades with the ability to explore the unmapped role of lipids in this disease: lipidomics. This technology, based on the combination of chromatography and mass spectrometry, has been extensively used to explore the lipid metabolism of NAFLD. In this review, we aim to summarize the knowledge gained through lipidomics assays exploring tissues, plasma, and lipoproteins from individuals with NAFLD. Our goal is to identify common features and active pathways that could facilitate the finding of a reliable biomarker from this field. The most frequent observation was a variable decrease (1-9%) in polyunsaturated fatty acids in phospholipids and non-esterified fatty acids in NAFLD patients, both in plasma and liver. Additionally, a reduction in phosphatidylcholines is a common feature in the liver. Due to the scarcity of studies, further research is needed to properly detect lipoprotein, plasma, and tissue lipid signatures of NAFLD etiologies, and NAFLD subtypes, and to define the relevance of this technology in disease management strategies in the push toward personalized medicine.PMID:39125855 | DOI:10.3390/ijms25158285

Int J Mol Sci. 2024 Jul 28;25(15):8248. doi: 10.3390/ijms25158248.ABSTRACTDomestic animals have multiple phenotypes of skin and coat color, which arise from different genes and their products, such as proteins and metabolites responsible with melanin deposition. However, the complex regulatory network of melanin synthesis remains to be fully unraveled. Here, the skin and tongue tissues of Liangshan black sheep (black group) and Liangshan semi-fine-wool sheep (pink group) were collected, stained with hematoxylin-eosin (HE) and Masson-Fontana, and the transcriptomic and metabolomic data were further analyzed. We found a large deposit of melanin granules in the epidermis of the black skin and tongue. Transcriptome and metabolome analysis identified 744 differentially expressed genes (DEGs) and 443 differentially expressed metabolites (DEMs) between the pink and black groups. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses revealed the DEGs and DEMs were mainly enriched in the pathways of secondary metabolic processes, melanin biosynthesis processes, melanin metabolism processes, melanosome membranes, pigment granule membranes, melanosome, tyrosine metabolism, and melanogenesis. Notably, we revealed the gene ENSARG00020006042 may be a family member of YWHAs and involved in regulating melanin deposition. Furthermore, several essential genes (TYR, TYRP1, DCT, PMEL, MLANA, SLC45A2) were significantly associated with metabolite prostaglandins and compounds involved in sheep pigmentation. These findings provide new evidence of the strong correlation between prostaglandins and related compounds and key genes that regulate sheep melanin synthesis, furthering our understanding of the regulatory mechanisms and molecular breeding of pigmentation in sheep.PMID:39125816 | DOI:10.3390/ijms25158248

Int J Mol Sci. 2024 Jul 27;25(15):8216. doi: 10.3390/ijms25158216.ABSTRACTSalt stress is a serious problem, because it reduces the plant growth and seed yield of wheat. To investigate the salt-tolerant mechanism of wheat caused by plant-derived smoke (PDS) solution, metabolomic and proteomic techniques were used. PDS solution, which repairs the growth inhibition of wheat under salt stress, contains metabolites related to flavonoid biosynthesis. Wheat was treated with PDS solution under salt stress and proteins were analyzed using a gel-free/label-free proteomic technique. Oppositely changed proteins were associated with protein metabolism and signal transduction in biological processes, as well as mitochondrion, endoplasmic reticulum/Golgi, and plasma membrane in cellular components with PDS solution under salt stress compared to control. Using immuno-blot analysis, proteomic results confirmed that ascorbate peroxidase increased with salt stress and decreased with additional PDS solution; however, H+-ATPase displayed opposite effects. Ubiquitin increased with salt stress and decreased with additional PDS solution; nevertheless, genomic DNA did not change. As part of mitochondrion-related events, the contents of ATP increased with salt stress and recovered with additional PDS solution. These results suggest that PDS solution enhances wheat growth suppressed by salt stress through the regulation of energy metabolism and the ubiquitin-proteasome system related to flavonoid metabolism.PMID:39125784 | DOI:10.3390/ijms25158216

Int J Mol Sci. 2024 Jul 27;25(15):8207. doi: 10.3390/ijms25158207.ABSTRACTFragrance is a valuable trait in rice varieties, with its aroma significantly influencing consumer preference. In this study, we conducted comprehensive metabolome and transcriptome analyses to elucidate the genetic and biochemical basis of fragrance in the Shangsixiangnuo (SSXN) variety, a fragrant indica rice cultivated in Guangxi, China. Through sensory evaluation and genetic analysis, we confirmed SSXN as strongly fragrant, with an 806 bp deletion in the BADH2 gene associated with fragrance production. In the metabolome analysis, a total of 238, 233, 105 and 60 metabolic compounds exhibited significant changes at the seedling (S), reproductive (R), filling (F), and maturation (M) stages, respectively. We identified four compounds that exhibited significant changes in SSXN across all four development stages. Our analyses revealed a significant upregulation of 2-acetyl-1-pyrroline (2AP), the well-studied aromatic compound, in SSXN compared to the non-fragrant variety. Additionally, correlation analysis identified several metabolites strongly associated with 2AP, including ethanone, 1-(1H-pyrrol-2-yl)-, 1H-pyrrole, and pyrrole. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) analysis highlighted the magenta and yellow modules as particularly enriched in aroma-related metabolites, providing insights into the complex aromatic compounds underlying the fragrance of rice. In the transcriptome analysis, a total of 5582, 5506, 4965, and 4599 differential expressed genes (DEGs) were identified across the four developmental stages, with a notable enrichment of the common pathway amino sugar and nucleotide sugar metabolism in all stages. In our correlation analysis between metabolome and transcriptome data, the top three connected metabolites, phenol-, 3-amino-, and 2AP, along with ethanone, 1-(1H-pyrrol-2-yl)-, exhibited strong associations with transcripts, highlighting their potential roles in fragrance biosynthesis. Additionally, the downregulated expression of the P4H4 gene, encoding a procollagen-proline dioxygenase that specifically targets proline, in SSXN suggests its involvement in proline metabolism and potentially in aroma formation pathways. Overall, our study provides comprehensive insights into the genetic and biochemical mechanisms underlying fragrance production in rice, laying the foundation for further research aimed at enhancing fragrance quality in rice breeding programs.PMID:39125774 | DOI:10.3390/ijms25158207