PubMed

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):29-36. doi: 10.7417/CT.2023.2469.ABSTRACTBACKGROUND: This article provides an overview of the application of omics sciences in melanoma research. The name omics sciences refers to the large-scale analysis of biological molecules like DNA, RNA, proteins, and metabolites.METHODS: In the course of this review, we have adopted a focu-sed research strategy, meticulously selecting the most pertinent and emblematic articles related to the topic. Our methodology included a systematic examination of the scientific literature to guarantee a thorough and precise synthesis of the existing sources.RESULTS: With the advent of high-throughput technologies, omics have become an essential tool for understanding the complexity of melanoma. In this article, we discuss the different omics approaches used in melanoma research, including genomics, transcriptomics, proteomics, and metabolomics. We also highlight the major findings and insights gained from these studies, including the identification of new therapeutic targets and the development of biomarkers for diagnosis and prognosis. Finally, we discuss the challenges and future directions in omics-based melanoma research, including the integration of multiple omics data and the development of personalized medicine approaches.CONCLUSIONS: Overall, this article emphasizes the importance of omics science in advancing our understanding of melanoma and its potential for improving patient outcomes.PMID:37994746 | DOI:10.7417/CT.2023.2469

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):21-28. doi: 10.7417/CT.2023.2468.ABSTRACTBACKGROUND: Cancer, a potentially fatal condition, is one of the leading causes of death worldwide. Among males aged 20 to 35, the most common cancer in healthy individuals is testicular cancer, accounting for 1% to 2% of all cancers in men.METHODS: Throughout this review, we have employed a targeted research approach, carefully handpicking the most representative and relevant articles on the subject. Our methodology involved a systematic review of the scientific literature to ensure a comprehensive and accurate overview of the available sources.RESULTS: The onset and spread of testicular cancer are significantly influenced by genetic changes, including mutations in oncogenes, tu-mor suppressor genes, and DNA repair genes. As a result of identifying these specific genetic mutations in cancers, targeted medications have been developed to disrupt the signaling pathways affected by these genetic changes. To improve the diagnosis and treatment of this disease, it is crucial to understand its natural and clinical histories.CONCLUSIONS: In order to comprehend cancer better and to discover new biomarkers and therapeutic targets, oncologists are increasingly employing omics methods, such as genomics, transcriptomics, proteomics, and metabolomics. Targeted medications that focus on specific genetic pathways and mutations hold promise for advancing the diagnosis and management of this disease.PMID:37994745 | DOI:10.7417/CT.2023.2468

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):11-20. doi: 10.7417/CT.2023.2467.ABSTRACTBACKGROUND: Thyroid cancer, a heterogeneous disease originating from the thyroid gland, stands as the predominant endocrine malignan-cy worldwide. Despite advances in diagnosis and treatment, some patients still experience recurrence and mortality, which highlights the need for more personalized approaches to treatment. Omics sciences, encompassing genomics, transcriptomics, proteomics, and metabolomics, offer a high-throughput and impartial methodology for investigating the molecular signatures of thyroid cancer.METHODS: In the course of this review, we have adopted a focu-sed research strategy, meticulously selecting the most pertinent and emblematic articles related to the topic. Our methodology included a systematic examination of the scientific literature to guarantee a thorough and precise synthesis of the existing sources.RESULTS: These techniques enable the identification of molecular markers that can aid in diagnosis, prognosis, and treatment selection. As an illustration, through genomics studies, numerous genetic alterations commonly discovered in thyroid cancer have been identified, such as mutations in the BRAF and RAS genes. Through transcriptomics studies, distinctively expressed genes in thyroid cancer have been uncovered, playing roles in diverse biological processes, including cell proliferation, invasion, and metastasis. These genes can serve as potential targets for novel therapies. Proteomics studies have unveiled differentially expressed proteins intricately involved in thyroid cancer pathogenesis, presenting promising biomarkers for early detection and disease progression monitoring. Metabolomics studies have identified alterations in metabolic pathways linked to thyroid cancer, offering promising avenues for potential therapeutic targets.CONCLUSIONS: Precision medicine in thyroid cancer involves the integration of omics sciences with clinical data to develop personalized treatment plans for patients. Employing targeted therapies guided by molecular markers has exhibited promising outcomes in enhancing the prognosis of thyroid cancer patients. Notably, those with advanced hyroid cancer carrying BRAF mutations have displayed substantial responses to specific targeted therapies, such as vemurafenib and dabrafenib.PMID:37994744 | DOI:10.7417/CT.2023.2467

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):1-10. doi: 10.7417/CT.2023.2466.ABSTRACTThis comprehensive review explores the potential of omics sciences - such as genomics, transcriptomics, proteomics, and metabolomics - in advancing the diagnosis and therapy of urothelial carcinoma (UC), a prevalent and heterogeneous cancer affecting the urinary tract. The article emphasizes the significant advancements in understanding the molecular mechanisms underlying UC development and progression, obtained through the application of omics approa-ches. Genomic studies have identified recurrent genetic alterations in UC, while transcriptomic analyses have revealed distinct gene expression profiles associated with different UC subtypes. Proteomic investigations have recognized protein biomarkers with diagnostic and prognostic potential, and metabolomic profiling has found metabolic alterations that are specific to UC. The integration of multi-omics data holds promises in refining UC subtyping, identifying therapeutic tar-gets, and predicting treatment response. However, challenges like the standardization of omics technologies, validation of biomarkers, and ethical considerations need to be addressed to successfully translate these findings into clinical practice. Omics sciences offer tremendous potential in revolutionizing the diagnosis and therapy of UC, enabling more precise diagnostic methods, prognostic evaluations, and perso-nalized treatment selection for UC patients. Future research efforts should focus on overcoming these challenges and translating omics discoveries into meaningful clinical applications to improve outcomes for UC patients.PMID:37994743 | DOI:10.7417/CT.2023.2466

J Sci Food Agric. 2023 Nov 22. doi: 10.1002/jsfa.13160. Online ahead of print.ABSTRACTBACKGROUND: Phenolic modulators have attracted attention for their potential in shaping functional traits in plants. This work investigated the impact of naringenin (Nar) and rosmarinic acid (RA) on the functional properties of Lepidium sativum leaves and roots.RESULTS: Untargeted metabolomics identified a diverse phenolic profile, including flavonoids, phenolic acids, low molecular weight phenolics, lignans, and stilbenes. Cluster, AMOPLS, and OPLS-DA multivariate analyses confirmed tissue-specific modulation of bioactive compounds. The tissue was the hierarchically most influential factor, explaining 27% of observed variability, while the treatment and their interaction were statistically insignificant. Thereafter, various in vitro assays were employed to assess antioxidant capacity, including DPPH, ABTS, CUPRAC, FRAP, metal chelating, and PMD assays. Extracts were also tested for inhibitory effects on cholinesterase, amylase, glucosidase, and tyrosinase enzymes. RA application positively impacted antioxidant and enzyme inhibitory activities, holding valuable implications in shaping the health-promoting properties of L. sativum.CONCLUSION: The untargeted metabolomics analysis showed a significant tissue-dependent modulation of bioactive compounds, determining no synergistic effect between applying phenolic compounds in combination. Specifically, the sole application of rosmarinic acid increased anthocyanins and hydroxyphenyl propanoic acid content on leaves, which was strictly related to enhancing the biological activities. This article is protected by copyright. All rights reserved.PMID:37994181 | DOI:10.1002/jsfa.13160

Nat Commun. 2023 Nov 22;14(1):7639. doi: 10.1038/s41467-023-43239-6.ABSTRACTWhile mesenchymal stem cells (MSCs) have gained enormous attention due to their unique properties of self-renewal, colony formation, and differentiation potential, the MSC secretome has become attractive due to its roles in immunomodulation, anti-inflammatory activity, angiogenesis, and anti-apoptosis. However, the precise stimulation and efficient production of the MSC secretome for therapeutic applications are challenging problems to solve. Here, we report on Acoustofluidic Interfaces for the Mechanobiological Secretome of MSCs: AIMS. We create an acoustofluidic mechanobiological environment to form reproducible three-dimensional MSC aggregates, which produce the MSC secretome with high efficiency. We confirm the increased MSC secretome is due to improved cell-cell interactions using AIMS: the key mediator N-cadherin was up-regulated while functional blocking of N-cadherin resulted in no enhancement of the secretome. After being primed by IFN-γ, the secretome profile of the MSC aggregates contains more anti-inflammatory cytokines and can be used to inhibit the pro-inflammatory response of M1 phenotype macrophages, suppress T cell activation, and support B cell functions. As such, the MSC secretome can be modified for personalized secretome-based therapies. AIMS acts as a powerful tool for improving the MSC secretome and precisely tuning the secretory profile to develop new treatments in translational medicine.PMID:37993431 | PMC:PMC10665559 | DOI:10.1038/s41467-023-43239-6

BMC Geriatr. 2023 Nov 22;23(1):769. doi: 10.1186/s12877-023-04485-x.ABSTRACTBACKGROUND: Sarcopenia is defined as the disease of muscle loss and dysfunction. The prevalence of sarcopenia is strongly age-dependent. It could bring about disability, hospitalization, and mortality. The purpose of this study was to identify plasma metabolites associated with possible sarcopenia and muscle function to improve disease monitoring and understand the mechanism of muscle strength and function decline.METHODS: The participants were a group of healthy older adult who live in retirement homes in Asia (Taiwan) and can manage their daily lives without assistance. The participants were enrolled and divided into four groups: control (Con, n = 57); low physical function (LPF, n = 104); sarcopenia (S, n = 63); and severe sarcopenia (SS, n = 65) according to Asian countries that used Asian Working Group for Sarcopenia (AWGS) criteria. The plasma metabolites were used and the results were calculated as the difference between the control and other groups.RESULTS: Clinical parameters, age, gender, body mass index (BMI), hand grip strength (HGS), gait speed (GS), blood urea nitrogen (BUN), hemoglobin, and hematocrit were significantly different between the control and LPF groups. Metabolite patterns of LPF, S, and SS were explored in our study. Plasma kynurenine (KYN) and acylcarnitines (C0, C4, C6, and C18:1-OH) were identified with higher concentrations in older Taiwanese adults with possible sarcopenia and S compared to the Con group. After multivariable adjustment, the data indicate that age, BMI, and butyrylcarnitine (C4) are more important factors to identify individuals with low physical function and sarcopenia.CONCLUSION: This metabolomic study raises the importance of acylcarnitines on muscle mass and function. It suggests that age, BMI, BUN, KYN, and C4/Cr can be important evaluation markers for LPF (AUC: 0.766), S (AUC: 0.787), and SS (AUC: 0.919).PMID:37993772 | DOI:10.1186/s12877-023-04485-x

ISME Commun. 2023 Nov 22;3(1):122. doi: 10.1038/s43705-023-00323-8.ABSTRACTIngestion of the cycad toxins β-methylamino-L-alanine (BMAA) and azoxyglycosides is harmful to diverse organisms. However, some insects are specialized to feed on toxin-rich cycads with apparent immunity. Some cycad-feeding insects possess a common set of gut bacteria, which might play a role in detoxifying cycad toxins. Here, we investigated the composition of gut microbiota from a worldwide sample of cycadivorous insects and characterized the biosynthetic potential of selected bacteria. Cycadivorous insects shared a core gut microbiome consisting of six bacterial taxa, mainly belonging to the Proteobacteria, which we were able to isolate. To further investigate selected taxa from diverging lineages, we performed shotgun metagenomic sequencing of co-cultured bacterial sub-communities. We characterized the biosynthetic potential of four bacteria from Serratia, Pantoea, and two different Stenotrophomonas lineages, and discovered a suite of biosynthetic gene clusters notably rich in siderophores. Siderophore semi-untargeted metabolomics revealed a broad range of chemically related yet diverse iron-chelating metabolites, including desferrioxamine B, suggesting the occurrence of an unprecedented desferrioxamine-like biosynthetic pathway that remains to be identified. These results provide a foundation for future investigations into how cycadivorous insects tolerate diets rich in azoxyglycosides, BMAA, and other cycad toxins, including a possible role for bacterial siderophores.PMID:37993724 | DOI:10.1038/s43705-023-00323-8

ISME J. 2023 Nov 22. doi: 10.1038/s41396-023-01552-4. Online ahead of print.NO ABSTRACTPMID:37993599 | DOI:10.1038/s41396-023-01552-4

J Mol Med (Berl). 2023 Nov 23. doi: 10.1007/s00109-023-02395-4. Online ahead of print.ABSTRACTHepatic fibrosis (HF) could be developed into liver cirrhosis or even hepatocellular carcinoma. Stress has an important role in the occurrence and development of various considerable diseases. However, the effect of a certain degree stress on HF is still controversial. In our study, stress was simulated with regular chronic restraint stress (CRS) and HF model was induced with CCl4 in mice. We found that CRS was able to attenuate CCl4-induced liver injury and fibrosis in mice. Surprisingly, behavioral analysis showed that the mice in the HF group exhibited depression-like behavior. Further, the metabolomic analysis revealed that 119 metabolites and 20 metabolic pathways were altered in mice liver, especially the betaine metabolism pathway. Combined with the results of Ingenuity Pathway Analysis (IPA), the key proteins INSR, PI3K, AKT, and p-AMPK were identified and verified, and the results showed that CRS could upregulate the protein levels and mRNA expression of INSR, PI3K, AKT, and p-AMPK in liver tissues of HF mice. It suggested that CRS alleviated CCl4-induced liver fibrosis in mice through upregulation of the INSR/PI3K/AKT/AMPK pathway. Proper stress might be a potential therapeutic strategy for the treatment of chronic liver disease, which provided new insights into the treatment of HF. KEY MESSAGES: Chronic restraint stress mitigated CCl4-induced liver injury and hepatic fibrosis. CCl4-induced liver fibrosis could cause depression-like behavior. Chronic restraint stress altered metabolomic profiles in hepatic fibrosis mice, especially the betaine metabolism pathway. Chronic restraint stress increased betaine levels in liver tissue. Chronic restraint stress regulated the INSR/PI3K/AKT/AMPK signaling pathway in hepatic fibrosis mice.PMID:37993562 | DOI:10.1007/s00109-023-02395-4

Commun Biol. 2023 Nov 22;6(1):1189. doi: 10.1038/s42003-023-05581-9.ABSTRACTCoumarins isolated from Hydrangea paniculata (HP) had a renal protective effect in experimental membranous nephritis (MN), but the mechanisms are not clear. Currently, we investigate whether the modulation of gut dysbiosis by HP contributes to its renal protection. Experimental MN rats were treated with HP for six weeks. Fecal 16S rDNA sequencing and metabolomics were performed. Fecal microbiota transplantation (FMT) was used for the evaluation study. The results demonstrate that deteriorated renal function and gut dysbiosis are found in MN rats, as manifested by a higher Firmicutes/Bacteroidetes ratio and reduced diversity and richness, but both changes were reversed by HP treatment. Reduced gut dysbiosis is correlated with improved colonic integrity and lower endotoxemia in HP-treated rats. HP normalized the abnormal level of fecal metabolites by increasing short-chain fatty acid production and hindering the production of uremic toxin precursors. FMT of HP-treated feces to MN animals moderately reduced endotoxemia and albuminuria. Moreover, major coumarins in HP were only biotransformed into more bioactive 7-hydroxycoumarin by gut microbiota, which strengthened the effect of HP in vivo. Depletion of the gut microbiota partially abolished its renal protective effect. In conclusion, the bidirectional interaction between HP and the gut microbiota contributes to its beneficial effect.PMID:37993541 | DOI:10.1038/s42003-023-05581-9

Environ Res. 2023 Nov 20:117665. doi: 10.1016/j.envres.2023.117665. Online ahead of print.ABSTRACTIn this investigation, the presence of antibiotics and pharmaceuticals in Costa Rican surface waters, specifically in regions near feline habitats, was examined. The study revealed that 47% of the water samples contained detectable traces of at least one antibiotic. Ciprofloxacin and norfloxacin were the most frequently detected compounds, each with a detection rate of 27%. Other antibiotics, such as erythromycin, roxithromycin, and trimethoprim, were also found but at lower frequencies, around 14%. Notably, all antibiotic concentrations remained below 10 ng/L, with ciprofloxacin, norfloxacin, and erythromycin showing the highest concentrations. Furthermore, the investigation revealed the presence of non-antibiotic pharmaceutical residues in the water samples, typically at concentrations below 64 ng/L. Tramadol was the most frequently detected compound, present in 18% of the samples. The highest concentrations were observed for acetaminophen and tramadol, measuring 64 and 10 ng/L, respectively. Comparing these findings with studies conducted in treated wastewater and urban rivers, it became evident that the concentrations of antibiotics and pharmaceuticals were notably lower in this study. While previous research reported higher values, the limited number of studies conducted in protected areas raises concerns about the potential environmental impact on biodiversity. In summary, these results emphasize the importance of monitoring pharmaceutical residues and antimicrobial resistance genes ARGs in vulnerable ecosystems, especially those in close proximity to feline habitats in Costa Rica. Additionally, the study delved into the detection of (ARGs). All tested water samples were positive for at least one ARG, with the blaTEM gene being the most prevalent at 82%, followed by tetS at 64% and qnrB at 23%. Moreover, this research shed light on the complexity of evaluating ARGs in environmental samples, as their presence does not necessarily indicate their expression. It also highlighted the potential for co-selection and co-regulation of ARGs, showcasing the intricate behaviors of these genes in aquatic environments.PMID:37993051 | DOI:10.1016/j.envres.2023.117665

Environ Res. 2023 Nov 20:117717. doi: 10.1016/j.envres.2023.117717. Online ahead of print.ABSTRACTUnderstanding the behavior and potential toxicity of copper nanoparticles (nano-Cu) in the aquatic environment is a primary way to assess their environmental risks. In this study, RNA-seq was performed on three different tissues (gills, intestines, and muscles) of zebrafish exposed to nano-Cu, to explore the potential toxic mechanism of nano-Cu on zebrafish. The results indicated that the toxic mechanism of nano-Cu on zebrafish was tissue-specific. Nano-Cu enables the CB1 receptor of the presynaptic membrane of gill cells to affect short-term synaptic plasticity or long-term synaptic changes (ECB-LTD) through DSI and DSE, causing dysfunction of intercellular signal transmission. Imbalance of de novo synthesis of UMP in intestinal cells and its transformation to UDP, UTP, uridine, and uracil, resulted in many functions involved in the pyrimidine metabolic pathway being blocked. Meanwhile, the toxicity of nano-Cu caused abnormal expression of RAD51 gene in muscle cells, which affects the repair of damaged DNA through Fanconi anemia and homologous recombination pathway, thus causing cell cycle disorder. These results provide insights for us to better understand the differences in toxicity of nano-Cu on zebrafish tissues and are helpful for a comprehensive assessment of nano-Cu's effects on aquatic organisms.PMID:37993046 | DOI:10.1016/j.envres.2023.117717

Front Neuroendocrinol. 2023 Nov 20:101113. doi: 10.1016/j.yfrne.2023.101113. Online ahead of print.ABSTRACTAdvances in neuroendocrinology have led to major discoveries since the 19th century, identifying adaptive loops for maintaining homeostasis. One of the most remarkable discoveries was the concept of neurosteroids, according to which the brain is not only a target but also a source of steroid production. The identification of new membrane steroid targets now underpins the neuromodulatory effects of neurosteroids such as pregnenolone, which is involved in functions mediated by the GPCR CB1 receptor. Structural analysis of steroids is a key feature of their interactions with the phospholipid membrane, receptors and resulting activity. Therefore, mass spectrometry-based methods have been developed to elucidate the metabolic pathways of steroids, the ultimate approach being metabolomics, which allows the identification of a large number of metabolites in a single sample. This approach should enable us to make progress in understanding the role of neurosteroids in the functioning of physiological and pathological processes.PMID:37993022 | DOI:10.1016/j.yfrne.2023.101113

Chemosphere. 2023 Nov 20:140767. doi: 10.1016/j.chemosphere.2023.140767. Online ahead of print.ABSTRACTGiven its wide distribution in the environment and latent toxic effects, 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ) is an emerging concern that has gained increasing attention globally. 1368-BCZ exposure is reported to have potential cardiovascular toxicity. Although atherosclerosis is a cardiovascular disease and remains a primary cause of mortality worldwide, no evidence has been found regarding the impact of 1368-BCZ on atherosclerosis. Therefore, we aimed to explore the deleterious effects of 1368-BCZ on atherosclerosis and the underlying mechanisms. Serum samples from 1368-BCZ-treated atherosclerotic model mice were subjected to metabolomic profiling to investigate the adverse influence of the pollutant. Subsequently, the molecular mechanism associated with the metabolic pathway of atherosclerotic mice that was identified following 1368-BCZ exposure was validated in vitro. Serum metabolomics analysis revealed that 1368-BCZ significantly altered the tricarboxylic acid cycle, causing a disturbance in energy metabolism. In vitro, we further validated general markers of energy metabolism based on metabolome data: 1368-BCZ dampened adenosine triphosphate (ATP) synthesis and increased reactive oxygen species (ROS) production. Furthermore, blocking the aryl hydrocarbon receptor (AhR) reversed the high production of ROS induced by 1368-BCZ. It is concluded that 1368-BCZ decreased the ATP synthesis by disturbing the energy metabolism, thereby stimulating the AhR-mediated ROS production and presumably causing aggravated atherosclerosis. This is the first comprehensive study on the cardiovascular toxicity and mechanism of 1368-BCZ based on rodent models of atherosclerosis and integrated with in vitro models.PMID:37992903 | DOI:10.1016/j.chemosphere.2023.140767

J Ethnopharmacol. 2023 Nov 20:117479. doi: 10.1016/j.jep.2023.117479. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Chifeng decoction (HQCF) combined with parsnips is a classic Chinese traditional medicine formula that has certain advantages in the clinical treatment of cardiovascular and cerebrovascular diseases. At present, there is an absence of research on the regulatory effect and mechanism of this formula on atherosclerosis (AS). The synergistic effect of Radix Saposhnikoviae (RS) in HQCF is also unclear.AIM OF THE STUDY: This study was designed to investigate the role of RS, which is designed as a guide drug for HQCF, in improving the lipid metabolism of AS.MATERIALS AND METHODS: In this study, we studied the effect of HQCF on ApoE-/- mice before and after RS compatibility. Hematoxylin and eosin (HE) staining and oil red staining were used to evaluate atherosclerotic lesions and lipid accumulation in the aorta and liver, respectively. The expression of adenosine monophosphate-activated protein kinase (AMPK) and pAMPK in the aorta was measured by immunofluorescence, and AMPK and sterol regulatory element binding protein-1 (SREBP-1),fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) in liver tissue were measured by Western blot analysis. Metabolomics was used to compare the changes in serum and liver metabolites of ApoE-/- mice before and after RS combination.RESULTS: Compared with the control group, the serum lipid levels of ApoE-/- mice increased, the aortic intima thickened with plaque formation, and liver tissue pathological changes and lipid deposition occurred. Both (HQCFT without RS)HQCS and HQCF can improve the pathological condition of tissue and regulate the blood lipid level. It was noted that HQCF could promote the phosphorylation of AMPK to activate it, inhibit the expression of SREBP-1c and FAS, reduce lipid synthesis, and inhibit ACC to promote the oxidative decomposition of fatty acids. Serum and liver metabolome results showed that HQCS and HQCF treated AS mainly by regulating glycerophospholipid metabolism, sphingolipid metabolism and the arachidonic acid metabolism pathway. Importantly, HQCF showed better efficacy in regulating lipid metabolism than the HQCS group.CONCLUSION: HQCF decoction reduces atherosclerotic lesions in the aorta and lipid accumulation in the liver, which may regulate lipid transport and metabolic function by activating the AMPK pathway. These effects can be attributed to the guidance and synergism of RS.PMID:37992882 | DOI:10.1016/j.jep.2023.117479

J Pharm Sci. 2023 Nov 20:S0022-3549(23)00492-6. doi: 10.1016/j.xphs.2023.11.018. Online ahead of print.ABSTRACTCisplatin is widely used for the treatment of various types of cancer. However, cisplatin-induced nephrotoxicity (CIN) is frequently observed in patients receiving cisplatin therapy which poses a challenge in its clinical utility. Currently used clinical biomarkers for CIN are not adequate for early detection of nephrotoxicity, hence there is a need to identify potential early biomarkers in predicting CIN. In the current study, a combination of in vitro toxicodynamic (TD) modeling and untargeted global metabolomics approach was used to identify novel potential metabolite biomarkers for early detection of CIN. In addition, we investigated the protective role of cimetidine (CIM), an inhibitor of the organic cation transporter 2 (OCT2), in suppressing CIN. We first characterized the time-course of nephrotoxic effects of cisplatin (CIS) and the protective effects of CIM in a human pseudo-immortalized renal proximal tubule epithelial cell line (RPTEC), SA7K cell line. Secondly, we used a mathematical cell-level, in vitro TD modeling approach to quantitatively characterize the time-course effects of CIS and CIM as single agents and combination in SA7K cells. Based on the experimental and modeling results, we selected relevant concentrations of CIS and CIM for our metabolomics study. With the help of PCA (Principal Component Analysis) and PLS-DA (Projection to Latent Structure - Discriminate Analysis) analyses, we confirmed global metabolome changes for different groups (CIS, CIM, CIS+CIM vs control) in SA7K cells. Based on the criterion of a p-value ≤ 0.05 and a fold change ≥ 2 or ≤ 0.5, we identified 20 top metabolites that were significantly changed during the early phase i.e. within first 12 hours of CIS treatment. Finally, pathway analysis was conducted that revealed the key metabolic pathways that were most impacted in CIN.PMID:37992870 | DOI:10.1016/j.xphs.2023.11.018

Sci Total Environ. 2023 Nov 20:168572. doi: 10.1016/j.scitotenv.2023.168572. Online ahead of print.ABSTRACTImidacloprid poses a significant threat to aquatic ecosystems. In this study, we investigated the visual toxicity of imidacloprid and the underlying molecular mechanisms in adult zebrafish. After exposure to imidacloprid at environmental relevant concentrations (10 and 100μg/L) for 21 days, the detectable contents of imidacloprid were 23.0 ± 0.80 and 121 ± 1.56 ng/mg in eyes of adult zebrafish, respectively. The visual behavior of adult zebrafish was impaired including a reduced ability to track smoothly visual stimuli and visually guided self-motion. The immunofluorescence experiment showed that the content of Rhodopsin (Rho) in the retina of zebrafish was changed significantly. The expression rhythm of genes played key roles in capturing photons in dim (rho) and bright (opn1mw3, opn1lw2 and opn1sw2) light, and in phototransduction (gnb3b, arr3a and rpe65a), was disrupted significantly throughout a 24-h period in adult zebrafish. Targeted metabolomics analysis showed that the content of 16 metabolites associated with neurotransmitter function changed significantly, and were enriched in top three metabolism pathways including Arginine biosynthesis, Alanine, aspartate and glutamate metabolism, and Tryptophan metabolism. These results indicated that imidacloprid exposure at environmentally relevant concentrations could cause optical toxicity through disturbing the expression of opsins and affecting the phototransduction in the retina of zebrafish adults.PMID:37992846 | DOI:10.1016/j.scitotenv.2023.168572

J Biol Chem. 2023 Nov 20:105485. doi: 10.1016/j.jbc.2023.105485. Online ahead of print.ABSTRACTEZH2 (Enhancer of Zeste Homolog 2), a subunit of Polycomb Repressive Complex 2 (PRC2), catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 inhibition can be achieved with the FDA-approved drug EPZ-6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in three-dimensional (3D) tissue and cell culture systems influences this blockade in terms of growth-related metabolic functions. Here, we show that EZH2 suppression reduced growth of human lung adenocarcinoma A549 cells in two-dimensional (2D) cultures but stimulated growth in 3D culture. To understand the metabolic underpinnings, we employed [13C6]-glucose Stable Isotope-Resolved Metabolomics (SIRM) to determine the effect of EZH2 suppression on metabolic networks in 2D versus 3D A549 cultures. The Krebs cycle, neoribogenesis, γ-aminobutyrate (GAB) metabolism, and salvage synthesis of purine nucleotides were activated by EZH2 suppression in 3D spheroids but not in 2D cells, consistent with the growth effect. Using simultaneous 2H7-glucose + 13C5,15N2-Gln tracers and EPZ-6438 inhibition of H3 trimethylation, we delineated the effects on the Krebs cycle, γ-aminobutyrate metabolism, gluconeogenesis, and purine salvage to be PRC2 dependent. Furthermore, the growth/metabolic effects differed for mouse Matrigel versus self-produced A549 extracellular matrix. Thus, our findings highlight the importance of the presence and nature of extracellular matrix in studying the function of EZH2 and its inhibitors in cancer cells for modeling the in vivo outcomes.PMID:37992808 | DOI:10.1016/j.jbc.2023.105485

Ecotoxicol Environ Saf. 2023 Nov 21;268:115723. doi: 10.1016/j.ecoenv.2023.115723. Online ahead of print.ABSTRACTHigh carbonate alkalinity is one of the major stress factors for survival of aquatic animals in saline-alkaline water. Exopalaemon carinicauda is a good model for studying the saline-alkaline adaption mechanism in crustacean because of its great adaptive capacity to alkalinity stress. In this study, non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analyses based on high-throughput RNA sequencing (RNA-Seq) were used to study the metabolomic responses of hepatopancreas in E. carinicauda at 12 h and 36 h after acute carbonate alkalinity stress. The results revealed that most of the significantly differential metabolites were related to the lipid metabolism. In particular, the sphingolipid metabolism was observed at 12 h, the glycerophospholipid metabolism was detected at 36 h, and the linoleic acid metabolic pathway was significantly enriched at both 12 h and 36 h. The combined transcriptome and metabolome analysis showed that energy consumption increased at 12 h, resulting in significant enrichment of AMPK signaling pathways, which contributed to maintain energy homeostasis. Subsequently, the hepatopancreas provided sufficient energy supply through cAMP signaling pathway and glycerophosphate metabolism to maintain normal metabolic function at 36 h. These findings might help to understand the molecular mechanisms of the E. carinicauda under carbonate alkalinity stress, thereby promote the research and development of saline-alkaline resistant shrimp.PMID:37992642 | DOI:10.1016/j.ecoenv.2023.115723