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Metabolomics-based predictive biomarkers of oral cancer and its severity in human patients from North India using saliva.
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-13 DOI: 10.1039/d4mo00166d
Rahul Yadav, Vyomika Bansal, Anamika Singh, Neeraj Sinha, Preeti Tiwari, Chandan Singh

Oral squamous cell carcinoma (OSCC) is frequently the outcome of oral submucous fibrosis (OSMF), a common possibly premalignant disease. In our study, a cohort of 50 patients with OSCC and OSMF, along with 50 healthy controls, was analyzed to identify significant metabolic differences between the patient and control groups through multivariate statistical analysis using NMR-based metabolomics in saliva samples. The 2D scatter plot of PC1 versus PC2 scores clearly show a distinction between the groups, with the principal component analysis (PCA) explaining 24.6% of the variance. Partial least-squares discriminant analysis (PLS-DA) demonstrated R2 and Q2 values of 0.94 and 0.90, respectively, indicating a robust model fit. A total of 20 distinct metabolites were identified, including 5 that were up-regulated and 5 that were down-regulated. Univariate ROC curve analysis identified nine salivary metabolites with AUC values exceeding 0.70, including acetone, tryptophan, 5-aminopentanoic acid, betaine, aspartic acid, ethanol, acetoacetate, adipic acid, and citrate. Notably, the distinct presence of three metabolites-acetone, tryptophan, and 5-aminopentanoic acid-yielded AUC values of 0.98123, 0.95358, and 0.91506, respectively. The refined statistical model was subjected to metabolic pathway analysis, revealing interconnected pathways. We were also able to predict the severity of the disease, specifically distinguishing between stage I and stage II OSCC. This differentiation was highlighted by the PCA score plot, which explained 28.6% of the variance. These results were further confirmed by PLS-DA. These insights pave the way for early diagnosis and predicting severity in patients with oral cancer, which will enable better management of the disease.

{"title":"Metabolomics-based predictive biomarkers of oral cancer and its severity in human patients from North India using saliva.","authors":"Rahul Yadav, Vyomika Bansal, Anamika Singh, Neeraj Sinha, Preeti Tiwari, Chandan Singh","doi":"10.1039/d4mo00166d","DOIUrl":"https://doi.org/10.1039/d4mo00166d","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is frequently the outcome of oral submucous fibrosis (OSMF), a common possibly premalignant disease. In our study, a cohort of 50 patients with OSCC and OSMF, along with 50 healthy controls, was analyzed to identify significant metabolic differences between the patient and control groups through multivariate statistical analysis using NMR-based metabolomics in saliva samples. The 2D scatter plot of PC1 <i>versus</i> PC2 scores clearly show a distinction between the groups, with the principal component analysis (PCA) explaining 24.6% of the variance. Partial least-squares discriminant analysis (PLS-DA) demonstrated <i>R</i><sup>2</sup> and <i>Q</i><sup>2</sup> values of 0.94 and 0.90, respectively, indicating a robust model fit. A total of 20 distinct metabolites were identified, including 5 that were up-regulated and 5 that were down-regulated. Univariate ROC curve analysis identified nine salivary metabolites with AUC values exceeding 0.70, including acetone, tryptophan, 5-aminopentanoic acid, betaine, aspartic acid, ethanol, acetoacetate, adipic acid, and citrate. Notably, the distinct presence of three metabolites-acetone, tryptophan, and 5-aminopentanoic acid-yielded AUC values of 0.98123, 0.95358, and 0.91506, respectively. The refined statistical model was subjected to metabolic pathway analysis, revealing interconnected pathways. We were also able to predict the severity of the disease, specifically distinguishing between stage I and stage II OSCC. This differentiation was highlighted by the PCA score plot, which explained 28.6% of the variance. These results were further confirmed by PLS-DA. These insights pave the way for early diagnosis and predicting severity in patients with oral cancer, which will enable better management of the disease.</p>","PeriodicalId":19065,"journal":{"name":"Molecular omics","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unmasking the lipid landscape: carbamazepine induces alterations in Leydig cell lipidome.
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-04 DOI: 10.1039/d4mo00221k
Inês Nobre, Inês M S Guerra, Marisa Pinho, Ana D Martins, Laura Goracci, Stefano Bonciarelli, Tânia Melo, Pedro Domingues, Artur Paiva, Pedro F Oliveira, M Rosário Domingues

Leydig cells rely on lipids and fatty acids (FA) for essential functions like maintaining structural integrity, energy metabolism, and steroid hormone synthesis, including testosterone production. Carbamazepine (CBZ), a common anticonvulsant medication, can influence lipid metabolism and profiles, potentially impacting Leydig cell function and testosterone levels. Understanding this interplay is crucial to optimize treatment strategies for individuals requiring CBZ therapy while mitigating any adverse effects on male reproductive health. This study focuses on evaluating the effects of selected CBZ concentrations on the lipid homeostasis of BLTK-1 murine Leydig cells. By employing liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), we aimed to uncover the specific changes in lipid profiles induced by CBZ exposure (25 and 200 μM). FA analysis demonstrated a significant decrease in FA 22:6 n-3 with increasing CBZ concentration and an increase in the n-6/n-3 ratio. Furthermore, changes in the lipidome, particularly in lipid species belonging to phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylglycerol (PG), and sphingomyelin (SM) classes were observed. PE and PC lipid species were significantly elevated in Leydig cells exposed to 200 μM CBZ, whereas PG and SM species were downregulated. CBZ treatment significantly altered the Leydig cell phospholipidome, suggesting specific phospholipids such as PG 40:4, PG 34:1, PC O-32:1, PC 32:2, and PE P-38:6, which exhibited the lowest p-values, as potential biomarkers for clinical assessment of CBZ's impact on Leydig cells. These findings underscore the intricate relationship between CBZ exposure and alterations in lipid profiles, offering potential insights for monitoring and mitigating the drug's effects on male reproductive health.

{"title":"Unmasking the lipid landscape: carbamazepine induces alterations in Leydig cell lipidome.","authors":"Inês Nobre, Inês M S Guerra, Marisa Pinho, Ana D Martins, Laura Goracci, Stefano Bonciarelli, Tânia Melo, Pedro Domingues, Artur Paiva, Pedro F Oliveira, M Rosário Domingues","doi":"10.1039/d4mo00221k","DOIUrl":"https://doi.org/10.1039/d4mo00221k","url":null,"abstract":"<p><p>Leydig cells rely on lipids and fatty acids (FA) for essential functions like maintaining structural integrity, energy metabolism, and steroid hormone synthesis, including testosterone production. Carbamazepine (CBZ), a common anticonvulsant medication, can influence lipid metabolism and profiles, potentially impacting Leydig cell function and testosterone levels. Understanding this interplay is crucial to optimize treatment strategies for individuals requiring CBZ therapy while mitigating any adverse effects on male reproductive health. This study focuses on evaluating the effects of selected CBZ concentrations on the lipid homeostasis of BLTK-1 murine Leydig cells. By employing liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS), we aimed to uncover the specific changes in lipid profiles induced by CBZ exposure (25 and 200 μM). FA analysis demonstrated a significant decrease in FA 22:6 <i>n</i>-3 with increasing CBZ concentration and an increase in the <i>n</i>-6/<i>n</i>-3 ratio. Furthermore, changes in the lipidome, particularly in lipid species belonging to phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylglycerol (PG), and sphingomyelin (SM) classes were observed. PE and PC lipid species were significantly elevated in Leydig cells exposed to 200 μM CBZ, whereas PG and SM species were downregulated. CBZ treatment significantly altered the Leydig cell phospholipidome, suggesting specific phospholipids such as PG 40:4, PG 34:1, PC O-32:1, PC 32:2, and PE P-38:6, which exhibited the lowest <i>p</i>-values, as potential biomarkers for clinical assessment of CBZ's impact on Leydig cells. These findings underscore the intricate relationship between CBZ exposure and alterations in lipid profiles, offering potential insights for monitoring and mitigating the drug's effects on male reproductive health.</p>","PeriodicalId":19065,"journal":{"name":"Molecular omics","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhanced anti-inflammatory and anti-fibrotic effects of nanoparticles loaded with a combination of Aloe vera-Moringa oleifera extracts.
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-29 DOI: 10.1039/d4mo00195h
Gabriela I Carballo-López, Jhordan Ojeda-González, Kevin D Martínez-García, Karla E Cervantes-Luevano, Aldo Moreno-Ulloa, Ana B Castro-Ceseña

Metabolic associated steatohepatitis characterized by lipid accumulation, inflammation and fibrosis, is a growing global health issue, contributing to severe liver-related mortality. With limited effective treatments available, there is an urgent need for novel therapeutic strategies. Moringa oleifera, rich in antioxidants, offers potential for combating steatohepatitis, but its cytotoxicity presents challenges. Aloe vera, renowned for its cytocompatibility and anti-inflammatory effects, shows promise in mitigating these risks. Using infrared spectrometry and mass spectrometry, we identified 1586 metabolites from both plants across 84 chemical classes. By encapsulating these phytochemicals in nanoparticles, we achieved increased solubility, cytocompatibility, and gene modulation to hepatic stellate cells affected by steatohepatitis. Chemoinformatic analysis revealed bioactive metabolites, including hesperetin analogs, known to inhibit TGF-β. Our results demonstrate that these nanoparticles not only improved gene expression modulation related to metabolic associated steatohepatitis, particularly TGF-β and COL1A1, but also outperformed free compounds, highlighting their potential as a novel therapeutic approach.

{"title":"Enhanced anti-inflammatory and anti-fibrotic effects of nanoparticles loaded with a combination of <i>Aloe vera</i>-<i>Moringa oleifera</i> extracts.","authors":"Gabriela I Carballo-López, Jhordan Ojeda-González, Kevin D Martínez-García, Karla E Cervantes-Luevano, Aldo Moreno-Ulloa, Ana B Castro-Ceseña","doi":"10.1039/d4mo00195h","DOIUrl":"https://doi.org/10.1039/d4mo00195h","url":null,"abstract":"<p><p>Metabolic associated steatohepatitis characterized by lipid accumulation, inflammation and fibrosis, is a growing global health issue, contributing to severe liver-related mortality. With limited effective treatments available, there is an urgent need for novel therapeutic strategies. <i>Moringa oleifera</i>, rich in antioxidants, offers potential for combating steatohepatitis, but its cytotoxicity presents challenges. <i>Aloe vera</i>, renowned for its cytocompatibility and anti-inflammatory effects, shows promise in mitigating these risks. Using infrared spectrometry and mass spectrometry, we identified 1586 metabolites from both plants across 84 chemical classes. By encapsulating these phytochemicals in nanoparticles, we achieved increased solubility, cytocompatibility, and gene modulation to hepatic stellate cells affected by steatohepatitis. Chemoinformatic analysis revealed bioactive metabolites, including hesperetin analogs, known to inhibit TGF-β. Our results demonstrate that these nanoparticles not only improved gene expression modulation related to metabolic associated steatohepatitis, particularly TGF-β and COL1A1, but also outperformed free compounds, highlighting their potential as a novel therapeutic approach.</p>","PeriodicalId":19065,"journal":{"name":"Molecular omics","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the phenotypic and metabolic responses induced by urea-encapsulated hydrogel beads on Brassica juncea (L.) Czern & Coss.
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-28 DOI: 10.1039/d4mo00192c
Muthumari Balakrishnan, Vignesh Kumar Balasubramanian, Kavitha Murugan, John Praveen Kumar John Kennedy, Subashri Dhanasekaran, Shih-Feng Fu, Shang-Tse Ho, Jothi Basu Muthuramalingam, Jui-Yu Chou

Hydrogels, three-dimensional polymeric networks capable of absorbing and retaining significant amounts of aqueous solution, offer a promising platform for controlled release of desired compounds. In this study, we explored the effects of urea delivery through galactoxyloglucan-sodium alginate hydrogels on the phenotypic and metabolic responses of Brassica juncea, a vital oilseed and vegetable crop. The experiments were conducted with four treatments: control (without hydrogel beads and urea), direct urea supplementation (U), hydrogel beads with urea (HBWU), and hydrogel beads without urea (HBWOU). Our findings revealed that HBWU-treated plants exhibited commendable plant growth with significantly higher chlorophyll content (11.06 mg/0.1 g) compared to the control (3.67 mg/0.1 g) and U-treated group (6.41 mg/0.1 g). Metabolic analysis identified 17 major intra-cellular metabolites involved in nitrogen metabolism. HBWU treatment significantly boosted nitrogen assimilation in plants, as evidenced by the upregulation of 9 metabolites. Furthermore, a proposed schematic diagram illustrates the HBWU induced-metabolic pathways and nitrogen metabolism in B. juncea. These findings demonstrate the potential of hydrogel-based controlled-release systems to enhance plant growth and nitrogen assimilation.

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引用次数: 0
The investigation of early metabolic level perturbation of northern quahog (Mercenaria mercenaria) in response to brevetoxin. 短叶毒素对北圆蚌早期代谢水平扰动的影响。
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1039/d4mo00207e
Bo Wang, Nicole McKenna, Julie Pollak, Moses Mayonu, Lin Jiang

Brevetoxins are a type of neurotoxin produced in red tide blooms. Northern quahogs (M. mercenaria) are extensively used in commercial aquaculture farming, and early-stage metabolomics studies can provide early warnings of brevetoxins for farmers. In this study, NMR-based metabolomics was performed to investigate the response of clam gills and digestive glands under a series of sublethal doses of brevetoxins. Our study showed that the brevetoxin PbTx-2 had minimal influence on the physical activities of M. mercenaria for a short exposure time (24 hours). However, major metabolic level perturbations were observed in the clam gill extracts from the 1 ppb treatment. In addition, in the low concentration (0.1 ppb) study, clam gills showed combinational metabolite perturbations, as observed by an OPLS-DA study. The highly disturbed metabolites in the gill samples were the upregulated serine, glucose, hypotaurine, and glycine and the downregulated lactate, leucine, isoleucine, threonine, biotin, taurine, and valine. The results indicated that the brevetoxin PbTx-2 potentially affects glycolysis, glycine, serine, and threonine metabolism, taurine and hypotaurine metabolism, and biotin metabolism. While the digestive gland had less significantly changed metabolites, the potential combinational metabolite changes from PCA were observed from the 5-ppb treatment. Glucose and glycine are the primary metabolites that showed high contributions to the OPLS-DA model, which indicates the potential influence of digestive activities. The study indicated that metabolomic analysis of the gills and digestive glands of M. mercenaria is a feasible method to monitor the toxicity of brevetoxins, especially under sublethal doses in marine water.

短毒素是一种在赤潮中产生的神经毒素。北方quahogs (M.雇佣兵)被广泛用于商业水产养殖,早期代谢组学研究可以为农民提供短暂毒素的早期预警。在这项研究中,基于核磁共振的代谢组学研究了一系列亚致死剂量的短毒素对蛤鳃和消化腺的反应。本研究表明,短毒素PbTx-2在短暴露时间内(24小时)对水蛭生理活动的影响最小。然而,在1 ppb处理的蛤鳃提取物中观察到主要的代谢水平扰动。此外,在低浓度(0.1 ppb)的研究中,正如OPLS-DA研究所观察到的那样,蛤鳃显示出组合代谢物扰动。鳃样品中高度紊乱的代谢物是上调的丝氨酸、葡萄糖、次牛磺酸和甘氨酸,以及下调的乳酸、亮氨酸、异亮氨酸、苏氨酸、生物素、牛磺酸和缬氨酸。结果表明,短叶草毒素PbTx-2可能影响糖酵解、甘氨酸、丝氨酸和苏氨酸代谢、牛磺酸和次牛磺酸代谢以及生物素代谢。虽然消化腺的代谢物变化不太明显,但从5ppb治疗中观察到PCA的潜在组合代谢物变化。葡萄糖和甘氨酸是对OPLS-DA模型贡献很大的主要代谢物,这表明消化活动的潜在影响。研究表明,利用鳃和消化腺的代谢组学分析是监测海水中短毒素毒性的一种可行方法,特别是在亚致死剂量下。
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引用次数: 0
Proteomic analysis reveals anticancer mechanisms of Bhallataka taila in inhibiting lung cancer progression and metastasis. 蛋白质组学分析揭示了黑尾草抑制肺癌进展和转移的抗癌机制。
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1039/d4mo00156g
Suchitha G P, Akhila B Rai, Ravishankar Pervaje, Chinmaya Narayana Kotimoole, Prashant Kumar Modi, T S Keshava Prasad, Shobha Dagamajalu

Lung cancer remains the leading cause of cancer-related deaths worldwide due to its poor prognosis. Despite significant advancements in the understanding of cancer development, improvements in diagnostic methods, and multimodal therapeutic regimens, the prognosis of lung cancer has still not improved. Therefore, it is reasonable to look for newer and alternative medicines for treatment. Bhallataka nut extract, derived from the seeds of Semecarpus anacardium, is known for its anti-inflammatory and antioxidant properties, suggesting potential as a treatment for cancer. In this study, we investigated the molecular networks associated with the Bhallataka taila-mediated inhibition of lung adenocarcinoma. Treating lung cancer cell lines with Bhallataka taila resulted in decreased colony formation, proliferation, and migration, and increased apoptosis. Using a tandem mass tag (TMT)-based temporal quantitative proteomic analysis, we identified 173 overexpressed and 249 downregulated proteins among a total of 2879 proteins. Significantly altered proteins are associated with lung cancer progression, metastasis, invasion, migration, and epithelial-mesenchymal transition (EMT). The analysis of these altered proteins revealed molecular networks underlying the anticancer mechanisms of Bhallataka taila. Validation of these proteins and pathways affected by Bhallataka taila confirmed its utility in cancer treatment.

由于预后不良,肺癌仍然是世界范围内癌症相关死亡的主要原因。尽管对癌症发展的认识、诊断方法的改进和多模式治疗方案取得了重大进展,但肺癌的预后仍未得到改善。因此,寻找更新的替代药物进行治疗是合理的。巴拉塔卡坚果提取物,从半仙人掌种子中提取,以其抗炎和抗氧化特性而闻名,这表明它有治疗癌症的潜力。在这项研究中,我们研究了与巴拉塔卡草叶介导的肺腺癌抑制相关的分子网络。用巴罗塔卡芥治疗肺癌细胞系可减少菌落形成、增殖和迁移,增加细胞凋亡。利用基于串联质量标签(TMT)的时间定量蛋白质组学分析,我们在总共2879个蛋白中鉴定出173个过表达蛋白和249个下调蛋白。显著改变的蛋白与肺癌的进展、转移、侵袭、迁移和上皮-间质转化(EMT)有关。对这些改变的蛋白质的分析揭示了Bhallataka taila抗癌机制的分子网络。这些蛋白质和受巴拉塔卡泰拉影响的途径的验证证实了它在癌症治疗中的效用。
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引用次数: 0
Differential modulation of the hepatocellular metabolome, cytoprotective and inflammatory responses due to endotoxemia and lipotoxicity. 内毒素血症和脂肪毒性引起的肝细胞代谢组、细胞保护和炎症反应的差异调节。
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1039/d4mo00140k
Jyoti Sharma, Priyankar Dey

The present work aimed to examine the primary mechanisms of liver damage, namely the impact of gut-derived endotoxins along the gut-liver axis and adipose-derived free fatty acids along the adipose-liver axis. These processes are known to play a significant role in the development of hepatic inflammation and steatosis. Although possible overlapping in the pathogenesis was expected, these processes have unique pathophysiological consequences. Therefore, we used HepG2 cells as a model system to investigate the impact of lipopolysaccharides (LPS) and free fatty acid (FFA; albumin conjugated palmitic acid) on the intracellular metabolome. Although both LPS and FFA triggered the expression of nuclear factor κB (NFκB)-dependent inflammation, only LPS treatment was able to trigger a Toll-like receptor 4 (TLR4) dependent response. The intracellular cytoprotective enzymatic levels (catalase, peroxidase, glutathione) were increased due to FFA but lowered due to LPS. The free-radical neutralizing efficacies of cell-free metabolites of FFA-treated cells were better than those of the LPS-treated ones. The use of untargeted metabolomics allowed for the identification of distinct metabolic pathway enrichments, providing further insights into the differential effects of LPS and FFA on the metabolism of hepatocytes. Collectively, the current study highlights the distinct impacts of endotoxemia and lipotoxicity on the metabolome of hepatocytes, hence offering valuable insights into hepatocellular function.

目前的工作旨在研究肝损伤的主要机制,即肠道内毒素对肠道-肝轴的影响和脂肪游离脂肪酸对脂肪-肝轴的影响。众所周知,这些过程在肝脏炎症和脂肪变性的发展过程中起着重要作用。虽然预计这些过程在发病机制上可能存在重叠,但它们具有独特的病理生理学后果。因此,我们以 HepG2 细胞为模型系统,研究脂多糖(LPS)和游离脂肪酸(FFA;白蛋白结合棕榈酸)对细胞内代谢组的影响。虽然脂多糖和游离脂肪酸都会引发依赖核因子κB(NFκB)的炎症表达,但只有脂多糖处理能引发依赖Toll样受体4(TLR4)的反应。细胞内的细胞保护酶(过氧化氢酶、过氧化物酶、谷胱甘肽)水平因 FFA 而升高,但因 LPS 而降低。经 FFA 处理的细胞游离代谢物的自由基中和效果优于经 LPS 处理的细胞游离代谢物。通过使用非靶向代谢组学,可以确定不同的代谢途径富集,从而进一步了解 LPS 和 FFA 对肝细胞代谢的不同影响。总之,本研究强调了内毒素血症和脂毒性对肝细胞代谢组的不同影响,从而为了解肝细胞功能提供了宝贵的信息。
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引用次数: 0
Selective labeling of tyrosine residues in proteins: insights from PTAD labeling and tandem mass spectrometry analysis. 蛋白质中酪氨酸残基的选择性标记:来自PTAD标记和串联质谱分析的见解。
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-24 DOI: 10.1039/d4mo00186a
Adway O Zacharias, Sharel Cornelius, Saiful M Chowdhury

Designing reagents for protein labeling is crucial for investigating cellular events and developing new therapeutics. Historically, much effort has been focused on labeling lysine and arginine residues due to their abundance on the protein periphery. The chemo-selectivity of these reagents is a challenging yet crucial parameter for deciphering properties specifically associated with the targeted amino acid. Consequently, there is a growing demand for new conjugation reagents and workflows that facilitate selective binding to amino acids other than lysine, cysteine, and arginine. Tyrosine, an aromatic amino acid, occurs moderately on the protein periphery, with its phenolic ring often buried within the tertiary protein structure. This presents a challenging environment for tyrosine-specific protein bioconjugation efforts. The hydrophobic aromatic side chain of tyrosine is known to engage in π-stacking interactions, while the hydroxyl group of the phenyl ring can participate in hydrogen bonding and form tyrosyl radicals involved in electron transfer. 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD) has been previously investigated for its ability to bind to tyrosine. This work presents an extensive structural proteomics investigation of tyrosine labeling across samples of varying complexity, ranging from peptides and proteins to entire cell lysates. Mass spectrometry is utilized to study the behavior of tyrosine-labeled samples through tandem mass spectrometry experiments. We believe these studies will offer valuable insights into tyrosine bioconjugation with PTAD and demonstrate its potential as a covalent labeling reagent for chemical proteomics research.

设计用于蛋白质标记的试剂对于研究细胞事件和开发新的治疗方法至关重要。从历史上看,由于赖氨酸和精氨酸残基在蛋白质周围的丰度,人们一直致力于标记赖氨酸和精氨酸残基。这些试剂的化学选择性是一个具有挑战性但至关重要的参数,用于破译与目标氨基酸特异性相关的特性。因此,对新的偶联试剂和工作流程的需求不断增长,这些试剂和工作流程可以促进与赖氨酸、半胱氨酸和精氨酸以外的氨基酸的选择性结合。酪氨酸是一种芳香氨基酸,适度分布在蛋白质外围,其酚环通常埋在三级蛋白质结构中。这为酪氨酸特异性蛋白的生物偶联工作提供了一个具有挑战性的环境。已知酪氨酸的疏水芳侧链参与π-stacking相互作用,苯基环的羟基参与氢键形成参与电子转移的酪氨酸自由基。4-苯基- 3h -1,2,4-三唑-3,5(4H)-二酮(PTAD)先前已被研究其与酪氨酸结合的能力。这项工作提出了一个广泛的结构蛋白质组学研究酪氨酸标记的不同复杂性的样品,从肽和蛋白质到整个细胞裂解物。质谱法通过串联质谱实验来研究酪氨酸标记样品的行为。我们相信这些研究将为酪氨酸与PTAD的生物偶联提供有价值的见解,并证明其作为化学蛋白质组学研究的共价标记试剂的潜力。
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引用次数: 0
Integrating OMICS-based platforms and analytical tools for diagnosis and management of pancreatic cancer: a review. 整合基于omics的平台和分析工具用于胰腺癌的诊断和管理:综述
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-23 DOI: 10.1039/d4mo00187g
Patrícia Sousa, Laurentina Silva, José S Câmara, Paula Guedes de Pinho, Rosa Perestrelo

Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular disease. From the different types of cancer, pancreatic cancer (PaC) has one of the lowest survival rates, with a survival rate of about 20% after the first year of diagnosis and about 8% after 5 years. The lack of highly sensitive and specific biomarkers, together with the absence of symptoms in the early stages, determines a late diagnosis, which is associated with a decrease in the effectiveness of medical intervention, regardless of its nature - surgery and/or chemotherapy. This review provides an updated overview of recent studies combining multi-OMICs approaches (e.g., proteomics, metabolomics) with analytical tools, highlighting the synergy between high-throughput molecular data generation and precise analytical tools such as LC-MS, GC-MS and MALDI-TOF MS. This combination significantly improves the detection, quantification and identification of biomolecules in complex biological systems and represents the latest advances in understanding PaC management and the search for effective diagnostic tools. Large-scale data analysis coupled with bioinformatics tools enables the identification of specific genetic mutations, gene expression patterns, pathways, networks, protein modifications and metabolic signatures associated with PaC pathogenesis, progression and treatment response through the integration of multi-OMICs data.

癌症仍然是全球第二大死因,仅次于心血管疾病。在不同类型的癌症中,胰腺癌(PaC)是生存率最低的癌症之一,诊断后第一年的生存率约为20%,5年后约为8%。缺乏高度敏感和特异性的生物标志物,加上在早期阶段没有症状,决定了晚期诊断,这与医疗干预的有效性降低有关,无论其性质如何-手术和/或化疗。本文综述了近期将多组学方法(如蛋白质组学、代谢组学)与分析工具相结合的最新研究,强调了高通量分子数据生成与精确分析工具(如LC-MS、GC-MS和MALDI-TOF ms)之间的协同作用。复杂生物系统中生物分子的定量和鉴定,代表了理解PaC管理和寻找有效诊断工具的最新进展。通过整合多组学数据,结合生物信息学工具进行大规模数据分析,可以识别与PaC发病、进展和治疗反应相关的特定基因突变、基因表达模式、途径、网络、蛋白质修饰和代谢特征。
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引用次数: 0
Phosphoproteomics guides low dose drug combination of cisplatin and silmitasertib against concurrent chemoradiation resistant cervical cancer† 磷蛋白质组学指导顺铂和silmitasertib低剂量联合治疗同步放化疗耐药宫颈癌。
IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-27 DOI: 10.1039/D4MO00147H
Irene A. George, Janani Sambath, R. E. Dhawale, Manisha Singh, Vinita Trivedi, R. Venkataramanan, Richa Chauhan and Prashant Kumar

Cisplatin-based concurrent chemoradiotherapy (CCRT) is the standard treatment for cervical patients with locally advanced disease. Despite the improved survival rates and prognosis observed in patients undergoing CCRT, over 30–40% do not achieve complete response and are at risk of locoregional recurrence. Targeting crucial molecules that confer resistance may improve the clinical outcomes of the treatment resistant patient cohort. Herein, we employed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based phosphoproteomic approach to identify the altered phosphophorylation events, activated kinases and dysregulated pathways involved in treatment resistance. We quantified 2531 unique phosphopeptides mapping to 1099 proteins of which 74 proteins were differentially phosphorylated between the cohorts. Pathway analysis revealed dysregulation of the DNA repair pathway and the proteins involved in DNA repair in the non-responder cohort. Additionally, we identified kinase signature associated with CCRT resistance. Kinases such as CSNK2A1, PRKDC, PLK-1, NEK2, ATM and CDK1 are predicted to be activated in non-responders. In particular, we showed that CSNK2A1 is involved in oncogenesis of cervical cancer and pharmacological inhibition led to reduced cell proliferation, migration and colony formation. Moreover, the combination of the CSNK2A1 inhibitor, silmitasertib with cisplatin demonstrated synergism (combination index < 1) and yielded a beneficial reduction in dosage. The dose reduced combination potentially reduced the proliferative, migratory and colony formation ability in vitro. Our findings highlight the potential of phosphoproteomics to identify clinically significant targets and pathways implicated in CCRT resistance. Our study also indicates that combination therapy could serve as an effective treatment strategy to improve the efficacy of patients undergoing CCRT.

以顺铂为基础的同步放化疗(CCRT)是局部晚期宫颈患者的标准治疗方法。尽管在接受CCRT的患者中观察到生存率和预后的改善,但超过30-40%的患者没有达到完全缓解,并且存在局部复发的风险。靶向产生耐药性的关键分子可能会改善耐药患者群体的临床结果。在此,我们采用液相色谱-串联质谱(LC-MS/MS)为基础的磷酸化蛋白质组学方法来鉴定与治疗抗性相关的磷酸化事件、活化激酶和失调通路的改变。我们量化了2531个独特的磷酸化肽,映射到1099个蛋白质,其中74个蛋白质在队列中磷酸化差异。途径分析显示,在无应答队列中,DNA修复途径和参与DNA修复的蛋白质出现了失调。此外,我们还发现了与CCRT耐药相关的激酶信号。预计CSNK2A1、PRKDC、PLK-1、NEK2、ATM和CDK1等激酶在无应答者中被激活。特别是,我们发现CSNK2A1参与宫颈癌的肿瘤发生,药理抑制导致细胞增殖、迁移和集落形成减少。此外,CSNK2A1抑制剂silmitasertib与顺铂联用显示出协同作用(联合指数< 1),并产生有益的剂量减少。剂量降低组合可能降低体外增殖、迁移和集落形成能力。我们的研究结果强调了磷酸蛋白组学在鉴别与CCRT耐药相关的临床重要靶点和途径方面的潜力。我们的研究也表明,联合治疗可以作为一种有效的治疗策略来提高CCRT患者的疗效。
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引用次数: 0
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