Longitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 1, 2024

Abstract Cetuximab therapy is the major treatment for colorectal cancer (CRC), but drug resistance limits its effectiveness. Here, we perform longitudinal and deep proteomic profiling of 641 plasma samples originated from 147 CRC patients (CRCs) undergoing cetuximab with multi-course treatment, 90 healthy controls (HCs). COL12A1, THBS2, S100A8, S100A9 are screened as potential proteins to distinguish CRCs HCs both in tissue validation cohorts. We identify biomarkers (RRAS2, MMP8, FBLN1, RPTOR, IMPDH2) initial response prediction. In a setting, two clusters distinct fluctuations construct model high accuracy predict response, further validated independent cohort. This study reveals heterogeneity different tumor diagnosis, prediction respectively first course may ultimately be useful monitoring intervention strategies CRC.

Язык: Английский

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Unraveling Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Use of Omics Technologies

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(4), С. 1589 - 1589

Опубликована: Фев. 13, 2025

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic (MASLD), is the most prevalent disorder globally, linked obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis cirrhosis hepatocellular carcinoma (HCC) crucial for patient management treatment strategies. The disease's complexity requires innovative approaches early detection personalized care. Omics technologies-such genomics, transcriptomics, proteomics, metabolomics, exposomics-are revolutionizing study of MASLD. These high-throughput techniques allow a deeper exploration molecular mechanisms driving progression. Genomics can identify genetic predispositions, whilst transcriptomics proteomics reveal changes in gene expression protein profiles during evolution. Metabolomics offers insights into alterations associated with MASLD, while exposomics links environmental exposures MASLD pathology. By integrating data various omics platforms, researchers map out intricate biochemical pathways involved This review discusses roles technologies enhancing understanding highlights diagnostic therapeutic targets within spectrum, emphasizing need non-invasive tools staging development.

Язык: Английский

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Human amniotic mesenchymal stem cells-derived IGFBP-3, DKK-3, and DKK-1 attenuate liver fibrosis through inhibiting hepatic stellate cell activation by blocking Wnt/β-catenin signaling pathway in mice

Stem Cell Research & Therapy, Год журнала: 2022, Номер 13(1)

Опубликована: Июнь 3, 2022

Liver fibrosis is an outcome of restoring process in chronic liver injury. Human amniotic mesenchymal stem cells (hAMSCs) derived from membrane have multilineage differentiation, immunosuppressive, and anti-inflammatory potential which makes them suitable for treating fibrosis. This study aimed to explore the effect mechanism hAMSCs on were transplanted into carbon tetrachloride (CCl4)-induced mice via tail vein, effects hepatic assessed. The conditional medium (CM) activation stellate (HSCs) investigated vivo vitro. Antibody array assay was used identify cytokines secreted by that may inhibit HSCs. Finally, underlying mechanisms explored assessing IGF-1R/PI3K/AKT GSK3β/β-catenin signaling pathways activated HSCs (LX-2) with transfected corresponding siRNAs. Our results showed possessed characterizations cells. significantly reduced improved function inhibiting vivo. Both hAMSC-CM remarkably inhibited collagen deposition LX-2 insulin-like growth factor binding protein-3 (IGFBP-3), Dickkopf-3 (DKK-3), Dickkopf-1 (DKK-1) highly expressed co-culture group compared group. Western blot demonstrated IGFBP-3, DKK-3, DKK-1 cell through blocking canonical Wnt pathway. Dkk3, attenuated depression Wnt/β-catenin pathway, suggesting or provides alternative therapeutic approach treatment

Язык: Английский

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Cholestatic liver diseases of genetic etiology: Advances and controversies

Hepatology, Год журнала: 2022, Номер 75(6), С. 1627 - 1646

Опубликована: Март 1, 2022

Abstract With the application of modern investigative technologies, cholestatic liver diseases genetic etiology are increasingly identified as root cause previously designated “idiopathic” adult and pediatric diseases. Here, we review advances in field enhanced by a deeper understanding phenotypes associated with specific gene defects that lead to There evolving areas for clinicians current era specifically regarding role biopsy opportunities “sequencing first” approach. Risk stratification based on severity defect holds promise guide decision pursue primary transplantation versus medical therapy or nontransplant surgery, well early screening HCC. In present era, expanding toolbox recently approved therapies hepatologists has real potential help many our patients causes cholestasis. addition, there promising agents under study pipeline. Relevant still gaps knowledge causation pathogenesis lack fully accepted biomarkers disease progression pruritus. We discuss strategies overcome challenges genotype–phenotype correlation draw attention extrahepatic manifestations these Finally, identifying treatments disorders, anticipate vibrant future this dynamic which builds upon therapies, real‐world evaluations individual combined therapeutics, incorporation effective editing additive technologies.

Язык: Английский

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Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease

EBioMedicine, Год журнала: 2023, Номер 92, С. 104620 - 104620

Опубликована: Май 22, 2023

Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic accumulation into the liver.

Язык: Английский

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GepLiver: an integrative liver expression atlas spanning developmental stages and liver disease phases

Scientific Data, Год журнала: 2023, Номер 10(1)

Опубликована: Июнь 10, 2023

Abstract Chronic liver diseases usually developed through stepwise pathological transitions under the persistent risk factors. The molecular changes during are pivotal to improve diagnostics and therapeutics yet still remain elusive. Cumulative large-scale transcriptomic studies have been revealing landscape of various conditions at bulk single-cell resolution, however, neither single experiment nor databases enabled thorough investigations dynamics along progression diseases. Here we establish GepLiver, a longitudinal multidimensional expression atlas integrating profiles 2469 human tissues, 492 mouse samples, 409,775 cells from 347 samples 27 cell lines spanning 16 phenotypes with uniformed processing annotating methods. Using demonstrated dynamic gene expression, abundance crosstalk harboring meaningful biological associations. GepLiver can be applied explore evolving patterns features for genes types respectively among phenotypes, assisting investigation informing biomarkers targets

Язык: Английский

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Exosomal miR-17-5p from human embryonic stem cells prevents pulmonary fibrosis by targeting thrombospondin-2

Stem Cell Research & Therapy, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 4, 2023

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by dysfunction, ultimately leading to respiratory failure. Many preclinical studies have investigated the therapeutic potential of stem cell-derived exosomes in this disease, particularly mesenchymal exosomes. However, effects embryonic IPF remain unclear. Methods We established bleomycin (BLM)-induced mice model administered human cell (hESC-exo) from first day after BLM treatment. The hESC-exo were assessed function tests, biochemical analysis, histochemistry, quantitative real-time polymerase chain reaction (qPCR), western blot (WB). RNA-seq was used screen for targets fibrotic lungs; identified signaling axis using luciferase assay, qPCR, WB. Results indicated administration notably alleviated inflammation, removed deposited collagen, rescued alveolar architecture lungs BLM-induced mice. In vivo vitro tests revealed that hESC-exo-derived miR-17-5p directly bound thrombospondin-2 (Thbs2) regulate inflammation fibrosis; thus, protected against toxicity via miR-17-5p/Thbs2 axis. Conclusion These results suggest promising new treatment fibrosis-associated diseases.

Язык: Английский

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Serum Thrombospondin-2 Levels Are Closely Associated With the Severity of Metabolic Syndrome and Metabolic Associated Fatty Liver Disease

The Journal of Clinical Endocrinology & Metabolism, Год журнала: 2022, Номер 107(8), С. e3230 - e3240

Опубликована: Май 9, 2022

Metabolic associated fatty liver disease (MAFLD) is the hepatic manifestation of obesity-related metabolic syndrome (MetS). Noninvasive biomarkers for monitoring progression and severity these comorbidities are needed.To investigate associations serum thrombospondin-2 (TSP2) with MetS MAFLD severity, potential diagnostic value TSP2 identifying at-risk steatohepatitis (MASH).Blood samples, clinical data, biopsies were collected from consecutively recruited 252 individuals morbid obesity receiving bariatric surgery. Histopathology samples examined in a blinded fashion by 3 independent pathologists. Serum levels measured enzyme-linked immunosorbent assay.Serum significantly elevated (1.58 [1.07-2.20] ng/mL) compared non-MetS (1.28 [0.84-1.73] ng/mL; P = .006) obese patients positively correlated increasing number components, fasting glucose, glycated hemoglobin, insulin, C-peptide, homeostatic model assessment insulin resistance after adjustment conventional confounders. differentiated MASH (1.74 [1.32-3.09] other non-MASH less severe groups: normal (1.41 [1.04-1.63] ng/mL), simple steatosis (1.45 [0.89-1.92] borderline (1.30 [0.99-2.17] (P < .05). Elevated was steatosis, inflammation, fibrosis, abnormal function age, sex adiposity. Furthermore, high identified area under operating curve 0.84 (95% CI 0.70-0.98).Serum closely MAFLD, promising noninvasive biomarker differentiating benign among obesity.

Язык: Английский

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Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease

Medical Review, Год журнала: 2024, Номер 4(2), С. 158 - 168

Опубликована: Март 18, 2024

Abstract Metabolic dysfunction-associated fatty liver disease (MAFLD) has reached epidemic proportions globally in parallel to the rising prevalence of obesity. Despite its significant burden, there is no approved pharmacotherapy specifically tailored for this disease. Many potential drug candidates MAFLD have encountered setbacks clinical trials, due safety concerns or/and insufficient therapeutic efficacy. Nonetheless, several investigational drugs that mimic actions endogenous metabolic hormones, including thyroid hormone receptor β (THRβ) agonists, fibroblast growth factor 21 (FGF21) analogues, and glucagon-like peptide-1 agonists (GLP-1RAs), showed promising efficacy excellent profiles. Among them, resmetirom, a liver-targeted THRβ-selective agonist, met primary outcomes alleviation steatohepatitis (MASH), advanced form MAFLD, fibrosis phase-3 trials. These hormone-based pharmacotherapies not only exhibit varied degrees mitigating hepatic steatosis, inflammation fibrosis, but also improve Furthermore, these three hormonal agonists/analogues act complementary manner exert their pharmacological effects, suggesting combined therapies may yield synergistic benefits. Further in-depth studies on intricate interplay among hormones are imperative development more efficacious combination therapies, enabling precision management associated comorbidities.

Язык: Английский

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Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms

Journal of Clinical and Translational Hepatology, Год журнала: 2023, Номер 000(000), С. 000 - 000

Опубликована: Май 31, 2023

Portal hypertension in cirrhosis is defined as an increase the portal pressure gradient (PPG) between and hepatic veins traditionally estimated by venous (HVPG), which difference free-floating wedged positions of a balloon catheter vein. By convention, HVPG≥10 mmHg indicates clinically significant hypertension, associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) common disorder heterogeneous course, includes development hypertension. There increasing evidence that NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis NAFLD, suggesting bidirectional relationship these pathological processes. Second, HVPG underestimates more prevalent this condition than currently believed. Third, cellular mechanoresponses generated early pathogenesis provide mechanistic explanation for pressure-fibrosis paradigm. Finally, better understanding mechanobiology may aid novel pharmaceutical targets prevention management disease.

Язык: Английский

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