Biomarker Research最新文献

Background: Activating the ubiquitin-proteasome system to dismantle disease- related proteins such as tau, β-amyloid, APP, and α-synuclein is an important focus in the research of neurodegenerative proteinopathy. By analyzing the serum RNA extracted from wild-type and Alzheimer's disease (AD) transgenic mice at different ages (4, 8, and 12 months), this study revealed a new protective role of FBXL16 in AD, primarily through facilitating the degradation of disease-related proteins via the ubiquitin proteasome system.

Methods: Proteomic analysis were conducted using protein lysates from HEK293 cells overexpressing FBXL16 to identify potential interacting proteins that interact with FBXL16. Subsequent experiments demonstrated that FBXL16 promotes the proteasomal degradation of the APP protein, as evidenced by co-immunoprecipitation with MG132 and cycloheximide (CHX), immunohistochemistry (IHC) and immunocytochemistry (ICC). Memory and cognitive improvements were observed in 3×Tg AD mice through the use of a lentivirus-mediated approach to generate a brain-specific AD mouse model overexpressing FBXL16 via stereotaxic injection. Furthermore, a brain-specific conditional knockout (cko) FBXL16 mouse model was generated and employed to further confirm the functional role of FBXL 16 in AD via various behavioral tests including Morris water maze and Y-maze.

Results: The level of FBXL16 in the brains of transgenic APP/PSEN mice with AD decreased with age. Accelerated degradation of APP was observed when FBXL16 was overexpressed in the hippocampi of these AD mice via a lentivirus. This process led to notable improvements in cognitive impairments and reductions in neuroinflammation. Further studies using proteomics and bioinformatics techniques identified transcription factors and binding proteins associated with FBXL16, providing deeper insights into the potential role of FBXL16 in the regulation of AD. Finally, the in vivo effects of FBXL16 deficiency were further substantiated in cko mice, which overexpress Aβ but specifically lack FBXL16 in the brain region.

Conclusions: These findings suggest that FBXL16 could be a new regulator of AD. These findings provide a foundation for further research into drug development and potential therapeutic strategies to combat other related neurodegenerative proteinopathies.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators responsible for gene transcription via binding histones or non-histone substrates, have grabbed considerable attention in drug discovery. There are also substantial evidences supporting that aberrant expressions and/activities of HDAC isoforms are reported in epilepsy and HDAC inhibitors (HDACi) have been successfully utilized for therapeutic purposes in this condition. However, the specific mechanisms underlying the role of HDACs in epileptic progression have not been fully understood. Herein, we reviewed the basic information of HDACs, summarized the recent findings associated with the roles of diverse HDAC subunits in epilepsy and discussed the potential regulatory mechanisms by which HDACs affected the development of epilepsy. Additionally, we also provided a brief discussion on the potential of HDACs as promising therapeutic targets for epilepsy treatment, serving as a valuable reference for basic study and clinical translation in epilepsy field.

Background: Circulating microRNAs (miRNAs) are recently a rapidly increasing of interest as non-invasive biomarkers for diagnosis and prognosis of acute myocardial infarction (AMI). Previous studies revealed that several miRNAs exhibited the capacity for diagnosis and prognosis of AMI, the reasons why these circulating miRNAs are concerned as targets for investigation are quite cryptogenic, presumably due to the lack of clues provided by global surveillance at the transcriptome level, and the current data for some miRNAs are controversial and inconsistent among independent studies.

Methods: To comprehensively profiling the potential miRNAs for diagnosis and prognosis of AMI, we reported transcriptomes of circulating miRNAs in the plasma of 27 healthy controls, 64 AMI patients (37 STEMI and 27 NSTEMI) and 20 AMI patients who were subjected to reperfusion therapy. Meanwhile, the cTnI of AMI patients was parallel determined. Differentially-circulated miRNAs were analyzed between each group. All detected circulating miRNAs were examined by ROC analysis and then LASSO dimension reduction to obtain an optimal panel for diagnosis of AMI. A five-year period follow-up towards the AMI and reperfusion patients was performed, and the prognostic value of circulating miRNAs in these patients was estimated by using the Cox regression model, ROC and Kaplan-Meier curves.

Results: Comprehensive global differences of miRNAs transcriptome among AMI, reperfusion patients and healthy controls were identified. A total of 40 miRNAs, called high diagnostic performance miRNAs, including several previous well-studied miRNAs with AUC greater than 0.85 were shown to discriminate AMI with healthy controls. In addition, 29 miRNAs were analyzed to be strongly correlated with the plasma cTnI level, of which 20 overlapped with high diagnostic performance miRNAs. These overlapped miRNAs are over-represented in the pathways which actually reflect the pathological cause of myocardial infarction, as well as the regulation of gene expression and energetic pathway of cellular response to hypoxia. Finally, two miRNAs were analyzed to be significantly correlated to all-cause mortality.

Conclusion: This is the first time to survey plasma miRNAs for the development of AMI diagnostic and prognostic biomarkers at the transcriptome level. A subset of miRNAs exhibited potential diagnostic and prognostic merits for AMI.

Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy.

Background: Metastatic prostate cancer is a highly heterogeneous and dynamic disease and practicable tools for patient stratification and resistance monitoring are urgently needed. Liquid biopsy analysis of circulating tumor cells (CTCs) and circulating tumor DNA are promising, however, comprehensive testing is essential due to diverse mechanisms of resistance. Previously, we demonstrated the utility of mRNA-based in situ padlock probe hybridization for characterizing CTCs.

Methods: We have developed a novel combinatorial dual-color (CoDuCo) assay for in situ mRNA detection, with enhanced multiplexing capacity, enabling the simultaneous analysis of up to 15 distinct markers. This approach was applied to CTCs, corresponding tumor tissue, cancer cell lines, and peripheral blood mononuclear cells for single-cell and spatial gene expression analysis. Using supervised machine learning, we trained a random forest classifier to identify CTCs. Image analysis and visualization of results was performed using open-source Python libraries, CellProfiler, and TissUUmaps.

Results: Our study presents data from multiple prostate cancer patients, demonstrating the CoDuCo assay's ability to visualize diverse resistance mechanisms, such as neuroendocrine differentiation markers (SYP, CHGA, NCAM1) and AR-V7 expression. In addition, druggable targets and predictive markers (PSMA, DLL3, SLFN11) were detected in CTCs and formalin-fixed, paraffin-embedded tissue. The machine learning-based CTC classification achieved high performance, with a recall of 0.76 and a specificity of 0.99.

Conclusions: The combination of high multiplex capacity and microscopy-based single-cell analysis is a unique and powerful feature of the CoDuCo in situ assay. This synergy enables the simultaneous identification and characterization of CTCs with epithelial, epithelial-mesenchymal, and neuroendocrine phenotypes, the detection of CTC clusters, the visualization of CTC heterogeneity, as well as the spatial investigation of tumor tissue. This assay holds significant potential as a tool for monitoring dynamic molecular changes associated with drug response and resistance in prostate cancer.

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantations (allo-HCT) used for the treatment of hematological malignancies and other blood-related disorders. Until recently, the discovery of actionable molecular targets to treat GVHD and their preclinical testing was almost exclusively based on modeling allo-HCT in mice by transplanting bone marrow and splenocytes from donor mice into MHC-mismatched recipient animals. However, due to fundamental differences between human and mouse immunology, the translation of these molecular targets into the clinic can be limited. Therefore, humanized mouse models of GVHD were developed to circumvent this limitation. In these models, following the transplantation of human peripheral blood mononuclear cells (PBMCs) into immunodeficient mice, T cells recognize and attack mouse organs, inducing GVHD. Thereby, humanized mice provide a platform for the evaluation of the effects of candidate therapies on GVHD mediated by human immune cells in vivo. Understanding the pathophysiology of this xenogeneic GVHD is therefore crucial for the design and interpretation of experiments performed with this model. In this article, we comprehensively review the cellular and molecular mechanisms governing GVHD in the most commonly used model of xenogeneic GVHD: PBMC-engrafted NOD/LtSz-Prkdc^scidIL2rγ^tm1Wjl (NSG) mice. By re-analyzing public sequencing data, we also show that the clonal expansion and the transcriptional program of T cells in humanized mice closely reflect those in humans. Finally, we highlight the strengths and limitations of this model, as well as arguments in favor of its biological relevance for studying T-cell reactions against healthy tissues or cancer cells.

Background: It is well-established that understanding the mechanism of prostate cancer (PCa)-associated metastasis is paramount for improving its prognosis. Metastasis is known to involve the communication between tumor-associated macrophages (TAMs) and tumor cells. Exosomes are crucial in mediating this intercellular communication within the tumor microenvironment. Nonetheless, the role of exosomal proteins in PCa metastasis is not yet fully understood. Here, we investigated the mechanisms of prostate cancer-derived exosomal PSM-E on regulating macrophage M2 polarization to suppress tumor invasion and metastasis.

Methods: PSM-E levels in exosomes were detected by transmission electron microscopy and Western blotting analysis. The diagnostic value of urine-derived exosomal PSM-E in PCa were evaluated by LC-MS/MS, correlation analysis, and ROC curves analysis. The mechanisms underlying the inhibitory effect of exosomal PSM-E on the M2 polarization of macrophages was investigated by co-IP, IHC staining, and PCa tumorigenesis model, etc. RESULTS: We revealed that exosomal PSM-E is upregulated in exosomes derived from the serum and urine of PCa patients. Clinically, an elevated exosomal PSM-E expression in urine is significantly correlated with an advanced pathological tumor stage and a high Gleason score. Our research also revealed that exosomal PSM-E inhibits prostate cancer cell proliferation, invasion, and metastasis by suppressing macrophage polarization in vitro and in vivo. Furthermore, we provided compelling evidence that exosomal PSM-E inhibits M2 polarization of macrophages by recruiting RACK1 and suppressing the FAK and ERK signaling pathways, consequently suppressing PCa invasion and metastasis. Furthermore, we found that the protease-associated domain of PSM-E and the fourth tryptophan-aspartate repeat of RACK1 are crucial for the interaction between PSM-E and RACK1.

Conclusions: Notably, exosomes carrying PSM-E from PCa urine could potentially serve as a biomarker for PCa, and targeting exosomal PSM-E may represent a strategy for preventing tumor progression in this patient population.

The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.

Lung cancer leads in causing cancer-related mortality worldwide, continually posing a significant threat to human health. Current imaging diagnostic techniques, while offering non-invasive detection, suffer from issues such as insufficient sensitivity and the risks associated with radiation exposure. Pathological diagnosis, the gold standard for confirmation, also faces challenges like invasiveness and high costs. In treatment, surgery, radiotherapy, and chemotherapy are the main modalities, each encountering challenges related to precision, environmental adaptability, and side effects. Nanotechnology's advancement provides new solutions for the diagnosis and treatment of lung cancer, promising to enhance diagnostic accuracy and reduce side effects during treatment. This article introduces the main types of nanomaterials used in the field of lung cancer, offering a comprehensive overview of current research on the application of nanotechnology in early screening, diagnosis, treatment, and monitoring of lung cancer, and summarizing ongoing clinical research findings.