MCL1 is a pivot member of the anti-apoptotic BCL-2 family proteins. While a distinctive feature of MCL1 resides in its efficient ubiquitination and destruction, the deubiquitinase USP9X has been ...implicated in the preservation of MCL1 expression by removing the polyubiquitin chains. Here we perform an unbiased siRNA screen and identify that the second deubiquitinase, USP13, regulates MCL1 stability in lung and ovarian cancer cells. Mechanistically, USP13 interacts with and stabilizes MCL1 via deubiquitination. As a result, USP13 depletion using CRISPR/Cas9 nuclease system inhibits tumor growth in xenografted nude mice. We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL. Collectively, we nominate USP13 as a novel deubiquitinase which regulates MCL1 turnover in diverse solid tumors and propose that USP13 may be a potential therapeutic target for the treatment of various malignancies.
Copper is a vital mineral, and an optimal amount of copper is required to support normal physiologic processes in various systems, including the cardiovascular system. Over the past few decades, ...copper-induced cell death, named cuproptosis, has become increasingly recognized as an important process mediating the pathogenesis and progression of cardiovascular disease (CVD), including atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. Therefore, an in-depth understanding of the regulatory mechanisms of cuproptosis in CVD may be useful for improving CVD management. Here, we review the relationship between copper homeostasis and cuproptosis-related pathways in CVD, as well as therapeutic strategies addressing copper-induced cell death in CVD.
Abstract
The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, ...localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct
BRAF
-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.
Rapid, accurate, portable and quantitative profiling of metabolic biomarkers is of great importance for disease diagnosis and prognosis. The recent development in the optical and electric biosensors ...based on the smartphone is promising for profiling of metabolites with advantages of rapid, reliability, accuracy, low-cost and multi-analytes analysis capability. In this review, we introduced the optical biosensing platforms including colorimetric, fluorescent and chemiluminescent sensing, and electrochemical biosensing platforms including wired and wireless communication. Challenges and future perspectives desired for reliable, accurate, cost-effective, and multi-functions smartphone-based biosensing systems were also discussed. We envision that such smartphone-based biosensing platforms will allow daily and comprehensive metabolites monitoring in the future, thus unlocking the potential to transform clinical diagnostics into non-clinical self-testing. We also believed that this progress report will encourage future research to develop advanced, integrated and multi-functional smartphone-based Point-of-Care testing (POCT) biosensors for the monitoring and diagnosis as well as personalized treatments of a spectrum of metabolic-disorder related diseases.
Quantitative measurement of metabolites in blood or other biological samples is important in diagnosis and healthcare. The smartphone has recently ignited tremendous interest as a portable and mobile device for point of care testing (POCT) alternative to laboratory-based testing. The recent trends in the development of smartphone-based intelligent POCT for disease-related metabolites detection within the past several years is herein summarized. Current challenges and prospective achievement are also highlighted. Display omitted
Many anti-cancer drugs have a common problem of poor solubility. Increasing the solubility of the drugs is very important for its clinical applications. In the present study, we revealed that the ...solubility of insoluble drugs was significantly enhanced by adding rubusoside (RUB). Further, it was demonstrated that RUB could form micelles, which was well characterized by Langmuir monolayer investigation, transmission electron microscopy, atomic-force microscopy, and cryogenic transmission electron microscopy. The RUB micelles were ellipsoid with the horizontal distance of ~25 nm and vertical distance of ~1.2 nm. Insoluble synergistic anti-cancer drugs including curcumin and resveratrol were loaded in RUB to form anti-cancer micelles RUB/CUR + RES. MTT assay showed that RUB/CUR + RES micelles had more significant toxicity on MCF-7 cells compared to RUB/CUR micelles + RUB/RES micelles. More importantly, it was confirmed that RUB could load other two insoluble drugs together for remarkably enhanced anti-cancer effect compared to that of RUB/one drug + RUB/another drug. Overall, we concluded that RUB-based micelles could efficiently load insoluble drugs for enhanced anti-cancer effect.
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET ...bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer.
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Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To ...assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8
T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8
T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.
Non-coding RNA (ncRNA) is a special type of RNA transcript that makes up more than 90 % of the human genome. Although ncRNA typically does not encode proteins, it indirectly controls a wide range of ...biological processes, including cellular metabolism, development, proliferation, transcription, and post-transcriptional modification. NcRNAs include small interfering RNA (siRNA), PIWI-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA), etc. The most researched of these are miRNA, lncRNA, and circRNA, which are crucial regulators in the onset of diabetes and the development of associated consequences. The ncRNAs indicated above are linked to numerous diabetes problems by binding proteins, including diabetic foot (DF), diabetic nephropathy, diabetic cardiomyopathy, and diabetic peripheral neuropathy. According to recent studies, Mir-146a can control the AKAP12 axis to promote the proliferation and migration of diabetic foot ulcer (DFU) cells, while lncRNA GAS5 can activate HIF1A/VEGF pathway by binding to TAF15 to promote DFU wound healing. However, there are still many unanswered questions about the mechanism of action of ncRNAs. In this study, we explored the mechanism and new progress of ncRNA-protein binding in DF, which can provide help and guidance for the application of ncRNA in the early diagnosis and potential targeted intervention of DFU.
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•We describe the pathogenesis of diabetic foot ulcers at the genetic level and the relationship between ncRNAs and targets.•We the effects of the combination of miRNAs with different target genes on diabetic foot ulcer cells and the effect.•We illustrate the important roles of ncRNAs in different cells through binding proteins involved in different pathways.•We summarizes the clinical and basic aspects of ncRNA participating in DF by binding to a variety of target proteins.
Autism Spectrum Disorder (ASD) has a significant impact on the health of patients, and early diagnosis and treatment are essential to improve their quality of life. Machine learning methods, ...including multi-classifier fusion, have been widely used for disease diagnosis and prediction with remarkable results. However, current multi-classifier fusion methods lack the ability to measure the belief level of different samples and effectively fuse them jointly.
To address these issues, a multi-classifier fusion classification framework based on belief-value for ASD diagnosis is proposed in this paper. The belief-value measures the belief level of different samples based on distance information (the output distance of the classifier) and local density information (the weight of the nearest neighbor samples on the test samples), which is more representative than using a single type of information. Then, the complementary relationships between belief-values are captured via a multilayer perceptron (MLP) network for effective fusion of belief-values.
The experimental results demonstrate that the proposed classification framework achieves better performance than a single classifier and confirm that the fusion method used can effectively fuse complementary relationships to achieve accurate diagnosis.
Furthermore, the effectiveness of our method has only been validated in the diagnosis of ASD. For future work, we plan to extend this method to the diagnosis of other neuropsychiatric disorders.
Thyroid cancer is a common malignant tumour of the endocrine system and ranks ninth in cancer incidence worldwide. An extensive body of evidence has demonstrated that lncRNAs play a critical role in ...the progression of thyroid cancer. The lncRNA MAPKAPK5-AS1 has been reported to be abnormally expressed and to play a role in the development of various human cancers. However, MAPKAPK5-AS1's potential role in thyroid cancer progression remains unknown. The objective of our study was to explore the role and mechanism of MAPKAPK5-AS1 in thyroid cancer cells and provide a potential target for its biological diagnosis and treatment. We transfected sh-MAPKAPK5-AS1 and sh-NC into BCPAP and TPC-1 cells for loss-of-function assays. Results of RT-qPCR analysis demonstrated that MAPKAPK5-AS1 was more highly expressed in thyroid cancer cells compared to normal cells. Functional assays demonstrated that interfering with the expression of MAPKAPK5-AS1 notably repressed proliferation and invasion and accelerated apoptosis of BCPAP and TPC-1 cells. Mechanistically, we found that miR-519e-5p was negatively regulated by MAPKAPK5-AS1 and that tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) was a target of miR-519e-5p. Additionally, rescue assays demonstrated that downregulation of MAPKAPK5-AS1 expression inhibited cell proliferation, migration, and invasion and promoted apoptosis by sponging miR-519e-5p, thereby increasing YWHAH expression. Ultimately, our study revealed that MAPKAPK5-AS1 promotes proliferation and migration of thyroid cancer cells by targeting the miR-519e-5p/YWHAH axis, which provides novel insight into the development and progression of thyroid cancer.
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