نتائج البحث

1

Degradation of lipid droplets by chimeric autophagy-tethering compounds

المؤلفون: Yu Ding, Yuhua Fu, Ziying Wang, Shouqing Luo, Ningxie Chen, Boxun Lu

المصدر: Cell Res
Cell Research

الوصف: Degrading pathogenic proteins by degrader technologies such as PROTACs (proteolysis-targeting chimeras) provides promising therapeutic strategies, but selective degradation of non-protein pathogenic biomolecules has been challenging. Here, we demonstrate a novel strategy to degrade non-protein biomolecules by autophagy-tethering compounds (ATTECs), using lipid droplets (LDs) as an exemplar target. LDs are ubiquitous cellular structures storing lipids and could be degraded by autophagy. We hypothesized that compounds interacting with both the LDs and the key autophagosome protein LC3 may enhance autophagic degradation of LDs. We designed and synthesized such compounds by connecting LC3-binding molecules to LD-binding probes via a linker. These compounds were capable of clearing LDs almost completely and rescued LD-related phenotypes in cells and in two independent mouse models with hepatic lipidosis. We further confirmed that the mechanism of action of these compounds was mediated through LC3 and autophagic degradation. Our proof-of-concept study demonstrates the capability of degrading LDs by ATTECs. Conceptually, this strategy could be applied to other protein and non-protein targets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae0e72d2c7388cf505e84854373ccc8aTest
https://doi.org/10.1038/s41422-021-00532-7Test

2

Preclinical efficacy and toxicity studies of a highly specific chimeric anti‐CD47 antibody

المؤلفون: Jing Gao, Teddy Yang, Yu Ding, Jingyun Yao, Dai Chaohui, Dongxu Wang, Zhiqiang Xu

المصدر: FEBS Open Bio, Vol 11, Iss 3, Pp 813-825 (2021)
FEBS Open Bio

مصطلحات موضوعية: 0301 basic medicine, Cell Survival, medicine.medical_treatment, haemagglutination, CD47 Antigen, Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, 4D10, Antigen, Cell Line, Tumor, antibody, SIRPα, medicine, Animals, Humans, CD47, lcsh:QH301-705.5, Research Articles, Cell Proliferation, Cluster of differentiation, biology, Chemistry, Antibodies, Monoclonal, phagocytosis, Immunotherapy, Xenograft Model Antitumor Assays, In vitro, Up-Regulation, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid, Acute, HEK293 Cells, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, Cancer cell, Toxicity, Cancer research, biology.protein, Antibody, Research Article

الوصف: Cluster of differentiation 47 (CD47) is a widely expressed self‐protection transmembrane protein that functions as a critical negative regulator to induce macrophage‐mediated phagocytosis. Overexpression of CD47 enables cancer cells to escape immune surveillance and destruction by phagocytes both in solid tumours and leukaemia. The usefulness of anti‐CD47 antibody has been demonstrated in multiple immunotherapies associated with macrophages. However, antigen sinks and toxicity induced by inadvertent binding to normal cells restrict its clinical applications. Here, a novel anti‐human CD47 antibody, 4D10, was generated, and its variable regions were grafted onto a human IgG4 scaffold. Compared with the anti‐CD47 antibody Hu5F9, the resulting chimeric antibody (c4D10) has consistently demonstrated good tolerance in in vitro and in vivo toxicity studies. Additionally, c4D10 showed effective therapeutic potential through inducing the eradication of human cancer cells. Thus, c4D10 is a promising candidate therapeutic antibody with higher efficacy and reduced side effects compared to earlier antibodies, and its use may reduce the dose‐limiting toxicity of CD47 antagonists for immunotherapy.
Cluster of differentiation 47 (CD47) is a critical negative regulator with respect to inducing macrophage‐mediated phagocytosis. Overexpression of CD47 enables cancer cells to escape immune surveillance and destruction by phagocytes. A novel anti‐CD47 antibody, c4D10, showed effective therapeutic potential through inducing the eradication of human cancer cells (A) and demonstrated good tolerance in in vitro and in vivo toxicity studies (B).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b84c9cab8f1cff50f295554e2979bacTest
https://doaj.org/article/f24f4bfc75e04c5fbf8c45925d98d14eTest

3

Bioactive peptides and gut microbiota: Candidates for a novel strategy for reduction and control of neurodegenerative diseases

المؤلفون: Mengfei Chen, Juan Wang, Shujian Wu, Alaa El-Din A. Bekhit, Yu Ding, Xiyu Liao, Qingping Wu

المصدر: Trends in Food Science & Technology. 108:164-176

مصطلحات موضوعية: 0301 basic medicine, biology, digestive, oral, and skin physiology, Gut flora, Bioinformatics, biology.organism_classification, digestive system, Disease etiology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Dual role, 030217 neurology & neurosurgery, Function (biology), Food Science, Biotechnology

الوصف: Background Neurodegenerative diseases are debilitating conditions that diminish the quality of life and pose significant financial and social burdens. Therefore, strategies to relieve and control these diseases are urgently required, which will improve the quality of patients’ lives. Dysbacteriosis of gut microbiota has been shown to be a key component of neurodegenerative disease etiology. The homeostasis of gut microbiota and the balance of reactive oxygen species (ROS) in the gut can be altered by bioactive peptides derived from food sources. Therefore, biopeptides that improve neurodegenerative diseases by regulating gut microbiota have received considerable attention. Scope and approach The impact of gut microbiota on the brain through the gut-brain axis has been summarized. Additionally, the dual role of ROS in regulating the homeostasis of gut and gut microbiota and the function of bioactive peptides in ameliorating neurodegenerative diseases via the microbiota-gut-brain axis are discussed. Potential strategies for the production and modification of peptides to improve their bioactivity are also highlighted. Key findings and conclusions Increasing evidence supports that the gut microbiota modulates neurodegenerative diseases. Bioactive peptides that modulate the gut microbiota can be used as novel and strategic molecules to control and reduce neurodegenerative diseases. The bioactivity of the peptides can be dramatically influenced by different production and modification strategies. Strategies for further development of functional foods to ameliorate neurodegenerative diseases by regulating the gut microbiota are available. Future work should focus on the bioavailability and interactions of bioactive peptides and their impact on neurodegenerative diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::43235b4a404d5054a278211c77340eceTest
https://doi.org/10.1016/j.tifs.2020.12.019Test

4

Mitochondrial ND1 T4216C and ND2 C5178A mutations are associated with maternally transmitted diabetes mellitus

المؤلفون: Shunrong Zhang, Zhaochang Jiang, Lili Teng, Yu Ding

المصدر: Mitochondrial DNA Part A. 32:59-65

مصطلحات موضوعية: 0301 basic medicine, Genetics, Mitochondrial DNA, endocrine system diseases, nutritional and metabolic diseases, Type 2 Diabetes Mellitus, Biology, medicine.disease, medicine.disease_cause, Mtdna mutations, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Diabetes mellitus, medicine, Molecular Biology, 030217 neurology & neurosurgery, Oxidative stress

الوصف: Mutations in mitochondrial DNA (mtDNA) are important causes for type 2 diabetes mellitus (T2DM). To investigate the association between mtDNA mutations/variants and diabetes, we reported here clini...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::95d3dae1298ff67dd9aad9f1bd7690eaTest
https://doi.org/10.1080/24701394.2020.1856101Test

5

Exploring prognostic indicators in the pathological images of hepatocellular carcinoma based on deep learning

المؤلفون: Guan Zehui, Han Jing, Lijie Ma, Liming Wang, Zheng Yuxuan, Guang-Yu Ding, Yu Guanzhen, Jia Fan, Ai-Wu Ke, Zhou Dong, Jie-Yi Shi, Haoqing Yang, Zhen-Bin Ding, Wang Xiaodong, Qiang Gao, Xiyang Liu, Ya Cao, Ai Lirong, Xiaoying Wang, Jian Zhou, Lei Zhang

المصدر: Gut. 70:951-961

الوصف: ObjectiveTumour pathology contains rich information, including tissue structure and cell morphology, that reflects disease progression and patient survival. However, phenotypic information is subtle and complex, making the discovery of prognostic indicators from pathological images challenging.DesignAn interpretable, weakly supervised deep learning framework incorporating prior knowledge was proposed to analyse hepatocellular carcinoma (HCC) and explore new prognostic phenotypes on pathological whole-slide images (WSIs) from the Zhongshan cohort of 1125 HCC patients (2451 WSIs) and TCGA cohort of 320 HCC patients (320 WSIs). A ‘tumour risk score (TRS)’ was established to evaluate patient outcomes, and then risk activation mapping (RAM) was applied to visualise the pathological phenotypes of TRS. The multi-omics data of The Cancer Genome Atlas(TCGA) HCC were used to assess the potential pathogenesis underlying TRS.ResultsSurvival analysis revealed that TRS was an independent prognosticator in both the Zhongshan cohort (ppredictive ability of TRS was superior to and independent of clinical staging systems, and TRS could evenly stratify patients into up to five groups with significantly different prognoses. Notably, sinusoidal capillarisation, prominent nucleoli and karyotheca, the nucleus/cytoplasm ratio and infiltrating inflammatory cells were identified as the main underlying features of TRS. The multi-omics data of TCGA HCC hint at the relevance of TRS to tumour immune infiltration and genetic alterations such as the FAT3 and RYR2 mutations.ConclusionOur deep learning framework is an effective and labour-saving method for decoding pathological images, providing a valuable means for HCC risk stratification and precise patient treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2e3ab750c7da9f13aea5e5c11736d2a9Test
https://doi.org/10.1136/gutjnl-2020-320930Test

6

miR-324-5p Contributes to Cell Proliferation and Apoptosis in Pancreatic Cancer by Targeting KLF3

المؤلفون: Ming Yang, Yadong Zhang, Xiaoli Chen, Xia Tian, Yiyuan Wan, Jinrong He, Xueting Cheng, Hesheng Luo, Bo Peng, Xiaodong Huang, Yu Ding, Ting Zhan

المصدر: Molecular Therapy: Oncolytics, Vol 18, Iss, Pp 432-442 (2020)
Molecular Therapy Oncolytics

الوصف: Pancreatic cancer cells are characterized by high cell proliferation and low cell apoptosis, but the factors involved in these processes remain to be further studied. In this study, we report that miR-324-5p regulates the proliferation and apoptosis of pancreatic cancer cells through regulating the expression of Krüppel-like factor 3 (KLF3). In both pancreatic cancer tissues and cell lines, the levels of miR-324-5p are significantly increased. Inhibition of miR-324-5p represses cell proliferation but promotes cell apoptosis, whereas overexpression of miR-324-5p exerts the opposite effect. Furthermore, we identified KLF3, a factor regulating pancreatic cancer cell proliferation and apoptosis, as a new direct downstream target of miR-324-5p. Our results suggest that miR-324-5p plays an important role in pancreatic cancer cell proliferation and apoptosis via downregulating the expression of KLF3.
Graphical Abstract
Pancreatic cancer cells are characterized by high cell proliferation and low cell apoptosis, but the factors involved in these processes remain to be further studied. In this study, Zhang and colleagues report that miR-324-5p plays an important role in pancreatic cancer cell proliferation and apoptosis through downregulating the expression of KLF3.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bbd54e717a36b6d6d3234f6f5e6b7149Test
https://doi.org/10.1016/j.omto.2020.07.011Test

7

RhoA/ROCK pathway mediates the effect of oestrogen on regulating epithelial‐mesenchymal transition and proliferation in endometriosis

المؤلفون: Qiong-Hua Chen, Qing-Xi Chen, Xiao-Mei Mao, Shao-Min Huang, Zhi-Xiong Huang, Rongfeng Wu, Xin‐Yu Ding

المصدر: Journal of Cellular and Molecular Medicine

مصطلحات موضوعية: endometriosis, 0301 basic medicine, MAPK/ERK pathway, RHOA, Endometriosis, Endometrium, Mice, 0302 clinical medicine, ROCK1, RNA, Small Interfering, oestrogen receptor α, skin and connective tissue diseases, Cells, Cultured, Oestrogen receptor α, Mice, Inbred BALB C, rho-Associated Kinases, Gene knockdown, Estradiol, Transition (genetics), biology, Chemistry, Recombinant Proteins, Ovarian Cysts, ERK, 030220 oncology & carcinogenesis, Molecular Medicine, Female, RNA Interference, Original Article, RhoA/ROCK pathway, Signal Transduction, Adult, Epithelial-Mesenchymal Transition, proliferation, 03 medical and health sciences, medicine, Animals, Humans, RNA, Messenger, Epithelial–mesenchymal transition, epithelial‐mesenchymal transition, Estrogen Receptor alpha, Estrogens, Original Articles, Cell Biology, medicine.disease, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Cancer research, biology.protein, rhoA GTP-Binding Protein, oestrogen

الوصف: Endometriosis is a benign gynaecological disease appearing with pelvic pain, rising dysmenorrhoea and infertility seriously impacting on 10% of reproductive‐age females. This research attempts to demonstrate the function and molecular mechanism of RhoA/ROCK pathway on epithelial‐mesenchymal transition (EMT) and proliferation in endometriosis. The expression of Rho family was abnormally changed in endometriotic lesions; in particular, RhoA and ROCK1/2 were significantly elevated. Overexpression of RhoA in human eutopic endometrial epithelial cells (eutopic EECs) enhanced the cell mobility, epithelial‐mesenchymal transition (EMT) and proliferation, and RhoA knockdown exhibited the opposite function. Oestrogen up‐regulated the RhoA activity and expression of RhoA and ROCK1/2. RhoA overexpression reinforced the effect of oestrogen on promoting EMT and proliferation, and RhoA knockdown impaired the effect of oestrogen. oestrogen receptor α (ERα) was involved with the regulation of oestrogen on EMT and proliferation and up‐regulated RhoA activity and expression of RhoA and ROCK1/2. The function of ERα was modulated by the change in RhoA expression. Furthermore, phosphorylated ERK that was enhanced by oestrogen and ERα promoted the protein expression of RhoA/ROCK pathway. Endometriosis mouse model revealed that oestrogen enhanced the size and weight of endometriotic lesions. The expression of RhoA and phosphorylated ERK in mouse endometriotic lesions was significantly elevated by oestrogen. We conclude that abnormal activated RhoA/ROCK pathway in endometriosis is responsible for the function of oestrogen/ERα/ERK signalling, which promoted EMT and proliferation and resulted in the development of endometriosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9fb53c71400bbbe4eb3925fecaa2d305Test
https://doi.org/10.1111/jcmm.15689Test

8

Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia

المؤلفون: Jian Wang, Xin Li, Qun Li, Juan Li, Fan Jiang, Niu Li, Yu Ding, Guoying Chang, Dan Lou, Qianwen Zhang, Xiaodong Huang, Xiumin Wang

المصدر: Journal of Diabetes Investigation

مصطلحات موضوعية: Blood Glucose, Male, 0301 basic medicine, Proband, Endocrinology, Diabetes and Metabolism, Disease, Diabetes mellitus, 0302 clinical medicine, Genetic etiology, Copy-number variation, Family history, Child, Sanger sequencing, medicine.diagnostic_test, High-Throughput Nucleotide Sequencing, Articles, General Medicine, Prognosis, Clinical Science and Care, Child, Preschool, symbols, Medical genetics, Original Article, Female, China, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, 03 medical and health sciences, symbols.namesake, Asian People, Internal medicine, Internal Medicine, medicine, Humans, Genetic Testing, Next‐generation sequencing, Genetic testing, Glycated Hemoglobin, business.industry, Infant, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, Hyperglycemia, Mutation, business, Biomarkers, Follow-Up Studies

الوصف: Aims/Introduction To investigate the genetic etiology and evaluate the diagnostic application of next‐generation sequencing for diabetes/persistent hyperglycemia in children and adolescents. Materials and Methods Patients with diabetes/persistent hyperglycemia, presenting with at least one other clinical manifestation (other than diabetes) or with a family history of diabetes, were recruited. The clinical and laboratory characteristics of the patients were recorded. Next‐generation sequencing was carried out, and candidate variants were verified by Sanger sequencing. Variant pathogenicity was further evaluated according to the American College of Medical Genetics and Genomics guidelines. Results This study included 101 potential probands, 36 of whom were identified as positive by genetic testing. A further 51.2 and 20.9% of variants were determined to be pathogenic or likely pathogenic, respectively. Variants associated with the disease were primarily identified in 21 genes and three regions of copy number variants. Among the 39 variants in 21 genes, 61.5% (24/39) were novel. The genetic diagnosis of 23 patients was confirmed based on genetic evidence and associated clinical manifestations. We reported GCK variants (21.7%, 5/23) as the most common etiology in our cohort. Different clinical manifestations were observed in one family with WFS1 variants. Conclusions Our findings support the use of next‐generation sequencing as a standard method in patients with diabetes/persistent hyperglycemia and provide insights into the etiologies of these conditions.
Few studies have focused on examining the genetic etiology of diabetes in Chinese children and adolescents. A total of 101 potential probands were included in this study to investigate the clinical and genetic features of monogenic diabetes and genetic syndromes associated with it, and evaluate the diagnostic use of next‐generation sequencing for diabetes/persistent hyperglycemia. Our findings expand the gene mutation spectrum and phenotypic spectrum of the rare monogenic diabetes and genetic syndromes associated with diabetes, and provide insights into the current understanding of the underlying etiologies of diabetes/persistent hyperglycemia and support the use of next‐generation sequencing as a diagnostic method in Chinese patients with diabetes/persistent hyperglycemia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ce10ce4ccbe726d291dc18a38e26371Test
https://doi.org/10.1111/jdi.13322Test

9

The roles of mitochondrial tRNA mutations in non-dystrophic myotonias

المؤلفون: Yu Ding, Xue-Jiao Yu

المصدر: Mitochondrial DNA. Part B, Resources
article-version (VoR) Version of Record

مصطلحات موضوعية: 0106 biological sciences, 0301 basic medicine, Genetics, phylogenetic analysis, mt-tRNA mutations, pathogenic, NDM, Biology, 010603 evolutionary biology, 01 natural sciences, Mitochondrial trna, 03 medical and health sciences, 030104 developmental biology, Molecular Biology, Rapid Communication, Research Article

الوصف: According a recent report by Heidari et al., a mutational screening for candidate pathogenic mitochondrial tRNA (mt-tRNA) mutations were performed in 45 Iranian patients with non-dystrophic myotonia (NDM) and 70 control subjects. Through PCR amplification and direct sequence analysis, nine mt-tRNA mutations were identified: tRNAMet T4454C, tRNATrp A5568G, tRNACys T5794C, tRNAArg A10438T and T10462C, tRNALeu(CUN) A12308G, tRNAThr A15907G, A15924G and G15928A. However, through the database searches and phylogenetic conservation analysis, we noticed that the tRNAThr A15924G, G15928A and tRNALeu(CUN) A12308G mutations should be classified ‘pathogenic’. Thus, the roles of mt-tRNA mutations in clinical expression of NDM needed to be further experimentally addressed.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b9556464eecf9b01c83cc194189721e5Test
https://doi.org/10.1080/23802359.2020.1839364Test

10

Emerging New Concepts of Degrader Technologies

المؤلفون: Boxun Lu, Yu Ding, Yiyan Fei

المصدر: Trends in Pharmacological Sciences. 41:464-474

الوصف: Traditional drug discovery focuses on identifying direct inhibitors of target proteins. This typically relies on a measurable biochemical readout and accessible binding sites whose occupancy influences the function of the target protein. These requirements preclude many disease-causing proteins from being 'druggable' targets, and these proteins are categorized as 'undruggable'. The proteolysis-targeting chimera (PROTAC) technology provides powerful tools to degrade these undruggable targets and has become a promising approach for drug discovery. However, the PROTAC technology has some limitations, and emerging new degrader technologies may greatly broaden the spectrum of targets that could be selectively degraded by harnessing a second major degradation pathway in cells. We review key emerging technologies that exploit the lysosomal degradation pathway and discuss their potential applications and limitations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dc7fd05e033a85af0a5e5bf7327d6461Test
https://doi.org/10.1016/j.tips.2020.04.005Test

تنقيح النتائج