المؤلفون: Desheng Wei, Zhifeng Ma, Ting Zhu, Haiyong Wang, Bin Wang, Linhai Fu, Guangmao Yu

المصدر: Acta Cirúrgica Brasileira, Vol 38 (2023)

مصطلحات موضوعية: MicroRNAs, HSP47 Heat-Shock Proteins, Esophageal Squamous Cell Carcinoma, Angiogenic Proteins, Wnt Signaling Pathway, Surgery, RD1-811

الوصف: ABSTRACT Purpose: Esophageal squamous cell carcinoma (ESCC) is characterized by early metastasis and late diagnosis. miR-29c-3p is confirmed to repress angiogenesis in multiple tumor types. Yet, the functions of miR-29c-3p in the mechanism of ESCC angiogenesis, which were not sufficiently explored previously, were exactly what we investigated here at the molecular level. Methods: The mRNA level of miR-29c-3p and Serpin peptidase inhibitor clade H member 1 (SERPINH1) in ESCC tissues were assessed via bioinformatics analysis. Thereafter, miR-29c-3p and SERPINH1 (HSP47) mRNA level in ESCC cell lines was evaluated via quantitative real-time polymerase chain reaction. The effects of abnormal miR-29c-3p and SERPINH1 expression on ESCC cell viability, proliferation, migration, invasion, and HUVEC angiogenesis were examined via CCK8, colony formation, transwell, and angiogenesis assays, respectively. The protein levels of SERPINH1, vascular endothelial growth factor-A (VEGFA), Wnt-1, ?-catenin, and p-?-catenin were evaluated via Western blot. Expression of VEGFA secreted by ESCC cells was measured via enzyme-linked immunosorbent assay. Treatment with the Wnt activator BML-284 further revealed the way miR-29c-3p mediated the Wnt signaling pathway and its effects on angiogenesis. Results: Herein, we revealed a decrease of miR-29c-3p expression in ESCC tissues and cells, while the overexpressed miR-29c-3p could remarkably suppress ESCC cell progression, as well as HUVEC angiogenesis. Meanwhile, overexpressed miR-29c-3p notably downregulated VEGFA and repressed the Wnt signaling pathway. Treatment with the Wnt activator BML-284 could reverse the inhibition of HUVEC angiogenesis caused by miR-29c-3p. SERPINH1 was a downstream target of miR-29c-3p. SERPINH1 knockdown suppressed the malignant phenotypes of ESCC cells and impeded the Wnt signaling activation, while such suppression was reversed through miR-29c-3p inhibitor. Conclusions: We confirmed the mechanism that miR-29c-3p targeted SERPINH1, thus regulating angiogenesis in ESCC through the Wnt signaling pathway. It improves the understanding of angiogenesis in ESCC and offers new ideas for the research of ESCC treatment strategies in the future.

وصف الملف: electronic resource

العلاقة: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-86502023000100255&lng=en&tlng=enTest; http://www.scielo.br/pdf/acb/v38/1678-2674-acb-38-e385223.pdfTest; https://doaj.org/toc/1678-2674Test

الوصول الحر: https://doaj.org/article/9a11fb643b6e4f1cab69d72c7e465123Test

المؤلفون: Syx, Delfien, Ishikawa, Yoshihiro, Gebauer, Jan, Boudko, Sergei P, Guillemyn, Brecht, Van Damme, Tim, D’hondt, Sanne, Symoens, Sofie, Nampoothiri, Sheela, Gould, Douglas B, Baumann, Ulrich, Bächinger, Hans Peter, Malfait, Fransiska

المصدر: PLOS Genetics. 17(2)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Pediatric, Genetics, Rare Diseases, Osteogenesis Imperfecta, Underpinning research, 1.1 Normal biological development and functioning, Amino Acid Sequence, Cells, Cultured, Child, Preschool, Collagen Type I, Fatal Outcome, Female, HSP47 Heat-Shock Proteins, Humans, Infant, Infant, Newborn, Models, Molecular, Mutation, Missense, Protein Binding, Protein Domains, Protein Processing, Post-Translational, Recombinant Proteins, Sequence Homology, Amino Acid, Developmental Biology

الوصف: Heat shock protein 47 (HSP47), encoded by the SERPINH1 gene, is a molecular chaperone essential for correct folding of collagens. We report a homozygous p.(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise. p.R222 is a highly conserved residue located within the collagen interacting surface of HSP47. Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen. This altered interaction leads to posttranslational overmodification of type I procollagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry. Since we also observed a normal intracellular folding and secretion rate of type I procollagen, this overmodification cannot be explained by prolonged exposure of the procollagen molecules to the modifying hydroxyl- and glycosyltransferases, as is commonly observed in other types of OI. We found significant upregulation of several molecular chaperones and enzymes involved in procollagen modification and folding on Western blot and RT-qPCR. In addition, we showed that an imbalance in binding of HSP47-R222S to unfolded type I collagen chains in a gelatin sepharose pulldown assay results in increased binding of other chaperones and modifying enzymes. The elevated expression and binding of this molecular ensemble to type I procollagen suggests a compensatory mechanism for the aberrant binding of HSP47-R222S, eventually leading to overmodification of type I procollagen chains. Together, these results illustrate the importance of HSP47 for proper posttranslational modification and provide insights into the molecular pathomechanisms of the p.(R222S) alteration in HSP47, which leads to a severe OI phenotype.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4qv6g1dnTest

المؤلفون: Lønsmann, Ida, Gudmann, Natasja Stæhr, Manon-Jensen, Tina, Thiele, Maja, Moreno, Ydalina Maria, Langholm, Lasse Løcke, Nielsen, Mette Juul, Detlefsen, Sönke, Karsdal, Morten Asser, Krag, Aleksander Ahm, Leeming, Diana Julie

المصدر: Lønsmann , I , Gudmann , N S , Manon-Jensen , T , Thiele , M , Moreno , Y M , Langholm , L L , Nielsen , M J , Detlefsen , S , Karsdal , M A , Krag , A A & Leeming , D J 2022 , ' Serologically assessed heat shock protein 47 is related to fibrosis stage in early compensated alcohol-related liver disease ' , Clinical Biochemistry , vol. 104 , pp. 36-43 . https://doi.org/10.1016/j.clinbiochem.2021.12.008Test

مصطلحات موضوعية: Biomarker development, Biomarker validation, Collagen chaperone, Fibrosis assessment, Non-invasive biomarker, Cross-Sectional Studies, HSP47 Heat-Shock Proteins/metabolism, Humans, Fibrosis, Liver Cirrhosis, Collagen/metabolism

الوصف: BACKGROUND AND AIMS: Heat shock protein (HSP)47 is a collagen-specific chaperone, essential for the correct formation of fibrillar procollagens. Collagen accumulation in the extracellular matrix (ECM) is a hallmark of fibrogenesis. The expression of HSP47 is proportional to the rate of collagen formation. Thus, HSP47 is a potential drug target for fibrotic diseases. We hypothesized that a C-terminal fragment of HSP47 (HSP47-C) could be quantified serologically and related to liver fibrosis stage. For this, a novel competitive enzyme-linked immunosorbent assay (ELISA) was developed. METHOD: An ELISA employing a monoclonal antibody targeting HSP47-C was developed and technically validated. The assay was evaluated in serum from a cross-sectional biopsy-controlled study of 281 patients with alcohol-related liver disease (ALD) and 50 gender, age and BMI matched healthy controls (HC). All liver biopsies from ALD patients were scored by one pathologist according to fibrosis stage (F0-4). RESULTS: The HSP47-C assay was technically robust and specific for the target sequence. HSP47-C was 39% higher in ALD patients (median 17.7 ng/mL, IQR 12.4-24.0 ng/mL) compared to HC (median 12.7 ng/mL, IQR 9.4-15.7 ng/mL, p<0.0001). In addition, HSP47-C was elevated in patients with severe fibrosis (F3-4, median 22.8 ng/mL, IQR 17.5-33.3 ng/mL) compared to none-to-moderate fibrosis (F0-2, median 16.5 ng/mL, IQR 11.8-22.5 ng/mL) with an AUROC of 0.72 (p<0.0001). HSP47-C also correlated with other liver disease parameters, albumin, bilirubin and aspartate transaminase. CONCLUSION: We developed a competitive ELISA for serological detection of HSP47-C. The study supports HSP47 as a potential marker of liver fibrosis in ALD.

وصف الملف: application/pdf

العلاقة: https://portal.findresearcher.sdu.dk/da/publications/5ac8c3df-73d1-4fff-8b0c-510c457140e8Test

الإتاحة: https://doi.org/10.1016/j.clinbiochem.2021.12.008Test
https://portal.findresearcher.sdu.dk/da/publications/5ac8c3df-73d1-4fff-8b0c-510c457140e8Test
https://findresearcher.sdu.dk/ws/files/202901221/1_s2.0_S0009912021003386_main.pdfTest

المؤلفون: Duran, Ivan, Nevarez, Lisette, Sarukhanov, Anna, Wu, Sulin, Lee, Katrina, Krejci, Pavel, Weis, Maryann, Eyre, David, Krakow, Deborah, Cohn, Daniel H

المصدر: Human Molecular Genetics. 24(7)

مصطلحات موضوعية: Biological Sciences, Genetics, Osteogenesis Imperfecta, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Adult, Amino Acid Sequence, Base Sequence, Child, Preschool, Collagen Type I, Female, HSP47 Heat-Shock Proteins, Humans, Male, Molecular Sequence Data, Pedigree, Procollagen, Protein Transport, Sequence Alignment, Tacrolimus Binding Proteins, Young Adult, Medical and Health Sciences, Genetics & Heredity

الوصف: Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10, which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47 and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47 but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2504q6kgTest

المؤلفون: Shang, Yudong, Zhang, Zhengyao, Ba, Hengxing, Wang, Datao, Qi, Xiaoyan, Li, Chunyi

مصطلحات موضوعية: HSP47, S100A4, antler stem cell, molecular dynamics, protein-protein docking, Animals, Antlers, Calcium, Deer, HSP47 Heat-Shock Proteins, S100 Calcium-Binding Protein A4, Stem Cells

الوصف: S100A4 is a multiple-function protein highly expressed in tumor or stem cells. We found S100A4 was a novel protein partner for heat shock protein 47 (HSP47) in deer antlerogenic periosteum cells (AP cells), indicating that S100A4 could bind with HSP47. S100A4 had both calcium-dependent and calcium-independent patterns (labeled as SCd and SCi, respectively) to execute different biological activities. Homology models of HSP47, SCd and SCi were constructed. HSP47:collagen model, HSP47:collagen I-V, HSP47:SCd and HSP47:SCi complexes were built using ZDOCK software. Together with free SCd and SCi, 200 ns molecular dynamic (MD) simulations were performed to analyze binding free energies and SCi/SCd conformational changes. The energetic results showed that SCi had the strongest affinity to HSP47, and followed by collagens. SCd had little interaction with HSP47. Decomposition energy results showed that collagen model interacted with HSP47 mainly though neutral amino acids. When SCi bound with HSP47, the majority of mediated amino acids were charged. These results indicated that SCi could compete with collagen on the binding site of HSP47. Root mean square fluctuation (RMSF) values and cross-correlation matrices of principal component analysis (PCA) were calculated to evaluate the SCi/SCd structural variation during MD simulation. Both HSP47 and Ca2+ could stabilize the conformation of SCi/SCd. The loops interacting with Ca2+s and linking the two EF-hand motifs were impacted particularly. The relative moving directions of α-helices in EF-hands were distinct by the binding effect of HSP47 and Ca2+. We found that SCi may regulate the differentiation of AP cells by disturbing the interaction between HSP47 and collagen. Communicated by Ramaswamy H. Sarma.

وصف الملف: Print-Electronic; application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/291313Test

الإتاحة: https://doi.org/10.17863/CAM.38492Test
https://www.repository.cam.ac.uk/handle/1810/291313Test

المؤلفون: Raihana Nasrin Ferdousy, Hiroya Kadokawa

المصدر: Reproduction, Fertility and Development. 34:619-632

مصطلحات موضوعية: Aging, Uterus, Oviducts, Endocrinology, Reproductive Medicine, Pregnancy, Genetics, Animals, Cattle, Female, Animal Science and Zoology, Collagen, HSP47 Heat-Shock Proteins, Molecular Biology, Molecular Chaperones, Developmental Biology, Biotechnology

الوصف: Collagen, the most abundant extra-cellular matrix in oviducts and uteri, performs critical roles in pregnancies. We hypothesised that the locations and amounts of both denatured collagen and the collagen-specific molecular chaperone 47-kDa heat shock protein (HSP47) in the oviducts and uteri of old cows are different compared with those of young heifers because of repeated pregnancies. Since detecting damaged collagen in tissues is challenging, we developed a new method that uses a denatured collagen detection reagent. Then, we compared damaged collagen in the oviducts and uteri between post-pubertal growing nulliparous heifers (22.1 ± 1.0 months old) and old multiparous cows (143.1 ± 15.6 months old). Further, we evaluated the relationship between denatured collagen and HSP47 by combining this method with fluorescence immunohistochemistry. Picro-sirius red staining showed collagen in almost all parts of the oviducts and uteri. Expectedly, damaged collagen was increased in the oviducts and uteri of old cows. However, damaged collagen and HSP47 were not located in the same area in old cows. The number of fibroblasts increased, suggesting the presence of fibrosis in the oviducts and uteri of old cows. These organs of old cows showed higher HSP47 protein amounts than those of heifers. However, the uteri, but not oviducts, of old cows had lower HSP47 mRNA amounts than those of heifers. These findings revealed the specific location and amounts of denatured collagen and HSP47 in the oviducts and uteri of old cows compared with those of heifers.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ef5a3cae7cb5f9eb96f709e59756fc5Test
https://doi.org/10.1071/rd21130Test

المؤلفون: Zhenzhen Hu, Linkai Xiong, Juntao Zou, Wei Wu

المصدر: Anti-Cancer Drugs. 33:268-277

مصطلحات موضوعية: Cancer Research, Lung Neoplasms, animal structures, Cell, Biology, medicine.disease_cause, Cell Movement, Epidermal growth factor, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Animals, Humans, Pharmacology (medical), Lung cancer, HSP47 Heat-Shock Proteins, Protein kinase B, Cell Proliferation, Pharmacology, Cell growth, Cancer, Cell migration, medicine.disease, respiratory tract diseases, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, embryonic structures, Cancer research, Carcinogenesis, Proto-Oncogene Proteins c-akt

الوصف: Lung cancer is one of the most lethal malignancies, with the highest number of cases and deaths. Non-small cell lung cancer (NSCLC) is the most ordinary type of pathology in lung cancer. Meanwhile, various researchers have reported that heat shock protein 47 (HSP47) plays a vital regulatory role in cancer. However, the role of HSP47 in NSCLC is not clear. Consequently, the current study set out to investigate the role of HSP47 in the pathogenesis of NSCLC. First, we evaluated the expression patterns of HSP47 in NSCLC cell lines related to human normal lung epithelial cells, and HSP47 was found to be highly expressed in NSCLC cell lines. In addition, inhibiting the expression of HSP47 brought about marked repression in cell proliferation, migration and invasion in PC-9 cells. On the contrary, cell proliferation, migration and invasion were all elevated after over-expression of HSP47. Mechanistical experimentation further illustrated that protein kinase B (AKT) signal was repressed after inhibition of HSP47, and the influence of sh-HSP47 on cell proliferation, migration and invasion was countered by epidermal growth factor. Lastly, in-vivo animal models demonstrated that inhibition of HSP47 repressed cell tumorigenesis and AKT signal. Collectively, our findings illustrated that HSP47 was highly expressed in NSCLC cell lines, whereas inhibition of HSP47 repressed cell migration and invasion by diminishing the AKT signal. Inhibition of HSP47 also exhibited strong therapeutic effects on NSCLC in vivo.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a976112aeaa21937d5c4d6540e04f338Test
https://doi.org/10.1097/cad.0000000000001262Test

المؤلفون: Komal Ramani, Nirmala Mavila, Aushinie Abeynayake, Maria Lauda Tomasi, Jiaohong Wang, Michitaka Matsuda, Eki Seki

المصدر: eLife. 11

مصطلحات موضوعية: Liver Cirrhosis, General Immunology and Microbiology, General Neuroscience, A Kinase Anchor Proteins, Cell Cycle Proteins, General Medicine, Cyclic AMP-Dependent Protein Kinases, Fibrosis, General Biochemistry, Genetics and Molecular Biology, Disease Models, Animal, Mice, Liver, Cyclins, Hepatic Stellate Cells, Animals, Collagen, Phosphorylation, HSP47 Heat-Shock Proteins, Protein Kinase C

الوصف: Trans-differentiation of hepatic stellate cells (HSCs) to activated state potentiates liver fibrosis through release of extracellular matrix (ECM) components, distorting the liver architecture. Since limited antifibrotics are available, pharmacological intervention targeting activated HSCs may be considered for therapy. A-kinase anchoring protein 12 (AKAP12) is a scaffolding protein that directs protein kinases A/C (PKA/PKC) and cyclins to specific locations spatiotemporally controlling their biological effects. It has been shown that AKAP12’s scaffolding functions are altered by phosphorylation. In previously published work, observed an association between AKAP12 phosphorylation and HSC activation. In this work we demonstrate that AKAP12’s scaffolding activity towards the endoplasmic reticulum (ER)-resident collagen chaperone, heat-shock protein 47 (HSP47) is strongly inhibited by AKAP12’s site-specific phosphorylation in activated HSCs. CRISPR-directed gene editing of AKAP12’s phospho- sites restores its scaffolding towards HSP47, inhibiting HSP47’s collagen maturation functions and HSC activation. AKAP12 phospho-editing dramatically inhibits fibrosis, ER stress response, HSC inflammatory signaling and liver injury in mice. Our overall findings suggest a pro-fibrogenic role of AKAP12 phosphorylation that may be targeted for therapeutic intervention in liver fibrosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::604d0b2156a11d8d0f47f76a1cddeaa4Test
https://doi.org/10.7554/elife.78430Test

المؤلفون: Jianxin, Li, Ting, Han, Xin, Wang, Yinchun, Wang, Xuan, Chen, Wangsheng, Chen, Qingqiang, Yang

المصدر: World Journal of Surgical Oncology. 20

مصطلحات موضوعية: MicroRNAs, Oncology, Carcinogenesis, Stomach Neoplasms, Humans, RNA, Long Noncoding, Surgery, HSP47 Heat-Shock Proteins, Biomarkers

الوصف: Background Increasing studies have indicated that noncoding RNA (ncRNA)-mediated competing endogenous RNA (ceRNA) network serves as a significant role in cancer progression, but the underlying regulatory mechanisms of which in gastric cancer (GC) remain largely unclear. Methods Based on Gene Expression Omnibus and The Cancer Genome Atlas datasets, potential biomarkers for GC were screened and validated by machine learning. Then, upstream regulatory ncRNA of potential biomarkers was identified to construct a novel ceRNA network in GC through means of stepwise reverse prediction and validation. Ultimately, tumor immune cell infiltration analysis was performed based on the EPIC algorithm. Results A total of 188 differentially expressed genes (DEGs) were screened, and three candidate diagnostic biomarkers (FAP, PSAPL1, and SERPINH1) for GC were identified and validated. Subsequently, H19 and miR-378a-5p were identified as upstream regulatory ncRNAs that could potentially bind SERPINH1 in GC. Moreover, Immune infiltration analysis revealed that each component in the ceRNA network (H19/miR-378a-5p/SERPINH1) was significantly correlated with the infiltration abundances of diverse tumor-infiltrating immune cells. Conclusions H19 may regulate the immune cell infiltration in carcinogenesis of GC through miR-378a-5p/SERPINH1 signaling.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23acc774f6a815b7bcc49cff8bd778a3Test
https://doi.org/10.1186/s12957-022-02760-6Test

المؤلفون: Eslam E. Abd El-Fattah, Amr Y. Zakaria

المصدر: Journal of translational medicine. 20(1)

مصطلحات موضوعية: Liver Cirrhosis, Humans, General Medicine, Collagen, HSP47 Heat-Shock Proteins, Fibrosis, General Biochemistry, Genetics and Molecular Biology, Heat-Shock Proteins

الوصف: Liver fibrosis is a liver disease in which there is an excessive buildup of extracellular matrix proteins, including collagen. By regulating cytokine production and the inflammatory response, heat shock proteins (HSPs) contribute significantly to a wider spectrum of fibrotic illnesses, such as lung, liver, and idiopathic pulmonary fibrosis by aiding in the folding and assembly of freshly synthesized proteins, HSPs serve as chaperones. HSP70 is one of the key HSPs in avoiding protein aggregation which induces its action by sending unfolded and/or misfolded proteins to the ubiquitin–proteasome degradation pathway and antagonizing influence on epithelial-mesenchymal transition. HSP47, on the other hand, is crucial for boosting collagen synthesis, and deposition, and fostering the emergence of fibrotic disorders. The current review aims to provide light on how HSP70 and HSP47 affect hepatic fibrogenesis. Additionally, our review looks into new therapeutic approaches that target HSP70 and HSP47 and could potentially be used as drug candidates to treat liver fibrosis, especially in cases of comorbidities.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::21f2373dab121be07648a5cc58ba71beTest
https://pubmed.ncbi.nlm.nih.gov/36435779Test