scholarly journals Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

2020 ◽  
Author(s):  
Riko Nishimura ◽  
Kenji Hata ◽  
Yoshifumi Takahata ◽  
Tomohiko Murakami ◽  
Eriko Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
Genetic Disorders ◽  
Genetic Disorder ◽  
Genetic Diseases ◽  
Mtor Inhibitors ◽  
Joint Diseases ◽  
Ectopic Ossification ◽  
Proliferation And Differentiation ◽  
Clinical Benefits

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. IL-1β also leads to osteoarthritis through NF-ĸB, IκBζ, and Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and TNFα play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as BMP, FGF, PTHrP, and Indian hedgehog, play roles regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling cause genetic disorders in cartilage and skeletal tissues. FOP, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. mTOR inhibitors were found to prevent ectopic ossification by ACVR1 mutations. ACH and related diseases are autosomal genetic diseases, which manifest severe dwarfism. CNP is currently the most promising therapy for ACH. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels sheds light on the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

scholarly journals Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1340 ◽  
Author(s):  
Riko Nishimura ◽  
Kenji Hata ◽  
Yoshifumi Takahata ◽  
Tomohiko Murakami ◽  
Eriko Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Genetic Disorder ◽  
Interleukin 1 ◽  
Genetic Diseases ◽  
Mtor Inhibitors ◽  
Joint Diseases ◽  
Ectopic Ossification ◽  
Parathyroid Hormone Related Protein

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

scholarly journals Fibroblasts of skin fragments as a tool for the investigation of genetic diseases: technical recommendations

2000 ◽  
Vol 23 (2) ◽  
pp. 269-271 ◽  
Author(s):  
Janice Carneiro Coelho ◽  
Roberto Giugliani
Keyword(s):  
Diagnostic Tool ◽  
Present Report ◽  
Genetic Disorders ◽  
Genetic Disorder ◽  
Genetic Diseases ◽  
Patient Discomfort ◽  
General Rules ◽  
Probability Of Success ◽  
Skin Biopsies ◽  
Technical Recommendations

Skin biopsies are frequently indicated for investigation and/or confirmation of genetic disorders. Although relatively simple and noninvasive, these procedures require care in order to increase probability of success and to avoid patient discomfort and unnecessary repeated analyses and associated laboratory fees. The present report highlights the importance of skin biopsies in genetic disorder diagnosis and presents general rules for collecting, storing, transporting and processing samples. We recommend its reading to professionals intending to use this important and sometimes fundamental diagnostic tool.

scholarly journals DNA Classification using Machine Learning for Detecting Genetic Disorders

2020 ◽  
Vol 9 (4) ◽  
pp. 1287-1291
Keyword(s):  
Machine Learning ◽  
Dna Sequences ◽  
Genetic Disorders ◽  
Genetic Disorder ◽  
Median Filter ◽  
Genetic Diseases ◽  
Minimal Amount ◽  
Base Pairs ◽  
Canny Edge ◽  
Dna Pattern

Deoxyribonucleic acid is a double- helical molecule composed of two chains that contains genetic instructions. Genetic diseases are caused by changes in pre-existing genes. A genetic abnormality results from the alteration in chromosomes. DNA classification helps to identify genetic disorders in organisms. DNA pattern recognition is a major issue in bioinformatics. DNA is classified into several categories on the basis of Structure, Location, Number of base pairs etc. Traditionally the DNA Molecule is studied by extracting it from the blood sample and is then manually analysed to find out the abnormalities. To increase the accuracy, a machine learning based DNA classification is done which helps in studying the extracted DNA image using various techniques. This consumes minimal amount of time and is more efficient. The image is preprocessed using median filter and canny edge detection. DNA sequences can be recognized correctly and effectively without any uncertainties with the help of Neural Network.The network successfully classifies an image given as input when it is trained with patterns. Thus, we can analyse if a person has a genetic disorder.

scholarly journals Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atlal El-Assaad ◽  
Zaher Dawy ◽  
Athar Khalil ◽  
Georges Nemer
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Free Energy Calculations ◽  
Missense Mutations ◽  
Biochemical Processes ◽  
Genes Encoding ◽  
Complex Models ◽  
Poisson Boltzmann

AbstractTranscription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.

scholarly journals Distinct Roles of Vav Family Members in Adaptive and Innate Immune Models of Arthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 695
Author(s):  
Javier Conde ◽  
Isabel Fernández-Pisonero ◽  
Myriam Cuadrado ◽  
Antonio Abad ◽  
Javier Robles-Valero ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Family Members ◽  
Experimental Models ◽  
Innate Immune ◽  
Main Role ◽  
Zymosan A ◽  
Proliferation And Differentiation ◽  
Signal Transduction Proteins ◽  
Selection Of

Genetic evidence suggests that three members of the VAV family (VAV1, VAV2 and VAV3) of signal transduction proteins could play important roles in rheumatoid arthritis. However, it is not known currently whether the inhibition of these proteins protects against this disease and, if so, the number of family members that must be eliminated to get a therapeutic impact. To address this issue, we have used a collection of single and compound Vav family knockout mice in experimental models for antigen-dependent (methylated bovine serum albumin injections) and neutrophil-dependent (Zymosan A injections) rheumatoid arthritis in mice. We show here that the specific elimination of Vav1 is sufficient to block the development of antigen-induced arthritis. This protection is likely associated with the roles of this Vav family member in the development and selection of immature T cells within the thymus as well as in the subsequent proliferation and differentiation of effector T cells. By contrast, we have found that depletion of Vav2 reduces the number of neutrophils present in the joints of Zymosan A-treated mice. Despite this, the elimination of Vav2 does not protect against the joint degeneration triggered by this experimental model. These findings indicate that Vav1 is the most important pharmacological target within this family, although its main role is limited to the protection against antigen-induced rheumatoid arthritis. They also indicate that the three Vav family proteins do not play redundant roles in these pathobiological processes.

scholarly journals Oligonucleotide Therapies in the Treatment of Arthritis: A Narrative Review

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 902
Author(s):  
Susanne N. Wijesinghe ◽  
Mark A. Lindsay ◽  
Simon W. Jones
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Joint Diseases ◽  
Synovial Joint ◽  
Pharmacological Treatments ◽  
In Vivo Models ◽  
Inflammatory Joint Diseases ◽  
Joint Pathology ◽  
Cellular Pathways

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common chronic inflammatory joint diseases, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. The pathology of both OA and RA involves multiple tissues within the joint, including the synovial joint lining and the bone, as well as the articular cartilage in OA. In this review, we discuss the potential for the development of oligonucleotide therapies for these disorders by examining the evidence that oligonucleotides can modulate the key cellular pathways that drive the pathology of the inflammatory diseased joint pathology, as well as evidence in preclinical in vivo models that oligonucleotides can modify disease progression.

scholarly journals The Importance of Early Detection of Genetic Diseases

2021 ◽  
Vol 4 (2) ◽  
pp. 133-141
Author(s):  
Suma Elcy Varghese ◽  
Rana Hassan Mohammad El Otol ◽  
Fatma Sultan Al Olama ◽  
Salah Ahmad Mohamed Elbadawi
Keyword(s):  
Early Detection ◽  
Newborn Screening ◽  
Health Authority ◽  
Genetic Screening ◽  
Screening Program ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Inborn Errors ◽  
The Usa ◽  
Premarital Screening

<b><i>Background:</i></b> Early detection of diseases in newborn may help in early intervention and treatment, which may either cure the disease or improve the outcome of the patient. Dubai’s Health Authority has a newborn screening program which includes screening for metabolic and genetic conditions, for hearing and vision, and for congenital heart disease. <b><i>Objectives:</i></b> The objectives of this study are to assess the outcome of the newborn genetic screening program, to correlate the association between the outcome of the program and demographic variables and to find out the percentage of the number of infants who were confirmed to have the genetic disease (by confirmatory tests) out of the total infants who had positive screening test results. <b><i>Methods:</i></b> During the period of the study from January 2018 to December 2018, a total of 7,027 newborns were tested in Dubai Health Authority facilities by the newborn genetic screening program (known as the “Step One Screening”). Blood samples were collected by heel prick on a collection paper. All samples were transported to PerkinElmer Genomics in the USA where the tests were done. The genetic disorders identified were correlated with different variables like gender and nationality. The data were entered in an excel sheet and analyzed by using SPSS software. All infants aged 0–3 months who have done newborn genetic screening at Dubai Health Authority facilities between January and December 2018 were included. <b><i>Results:</i></b> The incidence of screened disorders was 1:7,027 for congenital adrenal hyperplasia, 1:1,757 for congenital hypothyroidism, 1:1,757 for inborn errors of metabolism, 1:2,342 for biotinidase deficiency, 1:1,171 for hemoglobinopathies, 1:12 for hemoglobinopathy traits, and 1:10 for different genetic mutations of G6PD deficiency. <b><i>Conclusions:</i></b> There is a high incidence of different genetic diseases detected by newborn screening. These results justify unifying the program in the UAE and preventive programs like premarital screening and genetic counseling.

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