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Articular Cartilage Pathology and Therapies
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Some notable examples of genetic defects that lead to osteoarthritis are described here: Alkaptonuria is an autosomal recessive genetic disorder resulting in abnormal phenylalanine and tyrosine metabolism, wherein the tyrosine metabolic byproduct is not cleared (homogentisic acid, or alkapton) and builds up in cartilage (ochronosis), heart valves, and the kidneys. Ochronosis leads to articular cartilage degeneration. The defect lies in the homogentisate 1,2-dioxygenase enzyme produced by the HGD gene on chromosome 3. This enzyme participates in tyrosine metabolism by converting homogentistic acid into 4-maleylacetoacetate (Figure 3.5).
Analyzing Complex Polygenic Traits
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Bernard R. Lauwerys, Edward K. Wakeland
Surprisingly, Slel, Sle2 and Sle3 susceptibility alleles are all derived from the NZW genome. Yet, NZW mice do not develop significant autoimmune disease nor autoantibody mediated glomerulonephritis by contrast to (NZB × NZW)F1 hybrids, thereby suggesting that recessive genes in the NZW genome suppress the disease-facilitating effect of the susceptibility alleles. The observation that (B6.Slel × NZW)F1 hybrids develop a highly penetrant (>75%) severe disease is another indication that recessive genes displaying strong suppressor effects are present in the NZW genome. In order to identify these suppressor loci, Morel et al genotyped 122 microsatellite markers in (B6.Slel × NZW)F1 × NZW BC1 backcrosses, that are all homozygous for the Slel susceptibility allele. If a microsatellite marker is associated with disease suppression, it will be homozygous in healthy mice and heterozygous in affected mice. By contrast, a marker that is associated with disease susceptibility would be homozygous in diseased mice and heterozygous in healthy mice. Finally, a marker that is not associated with disease will be randomly distributed among the animals. The authors identified 4 loci, named Slesl-4, which showed evidence for linkage with disease suppression. In particular, the Slesl locus was found to completely abrogate the phenotype mediated by Slel in B6.Slel/Slesl bicongenic mice. Slesl is located on chromosome 17, close to the MHC region. Interestingly, Sles2 is located on chromosome 4, in a region that has been reported to contain NZB-derived susceptibility alleles (Nbal and Lbw5). The peak marker for Sles3 is on chromosome 3, close to the IL-2 gene that has been associated with susceptibility to diabetes and experimental autoimmune encephalomyelitis in other strains of mice. Finally, Sles4 is in the centromeric region of chromosome 9. Surprisingly, Sles4 displayed a suppressive effect on nephritis that was strongly gender-biased in that it was entirely male-specific.71-73
Investigate the role of PIK3CA gene expression in colorectal polyp development
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Ameer Ali Imarah, Rana Ahmed Najm, Haider Ali Alnaji, Saleem Khteer Al-Hadraawy, Abbas F. Almulla, Hussein Raof Al-Gazali
When colonic adenomas grow larger than 2 centimeters in diameter, they can be a precursor to colorectal adenocarcinoma, making them therapeutically significant [8]. The severity of this type of polyps came from the ability to cumulate mutations associated with cell cycle control over years [1] and PIK3CA, one of these genes [9]. The phosphatidylinositol 3-kinases (PI3Ks) are involved in signaling pathways important for tumorigenesis, including those involved in apoptosis, proliferation, and migration [10]. Phosphoinositide-3-kinase, catalytic alpha polypeptide (PIK3CA), is an integral member of the lipid kinase family, encoding the p110 catalytic subunit of the kinase [11]. PIK3CA gene is located on chromosome 3 long arm (3q26.32) and is involved in cell control via expression to catalytic subunit p110 in phosphatidylinositol 3 Kinase. Phosphoinositide 3 The kinase enzyme interacts with phosphatidylinositol-3-phosphate, a membrane component, to catalyze the phosphorylation of AKT, which then activates the signaling pathway. Because the activation of this pathway depends on outside signals like growth factors, this gene is classified as a proto-oncogene [12].
Phytochemical prospecting, isolation, and protective effect of the ethanolic extract of the leaves of Jatropha mollissima (Pohl) Baill
Published in Journal of Toxicology and Environmental Health, Part A, 2021
José Rafael da Silva Araújo, João Gabriel Silva Morais, Cleidiane Macêdo Santos, Kelvim Crist Araújo Rocha, Adriane da Cunha Aragão Rios Fagundes, Francisco Artur e Silva Filho, Francielle Alline Martins, Pedro Marcos de Almeida
Three strains of D. melanogaster were used for the test with recessive markers located on chromosome 3: (1) multiple wing hairs (mwh), with genetic constitution mwh/mwh (3– 0.3); (2) flare3 (flr3), with genetic constitution flr3/In(3LR)TM3, ri pp sep l(3)89Aa bx34e BdS (3–38.8); (3) Oregon-flare3 (ORR; flr3), with genetic constitution ORR/ORR; flr3 /In(3LR)TM3, ri pp sep l(3)89Aa bx34e BdS. The ORR strain possesses 1 and 2 chromosomes from the Oregon T strain (resistant to DTT), containing genes that are responsible for high levels of metabolizing enzymes (CYP) (Graf and van Schaik 1992). The strains were kept in a germination chamber with temperature control approximately 25°C and 12 hr light/dark cycle.
Genetic polymorphisms of PPAR genes and human cancers: evidence for gene–environment interactions
Published in Journal of Environmental Science and Health, Part C, 2019
The human PPAR-γ gene, which is located on chromosome 3 at position 3p25, encodes 4 mRNAs based on alternate splicing or transcription of separate promoters.55 Two isoforms γ1 and γ3 result in the same protein, while the third (γ2) varies with 28 amino acids extra and 5–6-fold increase in its ligand-dependent activating function.56 As for PPARγ4, its localization is still not clearly defined. The PPAR-γ gene has a commonly reported missense C > G mutation in exon B (codon12), which results in a proline to alanine (Pro12Ala) substitution in the protein.57 This Pro12Ala polymorphism causes a conformational change thought to be associated with a decreased transcriptional activity and a weaker transactivation of responsive promoters.58 However, its association with cancer risk is still an area of controversy.6 The Pro12Ala (CG) heterozygous genotype seems to be have a relatively higher prevalence in Caucasians compared to other ethnic groups; its prevalence was reported to be 28.7% in Finnish,59 18% in Italians,60 and 19% in US Caucasian populations,61 while it was found to be at 18.1% in a small Iranian population,62 11.7% in a Brazilian population,63 9.8% in aboriginal Arabs in Qatar,64 and 9.7% in a Chinese population.65 Other variants have been found to be in strong linkage disequilibrium with the Pro12Ala polymorphism, including the rs10865710 (C-681G), which resides in the promoter region, affecting gene regulation, as well as modulating the binding of transcription factor STAT5.66 Another identified PPAR- γ polymorphism is the His477His, which results in a silent substitution of histidine residue at exon 6 (C161T/C1431T; rs3856806).67