China
Africa
Explore chapters and articles related to this topic
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Many gene loci have been identified that describe a combination of NCCM and other congenital heart diseases, such as hypoplastic left-heart syndrome (Dystrobrevin α) or Ebstein anomaly (MYH7). Genetic variants that can be found code for sarcomeric proteins, nuclear envelope and Z-band components, as well as sarcolemma protein and ion channels. LVNC may occur in the setting of other developmental defects, where it is referred to as ‘syndromic LVNC’. LVNC has an estimated prevalence of 1/7000. Familial disease is more likely when the proband is of paediatric age. Genetic causes of LVNC are multiple and complex and include both autosomal dominant and X-linked recessive inheritance. The first mutation described was in the X-linked gene TAZ (which encodes for tafazzin) in children and is linked to Barth syndrome. Mutations in the G4.5 gene may be associated with various cardiac phenotypes, including infantile DCM, classic Barth syndrome, endocardial fibroelastosis, isolated LVNC, and a DCM–HCM overlapping phenotype. A single mutation in DTNA encoding α-dystrobrevin is associated with LVNC and congenital heart disease, including ventricular septal defects, patent ductus arteriosus, and hypoplastic left heart syndrome. Mutation of the FKBP12 gene produces ventricular septal defects, DCM and noncompacted cardiomyopathy. It may form part of various syndromes such as Barth, Noonan, Roifman or Toriello Carey syndrome.
Transplantation
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Jonathon Olsburgh, Rhana H. Zakri
TacrolimusDerived from Streptomyces tsukubaensis (macrolide antibiotic).Binds to a different immunophilin, FK506-binding protein 12 (FKBP12).Creates a complex that also inhibits calcineurin.Greater affinity than ciclosporin.
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
Rapamycin does not directly inhibit mTOR. Instead, it binds to the abundant 12 kD cytoplasmic FK506 binding protein FKBP12. The resulting rapamycin- FKBP12 complex binds to the FK-rapamycin binding domain of mTOR, leading to the disruption of TORC1 signaling and preventing phosphorylation of S6K and 4E-BP1 (2–4).
Preparation of a novel tacrolimus ion sensitive ocular in situ gel and in vivo evaluation of curative effect of immune conjunctivitis
Published in Pharmaceutical Development and Technology, 2022
TAC inhibits allograft rejection primarily by activating T cells after binding to the cellular receptors (FKBP12), thus blocking the activity of calcineurin and regulating the transcription of lymphokine IL-2 (Gratreak et al. 2020). Therefore, IL-2 is a vital target for the activation of a TCR-mediated signaling transmission pathway. Besides, inflammatory cytokine (such as IFN-γ and IL-17) also possess immunoregulatory. VEGF participates in the neovascularization process and promotes the contact between donor antigens and recipient blood lymphocytes, which enhances cornea immunological rejection (Di Tommaso et al. 2012). Therefore, to analyze the immunosuppressive effects of TAC in situ gel, we performed biochemical experiments to measure the expression levels of IL-2, IFN-γ, IL-17, and VEGF in the anterior segment of rats.
Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
The mTOR/PI3K pathway is a key regulator of metabolism, cell growth, proliferation, and survival and is often overactivated in cancer and neurodegenerative disease, while targeting the inhibition of mTOR has also been studied for the treatment of Alzheimer’s disease, Huntington’s disease and Parkinson’s disease [156–159]. mTOR kinase comprises two main TOR complexes, TORC1 and TORC2 with the former key to controlling cellular protein and lipid synthesis whilst the latter promotes metabolic activity, cell cycle, and cytoskeletal rearrangements. Rapamycin and derivatives (so-called Rapalogs) have long been established as immunosuppressive agents used for organ transplants that work through blocking TORC1 through formation of a TORC1/rapamycin/FK506 binding protein 12 (FKBP12) complex [160]. Rapalogs have also shown clinical efficacy in several other therapeutic areas, though amongst overall response rates as single agents in the treatment of major solid tumors have been modest owing to both limitations of dose due to side effects resulting from immunosuppressive action and activation of TORC2-dependent feedback loops by-passing TORC1 to promote tumor growth [161]. Given the latter, compounds targeting inhibition of both TORC1 and TORC2 have been developed and advanced in the clinic for the treatment of a range of cancers [162,163].
Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy
Published in Expert Opinion on Drug Discovery, 2019
In addition to a systematic, modular screening approach, consideration of the structure and mechanism of assembly of the multi-protein signaling complex containing ALK2 could enhance and streamline the development of an efficacious drug for the diverse, debilitating bone-forming musculoskeletal pathologies (cf. 5.4, below). In support of the proposed drug discovery approach, two proteins interacting with the cytoplasmic kinase of ALKs, a downstream-effector substrate (R-Smad3) [87] and a dampening protein (FK-506 binding protein 12 kDa, FKBP12; peptidylprolyl isomerase, EC 5.2.1.8) [88], can be degraded with hetero-bifunctional small molecules. In the case of the signaling-dampening binding protein, induced degradation should be avoided, since competitive inhibition of type I BMP receptor binding of FKBP12 by the FK506 ligand leads to receptor activation and promotes osteogenic differentiation [89].