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Endocrine hypertension
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Frances McManus, John M. Connell, Marie Freel
Liddle’s syndrome is a rare, autosomal dominant condition and associated with moderate-to-severe hypertension presenting in childhood, arising from over activation of the epithelial sodium channel (ENaC). In common with PA, patients are hypokalemic with a metabolic alkalosis and have a low plasma renin, but in this case plasma aldosterone concentrations are low.30 The genetic abnormality lies on chromosome 16, and “gain-of-function mutations” identified to date lie in the cytoplasmic C-terminal tails of the β- and γ-subunits of ENaC.31 These mutations result in loss of an adaptor motif that interacts with neural precursor cell-expressed, developmentally down regulated 4-2 (Nedd4-2). Nedd4-2 ligates a ubiquitin “tag” to the ENaC that targets it for internalization and subsequent destruction. This induces constitutive activity of the ENaC in the cortical collecting duct, as if activated by aldosterone. Importantly, in this condition, spironolactone is not effective because activation of ENaC is not due to excessive aldosterone levels and is independent of the MR. However, the ENaC is amiloride sensitive, and this is the treatment of choice in these patients.
Development and characterisation of SMURF2-targeting modifiers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Dhanoop Manikoth Ayyathan, Gal Levy-Cohen, Moran Shubely, Sandy Boutros-Suleiman, Veronica Lepechkin-Zilbermintz, Michael Shokhen, Amnon Albeck, Arie Gruzman, Michael Blank
Smad ubiquitination regulatory factor 2 (SMURF2) is a member of the HECT-type NEDD4 E3 ligase family. This family is characterised by the presence in the protein structure of the C2 domain (a calcium and lipid binding domain of ∼120 amino acids), several tryptophan-rich WW domains (∼40 residues long; play a role in protein–protein interactions via recognition of proline‐rich motifs in target proteins), and the catalytical carboxy-terminal HECT domain (∼350 residues). HECT domain consists of N- and C-terminal lobes connected through a flexible hinge allowing them to come together during ubiquitin transfer. The N-lobe interacts with E2, whereas the C-lobe harbours the active-site cysteine (Cys716 in SMURF2) forming the thioester bond with ubiquitin. Despite high similarities in the domain composition, NEDD4 E3s have distinct substrate repertoire and reveal distinct roles in physiological and pathobiological processes, including cancer1–4. In neoplastic diseases, SMURF2 was shown to exert both tumour-promoting and suppressor activities, depending on tumour type, stage, molecular and cellular contexts, and other still unidentified factors5.
The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease
Published in Expert Opinion on Therapeutic Targets, 2018
Patrick J. Moore, Robert Tarran
Both PKA and PIP2 affect ENaC Po [66]. However, ENaC N is also precisely regulated. ENaC can be ubiquitinated on all three subunits by the ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4 (NEDD4-2) also known as NEDD4L [67]. Each ENaC subunit has a PY motif (L/PPXY) that can bind to NEDD4-2 [68]. The subsequent ubiquitination of ENaC subunits leads to their rapid internalization and degradation [34]. Butterworth et al. demonstrated that inhibition of deubiquitinating enzymes increased ubiquitination and decreased surface αβγENaC [69]. Interestingly, deletions of the PY motifs cause spontaneous upregulation of ENaC and cause Liddle’s syndrome [66], which is characterized by increased renal ENaC activity, K+ excretion and Na+/H2O retention that lead to hypertension and metabolic alkalosis [70]. In addition to the mutations observed in the PY motifs, mutations in the C-terminus (β, R563Q) and the TM2 segment (γ, N530S) were also reported to be associated with Liddle’s syndrome [71,72]. Although these mutations are not associated with CF-like disease, mutations in individual ENaC subunits would likely influence the impact of posttranslational proteolytic cleavage of this subunit.
Advances in curcumin-loaded nanopreparations: improving bioavailability and overcoming inherent drawbacks
Published in Journal of Drug Targeting, 2019
Yanan Zhang, Abdur Rauf Khan, Manfei Fu, Yujia Zhai, Jianbo Ji, Larisa Bobrovskaya, Guangxi Zhai
Cancer is a group of diseases, manifested by unusual cell growth, high migratory and metastatic potential. Cancer usually manifests symptoms like lump, bleeding, and weight loss [8]. CUR is certified therapeutic agent to treat cancer of breast, colon, bladder, skin and pancreas. CUR is effective in breast cancer by inhibiting the activity of NF-κB as well as the transcription factors AP-1, EGR and β-catenin [9]. In addition, CUR was reported to suppress TGFβ-receptor-mediated Smad2/3 phosphorylation, resulting in the inhibition of bone metastatic breast cancer cells [10]. In colorectal cancer cells, CUR decreased the mRNA and protein levels of cyclin B1, which inhibited the transition from G2 to M phase in the cell cycle [11]. Besides, CUR reduced the content of anti-apoptotic proteins p-Akt, Akt, Bcl-2 and p-Bad, and induced the caspase 3/7 through PARP cleavage, preventing cell growth in colon cancer. While, scientists discovered that the silencing of heat shock protein-27 (HSP27) induced the drug resistance to CUR [12,13]. CUR facilitated the proteasomal degradation of oncogenic SIRT1 via covalent modification at the cysteine 67 residue, suppressing the oncogenicity of cancer cells [14]. While, in pancreatic cancer, neural precursor cells expressed gradually down-regulation of protein-4 (NEDD4), which was discovered to target and degrade the multiple tumour suppressor proteins. The inhibition of NEDD4 favoured the tumour killing. CUR increased the expression of NEDD4 subtypes, phosphatase and tensin homologue deleted on chromosome ten (PTEN) and p73 proteins, thus suppressed the growth, migration and invasion of pancreatic cancer cells (Figure 2) [15].