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Penoscrotal Pathology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Multifactorial causes:Genetic: mutations in subunits of gamma-secretase proteins.Environmental: obesity, smoking.Bacterial infection can worsen HS.
Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
The structure of the three secretase enzymes are important. The alpha secretase comprises metalloproteases of TNFalpha and disintegrin matrix (Periz and Fortini 2000). The beta secretase or BACE (beta site APP cleaving enzyme) has different isoforms which give rise to different populations of abeta (Vassar and Citron 2000). The gamma secretase is a multiprotein complex with presenilin 1 (PSEN1), nicastrin, Aph-1, and presenilin 2 (PSEN2) (Steiner 2004). Similar to BACE, different PSEN1 and PSEN2 isoforms process APP in different manner. To generate abeta, the APP has to be cleaved by gamma and beta secretase, and various signaling pathways are associated with this. It has been shown that oxidative stress enhances beta and gamma secretase activity and increases abeta production (Tamagno et al. 2002, Oda, Tamaoka, and Araki 2010).
The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Hayrettin Ozan Gülcan, Ilkay Erdogan Orhan
Gamma-secretase is a membrane bound proteolytic enzyme. APP is one of the substrates of this enzyme. Different than BACE-1, gamma-secretase cleaves APP any of multiple sites producing Aβ39–42 species. The first results on animal models in which gamma secretase inhibitors were utilized displayed promising results in terms of lowered Aβ levels (Dovey et al., 2001). Similar to the results obtained for BACE-1 inhibitors, these initial evaluation on gamma-secretase inhibitors led to the design of phase trials. Unfortunately, serious side effects were observed with gamma-secretase inhibitors. No cognitive improvement was observed (De Strooper, 2014). Very interestingly, long-term exposure to gamma-secretase inhibitors led to an increase in Aβ plasma levels (i.e., a rebound effect) (Siemers et al., 2007). The mechanism for this outcome has not been clarified yet. However, the disappointing results obtained after clinical trials almost totally abolished studies on the design of novel gamma secretase inhibitors (Sogorb et al., 2018).
Neuroprotective effect of quercetin through targeting key genes involved in aluminum chloride induced Alzheimer’s disease in rats
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Hala A Elreedy, Asmaa M. Elfiky, Asmaa Ahmed Mahmoud, Khadiga S. Ibrahim, Mohamed A Ghazy
Gamma-secretase is an intramembrane aspartyl protease which engaged in Alzheimer’s disease through the proteolysis of APP. Thus, gamma-secretase creates the pathogenic Aβ 1–42 peptide that causes amyloid plaques [43,44]. A protein called Presenilin I (PSEN1) belongs to the aspartic protease family and is involved in the control of intramembrane proteolysis [8]. PSEN1 was believed to be a central, catalytic moiety of the gamma-secretase complex. PSEN1 was reported to be capable of cleaving substrates in the absence of Nicastrin (NCT), APH1 and presenilin enhancer-2 (PEN-2) in an activity assay performed in the liposomes [45]. Therefore, PSEN1 is a candidate target gene in drug design against AD. In the current research, we evaluated the levels of PSEN1 and APH1, two different components of gamma-secretase, in the hippocampus of rat brains. Both PSEN1 and APH1 levels were elevated in the AlCl3-induced AD group in comparison with the normal group. Meanwhile, PSEN1 gene expression level was significantly decreased in co-administration of AlCl3 with Q 50 mg kg-1 to AlCl3-induced AD rat. Suggesting that polyphenols could act as an inhibitor of PSEN1, a study by Lakey-Beitia and Berrocal [46] intended that polyphenols could occupy the active site of gamma-secretase (displacing the water molecule needed for catalysis by the enzyme), would inactivate the enzyme and decrease Aβ formation. On the other hand, Q at 50 mg kg-1 to AlCl3 -induced AD rats showed no significant effect on APH1gene expression compared to AlCl3 group.
Effect of flavonoids rich extract of Capparis spinosa on inflammatory involved genes in amyloid-beta peptide injected rat model of Alzheimer's disease
Published in Nutritional Neuroscience, 2018
Nazanin Mohebali, Seyed Abolhassan Shahzadeh Fazeli, Hossein Ghafoori, Zeinab Farahmand, Elham MohammadKhani, Faezeh Vakhshiteh, Abdolreza Ghamarian, Mansoureh Farhangniya, Mohammad Hossein Sanati
Although there was a remarkable decrease detected in PSEN-1 in treated groups, controversial effect was observed between Aβ−/DW+ group and Aβ+/DW+ group. Another study conducted by Delabio et al.41 demonstrated that PSEN-1 showed no significant change in expression in normal and AD brain, which is in accordance to results obtained from the current study. It was also reported recently that 20 mg/kg/BW luteolin intraperitoneal injection for 30 days can cause a significant inhibition in gamma-secretase enzyme. Gamma-secretase is a complex enzyme consisted of different subunits including presenilins which are encoded by PSEN-1 and PSEN-2 and is involved in APP cleavage.42 Regarding PSEN-2, the expression in Aβ−/DW+ group was remarkably lower than Aβ+/DW+ group. Neither Aβ+/RU+ group nor Aβ+/CS+ group was effective on PSEN-2, which indicated that C. spinosa and flavonoids in general, function in different pathways. A study has shown flavonoids function as a neuroprotective factor in Aβ-induced models.43 This was also observed in the current study.
Advances in the treatment of platinum resistant epithelial ovarian cancer: an update on standard and experimental therapies
Published in Expert Opinion on Investigational Drugs, 2021
Shuk on Annie Leung, Panagiotis A. Konstantinopoulos
Notch pathway alterations, especially in Notch3, are preferentially amplified or upregulated in more than 20% of the ovarian serous carcinomas [74,75,76]. Dysregulated expression has been correlated with tumor recurrence, drug resistance, and shorter overall survival. While mechanisms are still being elucidated, it has been shown that chemotherapy induces Notch activation and inhibition of Notch sensitizes cancer to chemotherapy. It has been shown that the Notch signaling pathway and Notch3 in particular are critical for the regulation of cancer stem cells and tumor resistance to platinum therapy in ovarian cancer. While Notch3 overexpression results in expansion of cancer stem cells and increased platinum chemoresistance, gamma-secretase inhibitor, a Notch pathway inhibitor, depletes cancer stem cells and increases tumor sensitivity to platinum [77]. Gamma-secretase inhibitors have been investigated in clinical trials but causes intestinal toxicity due to its inability to distinguish individual Notch receptors [78]. Currently, nirogascestat and AL101 for the treatment of desmoid tumors and Notch-mutant adenoid carcinoma have received FDA Orphan Drug Designation and Fast Track Designation. Studies have described Notch-selective inhibitory antibodies that specifically inhibit individual Notch receptors by blocking their negative regulatory domains [79]. Other strategies to pharmacologically target Notch signaling include ligand-targeted antibodies (e.g., DLL-4 antibodies) and Notch transcription complex small-molecule inhibitors [74]. Furthermore, pre-clinical investigations into treatment-resistant cancer have demonstrated that tumor can be resensitized to standard treatments using a combinatorial strategy with a Notch pathway inhibitor (e.g., cisplatin [77]).