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Testicular germ cell apoptosis and spermatogenesis
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
This pathway serves to remove germ cells in response to external and internal stimuli, leading to mitochondrial permeabilization, which causes leakage of cytochrome c and activation of caspase-9. Mitochondria are armed with both proapoptotic and antiapoptotic machinery, which governs the cell fate (52). Cytochrome c is the most prominent among these (45) that get transported into the intermembranous space of mitochondria. The permeability of the mitochondria allows the cytochrome c to cross the outer mitochondrial membrane into the cytosol. This is a critical event for the initiation of mitochondria-dependent activation of caspases leading to apoptosis (53,54). Cytosolic cytochrome c triggers the association of apoptotic protease activating factor (APAF-1), dATP and procaspase-9 (55) to form the “apoptosome,” which further triggers the activation of the caspase cascade entailing cell death (56,57). Apoptosome, an adapter protein complex, carries out the activation of the initiator caspase (caspase-9) (58). Apoptosome is a multimeric complex, which includes Apaf-1 (apoptotic protease activating factor-1), procaspase-9, cytochrome c and dATP/ATP. The binding of cytochrome c and the hydrolysis of dATP induce a conformational change in Apaf-1 to unmask the caspase activation domain recruitment domain (CARD) at the C-terminal. The N-terminal CARD of Apaf-1 is proposed to function via interaction with the prodomain of procaspase-9, resulting in its activation (59). The activated caspase-9 gets detached from its complex, cleaves and activates its downstream executioner caspases 3, 6 and 7. The male germ cells respond to extracellular stimuli through changes in the internal environment, which decide the fate of the cell. In the course of the first wave of spermatogenesis, Bax is shown to be necessary for normal spermatogenesis, and its expression is increased on those cells, which are destined to undergo apoptosis. Studies have revealed that the Bax knockout mice possess a high number of spermatogonia and preleptotene spermatocytes due to failure of apoptosis during the first wave of spermatogenesis, and their spermatogenesis is unable to proceed normally (60). Insulin-like growth factor binding protein-3 (IGFBP-3) and Bax interaction activates germ cell apoptosis by the mitochondrial pathway (61). Another study has shown that phosphorylation of BCL2 at serine residue and activation of the MAPK14-mediated mitochondria-dependent pathway regulate male germ cell death in monkeys (61). The Bcl-2 family includes both proapoptotic (Bax, Bak, Bcl-xs and Bad) and antiapoptotic (Bcl-2, Bcl-XL, Mcl and M1) proteins, which are important for germ cell apoptosis (62). The ratio of pro- and antiapoptotic proteins decides whether a cell would survive or undergo apoptotic cell death (63,64). A high Bcl-2/Bax ratio results in cell survival, and on the contrary, a high Bax/Bcl-2 ratio leads to cell death (65). A dynamic change in Bcl-2 family proteins is continuous during the first cycle of spermatogenesis. The competitive action of proapoptotic and antiapoptotic Bcl-2 family proteins controls the activation of caspases and apoptosis (66).
Secretory autophagy: a turn key for understanding AMD pathology and developing new therapeutic targets?
Published in Expert Opinion on Therapeutic Targets, 2022
Janusz Blasiak, Kai Kaarniranta
Degradative autophagy was postulated as a functional therapeutic target for AMD in several studies. Mice lacking the apolipoprotein E (APOE) gene were used to model early AMD and assess the potential of metformin and trehalose to slowdown retinal dysfunctions [98]. Untreated animals showed reduced retinal functions and thickening of BM corresponding to an early AMD phenotype. They had decreased microtubule-associated protein 1 light chain 3 beta (MAP1LC3B/LC3) and lysosomal-associated membrane protein 1 (LAMP1) labeling in the photoreceptors and the RPE. This was associated with increased LC3-II/I ratio, and changes in protein expression in many autophagy pathways indicating that autophagy was slowed down. Metformin or trehalose improved retinal functions and decreased BM thickness, increased LC3 and LAMP1 labeling and reduced LC3-II:LC3-I ratio to control levels. Both agents improved ataxia telangiectasia mutated-5’ adenosine monophosphate-activated protein kinase (ATM-AMPK) driven autophagy and trehalose increased the phosphorylated mitogen-activated protein kinase 14 (MAPK14)/p38 to enhance autophagy. The ATM-AMPK pathway stimulates autophagy to promote cell survival in oxidative stress and MAPK14/p38 favors autophagy over apoptosis [99]. This study shows that targeting autophagy may ameliorate early AMD. Exploring the potential of metformin and trehalose to modulate secretory autophagy might shed some light on it as a therapeutic target, especially that metformin was reported to reduce the risk of AMD in humans [100].
The latest automated docking technologies for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
When approved drugs bind to off-targets they can cause side effects, but they could interact with a therapeutic target involved in another disease. In the last case, the drug could have a new use, which is repositioning (or repurposing). In a recent work, Li et al [51] developed a computational drug repositioning pipeline to perform large-scale molecular docking of 4621 approved and experimental small molecule drugs (from DrugBank) against 252 human protein drug targets, in order to map the drug-target interaction space and find novel interactions. An important result derived from this computational study is that authors found that the cancer drug nilotinib is a potent MAPK14 inhibitor in vitro, and they suggested that this drug could be repurposed for the treatment of inflammatory diseases. In a more recent work, Zhang et al [52] developed a computational protocol, including pharmacophore comparison and reverse ligand−protein docking in a high throughput manner, to assist in de novo identification of protein targets for herbal ingredients. As a validation, they identified current known targets of acteoside, quercetin, and epigallocatechin gallate. Authors proposed this protocol as a computational tool for drug repurposing from natural products. Very recently, the emergence of coronavirus disease COVID-19 has been tackled by using drug repurposing. Since the 3D structures of SARS-CoV-2 target proteins are available, many scientific groups from around the world have sought to identify potential drugs for repurposing by using molecular docking protocols [53,54].
Association of C3953T transition in interleukin 1β gene with idiopathic male infertility in an Iranian population
Published in Human Fertility, 2019
Tayyebeh Zamani-Badi, Mohammad Karimian, Abolfazl Azami-Tameh, Hossein Nikzad
Data from the String database reveals that IL-1β interacts with 10 other molecules (Figure 3): (i) Interleukin 1 receptor accessory protein (IL1RAP); (ii) Interleukin 1 receptor, type I (IL1R1); (iii) Caspase 1, apoptosis-related cysteine peptidase (CASP1); (iv) Interleukin 1 receptor, type II (IL1R2); (v) Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NFKB1); (vi) Interleukin 18 (IL18); (vii) Interleukin 1, alpha (IL1A); (viii) Mitogen-activated protein kinase 14 (MAPK14); (ix) Jun proto-oncogene (JUN); and (x) FBJ murine osteosarcoma viral oncogene homolog (FOS).