Testicular germ cell apoptosis and spermatogenesis
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Caspases are the initiators and executioners of apoptosis. They are synthesized in the form of procaspases, which get activated during the apoptotic process (73). These procaspases contain three domains: an NH2 domain and the p20 and p10 domains. Caspases are cysteine proteases that cleave their substrate protein after the aspartic acid residue that leads to cell death (45). The executioner caspases exist in the cytosol in the form of inactive dimers, and their activation is carried out by the initiator caspases through proteolytic cleavage of its catalytic domain to an active scaffold. The proteolytic cleavage allows the rearrangement of its mobile loop conferring it the catalytic activity (74,75). In the cytosol, caspase-3 and caspase-7 exist in their dimeric forms, and activation is through the cleavage within their respective linker segments (76). In human testis biopsies, effector caspase-7 seemed to be absent from normal human testes, whereas procaspase-3 and procaspase-6 were detected in germ cells. Increased germ cell apoptosis in patients with the spermatogenic arrest was associated with increased levels of active caspase-3, which indicates that caspase-3 is the major executioner of apoptosis in human infertility (77). Similarly, in rodents also caspase-3 appears to be the major executioner of apoptosis (78,79).
Immunomodulatory Activities of Silver Nanoparticles (AgNPs) in Human Neutrophils
Huiliang Cao in Silver Nanoparticles for Antibacterial Devices, 2017
We then performed another study using smaller AgNPs with a diameter of 15 nm, AgNP15. Similarly to AgNP20, AgNP15 were found to rapidly penetrate human PMNs (Liz et al. 2015). However, AgNP15 appears to induce unconventional apoptosis. Indeed, in contrast to the cell shrinkage and CD16 cell surface shedding (Dransfield et al. 1994) normally observed in human apoptotic PMNs that we routinely used in our laboratory as markers of apoptotic cells, we rather observed that AgNP15 increase the cell volume and do not induce CD16 shedding. This unconventional cell death was clearly distinct from cell necrosis and was reversed by the addition of a pan-caspase inhibitor known to mostly inhibit caspase-1, caspase-3, caspase-4 and caspase-7. Because of this, and since we previously published that the ER stress-induced cell apoptotic pathway was operational in human PMNs, including the fact that these cells were also found to express caspase-4 and that it could be activated (Binet et al. 2010), we then tried to inhibit AgNP15-induced atypical cell death by adding specific inhibitors to caspase-1 and to caspase-4. Interestingly, both of these inhibitors were found to prevent the effect of AgNP15. Knowing that these two inflammatory caspases are known to be involved in inflammasome activation and IL-1β production (Fernandes-Alnemri et al. 2007; Man and Kanneganti 2015), it was logical to verify if AgNP15 increase the IL-1β production and, if so, to determine if caspase-1 or caspase-4 is involved. We found that, indeed, AgNP15 increased the neutrophil IL-1β production and that both caspases are involved, although caspase-4 is more importantly implicated (Liz et al. 2015). In this study, we also demonstrated that AgNP15 increased ROS production and that ROS participate in AgNP15-induced cell death. Finally, we reported in this study that when PMNs were forced to adhere, AgNP15 induced the NET formation.
Edible Tuber Amorphophallus paeoniifolius (Dennst.) Extract Induces Apoptosis and Suppresses Migration of Breast Cancer Cells
Published in Nutrition and Cancer, 2021
Munmi Majumder, Manoj Sharma, Siddhartha Maiti, Rupak Mukhopadhyay
Induction of apoptosis is a possible mode of cell death in cancer cells. Treatment of APTE induced significant apoptosis in both MCF-7 and MDA-MB-231 cells. Dose-dependent increase of pro-apoptotic BAX and inhibition of antiapoptotic BCL-2 indicated induction of apoptosis by the extract. BAX is a key component for apoptosis via mitochondrial stress and increases membrane’s permeability. This results in the release of cytochrome c from mitochondria and initiation of CASPASE activation pathway for apoptosis. There are reports that demonsrtrate p53-mediated induction of BAX. However, APTE treatment did not induce p53 expression suggesting BAX activation in this case might be independent of p53 (35). The expression of CASPASE-7 is a major contributor to the execution of apoptosis. It is cleaved by different enzymes whose expressions are upregulated during apoptosis. The activated CASPASE-7 is responsible for cleavage of many substrates, including PARP. APTE successfully induced CASPASE-7 activation leading to cleavage of PARP in experimental cells (36). These observations suggest that APTE induces apoptosis in both MCF-7 and MDA-MB-231 cells possibly by a CASPASE-7 dependent pathway (37).
Design, synthesis, molecular modelling, and biological evaluation of novel substituted pyrimidine derivatives as potential anticancer agents for hepatocellular carcinoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Naglaa Mohamed Ahmed, Mahmoud Youns, Moustafa Khames Soltan, Ahmed Mohammed Said
The caspases are a family of endoproteases that provide critical links in cell regulatory networks through controlling inflammation and cell death (apoptosis). Caspase-3 and caspase-7 cleave proteins involved in programmed cell death events46. It is well established that the induction of the apoptotic cascade is one of the main mechanisms of most of the currently available anticancer agents45,47,48. To determine the mechanism involved in the antitumor activity of our PPADs demonstrated above whether is a result of apoptosis or not, Caspase-Glo 3/7 assay was performed47. HepG-2 (Figure 8) and Huh-7 cell lines (Figure 9) were treated with the target PPAD’s samples or DMSO (solvent control). Figures 8 and 9 show that PPADs 4e, 4i, 4m, and 4q stimulated caspase activity in both cell lines at all tested concentrations and caused significant increase in activation of caspase 3/7 in a dose-dependent manner. These results suggest that our compounds induced apoptosis is, in part, due to activation of caspses3/7 and apoptosis is may be the main mechanism of action. Moreover, the apoptosis induced by the tested target compounds on Huh-7 cell line was greater than its effect on HepG2 cell line.
A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Robert Czarnomysy, Arkadiusz Surażyński, Anna Muszynska, Agnieszka Gornowicz, Anna Bielawska, Krzysztof Bielawski
Reduction of MMP is known as an early apoptotic event and associated with the activation of caspases13. Our study showed that PtPz1–PtPz6 in MDA-MB-231 cells were able to activate caspase-8 and -9 followed by downstream caspase-3. A similar situation was observed for MCF-7 cells, except for caspase-3, which was not detected in this cell line. Despite the fact that MCF-7 lack the expression of executor caspase-3, known as CPP32, they undergo apoptosis after treatment with anti-cancer agents. The studied cell line has confirmed 47 kb deletion in exone 3 of the CPP32 gene. However, it appears that not only the activation of caspase-3, but also caspase-7, by the action of initiator caspase-8 and -9, enhanced the apoptosis process. Caspase-7 is strongly associated with caspase-3 and they exhibit the same substrate specificity in vitro41. Our results suggest that pyrazole-platinum(II) complexes regulate the apoptosis of breast cancer cells independent of caspase-3 status.
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