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Immunomodulatory Activities of Silver Nanoparticles (AgNPs) in Human Neutrophils
Published in Huiliang Cao, Silver Nanoparticles for Antibacterial Devices, 2017
Apoptosis is a highly regulated process that could be triggered through either the extrinsic pathway, the intrinsic pathway or the endoplasmic reticulum (ER) stress-induced pathway (Bettigole and Glimcher 2015; Boyce and Yuan 2006; Roy et al. 2014). The intrinsic pathway is initiated through the intracellular release of different mitochondrial signal factors. In brief, after its release, cytochrome c will form a complex with adenosine triphosphate (ATP) and the enzymatic protein Apaf-1. This complex will in turn activate the initiator caspase-9 that will interact with the complex cytochrome c–ATP–Apaf-1, forming an apoptosome, leading to activation of the effector caspase-3 and degradation of cellular structures, including the cytoskeleton (Robertson et al. 2002; Roy et al. 2014). The extrinsic pathway is rather initiated via the stimulation of the transmembrane death receptors, including Fas receptors (CD95), one of the best characterised ones (Lavrik 2014). During activation of this pathway, some ligand molecules will be released by other cells and will bind to transmembrane death receptors on the target cell, inducing apoptosis. For example, the binding of the Fas ligands (CD95L) to their receptors (CD95) will trigger cell surface receptor aggregation, leading to the recruitment of an intracellular adaptor protein, Fas-associated death domain protein or FADD, which, in turn, will interact with the initiator caspase-8 protein, forming a complex, the death-inducing signal complex or DISC (Ashkenazi and Dixit 1998; Lavrik 2014; Li et al. 1998). Then, activated caspase-8 could activate caspase-3, indicating that both intrinsic and intrinsic pathway can overlap. In this respect, activated caspase-8 can also activate a protein, BID, known to act as a signal on the membrane of mitochondria facilitating cytochrome c release.
Phytoconstituents from Neem with Multiple Activities
Published in Bhupinder Singh, Om Prakash Katare, Eliana B. Souto, NanoAgroceuticals & NanoPhytoChemicals, 2018
Suman Chaudhary, Rupinder Kaur Kanwar, Teenu Sharma, Bhupinder Singh, Jagat Rakesh Kanwar
Further, pretreatment of leukocytes with neem leaf preparations have been shown to inhibit 5-fluorouracil and cisplatin-induced apoptosis. It enhances the cytotoxicity by inducing the increase in the production of T cells and natural killer (NK) cells. Thus, neem leaf protein (NLP) can be used as an inexpensive substitute for granulocyte colony stimulating factor (GCSF) in reducing the side effects that are associated with cisplatin and 5-fluorouracil treatments (Ghosh et al., 2009). Another study conducted by Kumar et al. demonstrated the dose- and time-dependent cytotoxic potential of nimbolide, which is a limonoid of neem leaves and flowers, against human choriocarcinoma cells. It induces apoptosis by downregulating Bcl-2/Bax ratio, along with upregulating the expression of caspase-3, Apoptotic protease activating factor (Apaf)-1 and cleavage of poly(ADP-ribose) polymerase. Thus, it is validated that the apoptosis induced by nimbolide compound is mediated through mitochondrial pathway (Kumar et al., 2009). Consistent with the apoptosis-inducing potential of neem leaf, significant cytotoxic potential of neem leaf is also observed in various other cell lines, including leukemia (HL60), breast (SK-BR-3), lung (A549) and stomach (AZ521) cancer cell lines, with an IC50 value between 0.1 and 9.9 μm (Takagi et al., 2014). Although these studies have validated the anticancer potential of neem leaf, the studies lack complete evaluation of the dose-dependent toxicity associated with neem leaves. In vivo studies have indicated neem leaf–mediated decrease in heart rate and increased pulse rate in guinea pigs, along with genotoxicity as well as lethal toxicity in mice (Biswas et al., 2002). Therefore, critical evaluation of each fraction of neem leaves with potential cytotoxic properties is imperative. Such an analysis will not only facilitate a complete understanding of the mechanistic pathway involved but will also aid in preventing toxicity issues associated with neem leaves.
Monitoring Apoptosis and Anticancer Drug Activity in Single Cells Using Nanosensors
Published in Tuan Vo-Dinh, Nanotechnology in Biology and Medicine, 2017
There are two main pathways by which apoptosis can occur leading to cell death. The first one, the death receptor pathway, involves the interaction of a death receptor, such as the TNF receptor-1 or the Fas receptor with its ligand, and the second one, the mitochondrial pathway, involves physically compromised mitochondria, proapoptotic, and antiapoptotic members of the Bcl-2 family. The end result of both pathways is caspase activation and the cleavage of specific cellular substrates, resulting in the biochemical and morphologic changes associated with the apoptotic phenotype [9]. Keeping in mind that apoptosis is important in the development of disease and disease states, and that there was a limitation in the tools available to analyze the causative relationships in apoptosis at the single cell level, we developed a nanotechnology-based tool, optical nanosensor, and demonstrated, as a proof of principle, its practical application for single living cell analysis. Since apoptosis is a morphological process preceded by biochemical events, the optical nanosenor was used to analyze biochemical events that preceded the morphological process. Human mammary carcinoma (MCF-7) cells were exposed to a PDT drug, δ-aminolevulinic acid (ALA), to trigger the mitochondrial pathway of apoptosis. When activated using the appropriate wavelength, ALA leads to the production of ROS, which compromises mitochondrial structure and function. Upon initiation of the mitochondrial pathway of apoptosis, cytochrome c is released from mitochondria into the cytosol. In the cytosol, cytochrome c interacts with apoptotic protease activating factor-1 (Apaf-1) [10]. The cytochrome c/Apaf-1 complex cleaves the inactive caspase-9 proenzyme to generate active caspase-9 enzyme [11]. Activated caspase-9 exhibits distinct substrate recognition properties and initiates the proteolytic activities of other downstream caspases, which degrade a variety of substrates, resulting in the systematic disintegration of the cell [12–14] and ultimately, cell death. As the sequence of the mitochondrial pathway of apoptosis progresses, the proapoptotic member's cytochrome c, caspase-9, and caspase-7 can be detected and identified.
Synthesis, crystal structures and anti-cancer mechanism of Cu(II) complex derived from 2-acetylpyrazine thiosemicarbazone
Published in Journal of Coordination Chemistry, 2022
Yunyun Zheng, Bin Li, Yu Ai, Mengyao Chen, Xinhua Zheng, Jinxu Qi
Studies have shown that the mitochondrial membrane potential drops and Cyt C is released into the cytosol to induce cell apoptosis. Cyt C combines with apoptosis-related factor 1 (apaf-1) to form a polymer that promotes caspase-9 to combine with it and form apoptotic bodies. Caspase-9 is activated, which further activates other caspases, such as caspase-7, thus inducing apoptosis [51, 52]. Therefore, it is necessary to study the effect of the Cu(II) complex on the apoptosis of A549 cells. After being exposed to 2 μM of L4 and 4a for 24 h, the A549 cells were stained with Annexin V-FITC and propidium iodide (PI) and were analyzed using flow cytometry. After the A549 cells were exposed to 2 μΜ of L4 and 4a for 24 h, the apoptosis percentages were 8.49%, 12.6%, 67.1% and 37.3%, respectively, as shown in Figure 5.
Chlorogenic acid potentiates antitumor effect of doxorubicin through upregulation of death receptors in solid Ehrlich carcinoma model in mice
Published in Egyptian Journal of Basic and Applied Sciences, 2019
Nesma A. Abd Elrazik, Mohamed El-Mesery, Amro El-Karef, Laila A. Eissa, Amal M El Gayar
The Bcl-2 gene family which includes anti-apoptotic Bcl-2 is significant in the regulation of cell apoptosis [37]. Here, we found that Bcl-2 gene expression in tumor tissue was reduced by CGA. In addition, the combination of CGA and DOX significantly decreased the Bcl-2 gene expression level in comparison with each treatment alone. Thus, the reduction in gene expression of Bcl-2 leads to disruption of mitochondrial outer membrane permeability and the release of cytochrome-c into the cytoplasm. Cytochrome-c triggers the formation of apoptosome by binding to apoptosis protease activating factor-1 (Apaf-1) and pro-caspase-9, allowing the release of caspase-9. This process in turn activates downstream executor caspases-3, caspase-6 and caspase-7 [38,39].
Hesperetin upregulates Fas/FasL expression and potentiates the antitumor effect of 5-fluorouracil in rat model of hepatocellular carcinoma
Published in Egyptian Journal of Basic and Applied Sciences, 2020
Merna G. Aboismaiel, Mohamed El-Mesery, Amro El-Karef, Mamdouh M. El-Shishtawy
Both down-regulation of anti-apoptotic proteins such as Bcl-2 and Bcl-XL along with activation of pro-apoptotic proteins such as Bcl-2-associated X protein (Bax) and Bcl-2-antagonist killer protein (Bak) by tBid results in development of pores in the outer membrane of the mitochondria and discharge of cytochrome c to the cytoplasm. Cytochrome c mediates the formation of cytochrome c/Apoptotic protease activating factor-1 (Apaf-1)/caspase-9 apoptosome complex. Consequently, caspase-9 is activated which triggers caspase-3 activation, eventually resulting in apoptosis [35,36].