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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The BCL-2 family of proteins can either inhibit or promote apoptosis, and members are characterized by the BCL-2 homologous domains BH1, BH2, BH3, and BH4. The combinations of the different domains in the proteins determine their roles in the apoptosis process. Members of the family that inhibit apoptosis include BCL-2 itself, BCL-XL, and BCL-w, which possess all four of the domains. BCL-2 is the most well known of the antiapoptotic proteins, and is classified as an oncogene. Studies have shown that the BCL-2 oncogene may inhibit apoptosis in two ways, either by disrupting the channels that allow pro-apoptotic factors to leave the mitochondria or by directly controlling the activation of caspases. Over-expression of the pro-survival BCL-2 family members (e.g., BCL-2, BCL-XL, and MCL-1) is often associated with tumor maintenance, progression, and chemoresistance.
Apoptosis of Biliary Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Natalie J. Török, Gregory J. Gores
The members of the Bcl-2 family of proteins play major role in regulation of apoptosis. Bcl-2, the prototype of this family is known to inhibit apoptosis by preventing cytochrome-c release from the mitochondria thereby preventing caspase 3 activation. Bcl-2 was shown to be expressed by bile ductules and small bile duct epithelium, but not large bile duct epithelium.20,21 Expression of Bax, Mcl-1 and Bcl-XL was also detected in cholangiocytes isolated from normal livers and immortalized by SV-40.22 However, expression of Bak, Bcl-XS was not detected.
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
An intrinsic pathway is initiated in response to cell stress caused by DNA damage or growth factor deficiency. It is mediated by changes in permeability of the mitochondrial outer membrane which is regulated through interactions between pro- and anti-apoptotic members of the Bcl-2 family of proteins. This results in release of mitochondrial factors, most importantly cytochrome C, leading to loss of mitochondrial functions and initiation of a cascade of caspase protease activities and cell death, reviewed in Elmore (50); Noy (51); Tait and Green (52).
Grape seed extract proanthocyanidin antagonizes aristolochic acid I-induced liver injury in rats by activating PI3K-AKT pathway
Published in Toxicology Mechanisms and Methods, 2023
Shuang Wang, Zhihui Liu, Yao Wang, Bendong Shi, Yinzhu Jin, Yu Wang, Xiaowen Jiang, Mingxin Song, Wenhui Yu
Bcl-2 family proteins play an important regulatory role in a series of responses to apoptosis. They can be divided into two types of proteins with opposite functions: promoting apoptosis and inhibiting apoptosis. After the expression of Bax and Bcl-2 is unbalanced (Shen et al. 2022), Promote the release of excess cytochrome c from mitochondria, further activate the downstream apoptosis executor Caspase-3, and then start the caspase cascade reaction, and the cell will irreversibly undergo the process of apoptosis (Chawla-Sarkar et al. 2001; Chen et al. 2022). PI3K exists in most cells. After its signal pathway is activated, it catalyzes PIP2 to produce PIP3, which further activates the downstream of PI3K as a second messenger (Karar and Maity 2011), AKT is a downstream protein of PI3K. After phosphorylation, AKT can activate the downstream target protein Bcl-2 family, inhibit the activation of caspase-3, and achieve the purpose of anti-apoptosis (Tischner et al. 2010; Ma et al. 2021), studies have shown that when AKT activity is inhibited, the body will be more prone to oxidative stress damage (Lien et al. 2016). The results showed that GSPE could activate the PI3K-AKT pathway, inhibit the high expression of Bax, caspase-3 and caspase-9 induced by AA-I, and activate the expression of the Bcl-2 anti-apoptotic gene. Combined with the TUNEL staining results of liver tissue, GSPE can reduce the number of apoptosis-positive cells caused by AA-I, indicating that GSPE may inhibit the apoptosis pathway of liver cells by activating the PI3K-AKT pathway, and then improve the liver injury caused by AA-I.
Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease
Published in Drug Delivery, 2022
Jiao Wang, Liang Kong, Rui-Bo Guo, Si-Yu He, Xin-Ze Liu, Lu Zhang, Yang Liu, Yang Yu, Xue-Tao Li, Lan Cheng
As we all know, Aβ1–42 induces oxidative stress and neuroinflammation that results in DNA damage and caspase-dependent neuronal apoptosis, which plays a crucial part in neurodegeneration (Fang et al., 2018). Hence, alleviating the apoptosis may be a possible treatment for AD. The mitochondrial pathway is the main process of inducing apoptosis, mainly mediated by Bcl-2 family and caspase. The Bcl-2 family consists of pro-apoptotic proteins (Bax, Bad, and Bak) and anti-apoptotic proteins (Bcl-2 and Bcl-XL) (Pahrudin Arrozi et al., 2020). Bax can increase mitochondrial permeability, release pro-apoptotic factors, and inhibit anti-apoptotic Bcl-2 family proteins to trigger caspase signaling, leading to neuronal apoptosis (Lu et al., 2021). In order to evaluate the inhibitory effect of varying formulations on nerve cell apoptosis in vivo, the paraffin sections of brain tissue treated with free ICA/TSIIA, ICA/TSIIA liposomes or Ang2-ICA/TSIIA liposomes were stained by immunohistochemistry. The expression of Bax and caspase-3 was significantly increased, while Bcl-2 is not expressed or at a low level in the hippocampus and cortex of APP/PS1 mice. After Ang2-ICA/TSIIA liposomes treatment, the expression of Bax and caspase-3 was significantly decreased, while the expression of Bcl-2 was significantly increased (Figure 8(A–C)). These results indicated that Ang2-ICA/TSIIA liposomes could inhibit neuronal apoptosis in AD mice.
The Phytochemical Profile and Biological Activity of Liquidambar orientalis Mill. var. orientalis via NF-κB and Apoptotic Pathways in Human Colorectal Cancer
Published in Nutrition and Cancer, 2022
Sümeyra Çetinkaya, İlknur Çınar Ayan, İpek Süntar, Hatice Gül Dursun
It is clear that the promotion of apoptosis is one the most effective weapons in the fight against cancer. As a matter of fact, immune system cells destroy cancer cells by triggering apoptosis. Most chemotherapeutic agents also active apoptosis to prevent tumor proliferation. In addition, the presence of mutations in genes regulating apoptosis pathways such as p53 and Bcl-2 family members in most human cancers reveals the importance of apoptosis in the process of carcinogenesis (44). In our study, we performed TUNEL assay and flow cytometry analysis to confirm the effects of LM extract on apoptosis. TUNEL assay showed that the ratio of apoptosis in LM-treated cells in both cell lines was much higher than controls and 5-FU-treated cells. In HCT-116 cell line, the apoptotic percentages of colorimetric TUNEL test were 5.11 ± 1.57 in the control group, 30.58 ± 3.60 in extract-treated and 8.37 ± 1.73 in 5-FU-treated. On the other hand, the apoptotic percentages of control, extract-treated and 5-FU-treated were 3.47 ± 0.57, 21.56 ± 4.16 and 11.02 ± 1.25 in HT-29 cell line, respectively (p < 0.05) (Figure 3).