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Apoptosis

As one of the cellular death mechanisms, apoptosis, also known as programmed cell death, can be defined as the process of a proper death of any cell under certain or necessary conditions. Apoptosis is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body.

Many biochemical events and a series of morphological changes occur at the early stage and increasingly continue till the end of apoptosis process. Morphological event cascade including cytoplasmic filament aggregation, nuclear condensation, cellular fragmentation, and plasma membrane blebbing finally results in the formation of apoptotic bodies. Several biochemical changes such as protein modifications/degradations, DNA and chromatin deteriorations, and synthesis of cell surface markers form morphological process during apoptosis.

Apoptosis can be stimulated by two different pathways: (1) intrinsic pathway (or mitochondria pathway) that mainly occurs via release of cytochrome c from the mitochondria and (2) extrinsic pathway when Fas death receptor is activated by a signal coming from the outside of the cell.

Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis.

Caspase family comprises conserved cysteine aspartic-specific proteases, and members of caspase family are considerably crucial in the regulation of apoptosis. There are 14 different caspases in mammals, and they are basically classified as the initiators including caspase-2, -8, -9, and -10; and the effectors including caspase-3, -6, -7, and -14; and also the cytokine activators including caspase-1, -4, -5, -11, -12, and -13. In vertebrates, caspase-dependent apoptosis occurs through two main interconnected pathways which are intrinsic and extrinsic pathways. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP, and caspase-9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/TRADD), to recruitment, dimerization, and activation of caspase-8 (or 10). Active caspase-8 (or 10) then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. In a heat shock-induced death, caspase-2 induces apoptosis via cleavage of Bid.

Bcl-2 family members are divided into three subfamilies including (i) pro-survival subfamily members (Bcl-2, Bcl-xl, Bcl-W, MCL1, and BFL1/A1), (ii) BH3-only subfamily members (Bad, Bim, Noxa, and Puma9), and (iii) pro-apoptotic mediator subfamily members (Bax and Bak). Following activation of the intrinsic pathway by cellular stress, pro‑apoptotic BCL‑2 homology 3 (BH3)‑only proteins inhibit the anti‑apoptotic proteins Bcl‑2, Bcl-xl, Bcl‑W and MCL1. The subsequent activation and oligomerization of the Bak and Bax result in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and SMAC from the mitochondria. Cytochrome c forms a complex with caspase-9 and APAF1, which leads to the activation of caspase-9. Caspase-9 then activates caspase-3 and caspase-7, resulting in cell death. Inhibition of this process by anti‑apoptotic Bcl‑2 proteins occurs via sequestration of pro‑apoptotic proteins through binding to their BH3 motifs.

One of the most important ways of triggering apoptosis is mediated through death receptors (DRs), which are classified in TNF superfamily. There exist six DRs: DR1 (also called TNFR1); DR2 (also called Fas); DR3, to which VEGI binds; DR4 and DR5, to which TRAIL binds; and DR6, no ligand has yet been identified that binds to DR6. The induction of apoptosis by TNF ligands is initiated by binding to their specific DRs, such as TNFα/TNFR1, FasL /Fas (CD95, DR2), TRAIL (Apo2L)/DR4 (TRAIL-R1) or DR5 (TRAIL-R2). When TNF-α binds to TNFR1, it recruits a protein called TNFR-associated death domain (TRADD) through its death domain (DD). TRADD then recruits a protein called Fas-associated protein with death domain (FADD), which then sequentially activates caspase-8 and caspase-3, and thus apoptosis. Alternatively, TNF-α can activate mitochondria to sequentially release ROS, cytochrome c, and Bax, leading to activation of caspase-9 and caspase-3 and thus apoptosis. Some of the miRNAs can inhibit apoptosis by targeting the death-receptor pathway including miR-21, miR-24, and miR-200c.

p53 has the ability to activate intrinsic and extrinsic pathways of apoptosis by inducing transcription of several proteins like Puma, Bid, Bax, TRAIL-R2, and CD95.

Some inhibitors of apoptosis proteins (IAPs) can inhibit apoptosis indirectly (such as cIAP1/BIRC2, cIAP2/BIRC3) or inhibit caspase directly, such as XIAP/BIRC4 (inhibits caspase-3, -7, -9), and Bruce/BIRC6 (inhibits caspase-3, -6, -7, -8, -9). 

Any alterations or abnormalities occurring in apoptotic processes contribute to development of human diseases and malignancies especially cancer.

 

References:

1.Yağmur Kiraz, Aysun Adan, Melis Kartal Yandim, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biology, 2016, 37(7):8471.

2.Aggarwal B B, Gupta S C, Kim J H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.[J]. Blood, 2012, 119(3):651.

3.Ashkenazi A, Fairbrother W J, Leverson J D, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors[J]. Nature Reviews Drug Discovery, 2017.

4.McIlwain D R, Berger T, Mak T W. Caspase functions in cell death and disease[J]. Cold Spring Harbor perspectives in biology, 2013, 5(4): a008656.

5.Ola M S, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J]. Molecular and cellular biochemistry, 2011, 351(1-2): 41-58.

Products for  Apoptosis

  1. Cat.No. Product Name Information
  2. GC41183 α-Carotene α-Carotene is a precursor of vitamin A that has been found in various fruits and vegetables.
  3. GC45204 α-Ecdysone

    α-Ecdysone is a prohormone of 20-hydroxy ecdysone, an insect-molting, ecdysteroid hormone.

  4. GC45213 α-NETA Choline acetyltransferase (ChAT) mediates the synthesis of the neurotransmitter acetylcholine from acetyl-CoA and choline.
  5. GC41623 β-Elemonic Acid β-Elemonic acid is a triterpene isolated from Boswellia (Burseraceae) that exhibits anticancer activity.
  6. GC46008 (±)-Thalidomide-d4
  7. GC18516 (+)-Aeroplysinin-1 (+)-Aeroplysinin-1 is a metabolite originally isolated from the marine sponge V.
  8. GC17008 (+)-Apogossypol

    inhibitor of Bcl-2 family proteins

  9. GC45256 (+)-ar-Turmerone (+)-ar-Turmerone is an aromatic compound from the rhizomes of C.
  10. GN10654 (+)-Corynoline Extracted from corydalis sheareri S. Moore;Store the product in sealed,cool and dry condition
  11. GC31691 (+)-DHMEQ ((1R,2R,6R)-Dehydroxymethylepoxyquinomicin) (+)-DHMEQ是一种抗氧化转录因子Nrf2的激活剂。(+)-DHMEQ是(-)-DHMEQ的对映体。(+)-DHMEQ抑制NF-kB的活性低于(-)-DHMEQ。
  12. GC45274 (+)-Pinoresinol  
  13. GC41345 (-)-α-Bisabolol (-)-α-Bisabolol is a sesquiterpene alcohol that has been found in the essential oils of several aromatic plants, including C.
  14. GC11965 (-)-Huperzine A NMDA receptor antagonist/AChE inhibitor
  15. GC40698 (-)-Perillyl Alcohol (-)-Perillyl alcohol is a monoterpene alcohol that has been found in lavender essential oil and has diverse biological activities.
  16. GC34965 (20S)-Protopanaxatriol (20S)-Protopanaxatriol 是人参皂苷的代谢物,通过 glucocorticoid receptor 和 oestrogen receptor 起作用,同时为 LXRα 的抑制剂。
  17. GC60397 (5Z,2E)-CU-3 (5Z,2E)-CU-3是一种有效的选择性抗DGKα同工酶抑制剂,IC50值为0.6μM,竞争性抑制DGKα对ATP的亲和力,Km值为0.48mM。(5Z,2E)-CU-3靶向DGKα催化区域,但不靶向调节区域。(5Z,2E)-CU-3具有抗肿瘤和免疫原性作用,增强癌细胞的凋亡和T细胞的活化。
  18. GC60398 (6R)-FR054 (6R)-FR054是FR054的一个活性异构体。FR054是HBP酶PGM3的抑制剂,具有显著的抗乳腺癌活性。FR054可诱导内质网应激和ROS依赖的细胞凋亡。
  19. GC50482 (D)-PPA 1 PD-1/PD-L1 interaction inhibitor
  20. GA20156 (D-Ser(tBu)⁶,Azagly¹⁰)-LHRH (free base)
  21. GC34980 (E)-Ferulic acid (E)-Ferulic acid 是阿魏酸 (Ferulic acid) 的异构体,阿魏酸是芳香族化合物,在植物细胞壁中丰富。 (E)-Ferulic acid 引起 β-连环蛋白 (β-catenin) 的磷酸化,导致蛋白酶体降解,增加促凋亡因子 Bax 的表达并降低促存活因子存活蛋白的表达。(E)-Ferulic acid 可以有效去除活性氧 (ROS) 和抑制脂质过氧化。(E)-Ferulic acid 在人肺癌细胞系 H1299 中发挥抗增殖和抗迁移作用。

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