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Apoptosis(凋亡)

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. 产品名称 Information
  2. GC26092 Z-LEHD-FMK TFA Z-LEHD-FMK TFA (Caspase-9 Inhibitor) is a cell-permeable, competitive and irreversible inhibitor of enzyme caspase-9, which helps in cell survival.
  3. GC25743 PIM447 (LGH447) PIM447 (LGH447) is a novel pan-PIM kinase inhibitor with Ki values of 6 pM, 18 pM, 9 pM for PIM1, PIM2, PIM3 respectively. It also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). PIM447 induces apoptosis.
  4. GC25691 OTS514 hydrochloride OTS514 is a highly potent TOPK(T-LAK cell-originated protein kinase) inhibitor with an IC50 value of 2.6 nM. OTS514 induces cell cycle arrest and apoptosis.
  5. GC25673 Obatoclax (GX15-070) Obatoclax (GX15-070) is an antagonist of Bcl-2 with an Ki of 0
  6. GC25428 Foscenvivint (ICG-001) Foscenvivint (ICG-001) antagonizes Wnt/β-catenin/TCF-mediated transcription and specifically binds to CREB-binding protein (CBP) with IC50 of 3 μM, but is not the related transcriptional coactivator p300. ICG-001 induces apoptosis.
  7. GC25351 Dimethyl itaconate Dimethyl itaconate can reprogram neurotoxic to neuroprotective primary astrocytes through the regulation of LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome and nuclear factor 2/heme oxygenase-1 (NRF2/HO-1) pathways.
  8. GC25160 BMS-1001 BMS-1001 is a potent inhibitor of PD-1/PD-L1 interaction with EC50 of 253 nM. BMS-1001 alleviates the inhibitory effect of the soluble PD-L1 on the T-cell receptor-mediated activation of T-lymphocytes.
  9. GC67969 RIP1/RIP3/MLKL activator 1
  10. GC67966 Methylstat
  11. GC67936 Lupiwighteone
  12. GC67792 NSC49652
  13. GC67765 p53 Activator 5
  14. GC67694 PD-1/PD-L1-IN-9 hydrochloride
  15. GC67680 BIO8898
  16. GC52516 Erbstatin A tyrosine kinase inhibitor
  17. GC52489 Ceramide (hydroxy) (bovine spinal cord) A sphingolipid
  18. GC52486 Ceramide Phosphoethanolamine (bovine) A sphingolipid
  19. GC52485 Ceramide (non-hydroxy) (bovine spinal cord) A sphingolipid
  20. GC52476 Bax Inhibitor Peptide V5 (trifluoroacetate salt) A Bax inhibitor
  21. GC52472 Inostamycin A (sodium salt) A bacterial metabolite with anticancer activity
  22. GC52469 CL2A-SN-38 (dichloroacetic acid salt) An antibody-drug conjugate containing SN-38
  23. GC52467 Cell Death Screening Library For screening a variety of cell death pathways
  24. GC52455 Pixantrone-d8 (maleate) An internal standard for the quantification of pixantrone
  25. GC52372 Ac-VDVAD-AFC (trifluoroacetate salt) A fluorogenic substrate for caspase-2
  26. GC52371 Vimentin (G146R) (139-159)-biotin Peptide A biotinylated mutant vimentin peptide
  27. GC52370 Citrullinated Vimentin (R144) (139-159)-biotin Peptide A biotinylated and citrullinated vimentin peptide
  28. GC52367 Citrullinated Vimentin (G146R) (R144 + R146) (139-159)-biotin Peptide A biotinylated and citrullinated mutant vimentin peptide
  29. GC52364 Vimentin (139-159)-biotin Peptide A biotinylated vimentin peptide
  30. GC52358 Malachite Green (chloride) A triphenylmethane dye
  31. GC52355 BimS BH3 (51-76) (human) (trifluoroacetate salt) A Bim-derived peptide
  32. GC52344 Bak BH3 (72-87) (human) (trifluoroacetate salt) A Bak-derived peptide
  33. GC52325 MeTC7 A vitamin D receptor antagonist
  34. GC52318 Oleic Acid-13C5 An internal standard for the quantification of oleic acid
  35. GC52293 STAT3 Inhibitor 4m A STAT3 inhibitor
  36. GC52291 KAS 08 A STING activator
  37. GC52288 Fumonisin B1-13C34 An internal standard for the quantification of fumonisin B1
  38. GC52269 Cinnabarinic Acid-d4 An internal standard for the quantification of cinnabarinic acid
  39. GC52250 Mevalonate (lithium salt) An intermediate in the mevalonate pathway
  40. GC52245 CAY10792 An anticancer agent
  41. GC52227 5-(3',4'-Dihydroxyphenyl)-γ-Valerolactone An active metabolite of various polyphenols
  42. GC67618 α-Tocopherol phosphate disodium
  43. GC67272 N6-Benzyladenosine DNPH1i (N6-benzyladenosine,BAPR) is a competitive inhibitor of adenosine deaminase(ADA) from L-1210 cells in axenic culture as well as a potent antiproliferative agent in vitro and in vivo.
  44. GC66824 D-α-Tocopherol Succinate
  45. GC66479 GSK2593074A
  46. GC66462 MGH-CP1 MGH-CP1 is a potent and selective inhibitor of transcriptional enhanced associate domain (TEAD) palmitoylation. MGH-CP1 exhibits dose-dependent and potent inhibition of TEAD2/4 auto-palmitoylation in vitro with IC50 of 710 nM and 672 nM, respectively.
  47. GC66460 UCB-5307
  48. GC66403 Z-DEVD-AMC
  49. GC66394 Penpulimab
  50. GC66382 Lucatumumab
  51. GC66378 Serplulimab

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