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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. GC68757 BH3 hydrochloride BH3 hydrochloride 是能透过血脑屏障的多肽,通过直接激活促凋亡 Bax/Bak 或通过中和抗凋亡 Bcl-2 蛋白 (Bcl-2、Bcl-XL、Bcl-w、mcl1和A-1)来诱导细胞凋亡,通过与BH3 结构域结合。
  3. GC68744 BC-?1258 BC-1258 是一种 F-box/LRR-重复蛋白 2 (FBXL2) 激活剂,可以稳定和上调 FBXL2 水平。BC-1258 诱导致瘤细胞凋亡,并显着抑制小鼠的肿瘤形成。
  4. GC68729 Bax activator-1 Bax activator-1 (compound 106) 是一种 Bax 激活剂,诱导 Bax 依赖性肿瘤细胞凋亡。
  5. GC68700 ASR-488 ASR-488 可激活 mRNA 结合蛋白 CPEB1,诱导细胞凋亡 (apoptosis) 并抑制膀胱癌的生长。
  6. GC68632 AK-778-XXMU AK-778-XXMU是DNA结合2 (ID2) 拮抗剂的有效抑制剂,KD为129 nM。AK-778-XXMU 能抑制胶质瘤细胞株的迁移和侵袭,诱导细胞凋亡 (apoptosis),更重要的是能减缓肿瘤生长。
  7. GC68621 Ac-WEHD-AFC TFA Ac-WEHD-AFC TFA 是一种荧光 caspase-1 底物。Ac-WEHD-AFC TFA 可检测 caspase-1 荧光活性,用于肿瘤和炎症的研究。
  8. GC68600 Ac-DEVD-CMK TFA Ac-DEVD-CMK (Caspase-3 Inhibitor III) TFA 是一种选择性且不可逆的 caspase-3 抑制剂。Ac-DEVD-CMK TFA 显着抑制由高水平葡萄糖或 3,20-dibenzoate (IDB; 5) 诱导的凋亡。Ac-DEVD-CMK TFA 可以用于多种实验方法以抑制细胞凋亡。
  9. GC68562 5-Aminolevulinic acid-13C-1 hydrochloride 5-Aminolevulinic acid-13C-1 (5-ALA-13C-1) hydrochloride 是 13C 标记的 5-Aminolevulinic acid hydrochloride。5-Aminolevulinic acid hydrochloride (5-ALA hydrochloride) 是体内血红素生物合成的中间体,为四吡咯的前体。
  10. GC68537 3-IN-PP1 3-IN-PP1 是一种蛋白激酶 D (PKD) 抑制剂。 3-IN-PP1 对 PKD1、PKD2 和 PKD3 具有有效广泛的 PKD 抑制活性, IC50 值分别为 108、94 和 108 nM。3-IN-PP1 也是一种广谱抗癌剂,对多种肿瘤细胞的生长有抑制作用。3-IN-PP1 可用于癌症研究。
  11. 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.
  12. 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.
  13. 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.
  14. GC25673 Obatoclax (GX15-070)

    Obatoclax (GX15-070) is an antagonist of Bcl-2 with an Ki of 0

  15. 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.
  16. 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.
  17. 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.
  18. GC68470 SPD304 dihydrochloride SPD304 dihydrochloride 是肿瘤坏死因子 α (TNF-α) 的选择性抑制剂,能够促进肿瘤坏死因子三聚体的分离,从而阻断其与受体间的相互作用。SPD304 体外抑制肿瘤坏死因子 α 和受体 1 间结合的 IC50 值为 22 µM。
  19. GC68452 2,4,6-Triiodophenol 2,4,6-Triiodophenol 是一种具有口服活性的、强效的 leukotriene B4 (LTB4) 合成抑制剂。2,4,6-Triiodophenol 可诱导小鼠囊胚凋亡。
  20. GC68404 Human PD-L1 inhibitor IV Human PD-L1 inhibitor IV 是一种竞争性的 human PD-1 protein 抑制剂,Kd 值为 1.38 μM,可抑制人 PD-1/PD-L1 的结合。
  21. GC68388 XIAP degrader-1 XIAP degrader-1 是一种伯胺小分子,可促进X-连锁凋亡抑制蛋白(XIAP)的降解。
  22. GC68385 TNF-α-IN-6 TNF-α-IN-6 是一种口服有效的 TNFα 的变构抑制剂(KD = 6.8 nM)。
  23. GC68371 Mutant p53 modulator-1 Mutant p53 modulator-1 是一种突变型 p53 调节剂。Mutant p53 modulator-1 可减少含有 p53 突变的癌症的进展 (摘自专利 WO2021231474A1,化合物 231B)。
  24. GC68369 Belantamab Belantamab (GSK2857914) 是一种人源化 IgG1 抗 BCMA (TNFRSF17) 单克隆抗体。Belantamab 可用于合成抗体-药物偶联物 (ADC),Belantamab mafodotin。
  25. GC68308 Bisdemethoxycurcumin-d8 Bisdemethoxycurcumin-d8 (Curcumin III-d8) 是 Bisdemethoxycurcumin 的氘代物。Bisdemethoxycurcumin 是姜黄素衍生物,具有抗炎症和抗癌活性。
  26. GC68306 Deoxynyboquinone Deoxynyboquinone 是 NQO1 的底物,是有效的抗癌剂。Deoxynyboquinone 诱导癌症细胞凋亡 (Apoptosis)。Deoxynyboquinone 通过氧化应激和活性氧 (ROS) 的形成杀死癌细胞。
  27. GC68305 Dacetuzumab Dacetuzumab (SGN-40) 是一种人源化的 IgG1,抗 CD40单克隆抗体,具有抗淋巴瘤活性。Dacetuzumab 通过免疫效应作用(抗体依赖性细胞毒性和吞噬作用[ADCC/ADCP]) 杀死肿瘤细胞。Dacetuzumab ((SGN-40) 可用于多发性骨髓瘤研究。
  28. GC68288 Brentuximab Brentuximab 是靶向 CD30 的嵌合抗体。Brentuximab 可用于新兴靶向疗法的研究。
  29. GC68231 4-Methylsalicylic acid 4-Methylsalicylic acid 是一种水杨酸。其衍生物是一种选择性的组织-非特异性碱性磷酸酶 (TNAP) 和肠道碱性磷酸酶 (IAP) 抑制剂。
  30. GC68213 MitoBloCK-6 MitoBloCK-6 是一种有效的 Erv1/ALR 抑制剂,IC50 分别为 900 nM 和 700 nM。MitoBloCK-6 还抑制 Erv2 (IC50=1.4 μM)。MitoBloCK-6 可通过细胞色素 c 的释放诱导 hESCs 细胞凋亡。
  31. GC68051 Citric acid-d4 Citric acid-d4 是 Citric acid 的氘代物。Citric acid 是柑橘类水果中发现的弱有机三羧酸。柠檬酸是天然防腐剂和食品添加剂。
  32. GC68043 2-tert-Butyl-1,4-benzoquinone 2-tert-Butyl-1,4-benzoquinone 是 butylated hydroxyanisole 的亲电代谢产物,是 2-tert-butylhydroquinone 的氧化产物。
  33. GC68019 NPB NPB 是一种特异且有效的抑制 BAD Ser99 磷酸化的抑制剂, IC50 值为 0.41 μM。
  34. GC68012 BCL6-IN-7 BCL6-IN-7 是一种有效的 BCL6-corepressor 相互作用抑制剂。
  35. GC67969 RIP1/RIP3/MLKL activator 1 RIP1/RIP3/MLKL activator 1 (Compound 6i) 是一种有效的抗胶质瘤 (anti-glioma) 药物。RIP1/RIP3/MLKL activator 1 通过激活 RIP1/RIP3/MLKL 通路诱导细胞坏死 (Necroptosis)。 RIP1/RIP3/MLKL activator 1 可透过血脑屏障。
  36. GC67966 Methylstat Methylstat 是一种有效的组蛋白去甲基化酶 (histone demethylases) 抑制剂。Methylstat 具有抗增殖活性,低细胞毒性。Methylstat 诱导细胞凋亡 (Apoptosis) 和细胞周期停滞在 G0/G1 期。Methylstat 增加 p53 和 p21 蛋白水平的表达。Methylstat 抑制由各种细胞因子诱导的血管生成。Methylstat 可用作化学探针以解决其在血管生成中的作用。
  37. GC67936 Lupiwighteone Lupiwighteone 是一种广泛存在于野生植物中的异黄酮,具有抗氧化、抗菌和抗癌作用。Lupiwighteone 通过抑制 PI3K/Akt/mTOR 通路,诱导人乳腺癌细胞 caspase 依赖性和非依赖性凋亡 (Apoptosis)。
  38. GC67792 NSC49652 NSC49652 是一种可逆的、具有口服活性的 p75 neurotrophin receptor (p75NTR,也被称为 NGFR、TNFRSF16 和 CD271) 抑制剂。 NSC49652 作用于 p75NTR 的跨膜结构域。 NSC49652 诱导凋亡(Apoptosis),影响黑色素瘤细胞活力。
  39. GC67765 p53 Activator 5

    p53 Activator 5 (compound 134A) 是一种有效的 p53 激活剂,SC150 值 <0.05 mM。p53 Activator 5 可以结合突变体 p53 并恢复 p53 突变体结合 DNA 的能力。p53 Activator 5 具有抗肿瘤活性。

  40. GC67694 PD-1/PD-L1-IN-9 hydrochloride PD-1/PD-L1-IN-9 盐酸盐是一种有效和具有口服活性的 PD-1/PD-L1 相互作用抑制剂,IC50 值为 3.8 nM。PD-1/PD-L1-IN-9 盐酸盐可以增强免疫细胞对肿瘤细胞的杀伤活性。PD-1/PD-L1-IN-9 盐酸盐在 CT26 小鼠模型中表现出显着的体内抗肿瘤活性。
  41. GC67680 BIO8898 BIO8898 是一种有效的 CD40-CD154 抑制剂。BIO8898 抑制可溶性 CD40L 与 CD40-Ig 的结合,IC50 值为 25 µM。BIO8898 抑制 CD40L 诱导的细胞凋亡(Apoptosis)。
  42. GC52516 Erbstatin A tyrosine kinase inhibitor
  43. GC52489 Ceramide (hydroxy) (bovine spinal cord) A sphingolipid
  44. GC52486 Ceramide Phosphoethanolamine (bovine) A sphingolipid
  45. GC52485 Ceramide (non-hydroxy) (bovine spinal cord) A sphingolipid
  46. GC52476 Bax Inhibitor Peptide V5 (trifluoroacetate salt) A Bax inhibitor
  47. GC52472 Inostamycin A (sodium salt) A bacterial metabolite with anticancer activity
  48. GC52469 CL2A-SN-38 (dichloroacetic acid salt) An antibody-drug conjugate containing SN-38
  49. GC52455 Pixantrone-d8 (maleate) An internal standard for the quantification of pixantrone
  50. GC52372 Ac-VDVAD-AFC (trifluoroacetate salt) A fluorogenic substrate for caspase-2
  51. GC52371 Vimentin (G146R) (139-159)-biotin Peptide A biotinylated mutant vimentin peptide

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