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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. GC48292 α-MSH (human, mouse, rat, porcine, bovine, ovine) (trifluoroacetate salt)
  5. GC45213 α-NETA Choline acetyltransferase (ChAT) mediates the synthesis of the neurotransmitter acetylcholine from acetyl-CoA and choline.
  6. GC41499 α-Phellandrene α-Phellandrene is a cyclic monoterpene that has been found in various plants, including Cannabis, and has diverse biological activities.
  7. GC63941 α-Solanine α-solanine 是马铃薯中的一种生物活性成分,是主要的甾体类生物碱之一,可抑制癌细胞的生长并诱导其凋亡 (apoptosis)。
  8. GC48920 β-Carboline-1-carboxylic Acid
  9. GC41623 β-Elemonic Acid β-Elemonic acid is a triterpene isolated from Boswellia (Burseraceae) that exhibits anticancer activity.
  10. GC62478 Ζ-Stat ζ-Stat (NSC37044) 是一种特异且非典型的 PKC-ζ 的抑制剂,IC50 值为 5 μM。ζ-Stat 可以减少黑色素瘤细胞系的增殖并诱导细胞凋亡,在体外具有抗肿瘤活性。
  11. GC46008 (±)-Thalidomide-d4
  12. GC45618 (±)-trans-GK563
  13. GC45270 (±)10(11)-EDP Ethanolamide (±)10(11)-EDP ethanolamide is an ω-3 endocannabinoid epoxide and cannabinoid (CB) receptor agonist (EC50s = 0.43 and 22.5 nM for CB1 and CB2 receptors, respectively).
  14. GC49268 (+)-δ-Cadinene A sesquiterpene with antimicrobial and anticancer activities
  15. GC18516 (+)-Aeroplysinin-1 (+)-Aeroplysinin-1 is a metabolite originally isolated from the marine sponge V.
  16. GC17008 (+)-Apogossypol

    inhibitor of Bcl-2 family proteins

  17. GC45256 (+)-ar-Turmerone (+)-ar-Turmerone is an aromatic compound from the rhizomes of C.
  18. GN10654 (+)-Corynoline Extracted from corydalis sheareri S. Moore;Store the product in sealed,cool and dry condition
  19. 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。
  20. GC45265 (+)-Goniothalesdiol (+)-Goniothalesdiol, isolated from the bark of the Malaysian tree G.
  21. GC45274 (+)-Pinoresinol  
  22. GC18749 (+)-Rugulosin (+)-Rugulosin is a pigment and mycotoxin produced by certain fungi.
  23. GC41345 (-)-α-Bisabolol (-)-α-Bisabolol is a sesquiterpene alcohol that has been found in the essential oils of several aromatic plants, including C.
  24. GC49502 (-)-β-Sesquiphellandrene A sesquiterpene with antiviral and anticancer activities
  25. GC45244 (-)-(α)-Kainic Acid (hydrate) A potent central nervous system stimulant for induction of seizures
  26. GC45246 (-)-Chaetominine (-)-Chaetominine is a cytotoxic alkaloid originally isolated from Chaetomium sp.
  27. GC11965 (-)-Huperzine A NMDA receptor antagonist/AChE inhibitor
  28. GC40698 (-)-Perillyl Alcohol (-)-Perillyl alcohol is a monoterpene alcohol that has been found in lavender essential oil and has diverse biological activities.
  29. GC40076 (-)-Voacangarine (-)-Voacangarine is an indole alkaloid originally isolated from V.
  30. GC62193 (1S,2S)-Bortezomib (1S,2S)-Bortezomib 是 Bortezomib 的对映异构体。Bortezomib 是一种细胞渗透性、可逆性和选择性的蛋白酶体抑制剂,通过靶向苏氨酸残基有效抑制 20S 蛋白酶体 (Ki 为 0.6 nM)。Bortezomib 破坏细胞周期、诱导细胞凋亡以及抑制核因子 NF-κB。Bortezomib 是一种抗癌药物,也是第一种用于人类的蛋白酶体抑制剂。
  31. 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。
  32. 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。
  33. 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。
  34. GC50482 (D)-PPA 1 PD-1/PD-L1 interaction inhibitor
  35. GA20156 (D-Ser(tBu)⁶,Azagly¹⁰)-LHRH (free base)
  36. GC41700 (E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine (E)-2-(2-Chlorostyryl)-3,5,6-trimethylpyrazine (CSTMP) is a stilbene derivative with antioxidant and anticancer activities.
  37. GC41268 (E)-2-Hexadecenal Sphingosine-1-phosphate (S1P), a bioactive lipid involved in many signaling processes, is irreversibly degraded by the membrane-bound S1P lyase.
  38. GC41701 (E)-2-Hexadecenal Alkyne (E)-2-Hexadecenal alkyne is an alkyne version of the sphingolipid degradation product (E)-2-hexadecenal that can be used as a click chemistry probe.
  39. 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。
  40. GC34981 (E)-Flavokawain A (E)-Flavokawain A 是从卡瓦胡椒中提取的查尔酮,具有抗癌作用。(E)-Flavokawain A 通过介入 bax 蛋白依赖和线粒体依赖的凋亡通路,诱导膀胱癌细胞凋亡,抑制小鼠肿瘤生长。
  41. GC61437 (E)-Methyl 4-coumarate (E)-Methyl4-coumarate(Methyl4-hydroxycinnamate)在几种植物中发现,如葱(Alliumcepa)或noni(MorindacitrifoliaL.)叶中。(E)-Methyl4-coumarate与CarnosicAcid联用可诱导细胞凋亡,杀死急性髓性白血病细胞,但不能杀死正常的外周血单核细胞。(E)-Methyl4-coumarate具有抗氧化和抗菌活性。
  42. GC34125 (E)-[6]-Dehydroparadol (E)-[6]-Dehydroparadol来自专利US9272994化合物M15,能够抑制人体癌细胞生长并且诱导细胞凋亡。在HCT-116和H-1299细胞中的IC50值分别为43.02和41.59μM。
  43. GC49189 (E/Z)-4-hydroxy Tamoxifen-d5 An internal standard for the quantification of (E/Z)-4-hydroxy tamoxifen
  44. GN10783 (R) Ginsenoside Rh2 Extracted from Panax ginseng C. A. Mey. dried roots;Store the product in sealed, cool and dry condition
  45. GC15104 (R)-(+)-Etomoxir sodium salt carnitine palmitoyltransferase I (CPT1) inhibitor
  46. GC34096 (R)-(-)-Gossypol acetic acid (AT-101 (acetic acid)) (R)-(-)-Gossypolaceticacid(AT-101(aceticacid))是天然产物Gossypol的左旋异构体。AT-101结合到Bcl-2,Mcl-1和Bcl-xL蛋白,Ki值分别为260±30nM,170±10nM和480±40nM。
  47. GC41716 (R)-CR8 Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression and are therefore promising targets for cancer therapy.
  48. GC39281 (R)-CR8 trihydrochloride (R)-CR8 trihydrochloride (CR8 trihydrochloride) 是 Roscovitine 的第二代类似物,是一种有效的 CDK1/2/5/7/9 抑制剂。(R)-CR8 trihydrochloride 抑制 CDK1/cyclin B (IC50=0.09 μM)、CDK2/cyclin A (0.072 μM)、CDK2/cyclin E (0.041 μM)、CDK5/p25 (0.11 μM)、CDK7/cyclin H (1.1 μM)、CDK9/cyclin T (0.18 μM) 和 CK1δ/ε (0.4 μM)。(R)-CR8 trihydrochloride 诱导细胞凋亡并具有神经保护作用。
  49. GC41719 (R)-nitro-Blebbistatin (R)-nitro-Blebbistatin is a more stable form of (+)-blebbistatin, which is the inactive form of (-)-blebbistatin.
  50. GC60407 (R)-Verapamil D7 hydrochloride (R)-VerapamilD7hydrochloride((R)-(+)-VerapamilD7hydrochloride)是(R)-Verapamilhydrochloride的一种氘代化合物。(R)-Verapamilhydrochloride((R)-(+)-Verapamilhydrochloride)是一种P-糖蛋白抑制剂。(R)-Verapamilhydrochloride抑制MRP1介导的转运,导致MRP1过表达细胞对抗癌药产生化学敏感性。
  51. GC60408 (R)-Verapamil hydrochloride (R)-Verapamilhydrochloride((R)-(+)-Verapamilhydrochloride)是一种P-糖蛋白(P-Glycoprotein)抑制剂。(R)-Verapamilhydrochloride抑制MRP1介导的转运,导致MRP1过表达细胞对抗癌药产生化学敏感性。

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