*4.1.3. Hormone*

Apoptosis occurs in the embryonic development and during the formation of organs, Hormones is usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another place to affect physiological activity, such as growth, proliferation, metabolism. Some researchers also found that hormones can regulate the apoptosis, and through this way hormone can control the metabolism of tissues or organs. For example, the leptin is one hormone produced by adipocytes, and it has been found as a inhibitor of apoptosis, leptin can down-regulate cleaved caspase-3 and Bcl-2 associated X protein and up-regulate Bcl-2 protein, if this hormone level is normal, there will be no apoptosis, however, if the hormone level decreased, the apoptosis will happen[27], this is one mechanism by which the hormone act as inhibitor of apoptosis, the other mechanism is that hormone act as an inducer of apoptosis. The majority relations between the hormone and apoptosis are concluded as below the table 2

Extrinsic and Intrinsic Apoptosis Signal Pathway Review 13

Mycobacterium can be cleared by macrophage's apoptosis which was induced by the NO and IFN-γ[28]; Chlamydia pneumoniae infection can induce the human T lymphocyte cell apoptosis, through this way, Chlamydia pneumonia could induce immunologic tolerance and would make pathogen persistence infection and inflammation[29]; Dendritic cells(DC) were well known immune cells, as an antigen-process cell, DC can inhibit pathogen replication and diffusion by caspase-3 dependent apoptosis in early infection stage, For instance*, Legionella pneumophila* was unable replicated in DC, because DC go to apoptosis when *Legionella pneumophila* infected these cells in the early stage.[30] Beside the bacteria infection induced the apoptosis, some virus also be found to involve in the apoptosis. For example, transmissible gastroenteritis virus infection can up-regulate the FasL; Subsequently, the Bid protein can be cleaved and cytochrome c release; in the end, Caspase-8 can be activated and the host cell happen apoptosis. [31] Through this way, the pathogens, especially the obligate intracellular parasites, will lost the suitable environment for their life

From this part, we give the conclusion that apoptosis play the key role in host-pathogen confrontation. There are about two mechanisms in this confrontation, one mechanism is that pathogen's target cells can clear the pathogen and inhibit it persistence diffusion by itself apoptosis. Another is that pathogens infection didn't induce the targeted cell apoptosis but cause the related immune cells apoptosis. By this way, the host cells will fail to clear the pathogen. The loss function of host immune cells will benefit the pathogen's replication and help pathogen's diffusion persistence. There are always two sides to every thing, the

Although apoptosis is the programmed cell death and can be recognized as the normal cell death by the immune system; and apoptosis have many important functions in the tissue development. While everything have two sides, in some cases, apoptosis also have the damage and negative effect to the life healthy. Recently, food scientists and biologist found that some native compounds from the daily life dietary can block or hamper apoptosis, and

Vitamin E, another name is tocopherol. As an antioxidant, Vitamin E has an important role in redox balance. Recently, apart it's major role in antioxidant ability, vitamin E can block the reduction of the mitochondrial membrane potential and inhibit the activation of caspase-3, in a brief, vitamin E is conducive to cell viability through blocking the caspase-3 triggered apoptosis. [32] Moreover, Purple Sweet Potato Pigments can scavenge ROS and protect the murine thymocyte by inhibiting caspase-dependent pathway apoptosis also [33]. Lycopene, another name is rhodopurpurin, Lycopene can be taken from the tomatoes, fruits and vegetables easily. As an antioxidant, Lycopene was been found that it contribute to body's heath. Nearly, researchers found that lycopene have anti-prostate cancer activity; Apart from the anti-tumor properties, it have anti-infection ability. For example, Jang SH' group gave the proof that lycopene can inhibit ROS increased, DNA damage and apoptosis in

through this way, these native compounds can help to keep the body healthy.

and will die, however, the host will survival and suffer lowest bad effect.

apoptosis also have no exception..

*4.1.5. Native activities compounds* 


**Table 2.** Involvement of hormones in apoptosis

## *4.1.4. Pathogen effectors*

During the fight between host and pathogen, there are many roads that benefit the cell survival. There is the proverb "Survival of the fittest". If failing to defense the pathogen, host will be ill, and give the phenomenon of inflammation or cell death (apoptosis, necrosis, auto-phage, pyroptosis). In this part, we will give the conclusion about host cell apoptosis which can be triggered by some pathogens, If cell occured apoptosis, the pathogen can not survival either, so through this way, host cells can clear the pathogen with little bad effects. The pathogen effectors, which possess the ability to trigger apoptosis, have been found as following below:

Mycobacterium can be cleared by macrophage's apoptosis which was induced by the NO and IFN-γ[28]; Chlamydia pneumoniae infection can induce the human T lymphocyte cell apoptosis, through this way, Chlamydia pneumonia could induce immunologic tolerance and would make pathogen persistence infection and inflammation[29]; Dendritic cells(DC) were well known immune cells, as an antigen-process cell, DC can inhibit pathogen replication and diffusion by caspase-3 dependent apoptosis in early infection stage, For instance*, Legionella pneumophila* was unable replicated in DC, because DC go to apoptosis when *Legionella pneumophila* infected these cells in the early stage.[30] Beside the bacteria infection induced the apoptosis, some virus also be found to involve in the apoptosis. For example, transmissible gastroenteritis virus infection can up-regulate the FasL; Subsequently, the Bid protein can be cleaved and cytochrome c release; in the end, Caspase-8 can be activated and the host cell happen apoptosis. [31] Through this way, the pathogens, especially the obligate intracellular parasites, will lost the suitable environment for their life and will die, however, the host will survival and suffer lowest bad effect.

From this part, we give the conclusion that apoptosis play the key role in host-pathogen confrontation. There are about two mechanisms in this confrontation, one mechanism is that pathogen's target cells can clear the pathogen and inhibit it persistence diffusion by itself apoptosis. Another is that pathogens infection didn't induce the targeted cell apoptosis but cause the related immune cells apoptosis. By this way, the host cells will fail to clear the pathogen. The loss function of host immune cells will benefit the pathogen's replication and help pathogen's diffusion persistence. There are always two sides to every thing, the apoptosis also have no exception..

## *4.1.5. Native activities compounds*

12 Apoptosis and Medicine

*4.1.3. Hormone* 

apoptosis are concluded as below the table 2

**Known inhibitors of apoptosis**

**Act as inducers of apoptosis**

*4.1.4. Pathogen effectors* 

following below:

**Table 2.** Involvement of hormones in apoptosis

Apoptosis occurs in the embryonic development and during the formation of organs, Hormones is usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another place to affect physiological activity, such as growth, proliferation, metabolism. Some researchers also found that hormones can regulate the apoptosis, and through this way hormone can control the metabolism of tissues or organs. For example, the leptin is one hormone produced by adipocytes, and it has been found as a inhibitor of apoptosis, leptin can down-regulate cleaved caspase-3 and Bcl-2 associated X protein and up-regulate Bcl-2 protein, if this hormone level is normal, there will be no apoptosis, however, if the hormone level decreased, the apoptosis will happen[27], this is one mechanism by which the hormone act as inhibitor of apoptosis, the other mechanism is that hormone act as an inducer of apoptosis. The majority relations between the hormone and

**Hormones Apoptosis cell (Target) Reference** 

54

58

Testosterone Prostate 51 Oestradiol ovarian cells 53,52 Growth hormone Human monocytes or human promyelocytic leukaemia

Leptin myometrial cells 27 Dihydrotestosterone Prostate 51 progeterone cardiomyocytes 55

Glucocorticoids Human small cell lung cancer 56 progeterone human endometrial cell 57 Thyroid hormones Play an important role in Amphibian organ

inducing apoptosis

During the fight between host and pathogen, there are many roads that benefit the cell survival. There is the proverb "Survival of the fittest". If failing to defense the pathogen, host will be ill, and give the phenomenon of inflammation or cell death (apoptosis, necrosis, auto-phage, pyroptosis). In this part, we will give the conclusion about host cell apoptosis which can be triggered by some pathogens, If cell occured apoptosis, the pathogen can not survival either, so through this way, host cells can clear the pathogen with little bad effects. The pathogen effectors, which possess the ability to trigger apoptosis, have been found as

Estrogen Breast cancer cell 59 Phytoestrogens Breast cancer cell 60

remodeling during metamorphosis through

Although apoptosis is the programmed cell death and can be recognized as the normal cell death by the immune system; and apoptosis have many important functions in the tissue development. While everything have two sides, in some cases, apoptosis also have the damage and negative effect to the life healthy. Recently, food scientists and biologist found that some native compounds from the daily life dietary can block or hamper apoptosis, and through this way, these native compounds can help to keep the body healthy.

Vitamin E, another name is tocopherol. As an antioxidant, Vitamin E has an important role in redox balance. Recently, apart it's major role in antioxidant ability, vitamin E can block the reduction of the mitochondrial membrane potential and inhibit the activation of caspase-3, in a brief, vitamin E is conducive to cell viability through blocking the caspase-3 triggered apoptosis. [32] Moreover, Purple Sweet Potato Pigments can scavenge ROS and protect the murine thymocyte by inhibiting caspase-dependent pathway apoptosis also [33]. Lycopene, another name is rhodopurpurin, Lycopene can be taken from the tomatoes, fruits and vegetables easily. As an antioxidant, Lycopene was been found that it contribute to body's heath. Nearly, researchers found that lycopene have anti-prostate cancer activity; Apart from the anti-tumor properties, it have anti-infection ability. For example, Jang SH' group gave the proof that lycopene can inhibit ROS increased, DNA damage and apoptosis in

gastric epithelial AGS cells induced by helicobactera pylori infection. [34]. Soy isoflavone also have been documented as dietary nutrients broadly, it was been classified as "natural agents" which play the important role in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer's development and progression in vitro and in vivo. [35] Beside this soy isoflavone, in recent years, dietary compounds which was from the bounties of nature have been paid any attentions, the latest researches data have shown that there are some associations between the consumption of some native dietary compounds and the reduced risk of several types of cancers, [36, 37] because there are lots of active compounds containing in the food which have some associations with the apoptosis, and due by apoptosis, these native compounds will inhibit cell abnormal proliferation.

Extrinsic and Intrinsic Apoptosis Signal Pathway Review 15

61

**Native compound Caspase dependent apoptosis Reference** 

**Table 3.** Another native compounds which can trigger apoptosis apart from above paragraph's related

Keratin is a cytoskeleton protein which have some abilities to maintain the cell shape, Guo-Zhong Tao group found that keratin can modulate the shape of mitochondria and contribute to hepatocyte predisposition to apoptosis and oxidative injury [42].Depletion the mitochondria GSH in the human B lymphoma cell line by treatment with L-buthionine sulfoximine can induce caspase-3 activation and apoptosis, and indicating that GSH may be the potential early activator of apoptotic signal [43]. ROS is a type of toxic compound and usually detoxified by cells GSH, when the oxidative stress occur, the ROS detoxify will be

failed, and ROS will participate in apoptosis through redox-sensitive death pathway.

Cytochrome C, as a proapoptotic protein, plays an important role in triggering programmed cell death, The activation of cytochrome C is related with the changes of Bak/Bax ratio. The latest researches shown that the interactions of heterotypic mitochondrial membrane will change the lipid milieu, in the end, mitochondrial membrane will be permeatable and cytochrome c will release. [44]; Apart the changes of lipid milieu, arachidonic acid, triiodothyronine (T3), or 6-hydroxdopamine can also effect the permeability of mitochondrial membrane and release Ca2+ and cytochrome c. [45] Cytochrome c can thrigger caspase activation via oligomerization of APAF1 protein. Caspase activation can catalyze the PARP-1, Finally, the apoptosis will happen. In short, cytochrome C is the one of major

The concentration of calcium in vivo is the key role in maintain the permeatability of mitochondrial membrane. The increased intra-mitochondrial calcium can result in enhanced ROS, Furthermore, cytochrome c will be stimulated to release. [46] And calcium also trigger

Apigenin Induce cytochrome C release and ROS

<sup>β</sup>-Lapachone Leading ER stress and JNK activation and

phytosphingosine Leading caspase-8 activation and

**4.2. Intrinsic cell apoptosis signal materials** 

*4.2.1. Oxidative stress (ROS; NO; GSH).* 

intrinsic cell apoptosis signal molecules.

*4.2.2. Cytochrome C* 

*4.2.3. Calcium iron* 

Trigger mitochondria- dependent

apoptosis. And activate Bax, Bcl-xl, Bcl-2, Mcl-1, caspase-9, caspase-3, and PARP

enhance <sup>62</sup>

mitochondria-dependent cell death <sup>63</sup>

mitochondria mediate apoptosis <sup>64</sup>

luteolin

Apart from these food derived natural compounds, there are many plant components which can be used by Chinese traditional medicine (TCM), these plant active components can also have trigger apoptosis, such as fisetin, wongonin, emodin and so on. Fisetin is a natural flavonoid which can induce several type cancer cells to apoptosis by dose and time dependent manner. Fisetin can activate caspase-8/caspase-3 dependent apoptosis pathway, and these pathway transducer molecular will be the candidates for cancer therapy; [38] Wongonin, as an O-methylated flavonoind, was detected to have anxiolytic activity, and also have the ability to trigger some cancer cells apoptosis. For instance, wongonin and fisetin can make PARP to be cleaved, then pro-caspase-3 will be activated in HL-60 cells, while they can induce the ROS decreased, so it is not the ROS dependent apoptosis pathway. Several compounds have the similar structural with flaconoids, including the luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin, they all have biological activities. Up to now, wogonin and fisetin have been found that they have the potential ability to trigger apoptosis through caspase-8 dependent manner[40,41]. Rheum palmatum is traditional Chinese medicines which have anti-bacteria; anti-inflammation; and improving microcirculation, emodin is an active component of Rheum palmatum and have apoptosis-inducing activity, Chen YC group found that the emodin can activate caspase-3 cascade and trigger HL-60 cell apoptosis independent of ROS production also. [41]

Some researches gave us many inspirations in the apoptosis research. We known that many tradition Chinese medicines (TCM) have some active constituents, these active components have anti-tumor activity through apoptosis, so combination the molecular biology to dig out the mechanism of drug functions will be effective and scientifical, Now, the functions of some tradition Chinese medicines are still stay the phenomena, we did not know the real mechanism of activity materials. Although TCM have not curative effect faster than western medicine, but the TCM have the lowest side effect and help for prognosis, so many patients choose TCM to defense the diseases in china. More and more investigators are focusing on elucidating the molecular mechanisms of these natural products and identifying its targets. Moreover, I think the researches of active components from TCM will be meaningful and broadly potential in the future. In the table 3, we summarized some other native compounds that can trigger apoptosis, I hope that these informations will guild us to research some active components in the drug.


**Table 3.** Another native compounds which can trigger apoptosis apart from above paragraph's related
