**4.1. Extrinsic cell materials**

## *4.1.1. Cytokines*

TNF-alpha plus z-VAD can trigger cell apoptosis, and this method is well-known in creating cell apoptosis model. TNF-alpha can bind to extracellular domain of TNF-alpha receptor , and the cytoplasm domain can aggregate FADD and FLICE which can initiated the apoptosis; Another famous cytokine, IFN—γ, which can induce the macrophage apoptosis, plays a key role in clearance of the mycobacterium tuberculosis by inducing host cell apoptosis depended by the nitric oxide(NO).[19] TGF-β1 acts as a chemoattractant and is very important for the immune response, this cytokine also play a predominant suppressive role in inhibiting the cell proliferation and stimulating B cells to apoptosis. [20]

Above all, the cytokines are the positive inducer of apoptosis. The investigators also found another mechanism of cytokines related apoptosis which is negative induction by loss of suppressive signal. Many cells viability required supplying the constant or intermittent cytokines or growth factors, Lack of cytokine or growth factors, the cell will go to apoptosis. In this circumstance, these cytokines or growth factors act as the suppressors of apoptosis. For example, when we culture hematopoietic cells, we should add colony-stimulating factors and IL-3; In addition, IL-12 is required to maintain the viability of activated T cells in in vitro culture systerm; the neurorophic cells required the nerve growth factor (NGF) for survival. Moreover, there are many other cytokines and growth factors as the suppressors of apoptosis, such as: epidermal growth factor, platelet-derived growth factor and insulin like growth factor-I and so on. They are also act as the survival factors and inhibit the apoptosis, while if we block or remove these factors; the related cells will be in the procession of apoptosis. So in above all, we have known that cytokines may as inducer or suppressor to participate in apoptosis pathway.

#### *4.1.2. Drugs*

10 Apoptosis and Medicine

cell healthy.

mitochondrial morphology changes, there were two toxin proteins parkin and PINK1 which were detected to play a role in maintaining mitochondrial homeostasis through targeting the mitochondria and regulating the mitochondrial dynamics[15]; Fusion and fission often occur swiftly and are found to have relation with the mitochondria membrane potential changes .there are DRP1-dependent division and FZO1-dependent fusion reaction in mammalian cells, and division of mitochondria accompany with apoptosis., If mitochondrial fission/fusion dynamics losses balance, it will lead to some neurodegeneration diseases. So in brief, mitochondria act as the important role to keep

Mitochondrial iron transporter cytochrome C plays an classic role in apoptosis. As a bridge, it connect with caspase cascade reaction. When cytochrome C is released to the cytoplasm from the mitochondria as a result of response to some intrinsic or extrinsic ligands, it can trigger the downstream caspases and induce the intrinsic apoptosis. So mitochondria are not only the energy company of cell, but also have the ability to control the intrinsic apoptosis pathway through either cytochrome C, calcium, morphology changes(fission/fusion) or

Apoptosis, as a major cell death procession for healthy, play an important role in homeostasis of whole life. In the period of fetation, apoptosis happened, as the essential affair for the finger and toe formation. due the cells between fingers occured apoptosis, we can form five fingers per hand. Apoptosis also can enhance embryonic stem cell survival during stress by increased expression Bcl-2 protein which significantly weaken the apoptosis and help colony formation [16];Apoptosis also take part in some tissues regeneration and homeostasis [17,18]; In addition to the function that we have described above, apoptosis can still anti-inflammation and hamper pathogens persistence infection, especially interfering the intracellular parasites diffusion; In conclusion, apoptosis are good for people's healthy in variety aspects, and apoptosis become research areas hotspots at present. Summarizing the currently researcher's data, we found that many ligands can trigger or inhibit apoptosis. We classified these ligands to two parts by its derivation: 1. extrinsic signal ligands. 2. Intrinsic ligands. The details about the ligands which can trigger

TNF-alpha plus z-VAD can trigger cell apoptosis, and this method is well-known in creating cell apoptosis model. TNF-alpha can bind to extracellular domain of TNF-alpha receptor , and the cytoplasm domain can aggregate FADD and FLICE which can initiated the apoptosis; Another famous cytokine, IFN—γ, which can induce the macrophage apoptosis, plays a key role in clearance of the mycobacterium tuberculosis by inducing

some membrane proteins expression imbalance(Bcl-2).

the apoptosis will be described below:

**4.1. Extrinsic cell materials** 

*4.1.1. Cytokines* 

**4. Trigger apoptosis ligands and cell environment materials** 

Some cytotoxic drugs (Cispkatin, Gemcitabin, Tooitecan, and paclitaxel) can trigger apoptosis; Didymin induce apoptosis by preventing N-Myc protein expression and make the cell G2/M arrest, which may be a novel mechanism to anti-neuroblastoma.[21]; apart from this anti-neuroblastoma properties, didymin have an anti-no small cell lung cancer ability by induced the Fas-mediated apoptosis, it may be a novel new chemotherapeutic agent to treat the lung cancer. [22] Gomisin N have anti-hepatotoxic, anti-oxidative and anti-inflammation abilities, while it also have anti-cancer activity through triggered the TRAIL-induced apoptosis.[23] Andrographolide as an anti-bacteria drug have been found having anti-cancer activity adrographolide treated cancer cell can activate the p53 by increasing p53 phosphorylation, p53 activation can make DR4 protein expression increased and then trigger the TRAIL-induced apoptosis.[24] Ursolic acid can stimulate the ROS production and trigger JNK activation, ROS and activated JNK can make the DR up expression, and in the end, TRAIL-induced apoptosis happened in p53 independent manner.[25] Ciglitazone, as an anti-diabetic drug, has been found by Plissonnier ML group that ciglitazone have antineoplastic effectiveness in a lot of cancer cell lines through up-regulation of soluble and membrane bound TRAIL, make caspase activation, death receptor signal pathway activation and induce Bid to be cleaved as response to TRAIL. These data gave the evidence that ciglitazone can down regulate the c-FLIP and surviving protein, and then triggered the TRAIL-induced apoptosis to kill the cancer cell.[26] These data provided the powerful evidence that triggering apoptosis may be a feasible method for clinically cure.
