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1. Introduction
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Cell division is a common phenomenon that occurs in all living entities, except for cells that have completed somatic differentiation. When the cell reaches a certain volume, it performs division [1]. While the cell division leads to an increase in the number of individuals in single-celled organisms, in multicellular organisms, it ensures the growth of hair and nails, healing of wounds, cellular repair, somatic growth, and genesis of reproductive cells. Then, one might question that under what conditions do cells divide? Before moving on to the answer for this question, it is crucial to find the answer to this proposal: Do cells divide because they grow? Or do they grow because they need to be divided? The various assumptions about the view that advocates the premise that the cell divides because it grows are summarized below:
Overall control attenuates as the cell grows. Later in the process of cell growth, obstacles start to appear in the central management of the organelles in the cytoplasm. As a result, problems may arise in the way organelles perform their tasks and also in the control of the communication they perform with each other. In addition, the material exchange within the cell starts to become inextricable [2]. In summary, since the growth of the cell will cause a number of significant difficulties in performing intracellular coordination activities, the cell needs divisions to reduce its volume.
As the cell grows, the “cytoplasm/nucleus” ratio varies in favor of the cytoplasm. Since the increase in volume of the cytoplasm makes it difficult for the nucleus to maintain its control on the cell, it is crucial for cell to divide and restore the optimal cytoplasm/nucleus ratio [3].
Since the cell membrane does not enlarge as fast as the cytoplasm, it becomes difficult for the cell to exchange material from the external environment during continuous cell growth. To achieve sufficient material exchange from the membranes, the membrane-to-surface area must reach the optimum value [4]. As the cell continues to grow, difficulties in maintaining the surface-volume balance begin. Small or thin objects have a larger surface area than their volume. This gives them a large surface-to-volume ratio. However, large objects have a small surface area than their volume; thus they have a small surface-to-volume ratio [1].
This could be best explained by a balloon blowing event. As a balloon swells, the internal volume increases, but the membrane cannot simultaneously compensate for this volume increase and, thus, explodes after a certain time period. Cells need to divide to prevent this negative event (otherwise, cells would become lysed).
Environmental factors and hormones can lead the cell to division. In general, if any tissue has been damaged for any reason, cell division takes place and performs the repair process. In this context, growth hormone may be given as an example of the effect of hormones on cell division. These and similar hormones have mitogenic functions that trigger a cell division signal [5, 6, 7].
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In fact, from a scientific point of view, the cell is divided not because it grows, but rather it requires division. In the process of cell division, the dividing cell is called a parental or host cell. The parental cell is divided into two daughter cells. Subsequent divisions are then repeated via the so-called process, the cell cycle.
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Cells regulate the division process by communicating with each other through chemical signals generated by specific proteins called cyclin and cyclin-dependent kinases [8]. These signals play a key role in determining when cells will begin to divide and stop dividing. Cell division is important for the growth of the organism and wound healing. It is also important that the cells terminate dividing at the appropriate time [9]. Otherwise, cancer occurs because the cells do not stop the division at the required time.
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Cells in the organism perform division for growth and/or repair; on the one hand, they undergo apoptosis (by cellular turnover) for various reasons to maintain homeostasis. Because some cells, such as epidermal cells, are constantly lost, new cells must be produced via cell division. For instance, 30,000–40,000 epidermal cells are killed per minute by apoptosis [10]. In other words, we lose about 50 million cells each day. Therefore, cell division is very important in tissues where cells are lost very rapidly. However, other cells such as the nerve cells are either not divided or very rarely divided [11].
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Depending on the cell type, cell division has two mechanisms: mitosis and meiosis. Each of these cell division mechanisms has unique characteristics. In mitosis, the parent cell (diploid, 2n) is divided into two daughter cells with the identical number of chromosomes [12]. This type of cell division is essential for basic growth and repair. On the other hand, the parental cell in meiosis (diploid, 2n) is divided into four cells with two successive cleavages (meiosis I and meiosis II), and the number of chromosomes are half the main cell (haploid, n) [13]. The reduction of the diploid chromosome number to haploid is important for sexual reproduction, and recombination in meiosis I is the source of genetic diversity.
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The cell, which has not yet started to divide, is in the interphase of the cell cycle. Cells have to be divided by certain periods, though each cell actually passes most of its time in the interphase. The interphase is the period when a cell is prepared to divide and initiate the cell cycle [14]. During this time, the cells have to obtain nutrients and energy. The host cell also synthesizes a copy of its DNA to share equally between the two daughter cells.
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However, if cell division is not required for the functional integrity of the organism, negative regulation of the cell cycle is performed [15]. In contrast to the positive regulators, the negative regulators function in a direction that halts the cell cycle. In this process, a large number of molecular components and signaling are involved. The most well-studied negative regulatory molecules are the retinoblastoma protein (Rb), p53, and p21 [16]. These three proteins have been commonly referred as tumor suppressor proteins. Like the p53 and p21 proteins, Rb proteins are also a group of tumor suppressor proteins observed in many cell types. Most of the knowledge of cell cycle regulation have been obtained from studies using cells that have lost control of cell cycle regulation [17, 18, 19]. It has been discovered that cells that are uncontrolled (becoming cancerous) have these regulatory proteins damaged or nonfunctional [20, 21]. In each case, the major cause of uncontrolled progression through the cell cycle is errors in the abovementioned regulatory proteins. In this case, the possibility of uncontrolled cellular proliferation is raised. When DNA damage is detected, p53 protein halts the cell cycle and DNA repair enzymes are activated to repair the damage. However, if DNA damage cannot be repaired, the p53 protein may trigger apoptosis (programmed cell suicide) to prevent the replication of damaged chromosomes [22]. Different cellular death pathways including apoptosis, in the context of this chapter, are therefore summarized below.
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2. General mechanisms of cell death
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2.1 Apoptosis
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Apoptosis, also known as programmed cell death, is a regulated cellular destruction program that facilitates the removal of damaged or excess cells. This process is critical for many physiological processes including embryonic development and tissue homeostasis in adulthood [23, 24].
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Multicellular organisms have developed suppressive processes that prevent the proliferation of cells displaying aberrant proliferation or improper tissue infiltration. These processes function to block tissue hyperplasia, tumor formation, and metastatic distribution of tumors. Processes such as the cell cycle arrest, cellular aging, and apoptotic cell death, which remove malicious cells capable of initiating tumor growth, can also be included in this mechanism [25].
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2.2 Autophagy
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Autophagy (or autophagocytosis) (autóphagos in Ancient Greek) means “self-devouring.” It is the natural regulating mechanism that extracts the nonfunctional (junk) components of the cell [26]. The term “autophagy” was first used in 1963 by the Belgian biochemist Christian de Duve [27]. In the 1990s, the Japanese autophagy researcher Yoshinori Ohsumi discovered the mechanisms of autophagy in yeast cell by identification of autophagy genes and received the 2016 Nobel Prize in Physiology and Medicine for his studies [28]. Autophagy allows the regular degradation and recycling of cellular components [29]. The cytoplasmic components targeted in this pathway are separated by a double-membrane vesicle named autophagosome from the rest of the cell [30, 31]. The autophagosome then fuses with the lysosome and performs the digestion of the cellular components in between its membranes. In general, three types of autophagy have been reported to date, including macro- and microautophagy and chaperone-mediated autophagy. Although the autophagic process, in the context of the disease, was observed to be an adaptive stress response that increases survival, it has been observed in other cases that it increased cell death and morbidity. In the case of excessive cellular starvation, disintegration of cellular components promotes survival by ensuring that cellular energy levels remain constant [32]. Autophagy, which acts as a protective response to biological stress in mammalian cells, removes damaged proteins and organelles from the cytoplasm and allows for the reconstitution of components in their structure using lysosomal content. In the case of moderate stress, autophagy may undertake the task of survival; however, in the event of excessive stress, it can activate the programmed cell death pathway [33]. Because of the dysregulation of autophagy in many diseases including cancer, it is crucial to understand how the transition from autophagy to apoptosis occurs. Cells that respond to exogenous stress were found to be consistent in their quantitative autophagy and apoptosis measurements [34]. On the other hand, defective apoptosis in immortalized epithelial cells renders cells substantially tumorigenic. In apoptosis-defective cells, activation of AKT (protein kinase B) or allelic degradation of Beclin1 inhibits a pathway of survival due to autophagy, thereby enhancing susceptibility to metabolic stress. Although autophagy acts as a buffer against metabolic stress, the simultaneous disruption of apoptosis and autophagy mechanism promotes necrotic cell death in vitro and in vivo. Therefore, the inhibition of autophagy by certain conditions, such as nutrient starvation, may render apoptosis-resistant tumors susceptible to apoptosis [35]. While apoptosis acts as a cellular quality control mechanism in the organism, autophagy acts as an intracellular quality control mechanism. Collectively, autophagy and apoptosis are not interchangeable metabolic pathways, and autophagy can be assumed as one of the components of apoptosis.
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2.3 Necrosis
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Another pathway of cell death is necrotic cell death. Necrosis (Greek: death) is a form of cell injury that results in premature death of cells in living tissues through the mechanism of autolysis [36]. Necrosis is caused by factors other than cells or tissues, such as infection, toxins, or trauma, which cause irregular digestion of cell components. Unlike apoptosis, it is not a controlled or programmed type of death. Apoptosis is often beneficial to the organism, while necrosis is almost always disastrous and may be fatal [37]. Cell death from necrosis does not follow the path of apoptotic signaling, but more diverse receptors are activated, resulting in loss of cell membrane integrity and uncontrolled release of cell death products into the extracellular domain [36]. This initiates an inflammatory response in the surrounding tissue that activates leukocytes and nearby phagocytes and eliminates dead cells by phagocytosis. However, microbial damaging agents released by leukocytes can cause irreparable damage to the surrounding tissues from the lateral side [38]. There are six different models of necrosis recognized morphologically. These include coagulative necrosis, liquefactive necrosis, gangrenous necrosis, caseous necrosis, fat necrosis, and fibrinoid necrosis [39].
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2.4 Necroptosis
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Necroptosis is a programmed necrosis or inflammatory cell death pattern. Conventionally, necroptosis, unlike regularly programmed cell death by apoptosis, is associated with non-programmed cell death resulting from cellular damage or infiltration of pathogens. The discovery of necroptosis has shown that cells are capable of performing necrosis in a programmed manner and that apoptosis is not always the only preferred form of cell death [40].
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3. Cytotoxicity
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The effect of being toxic to cells caused by toxic agents is called cytotoxicity. Exposing cells to a cytotoxic compound may result in various outcomes in the cell. At this point, the cells may actively progress into the death phase. Furthermore, the cells may activate the controlled cell death (apoptosis) program, or necrosis may occur where the membrane integrity is lost and uncontrolled death is being executed due to cell lysis. Cells undergoing the process of necrosis commonly swell rapidly, lose membrane integrity, stop metabolism, and secrete their contents into the extracellular space. Furthermore, cells with rapid necrosis in vitro do not have enough time or energy to initiate apoptotic mechanisms and therefore will not express apoptotic indicators. Apoptosis is characterized by well-defined cytological and molecular events involving cytoplasmic shrinkage, nuclear condensation, and controlled cleavage of DNA by the endonucleases. Cells in culture undergoing apoptosis eventually undergo secondary necrosis. At this time, the cell stops metabolism and loses the integrity of its membrane [41].
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Cytotoxic agents are known as all the elements that are toxic to the cells, which include the factors that prevent their growth and sometimes cause death, and are also used to treat certain disorders. Chemical and biological substances or physical agents can cause cytotoxicity by affecting the cells in varying degrees. These agents include chemical agents that act by inhibiting synthesis (such as nucleic acid and protein synthesis) in the cell, by affecting cellular energy production pathways (mitochondrial effect), or by attenuating the integrity of the membrane in the cell (plasma membrane or intracellular organelles that have membranes).
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3.1 Chemical cytotoxic agents (cytostatics)
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Inhibitors of dihydrofolate reductase responsible for purine and pyrimidine biosynthesis.
Inhibitors of DNA biosynthesis (cytarabine).
DNA intercalators (anthracyclines and anthracenediones).
Agents inducing DNA strand break formation (bleomycin).
DNA topoisomerase inhibitors (camptothecin, anthracyclines, anthracenediones, anthrapyrazole, and etoposide).
Cytotoxic agents that cause formation of DNA adducts (cyclophosphamide, melphalan, chlorambucil, hexamethylmelamine, busulfan, dacarbazine, mitomycin C, and cisplatin).
RNA degradation (inhibition of RNA biosynthesis by anthracyclines).
Nucleoprotein (inhibition of nucleoprotein synthesis by L-asparaginase) and microtubule biosynthesis inhibitors (antitubulin, colchicine, dolastatin, taxol, tritlisin, vinblastine, and vincristine).
Agents that cause cytotoxicity by modulating the mitochondrial permeability transition pores and increasing the mitochondrial membrane potential and affecting the energy transmission pathways in neoplastic cells. These agents include staurosporine, poly (ADP-ribose) polymerase, 6-aminonicotinamide, 6-methyl-mercaptopurine ribid, 6-mercaptopurinoside, 6-aminonicotinamide and 6-methyl-mercaptopurinoside, and N- (phosphonacetyl)-L-aspartic acid [42].
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3.2 Biological cytotoxic agents
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In this group, toxic molecules derived from viruses, bacteria, fungi, plant, and animal origin are generally included. Bacterial endo-/exotoxins and antibiotics in this group are the most widely recognized molecules. Biological agents such as lipid hydrolyzing enzymes, sphingomyelinases C and D, cholesterol oxidase, helianthus toxin, streptolysin, and saponin damaged cultured human skin fibroblasts and erythrocytes with different cholesterol levels. However, erythrocytes with high cholesterol levels were found to be more sensitive to toxins [43]. Cytotoxic agents used by invertebrates include oxygen and nitrogen reactive intermediates, antimicrobial peptides, lectins, cytokines, and quinoid intermediates of melanin [44]. It has also been found that bacterial cytotoxins act by targeting the actin components of the cell skeleton of eukaryotic cells [45].
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3.3 Physical cytotoxic agents
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Physical agents such as heat, ultrasonic vibrations, and radiation have cytotoxic effects. The toxicity induced by “lethal heat shock” in Saccharomyces cerevisiae (yeast) cells was found to be primarily due to oxidative stress. The possibility that mitochondrial membrane disruption in aerobic cells exposed to heat stress is hundreds of times higher than cells in anaerobic conditions reinforcing this possibility [46]. An in vitro study of Chinese hamster ovarian (CHO) cells revealed that the cytotoxicity of drugs affecting the plasma membrane was synergistically increased by ultrasound application [47]. It has also been found that the use of ultrasonic microbubble increases the cytotoxic effects of chemotherapeutic drugs on tumor cells [48]. In addition, many studies in the literature on the cytotoxic effect of radiation can be found.
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4. Universal cytotoxicity parameters
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Assays to measure the reduction in the cell viability (inhibition of growth/division or death by apoptotic-necrotic pathways) are called “cytotoxicity” tests. These experiments can be performed by in vitro and/or in vivo test systems in different cell types using various techniques. While some of these parameters (mitotic index, replication index, nuclear division index, etc.) contribute to the indirect demonstration of cell division dynamics, some of them directly contribute to the demonstration of cell viability (MTT, MTS, XTT, WST, etc.) [49]. A brief summary of these methods can be found below; however, before explaining these test methods, brief information about some of the most commonly used cytotoxicity parameters that provide us quantitative information about the different cellular processes will be discussed.
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4.1 Mitotic index
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The mitotic index of a cell population is expressed as a proportion of the population at any mitotic stage (e.g., per mille = 1/1000). Mitotic index is an important criterion for the growth and multiplication of tissues. Because it is calculated in fixed and stained cell preparations at a particular divisional phase, the mitotic index reflects only the division stages of cells at the time of fixation [50]. Furthermore, since cell division is a process that follows DNA replication under normal conditions, the mitotic index is indirectly a parameter that is also associated with DNA replication. One can ask: why has mitotic index attracted considerable interest as a viability parameter for decades in genotoxicity tests? The answer to this question clearly lies in cell division. A successful cell division requires coordination between different cell cycle checkpoints, especially G1/S and G2/M transitions [51]. These cell cycle control points, which regulate the sequence and timing of sub-phase transitions, are essential in maintaining genomic integrity and in realizing a healthy cell division [52]. Therefore, no matter what type of cell is being examined under the microscope, the MI is a universal parameter capable of giving information indirectly about all the subcomponents and control points of the cell cycle and is used to measure cytotoxicity in living organisms. The calculation of MI shows minor differences between plant and animal cells. In plant and animal cells, the MI is simply calculated as follows and is given in percentage:
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Plant cells:
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\n\nMI\n=\n\n\nProphase\n+\nMetaphase\n+\nAnaphase\n+\nTelophase\n\nTotal number of cells\n\n×\n100\n\nE1
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Animal cells:
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\n\nMI\n=\n\nMetaphase cells\nTotal number of cells\n\n×\n100\n\nE2
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For the calculation of MI in animal cells, the reason for counting only the cells in the metaphase stage is the use of special chemicals (e.g., colchicine, vincristine, vinblastine) that inhibit microtubule polymerization in the metaphase stage during mitosis. Therefore, the cell cannot proceed further than the metaphase stage.
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Although not always, a significant decrease in MI correlates with genotoxicity. A reduction of MI by 50% or less indicates a lethal effect on the cells, and this is called lethal dose of 50 [53]. The decline in mitotic index may be related to inhibition of DNA synthesis or delay/stop in cell cycle phases (G1, S, or G2). Occasionally, there may be also significant increases in MI compared to control. This may be due to a reduction in the duration devoted to DNA repair [54] or the acceleration of the transition between the phases of the cell cycle [55]. Both events can result in an uncontrolled progression of cell proliferation.
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In recent years, a new formula of mitotic index has been developed which takes account of only actively dividing cells. According to this hypothesis, only actively dividing cells, i.e., metaphase and anaphase cells, are included in the calculation. This formula (active mitotic index) provides additional information on the percentage of actively dividing cells [56, 57]:
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\n\nAMI\n=\n\n\nMetaphase\n+\nAnaphase\n\nTotal number of cells observed\n\n\nE3
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Another characteristic of the MI is that it provides critical information about the progression of the disease and the course of treatment in certain diseases such as cancer. Since one of the hallmarks of cancer is a high rate of cell proliferation, MI can therefore be used as an important predictor in the prognosis of various types of cancer. In this context, high levels of MI were associated with hepatocellular carcinoma (HCC) and invasive breast carcinoma, while low MI values were associated with negative node status, diploid DNA content, low S-phase fraction, and positive estrogen (ER) and progesterone (PgR) receptor status in breast cancer [58, 59, 60].
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4.2 Nuclear division index (NDI)
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Such as the mitotic index, nuclear division index is a parameter that provides information about the numerical value of cell proliferation. The difference of NDI from MI is that NDI is calculated based on the number of nuclei in divided (or interphase) cells. Thus, NDI is a parameter that is directly related with the DNA replication. NDI may be used to gain quantitative information on cell cycle progression of the lymphocytes after phytohaemagglutinin (PHA) stimulation. This index is frequently employed as a useful research tool for understanding the kinetics of cell cycling in lymphocyte cultures. However, although it is simply a tool to measure the rate of division in viable cells, an increase in cell death via necrosis or apoptosis does not always cause a reduction of the NDI in surviving cells [61]. On the other hand, it has been experimentally shown that NDI was associated with various malignancies and could be used as a screening strategy as a cytogenetic biomarker in cancer such as the MI. It has been reported that the mean NDI values were significantly lower in patients with colorectal cancer (CRC) or polyps than in patients with normal colonoscopy. Therefore, NDI was proven to be useful in screening strategies for CRC [62]. The NDI is calculated as in the following formula:
where M1–M4 represent the number of cells with one to four nuclei and N is the total number of the cells scored [63].
\n
\n
\n
4.3 Proliferation index (replication index, BrdU incorporation)
\n
Proliferation index (PI) or replication index (RI) is a parameter that is used to investigate the rate of DNA replication. It is basically a method based on the principle of integration of BrdU into the strands of DNA. BrdU, deoxythymidine (dT), and deoxyuridine (dU) are molecules which are analogues of each other. The difference between these molecules is due to the fact that the chemical groups bound to the fifth C atom in the heterocyclic benzene ring are different (Figure 1\n).
\n
Figure 1.
Schematic representation of the differentiation of cells undergoing the first, second, and third mitotic division with the introduction of BrdU into DNA molecule.
\n
\n
\n
\n
5. In vitro cytotoxicity (cell viability) assays
\n
Before proceeding with the widely used in vitro cytotoxicity tests, it is worth mentioning why these tests are more preferred than animal tests:
Although animal tests can provide pathological information, these tests have ethical concerns.
In vitro tests conducted in a test tube using cells grown from an organ can be used to test the toxic effects of substances on specific tissues.
In vitro tests enable us to screen minimal quantities of chemicals.
It could be also possible to study specific subcellular pathways such as signaling pathways and oxidative stress.
\n\n
However, despite these advantages offered, in vitro cytotoxicity assays cannot fully substitute in vivo assays because:
The chemicals may be metabolized inside the whole body rather than specific organs.
In vivo tests can be conducted lifelong.
In vivo tests enable us to determine the presence of chemicals in multiple organs and their distribution in the body as a whole.
Specific systems such as the reproductive system and respiratory system can be examined in vivo.
Different routes of entry such as the skin, inhalation, and gut can be tested in vivo.
In vivo tests enable us to calculate and model toxicokinetic effects, in terms of uptake and removal, and the half-life of the chemical in the body.
\n\n
Cytotoxicity tests are among the first in vitro bioassays used to predict toxicity of various substances in different tissues. The need for safety assessment of drugs, cosmetics, food additives, pesticides, and industrial chemicals increases year by year. Figure 2\n demonstrates an overview of the compartments which are targeted by the cytotoxicity test systems within the cell.
\n
Figure 2.
Overview of general targets of cytotoxicity test systems in the cell.
\n
According to their targeted compartments in the cell, in vitro cytotoxicity assay methods could measure viability or toxicity basically in four different ways: (I) proliferation (direct viable cell count), (II) cell division (DNA synthesis by 3H thymidine uptake), (III) metabolism (MTT, alamar blue, ATP production), and (IV) membrane (leakage of lactate dehydrogenase from dead cells). However, many cytotoxicity tests, although they differ from each other in practice, allow testing of relatively similar cellular processes and endpoints. Therefore, these tests, below, are summarized without dividing into different categories.
\n
\n
5.1 Apoptosis assay
\n
Apoptotic cells are recognized by reduced DNA content and morphological changes such as nuclear condensation that can be detectable by flow cytometry, trypan blue, or Hoechst staining. Changes in the structure and function of the plasma membrane are determined by the appearance of phosphatidylserine on the plasma membrane that reacts with the Annexin V-fluorochrome conjugates. Propidium iodide (PI) staining allows distinction between early and late apoptotic events [64].
\n
\n
\n
5.2 ATP assay
\n
The assessment of metabolic functions by the cellular ATP content is an established method of measuring cytotoxicity that is essential for screening drugs and determining toxicological safety. As ATP plays a central role in cellular metabolism, the intracellular level of ATP is strictly regulated in normal cells. Furthermore, cell injury results in not only reduced ATP synthesis but also immediate diminution of endogenous ATP levels which is caused by the escape of ATP-converting enzymes (e.g., ATPase) [65]. Therefore, quantification of the intracellular ATP content is crucial for the assessment of the degree of cellular toxicity [66].
\n
\n
\n
5.3 Autophagy assay
\n
Autophagy is a process which is characterized by the formation of double-membraned vesicles called autophagosomes, which isolate the cellular components targeted for devastation and fuse with lysosomes to deliver their content for degradation. Autophagy can be determined by two different methods as direct and indirect. Direct tests are based on the turnover of long-lived proteins and lactate dehydrogenase (LDH) sequestration, while indirect tests include western blot-based assays, fluorescence microscopy-based methods, electron microscopy, and flow cytometry and imaging flow cytometry [67].
\n
\n
\n
5.4 BrdU assay
\n
BrdU is a thymidine analogue used in cell proliferation studies. BrdU in the cell culture medium is incorporated into DNA during DNA synthesis. Once the membrane permeabilization is performed, the cellular incorporation of BrdU can be detected by anti-BrdU-specific antibodies. For this purpose, flow cytometry or immunohistochemistry techniques can be used [68].
\n
\n
\n
5.5 Cell tracking
\n
This is a procedure used to monitor cell movement and location by the implementation of “tracking” probes that pass through the membrane into the cytoplasm and then become membrane impermeable. The “tracking” dyes to be used in this type of experiments should be passed to the daughter cells during multiple generations, but not transferred to the neighboring cells they are in contact [69].
\n
\n
\n
5.6 Gram staining
\n
Although traditionally named “Gram staining,” commercial kits for testing cell viability and proliferation now include dyes such as CF®488A WGA, DAPI, Ethidium Homodimer III (EthD-III), etc. in addition to the conventional Gram stain; CF-488A (WGA) stains N-acetylglucosamine structure in the peptidoglycan layer of Gram-positive bacteria with green fluorescence. EthD-III, which is a nucleic acid binding dye, is membrane impermeable and selectively stains the compromised plasma membranes of bacteria with red fluorescence. DAPI, which can pass through the membrane and bind to DNA, stains all bacterial cells in blue [21].
\n
\n
\n
5.7 LDH assay
\n
The cytoplasmic enzyme lactate dehydrogenase is a stable ubiquitous enzyme found in all cells. A key feature of apoptosis, necrosis, and other forms of cellular damage is that the LDH is released into the cell culture, while the plasma membrane is damaged. By using the NADH which is produced in a coupled reaction to reduce a second compound during the conversion of lactate to pyruvate, LDH activity can be quantified. In this protocol, the reduction by NADH of a yellow tetrazolium salt (INT) into a red water-soluble formazan-class dye is quantified at 492 nm absorbance. The amount of formazan occurring in culture is directly proportional to the amount of LDH and, indirectly, to the number of dead or damaged cells in the culture media [70].
\n
\n
\n
5.8 Live/dead staining
\n
Live/dead assay is used for quantification of cell viability using flow cytometry or fluorescence microscopy. This assay utilizes fluorescent dyes to label live and dead cells with a one-step protocol. “Live cell” dye stain intact and viable cells into green. It can pass through the membrane and does not fluoresce until the ester groups in the dye molecule are removed by the intracellular esterases. The excitation (max) and emission (max) are 494 nm and 515 nm, respectively. On the other hand, “dead cell” dye labels cells with damaged plasma membrane into red. It does not have the ability to pass through the plasma membrane and binds to DNA with a high affinity. The degree of the fluorescence emitted by this dye increases up to >30-fold when it is bound to DNA. The excitation (max) and emission (max) are 528 nm and 617 nm, respectively [71, 72].
\n
\n
\n
5.9 Lysosomal staining
\n
These dyes are fluorescent dyes such as “CytoPainter green” or “acridine orange” (AO), which are used to measure lysosomal integrity in proliferating and nonproliferating cells. These lysotropic dyes preferentially accumulate in lysosomes via the lysosome pH gradient. Their fluorescence is significantly increased after they become trapped in lysosomes. These dyes are also useful in cell adhesion, drug resistance, chemotaxis, apoptosis, cell viability, and adherent cell studies [73].
\n
\n
\n
5.10 Membrane potential assay
\n
Membrane potential or membrane voltage refers to the difference of electric charges across a cell membrane. Electrical potential difference across the cell membrane is a novel method to monitor cell death (apoptosis) in single cells. It has been shown that the depolarization of plasma membrane in response to microinjection of cytochrome c into the cytosol is a reliable indicator of apoptotic cell death [74]. The dye used for this assay is a lipophilic and anionic dye that can move across the cytoplasmic membrane of healthy cells, dependent on the membrane potential across the plasma membrane. The fluorescence intensity of the dye increases when the dye is bound to proteins in the cytosol. Following depolarization of the cells, more dye enters the cells, and the increased cellular concentration of dye binding to lipids and proteins results in an increase in fluorescence signal. On the other hand, following hyperpolarization, dye exits the cells, and the decreased intracellular concentration of dye results in a decrease of fluorescence signal. The excitation wavelength of the dye is 488 nm of the argon ion laser [75].
\n
\n
\n
5.11 Mitochondrial staining
\n
Although mitochondrial staining is performed in different compartments of mitochondria, it is usually a test performed on the mitochondrial membrane or mitochondrial matrix. Mitochondrial membrane dyes are cell permeant and accumulate in active mitochondria that have intact membrane potentials. The signal will be bright if the cells under examination are healthy and have functional mitochondria; however, if the mitochondrial membrane potential is lost, the signal will be dimmer or will disappear [76]. In addition to staining the mitochondrial membrane, some dyes stain specific molecules in the mitochondrial matrix. One of them is the “fluorescent mitochondrial hydrogen peroxide indicator” stain, which serves to visualize hydrogen peroxide in the mitochondrial matrix of living cells. This dye gives strong emissions at 528 nm in the presence of H2O2. In an in vitro model of Parkinson’s disease, it is used to detect the local increases in H2O2 [77].
\n
\n
\n
5.12 MTT, XTT, MTS, and WSTs assays
\n
\n
5.12.1 MTT assay
\n
In living cells, MTT (a yellow tetrazole) is reduced to formazan (purple). To convert (dissolve) the insoluble formazan into a colored solution, a solubilization solution (DMSO, acidic ethanol solution, or a solution of sodium dodecyl sulfate in diluted hydrochloric acid) is added. This colored solution can be quantified by measuring its absorbance using a spectrophotometer usually between 500 and 600 nm wavelength. The absorption degree of light depends on the solvent [78].
\n
\n
\n
5.12.2 XTT assay
\n
Due to its higher sensitivity and higher dynamic range, XTT has replaced MTT. Since the formed formazan dye is water-soluble, it eliminates the final solubilization step [79].
\n
\n
\n
5.12.3 MTS assay
\n
MTS, in the presence of phenazine methosulfate (PMS), forms a formazan product which has a max. Absorbance of 490 nm in PBS. The MTS assay is often regarded as a “one-step” MTT assay, since it offers the advantage of adding the reagent directly to the cell culture without any intermediary steps necessary in the MTT assay. Since the intermediary steps remove remnants of colored intermediates in the MTT assay, this advantage, however, makes the MTS assay sensitive to colorimetric interference as these intermediates remain in the one-step MTS assay [80].
\n
\n
\n
5.12.4 WSTs
\n
WSTs (water-soluble tetrazolium salts), a series of other dyes for MTT assays, are designed to give different absorption spectra for the formed formazans. WST-1, particularly WST-8, have advantages over MTT in that they are reduced outside the cells and form a water-soluble formazan. Finally, unlike MTT, WST assays (1) can be read directly, (2) provide stronger signal than MTT, and (3) are less toxic to cells (unlike membrane-permeable MTT, and the resulting insoluble formazan piles up inside the cells) [81].
\n
\n
\n
\n
5.13 In silico prediction of chemical toxicity
\n
A relatively newer discipline, and highly hot topic, which has become increasingly important in recent years, is the computer-aided in silico toxicity prediction of drugs, food additives, or various industrial chemicals for which a previous wet-lab toxicity outcome is available. For this purpose, QSAR, the CAESAR project, and other virtual screening methods such as docking (i.e., AutoDock, Surflex) software have found wide use in the last decade [82, 83, 84]. While these software use special parameters (e.g., genetic algorithms), the details of these parameters do not fall into the scope of the main subject of this review article.
\n
\n
\n
\n
6. Conclusion
\n
A thorough understanding of the molecular mechanisms of cell division makes it easy to understand cell death. Cells perform division at the right time according to the chemical signals from their internal and external environment. Aberrations in cell division often induce uncontrolled cell division and result in tumor formation. Here, the importance of cytotoxicity parameters and assays in experimentally normal or abnormally divided cells emerges. Many diseases show a direct correlation with the parameters used to measure the division behavior of cells. Thus, a detailed understanding of the molecular mechanisms of cell division and cell death by cell proliferation and cytotoxicity tests is critical in distinguishing between normal and healthy cells. Another important aspect is the selection of the right cytotoxicity assay when working on different cell death mechanisms such as apoptosis, necrosis, necroptosis, or autophagy. Although they appear to reveal very different death pathways, in fact, cytotoxicity assays mainly target a certain number of cellular compartments (lysosome, membrane, nucleus, cytoplasm, mitochondria). In recent years, with the development of in silico toxicity assessment software, cytotoxicity experiments have been transferred from the laboratory to the computer environment. However, the fact that the details of the intracellular milieu are not completely understood yet still keeps the accuracy of the in silico toxicity estimates at a certain level, and therefore it is logical to anticipate that the wet-lab applications (especially in vitro cytotoxicity tests) to measure cell proliferation and cytotoxicity will continue to be the first choice.
\n
\n
Conflict of interest
The authors declare that they have no competing interests.
\n',keywords:"cell division, DNA damage, cell cycle control, mutagens, cellular proliferation parameters, cytotoxicity assays",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68419.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68419.xml",downloadPdfUrl:"/chapter/pdf-download/68419",previewPdfUrl:"/chapter/pdf-preview/68419",totalDownloads:1504,totalViews:0,totalCrossrefCites:3,dateSubmitted:"May 31st 2019",dateReviewed:"July 3rd 2019",datePrePublished:"August 2nd 2019",datePublished:"October 2nd 2019",dateFinished:"August 2nd 2019",readingETA:"0",abstract:"Cell division is a phenomenon that is encountered in all cells in nature. While normal cell division results in proliferation in single-celled organisms, and development and repair in multicellular organisms, aberrant and untimely cell division results in tumor formation. Therefore, the understanding of the cell division is hidden in identifying the details of the molecular mechanisms that govern cellular division at the exact time and under right conditions. Sometimes these molecular mechanisms are distorted by both intrinsic and extracellular factors, and the division process halts or deviates to an abnormal pathway. At this point, it is essential that the abnormal cells are removed from the tissue by an appropriate mechanism. In this context, in this review, general and specific information about cell division and its molecular control mechanisms were discussed, and different types of cell death mechanisms were mentioned accordingly. In addition, chemical, biological, and physical cytotoxic agents that negatively affect cell division and their mechanisms of action are explained. Finally, a brief review of the principles of different cytotoxicity (cell viability and proliferation) test systems has been performed to provide a source of information for investigators who study cell viability, proliferation, or different types of cellular death pathways.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68419",risUrl:"/chapter/ris/68419",signatures:"Erman Salih Istifli, Mehmet Tahir Hüsunet and Hasan Basri Ila",book:{id:"8068",type:"book",title:"Cytotoxicity",subtitle:"Definition, Identification, and Cytotoxic Compounds",fullTitle:"Cytotoxicity - Definition, Identification, and Cytotoxic Compounds",slug:"cytotoxicity-definition-identification-and-cytotoxic-compounds",publishedDate:"October 2nd 2019",bookSignature:"Erman Salih Istifli and Hasan Basri Ila",coverURL:"https://cdn.intechopen.com/books/images_new/8068.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78984-755-0",printIsbn:"978-1-78984-754-3",pdfIsbn:"978-1-83962-286-1",isAvailableForWebshopOrdering:!0,editors:[{id:"179007",title:"Dr.",name:"Erman Salih",middleName:null,surname:"Istifli",slug:"erman-salih-istifli",fullName:"Erman Salih Istifli"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"179007",title:"Dr.",name:"Erman Salih",middleName:null,surname:"Istifli",fullName:"Erman Salih Istifli",slug:"erman-salih-istifli",email:"esistifli@cu.edu.tr",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/179007/images/system/179007.JPG",institution:{name:"Cukurova University",institutionURL:null,country:{name:"Turkey"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. General mechanisms of cell death",level:"1"},{id:"sec_2_2",title:"2.1 Apoptosis",level:"2"},{id:"sec_3_2",title:"2.2 Autophagy",level:"2"},{id:"sec_4_2",title:"2.3 Necrosis",level:"2"},{id:"sec_5_2",title:"2.4 Necroptosis",level:"2"},{id:"sec_7",title:"3. Cytotoxicity",level:"1"},{id:"sec_7_2",title:"3.1 Chemical cytotoxic agents (cytostatics)",level:"2"},{id:"sec_8_2",title:"3.2 Biological cytotoxic agents",level:"2"},{id:"sec_9_2",title:"3.3 Physical cytotoxic agents",level:"2"},{id:"sec_11",title:"4. Universal cytotoxicity parameters",level:"1"},{id:"sec_11_2",title:"4.1 Mitotic index",level:"2"},{id:"sec_12_2",title:"4.2 Nuclear division index (NDI)",level:"2"},{id:"sec_13_2",title:"4.3 Proliferation index (replication index, BrdU incorporation)",level:"2"},{id:"sec_15",title:"5. In vitro cytotoxicity (cell viability) assays",level:"1"},{id:"sec_15_2",title:"5.1 Apoptosis assay",level:"2"},{id:"sec_16_2",title:"5.2 ATP assay",level:"2"},{id:"sec_17_2",title:"5.3 Autophagy assay",level:"2"},{id:"sec_18_2",title:"5.4 BrdU assay",level:"2"},{id:"sec_19_2",title:"5.5 Cell tracking",level:"2"},{id:"sec_20_2",title:"5.6 Gram staining",level:"2"},{id:"sec_21_2",title:"5.7 LDH assay",level:"2"},{id:"sec_22_2",title:"5.8 Live/dead staining",level:"2"},{id:"sec_23_2",title:"5.9 Lysosomal staining",level:"2"},{id:"sec_24_2",title:"5.10 Membrane potential assay",level:"2"},{id:"sec_25_2",title:"5.11 Mitochondrial staining",level:"2"},{id:"sec_26_2",title:"5.12 MTT, XTT, MTS, and WSTs assays",level:"2"},{id:"sec_26_3",title:"5.12.1 MTT assay",level:"3"},{id:"sec_27_3",title:"5.12.2 XTT assay",level:"3"},{id:"sec_28_3",title:"5.12.3 MTS assay",level:"3"},{id:"sec_29_3",title:"5.12.4 WSTs",level:"3"},{id:"sec_31_2",title:"5.13 In silico prediction of chemical toxicity",level:"2"},{id:"sec_33",title:"6. 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Cancer Cell. 2006;10(1):51-64\n'},{id:"B36",body:'\nProskuryakov SY, Konoplyannikov AG, Gabai VL. Necrosis: A specific form of programmed cell death? Experimental Cell Research. 2003;283(1):1-16\n'},{id:"B37",body:'\nKasper DL, Zaleznik DF. Gas Gangrene, Antibiotic Associated Colitis, and Other Clostridial Infections. New York: McGraw-Hill, Medical Pub. Division; 2001. pp. 922-927. www.scienceopen.com\n\n'},{id:"B38",body:'\nRock KL, Kono H. The inflammatory response to cell death. Annual Review of Pathology. 2008;3:99-126\n'},{id:"B39",body:'\nAdigun R, Basit H, Murray J. Necrosis, Cell (Liquefactive, Coagulative, Caseous, Fat, Fibrinoid, and Gangrenous). Treasure Island, FL: StatPearls; 2019\n'},{id:"B40",body:'\nDhuriya YK, Sharma D. Necroptosis: A regulated inflammatory mode of cell death. Journal of Neuroinflammation. 2018;15(1):199\n'},{id:"B41",body:'\nRiss TL, Moravec RA. Use of multiple assay endpoints to investigate the effects of incubation time, dose of toxin, and plating density in cell-based cytotoxicity assays. Assay and Drug Development Technologies. 2004;2(1):51-62\n'},{id:"B42",body:'\nHyesun HO, Surapaneni S, Hui JY. Preclinical development of oncology drugs. In: Faqi AS, editor. A Comprehensive Guide to Toxicology in Preclinical Drug Development. London: Academic Press; 2013. pp. 543-565\n'},{id:"B43",body:'\nLinder R, Bernheimer AW. Action of bacterial cytotoxins on normal mammalian cells and cells with altered membrane lipid composition. Toxicon. 1984;22(4):641-651\n'},{id:"B44",body:'\nNappi AJ, Ottaviani E. Cytotoxicity and cytotoxic molecules in invertebrates. BioEssays. 2000;22(5):469-480\n'},{id:"B45",body:'\nAktories K, Barbieri JT. Bacterial cytotoxins: Targeting eukaryotic switches. Nature Reviews. Microbiology. 2005;3(5):397-410\n'},{id:"B46",body:'\nDavidson JF, Schiestl RH. Cytotoxic and genotoxic consequences of heat stress are dependent on the presence of oxygen in Saccharomyces cerevisiae. Journal of Bacteriology. 2001;183(15):4580-4587\n'},{id:"B47",body:'\nSaad AH, Hahn GM. Ultrasound enhanced drug toxicity on Chinese hamster ovary cells in vitro. Cancer Research. 1989;49(21):5931-5934\n'},{id:"B48",body:'\nMariglia J, Momin S, Coe IR, Karshafian R. Analysis of the cytotoxic effects of combined ultrasound, microbubble and nucleoside analog combinations on pancreatic cells in vitro. Ultrasonics. 2018;89:110-117\n'},{id:"B49",body:'\nBahadar H, Maqbool F, Niaz K, Abdollahi M. Toxicity of nanoparticles and an overview of current experimental models. Iranian Biomedical Journal. 2016;20(1):1-11\n'},{id:"B50",body:'\nWalker PMB. The mitotic index and interphase processes. The Journal of Experimental Biology. 1954;31:8-15\n'},{id:"B51",body:'\nVan\'t Hof J, Kovacs CJ. Mitotic delay in two biochemically different G1 cell populations in cultured roots of pea (Pisum sativum). Radiation Research. 1970;44(3):700-712\n'},{id:"B52",body:'\nGraña E. Mitotic index. In: Sánchez-Moreiras AM, Reigosa MJ, editors. Advances in Plant Ecophysiology Techniques. Switzerland: Springer; 2018. pp. 231-240\n'},{id:"B53",body:'\nSharma S, Vig AP. Antigenotoxic effects of Indian mustard Brassica juncea (L.) Czern aqueous seeds extract against mercury (Hg) induced genotoxicity. Scientific Research and Essays. 2012;7(13):1385-1392\n'},{id:"B54",body:'\nEvseeva TI, Geras\'kin SA, Shuktomova II. Genotoxicity and toxicity assay of water sampled from a radium production industry storage cell territory by means of Allium-test. Journal of Environmental Radioactivity. 2003;68(3):235-248\n'},{id:"B55",body:'\nAl-Ahmadi S. Effects of organic insecticides, Kingbo and Azdar 10 EC, on mitotic chromosomes in root tip cells of Allium cepa. International Journal of Genetics and Molecular Biology. 2013;5(5):64-70\n'},{id:"B56",body:'\nBorah SP, Talukdar J. Studies on the phytotoxic effects of extract of castor seed (Ricinus communis L.). Cytologia. 2002;67:235-243\n'},{id:"B57",body:'\nMadaan N, Mudgal V. Phytotoxic effects of selenium on the accessions of wheat and safflower. Research Journal of Environmental Sciences. 2011;5(1):82-87\n'},{id:"B58",body:'\nHa SY, Choi M, Lee T, Park CK. The prognostic role of mitotic index in hepatocellular carcinoma patients after curative hepatectomy. Cancer Research and Treatment. 2016;48(1):180-189\n'},{id:"B59",body:'\nGaffney EV 2nd, Venz-Williamson TL, Hutchinson G, Biggs PJ, Nelson KM. Relationship of standardized mitotic indices to other prognostic factors in breast cancer. Archives of Pathology & Laboratory Medicine. 1996;120(5):473-477\n'},{id:"B60",body:'\nMeyer JS, Cosatto E, Graf HP. Mitotic index of invasive breast carcinoma. Achieving clinically meaningful precision and evaluating tertial cutoffs. Archives of Pathology & Laboratory Medicine. 2009;133(11):1826-1833\n'},{id:"B61",body:'\nFenech M, Kirsch-Volders M. RE: Insensitivity of the in vitro cytokinesis-block micronucleus assay with human lymphocytes for the detection of DNA damage present at the start of the cell culture (Mutagenesis, 27, 743-747, 2012). Mutagenesis. 2013;28(3):367-369\n'},{id:"B62",body:'\nIonescu ME, Ciocirlan M, Becheanu G, Nicolaie T, Ditescu C, Teiusanu AG, et al. Nuclear division index may predict neoplastic colorectal lesions. Maedica (Buchar). 2011;6(3):173-178\n'},{id:"B63",body:'\nFenech M. The in vitro micronucleus technique. Mutation Research. 2000;455(1-2):81-95\n'},{id:"B64",body:'\nOancea M, Mazumder S, Crosby ME, Almasan A. Apoptosis assays. Methods in Molecular Medicine. 2006;129:279-290\n'},{id:"B65",body:'\nImamura H, Nhat KP, Togawa H, Saito K, Iino R, Kato-Yamada Y, et al. Visualization of ATP levels inside single living cells with fluorescence resonance energy transfer-based genetically encoded indicators. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15651-15656\n'},{id:"B66",body:'\nLee MS, Park WS, Kim YH, Ahn WG, Kwon SH, Her S. Intracellular ATP assay of live cells using PTD-conjugated luciferase. Sensors (Basel). 2012;12(11):15628-15637\n'},{id:"B67",body:'\nOrhon I, Reggiori F. Assays to monitor autophagy progression in cell cultures. Cell. 2017;6(3):E20\n'},{id:"B68",body:'\nB.D. Pharmingen. Bromodeoxyuridine (BrdU). 2014. Available from: http://www.bdbiosciences.com/ds/pm/tds/550891.pdf [Accessed: May 26, 2019]\n'},{id:"B69",body:'\nCell Tracking. 2019. Available from: https://www.thermofisher.com/tr/en/home/life-science/cell-analysis/cell-tracing-tracking-and-morphology/cell-tracking.html [Accessed: May 26, 2019]\n'},{id:"B70",body:'\nKumar P, Nagarajan A, Uchil PD. Analysis of cell viability by the lactate dehydrogenase assay. Cold Spring Harbor Protocols. 2018;2018(6):pdb prot095497\n'},{id:"B71",body:'\nAmirikia M, Ali Jorsaraei SG, Ali Shariatzadeh SM, Mehranjani MS. Differentiation of stem cells from the apical papilla into osteoblasts by the elastic modulus of porous silk fibroin scaffolds. Biologicals. 2019;57:1-8\n'},{id:"B72",body:'\nBahari L, Bein A, Yashunsky V, Braslavsky I. Directional freezing for the cryopreservation of adherent mammalian cells on a substrate. PLoS One. 2018;13(2):e0192265\n'},{id:"B73",body:'\nLysosomal Staining Reagent—Green—Cytopainter (ab176826). 2019. Available from: https://www.abcam.com/lysosomal-staining-reagent-green-cytopainter-ab176826.html [Accessed: May 26, 2019]\n'},{id:"B74",body:'\nBhuyan AK, Varshney A, Mathew MK. Resting membrane potential as a marker of apoptosis: Studies on Xenopus oocytes microinjected with cytochrome c. Cell Death and Differentiation. 2001;8(1):63-69\n'},{id:"B75",body:'\nMeasuring Membrane Potential using the FLIPR® Membrane Potential Assay Kit on Fluorometric Imaging Plate Reader (FLIPR®) Systems. 2019. Available from: https://www.moleculardevices.com/en/assets/app-note/reagents/measuring-membrane-potential-using-flipr-membrane-potential-assay-kit-on-flipr#gref [Accessed: May 26, 2019]\n'},{id:"B76",body:'\nThermoFisher. Functional Mitochondrial Staining Protocol. 2019. Available from: https://www.thermofisher.com/tr/en/home/life-science/cell-analysis/cell-analysis-learning-center/molecular-probes-school-of-fluorescence/imaging-basics/protocols-troubleshooting/protocols/functional-mitochondrial-staining.html [Accessed: May 26, 2019]\n'},{id:"B77",body:'\nTOCRIS. MitoPY1. 2019. Available from: https://www.tocris.com/about-tocris [Accessed: May 26, 2019]\n'},{id:"B78",body:'\nMosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods. 1983;65(1-2):55-63\n'},{id:"B79",body:'\nKuhn DM, Balkis M, Chandra J, Mukherjee PK, Ghannoum MA. Uses and limitations of the XTT assay in studies of Candida growth and metabolism. Journal of Clinical Microbiology. 2003;41(1):506-508\n'},{id:"B80",body:'\nCory AH, Owen TC, Barltrop JA, Cory JG. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Communications. 1991;3(7):207-212\n'},{id:"B81",body:'\nYin LM, Wei Y, Wang Y, Xu YD, Yang YQ. Long term and standard incubations of WST-1 reagent reflect the same inhibitory trend of cell viability in rat airway smooth muscle cells. International Journal of Medical Sciences. 2013;10(1):68-72\n'},{id:"B82",body:'\nYang H, Sun L, Li W, Liu G, Tang Y. In silico prediction of chemical toxicity for drug design using machine learning methods and structural alerts. Frontiers in Chemistry. 2018;6:30\n'},{id:"B83",body:'\nCassano A, Manganaro A, Martin T, Young D, Piclin N, Pintore M, et al. CAESAR models for developmental toxicity. Chemistry Central Journal. 2010;4(Suppl 1):S4\n'},{id:"B84",body:'\nMakarova K, Siudem P, Zawada K, Kurkowiak J. Screening of toxic effects of bisphenol a and products of its degradation: Zebrafish (Danio rerio) embryo test and molecular docking. Zebrafish. 2016;13(5):466-474\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Erman Salih Istifli",address:"esistifli@cu.edu.tr;, ermansalih@gmail.com",affiliation:'
Faculty of Science and Letter, Department of Biology, Çukurova University, Adana, Turkey
Faculty of Science and Letter, Department of Biology, Çukurova University, Adana, Turkey
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Our understanding of the cellular function of Rab35 reveals its role in development and diseases. In the developmental context, Rab35 has been shown to play an important role in regulating epithelial polarity, lumen opening, myoblast fusion, intercalation of epithelium, myelination, neurite outgrowth, and oocyte meiotic maturation. Disruption of recycling endosome mediated by Rab35 has been linked to several neurological diseases, including Parkinson’s disease and Down syndrome. In addition, because Rab35 modulates cell migration through its interaction with various effectors, Rab35 plays an important role in cancers. Lastly, the Rab35-mediated recycling endosomal pathway and exocytosis is utilized by pathogens or hijacked by pathogens to promote their infection and survival. This review summarizes the function of Rab35 in endocytosis and focuses on the role of Rab35 in the context of development and diseases.",signatures:"Jia L. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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The clinical presentation is rarely uniform and may manifest in symptoms besides chest pain, shortness of breath or decreased exercise tolerance. In addition to symptomatic patients, asymptomatic patients are especially important to screen as the effects of cardiac toxicity are reversible if caught early. There are new techniques more sensitive than traditional 2D echocardiography ejection fraction that may lead to earlier detection of cardiac dysfunction. Treatment methods have changed little in the recent past with the exception of miniaturization of support devices allowing for cardiac recovery or bridge to cardiac transplant.",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Jake A. Kleinmahon and Bruce F. 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The families of children with cancer often try the complementary and alternative medicine (CAM) to reduce their children’s experience of physical discomfort.",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Ayşe Gürol and Sevinç Polat",authors:[{id:"192610",title:"Associate Prof.",name:"Ayşe",middleName:null,surname:"Gürol",slug:"ayse-gurol",fullName:"Ayşe Gürol"},{id:"193414",title:"Prof.",name:"Sevinç",middleName:null,surname:"Polat",slug:"sevinc-polat",fullName:"Sevinç Polat"}]}],mostDownloadedChaptersLast30Days:[{id:"53759",title:"The Forgotten Children",slug:"the-forgotten-children",totalDownloads:1478,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"The “forgotten children” of pediatric cancer are the siblings. There is a dearth of literature published on the effects of cancer on the siblings’ psychosocial state. Despite significant improvements made in the survival of pediatric cancer patients, the psychosocial health of the siblings remains the same. The siblings’ need for support and understanding continue to go unnoticed. The aim of this chapter is to shed light on the roles siblings play in the pediatric cancer trajectory, as well as to recognize the emotional and psychological toll they endure through the experience of diagnosis, treatment, survival, and bereavement as the “forgotten children.”",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Christopher Kuo and Paul M. 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The clinical presentation is rarely uniform and may manifest in symptoms besides chest pain, shortness of breath or decreased exercise tolerance. In addition to symptomatic patients, asymptomatic patients are especially important to screen as the effects of cardiac toxicity are reversible if caught early. There are new techniques more sensitive than traditional 2D echocardiography ejection fraction that may lead to earlier detection of cardiac dysfunction. Treatment methods have changed little in the recent past with the exception of miniaturization of support devices allowing for cardiac recovery or bridge to cardiac transplant.",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Jake A. Kleinmahon and Bruce F. Landeck, II",authors:[{id:"192552",title:"Dr.",name:"Jake",middleName:null,surname:"Kleinmahon",slug:"jake-kleinmahon",fullName:"Jake Kleinmahon"},{id:"193398",title:"Dr.",name:"Bruce",middleName:null,surname:"Landeck",slug:"bruce-landeck",fullName:"Bruce Landeck"}]},{id:"55168",title:"Long-Term Survivors of Childhood Cancer: The Late Effects of Therapy",slug:"long-term-survivors-of-childhood-cancer-the-late-effects-of-therapy",totalDownloads:1482,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"The overall cure rate for pediatric malignancies is significantly improved to over 75% with an estimated 270,000 survivors of childhood cancer in the United States currently. The achievement of high cure rates for most pediatric malignancies has been accompanied by a growing population of childhood cancer survivors who are at an increased risk for a myriad of health problems resulting from their cancer or its treatment. Some cancer-related complications do not become apparent until several years following cancer treatment. As the survivors of childhood cancers age, the effects of therapy may be exacerbated by effects of aging on organ function. Late effects encompass a variety of detrimental conditions including organ dysfunction, psychosocial complications, and subsequent malignancies that may negatively impact quality of life and may predispose them to early mortality. In contrast to the multitude of publications describing treatment-related sequelae in childhood cancer survivors, relatively few provide specific recommendations for health screening and risk-reduction counseling to guide healthcare providers in monitoring this vulnerable population. In this chapter, we will summarize the evaluation and management of childhood cancer survivors who may be encountered across a wide variety of healthcare settings, salient issues influencing healthcare for childhood cancer survivors, of which guidelines currently available and limitations in current practice.",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Nupur Mittal and Paul Kent",authors:[{id:"192807",title:"Dr.",name:"Paul",middleName:null,surname:"Kent",slug:"paul-kent",fullName:"Paul Kent"},{id:"194608",title:"Dr.",name:"Nupur",middleName:null,surname:"Mittal",slug:"nupur-mittal",fullName:"Nupur Mittal"}]},{id:"55302",title:"Introductory Chapter: Pediatric Cancer Survivors",slug:"introductory-chapter-pediatric-cancer-survivors",totalDownloads:1031,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Karen Wonders and Brittany Stout",authors:[{id:"52860",title:"Dr.",name:"Karen",middleName:null,surname:"Wonders",slug:"karen-wonders",fullName:"Karen Wonders"}]},{id:"54437",title:"Used of Complementary and Alternative Medicine on Symptoms Management and Quality of Life",slug:"used-of-complementary-and-alternative-medicine-on-symptoms-management-and-quality-of-life",totalDownloads:1303,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Introduction: Children with cancer experience serious difficulties due to the diagnosis, the hospitalization, the symptoms that accompany the long and exhausting treatment process. Unrelieved symptoms related to either cancer or chemotherapy also lead to poorer quality of life, including increased distress and negatively impact healing process. The families of children with cancer often try the complementary and alternative medicine (CAM) to reduce their children’s experience of physical discomfort.",book:{id:"5542",slug:"pediatric-cancer-survivors",title:"Pediatric Cancer Survivors",fullTitle:"Pediatric Cancer Survivors"},signatures:"Ayşe Gürol and Sevinç Polat",authors:[{id:"192610",title:"Associate Prof.",name:"Ayşe",middleName:null,surname:"Gürol",slug:"ayse-gurol",fullName:"Ayşe Gürol"},{id:"193414",title:"Prof.",name:"Sevinç",middleName:null,surname:"Polat",slug:"sevinc-polat",fullName:"Sevinç Polat"}]}],onlineFirstChaptersFilter:{topicId:"1110",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:288,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. 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A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",isOpenForSubmission:!0,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null},{id:"28",title:"Animal Reproductive Biology and Technology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",isOpenForSubmission:!0,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). 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Portugal",institution:null},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:19,paginationItems:[{id:"81793",title:"Canine parvovirus-2: An Emerging Threat to Young Pets",doi:"10.5772/intechopen.104846",signatures:"Mithilesh Singh, Rajendran Manikandan, Ujjwal Kumar De, Vishal Chander, Babul Rudra Paul, Saravanan Ramakrishnan and Darshini Maramreddy",slug:"canine-parvovirus-2-an-emerging-threat-to-young-pets",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"81271",title:"The Diversity of Parvovirus Telomeres",doi:"10.5772/intechopen.102684",signatures:"Marianne Laugel, Emilie Lecomte, Eduard Ayuso, Oumeya Adjali, Mathieu Mével and Magalie Penaud-Budloo",slug:"the-diversity-of-parvovirus-telomeres",totalDownloads:23,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Recent Advances in Canine Medicine",coverURL:"https://cdn.intechopen.com/books/images_new/11580.jpg",subseries:{id:"19",title:"Animal Science"}}},{id:"79909",title:"Cryopreservation Methods and Frontiers in the Art of Freezing Life in Animal Models",doi:"10.5772/intechopen.101750",signatures:"Feda S. Aljaser",slug:"cryopreservation-methods-and-frontiers-in-the-art-of-freezing-life-in-animal-models",totalDownloads:172,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Animal Reproduction",coverURL:"https://cdn.intechopen.com/books/images_new/10664.jpg",subseries:{id:"28",title:"Animal Reproductive Biology and Technology"}}},{id:"79782",title:"Avian Reproduction",doi:"10.5772/intechopen.101185",signatures:"Kingsley Omogiade Idahor",slug:"avian-reproduction",totalDownloads:152,totalCrossrefCites:0,totalDimensionsCites:0,authors:[{name:"Kingsley O.",surname:"Idahor"}],book:{title:"Animal Reproduction",coverURL:"https://cdn.intechopen.com/books/images_new/10664.jpg",subseries:{id:"28",title:"Animal Reproductive Biology and Technology"}}}]},overviewPagePublishedBooks:{paginationCount:10,paginationItems:[{type:"book",id:"7233",title:"New Insights into Theriogenology",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7233.jpg",slug:"new-insights-into-theriogenology",publishedDate:"December 5th 2018",editedByType:"Edited by",bookSignature:"Rita Payan-Carreira",hash:"74f4147e3fb214dd050e5edd3aaf53bc",volumeInSeries:1,fullTitle:"New Insights into Theriogenology",editors:[{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}}]},{type:"book",id:"7144",title:"Veterinary Anatomy and Physiology",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7144.jpg",slug:"veterinary-anatomy-and-physiology",publishedDate:"March 13th 2019",editedByType:"Edited by",bookSignature:"Catrin Sian Rutland and Valentina Kubale",hash:"75cdacb570e0e6d15a5f6e69640d87c9",volumeInSeries:2,fullTitle:"Veterinary Anatomy and Physiology",editors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}]},{type:"book",id:"8524",title:"Lactation in Farm Animals",subtitle:"Biology, Physiological Basis, Nutritional Requirements, and Modelization",coverURL:"https://cdn.intechopen.com/books/images_new/8524.jpg",slug:"lactation-in-farm-animals-biology-physiological-basis-nutritional-requirements-and-modelization",publishedDate:"January 22nd 2020",editedByType:"Edited by",bookSignature:"Naceur M'Hamdi",hash:"2aa2a9a0ec13040bbf0455e34625504e",volumeInSeries:3,fullTitle:"Lactation in Farm Animals - Biology, Physiological Basis, Nutritional Requirements, and Modelization",editors:[{id:"73376",title:"Dr.",name:"Naceur",middleName:null,surname:"M'Hamdi",slug:"naceur-m'hamdi",fullName:"Naceur M'Hamdi",profilePictureURL:"https://mts.intechopen.com/storage/users/73376/images/system/73376.jpg",biography:"Naceur M’HAMDI is Associate Professor at the National Agronomic Institute of Tunisia, University of Carthage. He is also Member of the Laboratory of genetic, animal and feed resource and member of Animal science Department of INAT. He graduated from Higher School of Agriculture of Mateur, University of Carthage, in 2002 and completed his masters in 2006. Dr. M’HAMDI completed his PhD thesis in Genetic welfare indicators of dairy cattle at Higher Institute of Agronomy of Chott-Meriem, University of Sousse, in 2011. 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