\r\n\tCell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms inaction of certain genes, proteins, and pathways involved in cell survival or death after exposure to toxic agents. The methods used to determine viability are also common for the detection of cell proliferation. A cell viability assay is performed based on the ratio of live and dead cells. This assay is based on an analysis of cell viability in cell culture for evaluating in vitro drug effects in cell-mediated cytotoxicity assays for monitoring cell proliferation. Various methods are involved in performing a cell viability assay, including the dilution method, surface viable count, roll tube technique, nalidixic acid method, fluorogenic dye assay, and the Trypan Blue Cell Viability Assay. The cell viability assays can determine the effect of drug candidates on cells and be used to optimize the cell culture conditions. The parameters that define cell viability can be as diverse as the redox potential of the cell population, the integrity of cell membranes, or the activity of cellular enzymes. \r\n\tCytotoxicity is the degree to which a substance can cause damage to a cell. Cytotoxicity assays measure the ability of cytotoxic compounds to cause cell damage or cell death. Cytotoxicity assays are widely used in fundamental research and drug discovery to screen libraries for toxic compounds. The cell cytotoxicity and proliferation assays are mainly used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. In a cell-based assay, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be classified in to different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) Raman micro-spectroscopy. \r\n\tMedical devices have been widely used in various clinical disciplines and these devices have direct contact with the tissues and cells of the body, they should have good physical and chemical properties as well as good biocompatibility. Biocompatibility testing assesses the compatibility of medical devices with a biological system. It studies the interaction between the device and the various types of living tissues and cells exposed to the device when it comes into contact with patients.
\r\n
\r\n\t \r\n\tThe book will cover original studies, reviews, all aspects of Cell Viability and Cytotoxicity assays, methods, Biocompatibility of studies of biomedical devices, and related topics.
",isbn:"978-1-80356-246-9",printIsbn:"978-1-80356-245-2",pdfIsbn:"978-1-80356-247-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"ad664980a1e5007239b6de58fcf0bd9a",bookSignature:"Prof. Sukumaran Anil",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11678.jpg",keywords:"Cytotoxicity, Cytotoxicity Testing, Biocompatibility, ATP Assay, MTT Assay, Cell Viability, DNA Synthesis Cell Proliferation Assays, Raman Micro-Spectroscopy, Trypan Blue Dye Exclusion Assay, Medical Devices, Drugs, Safety Testing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 10th 2022",dateEndSecondStepPublish:"March 10th 2022",dateEndThirdStepPublish:"May 9th 2022",dateEndFourthStepPublish:"July 28th 2022",dateEndFifthStepPublish:"September 26th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Prof. Anil Sukumaran is currently Senior Consultant and Professor of Periodontics and Implant Dentistry, Hamad Medical Corporation/Qatar University, Doha, Qatar. 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1. Introduction
Cancer is a disease that occurs as a result of mutations in the genes responsible for the DNA repair, cellular proliferation, and cell cycle checkpoints, resulting from the unbalanced equilibrium of oncogenes and tumor suppressor genes that cause uncontrolled growth and invasive migration of the cells [1]. In healthy cells, DNA damage can be repaired by distinct DNA repair mechanisms and the cell can continue to its normal functions. However, if the repair mechanism is perturbed, cells can not correct the changes caused by mutations. In spite of this, the protein product of this gene can be degraded or during proliferation, checkpoints in the cell cycle detect the mutation and the cell undergoes apoptosis [2]. However, cancer cells are master to inactivate the cell cycle checkpoints by mutations on tumor suppressor genes and to activate tightly regulated proto-oncogenes. Proto-oncogenes are expressed only when required [3]. They are expressed in a controlled manner for cell growth and act as mitogens in healthy cells [4]. Due to their mitogenic roles, most of the mitogenic genes within the genome are upregulated in the case of cancer, and most of these genes are considered as proto-oncogenes. As a result of accumulated mutations on proto-oncogenes, the cell enters an uncontrolled division pathway [3]. Further at some point, accumulation of mutations in DNA repair mechanisms and tumor suppressor genes suppress cell death mechanisms in tumor cells and oncogenes are upregulated and over-activated in tumor cells. All of these changes cause loss of cell cycle checkpoints to control and DNA repair mechanism’s function, and the cell eventually is transformed into a cancer cell [5].
The TP53, which is known as the guardian of the genome and is one of the proteins that play the most important role in the cell cycle, was first noticed in animal experiments in 1979 when the tumor tissues were examined [6]. p53, a short-lived protein synthesized by the TP53 gene in cells, was named “p53,” taking its name from its molecular weight of 53 kDa (kilodalton) [7]. p53 is a transcription factor that regulates cell division. Specifically, p53 functions at cell differentiation and initiation of DNA repair mechanism, and is a protein that has a role in suppressing cancer in several organisms [8]. The principal mechanism can be summarized with the understanding that p53 is not always active in typical cells and their activity is minimal in the case of healthy cells. p53 protein is activated only after DNA damage.
There are two important steps in the p53 activation process. In the first step, the half-life of p53 increases dramatically, which means the amount of functional p53 increases and degradation of p53 decreases in the cell, then it is observed that p53 proteins rapidly accumulate within the cell due to the DNA damage as illustrated in Figure 1. Thereafter, conformational changes convert the protein into transcriptional regulatory protein form through phosphorylation and enable p53 to be functionally activated. Thus, the increased amount of functional p53 activates DNA repair mechanisms. Normally, when the cells have no DNA damage, the amount of p53 is kept at a low level by protein degradation.
Figure 1.
p53 activation summary; DNA damage enables p53 to become active by inhibition of MDM2 that results in cell cycle arrest, apoptosis, senescence, and DNA repair.
A protein called MDM2 (the murine double minute 2) interferes with p53 and inhibits the function of p53 and sends p53, which function in the nucleus, from the nucleus to cytosol. MDM2 also works as a ubiquitin ligase (Figure 2). This function of MDM2 helps the destruction of functional p53 by sending p53 to the ubiquitin proteasomal system (UPS), and the amount of p53 in the cell is reduced [1, 9, 10]. When genomic damage occurs in cells, cell growth halts, p53 stimulates programmed cell death-apoptosis [11]. Due to its cancer suppression ability, cancer cells adapted to inhibit p53 function in different ways and escape from senescence and apoptosis by distinct mechanisms [10].
Figure 2.
Overview of inactivation of p53 with distinct mechanisms in breast cancer (MDM2 PDB ID: 1T4F; p53 PDB ID: 1TUP and p63 PDB ID: 3US1).
These features and changes on the p53 gene contribute to cancer transformation via escaping from the cell cycle checkpoints and cell death. Therefore, p53 mutations are crucial for most of the cancer cells to sustain their existence. Observation of high-frequency p53 mutations in most of the cancerous cell types can be explained in this way [7]. However, it is known that each type of cancer follows different adaptations and genomic rearrangements depending on specific alterations and environmental factors. P53 mutations and functions also change according to the cancer types with distinct mechanisms. This review elaborates on these distinct mechanisms of p53 mutations in different cancer types.
1.1 Breast cancer
Breast cancer is considered as one of the most frequent types of cancer [12, 13]. Breast cancer morbidity and mortality rates are higher nowadays. There are many different treatment approaches for breast cancer [14]. However, breast cancer in different patients has a variety of symptoms, disease progression, and drug response which proved that breast cancer subtypes are distinct and need different treatment regimens. Breast cancer has a heterogenic nature. Thus, heterogeneity creates different clinical features in the cancer cells [15]. Breast cancer can show differences in the expression of the hormonal receptor as the result of different genetic alterations and rearrangements within the cell [16]. These differences cause different subtypes of breast cancer that show different strategies to survive. With the help of gene expression analysis (genome sequencing, transcriptional and translational analysis, etc.), luminal ER-positive (luminal A and luminal B), HER2 enriched, and triple-negative (basal-like) types are identified as three major types of breast cancer [17].
Mutant p53 plays a pivotal role in the prognosis of approximately 23% of breast cancer [18]. TP53 mutations are the most common genetic modifications in breast carcinomas, according to recent next-generation sequencing-based research, accounting for 30% of them. On the other hand, the distribution of these mutations is strongly associated with tumor subtypes. In 26% of luminal tumors (17% of luminal A, 41% of luminal B), 69% of molecular apocrine tumors, and 88% of basal-like carcinomas, mutations have been elucidated [19]. Further, protein kinases such as CHK1, CHK2 (Rad53), ATM (ataxia-telangiectasia mutated), and ATR (Rad53-related protein), which respond to DNA damage sentinels, such as BRCA1, also control p53 activity and stability. The kinases directly phosphorylate p53, affecting its instability and function [20].
Although the general prevalence of p53 mutation in breast cancer is around 20%, specific forms of the cancer are associated with greater rates (Figure 2). A number of studies, for example, have found an elevated rate of p53 alterations in malignancies caused by carriers of germline BRCA1 and BRCA2 mutations. Surprisingly, p53 mutation occurs in 100% of instances of typical medullary breast carcinomas. This is particularly interesting because it is now well accepted that medullary breast tumors exhibit clinicopathological characteristics with BRCA1-associated instances. Furthermore, methylation-dependent BRCA1 silencing is frequent in medullary breast tumors [21].
TP53 mutation is found in nearly half of HER2 amplified malignancies [13]. The type of change is clearly linked to the breast cancer subtype, with a higher frequency of substitutions in luminal tumors, resulting in a p53 protein with possible novel functionalities such as p63 inactivation. p63 is a member of the p53 family that also has a tumor suppressor activity [22]. The majority of mutations focused on missense mutations. The most frequent missense mutations in p53 are located within the DNA binding domain. Especially in six frequent “hotspot” amino acid codons (R175, G245, R248, R249, R273, and R282) (Figure 2) [23].
Some mutant p53 in the cancer cells lose its tumor-suppressive activity of the wild-type p53 and shows strong oncogenic functions, defined as a gain of function that provides a selective advantage during tumorigenesis progression [24]. Most of the p53 mutations are seen in the DNA binding domain that allows the expression of DNA repair system proteins [25].
Also, due to mutations, p53 can act like prions and cause accumulation within the cancer cells by binding other proteins, such as metabolism, RNA processing, and inflammatory response [18]. On the other hand, deregulation of MDM2-p53 pathway due to amplification and overexpression of MDM2 oncogene which is a master regulator of the p53 tumor suppressor activity, and mutations or deletions of p53 has been correlated to the initiation, progression, and metastasis of breast cancer [10].
Mutations in TP53, as well as the deletion of RB1 and CDKN2A, are among the most well-known genetic changes in tumor suppressor genes in basal-like breast cancer and triple-negative breast cancer [20]. Indeed, up to 80% of basal-like breast cancer have TP53 alterations, which include nonsense and frameshift mutations. The RNA of 99.4% of basal-like breast cancer patients had TP53 mutant-like status. TP53 mutations may have varied effects depending on the breast tumor subtypes. There is now evidence that inactivation of p53 by mutation, amplification of MDM2 or MDM4, or infrequent alterations in other p53 pathway components causes luminal cancers [26].
In conclusion, the activity of p53 can be inhibited by either mutation in p53 or mutations in p53-interacted proteins that regulate its function.
1.2 Bladder cancer
Up to 50% of cancer cases have acquired a mechanism that inactivates p53 function to bypass apoptosis. The most indisputable fact about p53 is its high frequency of modifications in human cancer. Mutant p53 proteins form a complex family of several 100 proteins with heterogeneous properties. The p53 tumor suppressor gene located on chromosome. 17p13 is one of the most frequently mutated genes in all human malignant diseases, including bladder cancer [27].
It is known that p53 gene mutations occur early in the pathogenesis of bladder cancer and late in other cancer types [28, 29]. Tumor protein p53 gene mutation is an important marker for bladder cancer progression and is associated with poor prognosis and recurrence [30]. The TP53 gene is responsible for maintaining genome integrity as it encodes a protein that is activated in response to cellular stress to repair possible DNA damage [31].
About 60% of bladder cancer cases result in mutp53 (mutant-p53) in exon 5–11. mutp53 is commonly associated with the mutRb gene in high-grade, invasive, and poorly prognostic bladder cancer [32]. Up to 20% of all BC cases were caused by the p53 gene mutation in exons 1–4, accompanied by mutCDKN2a and loss of ARF function. Therefore, it has been suggested that mutations in the RB, CDKN2a, and ARF genes may follow the p53 mutation [33].
1.2.1 p53 mutations in bladder cancer
The p53 gene is mutated in 20–60% of bladder tumors. Especially codon 80 and codon 285 are the regions where mutations are the most common. The gene encodes p53 has a conserved sequence and has 5 polymorphisms that are located in coding part of the gene. While four of them are codon 34, 36, 47, 72 in exon 4; one was found in exon 6 codon 213. Most of the polymorphisms in p53 were found in the intronic region. There are two in intron 1, one in intron 2, one in intron 3, two in intron 6, five in intron 7, and one in intron 9. Of these, polymorphisms at codon 72 and codon 47 are well characterized [34].
Codon 280 and 285 in exon 82 are hot regions for mutation formation. Codon 280 is common in 1.2% of all cancer types and mutant in 5.1% of urinary bladder cancers. These values are 0.82% of all cancer types for codon 285, compared to 4.3% of urinary bladder cancers [35].
1.2.2 p53 polymorphisms in bladder cancer
The incidence of the codon 72 arginine/proline (Arg-CGC/Pro-CCC) polymorphism varies by ethnic group and geography [36]. The region containing the five repeat pxxp sequence (proline) located between amino acids 61 and 94 in p53 is thought to be involved in the signal transduction of this motif through its binding activity to the SH3 region. In cell culture studies, defects in the suppression of tumor cell growth by p53 have been associated with the deletion of the proline-rich region. Conversion of the G base to the C base causes the conversion of arginine AA at codon 72 to proline AA. The Arg carrying a form of p53 was found to be significantly more associated with tumor growth than the proline carrying form [37]. In a study, it was shown that the Arg/Arg genotype increases the risk of developing bladder cancer [38]. In addition, Kuroda et al. found an increased risk of urethral cancer in smokers with the Pro/Pro genotype [39].
Silent mutations at codon 36 (CCG → CCT); It was observed that MDM2 decreased the affinity of TP53 mRNA and decreased the activity of P53 in apoptosis. Three similar polymorphisms, D21D (GAC → GAT), P34P (CCC → CCA), and P36P (CCG → CCA), are found in key regions in MDM2-binding TP53 mRNA. According to the latest findings, translation inhibition is inhibited by microRNA (miRNA) targeting gene coding sequences [40, 41].
1.3 Brain cancer
There are more than a 100 different types of brain tumors which are either primary brain tumors that arise from the central nervous system (CNS) cells or secondary brain tumors that have metastasized from other tissues in the body. While primary brain tumors make up about 2% of all cancers, secondary brain tumors are seen 10 times more often.
Brain tumors can be considered as a heterogeneous group of benign and malignant tumors. Even though most types are cancerous, benign tumors can also become damaging for the brain tissue. Their classification using various parameters and a grading system (I–IV) by the World Health Organization (WHO) is a helpful criterion when choosing the best approach in diagnosis and treatment. When classifying brain tumors, in addition to histological criteria, molecular genetic alterations are also taken into consideration and nomenclatured accordingly [42, 43].
Meningiomas, originating in the dura, are usually benign and can be removed by surgery; they represent around 36% of all primary brain tumors [43]. Almost 75% of malignant primary tumors and 29% of all brain tumors are gliomas. They originate from glial cells and are grouped as circumscribed (grade I) and diffusely infiltrating (grades II, III, and IV) gliomas. Circumscribed gliomas, called ependymomas, are usually benign and can be cured with complete resection. They make up about 7% of gliomas and mostly affect children. The latter group, including astrocytomas (about 75% of gliomas) and oligodendrogliomas (about 6% of gliomas), are usually malignant and difficult to cure. This group also includes mixed gliomas which are not easy to diagnose as the composition of cell type, whether astrocytes or oligodendrocytes, may not be accurately determined [42, 43, 44]. As the most common and deadly primary tumor, glioblastoma makes up almost half of all gliomas and about 80% of malignant gliomas. About 30% of glioblastomas have p53 mutations related to loss or gain-of-function, and also dominant-negative effects [45].
One of the most studied proteins, p53 is best known for its tumor suppressor role. In cases of tumor stress, it stops the cell cycle to either let DNA repair itself or cause cell death with interferes with tumorigenesis. Its involvement plays a major role in the regulation of apoptosis and therefore cases of p53 mutations lead to deregulation and dysfunction of apoptotic responses through p53-dependent mechanisms. It is already one of the most common mutant genes in human cancers, but it is also known to be closely involved with cancers related to CNS, and also other neurological diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease [46, 47]. Studies done with transgenic mice overexpressing amyloid-β have demonstrated increased expression and accumulation of p53 in the brain, which was also seen in the brains of Alzheimer’s patients [48, 49].
p53 has also been of great importance during the development of the brain and regulation of neuroinflammation [47, 50]. One of the earliest studies performed on p53-deficient mice has demonstrated abnormal brain development. As a result of decreased apoptosis, defects in the closing of the neural tube have occurred. This disruption has eventually led to exencephaly followed by anencephaly [51].
Inactivation of p53 happens through several mechanisms including the disruption of its gene expression or protein stability and also loss or mutation of the gene itself. These mechanisms result in malignant properties such as invasiveness, undifferentiated status, and genetic stability. The frequency of p53 mutations depends on the type of tumor. Glioblastoma, the most lethal one, has the highest incidence of 70%. Mixed gliomas and astrocytomas are moderate, 40%, and 50%, respectively. Oligodendrogliomas have the lowest incidence among all gliomas. In general, tumor grades are determinant in the occurrence rate of p53 mutations, of which missense mutation is the main one. C:G → A:T mutation is the most common mutation of p53 seen at CpG sites, affecting the DNA binding properties through three codons, R248, R273, and R175, in the DNA binding domain according to The Cancer Genome Atlas (TCGA). Mutations of this domain have led to gain-of-function to induce tumorigenesis. Additionally, splice site mutations, promoter methylations have also been identified [44, 47, 50].
An example of gain-of-function mutation is given in a recent study done on an invasive brain tumor, glioblastoma. Mutation in TP53 increases the tendency of aggregate formation via mutant P53 oligomerization due to exposed hydrophobic parts. Once aggregation of this protein takes place in the cell, conditions for cancer initiation and oncogenic activities are likely to be established [52].
Another group analyzed the key genes and pathways of p53 mutations in low-grade glioma patients. RNA-seq data from the TCGA database were analyzed by various bioinformatics tools to have a deeper understanding of the role of this protein in disease progression. Out of 508 patients, 49% had mutations such as amplification, deletion, truncation, in-frame mutations, and missense mutations throughout the whole gene. Cancer cells with these mutations were then found to be resistant to some chemotherapeutic drugs that are normally used to treat glioma. This is an indication that it is especially important to distinguish whether the patient has p53 mutation or not to avoid failure of the therapy. In addition, 1100 differentially expressed genes were identified, of which most were associated with pathways related to cancer development and progress [53].
In conclusion, primary brain tumors are difficult to deal with, in terms of understanding their basis and managing the progress. In cases of relevant p53 mutations, attention can be focused on avoiding the degradation of this protein or using chaperones to reestablish its structural integrity and biological activity. Upstream and downstream molecules can be alternatively targeted to develop other novel therapeutic strategies. Last but not the least, determination of p53 mutations is a significant step that helps to choose the best individualized therapy for cancer patients.
1.4 Liver cancer (hepatocellular carcinoma)
Liver cancer is the second most common cause of cancer-based mortality worldwide, accounting for 7% of all cancers with 854,000 new diagnoses each year. The main histological subtype of liver cancer is hepatocellular carcinoma (HCC) which originates from hepatocytes. Considering the population, the incidence of hepatocellular carcinoma increases with age, and male individuals are at greater risk. Based on etiological data in HCC; hepatitis virus and HIV infections, smoking and alcohol use, aflatoxin B1 exposure, and metabolic diseases are the factors associated with carcinogenesis. More effective therapies are still being investigated for HCC due to the fact that the methods used in the treatment are less effective, the treatment is accompanied by cirrhosis, liver failure, and the difficulty of grading-staging of the tumor [54, 55].
The functioning of hepatocellular carcinoma induced by carcinogens is caused by multiple dysfunctions on the MDM2-p53 axis. Oncogene activation, genotoxic and ribosomal stress, and hypoxia signals activate the p53 mechanism. p53, the most important tumor suppressor, is also associated with hepatocyte proliferation and metabolism. Hepatitis B virus-X protein (HBx), which binds p53 and sends it from the nucleus to the cytoplasm, has been shown to play an important role in the development of HCC. Special regions in MDM2 and p53 are linked to exposure to environmental carcinogens and the development of HCC. Mutations in the MDM2-p53 axis and chronic HCV infection have been shown to trigger the development of HCC [56]. Normally, if MDM2-p53 key regions are not phosphorylated, the increase in MDM2 levels leads to inhibition of p53 expression activity, which disrupts cell cycle control and stimulates tumor formation. The scientific findings accumulated due to these mechanisms indicate that p53 is critical for stopping the development of HCC [8, 57].
Clinical case studies suggest that control of p53 expression for regeneration of liver tissue after partial hepatectomy may regulate CDK2-CDK4 activity, which promotes DNA synthesis in hepatocytes. In addition, in mice with p53 defects, repair of liver failure and hepatocyte damage is delayed. According to these results; homeostasis of wild-type p53 expression controls the proliferation and apoptosis of normal hepatocytes. However, mutant p53 is predominantly a negative inhibitor compared to wild-type p53. The fact that mutant p53 oncogenic potential is a major factor in liver cancer, as with many malignant cancers [8, 54].
The basic mechanism of apoptosis formed by p53 depends on death signals that directly or indirectly target mitochondria through pro-apoptotic members of the TP53 and Bcl-2 family, both of which have mutations. Healthy liver cells are resistant to p53-mediated cell death, and the relationship between mitochondrial translocation of p53 and apoptosis after DNA damage is rare. In HCC cells, the activation of p53 encourages stopping the cell cycle instead of apoptosis, and mostly in hepatocytes, the mitochondrial-dependent p53 apoptosis pathway is blocked. The likely cause of this critical change is the increased expression of hepatic insulin-like growth factor binding protein-1 (IGFBP1), which antagonizes the mitochondrial p53 pathway and prevents apoptosis as a result of p53 activation [58, 59].
The main mutation of TP53 in hepatocellular carcinoma occurs in the DNA binding region of p53, which causes a lower affinity to bind specific response units of their targeted genes to the array, and p53-mediated MDM2 induction decreases. As a result, misregulation of MDM2 results in high levels of mutant p53 expression in many cancerous cells [58, 60].
The key role of 53 in tumor development has made p53 an inspiring target for drug studies that inhibit HCC development. Treatments to restore p53 function in HCC have been shown to damage cancer cells that express both mutant p53 and wild-type p53. Current treatment approaches for HCC; chemotherapy, radiotherapy, degradation pathways of ADP-ribosylation factor proteins inhibiting p53, inhibition of MDM2-p53 connectivity, and the addition of molecules regulating the active region of the p53 protein [61].
1.5 Osteosarcoma
Osteosarcoma, which can also be called osteogenic sarcoma, is a cancer type that is related to bones. It is a common pediatric bone tumor as it has an annual diagnose rate of 400 children [62]. This type of cancer starts to form when there is a problem with the cells that are responsible to make new bones [62]. Healthy bone cells may have alterations in their DNA, which can result to make new bones when there is no need for them. As a result of making new bones without a need, there will be a cell mass formed with poorly formed bone cells. Then, this cell mass will destroy the body tissue that was healthy in the first place by invading it. Also, as the cancer progress, some cells can spread through the body and metastasize.
There are two kinds of p53 with different effects on osteosarcoma. Wild-type p53 functions as a tumor suppressor and the mutant p53 have a carcinogenic effect and are found to be overexpressed in malignant osteosarcoma [63]. A study proves this overexpression point by using immunochemistry and concluding that mutant p53 had a 47.7% positive expression rate [63]. On the other hand, since wild-type p53 is a protein known to be a tumor suppressor, it is expected to have changes due to mutations, etc. in most cancers. With this change process, a response to DNA damage cannot be made and the genome destabilizes. Like other types of cancer, osteosarcoma is also known to have this type of relationship with the p53 protein. Changes in p53 are shown to have a correlation with the instability of the genome with osteosarcoma patients [64]. HDM2 is a protein that functions as a negative regulator of p53 [64]. It is found that if there is an amplification of the HDM2 protein, the expected instability of the genome does not happen. When HDM2 protein amplification happens without mutations happening in p53 protein, there is not a high level of instability in the genome. When these direct and indirect ways to change p53 are compared, the alterations that happen with HDM2 amplification do not even correspond to half of the alterations that destabilize the genome caused by a direct mutation in p53 [64]. So, this implies different ways that cause a change in the p53 protein happens to create different results. Since this is not a fully established subject, future studies on the different kinds of changes can be found helpful in the research of this disease and its treatments.
TP53 is a gene that works to help assemble the p53 (or TP53) protein. The prognostic values of osteosarcoma patients with TP53 mutations are also studied. An analysis was made using eight eligible studies which in total had 210 osteosarcoma patients [4]. Final data from this analysis concluded that in two-year survival of osteosarcoma patients, the mutations of TP53 had a negative impact when compared to wild-type ones. So, it is concluded that TP53 mutations are important for the patients’ survival rates and are prognostic markers [65]. Although the results from this study conclude that the mutations have an unfavorable impact on survival, there is still a need for larger-scale studies showing three-to-five-year survival of osteosarcoma patients.
The influence of TP53 mutations is also shown in another study, St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project (PCGP), which concludes that 90% of the patients with osteosarcoma showed a mutation in the TP53 gene [66]. This study also revealed the type of mutations upon whole-genome sequencing 34 osteosarcoma tumors [66]. They concluded that 55% of the TP53 mutations are caused by structural variants, and it is found to be second cancer with these types of mutations that is related to the rearrangement of chromosomes instead of point mutations [66]. This effect of TP53 mutations is believed to be the reason for the ineffectiveness of standard doses in radiation therapy.
1.6 Lung cancer
The TP53 gene mutation is one of the most common causes of lung cancer and has a key role in the carcinogenesis of lung epithelial cells. Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are two main types of lung cancer in humans. Approximately 80% of all lung cancers are NSCLC that creates most of the TP53 mutations [67].
The TP53 gene has been found in lung cancer pathogenesis with the frequent detection of loss of heterozygosity (LOH) at the location of the TP53 gene on chromosome 17p13 in lung cancer cell lines and tumor samples. Additionally, it has been shown that the mutations in the TP53 in lung cancers have been linked to a poorer prognosis and increased cellular resistance to therapy [68]. SCLC specimens have the highest prevalence of TP53 mutations [69]. However, in NSCLC tumor samples, squamous cell carcinomas have the highest frequency of TP53 mutations and adenocarcinomas have the lowest frequency. The location of TP53 mutations is mostly in the DNA-binding domain of TP53 and is detected in cancers with and without allele loss at 17p13 [70]. Acquired TP53 mutations are kept during tumor progression and metastatic spread since TP53 coding mutations appear early in the evolution of lung cancer and are possibly essential for maintaining the malignant phenotype. Chang and his colleagues clarified that TP53 mutations were found in 23.2% of primary tumors and 21.4% of metastatic lymph nodes. Moreover, there was 92.9% concordance between 56 patients with NSCLC who had surgical resection in primary tumors and metastatic lymph nodes [71]. This explains that the majority of TP53 mutations arise before the tumor spreads. They are subsequently preserved throughout the rest of the tumor’s development, therefore there is no selection for TP53 mutations during metastasis [67].
1.6.1 Tobacco-associated lung cancer and TP53 mutations
Tobacco smoking is the major cause of lung cancer, and the risk of lung cancer rises with the number of cigarettes smoked and the length of time spent smoking although 15% of men and 53% of women with lung cancer in the world are never smokers. Furthermore, in the United States and the European Union, tobacco smoking is responsible for more than 90% of lung cancer in males and 74–80% of lung cancer in women [72]. TP53 mutations are detected in more than half of lung cancers. Therefore, this makes the TP53 gene one of the most common targets of tobacco smoking-related DNA alterations.
Several studies have previously discovered hotspots on the TP53 gene, with G:C to T:A (G to T) transversions being a common finding in tobacco-related lung cancer [73]. In addition, 90% of the guanines that undergo these transversion events are found on the non-transcribed DNA strand. There was a lower incidence of G to T transversions in lung cancer tissues from never-smokers than from smokers [74]. Polycyclic aromatic hydrocarbons (PAH) that are found in tobacco smoke are thought to cause the spectrum of G to T transversions. The major metabolite of benzo[α]pyrene which is the most studied member of the PAH class is benzo[α]pyrene diol epoxide (BPDE). Moreover, it is one of the most dangerous carcinogens found in high concentrations of tobacco smoke [75]. A number of studies have demonstrated that BPDE-DNA adduct patterns in the TP53 gene in bronchial epithelial cells correspond to G to T mutational hotspots at codons 157, 248, and 273. At these codons, G to T transversions are common for bulky adduct-producing mutagens, such as PAHs and BPDE adducts [76].
1.6.2 TP53 mutations in never-smokers and smokers
Several studies have clarified that lung cancer from smokers shows a different and unique mutation spectrum in the TP53 gene than lung cancer from never-smokers. Up to 83% of TP53 mutations were transitioned in female never-smokers with adenocarcinoma patients. On the other hand, TP53 mutations in smokers were mostly transversions (60%) and deletions (20%). The incidence of TP53 mutations was shown to be proportional to the amount of tobacco smoking in patients with adenocarcinoma [77]. However, never-smokers with adenocarcinoma patients have more mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase than tobacco-associated lung cancer patients and have a higher response to its inhibitors. Additionally, in adenocarcinoma, TP53 mutations have been found to be closely linked to smokers, while EGFR mutations are statistically substantially more common in females and never-smokers. Moreover, the incidence of K-ras and TP53 mutations varies between never-smoker lung cancer patients and smoker lung cancer patients [78].
1.6.3 Therapeutic strategies for NSCLC patients with TP53 mutation
TP53 mutations show chemoresistance to lung cancer cells in vivo and in vitro, according to several studies. If TP53 status is determined, chemo or radiation therapy can be decided. For example, cancers carrying the mutant TP53 are known to be more resistant to ionizing radiation than tumors containing the wild-type TP53 [79]. To target the TP53 pathway in cancer, virus-based therapeutic strategies are one of the most advanced strategies. Because TP53 mutations are common in lung cancer, the treatment with various chemotherapy classes and TP53 gene replacement techniques has been investigated in both preclinical and clinical settings. When TP53 gene therapy was studied in lung cancer patients in clinical trials, some researchers have suggested that combining adenovirus (Adp53) gene therapy with chemotherapy medicines and radiotherapy can be effective [80]. For instance, 28 patients with NSCLC were given the Adp53 gene into their tumors without any other therapy in the phase I clinical trial. Two patients (8%) had a significant reduction in tumor size, and 16 patients (64%) had disease stabilization; the remaining seven patients (28%) had disease progression [81].
There are also several approaches such as rational design and screening of chemical libraries to identify small compounds that target mutant TP53. RITA was discovered in the National Cancer Institute’s (NCI) drugs that could reduce cell proliferation in a wild-type TP53-dependent way. It reactivates TP53 and promotes apoptosis by breaking the interaction with HDM-2 after attaching to it [82]. As a result, it has been proposed as a crucial drug to target tumors with wild-type TP53 that may be resistant to drugs that restore mutant TP53 activity, such as PRIMA-1 (p53 reactivation and production of large apoptosis). PRIMA-1 that is a low-molecular-weight drug has been discovered to suppress the growth of tumor cells expressing mutant TP53. It binds to the core of mutant TP53, restoring its wild-type conformation and inducing apoptosis in human tumor cells [83]. A study revealed that although PRIMA-1 did not cause apoptosis in human NSCLC cell lines encoding distinct TP53 proteins, such as A549 (p53wt), LX1 (p53R273H), and SKMes1, it did dramatically impair cell viability (p53R280K). In addition, PRIMA-1 enhances adriamycin-induced apoptosis in A549 and LX1 cells when used in combination with the drug. In a preclinical setting, Adp53 gene therapy and PRIMA-1 which can restore the transcriptional function of mutant TP53, or RITA, which inhibits MDM2-directed TP53 degradation, have been performed, and some of these techniques are now in clinical development [84]. Last but not least, the combination of the traditional and molecular-targeting cancer treatments with new TP53-based therapeutic methods for NSCLC can offer great potential for targeting only cancer cells.
2. Conclusions
P53 stands at the heart of the cancer mechanism due to its role in cell survival and death. TP53 essential role in cell fate decision attracts the interest of cancer researchers and makes the protein a superior target for anti-cancer drugs. Therefore, the focus on TP53 research at distinct cancer types increases dramatically and TP53 is targeted by drug designers to inhibit its mutant protein function. P53 and its partner proteins like its negative regulator MDM2 are of further interest for this purpose. This protein-protein interaction features specific properties for allosteric protein inhibition. Yet, the mutant composition of p53 alters among distinct cancer types. As it is illustrated in Figure 3, p53 follows various mechanisms in distinct cancer types.
Figure 3.
Roles of p53 in cancerous cells.
Acknowledgments
Merve Nur AL, Berçem Yeman, and Kezban Ucar Ciftci acknowledge YOK 100/2000 Scholarship. Nazlican Yurekli acknowledges TUBITAK 2247-C Scholarship.
\n',keywords:"p53, TP53, mutation, loss-of-function, breast cancer, bladder cancer, liver cancer, brain cancer, osteosarcoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80133.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80133.xml",downloadPdfUrl:"/chapter/pdf-download/80133",previewPdfUrl:"/chapter/pdf-preview/80133",totalDownloads:110,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:0,impactScoreQuartile:0,hasAltmetrics:0,dateSubmitted:"October 2nd 2021",dateReviewed:"December 9th 2021",datePrePublished:"January 20th 2022",datePublished:null,dateFinished:"January 20th 2022",readingETA:"0",abstract:"TP53 codes tumor protein 53-p53 that controls the cell cycle through binding DNA directly and induces reversible cell-cycle arrest. The protein activates DNA repair genes if mutated DNA will be repaired or activates apoptotosis if the damaged DNA cannot be fixed. Therefore, p53, so-called the “guardian of the genome,” promote cell survival by allowing for DNA repair. However, the tumor-suppressor function of p53 is either lost or gained through mutations in half of the human cancers. In this work, functional perturbation of the p53 mechanism is elaborated at the breast, bladder, liver, brain, lung cancers, and osteosarcoma. Mutation of wild-type p53 not only diminishes tumor suppressor activity but transforms it into an oncogenic structure. Further, malfunction of the TP53 leads accumulation of additional oncogenic mutations in the cell genome. Thus, disruption of TP53 dependent survival pathways promotes cancer progression. This oncogenic TP53 promotes cell survival, prevents cell death through apoptosis, and contributes to the proliferation and metastasis of tumor cells. The purpose of this chapter is to discuss the contribution of mutant p53 to distinct cancer types.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80133",risUrl:"/chapter/ris/80133",book:{id:"10246",slug:null},signatures:"Kubra Acikalin Coskun, Merve Tutar, Mervenur Al, Asiye Gok Yurttas, Elif Cansu Abay, Nazlican Yurekli, Bercem Yeman Kiyak, Kezban Ucar Cifci and Yusuf Tutar",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Breast cancer",level:"2"},{id:"sec_2_2",title:"1.2 Bladder cancer",level:"2"},{id:"sec_2_3",title:"1.2.1 p53 mutations in bladder cancer",level:"3"},{id:"sec_3_3",title:"1.2.2 p53 polymorphisms in bladder cancer",level:"3"},{id:"sec_5_2",title:"1.3 Brain cancer",level:"2"},{id:"sec_6_2",title:"1.4 Liver cancer (hepatocellular carcinoma)",level:"2"},{id:"sec_7_2",title:"1.5 Osteosarcoma",level:"2"},{id:"sec_8_2",title:"1.6 Lung cancer",level:"2"},{id:"sec_8_3",title:"1.6.1 Tobacco-associated lung cancer and TP53 mutations",level:"3"},{id:"sec_9_3",title:"1.6.2 TP53 mutations in never-smokers and smokers",level:"3"},{id:"sec_10_3",title:"1.6.3 Therapeutic strategies for NSCLC patients with TP53 mutation",level:"3"},{id:"sec_13",title:"2. Conclusions",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Xu Z, Wu W, Yan H, Hu Y, He Q, Luo P. 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The p53 family in hepatocellular carcinoma. Translational Cancer Research;5(6):632-638. DOI: 10.21037/tcr.2016.11.79'},{id:"B61",body:'Yang C, Huang X, Li Y, Chen J, Lv Y, Dai S. Prognosis and personalized treatment prediction in TP53-mutant hepatocellular carcinoma: An in silico strategy towards precision oncology. Briefings in Bioinformatics. 2021;22(3):bbaa164. DOI: 10.1093/bib/bbaa164'},{id:"B62",body:'Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treatment and Research. 2009;152:3-13. DOI: 10.1007/978-1-4419-0284-9_1'},{id:"B63",body:'Liu P, Wang M, Li L, Jin T. Correlation between osteosarcoma and the expression of WWOX and p53. Oncology Letters. 2017;14(4):4779-4783. DOI: 10.3892/ol.2017.6747. Epub 2017 Aug 10'},{id:"B64",body:'Overholtzer M, Rao PH, Favis R, Lu XY, Elowitz MB, Barany F, et al. The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. 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Role of p53 as a prognostic factor for survival in lung cancer: A systematic review of the literature with a meta-analysis. The European Respiratory Journal. 2001;18(4):705-719. DOI: 10.1183/09031936.01.00062201'},{id:"B69",body:'Sameshima Y, Matsuno Y, Hirohashi S, Shimosato Y, Mizoguchi H, Sugimura T, et al. Alterations of the p53 gene are common and critical events for the maintenance of malignant phenotypes in small-cell lung carcinoma. Oncogene. 1992;7(3):451-457'},{id:"B70",body:'Tammemagi MC, McLaughlin JR, Bull SB. Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers. Cancer Epidemiology, Biomarkers & Prevention. 1999;8(7):625-634'},{id:"B71",body:'Chang YL, Wu CT, Shih JY, Lee YC. Comparison of p53 and epidermal growth factor receptor gene status between primary tumors and lymph node metastases in non-small cell lung cancers. Annals of Surgical Oncology. 2011;18(2):543-550. DOI: 10.1245/s10434-010-1295-6. Epub 2010 Sep 2'},{id:"B72",body:'Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA: A Cancer Journal for Clinicians. 2005;55(2):74-108. DOI: 10.3322/canjclin.55.2.74'},{id:"B73",body:'Hainaut P, Pfeifer GP. Patterns of p53 G→T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis. 2001;22(3):367-374. DOI: 10.1093/carcin/22.3.367'},{id:"B74",body:'Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21(48):7435-7451. DOI: 10.1038/sj.onc.1205803'},{id:"B75",body:'Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996;274(5286):430-432. DOI: 10.1126/science.274.5286.430'},{id:"B76",body:'Smith LE, Denissenko MF, Bennett WP, Li H, Amin S, Tang M, et al. Targeting of lung cancer mutational hotspots by polycyclic aromatic hydrocarbons. Journal of the National Cancer Institute. 2000;92(10):803-811. DOI: 10.1093/jnci/92.10.803'},{id:"B77",body:'Kondo K, Tsuzuki H, Sasa M, Sumitomo M, Uyama T, Monden Y. A dose-response relationship between the frequency of p53 mutations and tobacco consumption in lung cancer patients. Journal of Surgical Oncology. 1996;61(1):20-26. DOI: 10.1002/(SICI)1096-9098(199601)61:1<20::AID-JSO6>3.0.CO;2-U'},{id:"B78",body:'Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Annals of Oncology. 2009;20(4):696-702. DOI: 10.1093/annonc/mdn679. Epub 2008 Dec 16'},{id:"B79",body:'Vogt U, Zaczek A, Klinke F, Granetzny A, Bielawski K, Falkiewicz B. p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer. Journal of Cancer Research and Clinical Oncology. 2002;128(3):141-147. DOI: 10.1007/s00432-001-0305-2. Epub 2002 Jan 26'},{id:"B80",body:'Leslie WT, Bonomi PD. Novel treatments in non-small cell lung cancer. Hematology/Oncology Clinics of North America. 2004;18(1):245-267. DOI: 10.1016/s0889-8588(03)00146-1'},{id:"B81",body:'Swisher SG, Roth JA, Nemunaitis J. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. Journal of the National Cancer Institute. 1999;91(9):763-771. DOI: 10.1093/jnci/91.9.763'},{id:"B82",body:'Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nature Medicine. 2004;10(12):1321-1328. DOI: 10.1038/nm1146. Epub 2004 Nov 21'},{id:"B83",body:'Selivanova G, Wiman KG. Reactivation of mutant p53: Molecular mechanisms and therapeutic potential. Oncogene. 2007;26(15):2243-2254. DOI: 10.1038/sj.onc.1210295'},{id:"B84",body:'Magrini R, Russo D, Ottaggio L, Fronza G, Inga A, Menichini P. PRIMA-1 synergizes with adriamycin to induce cell death in non-small cell lung cancer cells. Journal of Cellular Biochemistry. 2008;104(6):2363-2373. DOI: 10.1002/jcb.21794'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Kubra Acikalin Coskun",address:null,affiliation:'
Faculty of Medicine, Division of Medicinal Biology, Department of Basic Sciences, Istanbul Aydin University, Turkey
Hamidiye Faculty of Pharmacy, Division of Biochemistry, Department of Basic Pharmaceutical Sciences, University of Health Sciences-Turkey, Turkey
Division of Molecular Oncology, Hamidiye Health Sciences Institutes, University of Health Sciences-Turkey, Turkey
Validebağ Research Center, University of Health Sciences-Turkey, Turkey
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1. Introduction
Production levels of fishery and aquaculture have been increasing for the last 30 years, as fish is an important protein source for human consumption and it is expected to reach a production of 196 mt by 2025 [1]. As a result, more and more people depend on fish or other fisheries production, capture, processing and marketing. By 2018, aquaculture production in the world was estimated to reach over 178 million tons [2], whereas marine capture fisheries have been around half the global production [3].
A huge waste volume has been produced along with that production increase, too. Around 70% of fish is processed before final sale, producing between 20 and 80% of fish waste, depending on the fish type and its transformation technology [4]. Furthermore, important amounts of water are required for those processes [5]. That situation represents a challenge from an environmental perspective because around 50% of that fish waste is discarded without being used [6]. Most of it is buried or deposited in water sources, either in the ocean, rivers, or streams. In the case of landfills, it can lead to saturations that cause odor and leachate problems. As for dumping in water sources, aerobic bacteria use organic matter by the action of oxygen, releasing large amounts of phosphorus, nitrogen and ammonium, affecting pH, causing algae growth, and turbidity. The absence of oxygen in water results in the release of hydrogen sulfide, carbon dioxide, organic acids, methane, and ammonium [7].
These wastes contain important nutrient levels [8] and their composition depends on species, source organs or obtaining processes, as seen in Table 1. On the other hand, some of those nutrients represent an opportunity from an economic perspective, as in the case of the protein, which can be recovered to obtain high added-value compounds.
Process
Organic byproduct
%
Goal
Stunning
N/A
Decrease agony time to reduce undesirable compound production
Classification
Whole fish
Separate by size or species
Slime removal
Aqueous fluid
Reduce microbial contamination surface
Scaling
Scales
5
Reduce bacterial contamination
Washing
Washing water
100
Remove micro-organisms and contaminants
Head removal
Heads
9–32
Remove non-edible or low-value parts
Evisceration
Viscera
12–18
Remove internal organs to reduce microbial contamination
Fin Cutting
Fins
1–2
Remove non-edible parts
Skinning
Skin
3
Remove non-edible parts
Filleting
Fillet remains
15–20
Separation of dorsal and abdominal meat from fish
Bone/meat separation
Bones and skeletons
9–15
Separate meat from ribs and bones
Table 1.
Processes used for fish preparation after capture.
Among the methods used to add value to fish residues, there are protein hydrolysis, silage, and collagen recovery [9]. In the first hydrolysis tests evaluated, chemical processes and extraction with organic solvents were used, showing that they affected the nutritional quality of proteins and amino acids. For this reason, commercial enzymes have been increasingly applied to intend to obtain hydrolyzed protein of this substrate type [10]. These latter processes have moderate operating conditions, show greater reproducibility, and are more controllable and selective than chemical processes. Besides, they deliver products with techno-functional properties, excellent digestibility, rapid absorption, and amino acid balance, in addition to high levels of bioactive peptides [11].
This chapter will address the issue of protein residues used in fish processing aiming to obtain bioactive peptides through enzymatic hydrolysis using commercial enzymes. The basic concepts of fish processing, the characteristics of the waste generated, their use by enzymatic hydrolysis, and bioactive and functional peptide production will be addressed.
2. Fish post-harvest
Once the fish is harvested, it undergoes different processes intending to improve conservation conditions, separate the non-edible or low commercial value parts, and leave the product ready to deliver to the consumer. Table 1 lists, in general terms, the stages of fish processing, many of which release some type of organic by-product [3, 6].
3. Bromatological characteristics of the Main fish-farmed by-products
Fish by-products are made up of different compound types with food importance [12]. The major components are moisture, fat, and protein. However, the bromatological composition varies depending on the species, age, and gender of the fish, in addition to the part of the fish from which the by-product comes, or the processes to which it has been subjected [13]. Thus, Table 2 presents the bromatological composition of different fish by-products, for different species, fish parts, and processes.
Type of waste
Protein
Fat
Moisture
Ash
Reference
Freeze-dried Viscera of Yamú (Brycon siebenthalae)
Bromatological composition of fish by-products D.B.: Dry base.
As Table 2 shows, these residues contain mainly proteins, fats and water, but they may also contain high added-value compounds such as collagen and gelatin, polyunsaturated fatty acids (EPA and DHA), monounsaturated such as palmitic and oleic, in addition to minerals and enzymes such as pepsin, trypsin, chymotrypsin and collagenase [3]. Because of their nutrient richness, inappropriate dumping of these residues affects not only the area where they are directly discharged, but it can also alter natural ecosystems in a wider area. In this sense, phosphorus and dissolved nitrogen release can be favored and thus increase biochemical demand for oxygen (BDO), because at least 80% of the nutrients in fish residues are potentially eutrophic substances. This leads to the higher growth of macroalgae in aquifers [31].
In some regions of the world, alternatives to use by-products have been sought. That is how the demand for complete fish heads and skeletons as food for humans has increased in Asia and Africa [32]. Bones, which contain the highest protein levels among the residues (41–84%), are a good source of collagen and gelatin. Besides, their mineral content has been used in the manufacture of food products for schoolchildren (85 mg/kg zinc, 350 mg/kg iron, and 84 g/kg calcium) [32]. Whereas skeletons contain significant amounts of meat remaining after filleting, whose protein is highly digestible and can be extracted for different purposes since it has better nutritional properties than plant proteins, and better essential amino acids balance than other animal protein sources [33] but are more sensitive to heat [34]. On the other hand, fish skin, provides gelatin [32], such as, Nile Tilapia skin has been used to produce collagen [35], which can be used for tissue regeneration [36].
A fish by-product that has gained the most attention in recent years is the viscera (12–20% of the fish), which comprise all organs of the main body cavity, including gills, heart, liver, spleen, swim bladder, stomach, gonads, intestines and their contents [6]. This residue has an average composition of 8–21% proteins, 2–12% lipids, 60–81% humidity and 1–5% ash [6]. The high protein content, in addition to being an excellent enzyme source, makes them a potential source of added-value products with exceptional properties for different industrial applications [37].
Between 70 and 80% of fish muscle is a structural protein, between 20 and 30% sarcoplasma proteins, and the remaining 2–3% of proteins are insoluble connective tissue. The main food protein is myofibrillar, with 66–77% of the total in fish meat. This protein comprises between 50 and 60% myosin and 15–30% actin [38]. Myosin fibers are connected by actin molecules and can be cut at one end by trypsin and chymotrypsin, while at the other end by papain, to form they divide into two forms of meromyosin, heavy and light, with different functional properties [39].
Fish proteins contain between 16 and 18 amino acids, which have an excellent balance, usually 8 essential and 8 non-essential. This makes this type of protein very widely used for animal feed, although they are also used for fertilizer production, silage and in recent decades, bioactive peptide production [30, 40]. Table 3 shows the aminograms of different residues of several fish species, some raw and others that have undergone hydrolysis processes [14], atomization drying [40] and membrane fractionation [11].
FRTVH: Fraction <3 kDa of Red Tilapia Viscera Hydrolysates.
PI: Yamú Protein Viscera Isolate.
DH9: Yamú Protein Viscera Hydrolysates with 9% of Degree of hydrolysis.
DH28: Yamú Protein Viscera Hydrolysates with 28% of Degree of hydrolysis.
4. Enzymatic hydrolysis of fish by-product proteins
4.1 Protein hydrolysis
Protein hydrolysis occurs when a peptide bond is broken by water action, in the presence of a catalyst that may be an enzyme or a chemical agent [42]. Low-cost chemical processes can be by acid or alkaline hydrolysis, but they are non-specific, not reproducible and lead to amino acid denaturation. On the other hand, enzymatic hydrolysis is more expensive but does not deteriorate amino acids [43].
Once the native protein is broken, fragments of the native protein (oligomers) form, which can be a substrate for the subsequent hydrolysis process, so it is a multi-substrate reaction [44], especially in mediums where no pure protein is available, but mixtures of innumerable proteins, such as in fish residues and in general in other agro-industrial waste. Due to the hydrolysis process, the molecular characteristics of the proteins change, because the average molecular weight of the protein fragments present decreases, this increases the surface load, causes the release of hydrophobic groups, and changes functional properties, among other effects [45].
4.2 Enzymatic hydrolysis of protein
This process consists of decomposing proteins into smaller fragments, whose catalysts are enzymes called proteases [11]. This is a set of simultaneous link break reactions, consisting of serial stages, with different species loaded in equilibrium, giving fragments of decreasing size as follows [46]:
proteous→proteins→peptones→peptides→amino acid
The catalytic process that occurs is divided into three steps. First, the enzyme (E) should approach the substrate (S) and bind to form the enzyme-substrate complex (ES). Second, the rupture of the peptide bond results in the release of a peptide. Third, the remaining peptide is separated from the enzyme after a nucleophilic attack from a water molecule [11]. Each of these reactions has its speed as described in Eq. (1) [47]. This process can be repeated on any of the peptides formed [46].
E+S⇔K1ES→K2EP+H−P´+H2O→K3E+P−OH+H−P´E1
E: Enzyme, S: Substrate, P and P´: Resulting peptides, kx: Constant reaction rate.
This procedure has advantages over chemical hydrolysis as they have high selectivity and low contamination. It is a specific process that is carried out under moderate pH and temperature conditions, which makes it easy to control [30]. The product obtained is called protein hydrolyzate and it consists of peptides generally between 2 and 20 amino acids [48]. However, there are also disadvantages such as the high enzyme costs and long processing times [49].
Critical operating conditions in protein enzymatic hydrolysis include temperature, pH, enzyme type and concentration, substrate and concentration, cofactors, coenzymes, hydrolysis time [50], agitation speed [51], and presence of inhibitors, like fat in fish by-products [11].
On the other hand, variations that enzyme activity may suffer during the reaction should be controlled, such as denaturation, aggregation, or enzyme inactivation, which can be produced by temperature effects, pH shear stress or other substances that interfere with catalysis [12].
4.2.1 Enzymatic hydrolysis kinetics
During the reaction, the enzyme attacks the peptide bond as follows [52, 53]:
Under neutral or alkaline conditions, the dissociation of the amino group becomes significant, so a decrease in pH may occur due to the accumulation of the protons released, which makes it necessary to add a base to keep pH constant and prevent the enzyme from being affected in its activity [30]. The analysis of the equations above concludes that the amount of hydrolyzed protein is proportional to the amount of base required to neutralize the pH of the reaction medium [30].
4.2.2 Follow-up of hydrolysis reaction
The hydrolysis reaction progress is established by the Hydrolysis Degree (HD), expressed as a fraction or percentage of the number of broken peptide bonds at any given time (h) for the total peptide bonds in the intact protein (htot) (Eq. 5) [54]. Both can be expressed as protein meq/g or as protein mmol/g [30].
GH%=hhtot.100E5
Methods used to determine Hydrolysis Degree (HD) include the pH-stat method [52], O-phthaldialdehyde (OPA) [54], Trinitrobenesulfonic acid (TNBS) [55], formalin titration, and soluble nitrogen in trichloroacetic acid (TCA) [56]. The fundamental difference between these methods is in the principle that each one is based to measure the number of broken bonds (h) at any given time of the reaction, because htot is usually determined from the analysis of the total amino acid content in the intact protein [57].
4.2.2.1 pH-stat method
This method is based on the fact that in peptide bond hydrolysis, a carboxyl group and an amino group are released. In an aqueous solution, these groups will be more or less ionized depending on pH [55]. At neutral or alkaline pH, carboxyl groups are fully ionized and proton exchange occurs between the carboxyl group and the amino group. At alkaline pH, amino groups will also be partially or fully ionized depending on the pH and amino acid in question, since the pK of the free amino acids N-terminal amino group ranges from 9 to 10.8. The following equations show, in general, the chemical species involved in protein enzymatic hydrolysis [58].
P1−CO−NH−P2+H2O→proteaseP1−COOH+NH2−P2E6
P1−COOH→P1−COO−+H+E7
NH2−P2⇄NH3+−P2E8
The resulting free protons cause a pH decrease of the reaction mixture, and a base addition is required to keep pH constant. The amount of base required is directly related to the amount of hydrolyzed peptide bonds, and it can be used to estimate HD. Unfortunately, the relationship between HD and base consumption is not simple and depends on several variables, including pK of the α-amino group released, the temperature of the reaction mixture, and length of the peptide chain [52]. The relationship between the spent base volume and HD has been described by Adler-Nissen, 1986 [55] in Eq. (9).
GH%=BNBMpαhTot.100E9
where B is the base volume consumed in L to keep pH constant, MP is the protein mass in kg, NB is the base concentration, and α is the dissociation degree of the amino groups released in the reaction. α and pK are calculated with Eqs. (10) and (11), respectively, where T is the temperature (K) [59].
α=10pH−pK1+10pH−pKE10
pK=7.8+298−T298∗T∗2400E11
4.2.2.2 O-phthaldialdehyde method (OPA) and Trinitrobencenesulfonic acid method (TNBS)
Both methods are spectrophotometric, based on the determination of the α-amino groups released, by derivatization with trinitro-bencenesulfonic acid or ortho-phthaldialdehyde, respectively [56]. They are detected in the ultraviolet–visible range for the TNBS method, or fluorescent for the OPA. The absorbance value obtained is then converted into quantitative values using a standard curve prepared with a free amino acid, usually leucine, calculating HD as the percentage proportion of the amino acid released in the hydrolyzed regarding the amino acid amount of the whole protein [54, 55]. In Figures 1 and 2, reactions of an amino group with TNBS and OPA, respectively, take place [56].
Figure 1.
Reaction of OPA with amino acids. Source [60].
Figure 2.
Reaction of TNBS with amino acids. Source [61].
However, in these methods, derivatization reagents exhibit different reactivity to some amino acids, affecting measurement accuracy. For example, in the case of the OPA method, it will not be accurate when applied on proline- and cysteine-rich hydrolyzates [57].
4.2.3 Proteases most important characteristics
Proteases are the enzymes responsible for catalyzing the hydrolysis reaction of protein-peptide bonds, also known as peptidases [62]. Although, they can be obtained from plants, animals or microorganisms, most commercially viable proteases are obtained from this latter [63], especially Bacillus species, such as Bacillus licheniformis, Bacillus subtilis, and Aspergillus fungal species such as Aspergillus niger, A. flavus, Ammophilus fumigatus, and A. oryzae [64]. Some of the commercial proteases that have been used to obtain hydrolyzates from fish residues include trypsin, chymotrypsin, pepsin, Alcalase® 2.4 L, Flavourzyme® 500 L, E Properase, pronase, collagenases, bromelain and papain [50].
Proteases belong to the hydrolases group, they constitute a large and complex group of enzymes that differ from each other in their specificity due to substrate, their selectivity, the nature of their active sites, their catalytic mechanism, their stability profile, their pH, and optimum temperature. For these reasons, proteases cannot be classified under the general enzyme nomenclature system, but are classified according to their catalytic action, the nature of their active site, and their optimal pH value [63]. From the point of view of functional groups that have their active site, proteases can be classified into four main groups as follows [62]: Serine Proteases, Aspartic Proteases, Cysteine Proteases, Metalloproteases. On the other hand, when considering its catalytic mode of action, i.e., the excision site of the polypeptide chain, proteases are classified into exopeptidases and endopeptidases [65]. While, based on their optimal pH range, proteases can be classified into alkaline, neutral and acidic.
5. Production of bioactive and techno-functional peptides of fishery by-products
According to the HD achieved, the hydrolyzate obtained will potentially have biological activities or techno-functional properties. HD less than 10% result in improved techno-functional properties, such as emulsification, foaming capacity and greater solubility, whereas a higher HD tend to deliver hydrolyzates with greater potential as bioactive peptide sources [66].
5.1 Bioactive peptides
A bioactive peptide is a sequence of amino acids that is encrypted in the intact protein, in which it remains inactive, but once released, it can interact with certain receptors and regulate the physiological functions of the organism [67]. This may express some kind of effect on metabolic behavior, either human or animal [65]. These peptides can be released from the protein by gastrointestinal digestion, enzyme hydrolysis, or fermentation [68].
Among the most widely studied biological activities, are antihypertensive [69] Antioxidant [11] Antimicrobial [70], antithrombotic [71], anticancer [11] metal chelating agent, anticoagulants, among others [72].
One of the methods currently applied for obtaining bioactive peptides is enzymatic hydrolysis using commercial enzymes, which represents a reproducible, scalable, and industrial-application-capable method [73]. In this technology, biological activities of the peptides obtained may be affected by the operating conditions applied to isolate proteins, hydrolysis degree, protease type, peptide structure, the amino acids sequence, concentration, and the molecular weight of the peptides obtained [74].
The relationship between the peptide’s biological activity and their molecular weight has been widely documented [73], so the search for conditions that maximize HD has been one of the priorities in many studies [75] Peptide fractions with molecular weights between 1 and 4 kDa are of the greatest interest for nutritional and/or pharmaceutical uses in particular [75].
5.1.1 Antioxidant peptides
Free radicals and reactive oxygen species ROS [76], can cause DNA, protein, or lipid damage, resulting in human body damage from neurodegenerative, inflammatory, cardiovascular, diabetes, and cancer diseases [76]. This type of effect can be counteracted by substances with antioxidant capacity, which have different mechanisms of action depending on the free radical reduction form, among which are SET (single electron transfer), and HAT (hydrogen atom transfer) [77]. Based on these mechanisms, some methods to evaluate the antioxidant capacity of different substances have been designed. SET-based methods detect the antioxidant’s ability to transfer a chemical species such as metals, carbonyls and electrons, the most commonly used methods of this type are ABTS and FRAP. In the case of HAT methods, the antioxidant ability to inactivate a free radical is measured through the donation of a hydrogen atom, in which one of the most commonly used methods is ORAC [77].
On the other hand, some metals such as iron and copper, which are of importance at the physiological level, may also participate in the formation of reactive oxygen species [78], as in the case of hydroxyl radicals (OH), that are formed by the Fenton reaction and can cause damage to different types of tissues (Canabady-Rochelle et al., 2018). In this sense, metal chelation can counteract the formation of metal-catalyzed radicals in some way, which has somewhat been considered as a form of antioxidant activity [79].
Thus, peptide antioxidant activity is related to metal chelating activity and electron donation activity, which facilitates interaction with free radicals and cuts the reaction chain in which they participate [80]. In addition, the presence of hydrophobic sequences in peptides can interact with lipid molecules, eliminating the donation of protons to result in lipid radicals [81]. Thus, the imidazole group in histidine residues participates in hydrogen atom transfer, electron transfer, active oxygen extinction and capture of hydroxyl radicals [82].
The antioxidant capacity in these hydrolyzates has been attributed to the presence at the N-terminal end of peptide sequences of non-polar hydrophobic amino acids, such as phenylalanine, alanine and proline, and hydrophilic amino acids such as tyrosine, histidine and valine [6]. Thus, capturing the activity of hydrogen peroxide, the chelating activity of Fe2+, and reducing the power of Abalone (Haliotis discus hannai) hydrolyzates was related to hydrophobic amino acids in their peptides [83]. The capturing capacity of radicals has also been attributed to the presence of aromatic residues [84]. While tryptophan and tyrosine have been attributed antioxidant activity mediated by their phenolic and indolic groups, capable of donating hydrogen atoms [85]. The Table 4 lists several sequences of antioxidant peptides, from different kinds of fish by-products.
Amino acid sequence of antioxidant peptides from fish by-products.
5.1.2 Antihypertensive peptides
Hypertension is one of the most important cardiovascular risk factors worldwide, since high blood pressure currently affects about 20% of adults around the world [97]. In these blood pressure-increasing processes, the angiotensin I converter enzyme (ACE) plays a crucial role. This enzyme, a dipeptidyl carboxypeptidase (EC. 3.4.15.1), promotes the conversion of angiotensin I to a powerful angiotensin II vasoconstrictor, and inactivates the bradequinine vasodilator, which is a depressant of the renin-angiotensin system action [97]. Angiotensin II is also involved in the release of the steroid Na-retaining, which also tends to increase blood pressure [97]. For these reasons, a first step in the search for potentially useful substances to control high blood pressure is the ability test to inhibit ACE. In this sense, the search for peptides that can reach therapeutic tests as drugs for blood pressure control should initially be evaluated as ACE inhibitors [97]. The Table 5 lists several sequences of antihypertensive peptides, from different kind of fish by-products.
Amino acid sequence of ACE inhibitor peptides from fish by-products.
5.1.3 Anti-carcinogenic peptides
Cancer (malignant tumor), one of the most common diseases in the world [106], consists of abnormal and uncontrolled growth of cells, with proliferation and spread in surrounding tissues [11]. Thus, inhibition of deregulated cell proliferation is one of the strategies for treating this type of disease [107]. Among the broad list of substances that have been evaluated for this purpose are luteinizing hormone-releasing hormone and Atrial natriuretic peptide, for the treatment of prostate and colorectal cancer, respectively [106].
Various fish-derived proteins have been reported as sources of anticancer peptides [11, 108], as in the case with the antiproliferative activity of protein hydrolyzates of 18 fish species against breast cancer cell lines [109]. In Table 6, different fishery sources that have been active against some types of cancer are shown.
Use of peptides from fish by-products in cancer treatment.
There are three ways in which antiproliferative peptides act on cancer cells, apoptosis, necrosis, and cell cycle disturbances [11]. These mechanisms of action change according to structural characteristics such as molecular weight and amino acid composition. Thus, smaller peptides have greater molecular mobility and diffusivity, so they can interact better with the components of cancer cells. This activity has been attributed to amino acid sequences between 3 and 25 residues, with the predominance of hydrophobic amino acids, and one or more residues of Lys, Pro, Arg, Ser, Glu, THR Leu, Gly, Ala and Tyr. Because hydrophobic amino acids improve interactions between peptides and the outer surface of the bilayer of the tumor cell membrane, due to their phospholipid content and thus, they exert selective cytotoxic activity on these cells to healthy cells [107].
In addition to the amino acid sequence, the anti-cancer peptide’s function is influenced by net load, amphipathicity, hydrophobicity, structural membrane folding (including secondary structure, dynamics and orientation), oligomerization, and peptide concentration [11]. The cationic amphibious structure predisposes them to interact with the cell membrane anion surfaces [114]. The α helix is a main structural characteristic of this peptide type, with lateral chains of hydrophilic and hydrophobic amino acids, forming clear hydrophilic and hydrophobic surfaces. On the other hand, they concentrate on the N-terminal and the C-terminal to form different hydrophilic and hydrophobic domains. Anti-cancer peptides with a β sheet structure are generally stabilized by disulfide bonds, and these sheets are in β antiparallel formation. Meanwhile [11]. The net charge and positive charge number also influence these peptides activity, since their association with the cancer cell membrane occurs through electrostatic interactions due to its cationic condition and the anion lipopolysaccharide on the external membrane that causes its disturbance [115].
5.1.4 Anticoagulant peptides
Blood clotting is a crucial process for human health, excessive clotting that leads to blocked blood vessels causes strokes, heart attacks, and pulmonary embolism [11]. This makes anticoagulant compounds vital to preserving life quality in modern times. The anticoagulant is a compound that will stop blood clotting by binding to one or more coagulation factors, preventing it from binding to the membrane phospholipids [11]. Heparin is currently the anticoagulant most commonly used, but heparin has several disadvantages, including thrombocytopenia and non-specific plasma binding. In addition, it can cause platelet dysfunction and aggregation [116]. Therefore, there is a marked interest in the search for new anticoagulant compounds with minor collateral risks for the medical treatment of thromboembolic events [11].
Anticoagulant activity is less investigated than other biological activities, and specifically, peptides with this activity isolated from fish-based by-products have not been reported [11]. This way, an oligopeptide from the blue mussel, with a molecular mass of approximately 2,5 kDa has been isolated, showing anticoagulant activity by the prolongation of both thrombin time and activated partial thromboplastin time, by interaction specifically with blood clotting factors IX, X, and II. Nasri et al. [71], in 2012 isolated four anticoagulant peptides from protein hydrolyzates of goby muscle proteins, in which they found that they had Arg in the C-terminal position. Thus, concluding that small peptides with an amino acid charged at the C-end are considered potential thrombin inhibitors and/or other factors involved in the coagulation process [71]. Anticoagulant peptides from yellow-sole fish skeleton have also been isolated [117].
5.1.5 Antimicrobial peptides
The excessive use of conventional antimicrobial products has caused the emergence of resistant strains, which poses a health threat. Therefore, the development of antimicrobials using mechanisms other than traditional antibiotics is needed [11]. In this context, antimicrobial peptides effectively promote toxicity against invading pathogenic microorganisms, and also modulate the immune response in superior organisms [118]. These peptides are produced in all kingdoms, from bacteria to fungi and plants to mammals. Their unique intrinsic properties make them attractive therapeutic agents, since they show high biological activities associated with low toxicity and high specificity, as well as potentially useful as ingredients of functional or health-promoting foods [119]. These peptides generally contain less than 50 amino acid residues, with a molecular weight less than 10 kDa [120]. Despite their structural diversity, they have common physico-chemical characteristics; they are positively charged (+2 to +9) under physiological conditions due to the presence of lysine, arginine and histidine residues; and contain a substantial portion (50% or more) of hydrophobic residues [118]. These peptides commonly adopt an amphipathic conformation in which positively charged and hydrophobic groups are segregated into opposite faces of a α-helix, a β-leaf, or some other tertiary structure. This gives them the ability to cross the phospholipid membrane. The spectrum of different chemical properties of the amino acid side chain provides a variety of peptide sequences to show a cationic amphibious helical peptide [121]. Having a positive net charge allows them to interact with the anionic phospholipids of the bacterial membrane or other pathogens, and their amphipathicity, i.e., presence of apolar regions (with hydrophobic amino acids), and positive loads regions (cationic amino acids, Arg, Lys or His), facilitates them that, after initial interaction, the polar regions interact with the polar chains of the phospholipids, achieving the insertion of the peptide into the microbial membrane [122]. They are also flexible, which allows their internalization toward the bacterial cytoplasm, and leads to cell death due to ion and metabolic substances loss [123].
The most common mechanisms of action recognized in peptide antimicrobial activity include (i) the barrel model, in which a water-filled channel and an ion channel protein are formed by the interaction of peptides, acting as pores that disrupt the structure of the cell membrane; (ii) toroidal pore, in which less organized pore structures are formed; (iii) carpet models, in which the destabilization of the cell membrane in mycellar structures is caused by the accumulation of peptides above the limit concentration; (iv) molecular electroporation, following the concept that molecular electroporation can be achieved not only by electrical fields externally applied, but also by highly charged molecules that bind to the membrane surface; (v) sinking raft model, product of the induction of the membrane curvature by adsorbed peptides, which is relieved by its aggregation in the bilayer, allowing the aggregate to be translocated into the lumen of the gallbladder by a sinking raft process; and after membrane permeation, intracellular targets activation or blocking occurs [11]. These peptides not only generate toxic effects on microorganisms, but also exert important effects on the host, including immunomodulation, angiogenesis induction, wound healing and gene expression modulation. These effects may complement each other during the control of infectious and inflammatory diseases, and may be highly desirable when considered an optimal combination of an antimicrobial compound and regeneration booster [118]. In recent decades, barbel muscle antimicrobial peptides have been obtained by enzymatic hydrolysis of proteins from aquatic organisms [124]. Mustelus viscera [125], sea cucumber by-products [126], and different fish species [120], among others.
5.2 Commercial peptides obtained from fish sources
Thanks to their potential to produce bioactive compounds, fish parts and their residues have been used to obtain different types of functional inputs that have reached the market in different countries (Table 7). It should be noted, however, that few countries in which these products are being marketed. Given that fish, production extends to a much larger number of countries and that waste from that industry is proportional to production, it is clear that there is a latent possibility of expanding the market for products derived from fish sources.
Commercial name
Source
Functionality
Country
Custom Collagen®
Tilapia
Liver and kidney
US
Hydroiyzed Fish Collagen Type 1
Tilapia
Skin, tendons, and arteries
UK
Amizate®
Atlantic salmon
Muscle anabolism
North America
Protizen®
Stress, weight disorder, sleep trouble
UK
Levenorm®
Sarda
Antihypertensive
Canada
MOLVAL®
Molva
Cholesterol, stress, and cardiovascular health
UK
Norland Hydrolyzed Fish Collagen
Cod
Hair, skin and nails
US
PeptACE®
Sarda
Vascular function and blood pressure
Japan and US
Stabilium®200
Molva dypterygia
Stress, memory, and cognitive function
UK
Seacure®
Hake
Gastrointestinal and bowel function
Canada and US
Seagest™
White fish
Intestinal lining and health
US
Valtyron®
Sardine
Blood pressure
Vasotensin®
Tuna and verdel
Vascular function and blood pressure
Japan and US
Nutripeptin®
Cod
Weight and blood glucose
US and UK
Liquamen®
Molva
Oxidative stress, glycemic index, and stress
UK
Table 7.
Commercial products obtained by enzymatic Hydroiysis of fish protein by-products [37, 127].
\n',keywords:"bioactives peptides, enzymatic hydrolysis, protein revaluation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80465.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80465.xml",downloadPdfUrl:"/chapter/pdf-download/80465",previewPdfUrl:"/chapter/pdf-preview/80465",totalDownloads:63,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 19th 2021",dateReviewed:"December 22nd 2021",datePrePublished:"February 14th 2022",datePublished:null,dateFinished:"February 14th 2022",readingETA:"0",abstract:"The fishery industries have continuously increased over the last decade. This growth comes accompanied by a high volume of by-products released to environment, because these industries discard between 60 and 70% of their production as waste. This waste includes fish whole or part from these such as fillet remains (15–20%), skin and fins (1–3%), bones (9–15%), heads (9–12%), viscera (12–18%) and scales (5%). This by-products are rich in proteins and lipids which of several nature, which can be recovered to obtain compounds of high added value. In this chapter, some methods to recover compounds from fish by-products will be discussed. Among others, will be discussed topics about postharvest of fish, by-product releasing, enzymatic hydrolysis of by-product and bioactive peptide obtaining from fish waste.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80465",risUrl:"/chapter/ris/80465",signatures:"Jose Edgar Zapata Montoya and Angie Franco Sanchez",book:{id:"10841",type:"book",title:"Hydrolases",subtitle:null,fullTitle:"Hydrolases",slug:null,publishedDate:null,bookSignature:"Dr. Sajjad Haider, Assistant Prof. Adnan Haider and Prof. Angel Catala",coverURL:"https://cdn.intechopen.com/books/images_new/10841.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-163-0",printIsbn:"978-1-80355-162-3",pdfIsbn:"978-1-80355-164-7",isAvailableForWebshopOrdering:!0,editors:[{id:"110708",title:"Dr.",name:"Sajjad",middleName:null,surname:"Haider",slug:"sajjad-haider",fullName:"Sajjad Haider"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Fish post-harvest",level:"1"},{id:"sec_3",title:"3. Bromatological characteristics of the Main fish-farmed by-products",level:"1"},{id:"sec_4",title:"4. Enzymatic hydrolysis of fish by-product proteins",level:"1"},{id:"sec_4_2",title:"4.1 Protein hydrolysis",level:"2"},{id:"sec_5_2",title:"4.2 Enzymatic hydrolysis of protein",level:"2"},{id:"sec_5_3",title:"4.2.1 Enzymatic hydrolysis kinetics",level:"3"},{id:"sec_6_3",title:"4.2.2 Follow-up of hydrolysis reaction",level:"3"},{id:"sec_6_4",title:"4.2.2.1 pH-stat method",level:"4"},{id:"sec_7_4",title:"4.2.2.2 O-phthaldialdehyde method (OPA) and Trinitrobencenesulfonic acid method (TNBS)",level:"4"},{id:"sec_9_3",title:"4.2.3 Proteases most important characteristics",level:"3"},{id:"sec_12",title:"5. Production of bioactive and techno-functional peptides of fishery by-products",level:"1"},{id:"sec_12_2",title:"5.1 Bioactive peptides",level:"2"},{id:"sec_12_3",title:"Table 4.",level:"3"},{id:"sec_13_3",title:"Table 5.",level:"3"},{id:"sec_14_3",title:"Table 6.",level:"3"},{id:"sec_15_3",title:"5.1.4 Anticoagulant peptides",level:"3"},{id:"sec_16_3",title:"5.1.5 Antimicrobial peptides",level:"3"},{id:"sec_18_2",title:"5.2 Commercial peptides obtained from fish sources",level:"2"}],chapterReferences:[{id:"B1",body:'Ishak NH, Sarbon NM. A review of protein hydrolysates and bioactive peptides deriving from wastes generated by fish processing. Food and Bioprocess Technology. 2018;11:2-16'},{id:"B2",body:'FAO. The State of World Fisheries and Aquaculture: Meeting the Sustainable Development Goals. Rome: FAO; 2018'},{id:"B3",body:'Ghaly AE, Ramakrishnan VV, Brooks MS, Budge SM, Dave D. Fish processing wastes as a potential source of proteins, amino acids and oils: A critical review. 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Production of angiotensin I converting enzyme inhibitory peptides from sea bream scale. Process Biochemistry. 2004;39:1195-1200'},{id:"B101",body:'Bougatef A, Nedjar-Arroume N, Ravallec-Plé R, Leroy Y, Guillochon D, Barkia A, et al. Angiotensin I-converting enzyme (ACE) inhibitory activities of sardinelle (Sardinella aurita) by-products protein hydrolysates obtained by treatment with microbial and visceral fish serine proteases. Food Chemistry. 2008;111:350-356'},{id:"B102",body:'Ghassem M, Babji AS, Said M, Mahmoodani F, Arihara K. Angiotensin I-converting enzyme inhibitory peptides from snakehead fish sarcoplasmic protein hydrolysate. Journal of Food Biochemistry. 2014;38(2):14-19'},{id:"B103",body:'García-Moreno PJ, Espejo-Carpio FJ, Guadix A, Guadix EM. Production and identification of angiotensin I-converting enzyme (ACE) inhibitory peptides from Mediterranean fish discards. Journal of Functional Foods. 2015;18:95-105'},{id:"B104",body:'Wu X, Cai L, Zhang Y, Mi H, Cheng X, Li J. Compositions and antioxidant properties of protein hydrolysates from the skins of four carp species. International Journal of Food Science & Technology. 2015;50(12):2589-2597. DOI: 10.1111/ijfs.12927'},{id:"B105",body:'Chen J, Liu Y, Wang G, Sun S, Liu R, Hong B, et al. Processing optimization and characterization of angiotensin-Ι-converting enzyme inhibitory peptides from lizardfish (Synodus macrops) scale gelatin. Marine Drugs. 2018;16(7):228. DOI: 10.3390/md16070228'},{id:"B106",body:'Baig MH, Ahmad K, Saeed M, Alharbi AM, Barreto GE, Ashraf GM, et al. Peptide based therapeutics and their use for the treatment of neurodegenerative and other diseases. Biomedicine & Pharmacotherapy. 2018;103:574-581. DOI: 10.1016/j.biopha.2018.04.025'},{id:"B107",body:'Chalamaiah M, Yu W, Wu J. Immunomodulatory and anticancer protein hydrolysates (peptides) from food proteins: A review. Food Chemistry. 2018;245:205-222. 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Biochemistry and Cell Biology. 2002;80(1):49-63'},{id:"B123",body:'Villarruel R, Huizar R, Corrales M, Sánchez T, Islas A. Péptidos naturales antimicrobianos: Escudo esencial de la respuesta inmune. Investigación en Salud. 2004;6(3):170-179'},{id:"B124",body:'Sila A, Nedjar-Arroume N, Hedhili K, Chataigné G, Balti R, Nasri M, et al. Antibacterial peptides from barbel muscle protein hydrolysates: Activity against some pathogenic bacteria. LWT-Food Science and Technology. 2014;55(1):183-188. DOI: 10.1016/j.lwt.2013.07.021'},{id:"B125",body:'Abdelhedi O, Jridi M, Jemil I, Mora L, Toldrá F, Aristoy MC, et al. Combined biocatalytic conversion of smooth hound viscera: Protein hydrolysates elaboration and assessment of their antioxidant, anti-ACE and antibacterial activities. Food Research International. 2016;86:9-23. DOI: 10.1016/j.foodres.2016.05.013'},{id:"B126",body:'Tripoteau L, Bedoux G, Gagnon J, Bourgougnon N. In vitro antiviral activities of enzymatic hydrolysates extracted from byproducts of the Atlantic holothurian Cucumaria frondosa. Process Biochemistry. 2015;50:867-875. DOI: 10.1016/j.procbio.2015.02.012'},{id:"B127",body:'Sierra Lopera LM, Sepúlveda Rincón CT, Vásquez Mazo P, Figueroa Moreno OA, Zapata Montoya JE. Byproducts of aquaculture processes: Development and prospective uses. Review. Revista Vitae. 2018;25(3):128-140. DOI: 10.17533/udea.vitae.v25n3a03'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Jose Edgar Zapata Montoya",address:"edgar.zapata@udea.edu.co",affiliation:'
Nutrition and Food Technology Group, Universidad de Antioquia, Colombia
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The present study aimed to characterize and to analyze the temporal dynamics of precipitation and evapotranspiration in the Atlantic Rainforest remnants in São Paulo state, southeastern Brazil, for the period from January 2000 to December 2010. To achieve this, global precipitation and evapotranspiration data from TRMM satellite and MOD16 algorithm as well as forest remnant maps produced by SOS Mata Atlântica Foundation and Brazilian National Institute for Space Research (INPE) were used. Results found in this study demonstrated that the use of remote sensing was an important tool for analyzing hydrological variables in Atlantic Rainforest remnants, which can contribute to better understand the interaction between tropical forests and the atmosphere, and for generating input data necessary for surface models coupled to atmospheric general circulation models.",signatures:"Gabriel de Oliveira, Elisabete C. Moraes, Nathaniel A. Brunsell, Yosio\nE. Shimabukuro, Guilherme A.V. 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Dr. de Oliveira has large expertise working in the Amazon Rainforest, focusing on the use of orbital remote sensing imagery and ground observations in order to understand how deforestation, fire, and droughts affect the plant ecophysiological processes and, consequently, the regional climate due to the exchanges of water and carbon between the biosphere and the atmosphere. Addressing these questions is essential for an improved understanding of the survival and fitness of plants, plant species distribution, and for the prediction of ecosystem responses to future climate change.\n\nDr. de Oliveira has over 10 years of field experience in the Amazon Rainforest, and has traveled to most parts of the Brazilian Amazon and also parts of the Bolivian and Peruvian Amazon.\n\nDr. de Oliveira received a B.S. in Geography from the Federal University of Rio Grande do Sul (Brazil), and an M.S. and Ph.D. in Remote Sensing from Brazil’s Space Agency, the National Institute for Space Research. Following that, Dr. de Oliveira conducted Postdoctoral studies in the Department of Geography and Atmospheric Science at the University of Kansas (USA) and the Department of Geography and Planning at the University of Toronto (Canada). Dr. de Oliveira is a member of the American Geophysical Union (AGU) and the International Society of Photogrammetry and Remote Sensing (ISPRS), and has published his research in some of the most important scientific journals of his field, such as Science, Journal of Geophysical Research: Biogeosciences, Ecosphere, Theoretical and Applied Climatology, Agricultural and Forest Meteorology, Plant Science, International Journal of Remote Sensing, and International Journal of Applied Earth Observations and Geoinformation.",institutionString:"University of Kansas",institution:{name:"University of South Alabama",institutionURL:null,country:{name:"United States of America"}}},{id:"183354",title:"Dr.",name:"Marcos",surname:"V. W. Caldeira",slug:"marcos-v.-w.-caldeira",fullName:"Marcos V. W. Caldeira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"183355",title:"MSc.",name:"Franciele",surname:"F. M. Rovani",slug:"franciele-f.-m.-rovani",fullName:"Franciele F. M. Rovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"183356",title:"MSc.",name:"Kallil",surname:"C. Castro",slug:"kallil-c.-castro",fullName:"Kallil C. Castro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"190568",title:"Dr.",name:"Nathaniel",surname:"Brunsell",slug:"nathaniel-brunsell",fullName:"Nathaniel Brunsell",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190568/images/system/190568.jpg",biography:"Dr. Nathaniel A. Brunsell has a background in Earth and Planetary Sciences from the University of New Mexico (USA) with a PhD. in Biometeorology from Utah State University (USA). Dr. Nathaniel A. Brunsell is a professor in the Department of Geography and Atmospheric Science at the University of Kansas. He is a biometeorologist by training with extensive experience in land-atmosphere interactions, the impacts of land use/land cover change on water and carbon cycling and the role of spatial and temporal heterogeneity on influencing these exchange processes.",institutionString:"University of Kansas",institution:null},{id:"190573",title:"Dr.",name:"Yosio",surname:"E. Shimabukuro",slug:"yosio-e.-shimabukuro",fullName:"Yosio E. Shimabukuro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Dr. Yosio E. Shimabukuro has a background in Forest Engineering from the Federal University of Rio de Janeiro (Brazil) with a PhD. in Forest Sciences/Remote Sensing from Colorado State University (USA). He is currently a Senior Scientist at the National Institute for Space Research (INPE) (Brazil). His main research interests are linear mixing model, Landsat images, shade fraction image, reforested areas, mathematical modeling, carbon balance in Amazon forests from site to region: integrating remote sensing from satellites and aircraft with ground-based tower and biometric data, integrating coarse and fine resolution satellite data to monitor land cover change throughout Amazônia.",institutionString:null,institution:{name:"National Institute for Space Research",institutionURL:null,country:{name:"Brazil"}}},{id:"190574",title:"M.Sc.",name:"Guilherme",surname:"Mataveli",slug:"guilherme-mataveli",fullName:"Guilherme Mataveli",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"I am a geographer holding a Ph.D. in Physical Geography with a background in remote sensing and modeling interested in the understanding of how land use and land cover changes (LULCC) influence the emission of trace gases and aerosols from fires.",institutionString:null,institution:{name:"National Institute for Space Research",institutionURL:null,country:{name:"Brazil"}}},{id:"190575",title:"MSc.",name:"Thiago",surname:"V. 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At IntechOpen, we not only specialize in the publication of Book Chapters as part of our Edited Volumes, but also the publication and dissemination of longer manuscripts, known as Long Form Monographs. Monographs allow Authors to focus on presenting a single subject or a specific aspect of that subject and publish their research in detail.
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IntechOpen has collaborated with Enago, through its sister brand, Ulatus, which is one of the world’s leading providers of book translation services. The services are designed to convey the essence of your work to readers from across the globe in a language they understand. Enago’s expert translators incorporate cultural nuances in translations to make the content relevant for local audiences while retaining the original meaning and style. Enago translators are equipped to handle all complex and multiple overlapping themes encompassed in a single book and their high degree of linguistic and subject expertise enables them to deliver a superior quality output.
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Single or multiple author manuscript
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Edited Book - an edited collection of chapters contributed by various authors
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Conference Proceedings - collection of papers presented at a conference published in book format
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COST
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10,000 GBP Monograph - Long Form
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The final price includes project management, editorial and peer-review services, technical editing, language copyediting, cover design, book layout, book promotion and ISBN assignment.
\n\n
*The price does not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate applied in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT by providing us with their VAT registration number. This is made possible by the EU reverse charge method.
\n\n
Optional Services
\n\n
IntechOpen has collaborated with Enago, through its sister brand, Ulatus, which is one of the world’s leading providers of book translation services. The services are designed to convey the essence of your work to readers from across the globe in a language they understand. Enago’s expert translators incorporate cultural nuances in translations to make the content relevant for local audiences while retaining the original meaning and style. Enago translators are equipped to handle all complex and multiple overlapping themes encompassed in a single book and their high degree of linguistic and subject expertise enables them to deliver a superior quality output.
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IntechOpen Authors that wish to use this service will receive a 20% discount on all translation services. To find out more information or obtain a quote, please visit: https://www.enago.com/intech.
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FUNDING
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We feel that financial barriers should never prevent researchers from publishing their work. Please consult our Open Access Funding page to explore funding opportunities and learn more about how you can finance your IntechOpen publication.
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BENEFITS
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Your published content is immediately available to read, share and download for free
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+184,650 Web Of Science citations
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You retain copyright to your work
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Chapter and book statistics performance reports allowing you to examine the reach of your content
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Full PDF version of your book available to download
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Rapid publishing process with personal support
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Competitive pricing for publishing services and print products
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In this chapter, I describe the similarities and differences between the naïve and primed pluripotent states as exemplified by mouse embryonic stem cells (mESCs), mouse epiblast stem cells (mEpiSCs), human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). I also review the efforts for derivation of naïve human pluripotent stem cells by manipulating culture conditions during reprogramming of somatic cells and attempts to revert primed hESCs to the naïve state. Understanding the requirements for induction and maintenance of the naïve pluripotent state will facilitate studies on early human embryonic development and understanding the mechanisms involved in X inactivation in vitro. In addition, the development of naïve hiPSCs will improve the efficiency of gene targeting for the purpose of modeling human diseases as well as for generating gene‐corrected autologous pluripotent stem cells for regenerative medicine.",book:{id:"5207",slug:"pluripotent-stem-cells-from-the-bench-to-the-clinic",title:"Pluripotent Stem Cells",fullTitle:"Pluripotent Stem Cells - From the Bench to the Clinic"},signatures:"Daman Kumari",authors:[{id:"180527",title:"Dr.",name:"Daman",middleName:null,surname:"Kumari",slug:"daman-kumari",fullName:"Daman Kumari"}]},{id:"26987",doi:"10.5772/32381",title:"Markers for Hematopoietic Stem Cells: Histories and Recent Achievements",slug:"endothelial-cell-selective-adhesion-molecule-esam-a-novel-hsc-marker",totalDownloads:7216,totalCrossrefCites:7,totalDimensionsCites:12,abstract:null,book:{id:"694",slug:"advances-in-hematopoietic-stem-cell-research",title:"Advances in Hematopoietic Stem Cell Research",fullTitle:"Advances in Hematopoietic Stem Cell Research"},signatures:"Takafumi Yokota, Kenji Oritani, Stefan Butz, Stephan Ewers, Dietmar Vestweber and Yuzuru Kanakura",authors:[{id:"91282",title:"Dr.",name:"Takafumi",middleName:null,surname:"Yokota",slug:"takafumi-yokota",fullName:"Takafumi Yokota"},{id:"97447",title:"Dr.",name:"Takao",middleName:null,surname:"Sudo",slug:"takao-sudo",fullName:"Takao Sudo"},{id:"97448",title:"Dr.",name:"Kenji",middleName:null,surname:"Oritani",slug:"kenji-oritani",fullName:"Kenji Oritani"},{id:"97450",title:"Prof.",name:"Yuzuru",middleName:null,surname:"Kanakura",slug:"yuzuru-kanakura",fullName:"Yuzuru Kanakura"}]},{id:"18217",doi:"10.5772/23755",title:"Stem Cells: General Features and Characteristics",slug:"stem-cells-general-features-and-characteristics",totalDownloads:9708,totalCrossrefCites:5,totalDimensionsCites:12,abstract:null,book:{id:"216",slug:"stem-cells-in-clinic-and-research",title:"Stem Cells in Clinic and Research",fullTitle:"Stem Cells in Clinic and Research"},signatures:"Hongxiang Hui, Yongming Tang, Min Hu and Xiaoning Zhao",authors:[{id:"53560",title:"Dr.",name:"Hongxiang",middleName:null,surname:"Hui",slug:"hongxiang-hui",fullName:"Hongxiang Hui"},{id:"59235",title:"Mr",name:"Xiaoning",middleName:null,surname:"Zhao",slug:"xiaoning-zhao",fullName:"Xiaoning Zhao"},{id:"59236",title:"Mr",name:"Yongming",middleName:null,surname:"Tang",slug:"yongming-tang",fullName:"Yongming Tang"},{id:"118970",title:"Dr.",name:"Min",middleName:null,surname:"Hu",slug:"min-hu",fullName:"Min Hu"}]}],mostDownloadedChaptersLast30Days:[{id:"18220",title:"How do Mesenchymal Stem Cells Repair?",slug:"how-do-mesenchymal-stem-cells-repair-",totalDownloads:5970,totalCrossrefCites:9,totalDimensionsCites:16,abstract:null,book:{id:"216",slug:"stem-cells-in-clinic-and-research",title:"Stem Cells in Clinic and Research",fullTitle:"Stem Cells in Clinic and Research"},signatures:"Patricia Semedo, Marina Burgos-Silva, Cassiano Donizetti-Oliveira and Niels Olsen Saraiva Camara",authors:[{id:"28751",title:"Prof.",name:"Niels",middleName:"Olsen Saraiva",surname:"Camara",slug:"niels-camara",fullName:"Niels Camara"},{id:"30464",title:"Prof.",name:"Patricia",middleName:null,surname:"Semedo",slug:"patricia-semedo",fullName:"Patricia Semedo"},{id:"30465",title:"BSc.",name:"Cassiano",middleName:null,surname:"Donizetti-Oliveira",slug:"cassiano-donizetti-oliveira",fullName:"Cassiano Donizetti-Oliveira"},{id:"30466",title:"BSc.",name:"Marina",middleName:null,surname:"Burgos-Silva",slug:"marina-burgos-silva",fullName:"Marina Burgos-Silva"}]},{id:"61053",title:"Adult Stem Cell Membrane Markers: Their Importance and Critical Role in Their Proliferation and Differentiation Potentials",slug:"adult-stem-cell-membrane-markers-their-importance-and-critical-role-in-their-proliferation-and-diffe",totalDownloads:1329,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The stem cells are part of the cells that belong to the stromal tissue. These cells remain in a quiescent state until they are activated by different factors, usually those generated by an alteration in the parenchymal tissue. These cells have characteristic membrane markers such as CD73, CD90, and CD105. Those are a receptor, which in response to their ligand induces strong changes in different metabolic pathways that lead to these cells, both to generate molecules with different activities and to leave their stationary phase to reproduce and even differentiate. This review describes the metabolic pathways dependent on these membrane markers and how they influence on parenchymal tissue and other stromal cells.",book:{id:"6658",slug:"stromal-cells-structure-function-and-therapeutic-implications",title:"Stromal Cells",fullTitle:"Stromal Cells - Structure, Function, and Therapeutic Implications"},signatures:"Maria Teresa Gonzalez Garza",authors:[{id:"181389",title:"Ph.D.",name:"Maria Teresa",middleName:null,surname:"Gonzalez Garza",slug:"maria-teresa-gonzalez-garza",fullName:"Maria Teresa Gonzalez Garza"}]},{id:"63044",title:"Stromal-Epithelial Interactions during Mammary Gland Development",slug:"stromal-epithelial-interactions-during-mammary-gland-development",totalDownloads:1384,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"Mammary gland is an organ, which undergoes the majority of its development in the postnatal life of mammals. The complex structure of the mammary gland comprises epithelial and myoepithelial cells forming the parenchymal tissue and adipocytes, fibroblasts, vascular endothelial cells, and infiltrating immune cell composing the stromal compartment. During puberty and in adulthood, circulating hormones released from the pituitary and ovaries regulate the rate of development and functional differentiation of the mammary epithelium. In addition, growing body of evidence shows that interactions between the stromal and parenchymal compartments of the mammary gland play a crucial role in mammogenesis. This regulation takes place on a paracrine level, by locally synthesized growth factors, adipokines, and cytokines, as well as via direct cell-cell interactions. This chapter summarizes the current knowledge about the complex nature of interactions between the mammary epithelium and stroma during mammary gland development in different mammalian species.",book:{id:"6658",slug:"stromal-cells-structure-function-and-therapeutic-implications",title:"Stromal Cells",fullTitle:"Stromal Cells - Structure, Function, and Therapeutic Implications"},signatures:"Żaneta Dzięgelewska and Małgorzata Gajewska",authors:[{id:"165068",title:"Dr.",name:"Malgorzata",middleName:null,surname:"Gajewska",slug:"malgorzata-gajewska",fullName:"Malgorzata Gajewska"},{id:"249847",title:"Ms.",name:"Żaneta",middleName:null,surname:"Dzięgelewska",slug:"zaneta-dziegelewska",fullName:"Żaneta Dzięgelewska"}]},{id:"69757",title:"Flow Cytometry Applied to the Diagnosis of Primary Immunodeficiencies",slug:"flow-cytometry-applied-to-the-diagnosis-of-primary-immunodeficiencies",totalDownloads:1048,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Primary immunodeficiencies are the result of biological defects associated with functional immune abnormalities. It consists of a group of disorders showing a higher incidence and severity of infections, expression of immunological dysregulation such as inflammation and lymphoproliferation. The immunophenotyping and in vitro functional characterization of immunodeficient patients contribute, together with the clinical aspects, to define the underlying immune defect particularities. Flow cytometry applications in primary immunodeficiency assessment are multiple and include the study of a wide range of specific cell lymphocyte subpopulations. This chapter describes the main techniques used in the diagnosis of a wide variety of primary immunodeficiencies, in which intracellular proteins or activation markers involved in immunity are evaluated, as well as functional proliferation, cytokine production, phosphorylation of transcription factors, cytotoxic and degranulation capacity. Flow cytometry is a tool that allows rapid and accurate evaluation of multiple lymphocyte populations and immunological function, and this information is essential for the diagnosis and evaluation of patients with primary immunodeficiencies.",book:{id:"6913",slug:"innovations-in-cell-research-and-therapy",title:"Innovations in Cell Research and Therapy",fullTitle:"Innovations in Cell Research and Therapy"},signatures:"Mónica Martínez-Gallo and Marina García-Prat",authors:[{id:"286242",title:"Ph.D.",name:"Mónica",middleName:null,surname:"Martínez Gallo",slug:"monica-martinez-gallo",fullName:"Mónica Martínez Gallo"},{id:"286704",title:"BSc.",name:"Marina",middleName:null,surname:"García-Prat",slug:"marina-garcia-prat",fullName:"Marina García-Prat"}]},{id:"50685",title:"States of Pluripotency: Naïve and Primed Pluripotent Stem Cells",slug:"states-of-pluripotency-na-ve-and-primed-pluripotent-stem-cells",totalDownloads:4015,totalCrossrefCites:4,totalDimensionsCites:12,abstract:"Pluripotent stem cells are classified into naïve and primed based on their growth characteristics in vitro and their potential to give rise to all somatic lineages and the germ line in chimeras. 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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:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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