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",isbn:"978-1-80356-477-7",printIsbn:"978-1-80356-476-0",pdfIsbn:"978-1-80356-478-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"b306ce94998737c764d08736e76d60e1",bookSignature:"Dr. Alyssa A Brewer and Dr. Brian Barton",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11636.jpg",keywords:"Mammalian, Primate, Human, Genetics and Epigenetics, Individual Variability, Adaptation, Cortical Reorganization, Cortical Recovery, Visual Field Map, Sensorimotor Maps, Bottom-Up Sensory Processing, Top-Down Visual Attention",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 3rd 2022",dateEndSecondStepPublish:"May 4th 2022",dateEndThirdStepPublish:"July 3rd 2022",dateEndFourthStepPublish:"September 21st 2022",dateEndFifthStepPublish:"November 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Brewer is a Stanford-trained physician-scientist, tenured Associate Professor at UC Irvine, and Director of the mind space Lab, who uses cutting-edge computational neuroimaging to study the organization and plasticity of the human sensory cortex.",coeditorOneBiosketch:"Dr. Barton is a UCI-trained cognitive scientist who has pioneered the study of auditory field maps in the human cortex and currently focuses his research on computational neuroimaging measurements of audiovisual cortical processing and organization.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"115304",title:"Dr.",name:"Alyssa",middleName:"A",surname:"Brewer",slug:"alyssa-brewer",fullName:"Alyssa Brewer",profilePictureURL:"https://mts.intechopen.com/storage/users/115304/images/system/115304.jpg",biography:"Dr. Alyssa A. Brewer completed her undergraduate degrees at Stanford University, with a B.S. with Honors in Biological Sciences and an A.B. in Comparative Literature with interdisciplinary Honors in Humanities. She continued on at Stanford in a dual-degree graduate program, graduating with an M.D. and a Ph.D. in Neuroscience in 2007. Her work in graduate school with Brian Wandell, Ph.D., focused on computational neuroimaging measurements of visual cortex organization and plasticity in humans and macaque. She now is an Associate Professor in the Departments of Cognitive Sciences and Language Science, by courtesy, at the University of California, Irvine. Dr. Brewer’s research focuses on visual, auditory, and multi-sensory neuroscience, using behavioral, genetic, and high-resolution neuroimaging techniques to investigate questions ranging from the fundamental organization of human visual and auditory cortex to plasticity in visual, auditory, and sensorimotor regions.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"149246",title:"Dr.",name:"Brian",middleName:null,surname:"Barton",slug:"brian-barton",fullName:"Brian Barton",profilePictureURL:"https://mts.intechopen.com/storage/users/149246/images/system/149246.jpeg",biography:"Dr. Brian Barton received his B.S. in Psychology at the University of Oregon, where he studied visual attention and working memory with Edward Awh, Ph.D., and Edward Vogel, Ph.D. Dr. Barton then earned his Ph.D. in Psychology with a Concentration in Cognitive Neuroscience in 2013 at the University of California, Irvine (UCI), where he expanded his research into functional MRI measurements of visual cortex organization and plasticity with Alyssa A. Brewer, M.D., Ph.D. He continued on at UCI as a post-doctoral scholar for three years with Drs. Brewer, Greg Hickok, Ph.D., and Kourosh Saberi, Ph.D., applying his vision work to measurements of the organization of human auditory cortex. Dr. Barton’s current research focuses on the organization, function, and plasticity of sensory field maps in human visual and auditory cortex.",institutionString:"University of California, Irvine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of California, Irvine",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"18",title:"Neuroscience",slug:"life-sciences-neuroscience"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444316",firstName:"Blanka",lastName:"Gugic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/444316/images/20016_n.jpg",email:"blanka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Thiazoles are a basic scaffold found in many natural compounds as vitamin B1-thiamine, alkaloids, anabolic steroids, flavones [1].
The interest in the synthesis of compounds containing the thiazole moiety has been increasing steadily in view of their utility in the field of photosensitizers, rubber vulcanization [2], liquid crystals [3, 4], sensors [5], sunscreens [6], catalysts [7], dyes [8], pigments [1], and chromophores [9, 10]. Moreover, thiazoles occupy a prominent place in current medicinal chemistry due to their wide range of applications in the field of drug design and discovery [11]. They appear in the bacitracin, penicillin antibiotics [12], and various synthetic drugs as short-acting sulfa drug sulfathiazole [1]. Also, they are used as an antidepressant drug (pramipexole) [13], antiulcer agent (nizatidine) [14], anti-inflammatory drug (meloxicam) [15], HIV/AIDS drug (ritonavir) [16], and cancer treatment drug (tiazofurin) [17]. In fact, thiazole is a more common component of FDA-approved pharmaceuticals than related five-membered heterocycles such as isothiazole, thiophene, furan, isoxazole, and oxazole. On the other hand, the metal complexes of thiazole are widely used in photocatalysis [18]. 1,3-Thiazoles undergo different types of reactions to yield various biologically active fused heterocyclic moieties as thiazolopyrimidine, imidazothiazoles, thiazolopyridine, etc. [19, 20, 21].
Thiazole ring system were easily synthesized by well-known methods of Hantzsch [22], Cook-Heilbron [23], and Gabriel [24]. A number of compounds may serve as nucleophilic reagent in this reaction, such as thioamides, thiourea, ammonium thiocarbamate or dithiocarbamate, and their derivatives. Hantzsch synthesized the simple thiazole nucleus in 1887 [25]. This synthesis approach involves cyclization and condensation of haloketones with thioamide, and it is considered the most widely popular process for the synthesis of thiazole moiety. In contrast, Gabriel synthesized thiazoles by treating α-acylaminoketones with stoichiometric amounts of P2S5 or Lawesson’s reagent [26]. Also, Cook-Heilbron used versatile methods for the synthesis of substituted aminothiazoles involving the reaction of α-aminonitriles with dithioacids or esters, carbon disulfide, carbonyl sulfide, and isothiocyanates under mild conditions [27].
Lately, thiazole derivatives were synthesized in the presence of various catalysts [28, 29, 30, 31] and with the use of a microwave irradiation technique [32].
Thioamides and various α-halocarbonyl compounds were reacted to give numerous thiazoles with alkyl, aryl, arylalkyl, or heteroaryl of several functional groups at position 2, 4, or 5 (
Synthesis of 2-, 4-, 5-trisubstituted thiazole.
This class of synthesis gives 5-aminothiazole with different substituted in position 2 by interacting aminonitrile with salts and esters of dithioacids carbon oxysulfide, carbon disulfide, and isothiocyanates significantly [38, 39, 40].
The salts or the esters of both dithioformic and dithiophenacetic acids were reacted with α-aminonitriles to give 5-aminothiazoles (
Synthesis of 5-aminothiazoles derivatives.
This reaction was originally designated by Gabriel in 1910. The reaction of phosphorus pentasulfide with acylaminoketone gave 2-phenyl-5-alkyl-thiazole in good yield (
Synthesis of 2-phenyl-5-alkyl-thiazole derivatives.
The synthesis of thiazole derivatives involves vigorous reaction conditions and wastage of solvents and catalysts. To overcome these shortcomings, eco-friendly methods as microwave irradiation technique are commonly used for synthesis of thiazole derivatives [45]. Rapid and elegant synthesis of a series of thiazoles (
Synthesis of thiazoles under microwave irradiation.
Water is economically viable, nontoxic, and the most friendly reaction medium available, making it an environmentally acceptable solvent for the design and development of green chemistry technique. A three-component reaction of phenyl acetylene, N-bromosuccinimide, and thiourea in aqueous medium gave substituted thiazole derivatives (
Synthesis of 2-aminothiazole in aqueous medium.
An efficient and green method has been developed for the synthesis of new substituted Hantzsch thiazole derivatives (
Synthesis of thiazole derivatives using silica.
Hantzsch construction of thiazole derivatives (
Synthesis of thiazole derivatives.
The C − H substitution reaction of thiazole by the catalysis of the palladium/copper system is carried out in the presence of tetrabutylammonium fluoride under mild conditions. Various 2,5-diarylthiazole derivatives (
Synthesis of thiazole derivatives using palladium/copper.
The mixtures of thiourea and acetophenone were treated with various oxidizing gents as sulfuryl chloride, chlorosulfonic acid, thionyl chloride, sulfur monochloride, sulfur trioxide, sulfuric acid, nitric acid, and sulfur. In each case a large amount of 2-amino-4-phenylthiazole (
Synthesis of thiazole derivatives using oxidizing agents.
Thiazole and its derivatives are among the most active classes of compounds that are known for their broad spectrum of activity, e.g., antibacterial [53], antifungal [54], antimalarial [55], antitubercular [56], antiviral [57], anti-inflammatory [58], antidiabetic [59], anthelmintic [60], anticonvulsant [61], antioxidant [62], anticancer [63], and cardiovascular activities [64], and known as new inhibitors of bacterial DNA gyrase B [65]. Some drugs that already are on the market including the recent entry dasatinib possess thiazoles nucleus [66].
Compounds containing thiazole have marked their presence in a number of clinically available anticancer drugs such as tiazofurin [67], dasatinib [68], dabrafenib [69], patellamide A [70], ixabepilone [71], and epothilone [72].
Ramla et al. synthesized a variety of 4-amino-3-methyl-5-(2-methyl-1
Structure of compound
Popsavin et al. reported a set of 2-(2,3-anhydrofuranosyl) thiazole-4-carboxamide (2′,3′-anhydrotiazofurin) derivatives (
Structure of compound
A series of 5-arylidene derivatives were synthesized and evaluated for their antitumor activity. Compound 2-{2-[3-(benzothiazol-2-ylamino)-4-oxo-2-thioxothiazolidin-5-ylidenemethyl]-4-chlorophenoxy}-N-(4-methoxyphenyl)-acetamide (
Structure of compound
In another approach towards triple-negative breast cancer, Zhou et al. synthesized and optimized a series of hybrids of 2,4-diaminopyrimidine and thiazole derivatives (
Structure of compound
A series of 2-(4-benzoyl-phenoxy)-N-(4-phenyl-thiazol-2-yl)-acetamides were synthesized by Prashanth et al. The authors suggest that the effect of compound (
Structure of compound
Dae-Kee K et al. produced a set of 5-(pyridin-2-yl)thiazoles enclosing a
Structure of compound
A series of 2,4-disubstituted thiazole compounds containing
Structure of compound
Santos et al. synthesized 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole (
Structure of compound
El-Borai et al. synthesized a series of 2 6-substituted-3-(pyridin-3-yl)imidazo[2,1-b]thiazole (
Structure of compound
Fungal and bacterial resistance to antimicrobial drugs is increasing rapidly due to nonselective antimicrobial activities and a limited number of drugs. To overcome this situation, several molecules containing thiazole are synthesized to treat bacterial and fungal infections [83, 84].
El-Borai et al. work on an ongoing program in the field of synthesis and evaluated antimicrobial activity of medicinally important new compounds, taking the fused thiazole compounds as thiazolopyrimidines (
Structure of compounds
Vicini et al. synthesized a new set of 2-thiazolylimino-5-arylidene-4-thiazolidinones which were assayed in vitro for their antimicrobial activity against Gram-positive and Gram-negative bacteria and yeast. Compound (
Structure of compound
A series of thiazolyl thiazolidine-2,4-dione derivatives were synthesized by Dundar et al. These compounds were screened for their antibacterial and antifungal activities against methicillin-resistant
Structure of compound
Abdel-Wahab et al. synthesized 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4-(aryl)-1,3-thiazol-2-yl]-1
Structure of compound
Bera et al. Synthesized pyridinyl thiazole ligand having hydrazone moiety and its cobalt complex. Both ligand and its complex were tested for antibacterial properties towards Gram-positive and Gram-negative bacteria. The results revealed that the ligand (
Structure of compound
Narayana et al. synthesized a series of 5-(2-substituted–1,3-thiazol-5-yl)-2-alkoxybenzamides and 5-(2-
Structure of compound
Chimenti et al. reported the synthesis of a novel series of 2-thiazolylhydrazone derivatives and the influence of the substituents on the thiazole ring and on antifungal activity. Some of the tested compounds were found to possess significant antifungal activity when compared to clotrimazole, in particular compound (
Structure of compound
Antioxidants are of great interest due to their participation in important biological and industrial processes. They are generated in the human body and may cause damage to lipids, proteins, and DNA and thus may lead to various diseases such as cancer, atherosclerosis, diabetes, cirrhosis, and Alzheimer’s and inflammatory diseases [91]. Thiazole and derivatives are the core structure in a variety of pharmaceuticals with a wide range of biological activity [92, 93, 94].
The antioxidant potential compounds (
Structure of compound
Bozdag-Dundar et al. synthesized a series of 2, 4-dichlorothiazolyl thiazolidine-2,4-dione and 4-chloro-2-benzylsulfanylthiazolyl-thiazolidine-2,4-dione derivatives, and they were tested for their antioxidant properties. Compound (
Structure of compound
Gouda et al. synthesized 2-amino thiazole derivatives and evaluated their antioxidant activity. They reported that the three compounds (
Structure of compound
A series of N2-[2-chloro-4(3,4,5-trimethoxy phenyl) azetidin-1-yl)]-N4-(substituted aryl)-1,3-thioazol-2,4-diamine (
Structure of compound
Thiazole moieties have occupied a pivotal position in the modern organic and medicinal chemistry due to its broad-spectrum pharmacological and medicinal activities such as antimicrobial, anticancer, and antioxidant. The presence of thiazole ring in many drugs such as penicillin, pramipexole, tiazofurin, meloxicam, and nizatidine motivates the chemists to design new thiazole scaffolds. Thiazole nucleus exhibited an important role in finding new leads and drugs for various diseases. This chapter has illustrated the commonly used approaches to synthesize subsisted thiazole derivatives, described their key electronic properties, and highlighted their most important chemical reactivity. A particular focus has been on the use of thiazole in dyes and their metal complexes and miscellaneous applications of thiazole dyes. Also we have focused our attention on the biological application of thiazole derivatives.
The incidence of liver cancer is growing worldwide [1, 2] and research estimates that millions of people will be affected by the disease annually by 2025 [3]. Hepatocellular carcinoma (HCC) describes the most common type of liver cancer, responsible for nearly 90% of all cases. The most significant risk factor for HCC development is infection with the hepatitis B virus (HBV), accounting for 50% of all cases [4]. With antiviral drugs, patients have achieved sustained virological response (SVR), reducing the risk of hepatitis C virus (HCV) infection substantially [5]. Nevertheless, the risk of HCC for individuals with cirrhosis remains even after HCV clearance. Nonalcoholic steatohepatitis (NASH) is becoming the main cause of HCC in the West, since it is associated with metabolic syndrome and diabetes mellitus [6]. Furthermore, there have also been reports that aristolochic acid and tobacco are potentially pathogenic cofactors for HCC [7].
The incidence of HCC differs depending on the etiology and type of genotoxins, although there is a greater understanding of the pathophysiology and drivers of HCC over the past few years; clinical applications of these insights have yet to emerge. There are actionable mutations of HCC tumors in approximately 25% of cases; however, most mutations are less than 10%, making proof-of-concept studies difficult [7, 8]. The majority of mutations in HCC remain unsolvable, including those in TERT, TP53, and CTNNB1 [9]. Researchers are also still working on how to establish biomarkers that guide therapy based on molecular and immune classes.
Since the early 2010s, HCC management has vastly improved [8, 10, 11, 12]. The mainstay curative treatments in HCC cases have been hepatic resection and liver transplantation. For tumors down-staged beyond Milan criteria, refinements in patient selection have led to improved surgical resection results and outstanding 10-year post-liver transplantation survival rates [10, 13]. In nonsurgical early-stage HCCs, image-guided ablation using radiofrequency remains the gold standard despite advancements in alternative approaches [12]. Following these potentially curative methods, adjuvant therapies to prevent relapse are an unmet medical need, as randomized controlled trials (RCTs) have so far given poor results. The most frequently used and standard treatment for intermediate-stage HCC for the past two decades has been transarterial chemoembolization (TACE) [14]. Transarterial radioembolization (TARE) has been demonstrated to be effective in phase II studies [15], but guidelines have not yet established it as a primary standard of therapy. The arsenal of intermediate therapy is unlikely to improve in the immediate term with more locoregional devices or radiation oncology methods.
There has been a threat to the use of traditional HCC treatments from systemic medicines, such as tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and monoclonal antibodies. Patients with HCC are predicted to be exposed to systemic therapy 50–60% of the time over their lives, especially in advanced stages of the disease [8]. The development of systemic medicines has progressed dramatically in the last 5 years, with studies showing significant improvements in overall survival and quality of life for patients [8]. As a result of the combination of anti-PDL1 antibody atezolizumab and anti-VEGF antibody bevacizumab, patients with advanced-stage HCC have a quadrupled life expectancy and improved patient-reported outcomes [16]. The most successful single-drug therapies are still sorafenib [17] and lenvatinib [18]. Regorafenib [19], cabozantinib [20], and ramucirumab [21] have similarly shown enhanced survival advantages when switched to single-agent regimens. In 15–20% of responders, single-agent ICIs produce significant therapeutic advantages, although biomarkers have thus far failed to identify this group [22, 23]. Phase III trials are also underway that examine combinations of ICIs with TKIs or PD1/PDL1 axis inhibitors with CTLA4 inhibitors to examine the efficacy of these therapies. The findings of these studies are expected to alter the landscape of managing HCC at all stages of the disease.
In 2018, there were 841,080 new cases of liver cancer, making it the sixth most common cancer worldwide and the fourth leading cause of cancer-related death [3]. Despite an increase in HCC incidence and mortality in different parts of Europe and the United States [24], the highest rates are seen in East Asia and Africa. SEER reports that HCC has been the fastest-growing cancer-related cause of death in the United States since the early 2000s. HCC is expected to be the third leading cause of cancer-related death by 2030 if current trends continue [25].
Chronic liver disease is responsible for more than 90% of all cases of HCC. All forms of cirrhosis are major risk factors for HCC [10, 11]. Annually, 1–6% of patients with cirrhosis die of HCC. HBV and HCV infection, chronic alcohol consumption, and diabetes- or obesity-related NASH all increase the risk for HCC [26]. Hemochromatosis, antitrypsin deficiency, and cirrhosis from primary biliary cholangitis all represent less common risk factors for HCC. Up to 45% of people with hemochromatosis who develop cirrhosis over their lifetime will develop HCC [27].
The cause of HCC in Asia and Africa is 60% HBV infection, while it is 20% in the West [4]. HBV is a DNA virus that can cause insertional mutagenesis and activate oncogenes by integrating into the host genome [28]. HBV increases the risk of liver cancer even if there is no cirrhosis in most patients with HBV-induced HCC. Due to the high prevalence of endemic HBV in East Asia, males (40 years of age) and females (50 years of age) have a high risk of developing HCC, which necessitates surveillance programs. The incidence of HCC in patients in their early 30s or 40s in Africa is likely due to their exposure to aflatoxin B1, a carcinogen, which increases the risk of developing HCC in combination with HBV [29]. Many Asian countries still do not have universal immunization programs, despite the fact that HBV vaccination programs have reduced HCC incidence in some regions [30].
The most common underlying liver disease in North America, Europe, and Japan is chronic HCV infection [4]. In contrast to HBV, HCV is an RNA virus that does not integrate into the host genome, so those who develop cirrhosis or chronic liver disease with bridging fibrosis are at risk of developing HCC. Direct-acting antiviral (DAA) medications have enabled more and more people to achieve a sustained viral response (SVR), thereby reducing their risk of developing HCC by 50–80% [5]. A number of patients, especially those from minority racial or ethnic groups and those from low-income socioeconomic areas, have not been tested for HCV and thus have no idea of their infection [31]. Additionally, people with HCV-induced cirrhosis remain at risk of developing HCC even after they have achieved sustained virologic response (>2% per year) and, thus, they have to be monitored closely [32, 33].
HBV surface antigens are necessary for HDV to replicate and infect. HDV is an RNA virus. Twenty to forty million people are estimated to be infected with HDV worldwide, and these individuals experience more severe liver disease, notably fibrosis and cirrhosis, than people who have only HBV. Furthermore, several cohort studies have found that co-infection with HDV and HBV may lead to an increased risk of HCC than HBV infection alone. A study reported that patients with acute or chronic HDV infection were at a significantly higher risk of HCC than those with a sole HBV infection [34].
A fatty liver, cirrhosis, and HCC are all caused by excessive alcohol consumption. Cirrhosis caused by persistent alcohol consumption, also known as NASH, is becoming increasingly common. HCC is associated with alcohol-induced cirrhosis in 15–30% of cases depending on geographic region, with an annual incidence varying between 1% observed in population-based studies and 2–3% recorded in tertiary care referral centers [35]. There is also evidence that chronic alcohol consumption increases the risk of HCC from other causes; for example, several studies suggest that those who drink alcohol and are HBV carriers are more likely to develop HCC [36]. Although alcohol consumption has some similarities with other forms of cirrhosis, particularly NASH, in some pathophysiological processes, there is an indication that alcohol consumption may have different pro-tumorigenic mechanisms in individuals.
Patients with diabetes mellitus or obesity may also develop HCC from NASH, another major factor contributing to cirrhosis. Due to the rising incidence of obesity, NASH has become a leading cause of cirrhosis around the world. Since 2010, the proportion of HCC caused by NASH has risen quickly, now accounting for 15–20% of cases in the Western world [6]. The proportion of metabolic syndrome and NASH attributable to the population is expected to exceed 20% due to the co-occurrence of these two disorders [37]. The incidence of HCC in NASH-associated cirrhosis (1–2% per year) is lower than in virus-related cirrhosis (3–5% per year), but it remains >1.1% per year, demonstrating that surveillance is cost-effective [38]. Several studies have shown that 25–30% of NASH-related HCC occurrences develop without cirrhosis, limiting the relevance of current surveillance programs that primarily target individuals with cirrhosis. However, the National Veterans Affairs Health System has discovered that the incidence of HCC annually is below the cost-effective threshold in people with non-cirrhotic NASH and surveillance should not be performed [38, 39].
Many sociodemographic factors have been linked to HCC, particularly in individuals with cirrhosis. The risk of HCC increases with age, with those over 70 years of age showing the highest incidence [40]. HCC is also disproportionately male (male-to-female ratio of 2–3:1), which may reflect a clustering of risk factors among men, as well as differences in sex hormones [41]. HCC is more common in racial or ethnic minorities, particularly Hispanics, than in White people, according to studies. This disparity in prevalence could be related in part to the increased prevalence of single-nucleotide polymorphisms in PNPLA3, which are connected to NASH-associated HCC [42]. Smoking has also been linked to an increased risk of HCC in epidemiological studies [43]. Except for studies demonstrating a protective benefit of coffee and aspirin [44], the impact of diet in reducing the incidence of HCC is unknown.
HCC pathophysiology is a multistep process. The early stages of hepatocyte malignant transformation and HCC development are caused by the interaction of several variables. The cellular environment, immune cells, and the severity of chronic liver disease must all be considered, including genetic predisposition, and reciprocal interactions among viral and nonviral risk factors. From the early stages of transformation to invasion and then metastasis, the microenvironment plays an important role in cancer progression.
HCC’s cell of origin is a point of contention. It is possible for liver cancer to originate from liver stem cells, transit-amplifying populations, or mature hepatocytes, just like in any other type of cancer. There is general controversy over whether liver stem cells exist and function. Additionally, mature hepatocytes have a high proliferation capacity after injury, which allows them to survive for long periods of time. Several studies on mouse models reported that HCC is believed to develop from transformed mature hepatocytes; however, other studies suggest HCC may originate from putative stem cells in the liver [45]. Intrahepatic cholangiocarcinomas and tumors with mixed HCC or cholangiocarcinoma form, on the other hand, often appear to emerge from adult hepatocytes, highlighting the principles of metaplasia and cell plasticity (i.e. trans-differentiation). These data back the idea that a tumor’s form and epigenetic landscape may not always represent its cell of origin [46, 47].
High-throughput next-generation sequencing has identified cancer-driver genes recurrently changed in HCC with oncogenic or tumor-suppressive properties. In 80% of cases of HCC, driver gene alterations are found in the TERT promoter, chromosome translocations, telomerase activation, and gene amplification [7, 48]. Studies have shown that mutations in AXIN1 (inhibitors of the Wnt pathway), CTNNB1 (encoding-catenin), or APC (inhibitors of the Wnt pathway) inactivation activate the Wnt-β catenin signaling pathway in 30–50% of cases [7, 48]. CCNE1, TP53, ARID1A, RB1, CCNA2, PTEN, RPS6KA3, ARID2, and NFE2L2 are all known to have mutations or genetic changes that affect cell cycle control. AKT-mTOR and MAPK pathways, as well as genes involved in epigenetic regulation and oxidative stress, have been linked to HCC. AKT-mTOR and MAPK pathways, as well as genes involved in epigenetic regulation and oxidative stress, have been linked to HCC. The recurrent overexpression and activation of oncogenic signaling pathways, including receptor tyrosine kinases, are also linked to focal chromosomal amplification of MYC, CCND1, VEGFA, FGF19, and MET [49]. In spite of the fact that cancer-driver gene mutations can occur at random, certain genes seem to be associated with specific molecular HCC subclasses based on transcriptome profiles and histological phenotypes [8, 9, 50]. At least 20–25% of HCC patients have a potentially actionable mutation, according to current standards [7, 8, 51]. In the pathogenesis of HCC, it has been well documented that risk factors cooperate with cancer-driver mutations. In patients with a GSTT1 null mutation, for instance, the harmful effects of aflatoxin B1 are amplified by HBV infection [52, 53]. In addition, patients who use a lot of alcohol are more likely to have polymorphisms in PNPLA3, TM6SF2, and HSD17B13 [54, 55].
The TERT promoter is the most common locus of HBV-mediated insertional mutagenesis, resulting in overexpression of telomerase, the enzyme responsible for telomere length maintenance [56]. Telomerase activation inhibits the chromosomal erosion that occurs naturally with each cell division as people age. Telomerase activity on the ectopic enhances cell transformation and protects cells against senescence [57]. Other HBV-associated recurrent insertions have been shown to activate potent oncogenes involved in cell cycle control, such as CCNA2 or CCNE1. Replicative stress and complex rearrangements are caused by these oncogenic changes throughout the genome [58]. Adeno-associated virus 2 (AAV2) showed identical insertional oncogenic mutagenesis in a small group of HCC patients, with a shared hot point of the viral insertion inside the TERT promoter, CCNA2, and CCNE1 [59]. These findings show that viral infection activates particular oncogenes, which act as early facilitators of hepatocyte transformation. HCV infection, on the other hand, has no direct carcinogenic effect, and the induction of mutations is driven by the oxidative stress caused by persistent inflammation.
Hepatocytes are subjected to multiple genetic mutations and epigenetic alterations throughout the progression of chronic liver disease and cirrhosis, which are the most common causes of HCC. Several risk factors that cause DNA changes are linked to particular mutational signatures during this process [7, 60]. In exome sequencing analyses of HCC, patients from Asia and Africa who had been exposed to aristolochic acid (A > T mutations in CTG trinucleotide) and aflatoxin B1 (C > A mutations) had mutational signatures 22 and 24, respectively [7, 61]. Mutations of the C > A at dinucleotide sequences in signature 4 were linked with tobacco smoking, while the T > C mutations at TpA dinucleotide in signature 16 were related to alcohol consumption [62]. It remains to be seen whether this discovery can be turned into preventative measures. It is well known that the liver is capable of detoxifying a variety of chemicals that may cause mutations in the hepatocyte genome, leading to the development of cancer.
Several studies have created a molecular and immune categorization for HCC based on genomic, epigenomic, histopathological, and immunological analysis [1, 9, 63]. Molecular classes of HCC have been identified based on the principal molecular drivers and pathways involved [9, 63, 64, 65, 66, 67] or the tumor’s immunology status [8, 68]. The molecular classifications are associated with specific genomic abnormalities, histological signatures, and clinical outcomes. Approximately half of all HCCs are of the proliferation type [49]. The proliferation type is characterized by mutations in TP53 and FGF19 or CCND1 amplification, and it is more common in HBV-associated cancers with poor prognosis. Within the proliferation class, there are two subclasses: proliferation progenitor cells and proliferation-Wnt-TGF cells. Twenty-five to thirty percent of HCC are proliferation-progenitor cells, which are characterized by activation of classical cell proliferation pathways, i.e. the expression of progenitor cell markers (such as EPCAM and FTP) is also related to the activation of signaling pathways (PI3K-AKT-mTOR, RAS-MAPK, and MET and IGF signaling cascades [49, 64]. In alcohol- and HCV-related HCC, non-proliferative tumors represent more than half of all cases; these tumors have better outcomes and correspond to TCGA cluster 2 [65]. Within the nonproliferative class, at least two distinct subgroups have been described: one with dominant canonical Wnt signaling and mutations in CTNNB1 [69] and the other with IFN signaling activation [49].
Reports on the classification of HCC based on immune cell status have added to the knowledge of HCC’s molecular characteristics [68]. This categorization classifies HCC tumors into four subclasses: immunological-active, immune-exhausted, immune-intermediate, and immune-excluded, and gives additional information based on immune features. Immune cell infiltrations are categorized into two subclasses: immune-active and immune-exhausted. In HCC tumors that are immune-active, helper T (CD4+) and cytotoxic T (CD8+) cells are enriched and ICIs are effective. The depletion of CD8+ cells driven by TGF is prevalent in immune-exhausted tumors. In contrast, immune-excluded tumors lack T cell infiltrates and are characterized by a disproportionate increase in regulatory T cells (Tregs), as well as canonical Wnt signaling and other immune-suppressive pathways. Immune-excluded tumors often develop ICI resistance [70].
Obesity has been related to a higher risk of cancer in a variety of organs [71]. Obesity can cause systemic alterations, such as impaired immune function and endocrine abnormalities, which are common in cancers of many types. According to current research, fatty liver disease is quickly becoming the primary cause of HCC in the Western world [6]. The effects of metabolic and oxidative stress, immune dysfunction, abnormal inflammatory responses, impaired endocrine, and adipokine signaling have all been identified as pathways by which NAFLD or NASH cause HCC (Figure 1) [72, 73].
The molecular mechanism of HBV-induced HCC.
Several classical cell proliferation pathways are activated in HBV-associated HCC tumors, including PI3K-AKT-mTOR, RAS-MAPK, MET, and Wnt-TGF. A high chromosomal instability level and frequent TP53 and AXIN1 mutations are additional features of HBV-induced HCC (Figure 2).
The molecular pathogenesis of HCC induced by NASH, HCV, HDV, and alcohol.
Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and hepatitis C virus (HCV) infection promote the development of HCC tumors. Here, the risk factors cause chromosomal instability with frequent mutations in the TERT promoter sequence which, in turn, leads to the CTNNB1 mutations and activation of either WNT-β-catenin signaling pathway or IL6-JAK-STAT signaling pathway. The activation of either or both of these signaling pathway promote the proliferation of progenitor cells leading to an inflammatory tumor microenvironment and ultimately to HCC.
Fatty acid overload causes oxidative stress and endoplasmic reticulum (ER) stress in hepatocytes, resulting in pathological inflammation and cell death [72, 74]. HCC was induced in one study in mice following ER stress-induced inflammation via NF-κB and TNF-α signaling pathways [75]. These toxicological processes of HCC, however, are yet to be demonstrated in human. Hepatocytes with abnormal fatty acid metabolism are susceptible to DNA damage caused by reactive oxygen species (ROS) resulting from mitochondrial dysfunction [76]. Hepatocytes are also affected by changes in the expression of particular metabolic enzymes, which reduces their ability to repair DNA damage [77]. Changes in inflammatory signaling are also a result of the metabolic failure; for example, elevated levels of IL-17 (a tumor-promoting cytokine) have been seen in human NASH [78]. A number of pathogenic lipids are produced as oncometabolites in NASH in addition to increased lipid production [79, 80]. When mTORC2 is continuously activated in mouse hepatocytes, a high level of glucosylceramide is produced, increasing ROS production, which can lead to HCC [79]. Alterations in cholesterol metabolism may also have a role in HCC pathogenesis [80], possibly by causing the generation of pro-tumorigenic nuclear receptor ligands. Although autophagy has antitumor properties, one study found that lipophagy (autophagic destruction of lipid droplets) plays a crucial role in HCC progression. Hepatocytes from NASH patients and a mouse model of HCC overexpress sequestosome 1 (also called p62), a lipophagy regulator [81]. Patients with NASH had a higher risk of HCC than those with NAFLD according to studies [6]. In one experiment, fatty acid-induced oxidative stress in hepatocytes increased the expression of STAT1 and STAT3, two pro-inflammatory transcription factors that generally operate in tandem [82]. Surprisingly, a high level of STAT1 promoted NASH progression in this mouse model, while a high level of STAT3 promoted HCC, both independently [82]. Accordingly, similar inflammatory signals may promote progression from NAFLD to NASH or HCC in different ways. This is because NAFLD is more common in the general population than NASH [6]; the data indicate the need to understand how NAFLD, regardless of NASH, can lead to HCC. When hepatocytes are overloaded with fatty acids, the increased ER stress, pathological lipophagy, ROS generation, and a lowered reducing power (low NADH or NADPH levels) may combine to generate oncogenic genetic changes and accelerate the development of malignant cells.
Based on transcriptomic-based phenotypic classes, hepatocellular carcinoma (HCC) can be divided into two primary molecular groupings [49, 64, 65, 66, 67]. More aggressive tumors with weak histological differentiation, high vascular invasion, and higher levels of alpha-fetoprotein (AFP) belong to the proliferation class [50]. In S1 or iCluster 3 [64, 65], Wnt-TGF activation leads to an immune-exhausted phenotype [68], while in S2 or iCluster 1 [64, 65], stem cells markers (CK19, EPCAM) as well as IGF2 and EPCAM signaling pathways are expressed [50]. In hepatitis B virus (HBV)-associated tumors, cell proliferation pathways such as PI3K-AKT-mTOR, RAS-MAPK, MET, and IGF are usually activated. Furthermore, numerous TP53 mutations, high chromosomal instability, and widespread DNA hypomethylation are also characteristics of this group. The nonproliferation class consists of tumors that are less aggressive, well-differentiated histologically, have low AFP levels, and have fewer vascular invasions [50]. These tumors can be caused by nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or infection with hepatitis C virus (HCV) [49, 64, 65, 66, 67]. This class is divided into two distinct subgroups: the WNT––catenin CTNNB1 subclass has frequent CTNNB1 mutations and activated WNT––catenin signaling, leading to an immune-excluded phenotype with low immune infiltration [49, 67, 68]; and the interferon subclass has a highly activated IL6-JAK-STAT signaling pathway, leading to a more inflamed microtumor with many TERT promoter mutations, and this class has chromosomal stability [63, 64, 65, 66, 67, 68].
The histological characteristic of NASH is immune cell infiltration of the obese liver [72]. The establishment of animal models that accurately reproduce human HCC is critical for basic pathogenesis research as well as translational research [83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97]. Immune cells and cytokines have been found to have an essential role in the pathogenesis of HCC in several experimental types. In mouse models, for example, persistent NASH causes CD8+ T cell activation, which leads to hepatocyte destruction and HCC [98]. As a consequence of NAFLD, intrahepatic CD4+ T cells are selectively depleted, which are necessary to initiate an effective adaptive immune response against tumors [99]. Additionally, B cells, Treg cells, natural killer cells, and other myeloid cells have been associated with NASH-induced HCC [72, 73]. The activation and recruitment of platelets in the liver also contribute to HCC formation in mice, specifically via platelet glycoprotein Ib (GPIb) signaling, which is in line with clinical data [100], implying that this pathway has the therapeutic potential [101]. The causal function of NASH in HCC was also linked to a changed cytokine milieu [74]. NASH, for example, has been demonstrated to overexpress hepatic IL-6 and TNF-α, which are both causes of HCC in various etiologies [102].
On the background of fatty liver disease, all of the mechanisms described earlier could promote HCC at the same time. Their relative involvement to human HCC, however, is uncertain at this time. The comparison of mutational signatures in NASH-associated HCC versus HCC from other causes should aid in determining the relative contributions of different variables.
HCC is an archetypal inflammation-related malignancy, with chronic inflammation caused by viral hepatitis, excessive alcohol consumption, NAFLD, or NASH accounting for 90% of the HCC burden. In the development of HCC [103], the immunological microenvironment plays a critical role. Immune infiltrates are associated with a better prognosis in HCC, possibly due to more effective antitumor immunity [68, 104]. Immune signals such as IL-6, lymphotoxin-, and TNF-α have been shown to accelerate hepatocarcinogenesis and impact tumor aggressiveness in mouse models of HCC [47, 105], yet immune responses can also slow the course of liver cancer [103]. In addition, the liver has the greatest number of immune cells in the body and has a unique immunological state that allows it to survive the constant influx of inflammatory signals coming from the gut [103]. Understanding this specific hepatic immune system is likely important given the intricate interplay between malignant hepatocytes and the liver immune system [103, 106]. A surprising finding in mice and humans is that VEGF released by malignant hepatocytes creates an immune-tolerant, pro-tumorigenic microenvironment [49, 107], suggesting that inhibiting the VEGF cascade might have a positive effect on liver immunity by modifying VEGF production. Interestingly, the combination of ICIs and certain targeted medicines such as VEGF inhibitors had greater survival advantages than the use of single agents [16, 108].
It has been shown that hepatocytes in chronically inflamed livers interact with numerous cell types including macrophages, endothelial cells, stellate cells, and various types of lymphocytes [103, 106]. Due to its importance in immuno-oncology therapy, researchers are paying more attention to the adaptive immune system’s involvement. Mouse models have revealed that practically every immune cell type can play both pro-tumor and antitumor roles [103]. In addition to producing pro-tumorigenic cytokines and growth factors that support tumor cell proliferation or inhibit apoptosis, immune cells also diminish nearby lymphocytes’ antitumorigenic function. The NF-B and JAK-STAT pathways have been identified as major inflammatory signaling pathways implicated in the promotion of HCC in studies [109], and this assertion was confirmed in a transcriptomic analysis of human HCC [110]. Immune monitoring and the destruction of premalignant or completely changed malignant hepatocytes are the adaptive immune system’s main antitumor functions [104].
The main effectors of antitumor immunity are cytotoxic T (CD8+) cells. As a result, one study found that depleting these T cells in mice increased HCC burden [111], while another found that these T cells promote premalignant hepatocyte surveillance [112]. Several studies in mice have shown that the depletion of CD8+ T cells can also reduce tumor burden [98]. Analyses of human HCC samples suggest that some individuals have functional CD8+ T lymphocytes that produce antitumor effector molecules such as granzyme A, granzyme B, and perforin [113]. However, single-cell sequencing of human HCC T cells has revealed that the CD8+ T cells are often dysfunctional in HCC [114]. There is no clear understanding of the causes of CD8+ T cell dysfunction, which leads to diminished proliferation and the inability to generate cytotoxic effector molecules. Increasing numbers of Treg cells within the tumor are linked with poorer clinical outcomes in HCC, and Treg cells are thought to be a primary cause of T cell dysfunction [115]. Treg cells’ immunosuppressive capabilities may be mediated by CD10 and TGF116 production, suggesting that blocking these cytokines could make HCC more susceptible to ICIs. HCC-infiltrating Treg cells are known to suppress immune responses through the hyaluronic acid receptor, layilin, which is interesting [116]. As a result of a layilin induction, CD8+ T cells exhibited dysfunction in human HCC, and layilin overexpression was associated with distinct mRNA expression signatures in lymphocytes [114].
Although B cells were once assumed to be innocent bystanders in cancer, new data suggest that they have an active role in the adaptive immune system’s interaction with cancer [117]. B lymphocytes both stimulated and inhibited tumor growth in mice models of HCC [118]. Furthermore, one study found that IgA-expressing cells actively suppressed CD8+ T cell activity, which aided HCC growth [111]. Furthermore, studies in humans and mice have shown that tertiary lymphoid structures, which are crucial for adaptive immune responses to cancer [119], have both pro-tumor and antitumor capacity in HCC [120, 121].
The risk of HCC is high enough to warrant surveillance once the patient has reached cirrhosis, even though some etiologies (for instance, HCV versus autoimmune hepatitis) are more likely to cause HCC than others [10, 11]. In response to chronic injury, hepatic stellate cells play an important role [122]. Upon activation, it undergoes phenotypic changes and synthesizes components of the extracellular matrix, mainly collagen, as well as growth factors, which promote neoangiogenesis, endothelial cell migration, and fibrosis [123]. Cirrhosis and portal hypertension have a histological substrate in which the hepatic architecture is distorted and the vasculature is disordered. Premalignant senescent hepatocytes respond to this condition by secreting chemokines that impair senescent surveillance and immune-mediated tumor suppression in vivo [112]. Experimental models have also demonstrated that CD4+ cells are relevant in promoting NAFLD-related HCC [99], and the interaction between the innate immune system and the intestinal microbiota plays a role in promoting the development of HCC [124, 125]. In HCC, the immune system, in addition to fibrosis, plays a significant role in the cancer field effect. The cancer field effect refers to the favorable microenvironment in cirrhosis that favors tumor formation. The primary molecular elements unregulated in this microenvironment have been identified through various genomic investigations. Several gene profiles obtained from cirrhotic tissue are associated with the probability of developing HCC and can be utilized to risk stratify patients [110, 126, 127]. The presence of these gene signatures is associated with cancer risk, the incidence of hepatic decompensation in patients, and overall survival [126, 127]. More research has been done on the genetic characteristics of the cirrhosis inflammatory milieu that contribute to HCC development [128]. In 50% of neighboring cirrhotic tissue from HCC patients, an immune-mediated cancer field molecular subclass was observed. In addition to lymphocyte infiltration, this subclass can be further divided based on pro-inflammatory or immunosuppressive signal activation. In the immunosuppressive subclass, which accounted for 10% of patients and had a threefold higher risk of developing HCC, TGF signaling, T-cell exhaustion, and overexpression of immunological checkpoints (such as CTLA4, TIGIT, and LAG3) were shown to be more prevalent [128]. Modulating the tumor microenvironment’s role in HCC’s natural history would be a compelling reason for altering the dynamic crosstalk between hepatocytes and the hepatic immune system [103].
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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