\r\n\tWith the discovery of more unconventional heavier crude and alternative hydrocarbon sources, primary upgrading or cracking of the oil into lighter liquid fuel is critical. With increasing concern for environmental sustainability, the regulations on fuel specifications are becoming more stringent. Processing and treating crude oil into a cleaner oil with better quality is equally important. Hence, there has been a relentless and continuous effort to develop new crude upgrading and treating technologies, such as various catalytic systems for more economical and better system performance, as well as cleaner and higher-quality oil.
\r\n\r\n\tThis edited book aims to provide the reader with an overview of the state-of-the-art technologies of crude oil downstream processing which include the primary and secondary upgrading or treating processes covering desulfurization, denitrogenation, demetallation, and evidence-based developments in this area.
",isbn:"978-1-80356-681-8",printIsbn:"978-1-80356-680-1",pdfIsbn:"978-1-80356-682-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"808b0ddfb3b92e0636ae44a83ef7dbd9",bookSignature:"Dr. Ching Thian Tye",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11542.jpg",keywords:"Crude Oil Properties, Hydrocracking, Catalytic Cracking, Coking, Visbreaking, Thermal Cracking, Hydroprocessing, Hydrodesulfurization, Desulfurization, Denitrogenation, Demetallation, Dearomatization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 22nd 2022",dateEndSecondStepPublish:"April 19th 2022",dateEndThirdStepPublish:"June 18th 2022",dateEndFourthStepPublish:"September 6th 2022",dateEndFifthStepPublish:"November 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Associate professor at the School of Chemical Engineering in Universiti Sains Malaysia and dedicated researcher in fuel-related catalytic process and chemical reaction engineering. 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None of these activities has damaged the environment as severely as agricultural practices.
Current agricultural practices have negatively affected aquatic and terrestrial ecosystems by destroying habitats, deforesting to increase cropping areas and applying pesticides.
Pesticides are a heterogeneous category of chemical products destined to pest, disease and weed control including several types, such as insecticides, fungicides, herbicides, nematicides and others.
Nowadays, such chemical product applications have been considered the most efficient plant protection procedures and have significantly contributed to the improvement of crop productivity.
Nevertheless, the claimed objective of supplying the population with enough food does not justify damaging the environment, just because small quantities of pesticides are known to efficiently control pests, diseases and weeds. However, most of them are rapidly spread out affecting all living beings (flora and fauna, including humans).
The use of chemical molecules in agriculture increased after the Second World War with the advent of DDT (dichloro-diphenyl-trichloroethane). DDT was discovered in 1939 by Paul Müller (Swiss entomologist) and its worldwide use was rapidly expanded due to its large action range, low cost and efficiency in the control of tropical disease vectors, such as typhoid fever and malaria [1].
After the release of DDT, a large range of molecule groups destined to crop protection were developed and commercialized. In 1962, the book “Silent Spring” was the first act of environment manifest against DDT, describing the bird population decrease (from the top of the food chain) attributed to its indiscriminate use.
After the 1960’s, the use of chemical products in agriculture rapidly increased and it was associated with the appearance of environmental and human health problems.
The frequent and incorrect use of pesticides have caused soil, atmosphere, food and water resource (superficial/underwater) contaminations, negatively affecting aquatic and terrestrial organisms as well as frequently causing toxicity to the human population.
Therefore, studies are urgently needed to make environmental monitoring procedures viable in order to detect potential contamination risks and give support to public actions for environmental safety and agriculture sustainability.
Currently, product mixtures (associations between one or more molecules) are applied in agriculture instead of individual molecules; therefore, previous studies that focused on only one molecule should now consider molecule mixtures.
The existence of such a large variety of pests, diseases and weeds affecting yields have led farmers to use product mixtures, aiming at efficiently managing crop protection. Such mixtures, also called product associations, enter the environment in a different way compared to the individual product application. Thus, more studies are required about these mixture-environment interactions and possible interactions between molecules and consequent interferences in the environment.
Although mixtures have been intensively studied concerning their agronomic efficacy, little information is found about their implications on environmental safety.
In this chapter, the tank mixture subject is approached from an environmental point of view, explaining the chemical product mixture interactions and the possible contaminant effects. Studies on the product-environment interactions are presented to provide the main available information as support to future studies and decisions in environmental sustainability and safety.
Tank mixtures are associations among two or more chemical products (pesticides) or among chemical products and fertilizers in a unique tank for application in crops. This practice is common in Australia, Canada, U.S.A and United Kingdom, where there are recommendations on application procedures, incompatibilities, and safety [2].
Concerning agricultural practices, the tank mixture of two or more chemical products might be a good application strategy, saving fuel and labor-hours, causing less soil compaction, and possibly providing a larger pest control range and efficacy, when compared to the single product application. For these reasons, this technique is preferred by farmers [3].
Nevertheless, the herbicide mixture might induce, for instance, interactions before or after reaching the target-plant, by altering the product action in synergistic, antagonistic or additive ways. One common practice is the simultaneous application of herbicides with and without residual effect in order to increase the weed species control range and/or the control period. Another practice is the addition of adjuvants to improve herbicide performance to control weeds. The simultaneous application of pesticides (concerning the species-target to be controlled) might induce undesirable (antagonistic, synergistic or additive) reactions, depending on the herbicide type and plant species [4]. When the mixture induces an antagonistic reaction, it means that a lower weed control action than expected is observed. When the mixture induces a synergistic reaction, it means that a higher weed control than expected is observed. And, finally, when the mixture induces an additive reaction, it means that no change in weed control is observed.
Several studies have elucidated the questions about synergistic and antagonistic effects of active ingredient mixtures on weed control, for instance, the studies with glyphosate reported by Vidal et al. [4], Shaw and Arnold [3], Selleck and Baird [5].
The application of pesticides plus adjuvants has also been a usual practice. The adjuvant enhances the active ingredient action [6]. In other words, the adjuvant substance induces the herbicide molecule uptake by leaf tissues, by accelerating the product penetration through plant cuticles. The most common types are the biosurfactants, mineral or vegetal oils, synthetic or natural polymers, humectants, organic salts, buffer solutions, and others [7].
The tank mixture practice or different individual pesticide applications at short intervals might result in multiple pesticide residues on foods, as observed by Gebara et al. [8], when monitoring food samples in São Paulo metropolis, Brazil, during the period between 1994 and 2001. The authors found multiple pesticide residues in 5.8% of vegetable samples analyzed and 11.4% of fruit samples.
Gebara et al. [9] alerted for the violation risk of the Theoretical Maximum Dietary Intake (TMDI), which is calculated by the relationship between the Limit of Maximum Residues (LMR, mg kg-1) established for a pesticide in a food and the daily consumption (DC, kg day-1), based on the individual diet. The presence of multiple pesticide residues in foods due to the use of tank mixtures, might lead to the extrapolation of toxicological parameters for the acceptable daily intake (ADI), mainly for children and nursing women.
Weed control with pesticide tank mixtures has been widely studied concerning mixture effectiveness, component antagonism and/or synergism. However, there is little information on environmental issues.
Knowledge on soil-herbicide interactions when herbicide mixtures are applied is extremely relevant. However, few studies on herbicide associations and their soil interactions can be found, because most studies are restricted to the individual molecule behavior.
When a pesticide is released in the environment, it will probably enter the soil by direct application, or indirectly, by crop residue incorporation into the soil and molecule transport by spraying derivation. In the soil, several processes might occur, that is, molecule retention (adsorption, absorption), transformation (decomposition, degradation) and transport (spraying derivation, volatilization, lixiviation, superficial runoff). Such processes will determine the molecule destiny, persistence and agronomic efficiency. The main factors influencing those processes are the climatic conditions, the pesticide physical-chemical properties and the soil physical-chemical attributes. According to Oliveira [10], the complex molecule retention process by soil sorption/desorption directly or indirectly influences other factor activities.
Knowledge on pesticide physical-chemical properties is fundamental to predict soil interactions, potential contamination and transport risks when in the soil solution or associated to sediments. Studies on pesticide mixtures have been restricted to their phytotoxicity effects and few were dedicated to the interactions between two or more associated molecules.
Alves [11] demonstrated that ametryn mineralization half-life is longer when associated to glyphosate than when applied alone; but there was a synergistic effect in the soil, because ametryn half-life was 15 days for the ametryn + glyphosate mixture and 20 days for isolated ametryn in the soil. In the same study, the author observed increased glyphosate mineralization half-life from 55 to 119 days, when comparing single glyphosate and glyphosate + ametryn treatments, respectively; the glyphosate soil half-life could not be determined due to its strong soil sorption during extractions.
Yet in studies of soil microbial activity, Alves [11] observed that glyphosate (at a higher rate) enhanced microbial activity; meanwhile isolated ametryn (at a lower rate) negatively affected microbial activity, but a less negative effect of ametryn + glyphosate mixture (at a lower rate) was observed compared with single ametryn at the same rate. The ametryn + glyphosate mixture (at a higher rate) increased the microbial activity, evidencing a stronger mixture synergistic effect.
Alves [11] also studied the herbicide sorption/desorption in a red Ultisol. High glyphosate and low ametryn sorption were observed when herbicides were applied alone. Higher soil sorption was observed for both herbicides in mixture than for the single molecules. Low glyphosate desorption occurred at all rates in both application procedures (alone or in mixture), but ametryn desorption decreased when applied in mixture.
White et al. [12] studied the effects of chlorothalonil, tebuconazole, flutriafol and cyproconazole fungicides on the metolachlor herbicide dissipation kinetics. Significantly lower metolachlor dissipation was observed with chlorothalonil, when compared with soil treatments without chlorothalonil or with other fungicides. The authors observed significant reduction in metolachlor metabolites probably attributed to the fungicide effect on glutathione S-transferase enzyme activity. Overall, chlorothalonil fungicide induced a two-fold increase in metolachlor persistence.
Ke-Bin et al. [13] observed that atrazine and bentazon herbicides showed longer lag-phase and lower degradation rate when applied in tank mixture in a maize crop. Therefore, the association of atrazine-bentazon had longer soil persistence which means that higher environmental potential contamination risks might be expected.
The effect of glyphosate on atrazine degradation was studied by Krutz et al. [14] in a silt clayey soil (pH 8.3 and 10.6 g kg-1 of organic-C) from the Texas region in USA. Atrazine degradation was inversely related to glyphosate rate and microbial activity during an eight-day period, evidencing that glyphosate enhanced microbial activity and inhibited atrazine degradation. The authors discussed that atrazine degradation, when in association, is mainly a microbial mechanism, and the degradation reduction might be explained by a lower enzymatic activity and/or by microbial population suppression by glyphosate.
Similar results were reported by Haney et al. [15] for the same soil type, demonstrating the atrazine and glyphosate effects on soil microbial activity evaluated through the soil carbon (C) and nitrogen (N) mineralization. Soil plots treated with the herbicide mixture showed higher microbial activity than plots treated with single atrazine. The evaluated soil C and N flows allowed understanding of the microbial preference for glyphosate because this herbicide’s complete mineralization occurred in 14 days, followed by fast atrazine degradation.
Zablotowicz et al. [16] studied the effects of glufosinate (herbicide), ammonium sulfate (fertilizer) and both products in mixture on atrazine mineralization. The authors observed decreased atrazine mineralization when the product mixture was applied. The authors explained that an alteration in 14C-atrazine molecule partition into its metabolites and residues would occur caused by ammonium sulfate that would restrict the triazine ring cleavage. Such results evidenced that the application of glufosinate combined to a mineral N source might increase soil atrazine persistence, increasing its residual effect.
Lancaster et al. [17] observed that glyphosate increased soil C mineralization and fluometuron microbial degradation. The authors suggested that the increasing C mineralization might be related to the increasing fluometuron degradation or to a priming glyphosate effect.
Concerning the glyphosate and diflufenican association, Tejada [18] observed longer degradation periods for both herbicides in mixture than for the individual molecules. Furthermore, the glyphosate-diflufenican association increased both herbicide toxicities to the soil biological activity (measured by the microbial C biomass and enzyme activities - dehydrogenase, urease, β-glycosidase, phosphatase and arylsulfatase) and the individual herbicide persistence.
Pereira et al. [19] evaluated the application of isolated glyphosate and associated to endosulfan on the soil microbial activity in soybeans and observed reduced microbial activity and biomass, and also, reduced metabolic quotient.
In genetically modified glyphosate-tolerant maize cultivars, it is possible to mix glyphosate and atrazine. In the USA, there are a number of commercially available associations, among them, glufosinate or glyphosate mixed with atrazine [20]. Bonfleur et al. [21] observed that glyphosate mineralization was not affected by atrazine presence in a tropical soil. However, increased atrazine mineralization (measured by the 14CO2 release) was observed with increasing glyphosate rates. The authors observed a 100-day variation in the atrazine half-life when associated with a two-fold glyphosate rate. Therefore, the glyphosate-atrazine tank mixture allowed atrazine persistence reduction in the soil. The authors said that a possible explanation is the glyphosate contribution to the microorganisms as source of N, and this N supply might decrease the initial atrazine immobilization when this is the only substrate, and then, increasing its mineralization.
Fogg and Boxall [22] observed inhibitory effects of an isoproturon-chlorothalonil mixture on the isoproturon degradation in soils. Isoproturon half-life (DT50) values varied from 18.5 to 71.5 days when combined with chlorothalonil. This might be explained by the TPN-OH chlorothalonil metabolite inhibition and the reduction in the soil microorganism population involved in isoproturon degradation.
The soil degradation of pendimethalin (herbicide) was significantly reduced when mixed with mancozeb (fungicide) or mancozeb+thiamethoxam (insecticide) [23]. Pendimethalin herbicide half-life increased from 26.9 to 62.2 days when in single and combined (mancozeb + thiamethoxam) applications, respectively, in a sandy soil. On the other hand, the same authors observed that pendimethalin degradation is not affected by the presence of isolated metribuzin or thiamethoxam.
Several studies have pointed out the adjuvant influence on pesticide destiny in the environment, specifically their persistence and bioavailability. Cabrera [24], in laboratory studies, affirmed that metazachlor herbicide added to oil and surfactant showed reduced degradation rates and increased residues in the soil. Similar results to other pesticides were reported by Kucharski and Sadowski [25] and Rodríguez-Cruz et al. [26]. In a field experiment, Kucharski et al. [27] observed a 43% increase in lenacil herbicide residues in the superficial soil layer, with the addition of adjuvants (oil and surfactant).
High mobility pesticides used together with adjuvants present decreased movement along the soil profile. Reddy and Singh [28] evaluated bromacil and diuron herbicides lixiviation in soil columns. In treatments with adjuvant addition, the authors observed significant lower bromacil vertical movement and no effect on diuron movement. These two herbicides present distinct physical-chemical characteristics that explain their differential movement abilities in the soil. Thus, bromacil is an acidic molecule with high water solubility (815 mg L-1); meanwhile diuron is a non-ionic herbicide of low water solubility (42 mg L-1). From the environmental point of view, the adjuvant effect was positive in the case of bromacil, but the agronomic efficacy was restricted.
The results found in the literature have highlighted the interactions existing among several molecules, especially in the soil, but such interactions might be different under other environment compartments. For this reason, studies on environmental pesticide behavior and destination must include all aspects, bringing together laboratory and field approaches.
According to Botelho et al. [29], water resource contamination has currently been considered one of the greatest environmental problems on Earth.
Pesticides applied to field crops are released in the environment mainly through lixiviation (when molecules move into the soil and reach the underground waters), superficial runoff (when molecules move together with soil and water runoff), and spraying derivation (when molecules are carried by wind during pesticide spraying).
The situation is complex once crop diversity allied to the high number and diversity of pesticide products usually applied to field crops, and the short distances between fields and aquatic areas have exposed the water resources not only to individual products but also to all their associations [30].
Several products, mainly herbicides and insecticides, are common superficial water contaminants, due to their large application in agriculture and residential areas. Therefore, there is an increasing concern about superficial and underground water contamination, due to the lack of information on pesticide impacts mainly in aquatic systems.
In Brazil, several studies have been carried out to determine the presence of pesticides in aquatic ecosystems. Armas et al. [31] evaluated the presence of herbicides in the superficial water and sediments of Corumbataí River (State of São Paulo, Brazil). The authors found several herbicides - ametryn, atrazine, simazine, hexazinone, glyphosate and clomazone – and triazines were specifically found in higher levels, above the limits allowed for potable water by Brazilian legislation. Dores et al. [32] found herbicide residues from the triazine group and their metabolites, as well as metribuzin, metolachlor and trifluralin residues. Among the Brazilian literature, the research works of Caldas et al. [33], Lanchote et al. [34], Filizola et al. [35], Laabs et al. [36], Dores et al. [37], Jacomini et al. [38] are pointed out.
Other interesting results can be found in the literature: Benvenuto et al. [39] determined the presence of eleven pesticides in superficial waters of Italy and Spain and observed concentration values varying between 0.002 and 0.087 μg L-1. Yu et al. [40] determined the presence of nine (among eleven pesticides evaluated) herbicides of the triazine group in all water samples analyzed. Similar determinations were made by Ma et al. [41], Palma et al. [42], Balinova and Mondesky [43] and Segura et al. [44].
Understanding of how pesticides affect aquatic environments has been a challenge to researchers, and the science of ecotoxicology has helped to answer many questions on this subject.
The “ecotoxicology” term was first suggested by the French toxicologist René Truhaut, during the
Usually, ecotoxicological experiments follow standardized protocols developed by international organizations, for example, the Environmental Protection Agency (EPA); the Organization for Cooperation and Economical Development (OCDE); and the Brazilian Agency of Technical Norms (ABNT).
The toxicity tests allow evaluating the environmental contamination by different pollutant sources, such as agricultural, industrial and domestic residues, sediments, medicines and chemical products overall, as well as the results of their synergistic and antagonistic effects [47-48]. The ecotoxicological tests can also detect the toxic agent or mixture capacity of causing deleterious effects on living organisms, allowing determination of the harmful concentration ranges, and how and where the effects are expressed [49].
Several parameters have been used to determine the xenobiotic effects in different organisms. Among these variables, the lethality [50-51], immobility [52], gill alterations [53-56], and reproduction [57-59] are pointed out.
The ecotoxicological experiments consist of exposing living organisms to several concentrations of a specific product and evaluating the results that might be expressed according to the test type. For instance, the acute test consists of short-term exposure of organisms to several product concentrations, and then, the species life cycle is evaluated; the toxicity indicative parameters more frequently used are: lethality (expressed by the average lethal concentration - LC50), and immobility (expressed by the observable toxic concentration effect - EC50). It is important to highlight that both parameters take into consideration the effects for 50% of the organisms tested under the specific experiment conditions [60-61]. In the case of a chronic test, the organism is submitted to long-term product exposure and the observable effects are usually focused on organism reproduction, behavior, morphology, and size, among others.
Water quality tests have been important tools aiming to minimize the pollution effects on aquatic ecosystems and to implement remediation and monitoring programs, and for that, the ecotoxicological tests have been used.
In the case of pesticide mixtures, the ecotoxicological tests to determine toxicity effects are difficult to interpret, because toxicity symptoms might depend on interactions occurring among different chemical molecules in solution and their accumulative quantities in organisms [61].
When analyzing mixture toxicity effects, some approaches and definitions must be established. In the aquatic ecotoxicology, two different models have been used to describe the relationships between single compound effects and their mixtures: concentration addition model (CA) and independent action model (IA) [62]. In the CA model, each mixture component toxicity effect is induced through a same mechanism, meanwhile in the IA model, the combined components show different actions, inducing a unique toxicological response, but via distinct reactions within the organisms [63]. Nevertheless, both models are used as references to predict the expected mixture toxicity effect, based on the known toxicity of the individual compounds [62].
For a long time, there has been concern about mixture impacts on aquatic ecosystems, not only from pesticides but also from other compound groups, and several discussions and reviews have been reported. In 1984, Hermens and collaborators investigated organic mixture effects on mortality and reproduction of
Pesticide tank mixtures are currently and frequently used not only in developed countries with specific regulatory legislation for the practice, but also in all agricultural countries where information on harmful effects do not directly reach farmers.
From the agronomic point of view, an effective pest control with pesticide mixtures will depend on the molecule compatibility and also on specific control tests. When the farmer uses two chemically incompatible substances in tank mixture, high losses in crop yield and equipment problems might occur, for example, sprayer nozzle obstruction due to chemical reaction between molecules and subsequent compound precipitation.
Although the pesticide tank mixture may appear to be an efficient pest control practice with synergistic results, the aspects concerning environmental safety must be considered. Little specific information on associated pesticide residues is available in the literature concerning withholding periods and overall environmental behavior.
When a single pesticide is applied, the expected environmental results should be similar to previous results reported for the pesticide registration and before its commercial release. The environment (mainly aquatic and soil medium) is a large contaminant reservoir, where the chemical compounds used in agriculture can be found together. In spite of that, it is important to reinforce that a single pesticide interacts quite differently with the medium, compared to the mixture interaction, as already discussed in this chapter.
In light of the large global demand for food and the increasing crop productivity in the same cropping area, it is imperative to consider the environmental safety questions concerning tank chemical mixture applications in agriculture.
This is a relatively new science area that demands urgent studies on environmental safety, ecotoxicology and toxicology, in order to make highly prevalent the declaration of the United Nation Organization about the planet environment: “
E3 ubiquitin ligases play crucial roles in ubiquitin conjugation to substrates and therefore ubiquitin signalling. Protein ubiquitylation (also referred to as ubiquitination) is a dynamic multifaceted post-translational modification in which ubiquitin is covalently attached to a specific protein target in a three-step enzymatic cascade involving the action of an E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase [1]. An E3 ubiquitin ligase is the ultimate enzyme which directly or indirectly catalyses the transfer and subsequent ligation of an ubiquitin monomer to a specific target protein (i.e., the substrate). The aftermath of ubiquitylation is usually the formation of an isopeptide bond catalysed by the E3 ligase between the free carboxylate group of ubiquitin’s
In the initial ATP-dependent activation step of ubiquitylation, E1 catalyses the acyl-adenylation of ubiquitin’s
The ubiquitin-mediated proteasome proteolytic pathway. Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes, E1, E2 and E3 which specifically target proteins to either change their activity or their location, or in some cases earmark target proteins for proteasome-mediated degradation. E1 forms a thioester bond with ubiquitin which allows subsequent transfer of ubiquitin to E2, followed by the E3 ligation of an isopeptide bond between the carboxyl-terminus of ubiquitin and a Lys residue on the substrate protein. Isopeptide bonds between ubiquitin and ubiquitin or ubiquitin and other target proteins can, however, be hydrolysed by deubiquitylating enzymes (DUBs).
Ubiquitin’s versatility in the regulation of cellular processes is by virtue of its ability to covalently modify other proteins [18]. Post-translational modifications, which are usually covalent and reversible, may alter the properties and therefore, the functions of the modified protein. A major function of ubiquitin is regulation of the degradation of other specific proteins, literally referred to as
The functional consequences of ubiquitylation vary because of recognition by different ubiquitin-binding modules which can distinguish different polyubiquitin modifications. Monoubiquitylation is the conjugation of a single ubiquitin molecule to a single Lys of the target protein. Multimonoubiquitylation occurs when a target protein is tagged with more than one single molecule of ubiquitin. In polyubiquitylation, the target protein is tagged with an ubiquitin chain linked through the
Monoubiquitylation has been implicated in the endocytic trafficking of certain cargo proteins, e.g., small GTPases and receptors (e.g., Epidermal Growth Factor Receptor, EGFR) to specific cellular compartments at different stages of the endocytic pathway. Monoubiquitylation has also been implicated in gene expression and DNA repair [30, 31, 32, 33]. Multimonoubiquitylation is important for receptor endocytosis [34]. Lys48-linked polyubiquitylation (i.e., polyubiquitin chains linked via Lys48 of the proximal ubiquitin to the next ubiquitin moiety in the chain) has predominantly been linked to targeting proteins for proteasomal degradation [35]. Lys63-linked polyubiquitin chains function as scaffolds to assemble signalling complexes e.g., activation of transcription factor NF-
Based on considerations of structure, chemistry, and mechanisms by which ubiquitin is transferred to the substrate, four families of E3 ubiquitin ligases are distinguishable. These include homologous to the E6AP carboxyl terminus (HECT), Really Interesting New Gene (RING)-finger/U-box, RING-between RING (RBR) and the recently characterised plant homeodomain (PHD)-finger ligases.
The RING E3s constitute the largest family of E3 ligases. RING-finger E3 family of ligases include the U-box ligases. Although able to promote the formation of polyubiquitin chains, RING-Finger/U-box E3s lack a catalytic site and hence, do not participate directly in catalysis. RING-type E3s are characterised by the presence of the canonical Cys3HisCys4 amino acid motif (i.e., the RING domain) and consequently mediate the direct transfer of ubiquitin from E2 ~ ubiquitin complex to the substrate (Figure 2a). Each canonical Zn finger (Cys3HisCys4) type domain binds two Zn2+ ions which are critical to its stability. RING E3 ligases can exist and act as single-subunits e.g., CHIP/Stub1, mdm2, RNF4, RNF114, UBE4B (Figure 2a) or may be assembled on a Cullin scaffold to form multiple subunits. Multi-subunit RING E3s contain a substrate receptor (responsible for substrate specificity) at the
Illustration of RING/U-box E3 ligase types and their mechanism of ubiquitin transfer to target proteins.
The U-box proteins contain a U-box domain of ~70 amino acids which lacks the characteristic Zn chelating Cys and His residues in RING-finger domain and are characteristically stabilised by a network of H-bonds within each loop, flanked by a central α-helix [44, 45, 46]. U-box E3s are more abundant in plants than animals [47]. Both RING and U-box domains are responsible for binding the ubiquitin-charged E2 and stimulating the transfer of ubiquitin to substrate (Figure 2). Additionally, RING and U-box E3 ligases can function as monomers (Figure 2a), homodimers (Figure 2c and d), or heterodimers. In a homodimer, each monomer can bind an E2, but apparently not the case in the heterodimeric RINGs.
Another RING-related family of E3s are the PHD E3 ligases. Unique sequence and structural signatures that distinguish the PHD-finger from RING fingers have been demonstrated indicating that the PHD-fingers function primarily as E3 ligases that promote protein degradation and constitute a distinct class of E3 ligases. The PHD or leukaemia-associated-protein (LAP) domain resembles the RING finger domain [48, 49, 50]. It also has the eight conserved metal binding ligands, Cys4HisCys3 consensus, with similar spacing [51] however, it represents a variant of the RING finger. An example of a PHD domain E3 ligase is Mekk1 kinase. The second
Unlike the RING-finger E3s, the HECT type E3s instead contain a conserved
Mechanism of ubiquitin transfer to target protein by (a) HECT and (b) RBR E3 ubiquitin ligases.
RBR E3 ligases employ the characteristic RING-HECT hybrid mechanism [60, 61, 62, 63, 64, 65]. Like the HECT E3 ligases, the RBR E3 ligases catalyse the transfer of ubiquitin from E2 to the substrate through a three-step reaction where the RBR E3 first binds the E2, transfers the ubiquitin load to its catalytic Cys and subsequently to the substrate (Figure 3b). RBR E3 ubiquitin ligases differ from RING-type E3 mainly because they possess an active site which is absent in other RING-type E3s. However, like RING E3s, the RBR E3 ligases have four RING Zn2+ finger domains. Each of these domains coordinates two Zn2+ ions through His and Cys residues. They include the canonical Cys3HisCys4-type RING (named RING1) domain as in RING E3s, that binds the E2 enzyme followed by; in-between-RING (IBR) domain and RING2 domain which contains the active site Cys residue (Figure 3b). The name RBR was derived from the presence of two predictable RING1 and RING2, separated by an IBR (i.e., the RING1-IBR-RING2 module). Though RING2 domain possesses the catalytic Cys (Figure 3b), it does not conform to the canonical RING E3 structure, and it has also been called Rcat (required-for-catalysis) domain. The IBR domain is conserved among RBR E3 family of ligases. Its specific function remains elusive. The IBR domain adopts the same structural fold as RING2 domain, however, it lacks the essential catalytic Cys residue and is sometimes referred to as the BRcat (benign-catalytic) domain [66]. The Zn2+ ions bound within RING domains are also reported to be essential for structural stability and proper regulation of its intrinsic enzymatic activity. Their removal from parkin for instance, result in near complete unfolding of the protein [67, 68]. HHARI and Parkin were initially characterised to have the hybrid mechanism [64]. TRIAD1, RNF144A, HOIP, and HOIL-1 L have later been characterised to employ the same RING-HECT hybrid mechanism [69]. RBR RING domains are also normally involved in intramolecular interactions between amino acids of different domains that keep the enzyme in a coiled autoinhibited state. Through different molecular mechanisms such as phosphorylation and protein–protein interactions, the uncoiling of closed-compact or folded autoinhibited states of RBR E3 ligases may be triggered thereby exposing the catalytic sites and increasing the intrinsic E3 ligase activity.
Aberrations of ubiquitin signalling are often associated with pathogenesis of several diseases and genetic disorders [58, 70, 71, 72, 73]. Errors in ubiquitin signalling processes result in defective autophagy and mitophagy, DNA repair mechanisms, NF-
Parkin, a RBR E3 ligase functions in the covalent attachment of ubiquitin to specific substrates e.g., outer mitochondrial membrane proteins – Mfn1, Mfn2, and Miro GTPases [62]. Parkin is involved in protein degradation, collaborating with the ubiquitin-conjugating enzyme, UbcH7 [79, 80]. Even though much of the aetiology of Parkinson’s disease remains largely unknown, malfunctioning of PINK1 and/or parkin causes accumulation of damaged mitochondria, which trigger familial parkinsonism. Parkinson’s disease (named after Dr. James Parkinson, AD1783–1824) is a neurodegenerative movement disorder caused by the progressive death of dopamine producing neurons in the substantia nigra pars compacta of the mid-brain [81]. The characteristic symptoms of Parkinson’s disease include muscle tremor, muscle rigidity, slowness of movement (bradykinesia) and postural instability [82, 83, 84, 85]. Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s, affecting predominantly, individuals above 65 years even though earlier onset have been reported [79, 84, 86, 87]. Early-onset Parkinson’s disease (EOPD - onset in individuals before 50 years) which account for approximately 5–10% of all cases of Parkinson’s disease are attributable to monogenic causes [88, 89]. Mutations in coding regions of
The multi-functional pathways regulated by RING-type E3 ubiquitin ligases in inflammatory signalling and consequential inflammatory bowel disease have been expansively reviewed by several researchers [73]. Inflammatory bowel disease is characterised by inflammation of the digestive tract and patients present with anomalies in gut microbiota composition e.g., increased levels of harmful bacterial strains, reduced levels of bacterial diversity and protective probiotics. These trigger proinflammatory intestinal pathogenic immune responses which in turn induce intestinal mucosal inflammation. Examples of implicated RING E3 ligases in inflammatory bowel diseases include, TRAF5, TRAF3, TRAF2, UHRF1, RNF183, RNF40, RNF20, RNF170, and RNF186 [73]. For instance, RNF170 E3 ligase ubiquitylates TLR3 for proteasomal degradation. TLR3 is a pattern recognition receptor which recognises pathogen-associated molecular patterns (PAMPs) of lipopolysaccharides, flagellin, and microbial nucleic acids and triggers activation of downstream effectors in innate immune responses. Proteasomal degradation of TL3 therefore suppresses TLR3-mediated innate immunity in macrophages thereby promoting inflammatory diseases [95]. Several sites of the NF-
The roles of E3 ubiquitin ligases in the RTK pathway (e.g. EGFR) and MAPK pathway and other oncogenic/tumour suppressive signalling pathways in glioblastoma have been expounded including validation of the potential of E3 ligases as future therapeutic interventions for glioblastoma treatment [72]. Glioblastoma is a malignant brain tumour which is characterised by a mutation in the metabolic enzyme isocitrate dehydrogenase 1 with limited treatment options [100]. In glioblastoma, 67% of cases have mutation in at least 1 RTK and about 20% of classical tumours express a truncated form of EGFR (EGFRvIII). RTK signalling is down regulated by several E3 ligases such as Cbl, Chip and parkin [72]. Ubiquitylation of EGFR by Cbl E3 ligase results in clathrin-mediated internalisation of the receptor and subsequent sorting into lysosomes where the receptor is degraded and therefore reduces EGFR signalling in glioblastoma. LZTR1 is the substrate recognition domain of a Cul3 E3 ubiquitin ligase complex. Mutations in LZTR1 are associated with schwannomatosis and Noonan syndrome in which loss of LZTR1 function drives de-differentiation and proliferation of cells. LZTR1 is also mutated or deleted in about 4% or 20% of glioblastoma cases respectively, where mutations of LZTR1 increase Ras-dependent proliferation of cells coupled with increased resistance to tyrosine kinase inhibitors (glioblastoma chemotherapy) because of enhanced MAPK signalling [101, 102]. The MAPK pathway is a commonly mutated pathway in human cancers. It upregulates cellular phenotypes such as proliferation, differentiation, migration, and invasion.
The BRCA1 RING-type E3 ubiquitin ligase is a human tumour suppressor gene and plays critical roles in DNA repair. Mutation of BRCA1 is associated with the inherited predisposition for breast and ovarian cancers [102]. The E3/E4 ubiquitin ligase, mdm2 is an important negative regulator of the p53 tumour suppressor gene as mentioned earlier. p53 protein regulates the cell cycle, DNA repair and induces cell apoptosis, hence it functions as a tumour suppressor. Mdm2 serves as an E3 ubiquitin ligase of p53. This implies that increased activity of the mdm2 oncogenic protein via augmented mdm2 expression induces tumorigenicity especially those 50% that retain wild-type p53. In addition, inactive mdm2 results in increased cellular levels of p53, which is detrimental to cells and may accelerate the ageing process by excessive apoptosis [103]. It has also been reported that SIAH2 is a RING-finger E3 ligase which contributes to the progression of various malignant tumours, including breast carcinoma, lung and prostate tumours, and oral cancer [104, 105, 106]. Furthermore, the E3 ligase, c-Cbl has also been demonstrated to be frequently dysregulated in myelodysplastic myeloproliferative neoplasms and additionally associated with myelodysplastic syndromes, myeloid neoplasms, and primary colorectal cancer [75].
Multiple studies have implicated several E3 ubiquitin ligases in ovarian cancer chemoresistance which hamper improvement of ovarian cancer patient outcome through degradation of various chemoresistance-related substrates in ovarian cancer. Among several studies, [107] demonstrated that NEDD4-2 protein (an E3 ligase that regulates endocytosis and lysosomal degradation of ENaC and other channels) expression is reduced in invasive ovarian epithelial cancer tissues compared with non-cancer ovarian tissue suggesting an important role of NEDD4-2 in the regulation of chemoresistant ovarian cancer [58]. Indeed Nedd4-1 and Nedd4-2 E3 ligases have been demonstrated to mediate numerous pathophysiological processes [108]. Briefly, Nedd4-1 mediates endosomal trafficking of receptor tyrosine kinases, such as EGFR and fibroblast growth factor receptor (FGFR), by ubiquitylating endocytic or vesicle sorting proteins. Nedd4-1 is overexpressed in lung epithelial cells and is associated with lung cancer progression [109]. NEDD4-1 can promote Alzheimer’s disease by weaking synaptic strength through ubiquitylation of AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) and cytoplasmic internalisation. Nedd4-2 knockout mice reportedly die perinatally due to failure of the pups to breathe resulting from increased ENaC expression, extensive fibrosis, and infiltration of inflammatory cells in the alveolar spaces [110]. This indicates the important regulatory functions of Nedd4-2 in the respiratory system. Ubiquitylation of ENaC by Nedd4-2 E3 ligase through direct binding to its conserved proline-rich PY motif in the
BCL6 proto-oncogene is the transcription factor implicated in the pathogenesis of human B-cell chronic lymphocytic leukaemia. Deregulation of BCL6 expression or increased degradation are pathogenic events in many lymphomas. Mutation of the multi-subunit SCF FBXO11 E3 ligase is associated with the development of B-cell lymphomas. FBXO11 is the substrate recognition component of the ligase and functions as a tumour suppressor by targeting BCL6 transcription factor for proteasomal degradation [114, 115]. BCL6 binds to specific DNA sequences and down regulates transcription of a variety of genes involved in B-cell development, differentiation and activation including the transcription of STAT-dependent IL-4 responses of B-cells [116].
FANCL is a multisubunit E3 ubiquitin-protein ligase that monoubiquitylates FANCD2 and FANCI, a key step in the DNA damage repair pathway. FANCL contains a RING finger-like PHD domain with E3 activity [78, 117]. Mutations in 8 out of 13 components of the FANCL complex cause Fanconi anaemia (FA). Individuals with this condition experience severe multiple congenital and haematological abnormalities including predisposition to development of a variety of cancers [118]. Individuals may experience congenital skeletal anomalies especially of thumb and forearm. They also display endocrine abnormalities, short stature correlating to growth hormone production and hyperthyroidism among several other anomalies [119].
Mutations in von Hippel–Lindau (VHL), the substrate recognition component of Cullin RING E3 ubiquitin ligase (CRL2VHL), results in an autosomal-dominant familial VHL syndrome. This implies that a mutation in just one copy of the VHL gene in each cell is enough to increase risk of developing VHL disease. Substrates for CRL2VHL E3 ligase tumour suppressor include the hypoxia-inducible factor (HIF) family of transcription factors (HIF1-3α) which bind the VHL subunit when hydroxylated on two proline residues by prolyl hydroxylase. This results in ubiquitylation of HIF1-3α and subsequent proteasomal degradation which would otherwise accumulate and cause inappropriate upregulation of hypoxia-inducible genes such as Transforming growth factor alpha (TGF-α), Vascular endothelial growth factor A (VEGF-A), etc. leading to hyperangiogenesis in VHL mutant individuals [120]. VHL disease is characterised by benign and malignant tumours mostly clear cell kidney and lung carcinomas [121]. Hemangioblastomas that develop in the brain and spinal cord cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). If left untreated, hemangioblastomas may result in blindness, permanent brain damage or death. Pheochromocytomas develop and affect the adrenal glands, which may produce excess hormones thereby causing high blood pressure.
Angelman syndrome is a complex genetic disorder caused by a disruption of the UBE3A gene, which encodes the wild-type ubiquitin ligase E6 associated protein (E6-AP/UBE3) [122]. The disease occurs in individuals with a loss of expression or mutations in E6-AP. Angelman syndrome is characterised by intellectual disability, severe speech impairment, a tendency to jerky movement (ataxia), recurrent seizures (epilepsy) and a small head size [123, 124]. Even though investigations have established that E6-AP plays an essential role in the proteasome-dependent degradation of several identified cellular substrates and therefore promote Angelman syndrome, to date, the molecular mechanisms behind the disease pathology is poorly understood [125]. Identified E6-AP substrates include Sox9, C/EBPα, α-synuclein, p27, promyelocytic leukaemia (PML) tumour suppressor, annexin A1, amplified in breast cancer 1 (AIB1), hHR23A, etc. [126]. This indicates that a functionally defective E6-AP mutant cannot initiate degradation of substrates thereby promoting development of Angelman syndrome.
3-M syndrome is a rare autosomal-recessive growth retardation disorder associated with mutations of the Cullin7 (Cul7) E3 ligase [127]. 3-M syndrome is characterised by severe pre- and postnatal growth retardation, large head circumference, facial dysmorphia and skeletal abnormalities including dwarfism even though affected individuals exhibit normal intelligence [128]. Cul7 is a member of the Cullin family of proteins, which function as scaffolds in the formation of numerous E3 ligases with RING proteins, adaptor proteins and substrate recognition receptors [129]. The specific role and substrates of Cul7 are mostly unknown. Recently however, evidence of CUL7’s involvement in pivotal growth-regulatory signalling have begun to emerge. Cul7 interacts with both Skp1-Fbx29 heterodimer and the ROC1 RING-finger protein to form the Cul7 E3 ligase complex which ubiquitylates proteins for proteasomal and lysosomal degradation [130]. The insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signalling has been identified as a proteolytic target of the Cul7 E3 ligase [131]. Additionally, mammalian Eag1 potassium (Eag1 K+) channels, which are widely expressed in the brain, are novel targets of Cul7 E3 ligase [130]. Mutant Eag1 K+ channels are associated with congenital neurodevelopmental anomalies. Cul7 E3 ligase has also been implicated in the proteasomal degradation of cyclin D1 [132]. Cyclin D1 proto-oncogene is a vital regulator of cell cycle progression from G1 to S phase in several different cell types. Accumulation of cyclin D is associated with development and progression of cancer and deregulation of its expression is linked to resistance to hormone therapy in breast cancer [133]. Consequently, in many cancers, impaired activity of Cul7 is essentially responsible for cellular elevated levels of cyclin D1.
Ubiquilin (UBQLN), a ubiquitin binding protein, is a ubiquitin-like protein that shares a high degree of sequence similarity with ubiquitin across several species. UBQLNs contain both
The list of diseases associated with E3 ligase dysfunction is not exhaustive. More insights are available in the literature of which each apparently addresses a specified disease in more detail. It is anticipated that new discoveries in this regard will emerge in the future.
There remains a significant unmet need for novel therapeutic strategies for genetic disorders such as Alzheimer’s, Amyotrophic Lateral Sclerosis, Arthritis, cancer, etc. Owing to the critical cellular signalling role of the ubiquitin system in protein degradation, activation, subcellular localization and beyond, various targets of the ubiquitylation pathway are being earmarked to have potential for development of drugs to treat malignant cancers among several other diseases. Among these targets include the E3 ubiquitin ligases [41]. So far, some E3 ligase inhibitors including Velcade (bortezomib), Ninlaro (ixazomib), and Kyprolis (carfilzomib) have proved effective and have been approved by the US FDA for the treatment of multiple myeloma suggesting that specific E3 inhibitors are promising in anti-cancer therapy and beyond. This breakthrough has inspired researchers to probe more aspects of the ubiquitylation system for therapeutics [139]. Ideally, a potential cancer treatment target should be playing an essential role in carcinogenesis, it should overexpress in cancer cells and its activity inhibition or expression should induce growth suppression and/or apoptosis in cancer cells [140]. In addition, an ideal druggable candidate should be an enzyme or a G Protein Coupled Receptor (GPCR) and therefore druggable. More importantly, it is either not expressed or is only expressed at low levels in normal cells and its inhibition has minimal effect on normal cell growth and function. Inhibition of such a target would achieve a maximal therapeutic index with minimal toxicity [140]. Being enzymes and mostly natural tumour suppressors, many E3 ligases function within these criteria and are therefore attractive targets for therapeutic intervention of cancers. Several studies have explored and validated the therapeutic potential of E3 ligases [58, 71, 72]. In this section, the rationale for selected E3 ligases with pharmacological potential have been reviewed.
Firstly, one therapeutically significant pathway is the PINK1-parkin cascade for mitochondrial quality control. PINK1 and parkin appear to offer multiple therapeutic targets for the treatment of Parkinson’s disease and several other neurodegenerative disorders [141, 142]. Unidentified and putative members of this cascade may also be therapeutically relevant. Parkin displays low basal activity under normal physiological conditions [82]. Any means by which wild-type parkin activity may be increased for instance by development of small molecule activators could be significant in promoting mitophagy to downregulate progression of Parkinson’s disease and other PINK1-parkin pathway-mediated neurodegenerative diseases. In
As previously mentioned in Section 3.1, mdm2 is a direct downstream target of p53. P53, is a well-studied tumour suppressor which is often mutated in more than 50% of human cancers. This is because p53 induces growth arrest and apoptosis upon activation by different stimuli e.g., DNA damage [150]. Upon induction by p53, mdm2 in turn acts as an E3 ubiquitin ligase to ubiquitylate p53 for proteasomal degradation. This action reduces p53 levels and consequently inhibits p53-mediated cell apoptosis [151]. As such, inhibition of mdm2 E3 ligase activity is a potential approach to increasing p53 levels in order to induce cell apoptosis in human cancer cells harbouring wild-type p53. Mdm2 is usually expressed in low levels in normal cells but is overexpressed in several human cancers such as breast carcinomas, soft tissue sarcomas, oesophageal carcinomas, lung carcinomas, glioblastomas and malignant melanomas and will represent an excellent pharmacological candidate for further research [152].
Pirh2 has recently been found to be a major E3 ligase partnering mdm2 to target (tetrameric)p53 for proteasomal degradation. Further, the p53-Pirh2 complex promotes Twist1 degradation leading to inhibition of epithelial-mesenchymal transition in ovarian cancer [153]. Epithelial-mesenchymal transition is critical in cancer metastasis and chemoresistance implying that Pirh2 specific inhibition might be therapeutically relevant. Some IAPs (Inhibitor of Apoptosis Proteins) that are overexpressed in most common human cancers (correlating chemoresistance) also represent important therapeutic targets for drug development [154]. Examples of IAPs include XIAP, cIAP-1, cIAP-2, Ts-IAP, NAIP, Survivin, Livin/ML-IAP, and Apollon/Bruce. IAPs are characterised by the presence of BIR (baculoviral IAP repeat) domain(s) required for suppression of apoptosis. Additionally, some members of the family may contain a RING finger domain at the
Cbl E3 ligase (Section 3.1) ubiquitylates EGFR thereby reducing EGFR signalling in glioblastoma. Specific inhibitors of Cbl could helpfully target upregulating EGFR signalling in anti-glioblastoma therapy. As the MAPK pathway is commonly mutated in many cancers resulting from increase in cellular proliferation, differentiation, migration, and invasion, specific inhibitors of E3 ligases of the MAPK pathway (e.g., TRIM9, SCFFBXO31, KBTBD7, LZTR1) may have potential for anti-cancer therapy [72].
Research suggests that ubiquitylation of Plasmodium falciparum proteins play essential roles in parasite development. Recent data indicate ubiquitylation of several essential proteins (e.g., merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones) of the human malaria parasite,
Finally, besides small-molecule E3 ligase inhibitors, PROTACs (PROteolysis-TArgeting Chimeras) appear to have significant therapeutic potential. Reports indicate that small-molecule inhibitors have limitations [160]. For instance, small-molecule inhibitors are limited to molecules that have an active site (enzymes and receptors e.g., RTKs). The PROTAC technology has emerged to overcome these limitations and to facilitate the 75% of human proteome e.g., transcription factors, scaffolding proteins, and non-enzymatic proteins which are signal effector proteins but lack active sites and are thus undruggable. The emerging characteristics of PROTACs such as induction of substrate selectivity, rapid, profound, and sustained proteasomal degradation and consequential induction of robust inhibition of downstream signals coupled with overcoming resistance to small molecule inhibitors have been extensively reviewed [72, 160]. A PROTAC is a small heterobifunctional molecule consisting of an E3 binding domain and a substrate binding domain covalently joined together by a linker. This spatial arrangement enhances recruitment of the E3 enzyme in proximity with the specific substrate (e.g., an oncoprotein) for ubiquitylation and subsequent proteasomal degradation thereby inhibiting downstream signals and subsequently down regulating the cell cycle or inducing apoptosis. PROTAC technology therefore will utilise the E3-mediated ubiquitin proteasome mechanistic pathway to treat disease. It is a very promising alternative technique where E3 inhibitors are limited or will present less efficiency.
The biological importance of E3 ubiquitin ligases cannot be overemphasised because protein ubiquitylation is crucial in the regulation of numerous cellular processes. E3 ubiquitin ligases have therefore recently emerged as significant future therapeutic opportunities for drug development for treatment of several human diseases associated with ubiquitin-mediated signalling. Regrettably, the mechanisms by which the ubiquitin system regulates cellular signalling and pathogenesis remain largely unknown. Many questions remain unanswered considering the number of E3 ligases (over 600) in the human genome and lack of the most relevant technologies to assess these principles, coupled with the extreme complexity of ubiquitin signalling processes. Blocking protein–protein interactions is problematic, yet it is apparently the most effective treatment option for utilising the ubiquitin system. This option relies on blocking the E3 ligase at specific substrate recognition sites. Hypothetically, targeting rapid screening of small specific molecular inhibitors of E3s which have potential to selectively stabilise specific downstream cellular proteins regulated by specific E3s while avoiding unwanted effects on other cellular proteins will achieve less toxicity. Therefore, a complete understanding of the mechanisms involved in protein substrate recognition by E3 ligases and functions, as well as easy identification of aberrant entities within the ubiquitin pathway will be instrumental in understanding the aetiology of associated diseases. With the current advances in proteomics technology, more E3 substrates are being identified and more insights to E3 regulatory roles in many diseases are being better understood. Though new technologies such as the siRNA, for validation of many E3s, the Fluorescence Resonance Energy Transfer (FRET) for High throughput (HTS) assays for screening inhibitors of ubiquitin transfer from E2s to E3s, and electrochemiluminescence (ECL)-Based HTS for screening inhibitors of the ubiquitylation machinery have facilitated screening of compounds against E3s and improved research in this aspect so far, these methods are themselves not devoid of challenges. Development of more efficient, cheaper, and simpler techniques will fast-track understanding of the ubiquitin system and the drug discovery process. Predictably, E3 ubiquitin ligases will present one of the most efficacious targets for anti-cancer drug discovery and for other diseases in the future.
We thank IntechOpen Ltd. UK, for an opportunity to contribute to a book project.
The authors declare no conflict of interest.
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",metaTitle:"Team",metaDescription:"Advancing discovery in Open Access for the scientists by the scientist",metaKeywords:null,canonicalURL:"page/team",contentRaw:'[{"type":"htmlEditorComponent","content":"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
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\\n\\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
\n\nBut, one thing we have in common is -- we are all scientists at heart!
\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
\n\nAlex Lazinica is co-founder and Board member of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his Ph.D. in Robotics at the Vienna University of Technology. There, he worked as a robotics researcher with the university's Intelligent Manufacturing Systems Group, as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and, most importantly, co-founded and built the International Journal of Advanced Robotic Systems, the world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career since it proved to be the pathway to the foundation of IntechOpen with its focus on addressing academic researchers’ needs. Alex personifies many of IntechOpen´s key values, including the commitment to developing mutual trust, openness, and a spirit of entrepreneurialism. Today, his focus is on defining the growth and development strategy for the company.
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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. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. 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