",isbn:"978-1-80356-552-1",printIsbn:"978-1-80356-551-4",pdfIsbn:"978-1-80356-553-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"4c2e03f295fbc697350f0bf3bf89a14f",bookSignature:"Associate Prof. Murat Eyvaz, Dr. Ahmed Albahnasawi, M.Sc. Ercan Gürbulak and MSc. Mesut Tekbaş",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11840.jpg",keywords:"Aridity and Drought, Precipitation and Evapotranspiration, Land Use, Human Activity, Desertification, Desert, Soil Structure, Water Treatment, Water Scarcity, Irrigated Agriculture, Remote Sensing, Climate Change",numberOfDownloads:47,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 10th 2022",dateEndSecondStepPublish:"May 11th 2022",dateEndThirdStepPublish:"July 10th 2022",dateEndFourthStepPublish:"September 28th 2022",dateEndFifthStepPublish:"November 27th 2022",remainingDaysToSecondStep:"11 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Murat Eyvaz has co-authored many journal articles and conference papers and has taken part in many national projects. 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1. Introduction
1.1. Chloroplasts: from cyanobacteria to bioreactors
The chloroplasts are organelles that allowed obtaining electrons from water, as part of the basic photosynthetic machinery that have evolved from cyanobacteria to flowering plants. In most groups of plants, they are indispensable due to its role in metabolic process as photosynthesis, biosynthesis of fatty acids, amino acids, pigments and vitamins and any interruption of its normal metabolism can cause lethality in plants [1, 2].
All functions that occurs in the chloroplast are regulated by a genome that comprises around 120 genes grouped in a double stranded of ∼150 kb; these genes have implications on photosynthesis, replication, transcription and translation processes; the organization of the chloroplast genome allow the site-directed gene integration without altering the integrity of endogenous genes; this characteristic has allowed the expression of genes codifying enzymes with industrial value, antibodies, antibiotics, vaccines, antigens and also genes of environmental importance. Due to the genetic organization in operons, chloroplast genes can be expressed together and with the advantage of minor suppression effects, where chloroplast expression yields until 70% of total soluble protein (TSP), which has improved the vegetal biotechnology in agricultural, food, medicine and environmental areas [3, 4].
Currently, different industries require metabolites for improving production processes; in this sense, several technologies based on microorganisms has been used as source of such metabolites; nevertheless, they could not satisfy demands at the rate they are needed; on the other hand, overexpression of several proteins in chloroplast has proved its usefulness for specific protein production, although this technology force to know the metabolic route itself by the presence of multiple isozymes in the metabolic route what would considered a disadvantage currently. Chloroplast engineering has been efficiently used in the expression of omega-3 genes, desaturases of omega-6, tocopherols and tocotrienols, flavodoxin, carotenoid or vitamins in crops as tomato, cauliflower, cabbage, rape, poplar, beet, potato and eggplant [5, 6].
2. Applications for the agronomic traits
The increases of agriculture, industry and globalization have given the opportunity to transgenic crops production and trade; but chloroplast engineering gives the opportunity of generating transgenic crops with the possibility of containing the transgene flow to minimize the outcrossing transgenes related to weeds or crops; this characteristic has allowed the development of crops expressing genes with useful agronomic traits via the chloroplast genome [7]. In this sense, the requirements in the agriculture have focused in crop protection based on insect, herbicide resistance, drought and salt tolerance and phytoremediation. For example, the expression of ‘cry2Aa2’ operon bio-insecticidal protein from Bacillus thuringiensis known as Bt, which confers resistance to pests, was accumulated to up 45% of total soluble protein. Additionally, this technology has also been used to protect crops against bacteria and fungi when antimicrobial peptides are expressed [8, 9]. Also, the chloroplast engineering has impacted in the agriculture and environmental issues, by conferring crop tolerance to salinity through the expression of betaine aldehyde dehydrogenase gene or maximizing heavy metals removal through increasing efficiencies of absorption by the roots, shoots translocation and volatilization [10, 11].
The chloroplast engineering still has some obstacles because the transgene expression depends of factors such as the specie, the regulatory regions used (promoters, 5′-, and 3′-UTR) and efficient methods of tissue culture and regeneration protocols [12, 13]; also, recent studies indicate that protein overexpression can interact with intermediaries of metabolic pathways causing mutant phenotypes [14]; this coupled to somatic embryogenesis which cannot be achieving a homoplasmic state in monocotyledons is one of the biggest obstacles for plastids engineering in agronomic crops [15]. Despite not having a viable method for transgene integration to all crop species, currently transformations has been successfully done in tomato, cauliflower, cabbage, rape, poplar, beet, alfalfa, potato, carrot, cotton, oilseed rape, petunia, rice, soybean, sugar beet and eggplant [5, 6, 16, 17]. The efficient use of this technology in crops has shown that possibly in the future these could interact with the biopharmaceutical sector [18].
3. Enzymes to cellulose degradation
Plant lignocellulosic biomass is mainly compounded of polymeric sugars as cellulose, hemicellulose, pectin and polyphenolics (lignin); this complexity avoids its use because the residues are joined by forming crystalline microfibrils that are highly resistant to enzymatic hydrolysis [14, 19].
Nevertheless, despite this, cell wall constituents can be degraded with consortiums of enzymes such as pectin lyase capable of degrading the pectin through α-(1 → 4) bond hydrolysis of polygalacturonic acid [20, 21]. To degrade lignin residues imbibed in plant biomass an enzyme cocktail is required and usually includes laccase ‘Lac’, lignin peroxidase ‘LiP’ and manganese peroxidase ‘MnP’; interestingly, all ligninases exhibit high homology in their primary sequence [22, 23]. The ligninases are implicated in the removal of an electron of phenol moiety of lignin which is stabilized by organic acid chelators facilitating the degradation of phenolic compounds in the presence of H2O2; as lignin is the most important source of aromatic polymers in nature, its decomposition is also necessary for carbon recycling [24, 25].
Pectin and lignin constituents are not the only ones present in the cell walls, also the cellulose residues represent 40% of plant biomass, which placed it as the highest carbohydrate synthesized by plants, and it is formed of 100–14,000 residues of glucose with β-1-4 linkages forming a crystalline cellulose which needs synergistic action of several highly specialized enzymes to release glucose units, these are known as endo-β-glucanases (1,4-β-D-glucan-4-glucohydrolase ‘EC 3.2.1.4’) and hydrolyzed random internal glycosidic linkages, resulting in a decrease in polymer length and a gradual increase in the reducing sugar concentration [26, 27]; subsequently, a exoglucanases (1,4-β-D-glucanglucohydrolase ‘EC 3.2.1.74’ and 1,4-β-D-glucancellobiohydrolase ‘EC 3.2.1.91’) hydrolyse cellulose chains by removing cellobiose from the reducing or non-reducing ends and finally β-glucosidases (β-D-glucoside glycohydrolase ‘EC 3.2.1.21’) hydrolyse cellobiose to release D-glucose [28, 29].
However, the degradation mechanism of celluloses is different in several organisms; for example, the amorphous or soluble cellulose is degraded by the action of endocellulases alone, while crystalline cellulose first requires an exocellulase and then a cellobiase to release two glucose moieties and sometimes glucohydrolase may act as a component of the exoglucanase releasing glucose and not cellobiose from the non-reducing end of poly- and oligosaccharides [30]; also the cellobiose can be oxidatively degraded for a cellobiose-quinone oxidoreductase to cellobionic acid [31, 32, 33]. In symbionts of termites and fungi, endo-1,4 glucanases cleave inner-1,4-glycosidic bonds and generate oligosaccharides, then the cellobiohydrolases split off cellobiose from the non-reducing end of the oligosaccharide chain; whereas in aerobic bacteria, cellulose hydrolysis has been attributed to action of two types of enzymes that act like fungal endocellulases and cellobiases [32, 33, 34]. Exocellulases also have been found in few bacteria and the cleavage of crystalline cellulose is done by an intra-molecular synergism of bacterial endocellulases [35, 36]. However, despite the mechanism which the cell wall components are degraded, currently there are no enzymes with high capacity of degradation and the need for them increases [26, 37].
To supply the necessity of efficient enzymes in the industry, the microorganisms are the first potential source of enzymes to be used in genetic engineering [26, 38] and currently, from them it has been possible to obtain endoglucanases, xylanases, cellobiohydrolases, exoglucanases, glycosyl hydrolases, glucuronoyl esterases, ferulic acid esterase and acetylesterases [19]. However, the enzymatic activity obtained from microorganism’s expression is limited by the enzymatic capacity inherent to own system and the protein overexpression is only possible with the change of expression system; to supply the high quantities of proteins required by industry, currently, the chloroplast genetic engineering has been used to express several hydrolytic enzymes genes such as cellulases (bgl1C, cel6B, cel9A, xeg74, celA, celB, bgl1, Cel6, Cel7, EndoV, CelKI, Cel3, TF6A, Pga2, Vlp2 peroxidase genes), pectinases (PelA genes), ligninases (MnP-2 genes) and xylanases (xyn, xynA genes) [14, 39, 40, 41, 42, 43].
With the expression of hydrolytic enzyme in chloroplast genome, positive results have been observed in the expression of β-glucosidase (bgl1 gene) [41] when plants with longer internodes (150% of height) and increasing leaf area (resulting in 190% more biomass) and mature transplastomic plants with earlier flowering were obtained. The expression of β-glucosidase also increased twofold the levels of gibberellic acid precursor (GA53, GA44, GA19, and GA20), (GA1) hormone, and catabolite (GA8) and in the case of indolacetic acid and zeatin hormones had more than 200% of increases. Surprisingly the glandular trichomas density resulted up to 10-fold with more production of natural sugar esters that shown to be effective biopesticides against a range of insect species [44] in the β-glucosidase expression plants, they showed 18-fold less aphid and whitefly population by a toxicity increase in exudates of plants; but, there are report when the transplastomic plants that expressed lacasses showed slightly retarded vegetative growth with a light green leaf color may be attributable to copper deficiency induced by ligand chelation related to produced laccase [45]. In plants with xylanases overexpressed, a 60% increase of xylanase (xynA gene) was observed and the accumulation of the fungal enzymes was more than 10-fold higher levels but the transplastomic plants displayed pale-green-to-white leaf color and severely retarded growth [46]. In other researches using bgl1C, cel6B, cel9A and xeg74 as a cocktail genes, all transplastomic lines displayed strong mutant phenotypes showing severe pigment deficiency, slow growth in soil or even they did not survive due to their insufficient photosynthetic performance [14]. With manganese expression, the transplastomic plants showed mild phenotypic effects in green house with some leaves turning pale as they matured [47]. On the other hand, there are reports where transgenic plants are morphologically and agronomically indistinguishable from the untransformed plants. These open new avenues for large scale production of several other industrially useful cellulolytic enzymes through chloroplast expression [39, 48, 49].
Despite different results obtained in several researches; currently, enzymes with high capacity to degrade the plant biomass have been notoriety in industry. And due to extensive processes, that are involved as cotton processing, paper recycling, detergent enzymes, juice extraction and as animal feed additives, they are positioned as the third most common enzymes used [26, 37]. Today, enzyme treatments of plant biomass are considered more cost-effective compared with mechanical processes, resulting in 20–40% energy savings [50]; although, the costs associated with the production of microbial enzymes are expected to be high [51]. For this, the chloroplast technology can provide an inexpensive source of active cellulases, which is critical to efficient and cost-effective conversion of lignocellulosic biomass into the different industries [26, 38].
4. Factors involved in protein plastid expression
To achieve the gene expression successfully, several factors are involved in the gene regulation since their integration in the chloroplast genome until the concomitant modification of sequence to improve the translation.
4.1. Homologous recombination sequence
The recombination is a fundamental conserved process in all spices and is essential not only in the conservation of genome stability, facilitate the genetic diversity, but also is involved in the reparation, replication, maintenance and segregation of DNA [52, 53]; the principal role of recombination restores the DNA damage caused by photooxidation and other environmental stresses. It has proposed that the recA system regulate the recombination and that the mechanism is limited by enzymes availability more than substrates. Although recombination in chloroplast is well documented, its molecular mechanism is not well defined. However, the recombination is an advantage in chloroplast engineering because genes of interest and selectable marker genes flanked by homologous native chloroplast DNA sequences can be inserted in the chloroplast genome via homologous recombination [54].
4.2. Marker genes
The transplastomic lines and the gene of interest integration in the chloroplast genome must be confirmed with selectable marker genes that confer resistance to biotic or abiotic stress. The first selection marker gene was mutant from rRNA 16S that conferred the spectinomycin resistance [55]; however, the stable integration of a marker gene was reported by Goldschmidt-Clermont [56] with the aadA gene expression that confers spectinomycin and streptomycin resistance and this resulted 100-fold more that the previously obtained by Svab and Maliga [57]. In 1993, the neo gene (kanamycin-resistance) was used as an alternative of selection, but in 2002, the aphA6 gene was reported with the same resistance with high efficiency of transformation [58]; however, Kumar et al., [59] achieve results eightfold that aphA6 with a ‘double barrel’ from aphA6 and nptII genes, also, it has been activated other selection markers as aacC1 gene that confer gentamycin resistance or bar gene to phosphinothricin; multiple mechanisms have been used as selection method as codA gene used as negative marker [60]; recently, it has been used the cat gene to chloramphenicol resistance with low resistance compared with aadA gene, but without spontaneous resistant’s mutant [61]. Furthermore, Nuccio et al. [62] used the badh gene that confer salinity resistance and this selection marker gene was tested in chloroplast transformation of carrot by Kumar et al. [59] showing as a selection alternative against disadvantages of marker genes with antibiotics resistance.
The selection markers are chosen according to cellular autonomy and portability; thus some selection markers are dominant like the aadA gene, while other genes are recessives like the punctual mutation in the RNAr genes (rrnS and rrnL); the dominant markers are important for transformations of the highly polyploid plastomes because they increase the transformation frequency due to its effect at early stages of selection despite that may only integrate in the minority of the plastomes; on the another hand, recessive markers have lower efficiency in the transformation and only are efficient in random segregations if the plastids have sufficient copies of transformed genome [63, 64]. However, the selection markers and genes of interest can be added under one promoter because the polycistronic RNAs are efficiently translated in plastids [65]; also, it is possible to obtain a transductional fusion between a resistance gene and reporter gene like gfp gene avoid phenotypic marking in transformed cells with more results in the selection process from transformed tissue [66].
4.3. Promoter
To obtain high levels of protein expression in plastids, first, the levels of stable mRNA must be increased and then use a promoter with high efficiency [67]. To realize the protein expression, the plastomes of algae and higher plants account with a polymerase RNA cyanobacteria type usually named ‘PEP’ (plastid-encoded RNA polymerase) constituted by enzymatic cores encoded by rpoA, rpoB, rpoC1 and rpoC2 genes [68]. The PEP recognize promoters type σ70 and account with conserved region −10 (TATAAT) and −35 (TTGACA) which is responsible of start the transcription of 5–7 nucleotides downstream of −10 element of promoter; also, the PEP is associated at 8 auxiliary protein that regulate the transcription as kinase of plastid transcription (PTK) is regulated by a phosphorylation factor [69, 70].
The eubacteria enzymatic machinery has acquired a second polymerase type phage (NEP, nuclear-encoded plastid RNA polymerase), which is active in plastids; however, a nuclear gene encoded the catalytic core of NEP [71], which recognizes three different promoters: NEP type I with recognition in the region ∼15 nucleotides upstream (−14 to +1) from start codon (+1), a subtype promoter NEP Ib with a conserved motif to 18–20 nucleotides upstream of YTRa motif designed as ‘box II’ or ‘GAA box’ [72, 73] and promoter NEO type II that recognizes downstream region of start codon (−5 to +25) [74]. Several genes and photosynthetic operons have a PEP type promoters, the genes non-photosynthetic are transcribed as PEP as NEP, whereas the only a few genes are transcribed exclusively by NEP promoters [74].
The promoters recognized by PEP/NEP are regulated differentially which is tested with the expression level and their efficiency can be related with upstream sequences of start codon [73]. Recently, it has been reported with gfp expression that rrn promoter is 90-fold strong that psbA or of trc promoter, indicating that the transcription is more efficient in Prrn [75]; also, it has been recorded that other promoters such as PclpP-53 with high efficiency related with NEP non-dependent of enzymatic core of PEP [76]; several reports have ideated the analysis of the capacity of promoter from operon RNA (Prrn), which can be fused with control sequences to improve the protein expression [77]. In this sense, the expression levels of a protein are determined by their sequence or their promoter and different promoter can be used to improve the gene expression in chloroplast genome [78].
4.4. 5′ and 3′ UTR sequences
The transgene expression in the plastid genome required sequences that can be recognized by transcriptional machinery from the own plastid; however, the role and mechanism of the regulatory elements and flanked sequences is not well defined [16]. The protein expression in plastid depends of mRNA stabilization; also, the translation and accumulation efficiency of protein expressed by chimeric transgenes are determined by 5′3′UTR regions and the interaction of mRNA-rRNA [79]. The loss of regulatory elements 5′ and 3′UTR leads to fast degradation or low transcripts accumulation [80]. The start of translational activation is currently unknown, but it is possible that the ribosomal protein S1 media the mechanism of affinity from 5′UTR [81].
The 5′3′UTR elements are recognized by proteins that protect the mRNA against exonucleases 5′3′ and processional endonucleases 5′3′; the eukaryotic cells used this mechanism in the cytoplasm to remove defective mRNA capable of originate truncated proteins, and this shows how the untranslated region has influence in the stability and degradation of plastid mRNA [82]. The 5′UTR region is a rich A + T region and contains cis elements that determine the mRNA stability by interaction with the α subunit of RNA polymerase [83]. It has been reported that mutations in 5′UTR drastically decreased the protein expression [84]. On the contrary, the 3′UTR is considered as a stabilizing region of mRNA being able to be similar or different to Shine-Dalgarno sequences; however, the upstream region of ATG are highly dependent from individual mRNA; in this way, these sequences are critic to start translation. The 3′UTR region from plastid mRNA is an inverted repeat sequence that can be folded as stem and loop in involved structures in the termination of prokaryotes transcription [85]. It has been suggested that the 3′UTR is of less importance to mRNA stability [86]; however, the mRNA levels are mostly determined by 3′UTR more than 5′UTR [87]. Recently, it has been reported that clpP can be used as potential source to obtaining regulatory sequences based on results on potato [88].
4.5. Shine-Dalgarno sequences
The plastid gene expressions are controlled in post-transcriptional stage, especially, during the translation [89]. The prokaryotic mRNA normally contains with a 5′ untranslated region (5′UTR) and Shine-Dalgarno (SD) sequences as ribosome binding site [90]. The translational regulation is to be determined by untranslated region upstream at start codon that sometimes is specific to each mRNA [91, 92]. The localization of SD upstream start codon is 4–9 nucleotides as the optimum form [79]; however, several sequences has a SD at different distances; in these cases, specific proteins added at 5′UTR and redirectioned the 30S subunit to start codon or next AUG downstream [90].
The plastids and E. coli have an identical anti-SD sequence in 3′end from 16S rRNA (5′-TGGATCACCTCCTT-3′), because of this the SD sequence ‘GGAGG’ of plastids can be recognized in E. coli and vice versa; it has been reported that bacterial SD can be used to improve the expression of genes in plastid [93]; although, still it is unknown as the SD are recognized and how the used determine the efficiency translational [94]; in this sense, the cistron can be processed in both system, but the translation efficiency is major in plastids, this may be due at the presence of plastid ribosomal proteins ‘PSRPs’, and although this proteins are not well defined, they can be explained why this proteins were acquired in the evolution [94, 95].
It has been reported that is possible used multiple SD sequence upstream at the start codon to improve the translation; however, adjacent SD sequence are unrecognized by multiple ribosome at the same time. The organization of four SD sequence with sufficient spacer length (39-nt) that allow the incorporation of ribosomal units 30S can improve the expression until 71-fold hence attracting more ribosome; however, if there is a start codon, stop codon or mini ORF between two SD, the translation is low [94]. It is not well known the correlation between 5′UTR, SD and start codon number to the mRNA stability but the genes with polycistronic expression can contain SD canonic sequences upstream of each cistron indicating that initiation of internal translation can occur; sometimes, the polycistron does not make intercistronic cleavage and is efficiently translated and it is unknown as the SD downstream are recognized, but it is speculated that regulatory proteins are involved in the process [91, 92, 94].
5. Transformation methods
The plastid transformation is widely used in basic research and into biotechnological applications; initially developed in Chlamydomonas and tobacco, currently is feasible in several plant species [96]. This technology require the transfer of genes into chloroplast genome; now, the strategies more common to transgenes insertion in chloroplast genome are biolistic and polyethylene glycol (PEG); the biolistic has been tested with gold and tungsten particles; this method is efficient because there are no limits due to interaction of host-pathogen such as viruses and bacteria; the biolistic has no restriction by cellular species, foreign DNA length, sequence or conformation [97]. The reports suggest that particles of 0.4 μm improve fourfold the transformation efficiency more than 0.6 μm; also, exhibit less cellular damage [98]; it has been shown that charged particles can promote transformation events in isolated genomes as plastid or nuclei at the same time [99]. On the another hand, the PEG method is efficient and with low cost of transformation, eliminates the dependent of particle shots and decreases the risk of cellular death explosion and the dependence of species can be more efficient that particles bombardment; both methods are efficient but the use is crop dependent [100].
6. Elimination of marker gene
One the biggest impediments in the development of transgenic plants is that the manipulation and expression of multiple genes is difficult of achieve, still when new methods have been developed; nevertheless, when an integration and genetic expression has been achieved, the marker selection genes that allowed the detection of transformed tissue that need to be eliminated from the sequences at troubles associated to high-level protein expression and the possible effect of horizontal transference at microorganism [101]. Multiple strategies have been reported to eliminate the markers genes as co-transformation, transposons, homologous recombination, specific site recombination and even P-DNA [102].
One of the most studied site-specific system is the Cre/loxP which included two components: (a) two sites loxP, each one with 34 pb (inverted repeat) flanking the sequence to eliminate and (b) the gene Cre (recombinase of 38 kDa) that joins to loxP sites and cleavage the sequence between both sites; in this sense, placing Cre/loxP system under control of OsMADS45 promoter to improve an autocleavage from marker selection gene improve the efficacy [103]. Although the Cre/loxP system has been analyzed in multiple plants including Arabidopsis, Nicotiana tabacum Zea mays and Oryza sativa, only Brassica juncea has been reported complete efficiency until F2 progeny [103]. Other system to elimination specific site of marker selection genes was reported using phage phiC31 (INT) that media the recombination attB/attP, Flp/frt from Saccharomyces cerevisiae, R/RS from Zygosaccharomyces rouxii [104] and Gin/gix from Mu bacteriophage [105].
7. Conclusions
Chloroplast genetic engineering is still under development but is emerging as a promising tool in the improvement of agricultural crops, expression of biopharmaceuticals elements, and manufacturing of biomaterials. Although the chloroplast transformation has been achieved in several important crops is not well defined in crops such as cereals due to factors like regenerate through somatic embryogenesis by inefficient methods of tissue culture and regeneration protocols, although there have been some significant progress in this regard [103]. Also currently, the transformation methods for grasses are restricted to nuclear genome by Agrobacterium, electroporation, and biolistic [97, 106]. Furthermore, plastid genetic transformation has allowed phylogeny study, which is similar to transformation with emphasis in genetic improvement, requires knowledge of the genome that has not been studied in all species, this also makes a disadvantage. In this sense, although it would have to prepare a vector for each crop, there are reports of transformations using plastid vectors from tobacco in potato and tomato transformations [107], indicating that differences in mRNA processing are determined as a vector that can be used. On the other hand, although the transgenes could not escape through pollen, rare hybrids can be generated if modified crops are pollinated by wild relatives [108]; considering that of the 13 most important crops in the world, 12 of them hybridize with wild relatives [109]; coupled with this, it has been reported the transmission parental of chloroplasts in tobacco even when considering the strictly maternal inheritance of organelles [110]. Therefore, it should be considered new controls in transgene transmission contention, which makes it the biggest challenge to pursue in the development of genetically modified crops [15].
Conflict of interest
The authors declare that they have no conflicts of interest.
\n',keywords:"chloroplast engineering, foreign protein, biotechnological applications",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/60476.pdf",chapterXML:"https://mts.intechopen.com/source/xml/60476.xml",downloadPdfUrl:"/chapter/pdf-download/60476",previewPdfUrl:"/chapter/pdf-preview/60476",totalDownloads:1021,totalViews:183,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:10,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"October 20th 2017",dateReviewed:"February 22nd 2018",datePrePublished:"November 5th 2018",datePublished:"December 5th 2018",dateFinished:"April 4th 2018",readingETA:"0",abstract:"Chloroplast is responsible for the major metabolic process photosynthesis. These organelles have their own genome and in the last three decades, the chloroplast genome has been broadly studied and manipulated through genetic engineering tools. The transfer of genes into chloroplast provides advantage over the insertion of transgene into nuclear genome, including overexpression of foreign protein, no positional effects, absence of epigenetic effects and uniparental inheritance of the transgenes, the ability to express multiple transgenes in operons and the possibility of eliminate the marker gene after the transformation and integration of the foreign gene. Now more than 100 transgenes have been reported stably integrated into the chloroplast genome including genes encoding enzymes with industrial value, biomaterials, biopharmaceuticals, vaccines and genes with agronomic trails. The chloroplast genetic tools have been implemented in several important crops. So, the chloroplast engineering technology has been positioned as the most important for the production of proteins and metabolites with biotechnological applications.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/60476",risUrl:"/chapter/ris/60476",book:{id:"7246",slug:"plant-growth-and-regulation-alterations-to-sustain-unfavorable-conditions"},signatures:"Edward Alexander Espinoza Sánchez, Jorge Ariel Torres Castillo,\nQuintín Rascón Cruz and Sugey Ramona Sinagawa García",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Chloroplasts: from cyanobacteria to bioreactors",level:"2"},{id:"sec_3",title:"2. Applications for the agronomic traits",level:"1"},{id:"sec_4",title:"3. Enzymes to cellulose degradation",level:"1"},{id:"sec_5",title:"4. Factors involved in protein plastid expression",level:"1"},{id:"sec_5_2",title:"4.1. Homologous recombination sequence",level:"2"},{id:"sec_6_2",title:"4.2. Marker genes",level:"2"},{id:"sec_7_2",title:"4.3. Promoter",level:"2"},{id:"sec_8_2",title:"4.4. 5′ and 3′ UTR sequences",level:"2"},{id:"sec_9_2",title:"4.5. Shine-Dalgarno sequences",level:"2"},{id:"sec_11",title:"5. Transformation methods",level:"1"},{id:"sec_12",title:"6. Elimination of marker gene",level:"1"},{id:"sec_13",title:"7. Conclusions",level:"1"},{id:"sec_17",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Farquhar J, Zerkle AL, Bekker A. Geological constraints on the origin of oxygenic photosynthesis. Photosynthesis Research. 2011;107(1):11-36. DOI: 10.1007/s11120-010-9594-0'},{id:"B2",body:'Taylor NL, Stroher E, Millar AH. Arabidopsis organelle isolation and characterization. Methods in Molecular Biology. 2014;1062:551-572. DOI: 10.1007/978-1-62703-580-4_29'},{id:"B3",body:'Del LYM, Farran I, Becher ML, Sander V, Sanchez VR, Martin V, Veramendi J, Clemente M. 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Laboratorio de Biotecnología I, Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Nuevo Campus Universitario, México
Universidad Autónoma de Nuevo León, Facultad de Agronomía, Laboratorio de Biotecnología, Francisco Villa S/N Col. Ex hacienda El Canadá, México
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1. Introduction
The 7 transmembrane receptors (7TMRs) also known as G-protein coupled receptors (GPCRs) constitute the largest family of plasma membrane receptors. The superfamily of 7TMRs includes receptors for hormones, neurotransmitters and ion channels, and is critical to mediate physiological and cellular processes [1, 2].
Composed of seven transmembrane hydrophobic alpha (α) helices joined by three intracellular and three extracellular loop structures, a cytoplasmic carboxyl terminus and an extracellular amino terminus (Figure 1), 7TMRs signal by stimulating heterotrimeric G proteins following the presentation of an agonist to the receptor [3]. Agonist binding at the 7TMR extracellular region initiates the formation of a G protein. Guanosine diphosphate (GDP) is released from the G protein in exchange for guanosine triphosphate (GTP). The GTP bound α subunit disassociates from the βγ dimer, both of which activate several effectors such as adenylyl cyclase, phospholipases and ion channels [3]. The Gα subunit can be categorised in to sub groups Gαs, Gαi, Gαq/11 and Gα12/13 [3]. The Gα subunits and the Gβγ dimer deriving from the heterotrimeric G protein can combine with downstream effector molecules such as adenylyl cyclase or phospholipase C to control cellular signalling pathways involving secondary messengers [3]. Examples of secondary messengers include cyclic adenosine monophosphate (cAMP), inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) which elicit cellular and physiological responses [4].
Figure 1.
General structure of a seven transmembrane receptor (7TMR)/G protein coupled receptor (GPCR). Extracellular loops 1–3 (EL1–3) and intracellular loops (IL1–3) connecting the 7 transmembrane helices (TM1–7). NH2▬N-terminal chain and COOH▬C-terminal chain.
2. Cardiovascular effects of 7TMRs and therapeutic drug targets
7TMRs are the target for a large proportion of therapeutic drugs, currently encompassing more than 30% of prescription medications [5] which directly or indirectly alter cellular signalling mechanisms.
2.1 Adrenoreceptors (β-adrenergic receptors)
Adrenergic receptors (ARs; also known as adrenoreceptors) are a class of 7TMRs located in the heart and vasculature and are responsible for relaying sympathetic nervous system (SNS) messages into cardiovascular reactions [1]. The neurotransmitters norepinephrine (NE) and epinephrine (Epi), which originate from the SNS, exert their effects on cardiac cells and tissues by binding to adrenoreceptors [6]. A number of adrenoreceptor subgroups are present in the mammalian heart, including three α1-ARs, three α2-ARs and three β-ARs (β1, β2 and β3) [6].
β-Adrenergic receptors (β-ARs) are the most important and one of the most frequently studied receptors belonging to the family of G-protein coupled receptors [7]. There are three subtypes of β-ARs: β1, β2 and β3, activation of which regulates important cardiovascular functions [7, 8]. The β1-ARs are characterised mainly for the heart, β2-ARs for blood vessels and β3-ARs for adipose tissue [9]. Within the vasculature the predominant subtype is β2-AR, which is 65–70% homologous to β1- and β3-ARs [8]. The agonists that bind with all three subtypes of β-ARs are the hormones adrenaline and noradrenaline, which help regulate cardiovascular and pulmonary function [10, 11].
Human genes encoding the β2-ARs are without introns and have been mapped to chromosome 5q31–32 [12]. The β-ARs consist of 413 amino acid residues, approximately 46.5 kDa [8]. There are three domains of β2-ARs: The extracellular domain, the transmembrane domain responsible for the ligands binding and the intracellular domain, which interacts with G protein and kinases such as β-ARK [13]. β2-ARs occur mainly in the lungs, where their presence has been shown in airway smooth muscle (30,000–40,000 per cell), epithelial and endothelial cells, type II cells and mast cells [8]. Moreover β2-ARs are in heart, kidney and blood vessels—mainly arterioles [8, 14].
As in the other G-receptors the signalling pathway of β2-ARs, which bind with a hormone ligand includes three basic steps: Receptor binding, G protein activation and effector system activation. β2-ARs may occur in two forms, activated and inactivated [6]. The binding of β-ARs agonist with β2-receptor activates the pathway in which Gs coupled proteins are involved. The stimulation of G proteins causes guanosine triphosphate (GTP) to bind to the α-subunit (Gsα) that activates it. The G-subunits dissociate, and α-subunits stimulate adenylate cyclase (AC) to formation of cyclic adenosine 3′,5′-monophosphate (cAMP). It is stated that cAMP acts as a catalyst for the process of activation of protein kinase A (PKA) and due to that it is involved in control of muscle tone. On the other hand cAMP inhibits the release of cytosolic calcium ion (Ca2+) in the smooth muscle cells, which leads to vascular relaxation (vasodilation) [8, 15].
Although the β2-ARs activated by β2-ARs agonists mostly influence the blood vessels (mainly arterioles and coronary arteries), they can also act in the heart and kidney. In the atrial and ventricular myocardium, stimulation of β2-ARs leads to increase in cardiac muscle contractility or relaxation, whilst in the kidneys it stimulates the release of renin, what it turn influences activation of the renin-angiotensin-aldosterone system [1, 8].
The primary role of the β-ARs in the heart is to coordinate the heart rate and contractility in response to the SNS neurotransmitters [6]. β1-AR is the most abundant subtype accounting for 75–80% in a healthy myocardium [6]. Around 15–18% of cardiomyocyte β-ARs are β2-AR whilst the remaining 2–3% of β-AR density is composed of β3-ARs [6]. Activation of β1-ARs and to a smaller degree β2-ARs, leads to an increase in cardiac contractility and an accelerated cardiac rate. Stimulation of the two predominate β-ARs also increases impulse transmission via the atrioventricular node [6]. The activation of cardiomyocyte β1- and β2-ARs also leads to a significant increase in free intracellular Ca2+ concentration [6]. Calcium is a secondary messenger in many biological systems. In cardiomyocytes, calcium affects ion channels which regulate ionic currents, impacting upon action potentials and muscle contractility [16]. Β3-AR appears to illicit an opposite effect on cardiac function to that induced by β1- and β2-ARs in that it acts to prevent cardiac hyperstimulation from NE and Epi (Table 1) [6].
Action
β1-AR
β2-AR
Β3-AR
Heart muscle contraction
Yes
Yes
Increases cardiac output
Yes
Yes
Increases heart rate in SA node
Yes
Yes
Increases atrial contractility
Yes
Yes
Increases contractility and automaticity of ventricular muscle
Yes
Yes
Dilates muscular blood vessels
Yes
Yes
Increases perfusion in blood vessels
Yes
Metabolism/lipolysis/thermogenesis
Yes
Prevent cardiac hyperstimulation
Yes
Table 1.
Actions of β-adrenergic receptors.
Constant elevation of catecholamines leading to β-AR signalling changes results in overstimulation of cardiac function [1]. Reducing the β-AR activity is vital to alleviate the risk of long-term cardiac tissue damage such as cardiomyopathy. Propanolol was discovered to be a β-AR antagonist in 1964, a so called β-blocker. Alprenolol and Practolol β-blockers have also been used for the management of heart failure [1]. β-Blockers function to overcome the harmful effects of norepinephrine which overstimulate the β1-AR, leading to a reduction in cardiac workload [1]. The most recently used β-blockers bisoprolol and carvedilol target both β1- and β2-ARs produce a survival benefit for heart failure patients [1]. In rats β2-AR agonists (fenoterol and zinterol) were shown to reduce progression of left ventricular modelling in dilated cardiomyopathy in addition to decreasing myocardial cell death [17]. In a later study the same group determined that in a rat model of dilated ischemic cardiomyopathy, Metoprolol, a β1-AR blocker, action is enhanced when given in combination with the β2-AR agonist fenoterol [18].
The β2-ARs have also been directed implicated in patients with ischaemic cardiomyopathy. A Gln27Glu polymorphism of β2-AR was discovered in a study investigating 155 people with heart failure of ischaemic aetiology with impaired Left Ventricular Ejection Fraction ≤35% [19]. Three allele categories were discovered, the most common genotype in heart failure was Gln27Gln, and the least common was Glu27Glu, whilst Gln27Glu was not significantly different between heart failure and control subjects. The study concluded that the Glu allele was associated with lower myocardial infarction rate and highlighted that patient response to β-blockade therapy may be altered [19]. Likewise β1-AR (Ser49Gly, Arg389Gly) and β2-AR (Arg16Gly, Gln27Glu, Thr164Ile) polymorphisms did not alter in a Polish cohort study of patients with idiopathic dilated cardiomyopathy [20]. It is of interest that in patients with Takotsubo cardiomyopathy, β-AR polymorphisms (β1-AR (Gly389Arg) and β2-AR (Arg16Gly and Gln27Glu)) were significantly different to controls but similar to patients with ST-elevation myocardial infarction [21]. Work combining beta-blockers with ACE-inhibitors/angiotensin receptor blockers over the years using meta-analysis data has shown reduced recurrence of the disorder [22].
A murine model depleting levels of β2-ARs also resulted in diabetic cardiomyopathy in vivo and reduced β2-ARs in cardiomyocytes grown under in hyperglycemic conditions [23]. Conversely, overexpression of β2-ARs (by 300 fold) in mice showed that over time severe cardiomyopathy was observed, resulting in interstitial fibrosis, loss of myocytes and myocyte hypertrophy. In the majority of the 81% of mice that died within 15 months, heart failure was observed [24]. These results were similar to other transgenic overexpression mouse lines. The authors hypothesised that a number of mechanisms from activation of growth or transcriptional factors, cross-talk with other pathways, necrosis or apoptosis of cardiac myocytes and/or high heart rates limiting energy supply.
The human heart also possesses α1 adrenoreceptors (α1-AR) although in a smaller quantity to the β-ARs [25]. The α1-ARs are expressed in the heart, both the α1A-and α1B-AR subtypes are expressed in human myocytes, and have been shown to regulate contractility [26, 27]. The α1-ARs combine with the Gq/11 family of G proteins, in turn activating phospholipase C. The secondary messenger IP3 binds to receptors on the membrane of the sarcoplasmic reticulum, triggering the release of intracellular Ca2+ [6]. The raised Ca2+ level leads an increase in vasoconstriction [6]. The coupling of α1-ARs to the Gq/11 family of G proteins also produces DAG and subsequent protein kinase C [6].
In heart failure the α1-ARs may offer a protective benefit to maintain cardiac inotropy, preventing cardiomyocyte apoptosis and maladaptive cardiac remodelling [6]. Although a small study, loss of β1-AR and no change in β2-AR levels in end-stage dilated cardiomyopathy patients was observed alongside a loss of α1A-ARs [28]. Although the role of β1-AR in heart failure has long been described, this interaction between the α-ARs was novel as the few previous studies had shown no change or increases in α-ARs binding but these were different types of heart failure. In addition a total of 26 proteins of interest were also identified in the cardiomyopathy patients, some of which have been linked to G-protein coupled receptor signalling and desensitisation [28]. Prostatic binding protein levels decreased whereas increases in ANP32A and clathrin were noted. Also of interest are Takotsubo cardiomyopathy (also known as stress cardiomyopathy) patients. This condition is often reversible, and two studies have shown that several β1-AR and α2c-AR polymorphisms were not implicated in Takotsubo cardiomyopathy [29, 30].
2.2 Angiotensin II type 1 and 2 receptors
Angiotensin II (AngII) is an important protein in the renin-angiotensin system (RAS). In the bloodstream renin converts angiotensinogen (derived from liver) into angiotensin I, which in turn is transformed into AngII by angiotensin converting enzyme (ACE) [14, 31, 32]. AngII can be also secreted in some local tissues including within the brain, heart, arteries and kidney [32].
The Angiotensin II type 1 and 2 receptors (AT1 and AT2 receptors) belong to the wide family of G-protein coupled receptors (GPCRs), members of which have seven transmembrane spanning domains and is the biggest member of the human genome [31, 33]. The distinction and classification of AT1 and AT2 receptors is based on their varied affinity for different non-peptide antagonists [34]. Moreover the AT1 and AT2 receptors differ between each other in their number of amino acids, tissue-specific expression and mechanisms of signal transferring [13]. Both of these receptors occur in all mammals and bind a peptide hormone angiotensin II (AngII), which is the most important effector in the RAS [32].
The main role of angiotensin becomes apparent in the cardiovascular and endocrine systems where it regulates blood pressure and hydro-electrolytic homeostasis [32, 33]. It is stated that the main physiological functions of AngII (vasoconstriction, aldosterone secretion, renal regulations cellular dedifferentiation and proliferation) are mediated mostly by the AT1 subtype of angiotensin receptor [14, 31, 33, 34, 35, 36]. In humans, the genes encoding AT1 receptors are mapped on chromosome 3q21–3q25 [37]. The AT1 receptors consist of 359 amino acids, with a molecular weight of 41 kDa, and their amino sequence reveals 20–35% homology with other GPCRs [31].
In adult mammals, AT1 receptors are mainly expressed in kidney (glomeruli, proximal tubules, vasculature, medullary interstitial cells), adrenal glands (cortex, medulla), heart (myocardium, ganglia, conduction system), brain (circumventricular organs, thalamus, basal ganglia, cerebellar cortex, medulla oblongata) and vasculature (smooth muscles, adventitia) [32, 38]. Rats and mice can have two isoforms of the Angiotensin II 1 receptor: AT1A and AT1B with amino acid sequence convergence seen at 94% [14, 31, 33, 34]. AT1A receptors are present predominantly in vascular smooth muscle, liver, lung and kidney whilst AT1B receptors occur mainly in the adrenal gland and anterior pituitary [31, 34, 38]. The rodent AT1A and AT1B receptor genes are situated on chromosomes 17 and 2 respectively [38].
The activity of angiotensin II through AT1 receptors should be considered in physiological and pathophysiological conditions. The physiological signalling pathway involves the renin-angiotensin-aldosteron system and leads to changes in blood pressure primarily through vasoconstriction of arteries and arterioles, secretion of aldosterone from adrenal gland and sodium reabsorption by via the kidney tubules [32]. Ang II mediates vasoconstriction through the IP3/DAG pathway, which uses Gq/11 protein-coupled receptors. Gq/11 activates phospholipase C (PLC), which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) and produces diacyl glycerol (DAG) and inositol trisphosphate (IP3). IP3 causes an increase in intracellular calcium whilst DAG activates protein kinases C [31]. The increased concentration of calcium (Ca2+ ions) within vascular smooth muscle cells leads to vasoconstriction which results in an increase in blood pressure or may causing a localised reduction in blood flow in some specific tissues [32, 36]. AngII acting through the AT1 receptors located in the zona glomerulosa of the adrenal gland stimulates the release of aldosterone [32]. Aldosterone then acts on the distal convoluted tubules and the cortical collecting ducts in kidney, firstly causing sodium (Na+) retention, leading to increased peripheral resistance and secondly causing resorption of water from urine which also increases extracellular fluid volume. Both of these mechanisms lead to an elevation in arterial pressure [32].
Considering the pathological conditions, the activity of AngII through AT1 receptors may induce the proliferation of vascular smooth muscle cells which in turn promotes myocyte hypertrophy and causes vascular fibrosis. Proliferation of smooth muscle cells is also involved in the initial stages of atherosclerotic plaques formation in arteries [32]. AngII binding to AT1 receptors also activate the multiple intracellular signalling pathway that promotes atherosclerosis. The pathway includes oxidative stress, inflammation, endothelial dysfunction, tissue remodelling, proliferation fibrosis, thrombosis and autostimulation. Moreover AngII may participate in the process of atherosclerosis lesion formation as it stimulates the release of endothelin-1 (ET-1) from the endothelial cells [32]. In addition to inducing proliferation and atherosclerotic plaques formation, AngII may have an effect on the developing/developed plaques. Atherosclerotic plaque stability and disruption is in turn associated with matrix metalloproteinase (MMP) enzymes, the production of which can be stimulated by AngII [32]. The MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs) and disruption of the balance between MMPs and TIMPs may lead to cardiovascular diseases [37, 39]. Moreover, in pathological states, the activation of AT1 receptor by AngII may cause vascular remodelling and growth by expression of autocrine growth factors (including fibroblast growth factor and platelet-derived growth factor) in vascular smooth muscle cells [32, 40].
The activation of AT2 receptors by AngII has an opposite effect to AT1 receptors. It means that the functions of AngII mediated by AT2 receptors are vasodilation, natriuresis and inhibition of cellular growth and proliferation [14]. Genes encoding AT2 receptors are localised on chromosome Xq22-q2 [13, 31]. The molecular weight of AT2 receptors is approximately 41 kDa and they consist of 363 amino acids [13, 41].
AT2 receptor expression has been localised in both foetal and adult tissues. In foetuses, expression of AT2 receptors is intense, especially in a cardiovascular system [13]. In adult mammals the expression of AT2 receptor is still observed in heart (mainly in myocardium) and renal blood vessels but is significantly lower than before birth [13, 38]. Expression of AT2 receptors has been also noted in the adrenal gland (cortex and medulla), brain (thalamus, cerebellar cortex), mesenteric and uterine arteries [38, 42].
It is stated that the AT2 receptor acts to stabilise blood pressure by controlling vascular tone by vasodilation [13]. In this action the AT2 receptor together with other GPCR family B2 receptors for bradykinin form a stable functional heterodimer, which causes the increase of nitric oxide (NO) and stimulating cyclic guanosine monophosphate (cGMP) synthesis. The cGMP contributes to relaxation of smooth muscles, which in large veins, large arteries, and smaller arterioles leads to vasodilation and causes decreased blood pressure. It has also been suggested that activation of AT2 receptors by AngII may inhibit arterial and myocardial hypertrophy and fibrosis in the ageing heart and vasculature.
Therefore AngII exerts its influence via the activation of the Angiotensin II type I receptor (AT1R), a 7TMR located in vascular smooth muscle as well as in the kidneys, brain and adrenal glands in an effort to maintain sodium/water homeostasis and moderate vasoconstriction [1]. AT1R acts to control arterial pressure, blood volume and to encourage growth and proliferation through the activation of cellular signalling mechanisms [15]. The AT1R is a Gq/11 coupled receptor [25]. Stimulation by AngII leads to the activation of phospholipase C-β and the release of DAG and IP3, followed by the activation of protein kinase C and movement of intracellular calcium [3]. AT1Rs are upregulated in cardiac tissue in response to hypertrophic triggers, encouraging unfavourable cardiac remodelling in heart failure [9]. These complex roles have resulted in a number of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors to be developed and used as cardiovascular treatments. ARBs and ACE inhibitors have demonstrated a reduction in deleterious left ventricular remodelling, such as hypertrophy and myocardial stiffness which as associated with heart failure [6]. ACE inhibitors alongside antagonists of the AT1R, the -sartans, have become one of the main pharmaceutical treatments for hypertension and cardiovascular disease [1]. Commonly used ARBs include Losartan, Valsartan and Candesartan [43]. ARBs function to interfere with the renin-angiotensin system by preventing the binding of AngII to AT1R. This inhibition of AngII result in vascular smooth muscle relaxation, a reduction in cellular hypertrophy, and a decrease in plasma volume resulting from an increase in salt and water excretion [43].
A number of advances in terms of cardiomyopathy and ANGII and its receptors have been made in the last few years. In terms of cardiomyopathy, the AngII receptor inhibitor LCZ696 has been shown to inhibit extracellular signal-regulated kinase (ERK), resulting in increased survival in pregnancy-associated cardiomyopathy mice. The authors indicated that by reducing cardiac hypertrophy, fibrosis and apoptosis it could act as a potential treatment for this cardiomyopathy [44]. Another study showed that this angiotensin receptor-neprilysin inhibitor reduced inflammation, oxidative stress and apoptosis in vitro and in vivo [45]. It has also been stated that in end-stage hypertrophic cardiomyopathy, the modern Angiotensin receptor neprilysin inhibitor treatments are both safe and effective [46]. Angiotensin-converting enzyme 2 (ACE2) has also showed therapeutic potential when looking at doxorubicin-induced cardiomyopathy rat models [47]. The enzyme reduced apoptosis, inflammatory responses, and oxidative stress and reduced mortality and myocardial fibrosis whilst improving ventricular remodelling and cardiac function. They also showed activation of the AMPK and PI3K-AKT pathways, inhibition of the ERK pathway, and decreased TGF-β1 [47]. Sulforaphane, which activates nuclear factor erythroid 2-related factor 2 (Nrf2), has also been shown to present angiotensin II-induced cardiomyopathy via Akt/GSK-3ß/Fyn -mediated Nrf2 activation [48].
Aldehyde dehydrogenase 2 (ALDH2) has also been shown to protect against alcoholic cardiomyopathy [49]. By decreasing angiotensinogen and AngII this cardioprotective enzyme inhibited local RAS in mice by inhibiting the p38 MAPK/CREB pathway. In another form of cardiomyopathy, hypertrophic, ACE inhibitors angiotensin-receptor blockers have been used to try and regulate the renin-angiotensin-aldosterone system [50]. This has resulted in patients having a lower risk of developing atrial fibrillation which is associated with hypertrophic cardiomyopathy.
Much work has looked into polymorphisms in the angiotensin-converting enzyme gene itself in relation to hypertrophic cardiomyopathy risk; however, the studies have sometimes shown conflicting results. A systematic review and meta-analysis indicated that the ACE insertion/deletion (I/D of 287 base pairs in intron 16) polymorphism was probably a risk for hypertrophic cardiomyopathy [51]. People with the DD genotype have increased levels of ACE and angiotensin II and therefore more hypertrophy and fibrosis, as seen in other situations where their levels increase. Although many of the 1 in 500 people affected by hypertrophic cardiomyopathy have mutations in the genes coding for sarcomeric proteins, polymorphisms in the components of the RAS are implicated. ACE DD has also been associated with dilated cardiomyopathy patients, angiotensin receptor type 11166CC genotypes with both hypertrophic and dilated cardiomyopathy and the 235TT genotype of angiotensinogen (M235T) is associated with hypertrophic, dilated and restrictive cardiomyopathy [52].
Overstimulation of AngII has also been reported in dilated cardiomyopathy [53] and AT1R overexpression resulted in female mice being more affected (especially in terms of heart failure and increased mortality) than males [53]. In particular, ventricular hypertrophy and dilation and changes in Ca2+ activity and homeostasis were observed, and these reflect that clinical observations that dilated cardiomyopathy can be exacerbated in women in comparison to men. This can also be linked to oestrogen which increases angiotensinogen and decreased renin, ACE and AT1R expression but of course following menopause these effects are lost [54].
Much has been investigated in relation to the use of ACE inhibitors in patients with ischemic cardiomyopathy. Much work has been carried out in patients with an ejection fraction of less than 40% with these enzymes working well. More recently attention has turned to those with an ejection fraction of more than 40% who were studied less. In patients with 40–50% ejection fraction, the ACE inhibitors were seen to reduce the risk of mortality, nonfatal myocardial infarction and stroke by 21% [55].
2.3 Endothelin-1 (ET-1) receptor
There are three different forms of 21-amino acid peptides, which belong to the endothelin peptide family: ET-1, ET-2, and ET-3 [56]. They vary in biological function and may affect blood vessels as well as other tissues both within and outside of the cardiovascular system [56]. The predominant form of endothelin peptide is an isopeptide ET-1 with potent vasoconstrictor and proliferative properties [57]. ET-1 is synthetized by endothelial cells, airway smooth muscles cells, cardiomyocytes, macrophages, leukocytes and mesangial cells [57].
There are two subtypes of receptors which are mediated by endothelin, known as Endothelin Type A receptor (ETA) and type B (ETB) [57]. Although mediated by the same peptide agonist, activity of these two subtypes is usually opposite, as the ETA receptor promotes vasoconstriction, growth, and inflammation whilst ETB receptors may cause both vasoconstriction and vasodilation and also increases in sodium excretion and inhibition of growth and inflammation [57, 58, 59].
The potential to bind with ETA receptors is the same for ET-1 and ET-2 endothelin but lower for ET-3 endothelin, whilst the potential binding rate with ETB receptors is equal for every form of endothelin [57, 58]. In people the genes responsible for expression of the ETA receptors are situated on chromosome 4q31.22-q31.23, whilst genes encoding ETB receptors are mapped onto chromosome 13q22.3 [60]. The molecular weight of the ETA and ETB receptors are 48 and 50 kDa respectively [61, 62]. The human 427 amino acid long ETA receptors and 442 amino acid long ETB receptors are approximately 64% homologous [58]. The homology of ETA and ETB receptors in humans and other mammalian species is between 88% and 97% [58].
ETA receptors are expressed predominantly in the heart (coronary vasculature and cardiomyocytes), lungs (pulmonary artery), kidney (renal artery, afferent and efferent arteriole, cortical vasculature, mesangial cells), brain (cerebral vasculature) and adrenal gland. ETB receptors also occur in the heart (coronary vasculature and cardiomyocytes), lungs (pulmonary artery), kidney (renal artery, afferent and efferent arteriole, medullar vasculature), brain (cerebral vasculature) and adrenal gland [63].
The ETA receptors mediated by ET-1 endothelin in vascular smooth muscle cells promoting vasoconstriction, hypertension, hypertrophy, fibrosis and inflammatory changes, including atherosclerosis and due to that has activity similar to the AT1 receptors mediated by AngII [63]. The vasoconstrictive pathway of ETA receptors includes: Coupling to phospholipase C (PLC) via GTP-binding protein, phospholipase C activation, phosphatidyl inositol hydrolysis, inositol 1,4,5 triphosphate (IP3) generation and 1,2-diacylglycerol (DCG) accumulation. Inositol triphosphate is a signalling molecule that leads to mobilisation of Ca2+ from intra- and extra-cellular sources resulting in long-lasting vasoconstriction [56, 64].
The ETB receptors mediated by ET-1 endothelin in the vascular endothelium are involved in the clearance of ET-1 and stimulate vasodilation due to the nitric oxide and cyclooxygenase metabolites production, which also exert vasorelaxant effects on the underlying smooth muscle. Moreover, the ETB receptors have a natriuretic action causing sodium and water resorption from the distal tubules and collecting ducts in the kidney. The ETB receptors, which occur in smooth muscle cells, additionally act as vasoconstrictors [57, 63, 64].
In the last few years research into endothelin has progressed the information known about links to cardiomyopathies. Some of the early published studies showed that ET-1 and its receptor either played a causative role in hypertrophic cardiomyopathy, idiopathic dilated cardiomyopathy and uremic cardiomyopathy or could be a marker [65, 66, 67, 68]. Indeed work in cats has even reflected the increased ET-1 levels in cases of hypertrophic, dilated, restrictive and unclassified cardiomyopathy [69]. More work has now been carried out into other cardiomyopathies and the potential mechanisms of action. Much like ACE2, the endothelin receptor blocker bosentan has been shown to inhibit doxorubicin-induced cardiomyopathy in a rodent model [70]. This study looked at the receptor blocker as elevated levels of ET-1 were discovered in doxorubicin treated patients. The in vitro studies indicated that activation of the epidermal growth factor (EGF) receptor and the MEK1/2-ERK1/2 cascade were possible mechanisms of action [70]. A good review looking at endothelin-1 and atrial cardiomyopathy, published in 2019 brings together the information in this area. The work over the years has indicated that endothlin-1 plays an active role affecting Ca2+ levels, via the ET-1-superoxide-MMP9 cascade and via apoptosis, resulting in both electrical and anatomical remodelling [71].
Not only is endothelin-1 a potential therapeutic route but it also shows promise in predicting patient outcomes. A recent study investigating new-onset atrial fibrillation in patients with obstructive hypertrophic cardiomyopathy has shown that elevated pre-operative levels may indicate increased likelihood of atrial fibrillation [72]. Big endothelin-1, the precursor of endothelin-1 has also been shown to be useful when predicting prognosis for hypertrophic cardiomyopathy patients and the authors have suggested that it should be added to marker panels [73, 74]. Endothelin 1 has also been implicated as a modifier in dilated cardiomyopathy. With variations including the rare G > A and a C > T at c.90 seen in dilated cardiomyopathy patients and EDN1 polymorphisms linked to increased risk of the disorder, likely by altered the stability of the protein [75]. A model of diabetic cardiomyopathy in rats also showed that plasma endothelin-2 levels were higher that controls and that overexpression of the protein results in a more severe phenotype [76].
2.4 Muscarinic receptors
Cardiac function is controlled by the SNS and parasympathetic nervous system (PNS). Parasympathetic vagal nerves are distributed throughout all areas of the heart, particularly in the ventricles [77]. Cardiac muscarinic receptors are activated by acetylcholine, having been stimulated by vagal nerve activation. The muscarinic acetylcholine receptors (M-ChR) are glycoproteins belonging to the 7TMR superfamily [77]. The M2 subtype of M-ChR are the most prevalent group within the mammalian heart and their function is opposed to the β-ARs in that they cause a reduction in myocardium contractility and a lower cardiac rate [10]. M-ChR exert their influence on the myocardium via the Gα1-coupled receptors which inhibit adenylyl cyclase whilst the Gβγ dimer impedes the activity of potassium channels in the sinoatrial node [1]. M-ChR can also exert an effect over Ca2+ channels [77] affecting cardiac contractility.
Heart failure patients demonstrate an increase in M2 muscarinic receptor density, with activated M2 receptors encouraging an inotropic response [9]. One study using serum from a patient showed that when autoantibodies to the muscarinic receptors and β-ARs were activated it resulted in cardiomyopathy and atrial tachyarrhythmias [78]. Along a similar line, autoantibodies against β1-ARs have been shown to cause sudden death in idiopathic dilated cardiomyopathy patients [79]. Antibodies to β-ARs have been discovered in people with idiopathic dilated cardiomyopathy, even leading to the suggestion of a form of ‘adrenergic cardiomyopathy’ [80]. In addition autoantibodies against muscarinic receptors have also been noted in cases of peripartum cardiomyopathy [81], dilated cardiomyopathy [82, 83, 84, 85], and M2-muscarinic acetylcholine receptor autoantibodies have been implicated in playing a role in atrial fibrillation in dilated cardiomyopathy patients [86] Similar increases were not observed in patients with Takotsubo cardiomyopathy [87] or in rats with cirrhotic cardiomyopathy [88]. Autoantibodies against cardiomyocytes, β1- or β2-ARs or M2 muscarinic receptors were not noted in 20 people with Takotsubo cardiomyopathy in comparison to healthy controls, or in rats with cirrhotic cardiomyopathy.
3. Conclusions
The superfamily of 7TMRs includes receptors for hormones, neurotransmitters and ion channels, and are critical to mediate physiological and cellular processes [1, 2]. This chapter has investigated adrenoreceptors (both α- and β-adrenergic receptors) and the components of the renin-angiotensin system (RAS) especially AngII, ACE and the AT1 and AT2 receptors. The chapter has also looked at endothelin-1 (ET-1) and its receptor, and precursor Big endothelin-1 and finally the muscarinic receptors. By looking at their numerous effects in both healthy and diseased vasculature and cardiac disorders, especially cardiomyopathies, it can be seen that there are wide ranging effects. Developing these 7TMRs as markers of disease, for prognosis, diagnosis and therapeutic treatments is becoming more important as their many roles as being uncovered in the cardiovascular system.
Acknowledgments
The authors would like to thank their institutions for funding them. Ewelina Prozorowska, Kristýna Glocová, and Lucy Slater were undertaking research internships with Catrin Sian Rutland at The University of Nottingham, UK. Kristýna Glocová had her internship funded by The European Association of Veterinary Anatomists (EAVA), Young Research Career Development Award; therefore, Kristýna and Catrin would like to thank the EAVA. The ORCID ID of Catrin Rutland is https://orcid.org/0000-0002-2009-4898.
Conflicts of interest
The authors declare no conflicts of interest.
\n',keywords:"angiotensin, adrenoreceptors, cardiomyopathy, heart disease, endothelin-1, muscarinic receptors, vascular",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72238.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72238.xml",downloadPdfUrl:"/chapter/pdf-download/72238",previewPdfUrl:"/chapter/pdf-preview/72238",totalDownloads:701,totalViews:0,totalCrossrefCites:1,dateSubmitted:"October 17th 2019",dateReviewed:"April 22nd 2020",datePrePublished:"May 19th 2020",datePublished:"July 28th 2021",dateFinished:"May 19th 2020",readingETA:"0",abstract:"The G-protein-coupled receptors (GPCRs, also called seven-transmembrane receptor, 7TMRs, or heptahelical receptor) are a conserved family of seven transmembrane receptors which are essential not only in the healthy heart and blood vessels but also in for treatment and therapy of cardiovascular disease and failure. Heart failure is a global leading cause of morbidity and death and as such understanding 7TMRs, their functions, structures and potential for therapy is essential. This review will investigate the roles of the receptors in the healthy functioning cardiovascular system, and in cardiac disorders with an emphasis in cardiomyopathy. It will also explore the role of autoimmunity and autoantibodies against the G-protein-coupled receptors in cardiomyopathy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72238",risUrl:"/chapter/ris/72238",signatures:"Valentina Kubale, Ewelina Prozorowska, Kristýna Glocová, Lucy Slater and Catrin Sian Rutland",book:{id:"9578",type:"book",title:"Cardiac Diseases",subtitle:"Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions",fullTitle:"Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions",slug:"cardiac-diseases-novel-aspects-of-cardiac-risk-cardiorenal-pathology-and-cardiac-interventions",publishedDate:"July 28th 2021",bookSignature:"David C. Gaze and Aleksandar Kibel",coverURL:"https://cdn.intechopen.com/books/images_new/9578.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-162-2",printIsbn:"978-1-83968-161-5",pdfIsbn:"978-1-83968-163-9",isAvailableForWebshopOrdering:!0,editors:[{id:"71983",title:"Dr.",name:"David C.",middleName:null,surname:"Gaze",slug:"david-c.-gaze",fullName:"David C. Gaze"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",fullName:"Catrin Rutland",slug:"catrin-rutland",email:"catrin.rutland@nottingham.ac.uk",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",fullName:"Valentina Kubale",slug:"valentina-kubale",email:"valentina.kubaledvojmoc@vf.uni-lj.si",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",institution:{name:"University of Ljubljana",institutionURL:null,country:{name:"Slovenia"}}},{id:"315032",title:"Dr.",name:"Ewelina",middleName:null,surname:"Prozorowska",fullName:"Ewelina Prozorowska",slug:"ewelina-prozorowska",email:"ewelina.prozorowska@up.poznan.pl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"315033",title:"Dr.",name:"Kristýna",middleName:null,surname:"Glocová",fullName:"Kristýna Glocová",slug:"kristyna-glocova",email:"GLOCOVAK@VFU.cz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"317649",title:"BSc.",name:"Lucy",middleName:null,surname:"Slater",fullName:"Lucy Slater",slug:"lucy-slater",email:"lucyslater@aol.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cardiovascular effects of 7TMRs and therapeutic drug targets",level:"1"},{id:"sec_2_2",title:"2.1 Adrenoreceptors (β-adrenergic receptors)",level:"2"},{id:"sec_3_2",title:"2.2 Angiotensin II type 1 and 2 receptors",level:"2"},{id:"sec_4_2",title:"2.3 Endothelin-1 (ET-1) receptor",level:"2"},{id:"sec_5_2",title:"2.4 Muscarinic receptors",level:"2"},{id:"sec_7",title:"3. Conclusions",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"},{id:"sec_11",title:"Conflicts of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Foster SR, Roura E, Molenaar P, Thomas WG. G protein-coupled receptors in cardiac biology: Old and new receptors. Biophysical Reviews. 2015;7(1):77-89'},{id:"B2",body:'Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nature Reviews. Molecular Cell Biology. 2002;3(9):639-650'},{id:"B3",body:'Nieto Gutierrez A, McDonald PH. GPCRs: Emerging anti-cancer drug targets. 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Peptides. 2019;111:77-88'},{id:"B65",body:'Hasegawa K, Fujiwara H, Koshiji M, Inada T, Ohtani S, Doyama K, et al. Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension. 1996;27(2):259-264'},{id:"B66",body:'Hiroe M, Hirata Y, Fujita N, Umezawa S, Ito H, Tsujino M, et al. Plasma endothelin-1 levels in idiopathic dilated cardiomyopathy. The American Journal of Cardiology. 1991;68(10):1114-1115'},{id:"B67",body:'Wolf SC, Gaschler F, Brehm S, Klaussner M, Amann K, Risler T, et al. Endothelin-receptor antagonists in uremic cardiomyopathy. Journal of Cardiovascular Pharmacology. 2000;36(5 Suppl 1):S348-S350'},{id:"B68",body:'Kiowski W. The endothelin-type-A receptor in dilated cardiomyopathy: Another key player? European Heart Journal. 2001;22(20):1849-1851'},{id:"B69",body:'Prosek R, Sisson DD, Oyama MA, Biondo AW, Solter PE. Measurements of plasma endothelin immunoreactivity in healthy cats and cats with cardiomyopathy. Journal of Veterinary Internal Medicine. 2004;18(6):826-830'},{id:"B70",body:'Bien S, Riad A, Ritter CA, Gratz M, Olshausen F, Westermann D, et al. The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy. Cancer Research. 2007;67(21):10428-10435'},{id:"B71",body:'Matsubara TJ, Fujiu K. Endothelin-1 and atrial cardiomyopathy. International Heart Journal. 2019;60(2):238-240'},{id:"B72",body:'Song C, Wang S, Guo Y, Zheng X, Lu J, Fang X, et al. Plasma big endothelin-1 predicts new-onset atrial fibrillation after surgical septal myectomy in patients with hypertrophic cardiomyopathy. BMC Cardiovascular Disorders. 2019;19(1):122'},{id:"B73",body:'Wang Y, Tang Y, Zou Y, Wang D, Zhu L, Tian T, et al. Plasma level of big endothelin-1 predicts the prognosis in patients with hypertrophic cardiomyopathy. International Journal of Cardiology. 2017;243:283-289'},{id:"B74",body:'Schwebe M, Ameling S, Hammer E, Monzel JV, Bonitz K, Budde S, et al. Protective effects of endothelin receptor A and B inhibitors against doxorubicin-induced cardiomyopathy. Biochemical Pharmacology. 2015;94(2):109-129'},{id:"B75",body:'Matsa LS, Sagurthi SR, Ananthapur V, Nalla S, Nallari P. Endothelin 1 gene as a modifier in dilated cardiomyopathy. Gene. 2014;548(2):256-262'},{id:"B76",body:'Liefeldt L, Rylski B, Walcher F, Manhart J, Kron S, Rosenke YW, et al. Effects of transgenic endothelin-2 overexpression on diabetic cardiomyopathy in rats. European Journal of Clinical Investigation. 2010;40(3):203-210'},{id:"B77",body:'Dhein S, van Koppen CJ, Brodde OE. Muscarinic receptors in the mammalian heart. Pharmacological Research. 2001;44(3):161-182'},{id:"B78",body:'Yu X, Patterson E, Stavrakis S, Huang S, De Aos I, Hamlett S, et al. Development of cardiomyopathy and atrial tachyarrhythmias associated with activating autoantibodies to beta-adrenergic and muscarinic receptors. Journal of the American Society of Hypertension. 2009;3(2):133-140'},{id:"B79",body:'Iwata M, Yoshikawa T, Baba A, Anzai T, Mitamura H, Ogawa S. Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy. Journal of the American College of Cardiology. 2001;37(2):418-424'},{id:"B80",body:'Rosenbaum MB, Chiale PA, Schejtman D, Levin M, Elizari MV. Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas’ heart disease. Journal of Cardiovascular Electrophysiology. 1994;5(4):367-375'},{id:"B81",body:'Ma G, Wang Y, Hou D, Liu J, Zhang J, Xu L, et al. Association of autoantibodies against the M2-muscarinic receptor with long-term outcomes in peripartum cardiomyopathy patients: A 5-year prospective study. Journal of Cardiology. 2019;74(3):251-257'},{id:"B82",body:'Martinez CG, Zamith-Miranda D, da Silva MG, Ribeiro KC, Brandao IT, Silva CL, et al. P2x7 purinergic signaling in dilated cardiomyopathy induced by auto-immunity against muscarinic M2 receptors: Autoantibody levels, heart functionality and cytokine expression. Scientific Reports. 2015;5:16940'},{id:"B83",body:'Wallukat G, Fu HM, Matsui S, Hjalmarson A, Fu ML. Autoantibodies against M2 muscarinic receptors in patients with cardiomyopathy display non-desensitized agonist-like effects. Life Sciences. 1999;64(6-7):465-469'},{id:"B84",body:'Le Guludec D, Cohen-Solal A, Delforge J, Delahaye N, Syrota A, Merlet P. Increased myocardial muscarinic receptor density in idiopathic dilated cardiomyopathy: An in vivo PET study. Circulation. 1997;96(10):3416-3422'},{id:"B85",body:'Fu ML. Anti-M2 muscarinic receptor autoantibodies and idiopathic dilated cardiomyopathy. International Journal of Cardiology. 1996;54(2):127-135'},{id:"B86",body:'Baba A, Yoshikawa T, Fukuda Y, Sugiyama T, Shimada M, Akaishi M, et al. Autoantibodies against M2-muscarinic acetylcholine receptors: New upstream targets in atrial fibrillation in patients with dilated cardiomyopathy. European Heart Journal. 2004;25(13):1108-1115'},{id:"B87",body:'Juenemann M, Nef H, Mollmann H, Singh P, Troidl C, Schramm P, Kaps M, Gerriets T, Blaes F, Tschernatsch M. No evidence for humoral autoimmunity against cardiomyocytes, adrenergic or muscarinic receptors in patients with tako-tsubo cardiomyopathy. Immunobiology 2019;224(2):220-2'},{id:"B88",body:'Jaue DN, Ma Z, Lee SS. Cardiac muscarinic receptor function in rats with cirrhotic cardiomyopathy. Hepatology. 1997;25(6):1361-1365'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Valentina Kubale",address:null,affiliation:'
Veterinary Faculty, Institute for Preclinical Sciences, University of Ljubljana, Slovenia
School of Veterinary Medicine and Science, Medical Faculty, University of Nottingham, UK
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School of Veterinary Medicine and Science, Medical Faculty, University of Nottingham, UK
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"17",type:"subseries",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. 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