\r\n\tIn the future, with the artificial functional nucleotides, combinatorial chemistry of nucleotides fostering synthetic life would never have been a distant dream.
",isbn:"978-1-80355-628-4",printIsbn:"978-1-80355-627-7",pdfIsbn:"978-1-80355-629-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"365b4a84e87d26bcb24b7183814fba04",bookSignature:"Dr. Arghya Sett",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12176.jpg",keywords:"Next-Generation Sequencing, DNA, RNA, Modified Nucleotides, XNA, Hachimoji Bases, Antisense Oligonucleotides, Biosensor, Theranostic Module, Click Chemistry, Coupling Reactions, Backbone Modifications",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 18th 2022",dateEndSecondStepPublish:"July 19th 2022",dateEndThirdStepPublish:"September 17th 2022",dateEndFourthStepPublish:"December 6th 2022",dateEndFifthStepPublish:"February 4th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"24 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in aptamer oligonucleotide-based molecular diagnostics and therapeutics. Dr. Sett previously worked at the University of Bordeaux, France, with the team of Prof. Jean-Jacques Toulme, and he is currently a Postdoc Research Scientist at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"301899",title:"Dr.",name:"Arghya",middleName:null,surname:"Sett",slug:"arghya-sett",fullName:"Arghya Sett",profilePictureURL:"https://mts.intechopen.com/storage/users/301899/images/system/301899.jpg",biography:"Arghya Sett is a researcher by in Biotechnology who strives towards the integration of technology in the biology research. He is currently working as Postdoc Research Scientist at Institute of Organic Chemistry and Biochemistry AS CR, Prague. He did his PhD on 'Aptamers for Breast cancer protein Biomarkers” from IIT Guwahati, India. During this tenure, his research involved how aptamer-a magic molecule can help in the molecular diagnostics for breast cancer. Then, he moved to University of Bordeaux, France to continue his research with the team of Prof. Jean-jacques Toulme. There, he developed another diagnostic module-light up aptamers to detect pre-micro RNAs for muscular dystrophy. He is a very dynamic researcher and active in collaborative research. He has published more than 11 research articles, review articles, 3 book chapters in reputed International peer-review journals and filed 3 patents in India. He also participated in several international and national conferences. He was also invited to participate in EMBL conference in Heidelberg, Germany to present his work in 2018. His research works on development of low-cost diagnostics drew several media attention and several accolades.",institutionString:"Academy of Sciences of the Czech Republic",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Academy of Sciences of the Czech Republic",institutionURL:null,country:{name:"Czech Republic"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429342",firstName:"Zrinka",lastName:"Tomicic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429342/images/20008_n.jpg",email:"zrinka@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57802",title:"Control of Ribosomal RNA Transcription by Nutrients",doi:"10.5772/intechopen.71866",slug:"control-of-ribosomal-rna-transcription-by-nutrients",body:'\nThe ribosome is a unique machine for synthesizing protein in organisms. Protein synthesis is essential for all biological events, and the quantity of ribosomes substantially affects all biological activities. Rapidly growing cancer cells require synthesis of much protein and thus many ribosomes. In vertebrates, a ribosome consists of about 80 proteins and 4 structural ribosomal RNAs (rRNAs): 5S rRNA, 5.8S rRNA, 18S rRNA, and 28S rRNA [1, 2]. The construction processes are exceedingly complex and include rRNA transcription, rRNA processing, synthesis of ribosome proteins and regulatory proteins, assembly of rRNAs and ribosome proteins, and maturation of the ribosome (\nFigure 1\n). The entire process consumes up to 80% of the cell’s materials [3, 4], and 80% of the energy to proliferate cells [4, 5]. The materials for ribosome production are supplied by nutrients that are taken up from the environment. Therefore, the production of ribosomes is restricted by environmental conditions, and cells should have control of the mechanisms of ribosome production in order to reconcile demands for cell activities with the available biological resources.
\nProcesses of ribosome construction. Ribosomal RNA transcription, processing, and association of ribosomal proteins occur in the nucleolus. Mature ribosome functions in the cytoplasm. The process is outlined in the yellow box on the right side of this figure. Ribosomes contain four structural ribosomal RNAs (rRNAs): 5S rRNA, 5.8S rRNA, 18S rRNA, and 28S rRNA. The first step of ribosome construction is transcription of ribosomal RNA (rRNA) from the ribosome RNA gene (rDNA) repeating units in the nucleolus. RNA polymerase I (Pol I) transcribes pre-rRNA, which is processed to three structured rRNAs (18S, 28S and 5.8S rRNA). 5S rRNA is synthesized by RNA polymerase III. In the mature ribosome, 18S rRNA is contained in the 40S ribosome (small subunit of ribosome), and 28S, 5.8S, and 5S rRNAs are contained in the 60S ribosome (large subunit of ribosome). Ribosomal protein assembly, rRNA processing, and maturation occur in the nucleolus, and ribosomes are exported to the cytoplasm and perform the translation activity.
Three of the four structured rRNAs (18S, 28S, and 5.8S rRNA) constituting ribosomes are produced by processing of a precursor transcript, pre-ribosomal RNA (pre-rRNA). The pre-rRNA is coded by rRNA genes (rDNA) and specifically transcribed by RNA polymerase I (Pol I) in the nucleolus. Because a single copy of rDNA is not sufficient to supply the number of rRNA molecules required, there are 100–300 copies of tandemly repeated rDNAs per haploid genome in mammals. Paradoxically, only half the copies of rDNA are in transcriptionally active forms and the rest are silent, which may provide a control step for rRNA transcription [6, 7, 8, 9]. The transcription of rRNA is an essential step in ribosome biogenesis and affects the total number of ribosomes produced. It was suggested that 75% of total RNAs constitute rRNAs in Hela cells [10], and the rRNA transcription represents about 35% of all transcripts in proliferating cells [6], showing that rRNA synthesis uses a lot of materials. Therefore, the control of rRNA transcription plays a role in maintaining homeostasis in biological resources. In this review, we describe the control of rRNA transcription by various factors such as the cell cycle regulators, signal transduction pathways, growth factors, tumor-related proteins, and cell-damaging stresses. Then, we will discuss the control mechanisms of rRNA transcription in response to nutrients.
\nThe first step of rRNA transcription is the formation of the preinitiation complex (PIC) on the rDNA promoter. The upstream binding factor (UBF), the promoter selective factor 1 (SL1), transcription initiation factor IA (TIF-IA), and RNA polymerase I (Pol I) synergistically assemble at the rDNA promoter to form PIC (\nFigure 2\n). While the name SL1 is used for human proteins, that for mice is transcription initiation factor 1B (TIF-IB). UBF and SL1 bind to an upstream control element (UCE) and the core promoter region of rDNA, respectively. SL1 recruits Pol I through TIF-IA, and UBF stabilizes the binding of SL1 to Pol I at the rDNA promoter [6, 11].
\nPre-initiation complex for RNA polymerase I and rRNA processing. The basic composition of the pre-initiation complex (PIC) for RNA polymerase I is illustrated. PIC is assembled on the rDNA promoter by synergistic action of the upstream binding factor (UBF), which is bound at the upstream control element (UCE), selective factor 1 (SL1), which is bound to the core promoter through TATA-box binding protein (TBP), transcription initiation factor IA (TIF-IA), and RNA polymerase I (Pol I). SL1 contains TBP and Pol I-specific TBP-associated factors (TAFIs: TAFI110, TAFI68, TAFI48, TAFI41, and TAF12). SL1 on the core promoter recruits RNA polymerase I through TIF-IA, which associates with both components of Pol I and SL1. After the completion of PIC formation, Pol I is released from the promoter by regulation of TIF-IA and starts to transcribe pre-rRNA. This release is the initiation step of rRNA transcription. Pre-rRNA is processed to structured rRNA, 18S, 5.8S, and 28S rRNA to construct ribosomes.
SL1 is a protein complex consisting of TATA-box binding protein (TBP), Pol I-specific TBP-associated factors (TAFIs), including TAFI110, TAFI68, and TAFI48, which were originally identified with TBP as essential transcriptional factors by an
Factors regulating PIC formation. The PIC for Pol I transcription is controlled by various factors, including cell cycle signals, signal transduction pathways, stress signals, oncoprotein/tumor suppressors, and others. The classes of regulatory factors are expressed with specific color boxes as indicated in the box on the right. UBF is activated by cdk family proteins, ribosomal protein S6 kinase (S6K), casein kinase II (CK2), and CBP, and is repressed by the Rb/HDAC complex. SL1 is activated by c-Myc, PCAF, and cdc14B, and repressed by p53, SIRT1,cdc2/cyclin B, CK2, PTEN, and GSK3β. TIF-IA is activated by ERK1/2, RSK, mTOR, and CK2 (activated by Akt), and repressed by JNK2 and AMPK. RNA polymerase I (Pol I) is activated by SIRT7 and CBP.
The activities of all classes of RNA polymerases are controlled during the cell cycle progression [14, 15]. The cell cycle regulator cyclin/cdk complexes control the level of rRNA transcription (\nFigure 3\n). In the M phase, SL1 is inactivated by cdk1/cyclin B (cdc2/cyclin B) through phosphorylation of TAFI110 to silence rRNA transcription [16, 17]. On exiting mitosis, the phosphorylation in TAFI110 is removed by cell division cycle 14B (Cdc14B) [18]. Additionally, mitotic repression of rRNA transcription correlates with the hypo-acetylation of TAFI68 caused by Sirtuin 1 (SIRT1). The hypo-acetylation makes SL1 instable on binding to the rDNA promoter [18]. It was also reported that the site of deacetylation of TAFI68 by SIRT1 is acetylated by p300/CBP-associated factor (PCAF), which is correlated with the activation of rRNA transcription [18].
\nAfter mitosis, rRNA transcription is re-activated by G1/S-specific cyclins (cdk4/cyclin D, cdk2/cyclin E, cdk2/cyclin A) through phosphorylation of UBF on the specific sites (cdk4/cyclin D (S484), cdk2/cyclin E (S388, S484), cdk2/cyclin A (S388): in mouse) [19, 20].
\nProtein synthesis is required for cell growth, and the signal transduction pathways that affect cell growth, including phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling and ERK (MAPK) signaling, are involved in the regulation of rRNA transcription (\nFigure 3\n).
\nThe PI3K-AKT-mTOR signal pathway is stimulated by binding of insulin/Insulin-like growth factors (IGF) to their cognate receptors on the cell surface. AKT activates rRNA transcription through the phosphorylation of CK2. CK2 regulates rRNA transcription at multiple levels by affecting the formation of PIC, initiation, elongation, and reinitiation, through phosphorylation of several proteins including UBF, TAFI110 (SL1), and TIF-IA [21, 22, 23, 24, 25, 26]. mTOR activates rRNA synthesis by translocating TIF-IA into the nucleolus using kinase activity [27]. The ribosomal protein S6 kinase (S6K), which is a downstream kinase of mTOR, also activates rRNA synthesis through regulation of UBF-SL1 interaction by phosphorylation of UBF. The mTOR activity also enhances the expression of UBF [28]. SNF2 histone linker PHD RING helicase (SHPRH), which was identified as a RAD5 homolog and known as E3 ubiquitin-protein ligase, binds to rDNA promoters using its PHD domain and promotes recruitment of Pol I to rDNA (\nFigure 4\n). This activation of rRNA transcription by SHPRH is inhibited in an mTOR-dependent manner [29]. K-demethylase 4A (KDM4A)/JMJD2A activates rRNA transcription on serum stimulation (\nFigure 4\n). This activation is mediated through the PI3K/serum/glucocorticoid regulated kinase 1 (SGK1) signaling cascade independent of the AKT pathway. SGK1 is one of the downstream kinases of PI3K signaling. The serum-stimulated KDM4A decreases a repressive histone H3K9me3 mark modification in rDNA to activate rRNA transcription [30]. In mouse adipocytes, polymerase I transcription and release factor (PTRF)/Cavin-1 promotes rRNA transcription, which is induced by insulin and repressed by fasting (\nFigure 4\n). The stimulation of rRNA transcription by PTRF is mediated by the formation of the transcription loop that links the transcriptional start sites and termination sites. The formation may enhance transcriptional reinitiation [31].
\nSignal transduction pathways under growth factor controlled rRNA transcription. Growth factors including insulin, insulin-like growth factor (IGF-1), epidermal growth factor (EGF), and unidentified serum factors (Serum) control rRNA transcription through signal transduction pathways, such as PI3K/mTOR, PI3K/SGK and ERK1/2, which control PIC components (SL1, TIF-IA, and Pol I), transcription factors (PTRF/Carvin-1, c-Myc and SHPRH) or chromatin/nucleosome regulators (lncRNA, NuRD, and KDM2B).
The binding of epidermal growth factor (EGF) or its related ligands to their cognate receptors on the cell surface stimulates a signaling cascade including the GTPase Ras, the kinases Raf, MAP kinase-ERK kinase (MEK), and extracellular signal-regulated kinase (ERK). ERK activates rRNA transcription through phosphorylation of UBF in the promoter [32] and gene body regions [33] (\nFigure 3\n).This phosphorylation decreases the binding capacity of UBF to rDNA. In this case, it was reported that the dissociation of UBF from rDNA enhances Pol I release from the promoter, leading to activation of rRNA transcription. Additionally, ERK/90 kDa ribosomal S6 kinase (RSK) phosphorylates TIF-IA to activate rRNA transcription [34] (\nFigure 3\n). It is still unclear how the phosphorylation by RSK induces rRNA transcription.
\nElevation of the concentration of calcium ions (Ca2+) in the cytoplasm stimulates the signaling pathway of calcium/calmodulin-dependent protein kinase II (CaMKII). The stimulated CaMKII activates S6K, which phosphorylates UBF to activate rRNA transcription in colorectal cancer (CRC) (\nFigure 3\n). In CRC, the function of adenomatous polyposis coli (APC) gene is frequently lost and the level of Ca2+ is increased in the cells [35].
\nSerum, used to supplement the cell culturing medium, contains many factors that control rRNA transcription. Although all factors and signal cascades are not completely identified, they perform critical functions in the regulation of rRNA transcription (\nFigure 4\n).
\nDepletion of serum from a culture medium represses rRNA transcription. c-Myc plays a critical role for cell growth and proliferation in many types of cells, and is deregulated and overexpressed in tumor cells. c-Myc associates with the promoter and transcribed regions of rDNA and activates rRNA transcription in response to serum stimulation [36].
\nK-demethylase 2B (KDM2B)/JHDM1B is bound to rDNA to repress rRNA transcription. The repression is associated with the demethylation of trimethylated lysine 4 on histone H3 (H3K4me3) by KDM2B. Serum starvation increases the recruitment of KDM2B on rDNA, and resupply of serum decreases it. These data suggest that the activity of KDM2B in controlling rRNA transcription is regulated by serum factors [37].
\nThe specific long non-coding RNAs (lncRNAs) are induced during periods of quiescence, such as serum starvation, and increase the level of histone H4K20me3 on the rDNA promoter in a suppressor of variegation 4-20 homolog (Suv4-20 h)-dependent manner. The elevated level of H4K20me3 leads to chromatin compaction. The lncRNAs are antisense transcripts against rDNA, are termed the promoter and pre-rRNA antisense (PAPAS), and associated with rDNA [38].
\nA chromatin remodeling complex, nucleosome remodeling deacetylase (NuRD), establishes the poised state of rDNA through regulation of histone modifications and nucleosome positions. The level of the state of rDNA is increased in the growth-arrested conditions induced by serum starvation and differentiation [39].
\nTumor cells show abnormal growth that is thought to be associated with the elevation of ribosome biogenesis, and regulation of rRNA transcription by oncogenes and tumor-suppressor genes was reported.
\nThe oncoprotein c-Myc is the product of oncogene c-
The
A tumor-suppressor gene,
A variety of stresses such as UV, ionizing radiation, heat shock, and osmotic shock attack cellular vital components like DNA, proteins, and lipid membranes. These stresses also affect rRNA transcription.
\nc-Jun N-terminal kinase (JNK) phosphorylates c-Jun at the NH2-terminal Ser63 and 73 residues in response to UV irradiation and other stress stimuli [54]. JNK2 inactivates rRNA transcription through phosphorylation of TIF-IA to inhibit its function of bridging between Pol I and SL1 [55] (\nFigure 3\n).
\nThe DNA damage caused by ionizing radiation also induces the repression of rRNA transcription through other pathways, which involves Nijmegen breakage syndrome protein 1 (NBS1)-treacle, Ataxia Telangiectasia Mutated (ATM), and breast cancer susceptibility gene I (BRCA1). In the presence of double strand breaks induced by ionizing radiation, NBS1 translocates and accumulates in nucleoli in a treacle-dependent manner to silence rRNA transcription [56]. The
Heat shock at 42°C represses rRNA transcription through the inactivation of TIF-IA by inhibition of CK2-dependent phosphorylation of TIF-IA and the lncRNAs PAPAS-dependent nucleosome regulation by NuRD complex [59]. Hypotonic stress represses rRNA transcription through upregulation of PAPAS to trigger nucleosome repositioning by NuRD [60]. In these conditions, Suv420h2 was neddylated and the levels of Suv420h2 and H4K20me3 marks were increased. However, the relationship between PAPAS and Suv420h2 was not clear. Cytoskeletal stress, which is related to cell shape, represses rRNA transcription through Rho-associated protein kinase (ROCK). ROCK is one of the kinases of myosin and induces recruitment of HDAC on rDNA, resulting in deacetylation of histone acetylated lysine 9 and 14 on histone H3 (H3K9/14) [61].
\nCells obtain biological resources for cellular activities from their environment. The sensing of environmental nutrients is important for efficient usage of nutrients and maintaining cells. In murine intestinal epithelium, apical transcripts are more efficiently translated, because ribosomes were more abundant on the apical sides. Refeeding of fasted mice induces a basal to apical shift of mRNAs encoding ribosomal proteins, which is associated with an increase in their translation and increased protein production. These mechanisms allow efficient nutrient absorption in response to the rich conditions, although the molecular mechanisms are not clear [62]. It was shown that mTOR senses the levels of amino acids, especially leucine, in cells, and controls the translation activity through regulation of the eukaryotic translation initiation factor 4E binding protein (4E-BP)-eukaryotic translation initiation factor 4E (elF4E) axis and p70 S6K-S6 axis [4, 63, 64]. Recently, increasing evidence shows the presence of specific mechanisms to control rRNA transcription in response to nutrients (\nFigure 5\n).
\nGlucose and amino acids control rRNA transcription. Glucose, amino acids, and GTP control rRNA transcription through several pathways, such as ERK, mTOR/S6K, and AMPK, which control PIC components (UBF, SL1, and TIF-IA), transcription factors (c-Myc), or chromatin regulators (KDM2A, PIH1, and SIRT1/NML). High glucose activates ERK and mTOR/S6K pathways to control UBF. High glucose also activates PIH1 to control chromatin. Glucose depletion or low energy conditions activate SIRT1/NML and the AMPK pathway. Activated AMPK controls the activities of TIF-IA and KDM2A. Activated KDM2A controls rDNA chromatin to inhibit rRNA transcription. Amino acid depletion represses the mTOR pathway, resulting in the repression of TIF-IA, and decreases the expression of c-Myc. Guanosine triphosphate (GTP) is bound to TIF-IA, and the binding is required to control rRNA transcription.
The starvation of amino acids affects the frequency of initiation of nucleolar RNA polymerase, which was later established to be an rRNA transcription by Pol I [65]. The starvation of amino acids decreases the interaction of TIF-IA with SL1 and Pol I [66]. As described above in Section 4, mTOR controls rRNA transcription, and is important for regulation of rRNA transcription in response to amino acid levels. Amino acid starvation inhibits the activity of mTOR and its downstream kinase S6K. mTOR and S6K control TIF-IA and UBF, respectively, to regulate rRNA transcription [27, 67].
\nc-MYC is also involved in regulation of rDNA transcription in response to starvation of amino acids. Although translation of c-Myc is reported to be controlled by mTOR signaling [68, 69], the stabilization of c-Myc in response to amino acid starvation is controlled by an mTOR-independent pathway [70].
\nIt was reported that the sizes of ATP and GTP intracellular pools affect the level of nucleolar RNA synthesis (rRNA transcription) [71]. Recently, the consensus sequences for GTP binding were identified in TIF-IA [72], and the binding of TIF-IA to GTP is required for the interaction of TIF-IA with ErbB3-binding protein (Ebp1). Ebp1 controls ribosomal biogenesis when located in the nucleolus [73]. Therefore, the level of GTP appears to be sensed by TIF-IA to affect rRNA transcription (\nFigure 5\n).
\nThe major energy source for cells is glucose. Glucose is used to synthesize ATP. ATP is essential for most biological activities, including ribosome biogenesis. Several studies demonstrated that the levels of glucose and ATP production affect rRNA transcription.
\nRibosomal biogenesis including rRNA transcription was reported to be induced by high glucose treatment or diabetes. A high level of glucose activates UBF through ERK1/2 and mTOR in kidney glomerular epithelial cells of mice [74].
\nThe PIH1 domain-containing protein 1 (PIH1)/Nop17 is reported to enhance rRNA transcription through the recruitment of SNF5-Brg1 complex on the rRNA promoter [75] (\nFigure 5\n). The complex increases acetylation of several histones, except histone H4K16Ac, on rDNA in high glucose conditions. Until now, the acetylation marks of histone in rDNA, excluding the acetylation at K16 in histone H4 (H4K16Ac), are linked to activation of transcription. The acetylated histones function as active marks in transcription in many cases because the acetylation of histone weakens the interaction of histone octamers with DNA, and the acetylated histones are recognized by several transcription-activating factors. On the other hand, the H4K16Ac mark is reported to be recognized by nucleolar remodeling complex (NoRC) in rDNA, which induces chromatin-silencing status [76]. Glucose starvation dissociates PIH1 and the SNF5-Brg1 complex from rDNA and increases histone H4K16Ac marks, which repress rRNA transcription [75]. Another report suggested that PIH1 interacts with mTORC1 to stabilize it, resulting in enhancement of rRNA transcription [77].
\nGlucose starvation decreases ATP production and activates AMPK (\nFigure 5\n). The AMP-activated kinase (AMPK) is known as an energy sensor, which recognizes the ratios of AMP, ADP, and ATP and regulates many phenomena in cells to maintain energy homeostasis.
\nAdditionally, a recent study showed the existence of an AMP/ADP-independent mechanism that triggers AMPK activation (\nFigure 6\n). Glycolysis is a determined sequence of 10 enzyme-catalyzed reactions. In the fourth step, the hexose ring of fructose 1, 6-bisphosphate (FBP) is split by aldolase into two triose sugars: dihydroxyacetone phosphate (a ketose) and glyceraldehyde 3-phosphate (an aldose). When extracellular glucose is decreased, intracellular FBP is decreased, and aldolase unoccupied by FBP promotes the formation of a lysosomal complex containing v-ATPase axin, liver kinase B1 (LKB1), and AMPK, which regulates AMPK activity [78]. These results suggest that the decreased level of the metabolite in glycolysis controls AMPK before the reduction of ATP production just after changing environmental conditions, emphasizing that AMPK is a highly sensitive monitor of energy conditions.
\nControl of methylation by energy status and methyl marks as a reservoir for biological resources. Chromatin components are methylated and demethylated by specific enzymes influenced by metabolites in energy production. Formaldehyde is produced as a demethylation byproduct, directly generates one carbon unit, fuels the folate cycle through alcohol dehydrogenase 5 (ADH5) activity, and can be used as a source for production of SAM, which is used for methylation and nucleotides. AMPK, AMP-activated protein kinase; DHF, dihydrofolate; FBP, fructose 1, 6-bisphosphate; 3PG, 3-phosphoglycerate; SAM, S-adenosylmethionine; THF, tetrahydrofolate.
AMPK induces phosphorylation of TIF-IA (\nFigure 5\n). The phosphorylation of TIF-IA by AMPK reduces interaction of TIF-IA with SL1, decreases the TIF-IA amount on the rDNA promoter, and interrupts PIC assembly, which results in the reduction of rRNA transcription [79].
\nKDM2A, identified as mono- and di-methylated lysine 36 on histone H3 (H3K36me1/2) demethylase [80], is accumulated in the nucleolus and binds to rDNA [81]. The repression of rRNA transcription by KDM2A is induced in response to serum and glucose starvation (\nFigure 5\n). The repression requires the demethylase activity of KDM2A on the rDNA promoter [82]. The KDM2A-dependent regulation affects the levels of protein synthesis [81]. The demethylase activity of KDM2A proceeds with a co-reaction in which α-ketoglutarate (α-KG) is converted to succinate, both of which are organic acids constituting the TCA cycle. Interestingly, the enzyme activity of KDM2A is controlled by cell-permeable succinate (dimethyl succinate: DMS), suggesting that metabolites in the TCA cycle affect KDM2A activity. Recently, it was found that glucose starvation in the presence of serum induces the repression of rRNA transcription by KDM2A, in which activated AMPK induces KDM2A activity [83] (\nFigure 5\n). Interestingly, treatment with a low concentration of the glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces KDM2A-dependent repression of rRNA transcription associated with histone demethylation on the rDNA promoter, although it does not dissociate TIF-IA from the rDNA promoter. Treatment with a high concentration of 2DG induces both the dissociation of TIF-IA from the rDNA promoter and KDM2A-dependent demethylation of the rDNA promoter. These results suggest that the repression of rRNA transcription in response to glucose starvation is performed by two different mechanisms: epigenetic regulation by KDM2A and TIF-IA regulation, depending on the glucose starvation level.
\nAMPK phosphorylates dozens of proteins, but until now KDM2A has not been detected as a substrate of AMPK kinase activity. AMPK also controls the activity of mTOR [84], and mTOR is a candidate kinase for control of the states of histone methylation in the rDNA promoter, but currently there is no evidence connecting mTOR and KDM2A. Further studies are required to determine how the KDM2A activity in the rDNA promoter is induced by AMPK. H3K36me2 on the rDNA promoter which is demethylated by KDM2A on starvation is quickly restored by refeeding glucose and serum [82]. The data suggest that the control of H3K36me2 levels on rDNA promoters is reversible by changes in nutrient status, although which enzyme induces methylation of H3K36me2 on the rDNA promoter in response to refeeding of glucose and serum remains unknown. The control mechanism of rRNA transcription through epigenetic regulation by KDM2A may be a fine tuning device that quickly reflects nutrient states around cells.
\nSirtuins target a wide range of cellular proteins in the nucleus, cytoplasm, and mitochondria for post-translational modification by acetylation (SirT1, 2, 3, and 5) or ADP-ribosylation (SirT4 and 6). The deacetylase activity of sirtuins is controlled by the cellular NAD+/NADH ratio, where NAD+ works as an activator, while nicotinamide and NADH act as inhibitors (\nFigure 7\n). The acetylation regulates a wide variety of cellular functions. Sirtuins participate in various cellular processes, deacetylating both chromatin and non-histone proteins, and their roles in aging have been extensively studied. Sirtuins may also play a critical role in tumor initiation and progression as well as drug resistance. Reduced compounds such as glucose and fatty acids are oxidized, thereby releasing energy. This energy is transferred to NAD+ by reduction to NADH, as part of glycolysis, the citric acid cycle, and β-oxidation. The mitochondrial NADH is then oxidized in turn by the electron transport chain, which generates ATP through oxidative phosphorylation.
\nControl of acetylation by energy status and acetyl marks as a reservoir for biological resources. Chromatin components are acetylated and deacetylated by specific enzymes whose activities are influenced by metabolites in energy production. During deacetylation, the acetyl group from the substrate is accepted by the ribose to produce
SIRT1 was reported to be required for the recruitment of nucleomethylin (NML) on rDNA. In response to glucose starvation, rRNA transcription is repressed through NML-induced chromatin regulation [85]. Although it is not clear that SIRT1 shows deacetylase activity on starvation, SIRT1 induces the deacetylation of p53, and this deacetylation activity is required for the repression of rRNA transcription. Further, the NAD+ synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) modulates the repression of rRNA transcription [86]. As described above, SIRT1 is required for mitotic repression of rRNA transcription through deacetylation of TAFI68 (\nFigure 3\n and section 3). TAFI68 is acetylated by PCAF to restart transcription in the mitotic exit phase [18].
\nOn the other hand, SIRT7, another SIRT family member, was reported to activate rRNA transcription depending on the deacetylation activity, through regulation of PAF53, which is an important component of Pol I complex [87, 88, 89, 90, 91].
\nAcetyl-CoA is used as an acetyl group donor on acetylation of histone and other proteins (\nFigure 7\n). Acetyl-CoA is produced from pyruvate, acetate, or fatty acid oxidation in multiple metabolisms. The amount of acetyl-CoA affects the activity of histone acetyltransferases (HATs). S-adenosylmethionine (SAM) is known to be used as a methyl donor in DNA/histone (protein) methylation (\nFigure 6\n). SAM is produced through the condensation of methionine and ATP by methionine adenosyltransferase (MAT). The production of SAM is mediated through the folate and methionine cycles. The amount of SAM is thought to affect the activity of methylase. The production of the two epigenetic marks is clearly affected by energy production processes, suggesting that intracellular energy conditions affect the modifications of epigenetic marks [92, 93, 94].
\nFurther, enzymes detaching the marks are also affected by metabolites in energy production. NAD+ activates sirtuin deacetylase, while nicotinamide and NADH inhibit the activity (\nFigure 7\n). The demethylase activity of KDM2A is controlled by the amounts of intracellular ATP through AMPK (\nFigure 6\n), and probably more directly by succinate. In another report, chromatin-associated fumarase generating fumarate inhibits the demethylation activity of KDM2A on the promoter region of the RNA polymerase II gene [95]. Additionally, 2-hydroxy-glutarate (2-HG), which was produced from α-KG by a mutant type isocitrate dehydrogenase (IDH) also modulates several jmjC-type enzymes including the lysine-specific demethylases (KDMs) such as KDM2A and Tet methyl-cytosine dioxygenases (TETs) [96, 97, 98]. Therefore, metabolites reflecting intracellular energy conditions can control the enzymes for detaching the epigenetic marks as well as adding them.
\nInterestingly, during deacetylation, the glycosidic bond of the nicotinamide ribose is cleaved to yield nicotinamide, and the ribose accepts the acetyl group from the substrate to produce
Enlarged nucleoli have been recognized as a hallmark of cancer cells [101, 102]. Elevated levels of rRNA transcription and protein synthesis are often observed in cancer cells. These observations suggest the possibility that the control of rRNA transcription could regulate the proliferation of cancer cells. Actually, the anti-cancer effects of some compounds are associated with down-regulation of rRNA transcription. Cisplatin [103], mitomycin C [104], and 5-fluorouracil [105], well-known anti-cancer drugs, are reported to inhibit rRNA transcription [11]. However, it is not clear whether the reduction of rRNA transcription in cancer cells is causal or only as a consequence of inhibition of cell growth.
\nOn the other hand, there are drugs that appear to reduce rRNA transcription and then repress cancer growth. Actinomycin D (Dactinomycin) specifically represses rRNA synthesis at low concentrations through inactivation of transcriptional elongation by Pol I by interaction with GC-rich regions of rDNA, and thus inhibits growth of cancer cells. Actinomycin D is used as a chemotherapy medication to treat a number of types of cancer, including gestational trophoblastic neoplasia [106], Wilms tumor [107], rhabdomyosarcoma [108], Ewing’s sarcoma [109], and malignant hydatidiform mole [110].
\nCX-5461 was identified by screening for selective inhibitors of Pol I but not Pol II transcription. CX-5461 specifically inhibits ribosomal RNA transcription by impairment of SL1 binding to the rDNA promoter [111] and thus exhibits anti-cancer activity [83, 111]. The inhibition of rRNA synthesis by CX-5461 leads to senescence and autophagy in a p53-independent manner in a tumor cell line [111], to activation of p53-dependent apoptotic signaling in Myc-overexpressing B-lymphoma cells (Eμ-Myc lymphoma cells) [112], and to activation of the ATM/Ataxia Telangiectasia and Rad3-related protein (ATR
BMH-21, which was identified by cell-based screening, intercalates into GC-rich sequences, which exist at a high frequency in rDNA, and represses Pol I transcription [115]. Treatment with BMH-21 induces proteasome-dependent degradation of the largest catalytic subunit of Pol I, RPA194, resulting in a decrease of the Pol I level on rDNA. These effects were correlated to the anti-cancer activity of BHM-21. The anti-tumor activity of BMH-21 was demonstrated using human melanoma (A375) and colorectal carcinoma (HCT116) xenograft models with little effect on body weight [115]. These studies suggest that the chemicals that repress the rRNA transcription show anti-cancer activities.
\nEpigenetic controls of rDNA chromatin are also candidates for cancer therapy. For example, specific activation of KDM2A could reduce cancer cell proliferation. Because KDM2A activity is regulated by ATP levels through AMPK and also metabolites in energy production, control of these compound levels may regulate KDM2A activity and cell proliferation. As seen here, there are many elaborate mechanisms for control of rRNA transcription, some of which involve intracellular metabolites, which are produced from environmental nutriments. Further studies of the relationship between rRNA transcription and nutrients will provide information about the mechanisms by which cells reconcile demand and usage of biological resources, and clues for novel methods to treat cancers.
\nThe construction of ribosomes consumes the majority of the cell’s materials and energy. Because the materials for ribosome production are supplied by nutrients, the production of ribosomes is largely restricted by environmental nutrients and cells need mechanisms to control ribosome production in order to reconcile demands for cell activities with available resources. Transcription of rRNA is an essential step in ribosome biogenesis, and strongly affects the total amount of ribosome production. Ribosomal RNA transcription is controlled by many mechanisms, including the efficiency of PIC formation for Pol I and epigenetic marks in rDNA. These are affected by nutrients. Recent studies suggest that the epigenetic marks, such as acetylation and methylation, may be not only controlled by nutrients but also function as reservoirs for biological resources in chromatin. Elevated levels of rRNA transcription and protein synthesis are often observed in cancer cells, and the control of rRNA transcription can regulate their proliferation. Indeed some chemicals that repress the rRNA transcription show anti-cancer activities. Further studies of the relationship between rRNA transcription and nutrients will provide clues for novel methods to treat cancers.
\nThis work was supported by JSPS KAKENHI Grant numbers 17K07798 and 16K07358.
\nAMPK | AMP-activated kinase |
ATM | Ataxia telangiectasia mutated |
Cdk | Cyclin dependent kinase |
CK2 | Casein kinase 2 |
ERK | Extracellular signal-regulated kinase |
FBP | Fructose 1, 6-bisphosphate |
GSK3β | Glycogen synthase kinase 3β |
H3K36me2 | Dimethylated lysine 36 on histone H3 |
H4K20me3 | Trimethylated lysine 20 on histone H4 |
HDAC | Histone deacetylase |
KDM2A | Lysine(K)-specific demethylase 2A |
KDMs | Lysine(K)-specific demethylases |
lncRNAs | Long non-coding RNAs |
mTOR | Mammalian target of rapamycin |
NuRD | Nucleosome remodeling deacetylase |
PAPAS | Promoter and pre-rRNA antisense |
PCAF | p300/CBP-Associated factor |
PI3K | Phosphoinositide 3-kinase |
PIC | Preinitiation complex |
PIH1 | PIH1 domain-containing protein 1 |
Pol I | RNA polymerase I |
pre-rRNA | Pre-ribosomal RNA |
PTEN | Phosphatase and tensin homolog deleted from chromosome 10 |
rDNA | Ribosome RNA gene |
rRNA | Ribosomal RNA |
RSK | ERK/90 kDa ribosomal S6 kinase |
S6K | Ribosomal protein S6 kinase |
SAM | S-adenosylmethionine |
SIRT1 | Sirtuin 1 |
SL1 | Promoter selective factor 1 |
Suv420h2 | Suppressor of variegation 4-20 homolog |
TAFIs | TBP-associated factors for RNA polymerase I |
TBP | TATA-box binding protein |
TIF-IA | Transcription initiation factor IA |
UBF | Upstream binding factor |
Researchers have been attracted by the mystery of human neural development for hundreds of years. Numerous cellular and animal models have been explored to improve our understanding of neurogenesis in humans for hundreds of years. Although animal models have greatly improved our understanding of neural development, neurological disorders, cortical architecture, and functional regionalization, there are significant differences between the human and rodent brains. For example, the organization and behavior of neural progenitors during embryonic development determine the expansion and folding of the human neocortex to a large degree. Therefore, studying the development of the human brain requires models with human brain characteristics. Organoids are simply, self-organized three-dimensional (3D) tissue cultures that are derived from human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which has gained great interest in simulating tissue development and disease. This technology opens a window to observe some of the most elusive aspects of human biology. Compared with animal models or two-dimensional (2D) cell culture systems, 3D-cultured organoids can overcome the differences between species and closely represent the realistic human-specific development features, which can be utilized to mimic the architecture and functionality of the human tissues, having great advantages in explaining the unique human developmental processes [1, 2]. In the field of neurodevelopment and regenerative medicine, neural organoids replicate human specific features of neurodevelopment, contributing to modeling neurogenesis and neurological diseases [3, 4]. Central nervous system (CNS) injury or damage initiates spatial and temporal neurodegeneration, resulting in irreversible neuronal loss and functional deficits. The vertebrate retina is an extension of the CNS that is composed of seven main types of neurons and glial cells. In recent years, emerging organoid-based research studies of brain and retina have made progress in understanding neural organogenesis, which facilitates successful application of 3D organoid systems in disease modeling and regenerative medicine. In this chapter, we summarize the application of neural organoids of the brain and retina in neurodevelopment and regenerative medicine.
CNS is generally regarded as the most complex system in human body. Limited by accessibility of living neural tissues and ethical challenges, human-specific features of neurodevelopment and neurological diseases remain largely unknown to us. Recent advances in stem cell technologies and 3D culture neural organoids have opened a new avenue in exploring the mechanisms of neurodevelopment. Early versions of the neural organoids range from complex neural epithelial structures to disorganized brain regions with large cellular diversity [5]. By supplementing exogenous factors and assembly of organoids during embryonic brain development, efforts have been made to gain the well-developed multilayer neural organoids and higher-order functions in terms of controlling patterning, morphogenesis, and function [6, 7].
Through the embryonic brain development, neural progenitors progressively follow precise orchestration and coordination to acquire their spatial identities, a process characterized by successive changes in cellular composition and cytoarchitecture (Figure 1a). Dysregulation of this process may affect neurogenesis, synaptogenesis, and myelination and induce neurological or psychiatric disorders. To better investigate the early formation and function of the human brain
Schematic depiction of brain and eye development
The 3D cultured brain organoids have been proven useful for many applications in basic research, for example, the development of the human brain cortex. It firstly begins with the expansion of the neuroepithelium, and then folds into six different layers. The main principles of the cortical layer formation are similar between mammals, such as primates and humans; however, the morphological differences are unneglectable. It is well known that neuronal number in primates massively increases in cortical surface, which eventually leads to the gyrification of the cortex (the generation of gyri and sulci) [11]. However, the mechanisms controlling the generation of gyrification are still not clear during the formation of cortical areas. The application of cortical organoids has helped us better understand the rapid expansion of human neocortex and the formation of cerebral cortical sulcus and gyrus. Karzbrun et al. revealed two opposing mechanical forces with the usage of the brain organoids-on-a-chip: the middle cytoskeletal contraction and peripheral cell-cycle-dependent nuclear expansion, physically leading to differential growth and folding into brain wrinkling [12], and the extracellular matrix (ECM) components are implicated in neocortical expansion [13].
For another example, brain organoids are used to investigate the development of cellular interactions in the human brain. The human CNS originated from several distinct vesicles and then after a range of progenitors migrate and integrate, it moves into areas to generate multiple intertwined regions, ultimately resulting in emerging complex networks, neurons branching, and projecting. To model the intricate cellular interactions in human brain, fusing regionalized organoids into assembloids recapitulates more elaborate biological processes of brain development. This approach has been applied to study forebrain axis establishment, interneuron migration, oligodendrogenesis, and neuronal projections like the fused dorsal-ventral cerebral organoids to model interneuron migration in [7, 14, 15].
The eye originates from the ventral diencephalon, where a group of eye field transcription factors (EFTFs) are highly expressed such as PAX6, RAX, SIX3, and OTX2, and becomes specified as the eye field [16]. The eye field region is firstly split into optic vesicles in pairs and subsequently forms the optic cup by experiencing the valgus and invagination of the optic vesicle. The outer layer of the optic cup develops into retinal pigment epithelium(RPE) while the inner layer develops into neural retina. The neural retina with multilayered structure undergoes different phases of development, with different types of cells differentiating and maturing over the time (Figure 1a).
However, the understandings of the function and development of the human retinal are limited by scarce human fetal retina sample and species differences between animals and human. Since 2011, Sasai et al. released a landmark study to generate a self-organized 3D optic cup with layered neuroepithelia from mouse pluripotent stem cells (mPSCs), which opened a window for generating retinal models [17]. Many research groups have subsequently optimized the protocol to generate human retinal organoids derived from hPSCs. During retinal organoid generation, stem cell patterns the eye field-like regions expressing a complete component of the EFTFs to mimic the optic vesicle in early development [18]. What is encouraging, these tiny retinal organoids even contain almost all relevant retinal cell types: retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, Müller cells, and photoreceptors.
RGCs, the early-born neurons, transmit visual information between the eye and the brain, playing a critical role in retinal neuronal outputs. The loss of RGCs trends to result in a group of degenerative diseases such as glaucoma and optic nerve hypoplasia. Due to the specific time point of the RGC development, it is a challenge to obtain human fetus samples. In addition, the long-distance projection of neurites is the mostly important characteristic for RGC development as the extension of axons is regulated by extrinsic factors, including the ECM, growth factors, and glial cells. Recent several approaches have improved the capacity to differentiate hPSC-derived retinal organoids into RGCs that possess appropriate morphological and functional properties [19]. For example, Fligor et al. found that substrate composition including laminin and Matrigel shows the most conducive for RGC neurite outgrowth; similarly, the growth factors with Netrin-1 and BDNF have the ability to guide and direct RGC axons outgrowth [20]. Besides, single-cell RNA sequencing (RNA-seq) results proved that the ganglion cells of retinal organoids at day 60 give the similar clusters to the human fetal retina on day 59 [21]. Collectively, the established retinal organoids serve as effective models for investigations of RGC development and disease modeling and as a valuable tool for cell replacement.
Rod and cone photoreceptors are specialized neurons with functioning in the initial step of vision, which convert light stimuli into neurological responses. Rods are highly sensitive to light and operate under dim lighting conditions while the cones control color vision and high visual acuity. It is reported that the progressive loss of photoreceptors leads to blindness-associated inherited retinal diseases(IRDs), such as well-known retinitis pigmentosa (RP), congenital stationary night blindness(CSNB), and Leber congenital amaurosis (LCA). Therefore, it is particularly important to understand retinal progenitor fate choices toward rod photoreceptors and cone subtypes during retinogenesis. As such, the phototransduction mechanism requires a complicated cascade of gene regulatory networks. Aiming to induce hPCS-derived retinal organoids with mature photoreceptors, efforts of genetic manipulation and transcriptomic analysis have become the focal point for researchers [22]. Most recently, NRL (neural retina leucine zipper)-/- human-based 3D organoids were used to uncover the regulative role of MEF2C in cones’ development [22]. RNAseq analysis of hPCS-derived retinal organoids has identified certain molecular signatures related with human photoreceptors development [23]. In brief, these observations and datasets have enabled to reconstruct developmental trajectories and recapitulate dynamics
Neural organoids, which recapitulate the process of native neurogenesis in the development of CNS, have been applied in a large variety of areas including simulating brain development and retinogenesis. Moreover, emerging organoid-based cell transplantation has made considerable progress in reconstruction of lost neural circuits, damaged neural cortex and visual function, which facilitates the application of 3D organoid systems in disease modeling and regenerative medicine. Representative examples are involved in two aspects: (a) isolating neural progenitor cells (NPCs) from neural organoids; (b) transplanting neural organoids in immunodeficient animals. The stem cells in the organoids derived from hPSCs present a higher survival rate and closer connection with the surrounding tissues in the host. Distinct from conventional stem cell therapy usually focusing on specific populations of stem cells or NPCs, neural organoids offer an entire set of cell types of the human organs.
Brain disorders, such as Alzheimer\'s disease (AD), Parkinson\'s disease (PD), traumatic brain injury (TBI), and stroke, along with several other chronic neurodegenerative disorders, are debilitating diseases that have few treatment options. Stem cell therapy is likely to provide beneficial effects for the indications of these diseases. The current understanding of brain diseases is mainly based on traditional 2D monocultural cells, animal models, and postmortem examination. Because of the inherent species differences between animals and humans and the individual differences among genetic and environmental backgrounds, it remains a challenge to investigate brain development and associated disorders. To establish better models of human brain development, stem-cell-based 3D brain organoids systematically decipher the developmental rules, presenting the 3D architectures and physiology of the brain. These generated brain organoids show robust neuronal subtypes and glial subtypes and functionality to mimic
Recently, in two studies, scientists transplanted hPSC-derived cerebral organoids into mouse cerebral cortex and successfully generated vascularized organoids, which promoted the progressive neuronal differentiation and maturation and increased cell survival [26, 27]. They observed the widespread axonal extension and precise synaptic connectivity outside the graft area; however, the region-specific long projections and synaptogenesis mapping were not reported in the two studies. Previously, reported approaches produced brain organoids with large lumens and tubes, which results in insufficient oxygen and nutrients support in increasing metabolic needs, making them difficult to apply in transplantation therapy [10, 28]. Recently, an optimized culture protocol was developed to efficiently generate small human cerebral organoids, which presents the benefit of alleviating the risk of cell overgrowth and safety concerns after injecting into the mouse medial prefrontal cortex [29]. The transplanted cerebral organoids extended projections to basal brain regions and generated human glutamatergic neurons with mature electrophysiology [29]. Moreover, mice transplanted with cerebral organoids show potentiated auditory startle fear response, indicating that the organoids can be functionally integrated into preexisting host mouse neural circuits via building up bidirectional synaptic connections, which provides crucial therapeutic strategy for neurological diseases [29].
However, owing to the cellular composition of brain, organoids dramatically changes along the time course of the development, it is necessary to demonstrate which stage of the organoids is best suitable for transplantation. To address this limitation, Kitahara et al. transplanted hESC-derived cerebral organoids at 6w or 10w into mouse cerebral cortex and found that 6w-organoids extend more axons along corticospinal tracts but caused graft overgrowth with higher populations of proliferative cells while axonal extensions from 10w-organoids were smaller in number but enhanced after brain injury 1 week [30]. A similar study reported that 55d and 85d-cerebral organoids were transplanted into damaged motor cortex, indicating that 55d-cerebral organoids can be used as a better transplantation donor for traumatic brain injury (TBI) [31]. Cells from the transplanted cerebral organoids have the capability to support region-specific reconstruction of damaged brain cortex, upregulate hippocampal neural connection protein and neurotrophic factor, and improve of damaged motor cortex. It is also reported that cerebral organoids were transplanted at 55 days to explore the feasibility of organoid transplantation in stroke [32]. Cerebral organoids were transplanted at 6 h or 24 h after middle cerebral artery occlusion (MCAO) surgery, resulting in reducing brain infarct volume and improving neurological motor function. Furthermore, they also observed that the transplanted cerebral organoids were also related with increased neurogenesis, synaptic reconstruction, axonal regeneration and angiogenesis, decreased neural apoptosis, and rescued more survival neurons after stroke [32]. Although a few works with respect to transplanting brain organoid system were reported, it still has promising technologies in the future treatment of central nervous system diseases. Hence, the effects of the developmental organoid stage and host brain environment should be accurately evaluated when developing an organoid-replacement therapy for brain injury.
Retinal degenerative diseases, such as glaucoma, RP, and Age-Related Macular Degeneration (AMD), usually lead to irreversible blindness. So does the importance of finding a viable treatment. Regardless of the underlying etiology of retinal degeneration, the common endpoint is the loss of photoreceptors and underlying RPE. Cell replacement strategy provides a good solution for the treatment of retinal degeneration. Although plenty of studies have been made to understand the cellular and molecular mechanisms of retinal disorders, our knowledge is still in its infancy, and the immortalized retinal cell lines have not recapitulated the developmental stages of the human native retina. The new methodological advances in inducing hPSCs into human retina tissues have opened new possibilities for basic research on investigating the therapies or treatments in regenerative medicine [18, 33]. The generated retinal organoids closely resemble many aspects of the real human retina, including retina-specific ribbon synapse [34] and physiological-relevant response to light stimuli [35], which empower researchers to explore the pathogenesis of retinal diseases and pursue cell/tissue transplantation for developing novel treatment options. Because retinal organoids contain all the cell types of human retina, it plays a primary role in the field of transplantation therapy. In this section, we focus on single-cell suspensions isolated from retinal organoids and application of retinal organoids sheets transplantation used for cell therapies in regenerative medicine (Figure 1b).
During the previous decade, the aborted human fetal tissues and the hPSC-derived retinal progenitors were two cell sources for transplantation. Representative retinal cell replacement clinical trials are transplantation of hPSC-derived RPE for the treatment of retinal diseases, including AMD and Stargardt disease [36, 37, 38]. It has been proved that the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. In 2006, stem-cell-derived precursor photoreceptors were first integrated into the outer retinal layer of degenerating retina and had success in improving vision [39, 40]. However, the strong ethical restrictions and limited cell sources remain a challenge in current transplantation therapies. The retinal organoids that contain abundant retinal progenitor cells (RPCs) can act as an ideal cell source transplantation in retinal degenerative diseases. Zou et al. transplanted effectively purifying RPCs with the surface markers (C-Kit+/SSEA4−) into the retinal degeneration models of rats and mice, showing benefits to the improvement of vision and preservation of the retinal structure [41]. The RGCs are the earliest differentiated cells closely associated with glaucoma. But the population of RGCs in retinal organoids is not substantial as they gradually degenerate following long-term culture time. Thus, prolonging the survival time of RGCs may provide the possibility for RGC replacement therapy. Several approaches have been taken to improve the short life of implanted RGCs and the length of axons, such as adding extrinsic growth factors [20], combining 2D and 3D protocols [42], and co-culturing with Müller glia [43]. In another animal study, by transplanting purified rod photoreceptors isolated from retinal organoids in defective S- and M- cone opsins, Nrl-/- mouse retinas can restore rod-mediated visual function and be incorporated into the host retina with forming synaptic-like structures in close apposition to mouse interneurons [44]. Interestingly, recent studies contradicted the common view that transplanted photoreceptors integrate into the photoreceptor layer of recipients. They demonstrated that the material transfer between donor rod photoreceptors and host photoreceptors leads to the acquisition of proteins originally expressed only by donor cells [45, 46]. Thus, the mechanism of the photoreceptor transplantation demands reinterpretation.
A retinal sheet derived from cultured retinal organoids or fetal retina is another approach to preserving the neural circuitries and improving visual function. Cell suspension strategies consist of transplanting purified photoreceptor precursor cells, whereas retinal sheet transplantations engraft retinal organoids containing both photoreceptor cells and inner retinal neurons. The inner neurons located in the transplanted retinal sheet, which serves as a scaffold and nurturing microenvironment, are conductive to outer layer retinal cells in differentiation and maturation, preserving normal lamination structures. It is reported that the retinal sheet graft can produce less immune activation that enhances life span and the survival rate of transplanted cells, providing suitability approach for therapies of late-stage retinal diseases.
Furthermore, several studies have demonstrated that the transplantation of hPSC-derived RPE cells in AMD patients shows promising outcomes in clinical trials, such as improvement in retinal integrity, maintainability in visual acuity, and increase in vision-related quality of life [47]. Currently, the transplantation of early-stage retinal organoid sheets is verified to establish connections more effectively with host retinal degeneration, and these connections show higher survival rate over time. A series of studies have been performed to investigate whether the transplantation of retinal organoid sheets can differentiate, integrate, and improve visual function in animal models with severe retinal degeneration [48, 49, 50]. In 2016, Shirai et al. dissected “retinas” from organoids to get transparent and continuous neural retina sheets and transplanted them into two primate models with retinal degeneration. In both monkey and rat, grafted hESC-retina differentiated into a range of retinal cell types, such as photoreceptors. The photoreceptors were proved to have migrated to the outer nuclear layer and the host-graft synaptic connections were established in those animal models [51]. Similar results were achieved in another study of transplanting the sheets dissected from hESC-derived retinal organoids into retinal degenerate rats [48]. In addition, to enhance functional integration of transplanted retinal sheet, a method in which a genetic modification was used to reduce ON-bipolar cells resulted in efficiently restoring RGC light responsiveness in degenerated retina [52]. However, in those studies, the absence of a well-defined RPE monolayer presents a main limiting factor for retinal sheet transplantation. To overcome this limitation, hESC-derived retinal organoids and RPE monolayer were combined using different bio-adhesives to transplant into immunodeficient Royal College of Surgeons (RCS) rats. The co-grafts were observed to reconstruct the severely damaged retina structure and improve visual function [53]. Those studies demonstrate the clinical feasibility of hPSC-derived retinal organoids sheet transplantation and provide practical tools to optimize transplantation strategies for future clinical applications.
In retinal tissue engineering, biomaterials are utilized to optimize the models of the human retina. A growing number of biomaterials, especially synthetic polymer scaffolds, such as biodegradable polycaprolactone (PCL) and polylactic-coglycolic acid (PLGA), have been widely used. The remarkable properties of defined synthetic polymer substrate are thin and biodegradable, which can be placed into the retinal subretinal space with minimal physical distortion [54]. In terms of the report, transplanting mouse RPCs cultured on biodegradable thin-film PCL scaffolds with varying surface topographies into the retinal subretinal space help newly integrated mRPCs exhibit potential to guide stem cell differentiation toward photoreceptor fate and to help cells localized to the outer nuclear layer [55]. Another study implanted the human retinal organoids, which are seeded on PLGA sheets into both normal and Chronic Ocular Hypertension (OHT) rhesus monkey retinas. They found that despite the need of immunosuppression for dexamethasone after transplantation, survival and differentiation into retinal tissue were successfully improved [56]. Subsequently, the same group proved again that with the support of PLGA sheets, retinal organoids showed active proliferation, migration and projection of axons into the host optic nerve after transplanting into OHT rhesus monkey eyes [57].
Development of neural organoid techniques has yielded rapid progress in clarifying the mechanisms of human neural development. Organoids display many characteristics of the organs from which they were made, including cellular anatomy and interaction, genetics, and specific tissue functions, advancing our understanding the neuro of biology, developmental science, and regeneration. Some of the limitations and challenges of neural organoids have been addressed, but emerging technologies are still required to be applied in further study. With respect to brain organoids, many points are needed to be improved, such as the maturation of neuronal and glial cells, reliable anatomical organization, long-range axonal projection and synaptic connections, and the precise construction of neuronal circuits. Providing a physiologically relevant microenvironment and the more complex whole-brain organoids to reproduce the developmental events of the human nervous systems may be needed in the future. Retinal organoids serve as an ideal choice for therapeutic transplantation, which still face many challenges as following: low yield, high heterogeneity, degenerative inner cell layers, and cancerogenesis. The next-generation retinal organoids would be anticipated to have an integrated vascular network, mature microglia system, and pigment layer wrapping around as well as the integration of bioengineering technologies. To achieve the goal, several engineering approaches may be useful: (1) engineered biomaterials to investigate cell-cell and cell-matrix interactions; (2) genetic engineering technology to study various aspects of organoids development and performance; (3) organoid-on-a-chip device to create an optimal microenvironment with the purpose of generating organoids with higher physiological relevance. Furthermore, the next generation of organoids probably needs to integrate more bioengineering technologies, aiming to overcome each approach’s limitation and provide a superior, synergistic approach for constructing more complex organoids in regenerative and precision medicine.
The authors declare no conflicts of interest.
This study was supported by the funding from the National Key Research and Development Program of China (Grant No. 2018YFA0107302); the National Natural Science Foundation of China (Grant No. 31930068); and the Military Key Program (Grant No. 20QNPY025).
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Plant cell and organ culture systems are feasible option for the production of secondary metabolites that are of commercial importance in pharmaceuticals, food additives, flavors, and other industrial materials. The stress, including various elicitors or signal molecules, often induces the secondary metabolite production in the plant tissue culture system. The recent developments in elicitation of plant tissue culture have opened a new avenue for the production of secondary metabolite compounds. Secondary metabolite synthesis and accumulation in cell and organ cultures can be triggered by the application of elicitors to the culture medium. Elicitors are the chemical compounds from abiotic and biotic sources that can stimulate stress responses in plants, leading to the enhanced synthesis and accumulation of secondary metabolites or the induction of novel secondary metabolites. Elicitor type, dose, and treatment schedule are major factors determining the effects on the secondary metabolite production. The number of parameters, such as elicitor concentrations, duration of exposure, cell line, nutrient composition, and age or stage of the culture, is also important factors influencing the successful production of biomass and secondary metabolite accumulation. This chapter reviews the various abiotic and biotic elicitors applied to cultural system and their stimulating effects on the accumulation of secondary metabolites.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Poornananda M. Naik and Jameel M. Al–Khayri",authors:[{id:"176282",title:"Prof.",name:"Jameel M.",middleName:null,surname:"Al-Khayri",slug:"jameel-m.-al-khayri",fullName:"Jameel M. 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Due to advances in molecular approaches during the last decades, nowadays it is possible to develop economically important transgenic crops that have increased tolerance to stresses. This chapter discusses the oxidative stress and damage to plants. In addition, it reports the involvement of antioxidant enzymes in the tolerance of plants to various stresses.",book:{id:"5066",slug:"abiotic-and-biotic-stress-in-plants-recent-advances-and-future-perspectives",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives"},signatures:"Andréia Caverzan, Alice Casassola and Sandra Patussi Brammer",authors:[{id:"176303",title:"Dr.",name:"Alice",middleName:null,surname:"Casassola",slug:"alice-casassola",fullName:"Alice Casassola"},{id:"176409",title:"Dr.",name:"Andréia",middleName:null,surname:"Caverzan",slug:"andreia-caverzan",fullName:"Andréia Caverzan"},{id:"176410",title:"Dr.",name:"Sandra",middleName:null,surname:"Patussi Brammer",slug:"sandra-patussi-brammer",fullName:"Sandra Patussi Brammer"}]}],mostDownloadedChaptersLast30Days:[{id:"66996",title:"Ethiopian Common Medicinal Plants: Their Parts and Uses in Traditional Medicine - Ecology and Quality Control",slug:"ethiopian-common-medicinal-plants-their-parts-and-uses-in-traditional-medicine-ecology-and-quality-c",totalDownloads:4037,totalCrossrefCites:5,totalDimensionsCites:10,abstract:"The main purpose of this review is to document medicinal plants used for traditional treatments with their parts, use, ecology, and quality control. Accordingly, 80 medicinal plant species were reviewed; leaves and roots are the main parts of the plants used for preparation of traditional medicines. The local practitioners provided various traditional medications to their patients’ diseases such as stomachaches, asthma, dysentery, malaria, evil eyes, cancer, skin diseases, and headaches. The uses of medicinal plants for human and animal treatments are practiced from time immemorial. Stream/riverbanks, cultivated lands, disturbed sites, bushlands, forested areas and their margins, woodlands, grasslands, and home gardens are major habitats of medicinal plants. Generally, medicinal plants used for traditional medicine play a significant role in the healthcare of the majority of the people in Ethiopia. The major threats to medicinal plants are habitat destruction, urbanization, agricultural expansion, investment, road construction, and deforestation. Because of these, medicinal plants are being declined and lost with their habitats. Community- and research-based conservation mechanisms could be an appropriate approach for mitigating the problems pertinent to the loss of medicinal plants and their habitats and for documenting medicinal plants. Chromatography; electrophoretic, macroscopic, and microscopic techniques; and pharmaceutical practice are mainly used for quality control of herbal medicines.",book:{id:"8502",slug:"plant-science-structure-anatomy-and-physiology-in-plants-cultured-in-vivo-and-in-vitro",title:"Plant Science",fullTitle:"Plant Science - Structure, Anatomy and Physiology in Plants Cultured in Vivo and in Vitro"},signatures:"Admasu Moges and Yohannes Moges",authors:[{id:"249746",title:"Ph.D.",name:"Admasu",middleName:null,surname:"Moges",slug:"admasu-moges",fullName:"Admasu Moges"},{id:"297761",title:"MSc.",name:"Yohannes",middleName:null,surname:"Moges",slug:"yohannes-moges",fullName:"Yohannes Moges"}]},{id:"63148",title:"Domestic Livestock and Its Alleged Role in Climate Change",slug:"domestic-livestock-and-its-alleged-role-in-climate-change",totalDownloads:15893,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"It is very old wisdom that climate dictates farm management strategies. In recent years, however, we are increasingly confronted with claims that agriculture, livestock husbandry, and even food consumption habits are forcing the climate to change. We subjected this worrisome concern expressed by public institutions, the media, policy makers, and even scientists to a rigorous review, cross-checking critical coherence and (in)compatibilities within and between published scientific papers. Our key conclusion is there is no need for anthropogenic emissions of greenhouse gases (GHGs), and even less so for livestock-born emissions, to explain climate change. Climate has always been changing, and even the present warming is most likely driven by natural factors. The warming potential of anthropogenic GHG emissions has been exaggerated, and the beneficial impacts of manmade CO2 emissions for nature, agriculture, and global food security have been systematically suppressed, ignored, or at least downplayed by the IPCC (Intergovernmental Panel on Climate Change) and other UN (United Nations) agencies. Furthermore, we expose important methodological deficiencies in IPCC and FAO (Food Agriculture Organization) instructions and applications for the quantification of the manmade part of non-CO2-GHG emissions from agro-ecosystems. However, so far, these fatal errors inexorably propagated through scientific literature. Finally, we could not find a clear domestic livestock fingerprint, neither in the geographical methane distribution nor in the historical evolution of mean atmospheric methane concentration. In conclusion, everybody is free to choose a vegetarian or vegan lifestyle, but there is no scientific basis, whatsoever, for claiming this decision could contribute to save the planet’s climate.",book:{id:"7491",slug:"forage-groups",title:"Forage Groups",fullTitle:"Forage Groups"},signatures:"Albrecht Glatzle",authors:[{id:"252990",title:"Dr.",name:"Albrecht",middleName:null,surname:"Glatzle",slug:"albrecht-glatzle",fullName:"Albrecht Glatzle"}]},{id:"66714",title:"Biotic and Abiotic Stresses in Plants",slug:"biotic-and-abiotic-stresses-in-plants",totalDownloads:5794,totalCrossrefCites:54,totalDimensionsCites:96,abstract:"Plants are subjected to a wide range of environmental stresses which reduces and limits the productivity of agricultural crops. Two types of environmental stresses are encountered to plants which can be categorized as (1) Abiotic stress and (2) Biotic stress. The abiotic stress causes the loss of major crop plants worldwide and includes radiation, salinity, floods, drought, extremes in temperature, heavy metals, etc. On the other hand, attacks by various pathogens such as fungi, bacteria, oomycetes, nematodes and herbivores are included in biotic stresses. As plants are sessile in nature, they have no choice to escape from these environmental cues. Plants have developed various mechanisms in order to overcome these threats of biotic and abiotic stresses. They sense the external stress environment, get stimulated and then generate appropriate cellular responses. They do this by stimuli received from the sensors located on the cell surface or cytoplasm and transferred to the transcriptional machinery situated in the nucleus, with the help of various signal transduction pathways. This leads to differential transcriptional changes making the plant tolerant against the stress. The signaling pathways act as a connecting link and play an important role between sensing the stress environment and generating an appropriate biochemical and physiological response.",book:{id:"8015",slug:"abiotic-and-biotic-stress-in-plants",title:"Abiotic and Biotic Stress in Plants",fullTitle:"Abiotic and Biotic Stress in Plants"},signatures:"Audil Gull, Ajaz Ahmad Lone and Noor Ul Islam Wani",authors:null},{id:"62573",title:"Introductory Chapter: Terpenes and Terpenoids",slug:"introductory-chapter-terpenes-and-terpenoids",totalDownloads:7547,totalCrossrefCites:27,totalDimensionsCites:51,abstract:null,book:{id:"6530",slug:"terpenes-and-terpenoids",title:"Terpenes and Terpenoids",fullTitle:"Terpenes and Terpenoids"},signatures:"Shagufta Perveen",authors:[{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"},{id:"192994",title:"Dr.",name:"Areej",middleName:null,surname:"Al-Taweel",slug:"areej-al-taweel",fullName:"Areej Al-Taweel"}]},{id:"62876",title:"Introduction to Phytochemicals: Secondary Metabolites from Plants with Active Principles for Pharmacological Importance",slug:"introduction-to-phytochemicals-secondary-metabolites-from-plants-with-active-principles-for-pharmaco",totalDownloads:5789,totalCrossrefCites:10,totalDimensionsCites:25,abstract:"Phytochemicals are substances produced mainly by plants, and these substances have biological activity. In the pharmaceutical industry, plants represent the main source to obtain various active ingredients. They exhibit pharmacological effects applicable to the treatment of bacterial and fungal infections and also chronic-degenerative diseases such as diabetes and cancer. However, the next step in science is to find new ways to obtain it. In this chapter, we discuss about the main groups of phytochemicals, in addition to presenting two case studies. One of the most important secondary metabolites is currently Taxol, which is a natural compound of the taxoid family and is also known for its antitumor activity against cancer located in breasts, lungs, and prostate and is also effective with Kaposi’s sarcoma. Our case studies will be about Taxol, extracted from an unexplored plant species, and the production of Taxol by its endophytic fungi.",book:{id:"6794",slug:"phytochemicals-source-of-antioxidants-and-role-in-disease-prevention",title:"Phytochemicals",fullTitle:"Phytochemicals - Source of Antioxidants and Role in Disease Prevention"},signatures:"Nadia Mendoza and Eleazar M. Escamilla Silva",authors:[{id:"51406",title:"Dr.",name:"Eleazar",middleName:"Máximo",surname:"Escamilla Silva",slug:"eleazar-escamilla-silva",fullName:"Eleazar Escamilla Silva"},{id:"243304",title:"Ph.D. Student",name:"Nadia",middleName:null,surname:"Mendoza",slug:"nadia-mendoza",fullName:"Nadia Mendoza"}]}],onlineFirstChaptersFilter:{topicId:"41",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81798",title:"Protein Metabolism in Plants to Survive against Abiotic Stress",slug:"protein-metabolism-in-plants-to-survive-against-abiotic-stress",totalDownloads:29,totalDimensionsCites:0,doi:"10.5772/intechopen.102995",abstract:"Plants are frequently subjected to several abiotic environmental stresses under natural conditions causing profound impacts on agricultural yield and quality. Plants can themselves develop a wide variety of efficient mechanisms to respond environmental challenges. Tolerance and acclimation of plants are always related to significant changes in protein, cellular localization, posttranscription, and posttranslational modifications. Protein response pathways as well as pathways unique to a given stress condition shared by plants under different stressed environment are discussed in this chapter. The various signaling of protein such as fluctuation, overexpression, and silencing of the protein gene are observed to be modulated in drought-tolerant plants. Similarly, gene expression, RNA processing, and metabolic process take place to cope with drought conditions. For adaption in water-submerged conditions, plants undergo reactive oxygen species (ROS), cell wall modification, proteolysis, and post-recovery protein metabolism. Heat shock protein and protein and lipid contents vary and play pivotal role in resisting low and high temperatures. In a nutshell, this paper provides an overview of several modification, synthesis, degradation, and metabolism of protein in plants to cope with and revive again to normal growing conditions against abiotic stress, emphasizing drought, submerged, extreme cold, and heat temperatures.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Bharti Thapa and Abhisek Shrestha"},{id:"80923",title:"Salt Stress Tolerance in Rice and Wheat: Physiological and Molecular Mechanism",slug:"salt-stress-tolerance-in-rice-and-wheat-physiological-and-molecular-mechanism",totalDownloads:70,totalDimensionsCites:0,doi:"10.5772/intechopen.101529",abstract:"Salinity is a major obstacle to global grain crop production, especially rice and wheat. The identification and improvement of salt-tolerant rice and wheat depending upon the genetic diversity and salt stress response could be a promising solution to deal with soil salinity and the increasing food demands. Plant responses to salt stress occur at the organismic, cellular, and molecular levels and the salt stress tolerance in those crop plant involving (1) regulation of ionic homeostasis, (2) maintenance of osmotic potential, (3) ROS scavenging and antioxidant enzymes activity, and (4) plant hormonal regulation. In this chapter, we summarize the recent research progress on these four aspects of plant morpho-physiological and molecular response, with particular attention to ionic, osmolytic, enzymatic, hormonal and gene expression regulation in rice and wheat plants. Moreover, epigenetic diversity could emerge as novel of phenotypic variations to enhance plant adaptation to an adverse environmental conditions and develop stable stress-resilient crops. The information summarized here will be useful for accelerating the breeding of salt-tolerant rice. This information may help in studies to reveal the mechanism of plant salt tolerance, screen high efficiency and quality salt tolerance in crops.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Mohammad Hasanuzzaman"},{id:"80091",title:"Molecular Defense Mechanisms in Plants to Tolerate Toxic Action of Heavy Metal Environmental Pollution",slug:"molecular-defense-mechanisms-in-plants-to-tolerate-toxic-action-of-heavy-metal-environmental-polluti",totalDownloads:26,totalDimensionsCites:0,doi:"10.5772/intechopen.102330",abstract:"Toxic action of heavy metals on plants growing in contaminated soils intensified the research on detoxification and sequestering mechanisms existing in plants to understand and manipulate defense mechanisms that confer tolerance against metal ions. Increased biosynthesis of plant biomolecules to confer tolerance during toxic action of heavy metals is an intrinsic ability of plants. Induced formation of low-molecular weight amino acids, peptides or proteines as chelators such as proline (Pro), glutathione (GSH), phytochelatins (PCs) or metallothioneins (MTs) under heavy metal stress enhances metal binding and detoxification capability of plants. In addition, proline and GSH related enzymes such as GSH reductase, GSH peroxidases and glutathione S-transferases are also key components of the antioxidant defense system in the cells to scavenge reactive oxygen species (ROS). Protective action of oxidized fatty acids oxylipins at toxic levels of heavy metals is considered to activate detoxification processes as signaling molecules.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Istvan Jablonkai"},{id:"80723",title:"Intra-Annual Variation in Leaf Anatomical Traits of an Overwintering Shrub of High Elevations of Himalaya",slug:"intra-annual-variation-in-leaf-anatomical-traits-of-an-overwintering-shrub-of-high-elevations-of-him",totalDownloads:33,totalDimensionsCites:0,doi:"10.5772/intechopen.102016",abstract:"Trait variability in response to seasonal variations can be hypothesised as an advantageous strategy for overwintering shrubs. This hypothesis was tested by elucidating patterns of trait variation in an evergreen alpine shrub, Rhododendron anthopogon D. Don. The study site was established at Rohtang (3990 m a.s.l.) in western Himalaya. Its leaves were sampled at 10 time points spanning a period of 1 year (beginning from 22-August-2017 to 14-August-2018) for estimating anatomical traits using light and scanning electron microscopy. The data were analysed using one-way analysis of variance, and the trait-temperature relationships were analysed using linear regression. The results indicated a lower variability in the anatomical traits. A few traits (e.g. cuticle thickness and epidermal scales) were found to be significantly correlated with temperature (p < 0.05). Our analysis revealed increase in cuticle thickness and a decrease in epidermal scales (size) during low-temperature conditions. The lesser variability found in anatomical traits of overwintering shrub could be explained as ‘evolutionary gained adaptive traits’.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Nikita Rathore, Dinesh Thakur, Nang Elennie Hopak and Amit Chawla"},{id:"80587",title:"Morpho-Anatomical Adaptation against Salinity",slug:"morpho-anatomical-adaptation-against-salinity",totalDownloads:73,totalDimensionsCites:0,doi:"10.5772/intechopen.101681",abstract:"Plants tolerant of NaCl, implement several adjustments to acclimate to salt stress, such as biochemical, physiological, and morphological modifications. Besides, plants also adjust to saline circumstances by altering their anatomical structure of roots, leaves, and morphological modifications. The leaf and roots are among the essential plant organs and are involved in the transport of water and minerals used for photosynthesis. From a plant physiology perspective, water use efficiency in the quantity of CO2 fixed in photosynthesis compared to the leaf anatomy. In this review, we provide a comparative account of the morphology of the leaf and root under normal and salt stress circumstances. There is little information on the ultrastructure changes elicited in response to salt stress. The analysis expands our knowledge of how salt may impact the leaves and root anatomy.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Smita Srivastava"},{id:"80201",title:"Nutrients Deficit and Water Stress in Plants: New Concept Solutions Using Olive Solid Waste",slug:"nutrients-deficit-and-water-stress-in-plants-new-concept-solutions-using-olive-solid-waste",totalDownloads:81,totalDimensionsCites:0,doi:"10.5772/intechopen.101523",abstract:"Great efforts were deployed by researchers to mobilize water resources while is becoming rarer and to control with efficiency the water besides nutrient needs for the plant. Autonomous water and nutritional anti-stress device for plants (AWANASD) based on the recovery of rainwater patented by Medhioub et al. fits into this general framework. Scientific efforts were also dedicated to preserve the environment and minimize energy consumption through using agricultural waste materials in different fields. This chapter provides a new concept based on the use of the olive solid waste in AWANASD as water storage and nutrient elements for plants giving rise to the new system called AWANASD-OSW.",book:{id:"10905",title:"Plant Defense Mechanisms",coverURL:"https://cdn.intechopen.com/books/images_new/10905.jpg"},signatures:"Samir Medhioub, Slah Bouraoui, Ali Ellouze and Hassen Sabeur"}],onlineFirstChaptersTotal:9},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:16,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:4,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"June 23rd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:null},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null,editorialBoard:[{id:"114318",title:"Dr.",name:"David",middleName:null,surname:"Rodeiro",slug:"david-rodeiro",fullName:"David Rodeiro",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2a8QAC/Profile_Picture_2022-04-22T08:29:52.jpg",institutionString:null,institution:{name:"University of Santiago de Compostela",institutionURL:null,country:{name:"Spain"}}},{id:"114073",title:"Prof.",name:"Jörg",middleName:null,surname:"Freiling",slug:"jorg-freiling",fullName:"Jörg Freiling",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2UPQA0/Profile_Picture_1642580983875",institutionString:null,institution:{name:"University of Bremen",institutionURL:null,country:{name:"Germany"}}},{id:"202681",title:"Dr.",name:"Mojca",middleName:null,surname:"Duh",slug:"mojca-duh",fullName:"Mojca Duh",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD2dQAG/Profile_Picture_1644907300283",institutionString:null,institution:{name:"University of Maribor",institutionURL:null,country:{name:"Slovenia"}}},{id:"103802",title:"Ph.D.",name:"Ondrej",middleName:null,surname:"Zizlavsky",slug:"ondrej-zizlavsky",fullName:"Ondrej Zizlavsky",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQJQA0/Profile_Picture_1643100292225",institutionString:null,institution:{name:"Brno University of Technology",institutionURL:null,country:{name:"Czech Republic"}}},{id:"190913",title:"Dr.",name:"Robert M.X.",middleName:null,surname:"Wu",slug:"robert-m.x.-wu",fullName:"Robert M.X. Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/190913/images/system/190913.jpg",institutionString:"Central Queensland University",institution:{name:"Central Queensland University",institutionURL:null,country:{name:"Australia"}}}]},{id:"87",title:"Economics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. 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