\r\n\tSolar radiation is the radiant energy that originated from the sun in the form of electromagnetic radiation at various wavelengths. Solar radiation is the source of renewable energy and can be captured and converted into various forms of energy (e.g. electricity and heat) using different technologies.
\r\n\tA very vast amount of solar energy reaches the atmosphere and surface of the earth and solar energy has been used for heating purposes for a very long-time and after solar cells’ invention in 1954, solar cells have also been used widely for electricity generation. Solar cells convert the sunlight into electricity by the creation of voltage and electric current through the so-called photovoltaic effect.
\r\n\tPhotovoltaic (PV) solar energy has attracted significant attention in the recent decade as a reliable source for power generation due to various merits such as the free source of energy, abundant materials resources, environmentally friendly and noise-free, longtime service life, requiring low maintenance, technological advancements, market potential, and very importantly, low cost. The growth of using photovoltaic (PV) solar energy as a promising renewable energy technology, is being increased more and more worldwide. Therefore, much further research is needed for possible future developments in the field of solar photovoltaic energy.
\r\n\tThe aim of this book is to provide detailed information about solar radiation as the source of photovoltaic (PV) solar energy for a broad range of readership including undergraduate and postgraduate students, young or experienced researchers and engineers.
\r\n\tThis should be accomplished by addressing the various technical and practical aspects of solar radiation fundamentals, modeling and the measurement for photovoltaic (PV) solar energy applications.
\r\n\tThe majority of this book should describe the basic, modern, and contemporary knowledge and technology of extraterrestrial and terrestrial solar irradiance for photovoltaic (PV) solar energy.
\r\n\tThe book covers the most recent developments, innovation and applications concerning the following topics:
\r\n\t• Fundamental of solar radiation and photovoltaic solar energy
\r\n\t• Solar radiation and photovoltaic solar energy potential
\r\n\t• Solar irradiance measurement: techniques, instrumentation and uncertainty analysis
\r\n\t• Solar radiation modeling for photovoltaic solar energy applications
\r\n\t• Solar monitoring and data quality assessment
\r\n\t• Solar resource assessment and photovoltaic system performance
\r\n\t• Solar energy and photovoltaic power forecasting
\r\n\tThese are accompanied with other useful research topics and material.
",isbn:"978-1-83968-859-1",printIsbn:"978-1-83968-858-4",pdfIsbn:"978-1-83968-860-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"4c3d1319d7286e81bfb15c1f4b20460a",bookSignature:"Dr. Mohammadreza Aghaei",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9862.jpg",keywords:"Solar Radiation Modeling, Solar Data Assessment, Solar Monitoring, Solar Radiation Forecasting, Solar Irradiance Measurements, Solar Instruments, Solar Spectral Distributions, Uncertainty Analysis, Solar Cell Technologies, Photovoltaics (PV), Solar Resource Assessment, Photovoltaics Power Forecasting",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 17th 2020",dateEndSecondStepPublish:"October 15th 2020",dateEndThirdStepPublish:"December 14th 2020",dateEndFourthStepPublish:"March 4th 2021",dateEndFifthStepPublish:"May 3rd 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A senior researcher in the field of photovoltaic solar energy, a postdoctoral scientist at Eindhoven University of Technology (TU/e), Chair of the WG2: reliability and durability of PV in EU COST PEARL PV.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"317230",title:"Dr.",name:"Mohammadreza",middleName:null,surname:"Aghaei",slug:"mohammadreza-aghaei",fullName:"Mohammadreza Aghaei",profilePictureURL:"https://mts.intechopen.com/storage/users/317230/images/system/317230.jpg",biography:"Mohammadreza Aghaei is a senior researcher in the field of photovoltaic solar energy, Eindhoven University of Technology (TU/e), The Netherlands. He is chair of the Working Group 2: reliability and durability of PV in European Cooperation in Science and Technology, COST Action PEARL PV.\nHe received the M.S. degree in electrical engineering from the Universiti Tenaga Nasional (UNITEN), Selangor, Malaysia, in 2013, and the Ph.D. degree in electrical engineering from the Politecnico di Milano, Milan, Italy, in 2016.\nHe was a Postdoctoral Scientist with Fraunhofer ISE and Helmholtz-Zentrum Berlin (HZB)-PVcomB, Germany, in 2017 and 2018, respectively. He is a Guest Scientist with the Department of Microsystems Engineering (IMTEK), Solar Energy Engineering, University of Freiburg since 2017. He is currently a Postdoctoral Scientist with the Design of Sustainable Energy Systems Group, Eindhoven University of Technology (TU/e), The Netherlands. He has authored numerous publications in international refereed journals, book chapters, and conference proceedings. The main his research interests include Solar Energy, Photovoltaic systems, PV monitoring, LSC PV, solar cells, machine learning, and UAVs.\nDr. Aghaei is a member of the International Energy Agency, PVPS program-Task 13 and International Solar Energy Society, and also an MC member in EU COST Action PEARL PV.",institutionString:"Eindhoven University of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Eindhoven University of Technology",institutionURL:null,country:{name:"Netherlands"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"10",title:"Earth and Planetary Sciences",slug:"earth-and-planetary-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@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. 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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:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57163",title:"Small Non-Coding RNAs in Regulation of Course and Therapeutic Efficacy in Acute Myeloid Leukemia",doi:"10.5772/intechopen.70931",slug:"small-non-coding-rnas-in-regulation-of-course-and-therapeutic-efficacy-in-acute-myeloid-leukemia",body:'Small non-coding RNAs (sncRNAs) are oligonucleotides with length less than 200 nt. This is numerous family of non-coding genomic regulators. The most investigated sncRNAs are micro-RNAs (miRNAs) and small interfered RNAs (siRNAs). Less studied sncRNAs are piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) [1, 2].
All small non-coding RNAs before they become functionally active undergo different processes of biogenesis from their precursor form. This multistep maturation is necessary for normal functionality of small non-coding RNAs. Imbalance of one or more steps of sncRNAs biogenesis may results in development of different pathologic disorders and carcinogenesis [3].
miRNAs are small, single-stranded RNAs (ssRNAs) that are less than 24 nucleotides in length. They control translation of more than 60% of protein-coding genes. Four different mechanisms of regulation exist: inhibition of translation initiation, suppression of translation elongation, degradation of co-translational protein and initiation of translation termination [4, 5, 6, 7, 8].
The biogenesis of miRNAs was previously described [9, 10, 11, 12, 13]. Primary miRNAs (pri-miRNAs) are mostly transcribed by RNA Polymerase II (RNA Pol II). After that, pri-miRNAs undergo nuclear processing by the microprocessor complex of RNAse III enzyme Drosha/DGCR8 (DiGeorge syndrome critical region gene 8), followed by export into the cytoplasm as pre-miRNAs complexed with exportin5 and RAN GTP [9, 10, 11]. In the cytoplasm, immature miRNAs are duplexes by the cytoplasmic RNase III Dicer together with its catalytic partner Trans-activator RNA (tar)-binding protein (TRBP). Dicer/TRBP cleavage pre-miRNAs in duplex RNA (dsRNA) is loaded onto Argonaute (AGO) proteins to generate the RNA-induced silencing complex (RISC). RISC contains a single-stranded miRNAs and guide them to theirs target mRNAs [12, 13].
PiRNAs, 26–32 nt long small non-coding RNAs that are associated with the piwi-class AGO protein family, are generated independently of Dicer from single-stranded precursors [14]. The primary function of these sncRNAs is silencing of transposable elements through de novo DNA methylation [15]. Some piRNAs are silencing target protein-coding genes [16]. Recently two models of piRNA biogenesis were proposed: the primary processing and the secondary amplification (ping-pong amplification loop) pathways. In the germline, piRNA biogenesis involves both pathways. Two putative RNA helicases, Armi and FS(1)Yb (Female Sterile (1) Yb; also known as Yb) and a nuclease, Zuc (Zucchini), as factors of primary piRNA biogenesis. PiRNA precursors or intermediates obtained from uni-strand clusters are cut by Zuc to produce piRNAs that bind to piwi proteins. Amplification of loop pathway is activated by piRNA derived from primary biogenesis pathway. There should be a relative increase in abundance of complementary piRNAs due to the amplification. The primary pool of piRNAs amplifying sequences is silencing active transposons in the secondary ping-pong amplification loops cycles. The ping-pong amplification loop characterized in many animal species requires piwi subfamily proteins: piwi and Aub [17, 18, 19]. Sense-strand piRNAs react with Ago3 [20], whereas antisense piRNAs bound to Piwi or Aub [21]. In the ping-pong amplification loop model of piRNA biogenesis, antisense piRNAs in complex with Aub directly cleaves sense-strand transposon sequences, generating sense piRNAs for Ago3. The Ago3-piRNA complex then directs cleavage of antisense piRNA precursors, generating antisense piRNAs for Aub. The 5′-ends of amplified secondary piRNAs are determined by Aub and Ago3 Slicer [22, 23, 24, 25].
sncRNAs may play double-faced roles in carcinogenesis as oncogenes and tumor suppressors. As oncogenes sncRNAs function in tumor initiation, progression and resistance to therapies; as tumor suppressors, sncRNAs inhibit cell growth, induce apoptosis, block cell cycle and promote cell differentiation [26, 27]. In every pathologic condition, its own biomarker sncRNAs exist which indicate prognosis, course of disease and resistance or sensitivity to ongoing treatment. These biomarkers may be a basis for creation of new drugs for epigenetic therapy of cancers.
In acute myeloid leukemia (AML), some sncRNAs may play roles in oncogenes and other sncRNAs may be tumor suppressors. Oncogenic sncRNAs are miRNA-155, miRNA-17-92 cluster, miRNA-221, miRNA-21, etc. Tumor suppressive functions have miRNA-15a/16 cluster, miRNA-29b, miRNA-181b and members of let-7 cluster [28]. These sncRNAs may be determined as biomarkers and prognostic markers in AML.
Acute myeloid leukemia (AML) is a heterogeneous hematologic disease, which characterizes with disturbances of differentiation and maturation of hematopoietic stem cells or progenitor cells and appearance of immature blasts in periphery blood. Any classifications of AML are existing (WHO, 2008 with corrections in 2016) [29]. Classification of AML in dependence of genetic abnormalities is one of the basic classifications for this disease. All genetic changes in AML are also associated with imbalance of expression of different sncRNAs. These sncRNAs can be determined as biomarkers of particular type of AML. In Table 1, presents the most comprehensive analysis of dysregulated sncRNAs in dependence of AML type. All displayed sncRNAs profiles were taken from clinical investigations in AML patients.
Type of AML [29, 32] | Downregulated | Upregulated |
---|---|---|
AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 | miRNA-9, 18a, 19a–b, 20a, 92, 193a, 196 [34]; miRNA-196b [36]; 21, 26a, 125a, 142-3p, 196a, 494 [37]; 133, 17-3p, 17-5p [38]; let-7b, c [40] | miRNA-126, 130 [33, 36]; let-7a-3, 30a, b, c [34]; 27a, 146a, b, 150, 155, 181a, b, 223 [37]; 17–92, miRNA-24a, b [40] |
AML with inv.(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 | miRNA-30b, d, 335 [36]; 196a, b [37]; let-7b, c [40] | miRNA-126 [36]; 126 [40] |
AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A | miRNA-22, 24, 29a, b, 30a, 124, 132, 133a, 133b, 146a, b, 150, 155, 193b, 221, 222, 424, 503, 542 [33]; 23a, 181b, 210, 495 [34, 35]; let-7c, miRNA-26a, 30c, d, 100, 125b, 126-3p, 143, 181a, d [37]; 16, 29s, 34a [38]; let-7b, miRNA-29c [40] | Let-7a-3, miRNA-30a, b, c, 17h, g, 196b, 328 [34, 35]; 21, 196a, b [37]; 17–92, 196a, 219, 326 [38, 40] |
APL (M3) with a translocation between chromosomes 15 and 17 (PML-RARA) | Let-7c, miRNA-15b, 107, 143, 210, 223, 342 [33]; miRNA-16 [34]; 23a [35]; 485-5p [36]; let-7b, 18b, 22, 24, 27a, 126-3p, 150, 196a, b, 378 [37]; 17-5p, 20a [39] | Let-7a, let-7d, miRNA-142, 181b [33]; let-7a-3, miRNA-30a, b, c, 337-3p [34]; 125b [35, 37]; 29a, 100, 146a, 146b-5p, 181 a, b [37]; 127, 299, 323, 368, 382 [38, 40] |
AML with t(6;9)(p23;q34.1); DEK-NUP214 | ||
AML with inv.(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM | miRNA-449a [35] | |
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1 | miRNA-29a [37] | miRNA-335, miRNA-375 [37] |
AML with BCR-ABL1 | miRNA-203 [41]; 150 [42]; 451 [43]; 120, 151, 155, 31, 564 [44]; | miRNA-23a [41]; 125b, 96 [44]; |
AML with mutated NPM1 | miRNA-424, 181a, b [46]; 320, 145, let-7c [47]; 10b, let-7, miRNA-29, 181a, 124, 128, 194, 219, 220a [48]; 204, 126, 130a, 451 [38] | miRNA-10a-5p [45]; 155 [46]; 196a, b [47] |
AML with biallelic mutations of CEBPA | miRNA-34a [49] | miRNA-328 [44]; miRNA-181a [38, 48]; 335 [38] |
AML with mutated RUNX1 | Let-7, miRNA-223, 99a, 100 [48] | miRNA-24, 23, 27, 155, 211, 220, 595 [48] |
miRNA, which most often involved in pathologic processes in AML are let-7 family of miRNAs, miRNA-16, 17–92 cluster, miRNA-29, miRNA-30, miRNA-146, miRNA-150, miRNA-155, miRNA-196 and miRNA-223. The oncogenic markers are miRNA-17-92 cluster, miRNA-155 and miRNA-196; the tumor suppressive are miRNA-15/16, let-7 family, miRNA-29, miRNA-30, miRNA-146, miRNA-150 and miRNA-223 (Figure 1).
Influence of tumor suppressor sncRNAs and oncogenic sncRNAs on main functions of cells.
Let-7. The let-7 is a 13-member family of miRNAs expressed in human tissues. This sncRNAs are induced in embryogenesis and then its high levels are detected in different tissues. Down-expression of let-7 was obtained in early embryogenesis and its suppression was observed in many types of cancers. The main functions of let-7 miRNA are tumor suppression and supporting of cell differentiation. Let-7 targets a human rat sarcoma (RAS) ortholog, a high-mobility group AT-hook 2 (HMGA2) and MYC. These factors are human oncogenes. Let-7 regulates cell cycle suppression of any cyclins, such as cyclin A, cyclin D1 and cyclin-dependent kinase 4 (CDK4). It may indirectly suppress LIN28 by the direct inhibition of MYC [23, 24]. Let-7c induces megakaryocytic cell differentiation as the result of targeting of PBX2 in myeloid cells. This factor in cooperation with Meis1 and HoxA9 are required for MLL-dependent leukemogenesis. Acute promyelocytic leukemia (APL) decreases let-7c levels and cooperation of KRAS with PML-RARA results in poor prognosis of disease [25, 26, 50, 51]. One more novel axis was determined in poor prognosis leukemia. This is protein tyrosine phosphatase of regenerating liver 3: PRL-3/LIN28B/let-7 axis. PRL-3 induces activation the PI3K/AKT pathway and Src-ERK1/2 pathways. PRL-3 phosphatase activity upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. These pathways support epithelial-mesenchymal transition and results in metastatic processes. PRL-3 is detected in more than 50% of patients with AML [27, 52].
miRNA-16. miRNA-16 is tumor suppressor sncRNAs. miRNA-16 targets anti-apoptotic gene Bcl-2 (B-cell lymphoma 2) and numerous genes, which are involved in cell cycle regulation. Those genes are cyclin D1, D3, E1 and cyclin-dependent kinase 6 (CDK6). miRNA-16 regulates genes supporting Wnt-signaling pathway, such as WNT3A (wingless-type MMTV integration site family, member 3A). As a result, miRNA-16 can fine-tune cell cycle, support cell apoptosis and inhibit cell proliferation [28, 53]. Erythropoiesis is supported by miRNA-16 and its expression positively correlates with the appearance of erythroid surface antigens (CD36, CD71 and CD235a) [29, 54]. Its level is downregulated in APL. After treatment, ATRA levels of miRNA-16 increase [26, 51].
miRNA-17-92. miRNA-17-92 is one of the most investigated oncogenic miRNA complex in leukemia. Cluster 17–92 is complex of seven co-operating miRNAs. Members of this cluster are miRNA-17, miRNA-17*, miRNA-18a, miRNA-19a, miRNA-20a, miRNA-19b-1 and miRNA-92a-1. These miRNAs are located at 13q31. The majority of miRNAs from this cluster are overexpressed in MLL-rearranged AML. These miRNAs can support cell proliferation, cell viability, inhibit apoptosis, suppress cell differentiation and induce malignant transformation. In normal hematopoiesis, this complex plays essential roles in monocytopoiesis and megakaryocytopoiesis. Targets for 17–92 complex are factors of cellular proliferation E2F1, E2F2, E2F3, PTEN (tumor suppressor phosphatase and tensin homolog), BIM (pro-apoptotic molecule), AML1, TGFBR2, NCOA3, RBL2, DOCK5, THBS1 and CTGF. RASSF2 and RB1 genes are target genes in leukemia [29, 30, 31, 32, 33, 38, 54, 55, 56, 57]. In vivo cluster 17–92 expression significantly decreases leukemia latency [34, 40].
miRNA-29. The miRNAs-29 family consists of miRNA-29a, miRNA-29b and miRNA-29c, and is encoded and transcribed in tandem by two genes located on chromosome 7q32.3 (miRNA-29a/b1 locus) or chromosome1q32.2 (miRNA-29a/b2 locus), respectively. As was shown recently, miRNA-29a and miRNA-29b regulate critical anti-apoptotic genes, such as myeloid cell leukemia-1 (MCL-1) and play tumor suppressor role. These results indicated that miRNA-29a and miRNA-29b target Mcl-1 and play roles in regulation of apoptosis in AML. Bcl-2, Mcl-1 and Bcl-Xl are anti-apoptotic proteins and promote cell survival and proliferation. Both miRNA-29a and miRNA-29b not only directly target anti-apoptotic genes but also upregulate pro-apoptotic genes, such as BIM (BCL2L11), p53 and the tumor suppressor programmed cell death-4 (PDCD4) [35, 36, 58, 59]. Overexpression of miRNA-29a, miRNA-29b or miRNA-2c markedly inhibited cell proliferation and promoted cell apoptosis by targeting protein kinase B2 (AKT2) and cyclin D2 mRNAs.
miRNA-29b targets DNA methyltransferases (DNMTs) and downregulates DNA methylation in malignant cells. In AML cells, enhanced expression of miRNA-29b results in the reduction of the expression of DNMT1, DNMT3A and DNMT3B. miRNA-29b downregulates DNMT1 indirectly by targeting Sp1, a trans-activator of the DNMT1 gene due to a decrease in global DNA methylation and re-expression of p15 (INK4b) and ESR1. Moreover, miRNA-29 family members may downregulate the active DNA demethylation pathway members tet-methylcytosine dioxygenase (TET1) and thymine DNA glycosylase (TDG) [37, 60]. miRNA-29 targets CCNT2 that is a component of the positive transcription elongation factor b (P-TEFb). P-TEFb is essential for the elongation of transcription and co-transcriptional processing by RNA polymerase II. Different P-TEFb complexes can regulate subsets of distinct genes that are important for the embryonic development. miRNA-29 family miRNAs downregulate cyclin-dependent kinase 6. It provides a differentiation promoting activity of Runx proteins to be selectively activated in terminally differentiating cells [38, 61].
miRNA-30. miRNA-30 as was shown is tumor suppressor miRNA in AML. miRNA-30 downregulates NOTCH1 gene expression to promote granulocytic differentiation [39, 62].
miRNA-146. miRNA-146a and miRNA-146b are two miRNA, which are highly expressed in primitive bone marrow cells (lineage negative). In mature blood cells, their expressions are different. miRNA-146a is highly expressed in blood cells maturation lineage. The expression of miRNA-146a is regulated by a combination of PU.1 (spleen focus-forming virus proviral integration 1) and c-ETS. It was supposed, that miRNA-146a controls maturation of blood marrow stem cells in adults and plays role in the self-renewal of long-term hematopoietic stem cells. The decrease or deletion of miRNA-146 levels could result in development of AML in adults [40, 63]. miRNA-146a negatively regulates NF-kB by suppressing two signal transducers, TRAF6 (TNF receptor-associated factor 6) and IRAK1 (IL-1 receptor-associated kinase 1). Absence of miRNA-146a expression is due to NF-kB hyper-expression, which involves miRNA-146a/TRAF6/NF-kB/IL-6 pathway resulting in depletion of hematopoietic stem cells and the development of myeloproliferative diseases [41, 64]. miRNA-146a also downregulates CSF1R. Increased expression of this factor is strongly associated with the development of AML [42, 65]. Furthermore, high expression of miRNA-146a impaired bone marrow reconstitution in mice and reduced survival of hematopoietic stem cells. Treatment of AML patients with ATRA results in downregulation of miRNA-146a, which is associated with upregulation of Smad4 pathway [43, 66]. miRNA-146a is downregulated in MLL rearrangements. MLL-rearranged AML MEIS1 and HOXA9 are key target genes of MLL-fusion proteins. MEIS1/HOXA9 downregulate PU.1 expression, which is essential for miRNA-146a expression. Low levels of miRNA-146a result in high levels of SYK and its activation. SYK expression and activation is switch leukemic cellular transformation [44, 67].
miRNA-150. miRNA-150 is one of the main regulators of hematopoiesis. It is expressed in normal hematopoietic stem cells. The known target for miRNA-150 is Myb, which regulates differentiation of progenitor cells toward megakaryocytes and erythrocytes, supporting c-KIT expression. In majority of cases of patients with AML this miRNA is downregulated [45, 68]. Downregulation of miRNA-150 is associated with misbalance of regulatory factors. MLL-fusion proteins bind to the promoter regions of miRNA-150 and directly promote its expression, however, blocking maturation and biogenesis of this miRNA [46, 47, 69, 70]. Repression of miRNA-150 maturation is associated with expression of Myc protein. Myc is a direct target for MLL-fusion protein, which binds to the promoter region of LIN28 and activates its transcription [48, 71]. miRNA-150 is an important regulator of hematopoietic recovery after treatments with chemotherapeutic drugs. miRNA-150 targets other genes that are necessary for leukemogenesis. These genes are HOXA7, Meis1 and cyclin-dependent kinase 2 [38, 72].
miRNA-155. miRNA-155 expressed in high levels in normal HSC and in low in mature hematopoietic precursors. It controls early maturation of HSC until common myeloid progenitor stage. miRNA-155 supports the leukemogenesis by downregulation of SH2 domain-containing inositol 5′-phosphatase 1 (SHIP1) translation, activating SHIP1-mediated PI3K-Akt pathway. This event is due to myeloproliferation and decrease of erythropoiesis. SHIP1 downregulation results in activation of IL-6 signaling pathway and induces a reactive proliferation of the relatively apoptosis-resistant myeloid precursor cells [49, 73]. Key targets of miRNA-155 are PU.1 and Cebpb in myeloid progenitors. PU.1 transcriptionally activates miRNA-155, forming positive regulatory loop. PU.1 and CCAAT/enhancer-binding protein b (C/EBPb) transcriptionally regulate expression of myeloid-specific miRNA-223, which upregulates myelopoiesis by indirectly regulating C/EBPa [50, 51, 74, 75]. miRNA-155 promotes production of inflammatory cytokines in mature myeloid cells. It negatively regulates anti-inflammatory factors, such as SHIP1 and SOCS1 [52, 76]. miRNA-155 reduces apoptotic activity of myeloid cells in vitro and in vivo by the regulation of Akt-signaling pathway [53, 54, 77, 78]. In silico target prediction identified a number of putative miRNA-155 target genes, and the expression changes transcription factors of myeloid proliferation and apoptosis, such as MEIS1, GF1, cMYC JARID2, cJUN, FOS, CTNNB1 and TRIB2 [55, 79].
miRNA-196. miRNA-196 is a member of homebox regions (HOX) clusters family miRNAs: miRNA-10, 196 and 615. HOX genes encode transcription factors, which control embryonic development. miRNA-196 are highly expressed in AML. MLL-fusion proteins directly upregulate expression of miRNA-196, which is necessary for leukemic cells immortalization. miRNA-196 blocks granulocyte colony-stimulating factor-induced granulopoiesis [56, 80]. Recently it determined double-faced regulation by the miRNA-196 of MLL-associated AML. miRNA-196 may be double-faced Janus in MLL-rearranged AML. On the one hand, it targets MLL-associated HOXA9/MEIS1 oncogenes; on the other hand, it regulates first apoptosis signal (FAS) (also known as Apo-1 or CD95) tumor suppressor gene. High expression of miRNA-196 is associated with the more aggressive leukemic phenotypes and worse prognosis for patients with leukemia [38, 57, 81, 82].
miRNA-223. miRNA-223 is an intergenic miRNA, which is highly expressed in human peripheral blood granulocytes and bone marrow-committed myeloid precursors. It is regulated by two factors PU.1 and C/EBPb [40, 58, 59, 83, 84, 85]. miRNA-223 has tumor-suppressive role in AML, and its expression is downregulated in this disease. Targets for miRNA-223 are erythrocyte membrane protein band 4.1 like 3, septin 6, FBXW7, ataxia teleangiectasia mutated, insulin-like growth factor 1, paired box 6 and caprin-1. FBXW7 (F-box protein in the SCF E3 ligase complex) protein leads to ubiquitination of binding proteins and proteasomal degradation. It regulates cell proliferation, differentiation, cell cycle, migration and invasion. miRNA-223 downregulates this factor and results in inhibition of cell proliferation and enhancing apoptosis [60, 86]. Other target genes for miRNA-223 are LMO2, NFI-A, MEF2C (myocyte enhancer factor) and E2F1 (adenovirus E2 promoter-binding factor 1). In normal conditions, increased expression of miRNA-223 promotes differentiation toward granulocytes. Its repression associated with differentiation to erythrocytes and monocytes/macrophages [40, 61, 83, 87]. C/EBPa regulates miRNA-223 that blocks myeloid cell cycle progression by targeting E2F1. Overexpression of E2F1 results in repression of miRNA-223 gene expression by the negative feedback [62, 88].
Piwi-interacting RNAs is the most numerous class of sncRNAs, whose action in normal and malignant hematopoiesis is less studied. Piwi-regulatory proteins are Argonaute family proteins, which are essential for germ stem cells self-renewal and maintenance. They are encoded by highly conserved PIWI genes. Human genome has four piwi-coding genes: HIWI, HILI, HIWI3 and HIWI2. Piwi proteins are associated with piRNAs and they act in cooperation with each other. Firstly, piwi proteins were identified in germ cells and then in somatic cells [63, 89]. A growing number of studies have found that piwi proteins in humans and mice, specifically, HIWI, PIWIL2 and PIWIL2-like proteins, are expressed in various types of tumor cells. In addition, piRNAs were also detected in these cells [64, 90].
In AML, piwi proteins and piRNAs are deregulated. Recently, it was shown that high expression of piwi-like protein 4 in leukemic cells in 72% of the patients with different types of AML compared to healthy controls, and in 90% of the patients with MLL-AF9 rearranged AML [13, 65]. PiRNAs act as sequence-specific guides for piwi proteins, and they support biogenesis and stability of piRNAs. Piwi and piRNAs are involved in the intra-nuclear processes such as heterochromatin formation, mobile transposable elements (TE) silencing and repressive histone modifications (H3K9me3). The piwi protein PIWIL4 is overexpressed in a large proportion of AML leukemia patients. This knockdown results in gross changes in histone methylation and slowed leukemic growth. It suggests a tightly regulated piwi pathway is essential for normal hematopoiesis [66, 91].
Mobile transposable elements, which are under the control of piwi and piRNAs constitute approx. 44% of the human genome. TE could actively contribute to genetic heterogeneity, to alter the behavior during adaptation, and responses to stress. Somatic retrotransposition and its associated insertional mutagenesis have particularly important implications for carcinogenesis and are often associated with different cancers. TE activity can generate a wide spectrum of genomic mutations, ranging from point mutations to gross rearrangements. These events may be due to development of different diseases. Mobile transposable elements such as duplications caused by Alu-Alu (SINE type of TEs) recombination in intron 1 and 6, result in a duplication of exons 2–6 of gene MLL1 [67, 68, 92, 93]. Chromosomal rearrangements in MLL are result of Alu recombination. In partial duplication events, TEs are inserted near the translocation breakpoints. MYB and MLL duplications were also obtained in healthy controls, whereas leukemogenesis is induced by TE insertions during blood cell differentiation [69, 94]. Knockdown of the murine piwi protein MIWI2 leads to abnormal hematopoiesis and erythroid precursors take on characteristics of more differentiated erythroid cells [70, 71, 95, 96]. The roles of piRNAs in hematopoiesis have only just begun to be explored and it seems likely that more will be uncovered in the near future. Certainly, regulation of mobile transposable elements, histone modificatiowns, DNA methylation processes by piwi and piRNAs are important for leukemogenesis and for tumor suppression. Investigation of new piwi/piRNAs biomarkers will be a novel diagnostic tool and possible hopeful epigenetic treatment of patients with AML in future.
All sncRNAs from the view of chemoresistance and sensitivity of AML patients to the current treatment can be assigned to the two groups. Group 1 characterized with high level of expression of sncRNAs, which associated with sensitivity to therapy. This group members are miRNA-181a, b; let-7f, miRNA-9*, miRNA-96, miRNA-135a, miRNA-409, miRNA-10, miRNA-29b and miRNA-217 [72, 73, 97, 98, 99, 100]. Group 1 members act through activation of cellular differentiation, inhibition of leukemic cells proliferation and survival, regulation of cell cycle, inducing of apoptosis and suppression of migration and invasion. Group 2 characterized with high expression of sncRNAs, which associated with resistance to therapy. Group 2 members are miRNA-155, miRNA-125b, miRNA-126, miRNA-210, miRNA-3151, miRNA-196b, miRNA-199a, miRNA-191, miRNA-644, miRNA-363, miRNA-532-5p and miRNA-342-3p [74, 101].
miRNA-181a is the most investigated miRNA with its chemosensitive action on leukemic cells. Investigations of samples from cohort of patients of different ages, miRNA-181a was identified as marker of chemosensitivity [75, 102]. The main function of this miRNA is activation of apoptotic activity in cells and inducing sensitivity of leukemic to native immunity action. Direct targets for this miRNA are KRAS, NRAS, transcription factor Prospero homebox protein 1 (Prox1) and HMGB1, a member of the high-mobility group box DNA-binding proteins. The CD4 co-receptor is another target for miRNA-181a. Anti-proliferative effect of miRNA-181a is associated with targeting of FBJ murine osteosarcoma viral oncogene homolog (FOS), which is involved in Moloney murine sarcoma viral oncogene homolog (MOS)/dual specificity mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase (ERK) pathway [76, 103]. miRNA-181a can sensitize leukemic cells to natural killer (NK) cell action [77, 104]. miRNA-181a regulates mechanisms of cell proliferation, differentiation and apoptosis of normal cells. All regulated targets for miRNA-181a are aberrantly expressed and are frequently mutated in acute myeloid leukemia. Promotion of high expression of miRNA-181 in the case of AML may have partial positive effect for chemosensitivity of leukemic cells and for anti-leukemic activity [78, 79, 105, 106].
Other miRNA, which enhances chemosensitivity of leukemic cells is miRNA-217. This sncRNA decreases leukemic cell proliferation via the cell apoptosis pathway. It targets KRAS regulator of signaling links from extracellular space to the nucleus. KRAS connects multiple upstream signals to various downstream signaling pathways [97].
miRNA-155 is oncogenic miRNA, whose high expression is able increase chemoresistant effects of anti-leukemic drugs. Its increased expression is correlated with decreased CR rates and a shorter overall survival (OS) of patients with AML. In our laboratory, primary in vitro leukemic cells were transformed into megakaryocytes after using complexes of polymer carrier with antgo-miRNA-155 [80, 107].
Another miRNA from the second group is miRNA-126. High expression of this miRNA correlated with decreased CR rates and shortened OS. Treatment with nanoparticle-based antagonist of miRNA-126 results in strong anti-leukemic effects in murine leukemia models and chemo-sensitizing effects of cytarabine and idarubicin in AML cell lines.
Recently determined miRNAs predict the prognosis of AML. From the amount of miRNAs were indicated miRNAs, which expression is dysregulated in patients with poor prognosis of AML. miRNA-107, miRNA-155, miRNA-25, miRNA-29b and miRNA-196a are associated with short OS of patients. The worse prognostic marker was miRNA-25 expression dysregulation [76].
The normal bone marrow stressor or injury factors act as dysregulators of epigenetic and genetic program of hematopoietic stem cells, which is due to downregulation of separated sncRNAs and upregulation of other sncRNAs. These events result in the development of imbalance of regulating cell program and consequent transformation of normal hematopoietic cells into leukemic. In this case, genotypic and phenotypic markers of pathologic cells are changing. These cells change its functions. They lose possibility to normal lifecycle: to differentiation, maturation and death. As a consequence, leukemic cells produce abnormal proteins and express particular palette of sncRNAs, which worsens the negative impact into development of AML.
The chemotherapy may change expression map of sncRNAs in the advantageous or in the disadvantageous position. The study of this map may be useful tool for hematologists and hemato-oncologists in the diagnostic of course, efficacy and prognosis of AML in the particular case. In the course of chemotherapy, downregulation of oncogenic sncRNAs and inducing of tumor suppressor sncRNAs associates with favorable prognosis of disease. On the contrary, inhibition of sncRNAs with tumor suppressive properties and high expression of oncogenic sncRNAs due to unfavorable prognosis of AML.
Reversing of changed epigenetic program of cells and its supporting may be the novel tool for the treatment of different hematological malignancies even which have poor prognosis. Treatment with anti-oncomiRNAs and inducing of producing, biogenesis and maturation of miRNAs with tumor suppressive properties may be new therapeutic benefit in complex therapy of AML. However, limitations to this treatment modality include the instability of free-floating anti-miRNAs in the plasma and their vulnerability to breakdown by nucleases, nonspecific tissue uptake and renal clearance. These limitations can be overcome by nanoparticle-based delivery of the anti-miRNAs to target tissues.
The certified history of surfactants and detergents goes back to the Mesopotamian and Egyptian ages. In the Roman period, authors contemporary of Julius Caesar described the procedures in use from Gauls and Belges to produce soaps from the alkaline hydrolysis of beef fat [1]. They were horribly shocked for the excessive use of soaps that Gauls consumed in hair cleaning. Such procedures are still in use in the preparation of niche products as Marseille soap. In much more recent times, new procedures largely improved the preparation of surface-active products, synthetizing alkyl sulfates. These studies date back to the 1930s of the last century [2]. Later on, nonionic surfactants of the alkyl-polyoxyethylene family, as Triton TX-100, or zwitterionic ones were worked out and synthetized [3]. This induced chemists to prepare new classes of solid or liquid formulations, with better performances in terms of surface activity and solvent capacity. These efforts allowed preparing chemicals capable to operate in all working conditions, irrespective of pH, the presence of calcium, and ionic strength of the dispersant [4, 5, 6].
\nNowadays, focus is on surfactant mixtures, improving the intrinsic quality of formulations and allowing applications to much more cases than those originally intended for. Applications of surfactant-based systems are much more versatile with respect to canonical laundry and personal body care formulations that were exploited until now. Current research lines focus on unexpected fields, as applications in biomedicine and in the feminine personal hygiene formulations. We do not consider, in this review, the adjuvant action played by cosurfactants, as long-chain alkanols, glycerol, sterols, perfumes, softeners, bleaching adjuvants, and so forth. We mainly focus on the addition of species increasing the surface activity and solvency of existing surface-active/cleaning formulations and in applications thereof. In particular, the synergistic properties that are observed in surfactant mixtures [7, 8] are discussed.
\nCases of interest span from mixtures of ionic species of the same charge, to ionic/nonionic ones, and to mixtures of species having oppositely charged polar head groups. Relevant are also the cases where polymers, enzymes, and proteins are added. We discuss separately all the above fields taking into account the reasons underlying such research lines. In turn, focus is on the following aspects:
addition of polymers/biopolymers, referred to as PSSs [9]; and
use of mixtures made of oppositely charged surfactants, defined as Cat-An systems [10].
The above items are more strictly interconnected than one could think at a first glance. In both the organizing role played, surfactants are crucial both on small or medium size scale (for polymer/surfactant systems) and on a much larger size scale, in case of surfactant mixtures. Both classes of formulations are biomimetic, and the efficiency is related to biopolymer modifications induced by surfactants and to surfactant-driven vesicle formation, respectively.
\nAs a starting point, we report the essential details on the physical meaning of surface activity and solvent capacity; both requisites are necessary to understand biomimicry, surfactancy, and detergency on solid grounds. For more details, the interested reader is referred to pivotal books and reviews that have dealt with that field [11, 12, 13, 14]. In many aspects, we follow the “main street” that is suggested in a seminal book, which allowed scientists to unify in a whole field the formation of both micelles, vesicles, and biological membranes [15].
\nThe term surface active, or surfactant, refers to substances capable to lower significantly and permanently the surface tension of water, i.e., to decrease the work required increasing the surface area of a liquid. In terms of the classical Gibbs surface adsorption equation valid for aqueous binary mixtures, we define as surface active all species fulfilling the equation [16]:
\nwhere σ is the surface tension and a2 is the solute activity. G2, the surface excess concentration, indicates as to whether the surface tension will decrease, or increase, upon addition of a given solute. G2 is defined with respect to the concentration of the given chemical in the bulk and depends on its modulus. That is the rationale underlying the meaning of the term “surface active.” When dσ = 0, there is no more room for adsorption, and the surface is saturated. In addition, if dlna2 is zero, the solute activity is constant and a new phase is being formed. This is the basis for the so-called phase separation approach to micelle formation [17], discussed later on.
\nThe solvent capacity arises from a more subtle behavior and is univocally related to micelles onset. The organization of surfactant molecules arises from the “schizophrenia” that such molecules suffer from. They associate in micellar entities whose interior, mostly composed of alkyl groups, is capable to dissolve nonpolar (i.e., hydrophobic) molecules. The polar groups facing outward the bulk guarantee thermodynamic stability to the aggregates so formed. In words, the solubilizing capacity toward oils and fats starts to occur only when micelles do form. For this reason, micelles are swelling units which grow in size upon addition of fats and oils.
\nFrom a thermodynamic viewpoint, micelle formation is mainly entropy-driven. This is a rather counterintuitive behavior, if we consider that several molecules associate in a given entity. The reason underlying the entropy-based statement is that water molecules hydrophobically interacting with alkyl chains are released during micelle formation [15]. This substantially increases the number of degrees of freedom for H2O and those of the chains, as well. It is also worth noticing that an increase in temperature increases the number of rotational degrees of freedom of geometrically constrained surfactant alkyl chains, which are free to move into micelles. This is the main reason why micelle interior is assumed to be in a “liquid-like” form.
\nTo unify the above features, that is, surface activity and solvent capacity, in a whole definition, we assume that the point at which surface activity ends and micelles begin to form is a “pseudo” phase separation threshold, indicated as critical micellar concentration or cmc [18, 19]. The definition “critical” indicates the steep discontinuity in many thermodynamic quantities (molar volumes, dilution enthalpies, activity coefficients, and so forth) observed in close proximity of the cmc.
\nFor a given class of surfactants, such as alkali metal alkylsulfates, alkyltrimethylammonium halides, polyoxyethylene glycol alkyl ethers, etc., the two features jointly depend on the length of alkyl chains. The longer the latter are, the lower is the cmc, the steeper is the decrease in surface tension, and the more efficient is solvent capacity. We do not enter in more details about micelle sizes, shape, and polydispersity and assume, in a first approximation, that such aggregates are spheroidal colloids. For these reasons, they scatter light, have much lower diffusion coefficients than molecules from which they are made of, and their solutions can be moderately or significantly viscous. At high concentrations, they form ordered phases known as lyotropic liquid crystals [20, 21]. More aspects, such as the role of salts and cosolvents in micelle formation, shall be introduced when the need of “ad hoc” information will be necessary.
\nStudies on additives as salts and cosolvents have been widely investigated in the past and will not be reported, unless this is strictly necessary. Conversely, studies on systems containing synthetic polymers or biopolymers are still a matter of debate and investigation and will be discussed in this section. The first efforts along this line go back to the 1950s and were essentially dealing with protein separation from biological membrane lipids. These efforts were led to convergence in a classical textbook of the early 1990s [22]. This induced many scientists to focus on new and, sometimes, controversial fields [23, 24, 25].
\nThe underlying phenomenology can be understood by looking at Figure 1. In the plot the behavior of a ternary system containing water, surfactant, and polymer is reported. If the relative wt% of the latter substances is much lower than water, the ternary phase diagram can be simplified in a pseudo-binary one. As can be seen in Figure 1, a pseudo-phase behavior occurs in absence of polymer; the cmc is the point separating the micellar from the molecular regime. Added polymer induces the splitting of the solution phase into three regions. For finite amounts of polymer, the following areas are observed, from the left:
a molecular solution region, I;
a polymer-surfactant one, II; and
a region where free micelles coexist with polymer-surfactant adducts, III.
The surfactant behavior in presence of a nonionic polymer. The black line in the left bottom of the figure indicates the molecular solution region and the dotted one the micellar regime. The turquoise area indicates the molecular regime and is limited by the cac, above which the surfactant starts to interact with the polymer. The red area indicates the interaction regime; the yellow one, the saturation regime, occurs when the polymer is saturated. The line separating the red and yellow regions is indicated as cmc* line.
To build up the phase map, surface tension values are measured for a number of polymer wt% (Figure 2). There splitting of surface tension values in three regimes is evident. Cac and cmc* are easily determined form these and other experiments, as well [22].
\nPlot indicating how to get the cac, the first minimum, and the cmc*, at surface saturation, for a given amount of polymer vs. surfactant content. Black points refer to data in presence of polymer, the red ones to the surfactant alone.
On thermodynamic grounds, the line separating region I from II indicates the points above which polymer/surfactant interactions start to occur; the line position depends on polymer content and nature. There is an ensemble of critical points, whose location in the phase map depends on the polymer amount. Once the process has occurred, the surfactants located on the polymer backbone act as nucleation sites for the binding of more surface-active species. Thus, entities similar to micelles (emi-micelles) aggregate thereon: a sort of “pearl necklace” is formed [26]. Thus, the polymer backbone is decorated by a series of small aggregates, whose number is dictated by its length; the interacting polymer sections, the so termed “polymer binding sites”, are a few kdalton long. Surfactant nucleation thereon continues until all possible sites are saturated. In consequence of that, the polymer tends to assume a different conformation with respect to the native one, with subsequent changes in viscosity. This is the reason why polymer/surfactant systems act as “viscosity modulators” [27, 28]. Another important consequence is the fact that they are “kinetic buffers” as to matter exchange with the bulk is concerned [29].
\nAncillary effects are concomitant to the mentioned behavior. First, micelles of smaller size compared with free ones are formed; they behave as a whole kinetic entity with the polymer (i.e., the binding energy is significant). This is a feature similar to those occurring in biological systems, as in the binding of molecules to the protruding parts of a receptor. The line separating the two regions is defined as “critical aggregation concentration” or cac line. The nucleation of fat droplets on a cotton string is a pertinent example for the formation of polymer-surfactant adducts; their location thereon is energetically more favored than in free form. The cmc* one, conversely, is a polymer saturation threshold, above which there is no room for binding. As a consequence, free micelles do form and coexist with polymer-adsorbed ones. Technological applications find place in formulation. The viscoelastic properties that such systems exhibit are used in shampoos, eye-drop fluids, etc. [30, 31]. Viscoelasticity is simply detected by abruptly rotating the fluid-containing vials, with transient formation of ellipsoidal bubbles or, in a more quantitative way, by rheology [27, 28]. An alternative simple procedure requires pressing drops of these formulations between glass slides and looking by a polarizing microscope, to detect the preferred orientation that polymer-surfactant adducts assume during the flow.
\nThere is no significant difference when polyelectrolytes replace nonionic polymers. In cases like such, precipitation may also occur; cases are known [32], mostly as to biopolymers are concerned [33, 34, 35, 36]. In mixtures containing proteins, precipitates or, eventually, two-phase regions are usually met. As a rule, these are centered around the charge neutralization line, where precipitates or gels may coexist (Figure 3). In such systems relevant are the modifications observed in protein conformation. Changes in the relative amounts of alpha-helix, beta-sheet, and random coil conformations are concomitant to protein-surfactant interactions in a wide part of the interaction regime. Such changes are responsible for significant variations in protein activity and three-dimensional structure of the “adducts” that are formed. All these systems are characterized by a not univocally defined stoichiometry, and the definition of “adduct” is more correct with respect to that of “complex.” The rationale underlying that behavior finds origin in the fact that alkyl chains are essentially located in the protein hydrophobic tasks. Many possible locations are available in cases like such. The above statements are quite well acquainted from experiments on albumins and, more generally, on protein denaturation strategies [37]. Thus, biopolymer/surfactant systems offer the opportunity to prepare proteins in pure form from extensive dialysis of the corresponding mixtures. For these reasons they find extensive use in biochemically intended procedures.
\nPartial phase diagram for the system water-lysozyme-lithium perfluorononanoate (a stiff, fully fluorinated surfactant), at 25°C. The coexistence of a solution and precipitate occurs in the black area, whereas a pure gel, in dark gray, and one empty of particles, in light gray, are met. The charge neutralization limit is indicated as a blue line. This is the point at which all nominal charges on the protein, at the given pH, are fully neutralized. Partly redrawn from Ref. [26].
Pioneering studies in the field are due to Wennerstroem [38], who focused on the synthetic analogues of lipids and suggested that stoichiometric mixtures of oppositely charged surfactants could be good substitutes of lipids. The original hypothesis dealt with systems of 1–1 stoichiometry, in terms of charge. There, the electrostatic interactions between polar groups mimic charge separation among entities bound on a glycerol backbone, which is also joining two alkyl chains. The above systems are models of swelling, lamellar domains. The first experimental results were discouraging; in fact, these mixtures often show thermotropic rather than lyotropic behavior [39], due to the high “Krafft point” [40] of alkyl chains in such mixtures. Later work demonstrated that nonstoichiometric Cat-An mixtures were more promising. It was noticed there the presence of vesicular entities [41, 42]. Debates occurred on the stability of largely polydispersed in size vesicles. It is actually accepted that they are kinetically stable entities although thermodynamic stability is demonstrated in some cases [43, 44].
\nThe phenomenology of such systems, defined by the acronym “cat-anionic,” is extremely appealing from a bio-intended viewpoint. In the phase diagram, in particular, the vesicular areas are located in proximity of micellar ones and are clearly distinguishable from them. The observation is in favor of a significant modification in the micellar structure induced by the second surfactant. Cat-anionic mixtures, hereafter termed Cat-An’s, are characterized by a bluish color and may turn to yellowish or opalescent appearance when vesicle sizes exceed some 100 nms. They are both positively and negatively charged. This fact gives the opportunity to use Cat-An vesicles as vehiculating/binding agents of DNA (for positively charged ones) and proteins. In the latter eventuality, both positively and negatively charged vesicles may be used, depending on the demand dictated by protein charge.
\nDebates questioned on the possible protein denaturation that could be induced by the surfactants present in Cat-An formulations, until it was realized that the surfactant in molecular form is solely responsible for protein denaturation [45]. The amount of such species is orders of magnitude lower than in solutions of the single surfactants.
\nThe above behavior is supported by the following thermodynamic considerations. The mutual interactions between polar head groups and alkyl chain packing play a key role in such systems. The observed behavior is different from that expected if ideality of mixing holds. In words, when fluid chains are presumably miscible in all proportions, the effect of surface charges modulates the area on which alkyl chains insist and determines their optimal packing. This results in a strong nonideality of mixing. It is not surprising, therefore, that the cmc for an aggregate of given stoichiometry can be orders of magnitude lower than expected from primitive considerations. To quantify such effects, it was assumed the validity of regular solution theory, and it was imposed, accordingly, that “the free monomer has an activity coefficient of unity” [46]. This is an oversimplified viewpoint, since surfactant solutions are strongly nonideal even below the cmc. To proceed along, we assume that the concentration above which added surfactant preferentially enters into aggregates (disregarding their size and shape) is the saturation threshold for the molecular species. In this way, the difference in composition between molecular and micellar form is immaterial. In two-component surfactant mixtures, thus, the cmc of the mixed system is defined according to the relation [47].
\nwhere γ2 and γ3 are the activity coefficients of the surfactants, having cmc3 and cmc2 as the corresponding critical values. cmcmixt is the critical concentration of the mixed system. X’s are the mole fraction of the given surface-active species. In the limits dictated by the regular solution theory [48], the solute-solute interaction parameter, b, results to be [47].
\nThe underlying rationale is as follows. Micelles are in fluid state with freely moving polar head groups. They may change position, adsorb/desorb counterions, and so forth. The constraints acting on alkyl chains are such that polar head groups close each other attract/repel. In consequence of that, mixed systems show strong deviations from the ideal behavior. This tendency is quantified by the mentioned b parameter. The effect is substantial (Figure 4) and explains why the amount of both surfactants in molecular form is orders of magnitude lower than expected. In words, Cat-An’s are in equilibrium with their own counterions and with tiny amounts of free surfactants, as well. This is the basis for using cat-anionic vesicles as cargos for proteins and DNA [49, 50, 51].
\nDependence of the cmc (in mol kg−1) on cetyltrimethylammonium bromide, CTAB, mole fraction for SDS-CTAB mixtures, at 25°C. The red line is for visual purposes; the full on the top refers to ideal mixing and the vertical to the nonideality of mixing. The blue area indicates the precipitation regime.
Sizes of Cat-An vesicles strongly depend on the formulation stoichiometry. As mentioned above, 1–1 mixtures form indefinitely large smectic crystals; on both sides of this threshold, sizes depend regularly on composition and approach values pertinent to the pure surfactant aggregates. In words, the excess surface charge determines vesicles sizes (Figure 5). It is worth to note that similar trends are also observed in mixtures of oppositely charged lipids [52]. The surface charge versatility is reminiscent of statements based on the relations between particles size and surface charge density. The higher the former, the lower the latter. This fact has important consequences on the links between (nominal) surface charge density and sizes. It is a sort of charge-based size tailoring and is quintessential in choosing the proper particles for transfection technologies. Another pertinent possibility along this line arises from thermal cycling procedures, which allow getting stable particles of proper size by raising the temperature above a certain value (which depends on the composition of the Cat-An mixture [53]. Thermally quenched vesicles obtained accordingly retain their size for indefinitely long times.
\nVesicle size (in nm) for SDS-CTAB mixtures, at 25°C, vs. the nominal surface charge excess of the vesicular aggregate. The light blue area in the center of the figure refers to the precipitation regime.
Sound procedures based on the combination of the above features allow getting vesicles of the desired size and surface charge density. This allows using them for DNA transfection technologies and protein immobilization onto vesicles [54]. An interesting feature is that vesicles of a given composition are destroyed by adding amounts of surfactant required for the complete neutralization of the Cat-An mixture. In consequence of that, the biopolymer which is eventually bound onto vesicles is released in its pristine form [55]. This is a terrific possibility for bio-intended technologies.
\nThis contribution focuses on the possibilities offered by surfactants and their mixtures in selected bio-intended applications. The mentioned systems are niche fields, but are becoming of relevant impact in a lot of practical purposes. Think, for instance, that applications in shampoos and similar products almost always include silk proteins as adjuvants of hair state and health. Transfection, conversely, is quite appealing for biochemistry and molecular biology applications. In many aspects, thus, both fields of research are on the same line as those originally intended in the pre-Christian age. It is as if we were moving back to the roots of surfactancy. Luckily, we have much more knowledge in the field, and this allows us to exploit applications on more conscious grounds.
\nLicense
\n\nBook Chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen maintains a very flexible Copyright Policy that ensures that there is no copyright transfer to the publisher. Therefore, Authors retain exclusive copyright to their work. All Monographs are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).
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