\r\n\tNotably, the book encourages academic scholars and researchers to contribute to the modern concepts of CSR. Fundamentally, it speaks for well-developed literature for entrepreneurs and managers, thus assisting them in the decision-making process. \r\n\tFurthermore, this book is of great value to policymakers, practitioners, and corporations, thus contributing to various disciplines (e.g., social science and management). \r\n\tThese proposed themes encourage future researchers and professionals to share their ideas, concepts and work concerning these subject domains. All these suggested topics had recommended under the rubrics of CSR. Perhaps, all the professionals, researchers, and scholars are welcome to submit their piece of work, in particular to the suggested topics. \r\n\tIndeed, the recommended topics include the following but are not limited to these only. \r\n\t• Corporate Governance and Sustainability \r\n\t• Green Innovation and CSR \r\n\t• Social Entrepreneurship \r\n\t• Green Economy and Social and Environmental Sustainability \r\n\t• Sustainable Development and Industrialization
",isbn:"978-1-80356-165-3",printIsbn:"978-1-80356-164-6",pdfIsbn:"978-1-80356-166-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"e3be182f32c4d9b8e44e95e86ee1366b",bookSignature:"Dr. Muddassar Sarfraz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11602.jpg",keywords:"Sustainability, Stakeholders, Corporate Citizenship, Sustainable Development, Decision-making Process, CSR, Organizational Performance, Financial Performance, Corporate Reputation, Environmental Performance, Environmental Strategy, Green Innovation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 2nd 2022",dateEndSecondStepPublish:"March 2nd 2022",dateEndThirdStepPublish:"May 1st 2022",dateEndFourthStepPublish:"July 20th 2022",dateEndFifthStepPublish:"September 18th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in Business Management and Sustainability, Associate Editor of Frontiers in Psychology Journal, and published several research articles.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"260655",title:"Dr.",name:"Muddassar",middleName:null,surname:"Sarfraz",slug:"muddassar-sarfraz",fullName:"Muddassar Sarfraz",profilePictureURL:"https://mts.intechopen.com/storage/users/260655/images/system/260655.jpeg",biography:"Dr. Muddassar Sarfraz works as an assistant professor at Wuxi University, China. He completed a postdoctoral fellowship in Business Management at the Business School of Hohai University, China. He has published numerous papers in foreign authoritative journals and academic conferences at home and abroad. He is senior editor of Cogent Business & Management, associate editor of Frontiers in Psychology, Energies, and Future Business Journal, and guest editor of Frontiers in Environmental Sciences and INQUIRY. He is a member of the British Academy of Management, Chinese Economists Society (USA), World Economic Association (UK), and the American Economic Association, and an ambassador of the MBA program at Chongqing University, China. 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1. Introduction
\n
Psoriasis is a disease that has been accompanying the existence of humans. The ancient Greeks described an illness that seems to be psoriasis, but it could be confused with leprosy or Hansen’s disease [1]. Because psoriasis develops naturally in humans but rarely in other species [2, 3], the study of this disease was possible only after progress was made on immunology and on genetic engineering knowledge. Although reports on animals with psoriatic lesions due spontaneous mutations exist, the phenotype does not completely resemble human psoriasis, as occur with the homozygous asebia (Scd1ab/Scd1ab) mutant mice, the Flaky skin mice (Ttcfsn/Ttcfsn) and the spontaneous chronic proliferative dermatitis mutation mice [4, 5]. Now, with the advances on genetic engineering, some transgenic animals and animals with targeted mutations (knockout and knock‐in) have been developed to study psoriasis. In the case of knockout models, the targeted gene is inactivated and the phenotype is caused by the absence of the targeted gene product. In the case of knock‐in model, the gene is modified through targeted point mutation, with the addition or deletion of a nucleotide, instead of complete disruption of the target gene expression, and the phenotype depends on the expression of modified gene products. Knockout and knock‐in animals are also developed with the use of tissue specific promoters to eliminate or express the targeted gene, and even more, the expression or suppression of the gene could be controlled by specific promoter regulators, where antibiotics and hormones are frequently used [6].
\n
Another strategy to study psoriasis and other dermatologic illnesses in vitro is the development of 2nd‐ or 3rd‐dimensional cell co‐cultures. These systems have the limitation that so far has not been possible to include all the cellular types that are part of the skin, but have been very useful to evaluate new drugs for treatment [7].
Xenotransplantation was the first approach generated as animal model for the study of psoriasis and for the evaluation of anti‐psoriatic treatments that consists in the transplantation of human skin in the back of inmunodeficient mice. In 1994, the first murine psoriasis model done in mice with severe combined immunodeficiency (SCID) was described. These mice have the so‐called scid mutation that affects the “protein kinase DNA activated catalytic polypeptide” (Prkdc/DNA‐PKcs), causing a defect in the antigen receptor gene rearrangement of lymphocytes, and consequently a SCID of the T‐ and B‐cell systems [8]. In these mice, the psoriatic phenotype is kept for 2 months, enough time for the analysis of the disease. Later, it was demonstrated that mice with non‐psoriatic human skin transplants that received lymphocytes from the psoriatic skin developed psoriasis; these facts demonstrated the importance of the immunologic factor for the development of this disease [9]. Also, the so‐called nude mice are used to study psoriasis; these mice have a mutation in the forkhead box transcription factor N1 that results in defective thymus development, and therefore in lack functional T cells, or nude mice that lack recombinase activating genes 1 (Rag1) and 2 (Rag2) involved in the development of T and B cells.
This transient model of psoriasis‐like disease was developed by Van der Fits et al. [10], using non‐genetically modified healthy mice daily treated with topic imiquimod or resiquimod (TLR7‐TLR8 ligand) for 6 days. This simple model shows wide characteristics described in the human psoriatic skin lesions, including: activation of pDC, Th17 cells producing IL‐17, IL‐22 and IL‐23, activation of angiogenic process and hyperproliferacion of keratinocytes. IMQ‐Mu‐Pso model is generated due to an acute inflammation in the epidermis induced by imiquimod, hyperactivating the innate immunity and leading the adaptive immunity to produce great amounts of IL‐17. IL‐17, in turn, induces angiogenesis and proliferation of keratinocytes, as biological characteristics of psoriatic lesions. IMQ‐Mu‐Pso also demonstrated that undisrupted molecular and cellular mechanisms are able to break inflammation, as mice used for this model are healthy mice that show the highest production of inflammatory cytokines on the third day of treatment and show the highest development of psoriatic skin on the sixth day, but after this time, the mice are able to revert the inflammatory process as they are not genetically compromised. The short lasting presence of psoriatic lesions is an inconvenience of this model, although it has been widely used to elucidate the pathogenesis of psoriasis, and very interesting data have been published [10].
\n
\n
2.3. Intestinal microbiome affects the induction of psoriasis
\n
The absence of 100% concordance between monozygotic twins suggests a crucial role of environmental factors for the development of psoriasis, as only 35–75% of monozygotic twins develop psoriasis; alcohol intake and smoking are considered non genetic factors that predispose individuals to develop psoriasis [11]. Intestinal microbiota has an important effect on the development and function of the immune system, for instance, a specific subset of microbiota has been shown to play roles in the development of Th17, meanwhile other subset favors the development of Treg cells [12]. Another study showed that microbiota from skin of psoriatic patients is different from healthy subjects; Proteobacteria were present at significantly higher levels in the psoriatic skin compared to limb skin used as control (52 vs. 32%, p = 0.0113), and in the same study, both Staphylococci and Propionibacteria were significantly lower in psoriasis versus control (p = 0.051, 0.046, respectively) [13]. In 2015, Zanvit et al. demonstrated that psoriasis is mediated by the early interaction between certain subset of bacterial microbiota and cells of immune system [14]. They treated 4‐week‐old mice with oral antibiotics (vancomycin and polymyxin B) showing a decrease in the severity of psoriasis compared to mice without antibiotics using the IMQ‐Mu‐Pso model. IL‐17+ and IL‐22+ T cells were significantly decreased in skin and gut in the antibiotic‐treated mice; however, the Foxp3+ Treg cells were significantly increased in the skin of these mice. In contrast, when neonatal mice received the antibiotic treatment and the psoriasis was induced with imiquimod as 4‐week old, they observed an increase in the severity of disease compared to mice without antibiotic treatment evidenced by the presence of immunological cells infiltration and by the increase of thickness in dermis; besides they did not find augment of IL‐17+ cells, but significant increase of IL‐22+ cells. The intestinal microbiota was also considerably different between mice treated with antibiotics as adults from those treated as neonates [14]. These results settle that among the factors that predispose to psoriasis is intestinal microbiota that depends on breast feed as neonates, type of food intake, but also on the use of antibiotics.
\n
\n
2.4. Disruption of NFκB and AP‐1 to generate psoriasis in animal models
\n
Innate immunity in skin is mediated by the activation of membrane receptors expressed on dendritic cells, Langerhans cells and macrophages activated by pathogens‐ or damage‐molecular patterns (PAMP or DAMP). After ligand‐receptor interaction, molecular signaling events occur into the cell leading to the activation of transcription factors, such as NFκB and AP‐1 that translocate into the nucleus for the expression of cytokines and antimicrobial peptides [15]. The malfunctioning in the regulation of the activity of these transcription factors could lead to the development of psoriatic lesions, as we next describe.
\n
In unstimulated cells, NFκB dimers are sequestered in the cytoplasm by a family of inhibitors called IκB (Inhibitor of κB), and the IκB proteins mask the nuclear localization signals (NLS) of NFκB proteins and keep them sequestered in an inactive state in the cytoplasm. Activation of NFκB is initiated by the signal‐induced degradation of IκB proteins; this occurs primarily by the activation of a kinase called IκB kinase (IKK). When activated by PAMPs or DAMPs, IKK phosphorylates two serine residues located in IκBα’s regulatory domain, and then IκBα is ubiquitinated and degraded by the proteasome. With the degradation of IκBα, NFκB dimer is freed to enter into the nucleus to initiate the expression of specific genes that have DNA‐binding sites for NFκB at their promoter site. The transcription of the targeted genes initiates a physiological response, for example, inflammation, cell survival and cellular proliferation. In fact, NFκB turns on the expression of its own repressor, IκBα. The newly synthesized IκBα then inhibits NFκB activity controlling the function of NFκB in an oscillatory way [15].
\n
In IMQ‐Mu‐Pso, the severity of psoriatic lesions has been associated with a reduced presence of IκBα due over‐degradation and in consequence with an enhanced NFκB activation. IκBα knockout mice developed psoriasis and died within the 7th–10th day after birth. The histological analysis showed myelopoietic tissues enlarged and diffusely distributed, and also alterations in the liver with enhanced splenic extramedullary hematopoiesiswith increased presence of monocytes/macrophages was seen [16].
\n
“β‐transducin repeat‐containing protein” (β‐TrCP) serves as substrate recognition component of E3 ubiquitin ligase that control the stability of important regulators of signal transduction, including IκBα. Mice with down‐regulation of βTrCP ameliorate IMQ‐Mu‐Pso skin lesions, as IκBα does not degrade, keeping NFκB into the cytoplasm. This interesting finding suggests that βTrCP could be a novel target for developing agents to treat psoriasis, since it is involved in the NFκB signaling to regulate inflammation [17].
\n
IκBζ is another molecule that interacts with NFκB, but inside the nucleus. This molecule has been recently identified as a key regulator in the development of psoriasis [18]. IκBζ is increased in psoriatic skin compared to non‐psoriatic skin from the same patient. Some studies suggest that IκBζ associates with NFκB p50 subunit and binds to specific IκBζ response elements located in the promoter region of targeted genes consisting of NFκB‐ and C/EBP (CCAAT/enhancer‐binding protein)‐binding sites and exerts its transcription‐enhancing activity on secondary response genes primarily by chromatin remodeling [19]. IκBζ is expressed in human keratinocytes induced with IL‐17 and is a direct transcriptional activator of TNFα/IL‐17‐inducible psoriasis‐associated proteins such as IL‐8, IL‐17C, IL‐17A22, IL‐19, IL23, IL22, CCL20 and hBD220. Interestingly, in imiquimod‐treated IκBζ‐deficient mice, psoriatic skin is not observed, and the molecules induced by TNFα/IL‐17 are significantly down‐expressed [20].
\n
The dysfunctional activity of other transcription factors, for instance, AP‐1 and STAT3, also contributes to skin inflammation development [21]. Mice with deficient expression of JunB and c‐Jun, and mice with over‐expression of FOS, generate a phenotype resembling the histological characteristics of psoriasis, including the production pro‐inflammatory cytokines. Besides, JunBexpression is reduced in epidermal keratinocytes of psoriatic patients in comparison with cells from healthy subjects [21]. Moreover, STAT3 transgenic mice and SOCS3 knockout mice (the negative regulator of STAT3) have constitutive activation of STAT3 and both develop murine IL‐6‐driven psoriasis [22, 23].
\n
\n
2.5. The role of cytokines in psoriasis
\n
Other sort of psoriatic animal models includes those where cytokines and cells of immune system are involved. The importance of type I interferons in the psoriasis was demonstrated in “IFN regulatory factor‐2” (IFNR‐2)‐deficient mice, a transcriptional repressor for IFN‐αβ signaling. These mice developed skin lesions similar to human psoriasis [24], in fact, type I interferons promote the activation of dermal dendritic cells (dDCs) [25].
\n
Another cytokine with importance for the development of psoriasis is IL‐36, an IL‐1 family sub‐member. The over‐expression of IL‐36α in transgenic murine (K14/IL‐36) keratinocytes promotes acanthosis, hyperkeratosis, cells infiltration and increased expression of cytokines and chemokines [26]. The deficiency of IL‐36RA (the natural antagonist of IL‐36) in IL‐36α (K14/IL‐36, IL‐36RA−/−)‐transgenic mice exacerbates the severity of psoriasis; histological analysis reveals intracorneal and intraepithelial pustules, parakeratotic and orthokeratotic hyperkeratosis, dilated superficial dermal blood vessels, and dermal inflammatory infiltrate. Additionally, mice deficient to IL‐36 or in its receptor IL‐36R are protected from IMQ‐Mu‐Pso [26]. In turn, IL‐1β, TNFα, and IL‐36 activate dDC and induce the production of IL‐23, necessary for naive T cells to polarize to Th17, suggesting that IL‐23 could be the link between the innate and adaptive immune response that occur in psoriasis [27]. In fact, it is possible to obtain psoriasiform skin in wild‐type mice with nothing more but the inoculation of recombinant IL‐23 or IL‐17 [28]. In contrast, IL‐35 has a potent immunosuppressive effect on HaCaT keratinocytes treated with TNF‐α and IL‐17 suppressing the expression of IL‐6, CXCL8, and S100A7 [28]. In IMQ‐Mu‐Pso and K14‐VEGF transgenic mice model, IL‐35 reduced M1 macrophages (F4/80+CD80+), whereas anti‐inflammatory M2 macrophages (F4/80+CD206+) were increased in the spleen and ear. IL‐10–secreting CD4+, FoxP3+, CD25+ T cells were increased in those tissues, although IL‐10–secreting CD25‐T cells were also increased [29]. These results suggest that IL‐35 treatment for psoriasis increases M2 macrophages as well as IL‐10 production but suppresses Th17 cells development, consistent with the effect of IL‐35 on Treg expansion, although not all IL‐10 was secreted by Treg cells.
\n
\n
2.6. Cellular immunology in psoriasis
\n
The insufficient regulation of specific cellular immune response is also involved in the development of psoriasis [30]. In normal conditions, Treg cells regulate the activity of auto‐reactive Th1 and Th17 cells, but in psoriasis Treg cells might not be functional, as was evidenced in the CD18hypo mouse model [31]. Homozygous PL/J CD18 hypomorphic (CD18hypo)‐mice developed spontaneously psoriasis‐like skin in 12‐ to 14‐week‐old mice. CD18 is a molecule that together with CD11a constitutes an adhesion molecule of the β2 integrin family, important for the complete function of Treg cells. It has been suggested that CD18hypo mice induce psoriasis because CD18‐low expressing Treg cells, or with a not fully active molecule, cannot regulate the activity of auto‐reactive Th1 and Th17 cells, since these mice improve when Treg cells from normal mice are transferred [32]. In CD18hypo mice, psoriatic lesions meliorate when macrophages are eliminated by the use of clodronate liposomes in the skin [33]. These results show the importance of Treg cell and macrophages in the evolution of psoriasis.
\n
\n
2.7. Implantable synthetic cytokine‐converter cells model
\n
Schukur et al. [34] designed the so‐called implantable synthetic cytokine converter cells system based on the observation that psoriatic patients have high concentrations of TNFα and IL‐22, and on the fact that IL‐4 and IL‐10 cytokines have an important anti‐psoriatic effect. Considering the previous, they generated by genetic engineering human cells to react to high concentrations of TNFα and IL‐22; these cells would be implanted to psoriatic patients and activated by TNFα and IL‐22 from a psoriatic flare, and as a result, they would produce therapeutic doses of IL‐4 and IL‐10 to control inflammation. To achieve the goal, HEK‐293T cells were co‐transfected with the plasmids pNFκB‐hIL‐22RA‐pA, phCMV‐hSTAT3‐pA, pSTAT3‐mIL‐4‐pA and pSTAT3‐mIL‐10‐pA. The authors first confirmed that co‐transfected cells produced important levels of IL‐4 and IL‐10 when stimulated with TNFα and IL‐22 in vitro [34]. TNFα activated the production of IL‐22 receptor, and in turn IL‐22 activated STAT3 signaling to induce the production of IL‐4 and IL‐10, to generate an anti‐inflammatory environment. When co‐transfected HEK‐293T cells were intraperitoneally implanted into mice with IMQ‐Mu‐Pso the cytokines associated with the pathogenesis of psoriasis, such as IL‐17, IFNα and C‐X‐C motif chemokine 9 (CXCL9), decreased substantially and a considerable increase in the production of the anti‐inflammatory cytokines IL‐4 and IL‐10 was observed on day 5. Only the skin of animals with implanted co‐transfected cells containing the antipsoriatic cytokine converter showed reduced skin lesions, evidenced by the reduction of erythema, scaling, and thickening. This is an interesting approach to treat psoriasis, although the complexity relies on the requirement to co‐transfect cells from every single patient to avoid transplant rejection. Meanwhile, this system was also evaluated in vitro using blood from psoriatic patients and from healthy individuals, and interestingly only in blood from psoriatic patients increased levels of anti‐inflammatory cytokines were detected [34].
\n
\n
\n
3. Angiogenic factor in psoriasis
\n
The altered function of angiogenic molecules also produces psoriasis. “Vascular endothelial growth factor” (VEGF)‐transgenic mice [35], “endothelial specific receptor tyrosine kinase” (K5‐Tie2)‐transgenic mice [36], and “transforming growth factor beta 1” (K5‐TGFβ1)‐transgenic mice [37] are psoriasis animal models that highlight the importance of angiogenesis in this pathology. VEGF is a crucial factor that mediates the angiogenesis of blood vessels and is highly expressed in the psoriatic skin lesions. VEGF induces microvascular alterations in the dermal papillae, which facilitate the development and persistence of the psoriatic lesions [35]. Moreover, the increased vasculature and permeability provide nutrition to the hyperproliferating keratinocytes and promote the migration of inflammatory cells. The 6‐month‐ old K14‐VEGF mice develop psoriasis, but if these mice are treated with imiquimod at 8‐week old, the skin thickens, chemokines CXCL‐9/10, CCL‐20 and CCR6 increase, cytokines IL‐23, IL‐17, TNFα, and (IFN)‐γ rise, and the cells CD11c+ DCs, Th17, Th1, γδ‐T increase. In wild‐type mice IMQ‐Mu‐Pso skin lesions last until day 7 of treatment, but in K14‐VEGF mice treated with imiquimod, all the parameters described above are stable until day 14 [38]. This combined model IMQ‐K14‐VEGF is more appropriate for long‐term studies compared to IMQ‐Mu‐Pso model, which is only an acute chemical‐stimulated model.
\n
Tie2 is the angiopoietin receptor that together with VEGF is essential for proliferation, maturation and for the maintenance of blood vessels. Hyperproliferation of keratinocytes and abundance of immunological cells infiltration, including Th17 cells, are detected in psoriatic skin. The over‐expression of VEGF is promoted by TGFβ but also can be regulated by HIF‐1α, as it is over‐expressed in the psoriatic skin [36].
\n
\n
4. The role of keratinocytes in psoriasis
\n
4.1. PPAR β/δ
\n
The “peroxisome proliferator‐activated receptor” (PPAR β/δ) transgenic mice, and the human keratinocytes autocrine growth factor (amphiregulin) transgenic mice [39, 40] both resemble psoriasis because they participate in the proliferation and differentiation of keratinocytes [41]. PPAR β/δ receptor is induced by TNFα, contributes to STAT3 phosphorylation, blocks apoptosis in keratinocytes, induces angiogenesis, and is up‐regulated in human psoriatic skin [42]. In fact, PPAR β/δ directly induces the differentiation of keratinocytes, and in the transgenic mouse model, a light augment of Th17 is observed [43].
\n
\n
4.2. NFκB inhibits proliferation in keratinocytes
\n
Genome‐wide association studies suggest a link between psoriasis and the NFκB pathway, and this proposal has been supported by mouse models. Evidence gathered from diverse studies has shown that NFκB has a growth inhibitory function in the skin. Mice with epidermis‐specific deletion of IKK2 (which mediates canonical NFκB activation) develop severe inflammatory skin disease that is mediated by TNFα, suggesting the critical function of IKK2‐mediated NFκB activity in epidermal keratinocytes to regulate mechanisms that maintain the immune homeostasis of the skin [44].
\n
Grinberg‐Bleyer, et al. [45] described a murine psoriasis model that lacks the expression of p65 and c‐Rel in epidermal cells. After birth, these mice developed severe psoriasis; early lesions were well‐demarcated, scattered and rigid, with scaly plaques without edematous or exudative reaction aspect. H&E staining revealed epidermal thickening, hyperkeratosis and focal parakeratosis, as well as mononuclear infiltrates in the epidermis, which are features of psoriatic lesions. In this model, psoriatic lesions were resolved 30 days after birth by Treg cells effect, but when these cells were eliminated by the use of anti‐CD25 antibodies, the deficient mice showed a worsened pathology and the psoriatic lesions were reversed with anti‐TNFα treatment [45]. Also RelA has a growth‐inhibitory role in keratinocytes and prevents their differentiation [46]. Together, these results indicate that activation of canonical NFκB pathway in keratinocytes is required for their optimal differentiation and for the maintenance of immune homeostasis in the skin.
\n
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4.3. Prokineticin 2
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Prokineticin2 (PK2), also named Bv8, is a small 8 KDa protein found in serum and dermis of psoriatic patients. PK2 participates in numerous important physiological processes including inflammation, neurogenesis, tissue development, angiogenesis, and even nociception [47, 48]. This peptide is mainly expressed in brain but can also be found in skin, bone marrow, lymphoid organs, granulocytes, dendritic cells and macrophages [49]. He et al. [50] found that bacterial products, including LPS and DNA, promoted in macrophages the production of PK2 and inflammatory factors, suggesting that infection is a primary inducer of PK2. The authors demonstrated that in macrophages PK2 induced high production of IL‐1β, and in keratinocytes and fibroblast co‐cultures PK2 induced IL‐6, IL‐8 and GM‐SCF. In vivo PK2 promoted the differentiation of fibroblast and keratinocytes [51]. Besides, when PK2 was over‐expressed in psoriasis‐K14‐VEGF transgenic mouse model, psoriatic lesions were gradually aggravated, as evaluated by increase of redness, swelling, weight, thickness, scaly epidermis, keratinocyte hyper‐proliferation, and increase of IL‐1β, TNFα, IFNγ, IL‐12, IL‐22, IL‐23, IL‐17 in the ear; moreover, increase of lymph node weight was also seen. On the contrary, in psoriatic‐K14‐VEGF transgenic mouse model with PK2 down‐regulated, the psoriatic lesions were abrogated [50]. The results suggest that PK2 aggravates psoriasis by the promotion of keratinocytes and fibroblasts proliferation, inflammation, and angiogenesis.
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\n
4.4. Tnip1
\n
The big dilemma about psoriasis is whether the root of the problem falls on keratinocytes or on immunological cells dysfunction. It has been well described that IL‐23‐producing myeloid cells and IL‐17–producing T cells are abundant in psoriatic skin, and that IL‐23 and IL‐17 induce in keratinocytes and fibroblasts high production of chemokines, which in turn, recruit even more immunological cells creating a feedback loop that worsens the disease. In keratinocytes and immunological cells, “TNFAIP3‐inter‐acting protein 1” (Tnip1) down‐regulates the chemokines production induced by IL‐17 [50]. Ippagunta et al. [52], using the IMQ‐Mu‐Pso model under the Tnip‐keratinocyte‐specific‐deletion mice (Tnip1flox/flox K14‐Cre), found that keratinocytes contribute intrinsically to psoriasis because when keratinocytes lost Tnip1 function they could not control the production of chemokines induced by IL‐17. Tnip1flox/floxK14‐Cre mice developed severe psoriasis when low doses of imiquimod were used, even at concentrations on which WT mice do not develop psoriasis. Interestingly, when bone marrow cells from Tnip1‐/‐ mice were transferred to WT mice and treated with low doses of imiquimod, they did not developed psoriasis, confirming that the lack of function of Tnip1 in keratinocytes and fibroblast, but not in hematopoietic lineage cells, generate psoriasis [52]. With these results, the authors provide evidence that specifically skin‐resident keratinocytes contribute causally to psoriasis.
\n
\n
\n
5. In vitro models for the study of psoriasis
\n
As we previously mentioned, animal models have been very useful to dissect the molecular and cellular mechanisms for psoriasis development. These models have been also advantageous to evaluate new pharmaceuticals, nevertheless the physiology, anatomy and molecular differences between animal models and humans cause that only around 10% of new treatments assayed on phase I, be really useful in humans [53]. Although humanized models have also been developed, immunodeficient animals are most commonly used. Alternative methods have been developed to analyze the effect of new anti‐psoriatic drugs; 2D, 2D+membrane, and 3D cell cultures have been designed [54]. 2D model consists of primary explants of keratinocytes or fibroblasts from psoriatic patients cultured over extracellular matrix proteins to evaluate cellular proliferation, cellular differentiation and cytokines production [55]. In the 2D+membrane model, two cell types are co‐cultured separated by a synthetic membrane to evaluate the interconnection between two cell types in the pathology [56]. 3D cultures, also known as organotypic culture system (OCS), allow the growth of complex biological systems in vitro in a way that resembles part of their normal physiology and function. OCSs are powerful as experimental platforms in preclinical dermatological research, helping to validate mechanisms of diseases and to test the therapeutic potential of candidate drugs [57]. The new generation of 3D cultures connected to biosensors or chips allows real‐time monitoring of biological parameters such as loss of water and electrophysiologic parameters [58].
\n
\n
6. Conclusion
\n
The actual hypothesis about the cellular and molecular mechanisms that lead to the development of psoriatic lesions has been established by the use of animal models. The use of xenotransplants confirmed the important role of immunology in this disease. The studies done in genetically modified mice that overproduce (transgenic) or lack (knockout) certain proteins reveal specific protagonists of innate or adaptive immunity, angiogenesis or proliferation for the development of psoriasis.
\n
In Figure 1, we represent a developing inflammation mechanism generated in the skin of healthy individuals denoted as a brown cogwheel system, where a trigger induces the innate and adaptive immune response, and in turn angiogenesis and keratinocytes proliferation are activated. Every cog represents one participant in inflammation: cell (DCs, macrophages, iLC IL‐17+, Th1, Th17, keratinocytes, between others) or molecule (TLRs, NFκB, βTrCP, IκBζ, Stat3, TNFα, IFNα, IL‐12, IL‐36, IL‐23, Th1, IL‐6, Th17, IL‐17, CCR6, VEGF, Tie2 TGFβ1, PPARαβ, PK2, between others). The red arrows indicate the movement of the cogwheels for the progression of inflammation. In healthy people, the inflammation is controlled by the activation of anti‐inflammatory process after damage reparation. The cells (Treg and M2 macrophages) and molecules (IκBα, JunB, SOCS‐3, IFNR‐2, IL‐36RA, IL‐4, IL‐10, IL‐35, CD18, VHL, Tnip‐1, between others) involved in the anti‐inflammatory process are represented in the gray cogwheels. The blue arrows indicate the movement of the cogwheels for the progression of anti‐inflammation. The “ghost” cogs (discontinuous lines) represent those dysfunctional molecules or cells that disrupt effectiveness in the control of inflammation, favoring the development of psoriasis.
\n
Figure 1.
Inflammatory process. The developing inflammation mechanism generated in the skin is represented in this cogwheel system, where innate immune response, adaptive immune response, angiogenesis and cellular proliferation are represented in independent but interconnected cogwheels. Brown cogwheels represent inflammatory mechanisms moving in a pro‐inflammatory sense (red arrows), where each cog represents one participant in inflammation (cell or molecule). Gray cogwheels represent the anti‐inflammatory mechanism spinning the wheels in the opposite direction (blue arrows) to regulate inflammation. The “ghost” cogs (discontinuous lines) represent dysfunctional cells or molecules that disrupt effectiveness in the control of inflammation, favoring the development of psoriasis. Some antibodies interfere with the spinning of pro‐inflammatory cogwheels, representing therapies with antibodies developed to control psoriasis. Question marks represent molecules to be discovered.
\n
Based on all the facts discussed in this chapter, we can conclude that psoriasis occurs in individuals with the anti‐inflammatory regulation disrupted in immunological but also in non‐immunological skin‐resident cells.
\n
Acknowledgments
\n
This work was supported by a grant from the “SIP‐IPN” (Num. SIP20161111). SRM, JCCD, SMPT and MECD belong to COFAA, EDI‐IPN and SNI fellowships. IMT belongs to BEIFI and CONACyT fellowships.
\n
\n',keywords:"psoriasis, animal models, skin immunology, angiogenesis, keratinocytes",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54804.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54804.xml",downloadPdfUrl:"/chapter/pdf-download/54804",previewPdfUrl:"/chapter/pdf-preview/54804",totalDownloads:1805,totalViews:1225,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:63,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"October 4th 2016",dateReviewed:"March 3rd 2017",datePrePublished:null,datePublished:"July 5th 2017",dateFinished:"April 12th 2017",readingETA:"0",abstract:"Psoriasis is a skin disease mainly developed in humans, although it is also seen in monkeys and dogs. Animal models with psoriasis-like lesions have been a key factor for its understanding. Xenotransplants of human psoriatic skin in immunodeficient mice were the first approach for the association of immunologic problems with the development of psoriasis and have been also useful for the evaluation on new therapeutic agents. Imiquimod-induced murine psoriasis is nowadays one of the most used animal models to study this disease, perhaps because healthy wild-type mice are used, which means that it is an affordable model, easy to generate, and, more importantly, resembles the inflammatory, angiogenic and hyperproliferative characteristics of human psoriasis. Several transgenic (over-expressing VEGF, Tie2, TGFβ, STAT3, IL-36, PPARβ/γ) and knockout (lacking IκBα, JunB, IFNR-2, IL-36RA, CD18, IKK2) mice have been useful for the association of specific molecules for the development of psoriasis. Other approach has been the use of both transgenic/knockout mice and imiquimod treatment, where the importance of βTrCP, IκBζ, IL-35 and Tnip1 for the development of psoriasis was found. In this chapter, some of these animal models are discussed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54804",risUrl:"/chapter/ris/54804",book:{id:"5760",slug:"an-interdisciplinary-approach-to-psoriasis"},signatures:"Sandra Rodríguez‐Martínez, Juan C. Cancino‐Diaz, Isaí Martínez‐\nTorrez, Sonia M. Pérez‐Tapia and Mario E. Cancino‐Diaz",authors:[{id:"181148",title:"Dr.",name:"Juan C.",middleName:null,surname:"Cancino-Diaz",fullName:"Juan C. Cancino-Diaz",slug:"juan-c.-cancino-diaz",email:"jccancinodiaz@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Instituto Politécnico Nacional",institutionURL:null,country:{name:"Mexico"}}},{id:"184950",title:"Dr.",name:"Sandra",middleName:null,surname:"Rodríguez-Martínez",fullName:"Sandra Rodríguez-Martínez",slug:"sandra-rodriguez-martinez",email:"sandrarodm@yahoo.com.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"184951",title:"Dr.",name:"Mario E.",middleName:null,surname:"Cancino-Diaz",fullName:"Mario E. Cancino-Diaz",slug:"mario-e.-cancino-diaz",email:"mecancinod@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"205439",title:"Dr.",name:"Sonia M",middleName:null,surname:"Pérez-Tapia",fullName:"Sonia M Pérez-Tapia",slug:"sonia-m-perez-tapia",email:"smpt.2011@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"205440",title:"MSc.",name:"Isaí",middleName:null,surname:"Martínez-Torres",fullName:"Isaí Martínez-Torres",slug:"isai-martinez-torres",email:"isai_mtz88@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Immunological factors in psoriasis",level:"1"},{id:"sec_2_2",title:"2.1. Humanized animal models (xenotransplantation)",level:"2"},{id:"sec_3_2",title:"2.2. Imiquimod‐induced murine psoriasis (IMQ‐Mu‐Pso)",level:"2"},{id:"sec_4_2",title:"2.3. Intestinal microbiome affects the induction of psoriasis",level:"2"},{id:"sec_5_2",title:"2.4. Disruption of NFκB and AP‐1 to generate psoriasis in animal models",level:"2"},{id:"sec_6_2",title:"2.5. The role of cytokines in psoriasis",level:"2"},{id:"sec_7_2",title:"2.6. Cellular immunology in psoriasis",level:"2"},{id:"sec_8_2",title:"2.7. Implantable synthetic cytokine‐converter cells model",level:"2"},{id:"sec_10",title:"3. Angiogenic factor in psoriasis",level:"1"},{id:"sec_11",title:"4. The role of keratinocytes in psoriasis",level:"1"},{id:"sec_11_2",title:"4.1. PPAR β/δ",level:"2"},{id:"sec_12_2",title:"4.2. NFκB inhibits proliferation in keratinocytes",level:"2"},{id:"sec_13_2",title:"4.3. Prokineticin 2",level:"2"},{id:"sec_14_2",title:"4.4. Tnip1",level:"2"},{id:"sec_16",title:"5. In vitro models for the study of psoriasis",level:"1"},{id:"sec_17",title:"6. 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Bv8, the amphibian homologue of the mammalian prokineticins, induces a proin‐flammatory phenotype of mouse macrophages. British Journal of Pharmacology. 2006;147:225‐234. DOI: 10.1038/sj.bjp.0706467'},{id:"B50",body:'He X, Shen C, Lu Q, Li J, Wei Y, He L, Bai R, Zheng J, Luan N, Zhang Z, Rong M, Lai R. Prokineticin 2 Plays a Pivotal Role in Psoriasis. EBioMedicine. 2016;13:248‐261. DOI: 10.1016/j.ebiom.2016.10.022'},{id:"B51",body:'Callahan JA, Hammer GE, Agelides A, Duong BH, Oshima S, North J, Advincula R, Shifrin N, Truong HA, Paw J, Barrera J, DeFranco A, Rosenblum MD, Malynn BA, Ma A. Cutting edge: ABIN‐1 protects against psoriasis by restricting MyD88 signals in dendritic cells. The Journal of Immunology. 2013;191:535‐539. DOI:10.4049/jimmunol.1203335'},{id:"B52",body:'Ippagunta SK, Gangwar R, Finkelstein D, Vogel P, Pelletier S, Gingras S, Redecke V, Häcker H. Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function. Proceedings of the National Academy of Sciences U S A. 2016;113:E6162‐E6171. PubMed PMID: 27671649'},{id:"B53",body:'Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nature Biotechnology. 2014;32:40‐51. DOI: 10.1038/nbt.2786'},{id:"B54",body:'Krueger GG, Jorgensen CM. Experimental models for psoriasis. Journal of Investigative Dermatology. 1990;95:56S‐58S. DOI: 10.1111/1523‐1747.ep12505791'},{id:"B55",body:'Van Ruissen F, de Jongh GJ, Zeeuwen PL, Van Erp PE, Madsen P, Schalkwijk J. Induction of normal and psoriatic phenotypes in submerged keratinocyte cultures. Journal of Cellular Physiology. 1996;168:442‐452. DOI: 10.1002/(SICI)1097‐4652(199608)168:2<442::AID‐JCP23>3.0.CO;2‐3'},{id:"B56",body:'Auriemma M, Brzoska T, Klenner L, Kupas V, Goerge T, Voskort M, Zhao Z, Sparwasser T, Luger TA, Loser K. α‐MSH‐stimulated tolerogenic dendritic cells induce functional regulatory T cells and ameliorate ongoing skin inflammation. Journal of Investigative Dermatology. 2012;132:1814‐1824. DOI: 10.1038/jid.2012.59'},{id:"B57",body:'Van den Bogaard EH, Tjabringa GS, Joosten I, Vonk‐Bergers M, van Rijssen E, Tijssen HJ, Erkens M, Schalkwijk J, Koenen HJ. Crosstalk between keratinocytes and T cells in a 3D microenvironment: A model to study inflammatory skin diseases. Journal of Investigative Dermatology. 2014;134:719‐727. DOI: 10.1038/jid.2013.417'},{id:"B58",body:'Wufuer M, Lee G, Hur W, JeonB, KimB, ChoiT,LeeS. Skin‐on‐a‐chip model simulating inflammation, edema and drug‐based treatment. Scientific Reports. 2016;6:37471. DOI:10.1038/srep37471'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Sandra Rodríguez-Martínez",address:null,affiliation:'
Immunology Department, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
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Immunology Department, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
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Immunology Department, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
UDIBI, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
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1. Introduction
1.1 Mitochondria
Mitochondria are essential sub cellular mammalian organelles found in eukaryotes. It is surrounded by two lipid bilayers which is commonly associated with oxidative phosphorylation, a process that meets the majority of cellular energy demands. It is involved in many other cellular functions such as fatty acids oxidation, apoptosis, heme biosynthesis, metabolism of amino acids and lipids, and signal transduction [1]. They are central organelles controlling the life and death of the cell. Mitochondria contain their own DNA, which is maternally inherited. Mitochondrial density varies from one tissue to another [2]. Mitochondrial diseases are heterogeneous group of disorders, often characterized by morphological changes in the mitochondria, a defective respiratory chain and variable symptoms, ranging from severe metabolic disorders with onset in early infancy or childhood to late onset adult myopathies [3]. Mutations in mitochondrial DNA (mtDNA) are the most frequent cause of mitochondrial diseases in adults. However, the mtDNA encodes only a subset of proteins of the different complexes of the respiratory chain [4]. Nuclear genes encode all the other mitochondrial proteins and most of the mitochondrial disorders are caused by mutations in the nuclear genes [5].
Mitochondria are ~0.5 to ~3 μm long tubular organelles that undergo continuous remodeling of their network by fusion and fission events [6]. Mitochondria forms an extensive network preserved in many cells by an intricate balance between fission and fusion, mitochondrial biogenesis and mitophagy [7, 8]. Mitochondria was identified as the main source of cell energy, and indeed mitochondria is a major site of ATP and macromolecule development. Equivalent-reducing electrons are fuelled by the ETC to produce an electrochemical gradient required for both the production of ATP and the active transport of selective metabolites, such as pyruvate and ATP, through the IMM [9]. Mitochondria, however, plays a variety of roles beyond energy production, including generation of reactive oxygen species (ROS), redox molecules and metabolites, control of cell signaling and cell death, and biosynthetic metabolism.
While mitochondria is best known for harvesting and storage of energy released by oxidation of organic substrates under aerobic conditions by respiration, their many anabolic functions are often ignored [7]. Biosynthetic functions of mitochondria are essential for tumorigenesis and tumor progression [10]. Tumor cells easily survive under hypoxic conditions by recycling NADH to NAD+ through lactate dehydrogenase (LDH) and plasma membrane electron transport (PMET) to enable continued production of glycolytic ATP [11].
2. Mitochondrial genetics
The human mitochondrial genome consists of 16,569 pairs of nucleotides of double-stranded, closed-circular molecules. It was first sequenced in 1981 and updated in 1999 [12, 13]. mtDNA contains no introns and only encodes 13 polypeptides, 22 transfer RNAs (tRNAs), and the mitochondrial protein synthesis genes 12S and 16S rRNA [14]. The 13 polypeptides of the respiratory complexes (RC) encode subunits (7 of 45 for RC-I, 1 of 11 for RC-III, 3 of 13 for RC-IV, and 2 of 16 for RC-V). Along with the remaining 85% of the other RC subunits, the four subunits that make up RC-II are nuclear-encoded [14]. About 22,000 proteins are encoded by nuclear DNA, about 1,500 of which contribute to the mitochondrial proteome. These nuclear encoded proteins include TCA cycle enzymes, amino acids, nucleic acid and lipid biosynthesis, mtDNA and RNA polymerases, transcription factors, and ribosomal proteins, in addition to all DNA pathway repair components. In the cytoplasm, these proteins are expressed and folded through the TOM/TIM complex upon entry through the mitochondrial outer membrane. From there, they find the outer mitochondrial membrane (OMM), the IMM, the intermembrane space (IMS) or the mitochondrial matrix at their specific positions [15]. There is no structural association of mtDNA with histones, as is nuclear DNA. Rather, it is closely associated with a variety of proteins, about 100 nm in diameter, in discrete nucleoids.
Germline mutations resulting in reduced or lost expression of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase have been identified in inherited paragangliomas, gastrointestinal stromal tumors, pheochromocytomas, myomas, SDH, papillary renal cell cancer (FH) and gliomas [16]. mtDNA mutations have been involved in neuromuscular and neurodegenerative mitochondrial disease [17, 18, 19] and complex diseases such as diabetes [20], cardiovascular disease [21, 22], gastrointestinal disorders [23], skin disorders [24], aging [25, 26] and cancer. Different human populations have different human mtDNA haplotypes, each with a specific mtDNA polymorphism fingerprint, transmitted through the maternal germline. These haplotypes are associated with the geographic origin of the population. Some human haplotypes are at greater risk of developing a certain form of cancer or neurodegenerative disorder during their lifetime than others [27, 28, 29]. The 22 mitochondrial tRNA genes have more than 50 percent of the mtDNA mutations involved in carcinogenesis [29].
The single nucleotide polymorphism, 3243A > G, which alters leucine mt-tRNA and thus affects the translation of 13 respiratory subunits, leading to fewer mitochondrial subunits and impaired OXPHOS, is the most common mtDNA mutation [30, 31]. Individuals can develop maternally inherited diabetes and deafness with 10–30 percent defective copies of tRNALeu. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are likely to occur in people with 50–90% defective copies [20, 30, 31, 32, 33, 34, 35]. The mutation of tRNALeu results in variable types of mitochondrial RC deficiency in various patients. By far, complex I (RC-I) deficiency is the most common finding in MELAS, although some patients have combined RC-I, RC-III and RC-IV deficiencies [30, 36]. Other mutations in mt-tRNA that play a role in human disease include: tRNAlys, which is associated with myoclonal epilepsy, tRNASer with deafness, and tRNAIle with cardiomyopathy [21].
3. Drivers of mtDNA mutations
mtDNA mutations are caused by ROS-mediated oxidative damage [28, 37]. ROS generation in the respiratory chain is an inherent part of OXPHOS. ROS plays an important role in many signaling processes and their levels are regulated by the antioxidant enzyme systems in the mitochondrial matrix and the IMS. However, in situations where OXPHOS is compromised due to misshapen respiratory complexes resulting in increased leakage of electrons to oxygen, ROS levels can overwhelm the antioxidant protection system and damage to nearby mtDNA [38, 39]. DeBalsi and colleagues suggest that errors produced by mtDNA replication and repair machines may also cause mtDNA mutations [40].
Human cells contain 17 different human DNA polymerases, but in mtDNA replication and repair, only polymerase gamma (Pol-γ) functions. A catalytic subunit and an accessory subunit consist of a nuclear-encoded Pol-γ holo-enzyme [40]. Pol-γ replicates high fidelity mtDNA with one misinsertion in every 500,000 new base pairs due to nucleotide selectivity and proofreading capacity [41]. More than 300 Pol-γ mutations have been associated with human illness, some of which occur in adulthood and are associated with aging, including different types of progressive external ophthalmoplegia (PEO) and Parkinson’s disease (PD) [40]. The role of Pol-γ in restricting mtDNA mutations has been demonstrated by homozygous, but not heterozygous, mutator mice with re-reading-deficient Pol-g developing multiple age-related disorders and shortening their lifespan. As their antioxidant capacities were the same and the degree of oxidative damage was comparable to wild-type mice, they acquired mtDNA mutations that were not caused by oxidative damage.
Somatic point mutations, great deletions and several linear deleted mtDNA fragments were acquired by the mutator mice. The mtDNA-specific Twinkle helicase, which unwinds mtDNA for Pol-γ synthesis, is another n-mitoprotein involved in mtDNA replication [42]. Overexpression of Twinkle in transgenic mice resulted in increased copy number of mtDNA and OXPHOS and some twinkle mutations are associated with mitochondrial myopathy [40]. Oxidative damage and defective replication are both likely to add to the overall mutational load of the mtDNA cell, and the contribution of each mutational driver is likely to change over time. Inevitable respiratory electron leakage from complexes I and III results in the formation of superoxide, O2− that can react with lipids, proteins and DNA [43, 44, 45, 46]. Superoxide can be quickly converted to H2O2 either naturally or through a manganese superoxide dismutase (MnSOD) dysmutation reaction, a resident of the mitochondrial matrix. In the presence of redox active metal ions, H2O2 can generate a highly reactive hydroxyl radical through the Fenton reaction (OH-) [47]. Multiple mtDNA damage sites, including single and double-strand breaks, abasic sites and base changes, are responsible for the OH-radical. Another oxidative burden is caused by damage to mitochondrial protein centers caused by O2− to Fe-S and involves subunits of complexes I, II and III as well as aconitase [48, 49, 50]. A significant target for ROS is provided by Labile Fe-S enzymes such as mitochondrial aconitase.
Mitochondria located in cells exposed to visible light generate ROS through interactions with mitochondrial photosensitizers, such as cytochrome c oxidase, of particular relevance to the eye, to produce ROS and mtDNA damage [50, 51]. Transferring energy from photoactivated chromophores to oxygen contributes to the formation of singlet oxygen, 1O2, which occurs in an excited state. 1O2 can produce ROS, such as O2− by interacting with diatomic oxygen and directly reacting with dual-bond electrons without the formation of free radical intermediates [52]. It is also important to remember that, from non-mitochondrial sources, various tissues within the eye may also produce substantial amounts of ROS. For instance, lipofuscin (an age-related pigment that accumulates with age in RPE cells) is a potent photoinducible ROS generator, and NADPH oxidase is considered to be a major source of superoxide in microvascular endothelial cells. Studies indicate that ROS may also contribute to exogenous mitochondrial oxidative damage, exacerbating mitochondrial dysfunction [51, 53, 54].
4. Ophthalmologic mitochondrial dysfunction
Mitochondrial disease can manifest in any organ at any age. In general terms, tissues and organs (retina, optic nerve, brain, heart, testis, muscle, etc.) that are heavily dependent upon oxidative phosphorylation bear the brunt of the pathology. It is also puzzling that many mitochondrial disorders affect multiple organ systems, whereas others have a highly stereotyped and organ specific phenotype. These subtle interactions between nuclear and mitochondrial genes in health and disease will have broader relevance for our understanding of many inherited and sporadic disorders.
Mitochondrial disorder can be categorized according to several different criteria in the manifestations of ophthalmology diseases. They may be defined as isolated or nonisolated, occurring in combination with other manifestations of the organ. The dominant trait of the phenotype or a nondominant attribute can be ophthalmologic manifestations. Mitochondrial disorders with ophthalmic manifestations may be caused either by mutations in mtDNA or nuclear DNA. Ophthalmologic symptoms may be unique to syndromic mitochondrial disorder (e.g. Leber hereditary optic neuropathy) or nonspecific to syndromic mitochondrial disorder (eg, cataract). The cornea, iris, lens, ciliary body, retina, choroid, uvea, or optic nerve may be the primary manifestations of ophthalmologic mitochondrial disorder. There is growing evidence supporting an association between mitochondrial dysfunction and a number of ophthalmic diseases causing defects in OXPHOS and increased production of ROS triggering the activation of cell death pathway.
5. Corneal dystrophy
Some evidence has been given in recent years that the cornea may be involved in mitochondrial disorders. However, systematic studies have not been performed on this matter. Astigmatism, corneal dystrophy, corneal clouding, or corneal endothelial dysfunction are corneal disorders associated with mitochondrial dysfunction [55, 56]. Loss of SLC4A11 gene activity which is localized to the inner mitochondrial membrane of corneal endothelium, induces oxidative stress and cell death, resulting in Congenital Hereditary Endothelial Dystrophy (CHED) with corneal edema and vision loss [57]. Fuchs endothelial corneal dystrophy (FECD) is characterized by progressive and non-regenerative corneal endothelial loss. Variations in mtDNA affect the susceptibility of FECD. Mitochondrial variant A10398G and Haplogroup I were significantly associated with FECD [58]. There are few studies showing the role of mtDNA in the pathogenesis of FECD. Mitophagy activation leads to decrease in Mfn2 gene level and loss of mitochondrial mass in FECD [59]. In a study of 20 patients, keratoconus was related to increased oxidative stress due to mitochondrial respiratory chain complex-I sequence variation [60]. Progressive external ophthalmoplegia secondarily led to persistent conjunctivitis and keratitis in a patient with Kearns-Sayre Syndrome [61]. Corneal clouding has been documented occasionally in Kearns-Sayre syndrome due to structural changes in the endothelium or Descemet membrane [62]. Numerous distended mitochondria were present in the corneal epithelium in a child with Leigh syndrome due to the m.8993 T > G mutation [63]. There are also non-specific corneal alterations in a patient with Neurogastrointestinal mitochondrial encephalomyopathy [64]. Pathogenesis of type 2 granular corneal dystrophy (GCD2) is associated with alteration of mitochondrial features and functions that causes mutated GCD2 keratocytes, particularly in older cells [65].
6. Mitochondrial encephalomyopathy, lactic acidosis, and episodic stroke-like syndrome (MELAS)
Early onset of the disease and higher level of mtDNA heteroplasmy are associated with a worse prognosis in mitochondrial encephalomyopathy, lactic acidosis, and episodic stroke-like syndrome (MELAS). Iris involvement in mitochondrial disorders has been rarely mentioned in MELAS [66]. The m.3243A > G variant is the most common heteroplasmic mtDNA mutation in MELAS and underlies a spectrum of diseases. Patchy iris stroma atrophy has been identified in a patient carrying the m.3243A > G mutation in the tRNA (Lys) gene [66]. MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function, found to be depleted in MELAS and significantly associated with m.3243A > G mutation (heteroplasmic) in the mtDNA at a level of ∼50 to 90% [67]. Ability of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), improves the mitochondrial biogenesis/respiratory functions in MELAS cybrid cells containing >90% of the m.3243A > G mutation that found to be novel therapies to treat this disease [68]. Induced pluripotent stem cells (iPSCs) are appropriate for studying mitochondrial diseases caused by mtDNA mutations in MELAS. Increase of autophagy inpatient-specific iPSCs generated from fibroblasts are associated with mtDNA mutations and OXPHOS defects in patients with MELAS [69]. Studies demonstrated that defective MRM2 gene causes a MELAS-like phenotype which suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation [70]. Mutations caused by mitochondrial complex I deficiencies by alleviating ketone bodies are also associated with MELAS that leads to recurrent cerebral insults resembling strokes [71].
7. Cataract
Cataracts are the most common lenticular defects of mitochondrial disorders. In mitochondrial disorders, cataract is typically of the posterior subcapsular type [66]. Autophagic dysfunction and abnormal oxidative stress are associated with cataract. Cataract may be a phenotypic characteristic of MELAS syndrome, but a patient with nonsyndromic mitochondrial disorder due to mtDNA deletion has also been documented as an initial manifestation [66, 72, 73]. Oxidative stress plays an important role in cataractogenesis [74, 75]. Mitochondria are found in the epithelium and superficial fiber cells of the lens and it is extremely sensitive to ROS. Interestingly, mitochondria have been confirmed as the main source of ROS generation in these cell types [76]. A number of in vitro studies have shown that human lens cells are particularly sensitive to oxidative insults, where antioxidant activity was inversely proportional to the severity of cataracts [77]. Proteins, lipids and DNA oxidation have been found in cataract lenses [78, 79, 80]. Under high glucose conditions, fluctuations in autophagy and oxidative stress are found in mouse lens epithelial cells (LECs) that might attenuate high glucose-induced oxidative injury to LECs [81]. Cataract proteins lose sulfhydryl groups, contain oxidized residues, produce aggregates of high molecular weight and become insoluble [75]. In addition, cataract has been shown to be a symptom of a newly identified mitochondrial disorder called autosomal recessive myopathy, caused by growth factor mutations, increased liver regeneration gene, which affects protein levels of mitochondrial intermembrane space region [82].
8. Leigh syndrome
In mitochondrial disorders, involvement of ciliary body has rarely been reported. Leigh’s syndrome is the most common pediatric syndrome, characterized by symmetrical brain lesions, hypotonia, motor and respiratory deficits, and premature death are associated with pathways involved in mitochondrial diseases [83]. A case report showed ocular histopathological finding such as thinning of nerve fibers and ganglion cell layers in the nasal aspect of the macula, mild atrophy of the temporal aspect of the optic nerve head, and numerous distended mitochondria, non-pigmented cilla are associated with the m.8993 T > G mutation in the ATPase6 gene of mtDNA in patient with Leigh’s syndrome [63]. In addition, ciliary epithelium was also found to be impaired by a long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency [84]. Dysfunction of mitochondrial complex I are also associated with many brain pathologies including Leigh’s syndrome. Mitochondrial complex I activity facilitates organismal survival by its regeneration potential of NAD+, while optimal motor regulation involves mitochondrial complex I bioenergetic function in Leigh’s syndrome [85].
9. Retinitis pigmentosa
Retinitis pigmentosa is a central characteristic of Kearns-Sayre syndrome and neuropathic ataxia retinitis pigmentosa syndrome [72]. Typical for Kearns-Sayre syndrome is ‘salt and pepper’ retinitis, with areas of increased and decreased pigmentation, especially in the equatorial fundus [62]. Pigment retinopathy is only an uncommon characteristic of progressive external ophtalmoplegia and can be milder than in Kearns-Sayre syndrome [72, 86]. Only certain patients with MELAS or MERRF syndrome have mild posterior pole pigment retinopathy [72]. Mild pigmentary defects were also observed in 2 of 20 patients with Leber hereditary optic neuropathy due to mutation m.11778G > A [72]. Small pigment retinal defects have been identified in a 4-year-old female with a COX deficiency [87]. In addition, because of the mutation m.8993 T > GG retinitis pigmentosa has been identified in patients with Leigh syndrome [88].
In a sample of 44 Korean Leigh syndrome patients, pigmentary retinopathy was also observed in 22% of Korean patients [89]. In a study of 14 patients with pontocerebellar hypoplasia, 4 patients presented with retinopathy without disclosing information [90]. Occasionally, retinal dystrophy can manifest with photophobia. In a report of 46 mitochondrial disease patients, 4 had photophobia. Two patients had Leigh syndrome, 1 of which had rod-cone dystrophy on electroretinography, 1 had Kearns-Sayre syndrome with regular electroretinography, and 1 had MERRF syndrome with isoelectric electroretinography [91].
10. Diabetic retinopathy
It has been shown that mitochondrial dysfunction plays a significant role in diabetic retinopathy [92, 93]. Hyperglycemia causes retinal mitochondrial damages that plays a central role in the development of diabetic retinopathy. Retinal mitochondria undergo elevated oxidative stress in diabetes, and complex III is one of the key causes of increased O2− [94]. Superoxide levels are elevated in in the retina of diabetic rats and in retinal vascular endothelial cells incubated in high-glucose media [95] and the content of hydrogen peroxide is also increased in the retina of diabetic rats [96]. In diabetes, membrane lipid peroxidation and oxidative DNA damage, the effects of ROS-induced injury, are elevated in the retina [97]. Chronic overproduction of ROS in the retina results in aberrant mitochondrial functions in diabetes [92]. Overproduction of superoxide by the mitochondrial electron transport chain caused by hyperglycemia is considered to cause major hyperglycemic damage pathways by inhibiting the action of GAPDH. However, it is not yet fully understood the mechanism by which hyperglycemia induces an increase in mitochondrial ROS, with some suggesting a direct effect and others an indirect function via high-glucose-induced cytokines [98, 99, 100, 101].
Elevated levels of O2− activate caspase 3 in retinal capillaries contributes to cell death [92]. Upregulation of superoxide dismutase (SOD2) inhibited increased mitochondrial O2-induced diabetes, restored mitochondrial function, and prevented both in vitro and in vivo vascular pathology [94, 102, 103, 104]. However, the timing of such therapies is important because animal studies have shown that oxidative stress not only leads to the development of diabetic retinopathy, but also to the resistance of retinopathy to reversal [105]. The resistance to reversal of diabetic retinopathy may be due to the accumulation of weakened mitochondrial molecules and ROS-induced damage that is not readily removed even after the restoration of high glycemic control. However, the accumulation of advanced glycation end products is also involved in metabolic memory [106]. The mtDNA variation has also been associated with resistance to type 1 diabetes. A single nucleotide modification (C5173A) is associated with resistance to type 1 diabetes in the Japanese population, resulting in a leucine-to-methionine amino acid substitution in the mitochondrially encoded NADH dehydrogenase subunit 2 gene [107]. Similarly, in comparison with the diabetes-prone nonobese diabetic mouse strain, orthologous polymorphism (C4738A), resulting in L-to-M substitution, offers resistance against the development of spontaneous diabetes [108]. Gusdon et al., have shown that the replacement of methionine results in a lower level of development of ROS from complex III [109].
The product of mtDNA mutations is also known to result in many syndromic central nervous system diseases. The most common retinal pathology is pigmentary retinopathy, while optic neuropathy is an uncommon finding in these disorders. Neurogenic atrophy and retinitis pigmentosa syndrome results from point mutations in the mtDNA ATPase-6 gene, usually T8993G variation. Patients usually present with retinitis pigmentosa with or without optic neuropathy and may develop dystonia [110]. Several mtDNA point mutations may result from MELAS, although the A3243G mutation in the tRNALeu gene is the most common. Patients with MELAS undergo stroke-like episodes leading to recurrent retrochiasmal vision loss, but sometimes even to pigmentary retinopathy without optic atrophy [111]. Its contribution to the pathogenesis of maternally inherited diabetes and deafness is also evidenced by the spectrum of disease resulting from the A3243G point mutation [112, 113, 114]. This is a multisystemic disease characterized by sensorineural deafness, retinal defects and diabetes, generally occurring in the third to fourth decades of life [115]. The second phenotype is a pattern dystrophy, with diffuse granularity and pigment clumping, marked by relative sparing of the fovea, and retinal pigment epithelium within the vascular retinal arcades. However, with a strong prognosis, visual acuity is retained, despite the degree of atrophy [116, 117].
11. Macular degeneration
Age-related macular degeneration is a neurodegenerative late-onset disorder that shares certain characteristics of Alzheimer’s disease. In most cases, the build-up of protein plaques, known as drusen, in the central macular area of the retina involves age-related macular degeneration. Both age-related macular degeneration and Alzheimer’s disease pathogenesis can be driven by stress stimuli, including oxidative stress, aging, genetic factors and inflammation, including the deposition of protein plaques in the retina or brain [98]. Similarities in these two disorders are also found in the risk factor gene polymorphisms, APOE, associated with age-related macular degeneration [99, 100] and Alzheimer’s disease [101, 102]. The APOE gene controls the homeostasis of triglycerides and cholesterol [103], and the loss of function of APOE has been correlated with the deposit of senile plaques, consisting mainly of amyloid beta peptide [104], which is produced in drusen [105, 106] and is also associated with an additional risk factor for age-related macular degeneration, i.e. complement protein [107, 108]. Evidence shows that the APOE genotype can dictate the risk of stress stimuli, including oxidative stress, aging, genetic factors and inflammation, including the deposition of protein plaques in the retina or brain, can drive both age-related macular degeneration and Alzheimer’s disease pathogenesis. Alzheimer’s disease and other chronic disorders, primarily because of its effect on regulation of oxidative stress [109]. Age-related macular degeneration is split into two main forms, i.e. the “wet” form induced by leakage into the subretinal space from choroidal neovascularization and the more common “dry” form associated with the accumulation of drusen in the macula [75]. In patients with age-related macular degeneration, there is an increased incidence of large-scale mtDNA rearrangements and deletions in blood [76] and retinas [77, 78]. In the non-coding mtDNA control area (d-loop) in retinas with age-related macular degeneration, which has been found in Alzheimer’s disease and other conditions of oxidative stress, there are also increased rates of single nucleotide polymorphisms [79]. An increased rate of mtDNA deletions and single nucleotide polymorphisms are likely to decrease the amount and density of mitochondria [80].
Other than pigmentary retinopathy or macular degeneration, retinal anomalies include retinal dystrophy, retinal hypertrophy, and pigmentary maculopathy. Patients with Kearns-Sayre syndrome, Leigh syndrome, MELAS syndrome, MERRF syndrome, and Leber hereditary optic neuropathy will find retinal dystrophies that are most easily measured by electroretinography [91]. Retinal hypertrophy has been identified in patients with autosomal recessive spastic ataxia with leukoencephalopathy and autosomal recessive spastic ataxia with Charlevoix-Saguenay (ARSAL/ARSACS) [118]. Six affected males in a family with Mohr-Tranebjaerg syndrome had blindness resulting from unexplained retinal degeneration [119]. Treatment options for retinopathy are usually limited.
12. Choroidal dystrophy
Choroid and uvea are occasionally affected by mitochondrial disorders. Choroid atrophy is the most common manifestation of mitochondrial disorders [66]. Choroidal atrophy was especially identified in the sense of MELAS syndrome [66]. Choroid pigment epithelium atrophy also occurs in maternally inherited deafness and diabetes [120]. Central choroidal dystrophy was identified in 1 patient with Mohr-Tranebjaerg syndrome as confirmed by electroretinography [119]. In addition, chorioretinal dystrophy was reported in a single patient with a significant deletion of mtDNA [121].
13. Uveitis
A significant causative factor causing blindness from retinal photoreceptor degeneration is intraocular inflammation, also referred to as uveitis. Activated macrophages, which generate various cytotoxic agents, including inducible nitric oxide generated by inducible nitric oxide synthase, O2− and other ROS, are responsible for oxidative retinal damage in uveitis [122]. Oxidative stress plays an important role in the early stages of experimental autoimmune uveitis (EAU) in the photoreceptor mitochondria. mtDNA damage has been shown to occur early in the EAU; interestingly, nDNA damage occurred later in the EAU [123]. In addition, peroxynitrite-mediated nitration modifies mitochondrial proteins in the inner segments of the photoreceptor, which, in turn, contributes to increased mitochondrial ROS generation [124]. MnSOD has been shown to be upregulated during EAU to promote an increased state of mitochondrial oxidative stress, possibly to combat ROS [125]. In the early phase of the EAU, before leukocyte infiltration, recent data seem to indicate a causative function of oxidative mtDNA harm. Such mitochondrial oxidative damage can be the initial event that contributes to retinal degeneration in uveitis [123].
14. Optic atrophy
Optic atrophy is the principal mitochondrial dysfunction manifestation of the optic nerve. Optic atrophy is a prevalent manifestation of mitochondrial disorder but is often overlooked or misinterpreted. This is due to the difficulties of optic atrophy diagnosis. Funduscopy can more reliably determine optic atrophy if the distal portion of the optic nerve is impaired, or if the more proximal portions of the nerve are affected by orbital magnetic resonance imaging (MRI). A decreased amplitude of visually evoked potential is a sign of optic nerve atrophy [126]. Optic atrophy has been specifically identified in Leber hereditary optic neuropathy and autosomal dominant optic atrophy among syndromic mitochondrial disorders, conditions in which optic atrophy is the dominant phenotypic function [127]. MELAS syndrome, Kearns-Sayre syndrome, Pearson syndrome, pontocerebellar hypoplasia, Mohr-Tranebjaerg syndrome, Alpers-Huttenlocher disease or Wolfram syndrome have been documented more rarely, with optic atrophy [62, 90, 91, 127]. In patients with MERRF syndrome, partial or complete optic atrophy has also been identified [72, 91, 128]. Optical atrophy is a common phenotypic characteristic of inherited motor and sensory neuropathy type VI (HMSN-IV) due to MFN1 mutations [127]. In addition, C12orf65 (COXPD7) mutations manifest phenotypicly with optical atrophy and Leigh-like phenotype [129]. Optical atrophy associated with neuropathy ataxia retinitis pigmentosa syndrome due to m.8993 T > G mutation in the ATPase6 gene was only seen in a single family [110]. In a study of 44 Korean patients with Leigh Syndrome, 22.5 per cent of optical atrophy was identified [89]. Optical disk alterations have been observed only in a single patient with mitochondrial neurogastrointestinal encephalomyopathy [64]. Optical atrophy can also be a characteristic of childhood-onset spinocerebellar ataxia [130] or mitochondrial depletion syndrome. 39 Non-syndromic mitochondrial optic atrophy disorders is attributed to ACI1 mutation [131], due to ND5 mutation with cataract and retinopathy [132].
15. Glaucoma
Increased intraocular pressure (Glaucoma) is an unusual phenotypic characteristic of mitochondrial disorders. There are two primary types of glaucoma that can be distinguished, open-angle glaucoma and closed-angle glaucoma. In addition, normotensive and hypertensive glaucoma are distinguished. Open-angle glaucoma is seldom observed in patients with Leber inherited optic neuropathy or autosomal dominant optic atrophy. Funduscopic findings can indicate a mixture of abnormalities common for glaucoma retinopathy and an inherited Leber optic neuropathy fundus [133]. In a single patient with mitochondrial neurogastrointestinal encephalomyopathy, glaucomatous changes in the optic disc were observed by visual field assessment and optical coherence tomography [64]. In a study of 14 patients with pontocerebellar hypoplasia, one presented with glaucoma [90]. Normal pressure glaucoma is associated with polymorphism in the OPA1 gene [134].
Glaucoma has also been identified in a family with Wolfram Syndrome. There are signs that ND5 mutations are associated with the development of open-angle glaucoma. Glaucoma in mitochondrial disorders may be eligible for treatment with drugs or surgery [135, 136]. There is evidence in glaucoma that mitochondrial dysfunction can reduce the bioenergetic status of retinal ganglion cells, leading to increased susceptibility to oxidative stress and apoptotic cell death [93, 137]. Light exposure may also be an oxidative risk factor, reducing mitochondrial function and increasing the development of ROS in ganglion cells [138]. A defective mitochondria has been highly implicated in neuronal apoptosis in the experimental models of glaucoma [139, 140]. The mtDNA abnormalities further support the importance of mitochondrial dysfunction-associated stress as a risk factor for glaucoma patients [141].
16. Nystagmus
The central nervous system or vestibular involvement in mitochondrial disorders may cause nystagmus or roving eye movements and are the most common ophthalmological manifestations as a symptom in patients with pediatric mitochondrial disorder [142]. A Gaze-evoked nystagmus identified in a single patient with “Leber hereditary optic neuropathy plus” who not only possessed the “m.11778G > A” mutation in the hereditary Leber hereditary optic neuropathy gene but also the “m.3394 T > C” mutation [143]. Since patients with MELAS may display irregular eye movements on an eye movement cueing task, ultrasound records of eye movement may show abnormally slow saccadic reactions, prolonged saccades, impaired suppression of reflex eye movements, prolonged reaction during antisaccades, square-wave jerks, or impaired chase [144]. Patients have epilepsy due to MELAS may have epileptic nystagmus, disrupted smooth pursuit, or transient eye divergence, none of which are outward signs [145]. In addition, nystagmus was documented in a patient carrying a point mutation in the DGUOK gene who also had retinal blindness. Nystagmus, which is a common symptom of the disease along with retinitis pigmentosa, was also reported in a patient with nonsyndromic mitochondrial disorder due to the m.15995G > A mutation in the tRNA (Pro) gene manifesting as ataxia, deafness, and leukoencephalopathy [146]. Nystagmus was part of the phenotype in a study of 7 Czech patients with autosomal dominant optic atrophy [147]. Nystagmus is also a common characteristic of ARSAL/ARSACS [148]. Nystagmus was observed in 14 percent in a study of 44 Korean patients with Leigh syndrome [88].
17. Strabismus
Strabismus was the most common ophthalmologic abnormality in a study of 44 Korean patients with Leigh syndrome and was present in 41% of patients [89]. Of the strabismus patients, 13 had exotropia and 5 had esotropia [89]. In some patients with X-linked sideroblast anemia with ataxia, strabismus has also been identified [149]. In 25 percent of juvenile mitochondrial disorders, divergent strabismus has been identified as the presenting manifestation [150]. In a study of 14 patients with pontocerebellar hypoplasia, of whom 13 had a CASK mutation, 2 had strabismus. 9 Strabismus was also identified without knowing the underlying mutation in other patients with pontocerebellar hypoplasia [151, 152]. The initial presentation at birth was cataract and strabismus in a child with a significant mtDNA deletion. Later on, he experienced Leigh-like pathologies and episodes of stroke [153]. In certain instances, surgery can have a beneficial effect on strabism.
18. Progressive external ophthalmoplegia
In mitochondrial disorders, affectation of the extraocular muscles results in progressive external ophthalmoplegia. The recurrent ophthalmologic manifestation of mitochondrial disorders is progressive external ophthalmoplegia. It may be complete, resulting in, or partial, walled-in bulbs. Both directions of bulb movements or only some of them can be affected. One eye or both eyes can be affected by it. Single or multiple mtDNA deletions are most often associated with progressive external ophthalmoplegia. Progressive external ophthalmoplegia, Kearns-Sayre syndrome or Pearson syndrome can cause single mtDNA deletions [154]. Multiple deletions of mtDNA may be due to mutations in nuclear genes such as PEO1, POLG1, SLC25A4, RRM2B, POLG2, or OPA1, along with progressive external ophthalmoplegia [154]. In addition, progressive external ophthalmoplegia, especially in the transfer of RNA (eg, tRNA(Lys)) genes, may be due to mtDNA point mutations [154]. Transfer RNA mutations with progressive external ophthalmoplegia are mostly sporadically similar to mtDNA deletions and can only be observed in muscle deletions [155]. The sole manifestation of the m.3243A > G mutation, which often manifests as MELAS syndrome, may be progressive external ophthalmoplegia [156]. In a patient with mitochondrial neurogastrointestinal encephalomyopathy, progressive external ophthalmoplegia was a phenotypic feature [64], Wolfram syndrome [157], Leigh syndrome, autosomal dominant optic atrophy, and mitochondrial recessive ataxia syndrome. In MERRF syndrome, progressive external ophthalmoplegia has also been described [158].
Infantile-onset spinocerebellar ataxia is a Finnish disorder, with some of the 24 cases identified to date developing ophthalmoplegia [130]. Ophthalmoparesis is a hallmark of sensory ataxic neuropathy with ophthalmoparesis syndrome and dysarthria [159]. Sensory ataxic neuropathy with dysarthria and ophthalmoparesis is due to mutations in either the POLG1 or PEO1 gene resulting in multiple mtDNA deletions [159]. Furthermore, ophthalmoparesis can be observed in patients with mitochondrial depletion syndrome [160] or nonsyndromal mitochondrial disorders [161]. In patients with Leber inherited optic neuropathy and progressive external ophthalmoplegia, ultrastructural variations in muscle biopsy from the extraocular muscles clearly differ [162].
19. Eyelid
Ptosis is one of the most common forms of mitochondrial dysfunction. It can occur unilaterally at onset, but during the course of the disease, it usually becomes bilateral. Ptosis can be the sole manifestation, particularly at the onset of the disease, of a mitochondrial disorder or associated with other manifestations. Particularly at the onset of the disease, ptosis can show dynamic alterations, leading to misinterpretation as myasthenia gravis [163]. Ptosis may be discrete, especially at initiation, so that it is missed on clinical review. Progressive external ophthalmoplegia or other ocular symptoms of mitochondrial disease can be associated with ptosis. Ptosis of syndromic as well as nonsyndromic mitochondrial disorders may be a phenotypic manifestation. In particular, ptosis was identified in progressive external ophthalmoplegia, MELAS, MERRF, Kearns-Sayre syndrome, sensory ataxic neuropathy with dysarthria and ophthalmoparesis [164], Pearson syndrome, mitochondrial neurogastrointestinal encephalomyopathy, and autosomal dominant optic atrophy, among the syndromic mitochondrial disorders [91]. Ptosis was present in 16 percent in a group of 44 Korean patients with Leigh syndrome [89]. Ptosis was also present in isolated cases of maternally inherited deafness and diabetes [156], mitochondrial neurogastrointestinal encephalomyopathy [64], or mitochondrial depletion syndrome [160]. Poor lid closure was found in a Persian Jew with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia due to a PUS1 mutation [165].
20. Leber hereditary optic neuropathy
Leber hereditary optic neuropathy is a maternally inherited blindness condition caused by gene mutations encoding the respiratory-chain complex I subunits. Nearly 90 percent of all cases of Leber inherited optic neuropathy contain mutations in 3 genes [128]. The m.3460A > G mutation in the ND1 gene, the m.11778G > A mutation in the ND4 gene and the m.14484 T > C mutation in the ND6 gene are the 3 most common Leber hereditary optic neuropathy mutations (primary Leber hereditary optic neuropathy mutations) [128]. Leber inherited optic neuropathy is clinically characterized as bilateral, painless, subacute vision impairment that occurs during young adult life [134].
Compared with women, Leber hereditary optic neuropathy is 4 to 5 times more common in males. Individuals affected are usually completely asymptomatic until they experience visual blurring in 1 eye affecting the central visual field [134]. On average, 2 to 3 months later, similar signs develop in the other eye. In most cases, visual acuity is greatly diminished or even worse when counting fingers, and visual field examination reveals an expanded central or ceco-central thick scotoma [134]. After the acute process, the optical disks become atrophic. Funduscopic findings characteristic of Leber inherited optic neuropathy include microangiopathy, hyperemic disks, retinal telangiectasis (ectatic capillaries), peripapillary microangiopathy, and tortuosity of vessels (twisted vessels). (twisted vessels). The orbital MRI can display atrophy of the nerve with a compensated widening of the space below the optic sheath. Mutations in mitochondrial ND3, ND4, or ND6 genes can cause hereditary Leber optic neuropathy with dystonia [166].
21. Autosomal dominant optic atrophy
Autosomal dominant optic atrophy is a blindness condition which does not display a gender disparity, unlike Leber inherited optic neuropathy [127]. It is caused by mutations in the nuclearly encoded OPA1 gene [127]. Autosomal dominant optic atrophy can also be due to OPA3 mutations that are associated with cataract [167]. Progressive, painless, bilateral symmetrical vision loss clinically characterizes autosomal dominant optic atrophy [154]. Central, ceco-central, or para-central scotomas, consistent with early involvement of the papillo-macular bundle, are the most common visual field anomalies in autosomal dominant optic atrophy [154]. OPA1 mutations can manifest not only with optic atrophy in some families, but also with progressive external ophthalmoplegia, ptosis, and hypoacusis [168]. Since glaucoma neuropathy, autosomal dominant optic atrophy, and Leber hereditary optic neuropathy often have similar changes in the topographic optic disc, they cannot be discriminated against alone by disc evaluation [169]. There is currently no appropriate treatment available.
22. Retinoblastoma
Retinoblastoma (Rb) is the most common intraocular cancer in children that arise from retinal precursor cells. Electron microscopy revealed numerous morphological and pathological changes in mitochondria of retinoblastoma patients. Cristolysis and degenerated mitochondria were the most frequently observed features in Rb [170]. A study suggested that T16519C, C16223T, A263G and A73G mtDNA D-Loop mutations plays a significant role in the etiology of retinoblastoma. This was the first study to examine the mtDNA D-loop mutation in retinoblastoma and its correlation with various parameters and patient outcome [171]. Their findings imply a strong inhibition of mitochondrial oxidative phosphorylation complexes in these patients. Loss of mitochondrial complex I was found in majority of the cases whereas expression of mitochondrial complex III, IV and V were found in more than 50% of the cases. Expression of mitochondrial complex I was associated with good prognosis and better overall survival [172]. Another consequence of alteration in OXPHOS complexes is an increased production of reactive oxygen species (ROS). NADPH oxidases (NOX4) are a major intracellular source of ROS and it was found to be overexpressed in retinoblastoma [173]. Increased expression of ROS and decreased expression of OXPHOS complexes modulates the apoptotic pathway involved in mitochondria by altering BCl-2 family proteins. Singh et al. showed a differential expression of apoptotic regulatory proteins (Bax, BCl-2, PUMA and p53) where they found increased expression of BCl-2 and PUMA along with loss of Bax and p53, which might contribute to carcinogenesis in Rb [174].
23. Conclusion
Researchers found that these findings are important because they indicate that mtDNA damage can be caused by both spontaneous ROS and by inherited mtDNA mutations. Continued study in this clinically important area would certainly provide a better understanding of how deficiencies/mutations of the mitochondrial genome contribute to the pathogenesis of ocular diseases. The biggest problems with the future of mitochondria are the advancement of therapeutic strategies to target mitochondria and modify its DNA using nucleotide precursors to retain mitochondrial integrity. These therapeutic strategies can potentially be used to block or slow down the effects of mitochondrial disease in future.
Department of Dermatology, University of Wisconsin, USA
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
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\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",annualVolume:11968,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorialBoard:[{id:"220987",title:"Dr.",name:"António",middleName:"Onofre",surname:"Soares",fullName:"António Soares",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNtzQAG/Profile_Picture_1644499672340",institutionString:null,institution:{name:"University of the Azores",institutionURL:null,country:{name:"Portugal"}}}]},{id:"41",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",annualVolume:11969,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",institutionString:"China Institute of Water Resources and Hydropower Research",institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"216491",title:"Dr.",name:"Charalampos",middleName:null,surname:"Skoulikaris",fullName:"Charalampos Skoulikaris",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRMsbQAG/Profile_Picture_2022-04-21T09:31:55.jpg",institutionString:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"300124",title:"Prof.",name:"Thomas",middleName:null,surname:"Shahady",fullName:"Thomas Shahady",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002kuIgmQAE/Profile_Picture_2022-03-18T07:32:10.jpg",institutionString:null,institution:{name:"Lynchburg College",institutionURL:null,country:{name:"United States of America"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/46488",hash:"",query:{},params:{id:"46488"},fullPath:"/profiles/46488",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()