Prevalence of ANA antibodies in different autoimmune diseases [20, 21].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3205",leadTitle:null,fullTitle:"Design of Experiments - Applications",title:"Design of Experiments",subtitle:"Applications",reviewType:"peer-reviewed",abstract:"This book is a research publication that covers original research on developments within the Design of Experiments - Applications field of study. 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Milk processing allows the preservation of milk for days, weeks, or months and helps to reduce food-borne illness.",isbn:"978-1-78985-730-6",printIsbn:"978-1-78985-729-0",pdfIsbn:"978-1-78985-919-5",doi:"10.5772/intechopen.73442",price:119,priceEur:129,priceUsd:155,slug:"milk-production-processing-and-marketing",numberOfPages:202,isOpenForSubmission:!1,hash:"d0b383fbc5e2a2fcc9da5bd58766529d",bookSignature:"Khalid Javed",publishedDate:"July 17th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6911.jpg",keywords:null,numberOfDownloads:6071,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:3,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 12th 2018",dateEndSecondStepPublish:"August 2nd 2018",dateEndThirdStepPublish:"October 1st 2018",dateEndFourthStepPublish:"December 20th 2018",dateEndFifthStepPublish:"February 18th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"136829",title:"Dr.",name:"Khalid",middleName:null,surname:"Javed",slug:"khalid-javed",fullName:"Khalid Javed",profilePictureURL:"https://mts.intechopen.com/storage/users/136829/images/system/136829.jpeg",biography:"Dr. Khalid Javed is a Professor of Animal Breeding and Genetics in the Department of Livestock Production at the University of Veterinary and Animal Sciences, Lahore. He graduated in Animal Husbandry from University of Agriculture, Faisalabad in 1982. He earned his Master’s and Doctorate degrees in Animal Breeding and Genetics from University of Agriculture, Faisalabad. He joined Government of Punjab, Livestock and Dairy Development as Veterinary Officer in 1983 and remained engaged in research in different capacities. Dr. Khalid conducted research, trainings and teaching in the fields of Animal Breeding, Population/Quantitative Genetics, and Statistical Genetics. He analyzed the production data of various livestock species (e.g., cattle, buffalo, sheep, goats, chicken) to characterize the phenotypic and genetic structure related to different traits of economic importance and subsequent selection. Moreover, he has been engaged in inter-disciplinary collaborative research with colleagues from various academic and research institutes to study the genetic, breeding, management and environmental factors affecting productivity of livestock species. He joined University of Veterinary and Animal Sciences during 2003 as Assistant Professor where he was later selected and appointed as Associate Professor and Professor, in 2006 and 2011 respectively. His research focus is on selection and breeding of large and small ruminants. He also supervises and evaluates postgraduate research to ensure successful and timely completion of the projects focusing on genetic improvement, enhancing breeding efficiency and production enhancement of farm animals. In addition, he participates and conducts trainings, workshops, conferences and seminars, and writes scientific publications to disseminate knowledge and techniques to the researchers and livestock producers about various areas of animal husbandry for improving behaviour, health, growth, fertility and production of livestock. He has more than 200 publications/research articles published and is working as Senior Editor of an internationally recognized Journal of Animal and Plant Sciences-JAPS.",institutionString:"University of Veterinary and Animal Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Veterinary and Animal Sciences",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"326",title:"Food Industry",slug:"food-industry"}],chapters:[{id:"65652",title:"Current Standing and Future Challenges of Dairying in Pakistan: A Status Update",slug:"current-standing-and-future-challenges-of-dairying-in-pakistan-a-status-update",totalDownloads:1359,totalCrossrefCites:0,authors:[{id:"270832",title:"Dr.",name:"Muhammad Naeem",surname:"Tahir",slug:"muhammad-naeem-tahir",fullName:"Muhammad Naeem 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Autoimmune process taking place in pSS affects exocrine glands primarily, causing their dysfunction and the development of symptoms of mouth and eye dryness. Through the formation of infiltrates consisting of different autoreactive cells (e.g., B and T cells, macrophages, and dendritic cells), pSS may affect other organs as well as whole systems (e.g., lungs, respiratory, urinary, and alimentary tract).
\nIn the pathogenesis of primary Sjögren’s syndrome, certain genetic factors play a significant role, such as the presence of HLA-B8, HLA-DW3, HLA-DR3, and DRw52 genes or interferon regulatory factor 5 (IRF 5) gene polymorphism [1, 2]. Not only viral infections have been recognized as the pSS triggering factors, mainly Epstein-Barr virus (EBV) [3], but also human T-cell lymphotropic virus type-1 (HTLV-1), cytomegalovirus (CMV), and hepatitis C virus (HCV) [4, 5]. Bacterial infections Staphylococcus aureus, Chlamydia pneumoniae, Chlamydia trachomatis, M. hominis, U. urealyticum, and H. pylori may also play part in the development of pSS [6, 7, 8]. In many of the autoimmune rheumatic diseases, ultraviolet (UV) radiation is a recognized factor influencing the activity of the autoimmune process. The UV radiation causes movement of antigen molecules, bound with/to ribonucleoprotein, between cytoplasm and cell membrane (SS-A/Ro) and cell nucleus and cytoplasm (SS-B/La). UVB radiation affects epithelial damage, activates plasma dendritic cells, and increases the risk of their apoptosis and (risk?) of the IFN signaling pathway activation. Different observations concerning UVA radiation suggest that it inhibits the production of autoantibodies [9, 10].
\nThe hormonal state of the individual may also play a role in the pSS development. The imbalance of sex hormones and its receptors, dependent on hypothalamic-pituitary-adrenal axis (HPA or HTPA axis), interferes with the ratio of estrogens to androgens, especially in genetically predisposed patients [11]. This influences the stimulation of the autoimmune process and may explain the more frequent occurrence of pSS in women, especially in middle-aged. In recent years, attention has been paid to the role of the deficiency of dehydroepiandrosterone (DHEA) and of DHEA-S, its metabolite, in pSS and other autoimmune diseases [12].
\nAs the epithelial cell damage and apoptosis provide basis for the pSS pathogenesis, the first step of the whole process is the activation of innate immunity, as the virus or bacteria antigen activates pattern recognition receptors (PRR) via Toll-like receptors (especially TLR 3, 7, 9). Activation of innate immunity leads, in turn, to the damage of epithelial cells, their apoptosis and the release of antigens and RNA complexes that strongly stimulate plasmacytoid dendritic cells (pDCs). These produce interferon alpha (IFN-α)—a factor strongly stimulating epithelial cells, dendritic cells and neutrophils to produce B-cell activating factor (BAFF) [13, 14, 15, 16]. All processes initiating epithelial damage lead to the apoptosis of cells, activation of congenital and acquired immune systems and the cascade effect of pathophysiological phenomena, resulting primarily in the overproduction of BAFF and other B-cell stimulating cytokines including APRIL (proliferation inducing ligand), similar in its actions to BAFF. Both BAFF and APRIL belong to the tumor necrosis factor superfamily (TNF) [17, 18]. The antigens released from damaged cells, primarily SS-A and SS-B ribonucleoproteins are targets for B cells and cause the production of specific anti-SS-A/Ro and anti-SS-B/La autoantibodies. Plasmocytoid dendritic cells also stimulate T lymphocytes, particularly the CD4+ subtype, which is later the main component of infiltrates in the endocrine glands. The Th1-type immune response is predominant, with activation of Th17 cells secreting interleukin 17 (IL-17). Th1 cells produce IFN-γ, which, in addition to the increase of BAFF secretion, induces the production of plasminogen activator, which—simultaneously with IL-17—causes the development of local inflammatory process. As a result of the abovementioned changes, leading to the hyperstimulation of B lymphocytes, autotolerance is disturbed and further production of autoantibodies [19].
\nA primary test for autoantibodies, finding the use in the diagnostics of pSS and other systemic autoimmune rheumatic diseases (SARD), is the determination of anti-nuclear antibodies (ANAs) [20, 21]. ANA are found in 80–90% of patients with pSS. These antibodies react with the components of the cell nucleus and are most often tested with indirect immunofluorescence (IF) on HEp-2 (human epithelial cell) cell line. In pSS, ANA often occur in higher titers (above 1:320), but may be also detected in lower titers (1:160) and in the concurrent presence of other autoantibodies. InTable 1, the prevalence of ANA antibodies in different autoimmune diseases was presented.
\nDisease | \nSLE | \nSSc | \npSS | \nMCTD | \n
---|---|---|---|---|
ANA sensitivity% | \n95 | \n70–90 | \n50–80 | \n90 | \n
In recent years attention has been paid to the frequent occurrence of dense fine speckled pattern (DFS70) on HEp-2 in both healthy people and patients with ANA associated autoimmune rheumatic diseases (AARD). DFS70 antibodies bind a ubiquitinated protein called lens epithelium derived growth factor (LEDGF), which occurrence was associated in first observations [22] with asthma and atopic dermatitis. However, the high prevalence of DFS70 autoantibodies in normal population, without any symptoms of any AARD, was observed. Therefore, in the case of positive result of the screening for ANA antibodies in individuals without symptoms suggestive of a systemic autoimmune rheumatic disease (SARD/AARD), it is advisable to detect DFS70 antibodies using specific tests (e.g., ELISA/EIA; CLIA/CIA) [23, 24]. Even up to 1/3 of positive cases for ANA are also positive for DFS70 antibodies [23, 24].
\nIn 1959, Holman et al. recorded a reaction of sera from SLE patients with extractable nuclear antigens (ENA) isolated from a crushed calf thymus. This observation confirmed the reaction of autoantibodies in the SLE sera with soluble nuclear antigens. The nomenclature of ENA autoantibodies derived from the group, in which they were first described, and corresponds to the nuclear function of the antigen (RNP) or the name of the patient providing the prototype serum (Ro, La, Sm, Jo, Mi), as well as the disease from which the patient suffered (SSA, SSB, SSC, Scl-70, PM-1, PM-Scl) [23]. The set of all ENA includes more than 100 soluble and cytoplasmic antigens. In clinical practice, until present day, only few of the them are finding use as a immunological hallmarks of certain autoimmune diseases or being used as immunological prognostic factors. Among them the most prominent are as follows: anti-RNP (anti-ribonucleoprotein anti-U(1)RNP), anti-Sm RNP, anti-SSA/Ro, anti-SSB/La, anti-Sm (Smith) antibody, anti-Scl-70 (anti-topoisomerase antibodies), anti-Jo-1 (anti-histidyl-transfer RNA synthase antibodies). The pattern of positive and negative results obtained with an ENA panel should be evaluated in conjunction with all clinical findings. Main autoantibodies and disease which they are typical to are presented in Table 2. Selected autoimmune diseases along with their predominant autoantibodies are presented in Table 2. Figure 1 shows a simplified diagnostic algorithm of immunological diagnosis.
\nDisease. | \nRA | \npSS | \nMCTD | \nSLE | \ndSSc | \nlSSc | \nPM | \nDM | \nGPA | \nMPA | \n
---|---|---|---|---|---|---|---|---|---|---|
Antibodies | \nACPA RF | \nAnti-SS-A/Ro60 Anti-SS-A/Ro52 Anti-SS-B/LA RF | \nRNP RF | \nAnti-dsDNA Anti-Sm Anti-Ro60 | \nAnti-Scl-70 | \nAnti-CENP-A,B,C | \nAnti-Jo-1 Ro-52 Other anti-synthetase antibodies, Anti-Mi-2 Anti-SRP | \nAnti-Ro-52 Anti-Mi-2 | \ncANCA | \npANCA | \n
RA—rheumatoid arthritis; pSS—primary Sjogren’s syndrome; MCTD—mixed connective tissue disese; SLE—systemic lupus erythematosus; dSSc—disseminated systemic sclerosis, lSSc-localized systemic sclerosis; PM—polymyositis; DM—dermatomyosistis; GPA—granulomatosis with polyangiitis; MPA—microscopic polyangiitis.
Simplified algorithm of immunological diagnosis of rheumatic diseases [22, 23, 24]. ANA—antinuclear antibodies; DFS70—dense fine speckled pattern antibodies; ENAs—extractable nuclear antigens; dsDNA—anti-double stranded DNA antibodies.
From 1981, it is known [26] that SS-A/Ro antigens are associated with small cytoplasmic RNAs. In 1984 Ro60 kD protein was discovered and Ben-Chetrit et al. in 1988 demonstrated second part of SS-A/Ro complex—a 52 kD protein [25, 26, 27]. As we have recently learned, the SS-A/Ro antigen consists of two different proteins Ro60 and Ro 52, with different gene localization: Ro60 is located on chromosome 19, while Ro-52 on chromosome 11. It was also revealed that these antigens, in physiological conditions, are found in different cell compartments. The detection of their presence determines different clinical implications. Presently, this problem needs still further investigation.
\nSS-A/Ro (60KD + 52KD) is a complex present on most cells, including platelets and red blood cells. It is considered that the anti-SS-A antibody plays a pathogenic role in pSS and its presence is associated with more severe symptoms, resulting from the involvement of endocrine glands, lymphadenopathy, larger salivary glandular infiltrates, characteristic vasculitis and longer duration of the disease [28, 29]. Also the occurrence of interstitial lung disease (ILD) is associated with the presence of antibodies against SS-A/Ro antigens, primarily Ro52KD and is associated with a higher degree of inflammatory changes in the salivary glands.
\nThe formation of anti-SS-A is affected by the UV radiation, which increases the expression of antigens on the cell surface. Anti-SS-A/Ro antibodies are considered as a triggering factor for photosensitivity in SCLE and NLE, although patients with DLE, but without anti-Ro antibodies, present skin changes after sun/light exposition as well, probably due to other pathomechanism (the presence of autoantibodies/immunoglobulins between skin and the epidermis) [30].
\nRo60 antigen attaches to uncoded RNA to form a complex (hY-RNA) that plays a role in inhibiting the immune response. Ro52 antigen is a phosphoprotein forming due to stimulation by viral infection, type I interferon pathway and through Toll-like receptors [28].
\nAutoantibody Ro60 has been associated with Sjögren’s syndrome in particular but also occur in SLE (50%), and subacute cutaneous lupus (SCLE) (60%) and neonatal lupus (NLE) [31]. Anti-Ro antibodies in SLE and SCLE are associated with photosensivity and skin changes (SCLE, NLE). In SCLE, negative results for ANA screening or finding ANA in low titer do not exclude the presence of anti-SSA/Ro antibodies (antibody—negative SCLE). Anti-SS-A antibodies are also found in systemic sclerosis, RA and polymyositis, as well as dermatomyositis (PM/DM) and autoimmune hepatitis, with antibodies to the Ro52 antigen present more frequently. Anti-Ro52 antibodies frequently occur in association with anti-Ro60 antibodies, especially in the context of SLE, Sjögren’s syndrome, subacute cutaneous lupus and neonatal lupus congenital heart block [31, 32]. However, the presence of anti-Ro52 alone, without anti-Ro60, was reported in inflammatory myopathy and in systemic sclerosis. It was also observed, that anti-Ro52 antibodies are, to larger extent than anti-Ro60, associated with primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) with co-expression of anti SLA antibodies (soluble liver antibodies) [33].
\nAnti-SS-B/La antibodies are less common and usually coexist with anti-SS-A antibodies, and their presence in other systemic diseases, especially in SLE (25% of patients with TRU), is associated with skin lesions (erythema, alopecia), inflammation of the serous membranes, leukopenia, symptoms of dryness and they often coexist with the presence of anti-SS-A antibodies (secondary SS) [28]. Rao et al. have noted that anti-SSB antibodies are important for the SLE diagnosis. They are associated with cheek erythema, alopecia, serositis, secondary Sjögren’s syndrome, and hematological changes such as leukocytopenia, thrombocytopenia, and immunoglobulins elevation. They are often accompanied by the presence of anti-/Ro or anti-SSA/Ro52 antibodies [34]. These autoantibodies may also be found before the SLE-specific antibodies can be detected [35].
\nRheumatoid factor (RF) is an autoantibody directed against the CH2 and CH3 domains of an Fc region of a class G immunoglobulin (IgG). RF is produced by plasmatic cells (RF-PCs) that are formed from B cells activated both dependently and independently of T lymphocytes. Thus, RF producing B cells (RF-PC) become cells with ability of antigen presentation (APC) and of binding IgG. As this cascade of events constitutes a method of immune response against the infectious antigens, the RF production during infections protects the host organism. This phenomenon explains the occurrence of RF in the course of many viral (e.g., HCV, Herpes virus, and HIV), bacterial (e.g., subacute bacterial endocarditis, Chlamydia pneumoniae, Klebsiella pneumoniae, tuberculosis, and syphilis) and even parasitic (malaria, onchocerciasis, and toxoplasmosis) infections. In those autoimmune diseases, in which B-cell hyperactivity occurs, rheumatoid factors, particularly clinically relevant RF-IgM, also appears [36]. It should be remembered that RF appears in 4% of a healthy population and its incidence increases with age; after 75 years of life, RF can be observed even in 10–25% of individuals [37, 38]. The frequency (%) of RF in various CTD is presented in Table 3. The primary Sjögren’s syndrome is one of the autoimmune diseases in which the majority of patients have a rheumatoid factor (some authors report up from 60 to 90% of patients)—specifically its most common IgM class isotype. The presence of RF IgM is associated with the occurrence of leukopenia, increased erythrocyte sedimentation rate (ESR), higher concentration of gamma globulins and lower C4 complement component concentration. Observations of a positive correlation of the rheumatoid factor with symptoms of dryness, hypergammaglobulinemia, presence of higher ANA antibody titers, presence of anti-SS-A antibodies, anti-SS-B, increased ESR and leukopenia were presented in their work by Witte et al. [39]. The presence of RF in patients with pSS, as well as in other autoimmune diseases, and in acute infections, indicates the formation of a large number of other antibodies and the formation of antigen complexes with antibodies. The frequency of RF in various CTD was presented in Table 3 [39].
\nAutoimmune connective tissue disease | \nRF frequency% | \n
---|---|
Primary Sjögren’s syndrome | \n75–90 | \n
Rheumatoid arthritis | \n70–90 | \n
Mixed connective tissue disease | \n50–60 | \n
Systemic sclerosis | \n20–30 | \n
Systemic lupus erythematosus | \n15–20 | \n
Dermato/polymyositis | \n20 | \n
Vasculitis (GPA and MPA) | \n5–20 | \n
Other CTD* as psoriatic arthritis, juvenile idiopathic arthritis, and reactive arthritis | \n5 and <5 | \n
The frequency of RF in various connective tissue diseases [39].
Anti-centromere antibodies (ACA) are directed to six antigens associated with centromere (composed of a complex of kinetochore proteins). Currently identified anti-centromere antibodies (CENP) have been assigned designations with letters from A to F. The most common are CENP-A, B and C. CENP-B is also the most frequently occurring anti-centromere antibody in patients with pSS. The incidence of ACA antibody described in the literature ranges from 3.7 to 4% [40, 41]. This antibody, with a mass of 80 kDa, is a DNA-binding protein involved in the heterochromatin folding. Anti-centromere antibodies (A, B, C) occur mainly in limited systemic sclerosis (LSSc) and are associated with the prevalence of telangiectasia, higher severity of Raynaud’s symptom, lung involvement such as interstitial lung disease [ILD] and fibrosis [42]. Their relationship between the presence of ACA antibodies and the involvement of endocrine glands has been demonstrated; in the ACA+ group, anti-SS-A and anti-SS-B autoantibodies were less frequent [42].
\nThe association of ACA antibodies with non-Hodgkin’s lymphomas (CENP-F) including MALT lymphomas was also described [43], as well as the case reports of CENP-B presence in small-cell lung cancer [44].
\nInterestingly, it has also been demonstrated that the presence of anti-CENP-B antibodies is associated with prolonged survival in a breast cancer [45].
\nCitrullination is the post-translational process in proteins of deamination/conversion of the amino acids: arginine into citrulline. ACPA positive sera include antibodies to citrullinated proteins, such as fibrin and fibrinogen, vimentine (MCV—mutated citrullinated vimentine) and alpha-enolase (CEP-1).
\nIt is known that arthritis may be one of the clinical symptoms of pSS. However, most of the pSS patients suffer from arthralgia, and only minority develop non-destructive arthritis. ACPA antibodies, a main marker of rheumatoid arthritis, are usually present in low concentrations in pSS according to various studies they are present in 3–22% of cases [46]. A higher incidence of arthritis was found in pSS patients with ACPA presence compared to patients without these antibodies [47]. It seems, however, that patients with pSS and ACPA positive require further observation toward the development of rheumatoid arthritis [48].
\nIt should also be remembered that smoking and periodontal infection by Porphyromonas gingivalis are strong environmental factors stimulating protein citrullination and the emergence of ACPA antibodies [49].
\nCitrullinated alpha enolase (CEP-1) is an antigenic target for antibodies against citrullinated proteins (ACPA). In the Nezos et al. study [50], it was shown that CEP-1 antigen is a major antigen target in the ACPA positive subgroup of patients with pSS. The frequency of CEP-1 antibody in the RA ACPA positive group was not as high, while it was not found healthy group at all. The authors drew attention to the link of anti-CEP-1 antibodies presence to arthritis as well as to renal tubular dysfunction.
\nIn recent years, researchers identified autoantibodies to carbonic anhydrase 6 (anti-CA6 antibodies), anti salivary gland protein 1 (SP-1) and anti-parotid secretory protein (PSP) [51]. These antibodies may emerge before pSS marker antibodies such as SS-A/Ro or SS-B/La and are associated with a minor focus score; these antibodies also occur more often in patients who did not have anti-SS-A/Ro antibodies [52]. Interestingly, in Langhe et al. work, anti CA6-IgA antibodies were detected primarily in patients with long pSS duration; other autoantibodies such as anti-CA6, PSP, and SP1 in IgG and IgM class were more frequently observed in SSc and MCTD with secondary SS. These autoantibodies do not allow distinguishing SLE from secondary SS. However, the described study was limited by a small group of SLE patients [52]. In the literature, some cases have been reported of patients with severe symptoms of eye or mouth dryness, in which there was no SS-A/Ro antibodies, but the presence of anti SP-1 antibody was confirmed [53]. It may suggest, that in case of a patients presenting unexplained dryness with no serology markers defined in current criteria for pSS, performing the test for novel, early antibodies to Sp1 and PSP may still be useful for diagnosing patient’s condition [53].
\nMuscarinic 3 receptor (M3R) is found in various places in the body, such as smooth muscles, the endocrine and the exocrine glands, lungs, pancreas and even the brain. This receptor is also expressed on pancreatic beta cells, modulating insulin secretion. Activation of the M3R receptor induces smooth muscle constriction and increase glandular secretions [54].
\nIt has been demonstrated that muscarinic acetylcholine type 3 receptor (M3R) antibodies are present in the serum of patients with pSS [54]. As it was presented by Kovacs et al., M3R antibodies are found in up to 90% of subjects with pSS [55]. In the group with M3R antibodies, leucopenia was more frequently observed [55]. Immune response to muscarinic receptor 3 plays a role in the pathogenesis of autoimmune sialoadenitis [56] and diabetes mellitus type 2. MR3 antibodies may be present in other autoimmune diseases and do not allow for differentiation between primary and secondary Sjögren’s syndrome. The severity of symptoms of dryness or dysfunction of the exocrine system in pSS may be related not only to MR3 antibodies presence but also to other autoantibodies such as, for example, antibodies to aquaporins [57].
\nAquaporins (AQP; water channels) are integral membrane proteins that form pores in the membrane of biological cells, enabling transport of water between cells. Some genetic defects of aquaporin genes have been associated with diseases as neuromyelitis optica (Devic’s syndrome) and nephrogenic diabetes insipidus. First, aquaporin—“aquaporin-1” was described in 1992 by Peter Agre, until today we know 13 aquaporins, of which four are best defined [58]. Because of their influence of water transport, aquaporins have an impact on saliva and tear production and changes in AQP expression may lead to dryness symptoms [59, 60]. Aquaporin-4 (AQP4) is found on perivascular and ependymal cells, but it has also been discovered in sera of patients with NMO and multiple sclerosis. Tzartos and his colleagues detected aquaporin antibodies (AQP-1, -3, -8, and -9) in pSS patients sera [61]. What is interesting in the pSS group, AQP-4 and AQP-5 antibodies were not present. The presence of AQP antibodies was associated with more severe xeropthalmia; the authors suggest potential role of AQ P-Ab in salivary gland secretions. Such hypothesis requires further research.
\nStathmins (STMN) are phosphoproteins which play a role in neuronal development and interact with tubulin. Presently, four stathmins have been identified. Stathmins are upregulated in a number of cancers and neuropathies [62]. Anti-stathmin-4 antibodies in IgG3 class were proposed as a biomarker of polyneuropathy and such observations were presented by Duda et al. in their study. The authors described anti-STMN4 antibodies in 33% of pSS patients with polyneuropathy (PNP)—vs. 7% of those without PNP—and in 45% of individuals with vasculitis skin changes (as opposed to 13% in individuals without them) [63].
\nAlpha fodrin is an actin-binding, organ-specific protein of the cytoskeleton. Antibodies against alpha-fodrin are detected in serum samples from patients with primary or secondary Sjögren’s syndrome especially with sicca symptoms. Some authors suggest that they can be detected earlier in the course of pSS, sometimes before the emergence of anti SS-A or SS-B antibodies [64]. These antibodies, in the IgA and IgG class of immunoglobulins, are found in the serum and salivary glands of patients with pSS. However, other researchers did not describe any significant sensitivity and specificity of these antibodies [65, 66, 67].
\nMajor salivary glands are the main extra endocrine glands targeted in pSS and saliva of patients with pSS is also a source of antibodies and cytokines. Large salivary glands are also the site for MALT lymphoma development. Investigators are interested in finding biomarkers in saliva, that allow for early pSS diagnosis, as well as the detection of mucosa associated lymphoma (MALT lymphoma). Cui et al. suggest set of three autoantibodies such as anti-cofilin-1 antibodies, anti-alpha enolase and anti-Rho GDP dissociation inhibitor 2(RGI2) antibodies, which, due to high specificity and sensitivity, may play a role as such biomarkers [68].
\nIn the current pSS criteria, only anti-SS-A/Ro antibodies are taken into account as the most sensitive and specific for pSS diagnosis. Still, the multisymptom picture of this rheumatic disease compels the search for other immunologic markers of at least equal prognostic importance.
\nThe occurrence of some of the identified antibodies has been associated with the specific clinical features such as interstitial lung disease, increased eye dryness, increased risk of nephrolithiasis and tubular distal acidosis or MALT lymphomas. In Table 4, autoantibodies frequently occurring in pSS and their association with clinical manifestation were presented.
\nAuto-antibody | \nClinical findings | \n
---|---|
Anti-Ro52 kD | \nInterstitial lung disease | \n
Anti-Ro60 kD | \nHematologic changes, photosensitivity, skin involvement, Raynaud’s phenomena, and dryness | \n
Anti-SS-B/La | \nLiver (autoimmune disease) PBC | \n
RF | \nDryness, hypergammaglobulinemia, and leukopenia | \n
ACPA | \nArthralgia and arthritis | \n
Anti-CENP-B | \nInterstitial lung disease and fibrosis | \n
Novel autoantibodies | \n|
Anti-CA6 | \nDryness and renal tubular acidosis | \n
Anti-PSP | \nDryness | \n
Anti-SP1 | \nDryness | \n
Anti-CEP-1 | \nArthritis and renal tubular dysfunction. | \n
Antibodies in pSS and their association with clinical manifestation.
pSS is a still not fully understood autoimmune disease, requiring doctor’s vigilance. Even despite of a pSS having a mild course for a long time, there is a risk of organs and systems involvement. As it has been known for many years already, the risk of developing lymphomas is particularly increased in pSS patients compared to the healthy population. Although only one antibody (SS-A/Ro) has been included in the pSS diagnostic criteria, a lot of attention has been paid to new autoantibodies that can help clinicians in patient stratification in the early stages of diagnosis or may have a prognostic value.
\nThe authors declare no conflict of interest.
Pests and diseases have always had repercussions directly on losses of crops and livestock products and indirectly over the income decreases due to insufficient harvests of commercial crops. Chemical pesticides are used in an excessive way and without prior technical assistance to pest distribute control, which instead of solving the problem, has produced strong damage to agricultural and livestock productivity, as well as important environmental effects with implications to public health [1]. Pesticides are chemical substances designed to prevent, delay, repel or fight any pests [2].
In [3], it was mentioned that Mexico ranked fifth in the world in the use of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) in agricultural programs and fourth place for its use in public health. As many as 69,545 ton of DDT were used in health campaigns for the control of malaria and agricultural activities, from 1957 onward, DDT was applied every 6 months indoors and outdoors with a coverage of 2 g/m2, and almost 1000 ton DDT/y were used in agricultural areas [4]. Indeed, DDT was used in Mexico until the year 2000, and DDT and its metabolites have been found in the environment [5] as well as in human tissues [5, 6], breast milk [7], raw cow’s milk and bovine meat [8, 9]. DDT is a very stable organochlorine pesticide that is almost completely metabolized, but small percentage remains as o,p´-DDT, while the most of its concentration is transformed into p,p´-DDE, which is characterized for its poor solubility in water and high affinity for lipids. It is considered a pollutant of high persistence due to its half-life of up to 15 years in the environment [10]. This pesticide persistence is responsible of the wild flora and fauna deterioration, as well as the contamination of soil, water table, continental, and coastal waters. Besides, pesticides can be incorporate into pasture, vegetables, and edible animals, which when consumed, act as transporters facilitating its accumulation in living organisms [11, 12].
In the state of Chiapas, México, [13] found high levels of total DDT in outdoor soil samples that ranged from 0.002 to 27 mg kg−1, while the levels found by [4] in Chihuahua, México, ranged from 0.001 to 0.788 mg kg−1. Taking into account the guideline for total DDT in residential soil of 0.7 mg kg−1 in Canada [14], the soil samples from Chiapas had levels higher than the guideline. The high levels of OCs observed may be due to ongoing usage as well as the emission of old residues from soil. Soils are an important sink and source for persistent organic pollutants to the atmosphere. In many of the cases, the contamination of soil with pesticides is due to its incorrect storage, either by leakage of corroded tanks containing liquid pesticides or by aerial dissemination of powder pesticide. However, when pesticides infiltrate the soil, their dissemination depends on the nature of the pesticide, as well as the composition, moisture, pH, and temperature [12, 15]. Because of that, a small portion of spilled pesticides can generate a high soil contamination. Moreover, soil pesticides infiltration can cause their introduction and distribution in the food chain, accumulating successively on each ecological niche until reaching lethal doses for some constituent organisms of the chain, or until reaching high levels of the trophic network [16].
This problem is aggravated due to the excessive use of pesticides in the agricultural sector, the absence of technological remediation and the lack of safety interval (waiting period) for the harvest of agricultural products, which has significant impacts on public health [17]. Some of the toxic effects of DDT and its metabolite identified in mammalian have been alterations in fetal development and adverse effects on testicular function (semen, sperm, and sperm motility decrease) due to the mimetization or antagonism of reproductive hormones [18, 19]. Thus, DDT metabolites and DDT are considered endocrine disruptors, with estrogenic properties related to several types of estrogen-dependent cancers, such as breast cancer; therefore, the use of this pesticide was prohibited on the decade of the 1970s in most countries [20]. Nevertheless, pesticides remain in the environment (persistence); therefore, the pesticides have been widely distributed, and their traces can be detected in all areas of the environment (air, water, and soil) [21, 22]; therefore, current tendency is focused on natural sources for biological pesticide control. On the other hand, the indiscriminate and uncontrolled application of synthetic pesticide besides to accumulate residues in the environment and, in some cases, in living beings, has caused resistance in some pest. The first case reported of DDT resistance occurred in 1947, and since then, it has increased alarmingly, and it has been estimated that there are currently around 489 species of pest resistant to 400 different pesticides in the world [23]. The irrational use of synthetic pesticide has produced genotypic and phenotypic changes in many species, generating resistance to the action of most of them, including inorganics, DDT, cyclodienes, organophosphates, carbamates, pyrethroids, juvenile hormone analogues, avermectins, neonicotinoids, and antimicrobial [22, 23, 24].
Though the use of pesticides has offered significant economic benefits by enhancing the production and yield of food and fibers and the prevention of vector-borne diseases, evidence suggests that their use has adversely affected the health of human populations and the environment [21]. Because of this problem, several researchers are focused their studies on the identification of new natural sources containing active metabolites that could be used on the control of pest [25, 26].
The development of essential oils (EOs) as plant protection products is especially suited to organic farming as well as to integrated pest management. They are natural in origin and biodegradable, have diverse physiological targets within insects, and, consequently, may delay the evolution of insect resistance [27]. EOs act as fumigants, pesticides, repellents, and antifeeds that could affect some biological parameters such as grown rate, biological cycle, and reproduction [26]. One of the most widely analyzed oils is neem (Azadirachta indica) which has a toxic effect over several pests and it is a potential alternative to the synthetic pesticide [28]. Neem oil active compounds are azadirachtin, salannin, nimbin, and their respective analogues; being the azadirachtin the most abundant compound [29]. Azadirachtin acts on the immature stages of the insects avoiding their molt or maturation from larva to pupa and generating mutations in the development of different essential parts for their survival, because it affects their ability to oviposit in mature stage and hatch during the larval stage [30]. Its effect is reinforced by the action from the rest of limonoides, such as salannin and nimbin, which have repellent and antifeeder effects over many insects [31]. Although the concentration of azadirachtin is sufficient and its location well established in the seed, its extraction presents some problems, because it is soluble in polar organic solvents, but slightly soluble in water, besides is photosensitive and thermolabile, which conditions its activity in the oil.
Among the methods used for the extraction of azadirachtin, it could be mentioned the cold extrusion in a mechanical press, maceration, and percolation with the use of organic solvents. Each of the proposed methods stimulates the extraction of azadirachtin but in different proportions. Various researchers have suggested that the high variability in the extraction of azadirachtin from neem depends on several factors as age of the tree, region of its production, stage of fruit development, availability of the internal portion of the seed, storage conditions of the seed, methods and solvents used for its extraction, and the particle size [32, 33, 34, 35]. However, one aspect that has not been taken into account is the physical barrier exerted by the cell wall of the seed that directly affects the availability and extraction of azadirachtin and other acaricidal compounds. This problem has been overcome with great success in the plant extract industry through the application of cellulases or preparations with multiple enzymatic activities (cellulases, hemicellulases, and pectinases) [34, 36, 37].
The assisted extraction by cellulolytic enzymes has proven to be a viable and feasible tool to obtain bioactive metabolites from plants, due to its effect on lignocellulosic structures of its cell wall, which increase the yield of oils, pigments, flavorings, and aromas extracted in comparison with traditional extraction methods [38]. Due to the advantages of the use of cellulolytic enzymes for the production of bioactive metabolites from plants and the inherent need to develop sustainable and environmentally friendly alternatives that avoid the resistance phenomenon, the present study had the purpose of evaluating the use of food-grade enzyme preparation on the hydrolysis of the neem seed to obtain extracts with higher concentrations of azadirachtin, but without the use of solvents.
The study was divided into two stages: (1) determination of optimum activity conditions of four enzyme preparations and (2) evaluation of the azadirachtin release kinetics under optimal conditions of enzyme preparation activities. The enzyme preparations used in this study were Crystalzyme PML-MX, Cellulase 17600, Crystalzyme Cran, and Crystalzyme 100XL, and their optimum pH and temperature conditions were identified by using dehydrated and pulverized neem seed. Then, four volumes (1, 2, 3, and 4 mL) of each enzyme were tested to determine the optimum enzyme concentration to neem seed hydrolysis.
Evaluations of azadirachtin release kinetics were conducted at optimum pH and temperature for each enzyme preparation, and the maximum time required for the azadirachtin extraction was determined.
Neem seeds were provided by a local producer from Jamapa, Veracruz during June, 2017. One kilogram of 110–120 day old neem seeds (green-yellow coloration) was collected. Harvested seeds were washed and cut in half to extract the cotyledon extraction, which was stored by in freezing at −20°C for 24 h before using.
Each preparation enzymatic activity was measured by filter paper test [39], where the activity was defined as filter paper units per enzyme milliliter (FPU.mL−1). After FPU.mL−1 determination, the effect of the enzyme concentration on the hydrolysis of the neem seed cellulose structures and the azadirachtin release was evaluated. Neem seed hydrolysis was indirectly determined by the quantification of reducing sugar released during the enzymatic reaction. Total protein was estimated with [40] bovine serum albumin (BSA) as standard, and enzymatic activity (EA) for each enzymatic preparation was defined as changes in absorbance in 0.001 of reducing sugars mg protein−1 min−1.
The optimal conditions of pH and temperature were established based on the enzymatic hydrolysis of the neem seed and the release of azadirachtin. To determine the optimum pH of the enzymatic preparations, 1 g of the dehydrated seed was homogenized with 19 mL of phosphate buffer (3.0, 3.5, 4.0, 4.5, 5.0, and 5.5) and was conditioned at 50°C for 5 min and after 1 mL of the corresponding enzyme preparation was added. The enzymatic reaction was carried out for 2 h and was stopped by immersion in ice water. Subsequently, 1 mL of the sample was taken for reducing sugar determination and 1 mL for azadirachtin quantification by HPLC [41]. Once the optimum pH of each enzyme preparation was identified, the effect of the temperature at 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70°C was evaluated. Additionally, one extract without enzyme added was prepared as control, and the concentrations of reducing sugars released were subtracted from the values obtained in each of the enzymatic treatments. Furthermore, enzyme:neem seed (dry base) ratio was evaluated under optimal conditions of pH and temperature, and for this, 2 g of neem seeds (wet base) were used and 0.5, 1.0, 2.0, and 4 mL of each of the enzyme preparations were tested.
To determine kinetics of azadirachtin release, 100 g of neem seed (wet base) was homogenized with phosphate buffer at the optimum pH previously identify (1:10, w v−1) ratio for 3 min using an Ultra Turray homogenizer, T-25 basic (IKA®, Wilmington, NC). Five extracts were elaborated, one for each enzyme preparation and one without enzyme (control), and were incubated at optimum temperatures for each one. An aliquot was taken at 0, 2, 4, 6, 12, 18, and 24 h for the determination of azadirachtin. All samples were analyzed by triplicate.
Azadirachtin quantification was carried out by the HPLC technique proposed by [41], using a binary HPLC system (Waters 1525) and a photodiode detector (Waters 2996). The analytical separation was carried out with a Nova-Pak C18 column of 4 μm (3.9 × 150 mm) SUM (Waters® Milford, MA). Neem samples were centrifuged and diluted with acetonitrile (1:1, v v−1) before analyzing by HPLC. The samples were filtered through acrodiscs (Millipore) of 0.22 μm, and 20 μl was injected into the column. The flow rate was set at 1 mL min−1, the mobile phase was acetonitrile: water (40:60, v v−1), and azadirachtin was read at 217 nm in a retention time of 3.1 min.
The optimal conditions of pH, temperature, and the enzyme:substrate ratio were analyzed by means of analysis of variance (ANOVA) at a level of significance of p < 0.05, and Tukey’s tests were used to evaluate the differences between means with the statistical program Minitab 17.3. The kinetics of release of reducing sugars and azadirachtin were analyzed by a first-order empirical equation Yi = Ye (1−e−kt), in which the equilibrium concentrations (Ye) and its release rate constant (k) were determined, and the results were analyzed by ANOVA (p < 0.05) to determine differences between treatments.
In order to achieve the optimum cellulolytic activity of the enzyme preparation, filter paper units (FPU.mL−1) of each one were first determined. Crystalzyme PML-MX and Cellulase 17600 L showed the highest cellulolytic activities with 6.96 and 5.60 FPU.mL−1, respectively. This result is probably due to the presence of cellulases in these enzymatic preparations, since the determination of the activity is carried out with filter paper, which is formed by cellulose [42], while the enzymatic preparations, Crystalzyme 100XL and Crystalzyme Cran, showed lower activities with 2.65 and 2.38 FPU mL−1, respectively, and do not contain cellulases (Table 1). These results were used as reference to define the amount of enzyme needed to hydrolyze the neem seed cellulolytic structures and extract the highest concentration of azadirachtin.
Enzyme preparations | Cellulolytic activity | Activity (FPU mL−1) |
---|---|---|
Crystalzyme PML-MX | Pectinase, endoglucanase, exoglucanase, hemicellulase | 6.96 |
Crystalzyme Cran | Pectinase | 2.38 |
Crystalzyme 100XL | Pectinase and arabinase | 2.65 |
Cellulase 17600 | Endoglucanase, exoglucanase, β-glucosidase, pectinase and arabinoxylanase | 5.6 |
Enzymatic activities of the food-grade enzyme preparations.
Determination of the optimal reaction conditions was carried out at 50°C, taking into account that temperature is indicated by the enzyme preparation supplier as the optimum. However, in the evaluations, dehydrated neem seed was used instead of filter paper or crystalline cellulose. Figure 1 shows the determinations of the optimum pH of each enzyme preparations, and the results indicate that all enzyme preparations perform the hydrolysis of the neem seed under very similar pH conditions regardless of the combinations of cellulolytic activity they contain. Optimal pH of the enzymatic preparations was 5.0 for Crystalzyme Cran and 4.5 for Crystalzyme PML-MX, Cellulase and Crystalzyme 100XL. Of the four enzyme preparations, Crystalzyme PML-MX exhibited the highest hydrolysis of the neem seed with 2.2114 (± 0.1879) mg reducing sugars mL−1extract. A second reaction was carried out adjusting each hydrolysis to the optimum pH of each enzyme, and the effect of the temperature in the range of 25–70°C was evaluated (Figure 2).
Optimum pH of food-grade enzyme preparations: (A) Crystalzyme PML-MX, (B) Cellulase 17600, (C) Crystalzyme Cran, and (D) Crystalzyme 100XL.
Optimum temperature of food-grade enzyme preparations: (A) Crystalzyme PML-MX, (B) Cellulase 17600, (C) Crystalzyme Cran, and (D) Crystalzyme 100XL.
Cellulase 17600L, Crystalzyme Cran, and Crystalzyme 100XL shown higher activity at 50°C, while to Crystalzyme PML-MX was at 45°C. These conditions are within the limit considered by [34] to maintain the neem extracts without the loss of azadirachtin. However, it is necessary to evaluate these conditions on the release of azadirachtin, since it is unknown whether the highest hydrolysis of the neem seed ensures maximum concentration of azadirachtin.
Results of the enzyme concentration effect over hydrolysis of neem seeds could be observed in Figure 3. Reducing sugar release was used as indirect measure of neem seed hydrolysis.
Optimum filter paper unit (FPU) of the food-grade enzyme preparations for hydrolysis of neem seeds. (A) Crystalzyme PML-MX, (B) Cellulase 17600, (C) Crystalzyme Cran, and (D) Crystalzyme 100XL.
Reactions catalyzed by Crystalzyme PML-MX and Cellulase 17600 L presented the highest hydrolysis of the neem seed, probably due to the presence of cellulases in its composition. A total of 1.8072 (± 0.0021), 2.0635 (± 0.0689), 2.0493 (± 0.0521), and 2.0742 (± 0.0283) g L−1 reducing sugars were released when 0.5 (3.48 FPU), 1 (6.96 FPU), 2 (13.92 FPU), and 4 mL (27.84 FPU) of Crystalzyme PML-MX were used. On another hand, 1.8034 (± 0.0387), 2.0809 (± 0.0023), 1.9921 (± 0.0456), and 1.9383 (± 0.0781) g L−1 reducing sugars were released when 0.5 (2.80 FPU), 1 (5.60 FPU), 2 (11.2 FPU), and 4 mL (22.4 FPU) of Cellulase 17600 were used. These results suggest that an increasing of enzyme concentration in the reaction not necessarily imply higher hydrolysis of the neem seed. Therefore, it is advisable to use the lowest concentration in which the same results were obtained for each enzyme preparation. Crystalzyme Cran and Crystalzyme 100XL showed less hydrolysis of the neem seed after 18 h. Crystalzyme Cran released 1.0022 (± 0.0576) g L−1 with the highest concentration of enzyme used (4 mL, 9.52 FPU); however, these results were not statistically different from those found when using 1 (2.38 FPU) and 2 mL (4.76 FPU), since the equilibrium concentration of reducing sugars was 0.9323 (± 0.0786) and 0.9859 (± 0.0341), respectively. On the other hand, the samples hydrolyzed with Crystalzyme 100XL had a maximum reducing sugar release when 4 mL of enzyme (21.2 FPU) was used.
In order to determine the optimum enzyme concentration to neem seed hydrolysis, equilibrium concentration and release rate of the reducing sugars were evaluated. The analysis of the results showed that reducing sugar release rate was not statistically different when 1, 2 or 4 mL for both Crystalzyme PML-MX and Cellulase 17600 L were used. When Crystalzyme Cran was evaluated, the higher rates of release of reducing sugars were obtained with 2 and 4 mL. In contrast, the highest reduced sugar release rate for Crystalzyme 100XL was presented when 1 mL (5.30 FPU) of this enzyme was added. Therefore, based on the analysis of results, it was considered that the units of activity necessary to hydrolyze the neem seed are 6.96, 5.60, 4.76, and 5.3 FPU mL−1 for Crystalzyme PML-MX, Cellulase 17600 L, Crystalzyme Cran, and Crystalzyme 100XL, respectively.
After optimum conditions of pH, temperature and enzyme concentration were determined, and the kinetics of azadirachtin released was carried out but using fresh seed instead of dehydrated seed to minimize the risk of losses due to the dehydration process.
Evaluation of the azadirachtin release kinetics was conducted with 100 g of neem seed homogenized and adjusted at 1:10 (w v−1) ratio with phosphate buffer. Enzymatic hydrolysis was conducted under optimal conditions of each enzyme preparation, and azadirachtin were quantified at 0, 2, 4, 6, 12, 18, and 24 h by the HPLC technique, and the results were presented on base of the quantity of neem seed (dry base) used for the neem seed extract elaboration (Figure 4). The highest azadirachtin concentrations obtained in this study were 2.55 g kg−1 (2550 ppm) and 2.35 g kg−1 (2350 ppm) neem seed when Cellulase 17600 L and Crystalzyme PML-MX enzyme preparations were used, respectively. Both of this enzyme preparation include cellulases and pectinases and were statistically different (p < 0.05) from the enzymatic preparations, Crystalzyme Cran (pectinases) and Crystalzyme 100XL (pectinases and arabinases).
Azadirachtin release kinetics from neem seeds extracted with food-grade enzyme preparations.
Azadirachtin concentrations found in this study were higher than those reported by other authors when conventional methods such as extrusion, extraction with solvents (hexane, methanol), and aqueous extraction which reported concentrations of 1080, 565, 400, 150 ppm, respectively [33] and were similar to the obtaining by cold methanol extrusion [32]. However, the concentration obtained is lower than those reported with nonconventional technologies such as extraction with pressurized solvents, which reported concentrations of up to 9510 ppm of azadirachtin [34].
One of the advantages of the use of organic solvents in the extraction process is to improve the solubility of nonpolar components which increase their extraction from vegetable matrices. However, in the present study, only phosphate buffer was used, which could explain the differences of azadirachtin extraction with the pressurized solvent method [34]. Also, in [43], it was reported that in the tropical regions, there are lower concentrations of azadirachtin after extraction processes due to high temperatures, moisture, and storage conditions that could encourage the azadirachtin degradation.
Although the highest concentrations of azadirachtin were obtained with the enzymatic preparations, Cellulase 17600L and Crystalzyme PML-MX, also Crystalzyme Cran and Crystalzyme 100XL could be used to elaborate neem extracts because of their azadirachtin concentrations of 1540 and 1690 ppm, respectively, are similar to those contained in commercial acaricidal products elaborated based on neem, but with the use of solvents [32]. This result indicates an advantage and a possible solution to the indiscriminate use of synthetic pesticides and the organic solvents employed in several extractions of active biomolecules. On the other hand, after 18 h of enzymatic hydrolysis, there are no changes on azadirachtin release, which means it is time required to carry out the obtaining of neem seed extracts. In addition, the conditions identified in this study as necessary to neem seed hydrolysis are not extreme or aggressive and could be easily scalable.
The present study had the objective of generating an alternative solution to the multiple problems generated by the indiscriminate use of synthetic pesticides. The use of enzymes in the production of metabolites with biological interest has been widely studied in the last decade, due to their specificity and their effect on the cellulose substrate hydrolysis, minimizing the times of obtaining and the necessary costs for their implementation. In addition, its application allows reducing the use of solvents, normally employed in the extraction of neem oil. Besides, the conditions required for neem seed hydrolysis under optimal activity of the enzyme preparations can be easily standardized and scaled for its industrial production. In addition, it was found no affectations on azadirachtin concentration when temperatures of 45 and 50°C were used during enzymatic hydrolysis coinciding with that reported in [34]. However, more studies are needed to determine the stability of azadirachtin under different temperatures and pH conditions during storage.
Although the enzyme-assisted extraction allows the obtaining of neem extracts with higher azadirachtin concentrations than those obtained with conventional methods such as extrusion, cold extrusion, water maceration, and percolation with hexane [32, 33] and in similar concentrations to those obtained by extrusion with cold methanol [32], the amount of neem seeds used in this method was lower, and therefore, the yield was higher than obtained with all these methods. In next studies, components identified as repellents and/or acaricides such as salannin and nimbin should be analyzed. In addition, it is necessary to carry on shortterm and long-term in vitro and in vivo analysis of enzymatic neem extracts on pest with public health impact, defining the vehicle of application and the lethal concentrations for its implementation.
This study was funded by the Dirección General de Educación Superior Universitaria (DGESU/SEP) (Project DSA/103.5/14/7147).
All authors who participate in the elaboration of this manuscript have no conflict of interest to declare.
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