Databases containing the information on aprotinin and SBTI.
\\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!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 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 261 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!
Note: Edited in March 2021
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Interested readers will find in this book the topics of image compression, groundwater quality, establishing the downscaling and spatio-temporal scale conversion models of NDVI, modelling and optimization of 3T fractional nonlinear generalized magneto-thermoelastic multi-material, algebraic fractals in steganography, strain induced microstructures in metals and much more. The book will definitely be of interest to scientists dealing with fractal analysis, as well as biomedical engineers or IT engineers. I encourage you to view individual chapters.",isbn:"978-1-83962-483-4",printIsbn:"978-1-83962-482-7",pdfIsbn:"978-1-83962-484-1",doi:"10.5772/intechopen.87695",price:119,priceEur:129,priceUsd:155,slug:"fractal-analysis-selected-examples",numberOfPages:128,isOpenForSubmission:!1,hash:"f0c3d700a69d15b52ff8a59fe7e99062",bookSignature:"Robert Koprowski",publishedDate:"September 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9886.jpg",keywords:null,numberOfDownloads:1093,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 1st 2019",dateEndSecondStepPublish:"March 3rd 2020",dateEndThirdStepPublish:"May 2nd 2020",dateEndFourthStepPublish:"July 21st 2020",dateEndFifthStepPublish:"September 19th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://mts.intechopen.com/storage/users/50150/images/system/50150.jpg",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia in Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years he has studied the analysis and processing of biomedical images with particular emphasis on the full automation of measurement for a large inter-individual variability of patients. He is the author of dozens of papers with the impact factor (IF) and more than a hundred other papers, as well as the author or co-author of six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in the field of biomedical engineering.",institutionString:"University of Silesia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1407",title:"Applied Mathematics",slug:"numerical-analysis-and-scientific-computing-applied-mathematics"}],chapters:[{id:"72917",title:"Optimization of Fractal Image Compression",slug:"optimization-of-fractal-image-compression",totalDownloads:190,totalCrossrefCites:0,authors:[null]},{id:"72577",title:"Fractal Analysis for Time Series Datasets: A Case Study of Groundwater Quality",slug:"fractal-analysis-for-time-series-datasets-a-case-study-of-groundwater-quality",totalDownloads:172,totalCrossrefCites:0,authors:[null]},{id:"71255",title:"Establishing the Downscaling and Spatiotemporal Scale Conversion Models of NDVI Based on Fractal Methodology",slug:"establishing-the-downscaling-and-spatiotemporal-scale-conversion-models-of-ndvi-based-on-fractal-met",totalDownloads:207,totalCrossrefCites:0,authors:[null]},{id:"72883",title:"A New BEM for Modeling and Optimization of 3T Fractional Nonlinear Generalized Magneto-Thermoelastic Multi-Material ISMFGA Structures Subjected to Moving Heat Source",slug:"a-new-bem-for-modeling-and-optimization-of-3t-fractional-nonlinear-generalized-magneto-thermoelastic",totalDownloads:154,totalCrossrefCites:0,authors:[{id:"233766",title:"Prof.",name:"Mohamed Abdelsabour",surname:"Fahmy",slug:"mohamed-abdelsabour-fahmy",fullName:"Mohamed Abdelsabour Fahmy"}]},{id:"71839",title:"Using Algebraic Fractals in Steganography",slug:"using-algebraic-fractals-in-steganography",totalDownloads:178,totalCrossrefCites:0,authors:[null]},{id:"71305",title:"Fractal Analysis of Strain-Induced Microstructures in Metals",slug:"fractal-analysis-of-strain-induced-microstructures-in-metals",totalDownloads:195,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6692",title:"Medical and Biological Image Analysis",subtitle:null,isOpenForSubmission:!1,hash:"e75f234a0fc1988d9816a94e4c724deb",slug:"medical-and-biological-image-analysis",bookSignature:"Robert Koprowski",coverURL:"https://cdn.intechopen.com/books/images_new/6692.jpg",editedByType:"Edited by",editors:[{id:"50150",title:"Prof.",name:"Robert",surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6138",title:"Time Series Analysis and Applications",subtitle:null,isOpenForSubmission:!1,hash:"d33ee38578b81585416062fea4979bbf",slug:"time-series-analysis-and-applications",bookSignature:"Nawaz Mohamudally",coverURL:"https://cdn.intechopen.com/books/images_new/6138.jpg",editedByType:"Edited by",editors:[{id:"119486",title:"Dr.",name:"Nawaz",surname:"Mohamudally",slug:"nawaz-mohamudally",fullName:"Nawaz Mohamudally"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9966",title:"Dynamic Data Assimilation",subtitle:"Beating the Uncertainties",isOpenForSubmission:!1,hash:"e7fde2a36354a2f5a4282fdf9c743380",slug:"dynamic-data-assimilation-beating-the-uncertainties",bookSignature:"Dinesh G. Harkut",coverURL:"https://cdn.intechopen.com/books/images_new/9966.jpg",editedByType:"Edited by",editors:[{id:"216122",title:"Dr.",name:"Dinesh G.",surname:"Harkut",slug:"dinesh-g.-harkut",fullName:"Dinesh G. Harkut"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7614",title:"Fourier Transforms",subtitle:"Century of Digitalization and Increasing Expectations",isOpenForSubmission:!1,hash:"ff3501657ae983a3b42fef1f7058ac91",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",bookSignature:"Goran S. Nikoli? and Dragana Z. Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editedByType:"Edited by",editors:[{id:"23261",title:"Prof.",name:"Goran",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6230",title:"Topics in Splines and Applications",subtitle:null,isOpenForSubmission:!1,hash:"93059c7907be129c419e4f9960b4e9c3",slug:"topics-in-splines-and-applications",bookSignature:"Young Kinh-Nhue Truong and Muhammad Sarfraz",coverURL:"https://cdn.intechopen.com/books/images_new/6230.jpg",editedByType:"Edited by",editors:[{id:"207517",title:"Dr.",name:"Young Kinh-Nhue",surname:"Truong",slug:"young-kinh-nhue-truong",fullName:"Young Kinh-Nhue Truong"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10062",title:"Forecasting in Mathematics",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"9a3ad05fef0502040d2a238ad22487c0",slug:"forecasting-in-mathematics-recent-advances-new-perspectives-and-applications",bookSignature:"Abdo Abou Jaoude",coverURL:"https://cdn.intechopen.com/books/images_new/10062.jpg",editedByType:"Edited by",editors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoude",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoude"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8655",title:"Advances in Complex Analysis and Applications",subtitle:null,isOpenForSubmission:!1,hash:"6abcaa5b5cf98a51a769d1bce7e5ebe5",slug:"advances-in-complex-analysis-and-applications",bookSignature:"Francisco Bulnes and Olga Hachay",coverURL:"https://cdn.intechopen.com/books/images_new/8655.jpg",editedByType:"Edited by",editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8600",title:"Recent Advances in Integral Equations",subtitle:null,isOpenForSubmission:!1,hash:"55d44e96dac2ef01fb52708933293c71",slug:"recent-advances-in-integral-equations",bookSignature:"Francisco Bulnes",coverURL:"https://cdn.intechopen.com/books/images_new/8600.jpg",editedByType:"Edited by",editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"39507",title:"Effects of Soybean Trypsin Inhibitor on Hemostasis",doi:"10.5772/52600",slug:"effects-of-soybean-trypsin-inhibitor-on-hemostasis",body:'\n\t\tSoy bean trypsin inhibitor (SBTI) belongs to the family of serpins – serine protease inhibitors widely distributed in the nature [Silverman G.A. et al., 2004; 21]. Serpins participate in the regulation of proteopytic reactions underling very important physiological and pathological processes such as digestion [16], blood clotting [3, 14, 17], immunity [44] apoptosis [36, 42], inflammation [10], dystrophy [31], carcinogenesis [22, 11] and so on. Despite the apparent importance of the correction of imbalances of the proteolysis in pathology, in fact only the pancreatic trypsin inhibitor (aprotinin) is used more or less widely as a protease inhibitor drug (Trasisol, Contrical, Gordox etc) in the treatment of some diseases [24, 13, 40]. Being the animal protein aprotinin possesses substantial disadvantages [23, 12] and attempts to develop new drug on the base of plant or recombinant proteins or peptidomimetics are undertaken [35, 27]. SBTI is one of the candidates for such a role [34].
\n\t\t\tAmong proteolytic processes hemostasis is of special importance because of the high frequency of it’s disturbances, accompanied many pathological processes and diseases [20, 18]. At first sight it looks strange to expect that plant protease inhibitor SBTI should influence hemostasis in humans because blood clotting represents the cascade of proteolytic reactions catalyzed by highly specific proteases [43]. However, results of the very early studies support such possibility [26, 41]. The present study was aimed to investigate the influence of SBTI and aprotinin on hemostasis using modern bioinformatics approach and classical in vitro methods. The concrete purposes of the study included:
\n\t\t\tTo establish the extent of structural homology, compare functional activities and evaluate potential targets of SBTI and aprotinin among the human proteases by bioinformatics (
To investigate the influence of trypsin, SBTI and aprotinin on some indexes of blood clotting, fibrilolysis and platelet aggregation as well as on the hemolytic activity of the complement
To elucidate the possibility of the regulation of the total proteolytic and tripsin-inhibiting activity of blood plasma
\n\t\t\t\t
From fifty databases we had browsed in the INTRNET nine contained information on aprotinin and SBTI (Table 1). From these PDB (Protein Data Bank) and UniProt/Swiss-Prot were the most informative and we used these databases in our study.
\n\t\t\t\nUniProt-Swiss-Prot http://www.expasy.org | \n\t\t\t\t\t\tBPT1_BOVIN (P00974) | \n\t\t\t\t\t\tITRA_SOYBN (P01070) | \n\t\t\t\t\t
Blocks - most highly conserved regions of proteins http://www.ebi.ac.uk | \n\t\t\t\t\t\tP00974 | \n\t\t\t\t\t\tIPR002160 | \n\t\t\t\t\t
COG - the database of Clusters of Ortologous Groups of proteins http://www.ncbi.nlm.nih.gov | \n\t\t\t\t\t\tPrecursor P00974; NP_001001554; | \n\t\t\t\t\t\t- | \n\t\t\t\t\t
GTOP - Genomes TO Protein structures and functions http://spock.genes.nig.ac.jp | \n\t\t\t\t\t\tbtau0:ENSBTAG00000017328 | \n\t\t\t\t\t\t?atha0:At1g17860.1 | \n\t\t\t\t\t
iProClass - an integrated, comprehensive and annotated Protein Classification database http://pir.georgetown.edu | \n\t\t\t\t\t\tP00974/BPT1_BOVIN; PIRSF001621 | \n\t\t\t\t\t\t- | \n\t\t\t\t\t
LIGAND - LIGAND chemical database for enzyme reactions http://www.pasteur.fr | \n\t\t\t\t\t\t50059016; 3809839; bta:616039; 100156830; Bt.32343;BPT1_BOVIN | \n\t\t\t\t\t\t- | \n\t\t\t\t\t
MMDB - Molecular Modeling Data Base http://www.ncbi.nlm.nih.gov | \n\t\t\t\t\t\tP00974 (Precursor); 1QLQ0 | \n\t\t\t\t\t\t1AVU | \n\t\t\t\t\t
PDB - Protein Data Bank http://www.rcsb.org | \n\t\t\t\t\t\t1OA6 | \n\t\t\t\t\t\t1AVU; 1BA7 | \n\t\t\t\t\t
MEROPS (peptidases) http://merops.sanger.ac.uk | \n\t\t\t\t\t\tI02.001 | \n\t\t\t\t\t\tI03.001 | \n\t\t\t\t\t
Databases containing the information on aprotinin and SBTI.
To investigate the homology of the primary structures of SBTI and aprotinin we used BLAST (Basic Local Alignment Search Tool) algorithm, sequence alignment editor Bio Edit 5.0.9 and got information on these proteins from Protein Data Bank and Uni Prot using FASTA (Table 2), MOL and PDB format-files. The extent of homology of the total sequences of SBTI and aprotinin, calculated by the method of the multiple paired alignment, makes up 10% (Figures 1 and 2). The low homology of the total sequences of should be attributed to the different lengths of polypeptide chains these proteins – 58 amino acids in aprotinin [45] and 181 in SBTI [39].
\n\t\t\t\tAla | \n\t\t\t\t\t\t\tAsn | \n\t\t\t\t\t\t\tCys | \n\t\t\t\t\t\t\tAsp | \n\t\t\t\t\t\t\tGlu | \n\t\t\t\t\t\t\tPhe | \n\t\t\t\t\t\t\tGly | \n\t\t\t\t\t\t\tHis | \n\t\t\t\t\t\t\tIle | \n\t\t\t\t\t\t\tLis | \n\t\t\t\t\t\t\tMet | \n\t\t\t\t\t\t|
A | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tC | \n\t\t\t\t\t\t\tD | \n\t\t\t\t\t\t\tE | \n\t\t\t\t\t\t\tF | \n\t\t\t\t\t\t\tG | \n\t\t\t\t\t\t\tH | \n\t\t\t\t\t\t\tI | \n\t\t\t\t\t\t\tK | \n\t\t\t\t\t\t\tM | \n\t\t\t\t\t\t|
\n\t\t\t\t\t\t | |||||||||||
Asn | \n\t\t\t\t\t\t\tPro | \n\t\t\t\t\t\t\tGln | \n\t\t\t\t\t\t\tArg | \n\t\t\t\t\t\t\tSer | \n\t\t\t\t\t\t\tTre | \n\t\t\t\t\t\t\tVal | \n\t\t\t\t\t\t\tTrp | \n\t\t\t\t\t\t\tTyr | \n\t\t\t\t\t\t\tGlu | \n\t\t\t\t\t\t\t* | \n\t\t\t\t\t\t|
N | \n\t\t\t\t\t\t\tP | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tR | \n\t\t\t\t\t\t\tS | \n\t\t\t\t\t\t\tT | \n\t\t\t\t\t\t\tV | \n\t\t\t\t\t\t\tW | \n\t\t\t\t\t\t\tY | \n\t\t\t\t\t\t\tZ | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Designation of aminoacids in FASTA format. *- symbol in FASTA format corresponds to the gap of unlimited length
Comparison of the separate domains of SBTI and aprotinin reveals greater sequence similarity. Thus, the extent of homology of the N-terminal region of SBTI (5-60 amino acid residues) and the sequence of aprotonin without last two amino acids makes up 21%. The central region of SBTI (85-116 amino acid residues) and the region of aprotinin within 25-56 amino acids show 24% similarity. The highest extent of homology up to 35% is characteristic for C-terminal region of SBTI (132-181 amino acid residues) and aprotenin sequence without six C-terminal amino acids.
\n\t\t\t\tThe screen of the Bio Edit 5.0.9 with the results of calculation of homology of Aprotinin and SBTI. The identical amino acids are marked with black and similar with gray. Amino acid sequence are represented in FASTA format.
Homological regions of Aprotinin and SBTI (according to Bio Edit 5.0.9). The identical amino acids are marked with black and similar with gray.
For the visualization of the 3D-structures of SBTI and aprotinin we used Chem Office 5.0 and Yasara 6.2.5 software. The files in MOL format, containing the information on the sequences of these protease inhibitors, were imputed into Chem Office 5.0 software and converted in PDB format. The obtained PDB files were imputed into Yasara 6.2.5 software. The results of the generation of the electronic 3D-structures of aprotinin and SBTI are presented in Figure 3. Apparently there there is similarity of 3D-structures of these proteins.
\n\t\t\t\tWe failed to find molecular targets of SBTI and aprotinin because there was no necessary software in free excess.
\n\t\t\t\tElectronic 3D-structures of SBTI and aprotinin. Left – model with the single surface (Chem Office 5.0). Right- ribbon diagram (Yasara 6.2.5).
The exploiting the PASS software shows four potential activities of aprotinin and three for SBTI. Both SBTI and aprotinin may inhibit rennin as well as angiotensin- and endothelein-converting enzymes according to the revealing of the possible biological activities of these protease inhibitors by ISIS/Draw 2.4 and PASS Professional chemical structure drawing programs (Figure 4). The possibility of exerting of such effects (drug-likeness) is nearly the same in both protease inhibitors. Aprotinin may inhibit neutral endopeptidase, also. For all the abovementioned activities probability of the activity (Pa) is higher than the probability of the lack of activity (Pi). SBTI and aprotinin should not reveal serious toxicity, mutagenic, carcinogenic and teratogenic effects according to in silico, in vitro and in vivo studies.
\n\t\t\t\tSpectra of the biological activities of aprotinin and SBTI according to PASS software. Drug-Likeness – probability of exerting the effect. Probability of the activity (Pa) and the lack of activity (Pi). The average accuracy of the prognosis makes up more than 85%.
\n\t\t\t\t
We measured tyipsin-inhibitory activity of aprotinin, SBTI and low molecular weight protease inhibitors (ε-aminocapronic acid and D-lysine) by their ability to inhibit BAEE-esterase activity of the trypsin [33]. The results are presented in the table 3.
\n\t\t\t\tTrypsin-inhibitory activity (IU/mg) | \n\t\t\t\t\t\t\t141±13 | \n\t\t\t\t\t\t\t61±0,9 | \n\t\t\t\t\t\t\t1,36±0,04 | \n\t\t\t\t\t\t\t1,31±0,02 | \n\t\t\t\t\t\t
Trypsin-inhibitory activity (IU/nmole) | \n\t\t\t\t\t\t\t0,922±0,085 | \n\t\t\t\t\t\t\t1,23±0,02 | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t
Trypsin-inhibitory activity of aprotinin, SBTI, ε-aminocapronic acid and D-lysine.
Trypsin-inhibitory activity aprotinin, SBTI, ε-aminocapronic acid and D-lysine was measured as their ability to inhibit BAEE-esterase activity of trypsin.
\n\t\t\t\tTyipsin-inhibitory activity, calculated per mg of inhibitor, decrease down in the order: aprotinin > SBTI > aminocapronic acid > D-lysine. Thus, tyipsin-inhibitory activity of aprotinin is 2-times higher than similar activity of SBTI. However, taking into account that molecular weight of SBTI (20100) is 3-times higher than molecular weight of aprotinin (6514), it should be concluded that the trypsine-inhibitory activity of SBTI, calculated per mole of the inhibitor, should be nearly 1,5-times higher than trypsine-inhibitory activity of aptotinin. Trypsine-inhibitory activity of ε-aminocapronic acid and D-lysine when calculated per mole of the inhibitor is negligibly low because of the low molecular weight.
\n\t\t\tThe following indexes, characterizing mainly the first and the second phases of blood clotting, were measured: prothrombin time (reflects activity of coagulation factors YII, V, X and II), activated partial thromboplastin time (reflects activity of coagulation factors YII and VIII), activated clotting time (a measure of the anticoagulation affects of heparin) and thrombin time (time of the formation of fibrin clot). Results are summarized in the table 4.
\n\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t | ||||||
Prothrombin time | \n\t\t\t\t\t\t\t20±0,9 | \n\t\t\t\t\t\t\t13±0,9 Р1-2<0,0001 | \n\t\t\t\t\t\t\t21±0,9 Р1-3"/0,05 | \n\t\t\t\t\t\t\t31±0,9 Р1-4<0,0001 | \n\t\t\t\t\t\t|||
Activated partial thromboplastin time | \n\t\t\t\t\t\t\t36±1,7 | \n\t\t\t\t\t\t\t3±0,9 Р1-2<0,0001 | \n\t\t\t\t\t\t\t113±1,8 Р1-3<0,0001 | \n\t\t\t\t\t\t\t105±2,7 Р1-4<0,0001 | \n\t\t\t\t\t\t|||
Thrombine time | \n\t\t\t\t\t\t\t16±0,9 | \n\t\t\t\t\t\t\t2,5±0,5 Р1-2<0,0001 | \n\t\t\t\t\t\t\t24±0,9 Р1-3<0,0001 | \n\t\t\t\t\t\t\t∞ | \n\t\t\t\t\t\t|||
Ativated clotting time | \n\t\t\t\t\t\t\t88±9,7 | \n\t\t\t\t\t\t\t58±4,7 Р1-2<0.002 | \n\t\t\t\t\t\t\t157±12 Р1-4<0.0001 | \n\t\t\t\t\t\t\t258±17 Р1-4<0.001 | \n\t\t\t\t\t\t|||
Euglobulin lysis time | \n\t\t\t\t\t\t\t400±34,7 | \n\t\t\t\t\t\t\t182±7 Р1-2<0,0001 | \n\t\t\t\t\t\t\tNo lysis of blood clot | \n\t\t\t\t\t\t\tNo lysis of blood clot | \n\t\t\t\t\t\t
The influence of trypsin, SBTI and aprotinin on the indexes of hemostasis
Prothrombin time decreases 33-35% in the presence of trypsin from 20±0,9 to 13±0,9 sec, increases insignificantly in the presence of aprotinin and increases 1,5-times up to 31±0,9 sec in the presence of SBTI. Activated partial thromboplastin time sharply decreases by trypsin from 36±1,7 sec in the control samples to 3,0+0,9 sec and increases 3-times by aprotinin (113±1,8 sec) and SBTI (105±2,7 sec). The changes of the activated clotting time under the influence of trypsin, aprotinin and SBTI are similar. Thrombin time decreases nearly 7-fold in the presence of trypsin from 16±0,9 to 2,5±0.5 sec and increases on 50% by aprotinin to 24±0,9 sec. SBTI completely blocked the formation of fibrin clot at least within 10 min. Similar effects trypsin and it’s inhibitors exerts on fibrinolysis. Euglobulin lysis time (factor XII–callicrein-dependent fibrinolysis) decreases 60% by trypsin from 400±35 to 182±7 sec. Aptotinin and SBTI in the abovementioned concentrations entirely inhibit the lysis of fibrin clot (Table 4).
\n\t\t\tResults of the study of the influence of SBTI and aprotinin on platelets aggregation are presented in the table 5 and Figures 5-8.
\n\t\t\t\n\t\t\t\t\t\t | ||||
Reversible (ADP) ТМА\n\t\t\t\t\t\t | \n\t\t\t\t\t\t 22±1,8 55±4,7 | \n\t\t\t\t\t\t 14±0,9 Р1-2<0,01 55±4,7 | \n\t\t\t\t\t\t 15±0,9 Р1-3<0,01 55±4,7 | \n\t\t\t\t\t\t 34±0,9 Р1-4<0,01 65±15 | \n\t\t\t\t\t
Two-phase (ADP): Fist phase МА ТМА Second phase МА ТМА | \n\t\t\t\t\t\t 48±1,8 85±4,7 \n\t\t\t\t\t\t\t 70±2 350±9,2 | \n\t\t\t\t\t\t 35±0,9 Р1-2<0,01 68±10,5 \n \n\t\t\t\t\t\t\t 56±2 Р1-2<0,02 325±9,2 | \n\t\t\t\t\t\t 34±1 Р1-3<0,01 70±9 \n\t\t\t\t\t\t\t 58±1 Р1-3<0,05 320±9,3 | \n\t\t\t\t\t\t 57±3 Р1-4<0,01 80±10 \n\t\t\t\t\t\t\t 99±1 Р1-4<0,02 310±9,2 | \n\t\t\t\t\t
Irreversible (ADP) МА ТМА\n\t\t\t\t\t\t | \n\t\t\t\t\t\t 49±0,9 400±18 | \n\t\t\t\t\t\t 33±0,9 Р1-2<0,02 410±9,3 | \n\t\t\t\t\t\t 29±0,9 Р1-3<0,02 410±9,3 | \n\t\t\t\t\t\t 100 Р1-4<0,001 210±26,4of | \n\t\t\t\t\t
Two-phase (adrenalin): Fist phase МА ТМА Second phase МА ТМА | \n\t\t\t\t\t\t 23±0,9 110±9,3 \n\t\t\t\t\t\t\t 47±2,4 390±9,3 | \n\t\t\t\t\t\t 16±1,8 Р1-2<0,02 125±13,1 \n\t\t\t\t\t\t\t 44±2 Р1-2"/0,05 430±18 | \n\t\t\t\t\t\t 16±1,8 Р1-3<0,02 125±13,1 \n\t\t\t\t\t\t\t 44±1,8 Р1-3"/0,05 430±18 | \n\t\t\t\t\t\t 32±0,9 Р1-4<0,01 130±9,3 \n\t\t\t\t\t\t\t 55±0,9 Р1-4<0,02 435±16,2 | \n\t\t\t\t\t
The effects of aprotinin, SBTI and trypsin on the aggregation of platelets initiated by ADP (reversible, two-phase and irreversible aggregation) and adrenalin (two-phase aggregation). MA – maximum aggregation (transmittance, %), ТМА – time of accomplishment of maximum aggregation (sec).
The effects of trypsin, SBTI and aprotinin on the aggregation of platelets initiated by ADP (reversible, two-phase and irreversible aggregation) and adrenalin (two-phase aggregation) are similar to their effects on blood coagulation and fibrinolysis. Trypsin increases platelet aggregation (the increase of the maximum of all types of aggregation and decrease of maximum aggregation time of irreversible ADP-initiated aggregation). SBTI and aprotinin reveals anti-aggregation effect manifested by the decrease of maximum aggregation.
\n\t\t\tADP-initiated reversible aggregation of platelets in the presence of aptotinin, SBTI and trypsin in vitro. The platelet aggregation was initiated by the addition of the 5 mkM ADP. 1 – controle; 2 – aprotinin - 1%; 3 – SBTI - 1%; 4 – trypsin – 0,1%.
ADP-initiated two-phase aggregation of platelets in the presence of aptotinin, SBTI and trypsin in vitro. The platelet aggregation was initiated by the addition of the 5 mkM ADP. 1 – controle; 2 – aprotinin - 1%; 3 – SBTI - 1%; 4 – trypsin – 0,1%.
ADP-initiated irreversible aggregation of platelets in the presence of aptotinin, SBTI and trypsin in vitro. The platelet aggregation was initiated by the addition of the 25 mkM ADP. 1 – controle; 2 – aprotinin - 1%; 3 – SBTI - 1%; 4 – trypsin – 0,1%.
Adrenalin-initiated two-phase aggregation of platelets in the presence of trypsin, aptotinin and SBTI in vitro. The platelet aggregation was initiated by the addition of the 25 mkM adrenalin. 1 – controle; 2 – trypsin - 0,1%; 3 – aprotinin - 1%; 4 – SBTI - 1%.
So, the results of
Limited cascade proteolysis underlies the activation of the complement system, which includes nearly 20 individual proteins [30, 37]. Majority of these proteins belongs to the serine protease family (subunits C1r and C1s, С3/С5-cinvertase of the classical way of activation, factors I and D) [15]. While complement system does not have direct relation to hemostasis and targeted on alien cells and microorganisms, in some conditions complement system may play a role in the disruption of intrinsic cells of the organism and among them blood cells [15, 37]. Because of this we investigated the influence of trypsin, SBTI and aprotinin on the hemolytic activity of the complement assuming that SBTI and aprotinin may retard hemolysis of red blood cells by inhibiting activation of some components of the complement system. Results are presented in the table 6 and Figures 9-10.
\n\t\t\t\t\n\t\t\t\t\t\t\t | ||
Control (1) | \n\t\t\t\t\t\t\t3,5±0,5 | \n\t\t\t\t\t\t\t8,5±1,5 | \n\t\t\t\t\t\t
Aprotinin (1%) (2) | \n\t\t\t\t\t\t\t3,2±0,15 Р1-2"/0,05 | \n\t\t\t\t\t\t\t7,25±0,25 Р1-2"/0,05 | \n\t\t\t\t\t\t
SBNI (1%) (3) | \n\t\t\t\t\t\t\t3,2±0,15 Р1-3"/0,05 | \n\t\t\t\t\t\t\t7,25±0,25 Р1-3"/0,05 | \n\t\t\t\t\t\t
Trypsin(0,01%) (4) | \n\t\t\t\t\t\t\t4,25±0,25 Р1-4<0,02 | \n\t\t\t\t\t\t\t15,5±0,5 Р1-4<0,02 | \n\t\t\t\t\t\t
The influence of aprotinin, SBTI and trypsin on the hemolytic activity of complement
The hemolytic activity of the complement in the presence of aprotinin, SBTI and trypsin in vitro. The lag-phase is not shown. 1 – controle; 2 – aprotinin - 1%; 3 – SBTI - 1%; 4 – trypsin – 0,1%.
The hemolytic activity of the complement in the presence of different concentrations of trypsin in vitro. The lag-phase is not shown.
SBTI and aprotinin in the final concentrations 0,001-0,1% do not influence hemolysis time and the only statistically insignificant effect consists of small decrease of lag-phase from 3,5±0,3 to 3,2±0,15 min (p>0,05) and total time of hemolysis from 8,5±1,5 to 7,25±0,15 min (p>0,05). Trypsin suppresses the hemolytic activity of the complement in the concentration-dependent manner. In the presence of 0.0001% and 0,001% trypsin the lag-phase of the hemolysis increases to 4,25±0,25 min (p<0,02) and total time of hemolysis to 11,5±0,5 min (p<0,02) and 15,5±1,6 min (p<0,01), respectively. 0,01% trypsin entirely blocks the hemolysis. The inhibiting effect of trypsin should be attributed to the disruption of С3 component of the complement system.
\n\t\t\t\tThus, the results obtained show that aprotinin and SBTI in the abovementiioned concentrations do not influence the hemolytic activity of the complement.
\n\t\t\tSoya is cultivated as a foodstuff, having favorable effect on human health, more than 3000 years [28]. Within the last decades soy foods have started to be used in Europe, USA and in Russia as dietotherapy means at a number of diseases [6, 29]. In particular, we have shown the cholesterol-lowering effect of soy protein, resulting from the consumption of SPI enriched cookies by persons with modern hypelipidemia [7, 9]. The consumption of soy foods is followed by the antioxidant effect [Santana et al., 2008, 8, 9] due to the high antioxidant content in these foods [2, 9]. Antioxidant effect is important for the treatment of diseases followed by the development of the oxidative stress [1, 38].
\n\t\t\tThe other possible use of soy foods in dietotherapy may be the correction of disturbances of proteolytic processes. Activation of the tissue proteolysis accompanies different diseases and pathological processes [34]. Soy protein foods contain Bouman-Birk type trypsin inhibitor – SBTI [4]. This protease inhibitor has been officially recognized as a component of foodstuff [25]. There are data showing the possibility of absorbtion of SBTI in the intestin after the consumption of soy protein foods [22]. So, it seams reasonable to assume that the consumption of soy foods will follow anti-proteolytic effect. Because of this it was interesting to elucidate whether prolonged consumption of the cookies enriched with soy protein isolate (SPI) will influence total proteolytic and trypsin-inhibiting activity of the blood plasma in humans or not?
\n\t\t\tAccording to the characteristics, specified by manufacturer, protein content of SPI consists of 90%. From this 10% belongs to protease inhibitors [32]. Within the processing of soy beans into SPI the former are expoused to high temperatures, which inactivates the major part of soy proteins. However, about 5-20 % of SBTI are represented by the thermostable fraction [19, 22]. The measurement of the trypsin-inhibiting activity of SPI shows that trypsin-inhibiting activity of SPI consists of 1,4±0,1 IU/mg of SPI. For example 1 mg of pure SBTI possesses activity equal nearby 60 IU. Thus, the active SBTI makes up 2,7% from SPI mass.
\n\t\t\t30 adult people aged 35-67 years without the expressed signs of chronic diseases consumed cookies, enriched with SPI (30% protein content), for two months [7]. Fasting blood samples were drawn before and after the dietary treatment. Serum samples were frozen and analyzed for total proteolytic (BAEE-esterase activity) and tripsin-inhibiting activity [33]. Daily intake of 100g of cookies corresponds to consumption of 30g of SPI and about 0,85g of the active SBTI (nearly 52 00 IU). The total consumption of SPI for two months consists of 1,8 kg or 50 g of an active SBTI. Twenty-eight participants (19 females and 9 males) could complete the trial. Results are presented in the table 7.
\n\t\t\t\t\n\t\t\t\t\t\t\t | ||
Before the consumption | \n\t\t\t\t\t\t\t0,343±0,010 | \n\t\t\t\t\t\t\t113±3,6 | \n\t\t\t\t\t\t
After the consumption | \n\t\t\t\t\t\t\t0,282±0,008 р<0,05 | \n\t\t\t\t\t\t\t137±5,3 р<0,01 | \n\t\t\t\t\t\t
Total proteolytic and trypsin-inhibitory activity of blood serum of healthy persons before and after two months consumption of soy protein isolate.
Total proteolytic activity of blood serum was measures as serum BAEE-esterase activity and trypsin-inhibitory activity by inhibiting by serum of BAEE-esterase activity of trypsin.
\n\t\t\t\tTwo months long SPI consumption was followed by 18% decrease of total proteolytic activity of blood serum from 0,343±0,010 to 0,282±0,008 relative units (р<0,05) and by 21% increase of trypsin-inhibiting activity from 113±3,6 to 137±5,3 IU/ml ( р<0,01). The results obtained show possibility of the regulation of proteolysis
The disturbances of the hemostasis accompany many pathological processes and diseases [20, 18]. Both blood clotting and fibrinolysis represents the cascade of proteolytic reactions catalyzed by highly specific proteases [43]. To correct disturbances of the fibrinolysis as well as imbalances of the other proteolytic processes the animal trypsin inhibitor aprotinin is used as a drug (Trasisol, Contrical, Gordox etc) [24, 13, 40]. The effectiveness of the aprotinin in the treatment of some diseases has been questioned recently because of it’s substantial disadvantages [23, 12]. Following consultation with the German Federal Institute for Drugs and Medical Devices, the U.S. Food and Drug Administration, Health Canada, and other health authorities, the producer of Trasilol - Bayer announced in 2007 that it has elected to temporarily suspend worldwide marketing of Trasylol® (aprotinin injection) until final results from the Canadian BARTtrial can be compiled, received and evaluated. Information regarding the decision has been posted to Bayer’s websites [5]. Because of this attempts to develop new protease inhibitor drug are undertaken [35, 27]. One of the candidates for such a role is plant protease inhibitor - SBTI.
\n\t\t\tIn the present study we exploited the advantages of the modern bioinformatics for establishing the extent of structural homology, comparing functional activities and evaluating potential targets of SBTI and aprotinin among the human proteases. The results of
While the major part of SBTI is disrupted by heating, nearly 20% of inhibitor are thermostable and remains active in soy foods [19]. Part of the consumed SBTI are absorbed in the intestine after the consumption of soy foods [22]. Because of this we elucidated whether prolonged consumption of the cookies, enriched with SPI, will influence total proteolytic and trypsin-inhibiting activity of the blood plasma in humans or not? Daily intake of 100g of cookies corresponds to consumption of about 0,85g of the active SBTI. The total consumption of SBTI for the study period consists of 50 g of an active inhibitor. The consumption of 100 g of cookies daily for two months was followed by 18% decrease of total proteolytic activity of blood serum and by 21% increase of trypsin-inhibiting activity. The results obtained testify possibility of the soft regulation of proteolysis
At first, the ability of SBTI to inhibit blood clotting was shown more than half a centaury ago [26, 41]. However, these results had no any practical consequences and in fact were forgotten for a long time. Our study represent new attempt to revive interest to SBTI as possible protease inhibiting drug.
\n\t\tThere is much evidence that significant changes in the body and fat weight in men with metabolic disorders, such as severe obesity and type 2 diabetes mellitus (DM2), and with long-term fasting can lead to the alteration in the hypothalamic-pituitary-gonadal (HPG) axis, as illustrated by the changed secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins, the reduced testosterone (T) production by Leydig cells and the impaired spermatogenesis. The alterations in the HPG axis, as a result, lead to infertility [1, 2, 3]. The relationship between the fat content and androgens level has been demonstrated in animals with obesity and DM2, as well as in fasting conditions [4, 5, 6]. All this indicates that adipocyte-produced factors can play an important role in controlling the HPG axis and in regulating the steroidogenesis in Leydig cells. Among these factors, the most interesting are adipokines, such as leptin, adiponectin, resistin and visfatin [3, 7, 8]. It is well known that in metabolic disorders, the plasma levels of these adipokines and the functional activity of adipokines-regulated signaling systems in the target tissues undergo significant changes, which can be considered to be one of the key causes of abnormalities in the HPG axis and androgen deficiency [9, 10, 11].
\nThe regulatory effects of the plasma, pituitary and testicular leptin on the male HPG axis and the testosterone synthesis in the testes in the norm and in the metabolic disorders. Abbreviations: p-Lep and t-Lep, the pituitary and testicular leptin; LepR, leptin receptor; GnRH, gonadotropin-releasing hormone; GnRH-R, receptor of GnRH; LH, luteinizing hormone; T, testosterone; AMPK, AMP-activated protein kinase; CREB, cAMP response element-binding protein; Nur77, c-Jun, c-Fos and Sf1, transcription factors Nur77, c-Jun, c-Fos and Sf1; SREBP1, sterol regulatory element-binding protein-1; cAMP-PDE, cAMP-specific phosphodiesterase; StAR, steroidogenic acute regulatory protein; P450scc and P450c17, cytochromes P450scc (P450 cholesterol side chain cleavage enzyme) and P450c17; 3β-HSD, 3β-hydroxysteroid dehydrogenase; α-MSH, α-melanocyte-stimulating hormone; AgRP, agouti-related peptide; NPY, neuropeptide Y; BBB, blood-brain barrier; BTB, blood-testicular barrier.
The regulatory effects of adiponectin circulating in the blood and adiponectin synthesized in the pituitary and testes on the activity of the male HPG axis and the testosterone production. Abbreviations: AdipoR1 and AdipoR2, adiponectin receptors of the types 1 and 2; ERK1/2, extracellular signal-regulated kinases 1/2; Sp1, transcription factor Sp1. The other abbreviations are the same as in
There is evidence that adipokines affect the different components of the male HPG axis. Transferred to the brain through the blood-brain barrier (BBB), adipokines act on the activity of hypothalamic GnRH-expressing neurons, thus changing the GnRH-stimulated production of luteinizing hormone (LH), the main regulator of T synthesis, by pituitary gonadotrophs [12, 13]. The adipokines can directly affect the gonadotrophs producing LH, and in this regulation both the adipokines circulating in the bloodstream and the adipokines synthesized within the pituitary can be involved [14, 15]. Some adipokines can also directly affect the functions of Leydig cells, as indicated by a high level of adipokines expression in the testes, as well as detection of the main components of the adipokine signaling, including adipokine-specific receptors, in testicular cells, including Leydig cells [16, 17, 18, 19]. The study of the effects of leptin, adiponectin and other adipokines on the male HPG axis and their role in the regulation of steroidogenesis is a major problem of clinical endocrinology and reproductive medicine. The solution of this problem will allow developing the new approaches for restoring the reproductive functions and androgen status in men with endocrine and metabolic disorders, which is based on the normalization of the adipokine signaling in the CNS and at the periphery.
\nThis review presents the comprehensive analysis of the involvement of leptin, adiponectin, resistin and visfatin in the regulation of the male HPG axis and steroidogenesis, as well as of the possible mechanisms of this regulation. The role of adipokines in the dysregulation of the male reproductive system and the impaired steroidogenic activity in the testes in obesity and DM2 are also discussed.
\nLeptin, a 167-amino acid polypeptide hormone encoded by the
The regulatory effects of leptin are realized due to its specific interaction with leptin receptors (Ob-R) that are generated by alternative splicing and include at least six isoforms [26]. The full-length isoform Ob-Rb is active and expressed in the hypothalamus with high intensity [27, 28]. The truncated isoforms, Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf are inactive, but retain the ability to bind to leptin at its excess. It is assumed that they carry out the receptor-mediated transport of leptin through the BBB and, possibly, through other tissue barriers [29, 30]. In the arcuate nuclei (ARC) of hypothalamus, leptin binds to Ob-Rb receptor, which leads to the phosphorylation of JAK2, a non-receptor tyrosine kinase, that phosphorylates the Tyr985, Tyr1077 and Tyr1138 residues located within the intracellular domain of Ob-Rb, each responsible for the activation of certain signaling cascade [23]. It has been shown that the phospho-Tyr985 is responsible for activation of Src Homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) and the mitogen-activated protein kinases (MAPK), such as extracellular signal-related kinases-1/2 (ERK1/2), c-Jun amino-terminal kinases (JNK) and p38-MAPK, which are involved in the regulation of cell growth and differentiation. The targets of MAPK are different transcription factors, including c-Fos, c-Jun and cAMP response element-binding protein (CREB), which control the expression of a large number of genes [3, 31]. The phospho-Tyr1138 is responsible for activation of the transcription factor STAT3 (signal transducer and activator of transcription-3) regulating the expression of genes involved in metabolic and growth processes. In turn, phospho-Tyr1077 induces the activation of the transcription factor STAT5, responsible for the regulation of energy metabolism and endocrine system [23, 32].
\nAnother mechanism of leptin action is the activation of 3-phosphoinositide pathway, which involves phosphatidylinositol-3-kinase (PI3K) and Akt kinase controlling the activity of the multi-component kinase mTOR complex 1. Since Akt-mediated inhibition of this complex in the hypothalamic ARC leads to a decrease in the expression of the
In the recent years, the evidence has been obtained that leptin plays a very important role in the control of male reproductive functions and puberty, which is based on leptin-mediated regulation of the HPG axis [8, 37]. The
A survey of men from Slovenia, Macedonia and Serbia with three different mononucleotide mutations within the
The mutations within the
The effects of leptin on the male HPG axis can be carried out at the level of hypothalamic neurons, pituitary gonadotrophs and testicular cells. It is important to note that the response of the HPG axis to leptin depends on the dose of this adipokine and the duration of treatment, the metabolic and hormonal status, as well as the functional state of the leptin signaling system in the target tissues. This is well illustrated by the data on the influence of leptin on the hypothalamic structures. It is shown that a single i.c.v. administration of leptin to ovariectomized female rats under starvation conditions, when the leptin level was reduced, led to a rapid increase in the plasma LH level, which demonstrates leptin-mediated stimulation of secretory activity of the GnRH-neurons [12, 46]. At the same time, under conditions of prolonged administration of leptin, an increase in LH level [47] or lack of leptin effect on LH secretion [48] were detected, which may be assumed to be due to varying degrees of leptin resistance in the case of long-term action of leptin on hypothalamic neurons. This was supported by the fact that the action of low, nanomolar concentrations of leptin on the ARC and the ventromedial nuclei of the hypothalamus led to an increase in the GnRH secretion, while high, micromolar leptin concentrations did not cause this effect [5, 37]. The i.c.v. administration of leptin to fasting cows led to an increase of both basal and GnRH-stimulated LH secretion, while the administration of leptin to fed animals with the increased leptin level did not induce significant changes in LH level [49, 50]. Thus, the stimulating effect of leptin on the HPG axis at the hypothalamic level was largely dependent on eating behavior, and was the main mechanism that mediates the relationship between the satiety and metabolic status, on the one hand, and the gonadotropins levels and activity of the steroidogenesis system, on the other.
\nThe central effects of leptin on the HPG axis are mediated through its interaction with leptin receptors located on hypothalamic ARC neurons expressing either pro-opiomelanocortin (POMC) or agouti-related peptide (AgRP) and neuropeptide Y (NPY). Due to activation of these neurons by leptin, the positive (POMC-neurons) or negative (AgRP/NPY-neurons) regulation of GnRH-neurons occurs, especially since these neurons themselves do not contain the receptor Ob-Rb and, therefore, can not be target for leptin (Figure 1).
\nLeptin-induced activation of ObRb located on the POMC-neurons leads to an increase in the production of POMC-derived melanocortin peptides, primarily α-melanocyte-stimulating hormone (α-MSH), an agonist of types 3 and 4 melanocortin receptors (MC3R and MC4R) [51]. The α-MSH binds to MC3/4R located on GnRH-neurons, and stimulates the GnRH secretion by them. In favor of this mechanism, there is evidence that the administration of leptin to the preoptic area of the hypothalamus leads simultaneously to an increase in α-MSH level and a stimulation of GnRH secretion [52]. The MC3/4R agonists, such as α-MSH and its analogue melanotan-II are also effective, increasing GnRH release [53, 54]. It should be noted that at least 70% of GnRH-neurons are activated by α-MSH [53]. Both MC3R and MC4R are involved in the effects of melanocortin peptides on GnRH-neurons, since mice lacking only one type of MCR remain capable of reproduction [55, 56].
\nAnother mechanism for leptin regulation of GnRH secretion, in which the melanocortin peptides also participate, is more complex. In accordance with this, in the first stage the melanocortin peptides secreted by POMC-neurons interact with MCR located on the KNDy-neurons. Kisspeptin released from KNDy-neurons binds to the kisspeptin receptors located on GnRH-neurons and stimulates GnRH secretion [57]. In the hypothalamic ARC, the outgrowths of POMC-neurons form the contacts with the bodies of KNDy-neurons, and a release of α-MSH by POMC-neurons causes a rapid depolarization of KNDy-neurons. Pharmacological inhibition of MC3R and MC4R by the antagonist SHU9119 decreases the expression of kisspeptin by 45%. The stimulating effect of melanotan-II on LH production in mice lacking the kisspeptin receptor GPR54 was reduced significantly [57].
\nThe AgRP, the endogenous MC3/4R antagonist, and NPY, both produced by the AgRP/NPY-neurons, mediate the inhibitory effect of leptin on LH production by pituitary gonadotrophs. However, the degradation of AgRP/NPY-neurons and the knockout of the
Leptin can stimulate LH production, acting directly on gonadotrophs (Figure 1). Unlike the hypothalamus, where leptin is mainly transferred from the bloodstream, its source in gonadotrophs can be either the plasma leptin or pituitary leptin synthesized by gonadotrophs [67, 68]. There is a good reason to believe that pituitary leptin functions as a paracrine and autocrine regulator controlling the survival and functional activity of gonadotrophs, since the plasma leptin can not mediate the complex pattern of pituitary hormone secretion [69]. This assumption is supported by the data obtained in mice with tissue-specific knockout of the
The functions of the autonomous leptin system in the pituitary, its participation in gonadotropins production and the relationship between the activity of this system and the physiological state of the HPG axis are supported by the following facts. The
Currently, there is evidence that leptin not only indirectly affects the steroidogenesis in Leydig cells through the regulation of the HPG axis but is also capable of directly affecting the activity of steroidogenesis system [3, 8]. The following facts support this: (1) the transport of leptin circulating in the bloodstream through the blood-testicular barrier (BTB) and the synthesis of leptin in the testicular cells; (2) the expression of leptin receptors and the presence of effector components of the leptin signaling in Leydig cells and (3) the results of the
In 1999, Banks and coauthors showed that leptin circulating in the blood was transported through the BTB, and the permeability was higher than in the case of the BBB [75]. Based on high rate of leptin transport through the BTB and high permeability of this barrier to other proteins, it was concluded that the mechanisms of leptin transport through the BBB and BTB differ significantly. However, taking into account the high density of the truncated isoform Ob-Ra of leptin receptor on the surface of endothelial cells forming the BTB, there is reason to believe that, like the BBB, leptin transport through the BTB is also a receptor-dependent [37]. In this case, one should expect its dependence on the activity of the leptin signaling system at the periphery and its decrease in the conditions of leptin resistance. Another source of intratesticular leptin was its synthesis in the testes of adult men and animals. The highest level of the
The effectors, whose activity is regulated by leptin through the activated forms of Ob-Rb and JAK2, control the activity of the transcription factors regulating the expression of steroidogenesis genes in different ways [3]. Leptin-induced stimulation of Akt-kinase and MAPK results in the phosphorylation and activation of the transcription factor CREB that is also activated by gonadotropins via cAMP-dependent pathways [81]. The activation of p38-MAPK and JNK leads to the stimulation of the transcription factors Nur77 and c-Jun [82, 83]. The main targets for these factors are the genes encoding StAR protein responsible for transport of cholesterol into the mitochondria and P450 cholesterol side chain cleavage enzyme (cytochrome P450scc) converting cholesterol to pregnenolone [84] (Figure 1). Along with this, the activation of MAPK cascade results in an increase in the expression of Sf-1 factor, the coactivator of expression of the gene encoding StAR and the genes
Leptin activation of the STAT3 and STAT5, as well as leptin-induced ERK1/2-dependent activation of the factor c-Fos lead to the opposite effect and suppress steroidogenesis in Leydig cells. An increase in ERK1/2 activity may be due to the prolonged leptin effect on the system Ob-Rb/JAK2 and, as a result, the activation of SHP-2 phosphatase, which affects the activity of MAPK cascade [89]. A decrease in T production by Leydig cells can be the result of AMPK activation, which suppresses the activity of sterol regulatory element-binding protein-1 (SREBP1) [90]. As is well known, SREBP1 positively regulates the
In addition to direct leptin effect on the expression of steroidogenesis genes, this adipokine can modulate the gonadotropin signaling pathways in Leydig cells, inducing an increase in gonadotropin-stimulated T production. It is well known that LH and human chorionic gonadotropin (hCG) specifically bind to LH/hCG receptors located on Leydig cells and stimulate the activity of adenylyl cyclase catalyzing cAMP synthesis, which leads to the activation of protein kinase A and CREB. Further, the level of intracellular cAMP is reduced due to its hydrolysis by cAMP-specific phosphodiesterases (cAMP-PDE), which leads to the attenuation of signal transduction generated by gonadotropins and inhibits their stimulating effect on steroidogenesis. Leptin suppresses the cAMP-PDE activity, maintaining the increased level of intracellular cAMP and thereby potentiates steroidogenic effect of gonadotropins (Figure 1). This is supported by the data that leptin enhances the stimulating effect of hCG on the cAMP level in rat Leydig cells [77].
\nAlong with the regulation of T synthesis in Leydig cells, leptin controls the mass and size of the testes, diameter of the seminiferous tubules and spermatogenesis and affects the survival of Leydig cells and other testicular cells [26, 93]. Leptin also regulates steroidogenesis in the ovaries and adrenal glands, and the mechanisms of its regulatory effect are believed to be similar to those in Leydig cells [37, 94].
\nIn men with obesity, metabolic syndrome and DM2, the activity of the male HPG axis and the T production are decreased, which lead to androgen deficiency [95, 96, 97]. Along with this, in diabetic men the plasma level of estrogens and the ratio of estrogen/T are significantly increased, which due to the increased activity of aromatase and the altered production of sex hormone-binding globulin [98, 99, 100, 101]. The elevated concentrations of reactive oxygen species and inflammatory factors lead to the damage in Leydig cells and reduce their steroidogenic activity [97, 102].
\nIn obesity and DM2, the plasma leptin level is significantly increased [103, 104], which leads to leptin resistance. As a result, the receptor-mediated transport of leptin through the BBB is reduced, which leads to a decrease in the intrahypothalamic leptin level and to a weakening of the regulatory effects of leptin on hypothalamic neurons and GnRH secretion (Figure 1). It is also not possible to exclude the possibility of reducing leptin transport through the BTB, although such data have not yet been obtained.
\nThe detailed study of the relationships between the leptin signaling and androgen deficiency in men with obesity and DM2 are not currently available. In rats with diet-induced obesity, severe hyperleptinemia and leptin resistance was associated with a decrease in the number of Leydig cells by 30%. This can be caused by the reduced intratesticular levels of leptin or the decreased sensitivity of testicular cells to this adipokine that participates in the regulation of survival and proliferation of Leydig cells (Figure 1). Although the plasma T level in obese male rats did not change, in the testes of animals it decreased by 25%, which was associated with a decrease in the expression of the
The deterioration of reproductive functions was found in mice with a knockout of the gene encoding the catalytic p110α-subunit of PI3K in the adipose tissue [106]. In the testes of 30-day knockout mice with severe hyperleptinemia, the expression of the gene encoding leptin was increased, while the expression of the genes encoding StAR and P450scc was reduced. Adult knockout mice had a severe form of hyperleptinemia, obesity, hepatic steatosis and the impaired glucose tolerance, and were infertile. It was quite unexpected that in the testes of knockout animals the expression of the
Polypeptide hormone adiponectin is produced mainly by the adipose tissue [109, 110], but despite this, the plasma adiponectin level is negatively correlated with the body mass index and the reserves of adipose tissue [111]. The plasma level of adiponectin is characterized by gender specificity and significantly lowers in males, which is true for humans and rodents [112]. Adiponectin can be synthesized not only by the adipose tissue but also by the brain, pituitary, testes and others [17, 113]. Adiponectin is consists of a variable N-terminal domain, a large globular C-terminal domain and a collagenous domain located between them, containing 22 collagenous Gly-XY repeats [114, 115, 116]. Using the collagenous repeats, adiponectin molecules interact with each other to form the homotrimeric complexes that aggregate into the hexamers and high-molecular complexes similar to those in the case of tumor necrosis factor-α (TNF-α) [117]. To form the trimeric complex, hydroxylation of the proline and lysine residues in the collagenous repeats is necessary, since the lack of this modification does not allow the formation of such complex and leads to a loss in the adiponectin activity [118, 119]. High-molecular complexes of adiponectin are stabilized by disulfide bonds formed between the trimers [120]. The trimeric, hexameric and high-molecular complexes are present in the bloodstream, while the monomeric forms are found in trace amounts [115, 121, 122, 123]. Post-translational modifications of adiponectin and its oligomerization significantly affect the bioavailability, binding characteristics and pattern of specific activity of adiponectin [115, 120, 123, 124, 125].
\nThe tissues, the targets of adiponectin, express the adiponectin receptors AdipoR1 and AdipoR2, which bind specifically to various forms of adiponectin with different affinity [111, 125, 126, 127]. Despite the fact that both these receptors seven times penetrate the plasma membrane, like classical G protein-coupled receptors, they differ significantly from them in membrane topology, having the extracellular C-terminal domain and the intracellular N-terminal domain. In addition, the adiponectin receptors interact with APPL proteins (adaptor protein, phosphotyrosine interacting with plekstrin-homologous domain and leucine zipper), but not with heterotrimeric G-proteins. The AdipoR1 binds with a high affinity to the truncated globular form of adiponectin and with a low affinity with the oligomeric and high-molecular forms of full-length adiponectin, while AdipoR2 binds with an intermediate affinity to both the full-length and globular forms. The both receptors interact with two isoforms of the APPL proteins, APPL-1 and APPL-2 [128, 129]. The interaction of adiponectin-activated AdipoR1 with APPL-1 leads to the activation of AMPK and the 3-phosphoinositide and MAPK cascades. The APPL-2 forms a complex with APPL-1 and prevents APPL-1-mediated regulations. When adiponectin binds to AdipoR1, the APPL-1/APPL-2 complex dissociates, resulting in the release of APPL-1 to interact with the downstream effector proteins [116, 130].
\nAdiponectin is able to control steroidogenic function in the testes directly, acting on Leydig cells, and indirectly, acting on the HPG axis at the hypothalamic and pituitary levels. To interact with hypothalamic neurons, the main target of adiponectin in the CNS, it is necessary to transport adiponectin into the brain through the BBB. It is suggested that the receptor-mediated transport of adiponectin through the BBB can be carried out through the AdipoR1 and AdipoR2 receptors located on the endothelium of cerebral vessels (Figure 2). In addition, a large number of adiponectin receptors and the components of adiponectin-regulated signaling pathways have been identified in the ARC and paraventricular nuclei of the hypothalamus [131, 132, 133, 134] and in other brain areas [13]. Adiponectin is easily transferred from the bloodstream to the brain and cerebrospinal fluid (CSF), although its concentration in the CSF is low, being only 0.1% of that in the blood [132, 133, 134, 135]. In obesity, which was characterized by the reduced plasma level of adiponectin [134, 136, 137], its concentration in the brain areas was also decreased [134]. It should be noted that, as in the case of circulating adiponectin, a negative correlation was found between the adiponectin level in the CSF and the body mass [133, 134]. Thus, unlike leptin, intracerebral adiponectin deficiency in obesity is caused by a reduced level of this adipokine in the blood. Although there is evidence that adiponectin can be synthesized in the CNS [17, 113], the greatest, if not all, amount of this adipokine comes from the periphery, and the intracerebral level of adiponectin depends on the activity of adiponectin-transporting system of the brain.
\nUpon binding to adiponectin receptors in neurons of the paraventricular nuclei and the periventricular region of the hypothalamus, adiponectin activates AMPK [13, 138], decreases the activity of ERK1/2 [13], causes a weakening of the calcium-dependent signaling pathways and inhibits the hyperpolarization-activated cationic currents responsible for pacemaker activity of GnRH-neurons [139]. It is important to note that the inhibition of ERK1/2 activity is due to an increase in AMPK activity [13]. The main result of adiponectin action on GnRH-neurons is a decrease in the synthesis and secretion of GnRH and, as a consequence, a decreased LH production by gonadotrophs [13, 139] (Figure 2).
\nAdiponectin also interacts with the KNDy-neurons expressing kisspeptin. Adiponectin-induced increase in AMPK activity in these neurons results in the inhibition of AMPK-dependent transport of the transcription factor SP1 into the nucleus, which is illustrated by SP1 accumulation in the cytoplasm. As a result, the expression of the
The inhibitory effect of adiponectin on LH production can be carried out at the pituitary level, since both adiponectin receptors were detected in the LH-expressing gonadotrophs of human and rats [14, 142, 143]. In addition, the expression of the
As noted above, the expression of the
The main regulators of the
The AdipoR2 was located on the surface of Leydig cells, while AdipoR1 was found in the epithelium of the seminiferous tubules. In spermatozoa there are both types of the adiponectin receptors [17, 148, 149]. The
All of the above indicates that adiponectin positively regulates the T synthesis (Figure 2). Indeed, treatment of the MA-10 Leydig cells with adiponectin at the concentrations of 50–5000 ng/mL resulted in an increase in the production of progesterone, a precursor of T, which was associated with cAMP-dependent activation of StAR and cytochrome P450scc [151]. In the earlier studies, it was shown that adiponectin, acting on the testes, suppressed both the basal and hCG-stimulated T production, although the expression of the steroidogenesis enzymes, such as cytochrome P450scc and dehydrogenases 3β-HSD and 17β-HSD3, did not change [17, 148]. The mechanisms of adiponectin action on Leydig cells include the stimulation of PI3K and Akt kinase, which results in the changed expression of Akt-dependent genes, as well as the regulation of ERK1/2, whose activity decreases at low concentrations of adiponectin and increases at its high concentrations [148]. It can be assumed that the dependence of adiponectin effect on ERK1/2 on its concentration, as well as a set of the effector components of MAPK cascade regulated by adiponectin are responsible for the different mode of the regulation of steroidogenesis by this adipokine. The treatment of Leydig cells with adiponectin did not affect the expression of LH receptor, and this indicates the preservation of the sensitivity of these cells to gonadotropins [148].
\nVisfatin produced by the adipose tissue is a multifunctional protein that functions as a signal molecule and as a nicotinamide phosphoribosyltransferase (NAMPT) catalyzing the synthesis of nicotinamide adenine mononucleotide from nicotinamide and 5-phosphoribosyl-1-pyrophosphate [152, 153, 154]. In humans, visfatin includes 491 amino acids and forms a functionally active homodimer complex [10, 155, 156]. Paradoxically, the receptor for visfatin has not yet been found. It is known that the main targets of visfatin, as in the case of most other adipokines, are the MAPK and PI3K/Akt pathway, and the activation of Akt kinase occurs 5 min after treatment of cells with visfatin [156, 157, 158].
\nThe highest concentration of visfatin is detected in the white adipose tissue. In obesity and DM2, the plasma visfatin level is steadily increased, and the degree of this increase varies greatly, due to both the individual characteristics of patients and the various approaches to measure the visfatin concentration [2, 155]. The visfatin level is also increases in women with a polycystic ovary syndrome, for which obesity and insulin resistance are characteristic [155]. Despite an increase in the plasma level of visfatin, its concentration in the CSF decreases, and this is probably due to the impaired transport of visfatin through the BBB. These data suggest that, as in the case of leptin and insulin, the transport of visfatin into the brain can be receptor-mediated, and decreases in the conditions of visfatin resistance.
\nThe data on the involvement of visfatin in regulation of the reproductive system are mainly related to the female HPG axis, folliculogenesis and steroidogenesis in the ovaries [7]. There is a positive correlation between the visfatin level in follicular fluid and the quantity and quality of the follicles [159]. It is assumed that the effect of visfatin on the ovarian steroidogenesis system can be realized via the mechanisms that lead to an increase in the production of insulin-like growth factor-1 (IGF-1), a stimulator of steroidogenesis [138]. In this case, the effects of visfatin are characterized by species specificity. The introduction of recombinant human visfatin into chicken did not stimulate, but, on the contrary, suppressed the basal and IGF-1-stimulated expression of the
In the case of the male reproductive axis, the targets for visfatin may be all of its components. Information on the central mechanisms of action of visfatin is limited to its effect on the hypothalamic neurons responsible for control of glucose homeostasis [160]. However, the fact that visfatin, like leptin, affects the activity of 3-phosphoinositide pathway, supports its possible participation in the regulation of GnRH-neurons activity. The evidences were obtained in favor of the regulation of LH-expressing pituitary gonadotrophs by visfatin. Firstly, the mRNA for visfatin was detected in gonadotrophs, which indicates its synthesis in them and the role of visfatin in the autocrine and paracrine regulation of the anterior pituitary. Secondly, visfatin stimulates the AMPK activity in the cultured murine gonadotroph-like cells LβT2, resulting in a decrease in LH secretion [161].
\nThe ability of visfatin to influence the testicular functions and the T synthesis is supported by the following data. Visfatin is expressed in Leydig cells, spermatocytes and spermatozoa [19], and its level in the seminal fluid is much higher than in the blood [162]. When exposed to Leydig cells, visfatin increases the T production, and the maximal effect of visfatin is achieved at its concentration of 10−6 M [163]. The inhibitor of Raf-1 kinase reduces the stimulating effect of visfatin on steroidogenesis, while the inhibitors of the protein kinases A and C have a little influence on this effect. It is assumed that the effects of visfatin on steroidogenesis may be due to activation of insulin receptors [163], which are widely represented in Leydig cells, especially since previously it has been reported that insulin receptor can interact with visfatin [154, 164]. However, despite the similarity of regulatory effects of insulin and visfatin, in the recent years the ability of visfatin specifically binds to insulin receptor has been questioned [157].
\nResistin is a polypeptide with a molecular mass of 12.5 kDa, which forms a homodimer stabilized by disulfide bonds [138]. Although resistin is mainly secreted by adipocytes of the white and brown adipose tissues and macrophages [165, 166], its expression is also shown in the testes in the Sertoli and Leydig cells, which indicates the participation of resistin in the autocrine and paracrine regulation of testicular cells [16]. The expression of the
The level of resistin in the bloodstream, from which it is able to be transported to the testes, varies greatly depending on the metabolic status, gender and species. Fasting leads to a decrease in the plasma resistin level and the
Using the primary culture of pituitary cells of rhesus monkey it was shown that resistin activates a number of signaling pathways, including cAMP-dependent and 3-phosphoinositide cascades regulating the cell survival and secretory activity. Resistin affects the secretion of growth hormone and adrenocorticotropic hormone, although LH secretion remains unchanged. It should be noted, however, that the treatment of pituitary cells with leptin and adiponectin also did not affect LH secretion, which is probably due to the peculiarities of cultured cells used in the experiment [174].
\nResistin was found in the brain and CSF, and although its concentration was much lower than in the bloodstream, it can be assumed that resistin affects the activity of hypothalamic neurons controlling GnRH secretion [116, 133]. One of the mechanisms of this may be the influence of resistin on the adiponectin signaling in hypothalamic neurons. A prolonged i.c.v. administration of resistin into rats and mice results in a decrease in the expression of both types of adiponectin receptors, AdipoR1 and AdipoR2, and also reduces the functional activity of APPL-1 protein, thereby weakening the APPL-1-mediated adiponectin signaling. There is reason to believe that this effect of resistin is implemented through the receptor TLR4, since the inhibiting effect of resistin on the adiponectin signaling was not detected in mice lacking TLR4 [175].
\nThe
The regulation of the male gonadal axis by adipokines can be carried out both through the changes in the plasma level and bioavailability of adipokines produced (a systemic regulation) and through the changes in the expression and specific activity of adipokines in the target tissues, the components of the HPG axis, such as the hypothalamus, pituitary and testes (an autonomous regulation). In the case of systemic adipokines regulation, the changes in the plasma level of adipokines that are associated with feeding behavior, physiological conditions, and also with an imbalance of adipokines and a resistance to them in obesity, DM2 and other metabolic disorders directly affect the functional activity of the male HPG axis and T production. Of great importance is the activity of the adipokine-transporting system, which transfers the adipokines through the BBB into the brain, where they regulate the GnRH- and KNDy-neurons involved in GnRH secretion, and also through the BTB into the testes, where they control the steroidogenesis system and the synthesis of T, the main effector hormone of the male HPG axis. In the case of autonomous regulation, the adipokines synthesized in the pituitary and testes function as the autocrine and paracrine factors and to a large extent determine functional activity of the components of the HPG axis. On the one hand, they regulate proliferation and survival of gonadotrophs and testicular cells, primarily Leydig cells, and on the other, affect their ability to produce gonadotropins and steroid hormones. It is important to note that between the systemic and autonomous adipokine-mediated regulation of the male HPG axis there are the complex integrative relationships and interactions that are realized at different levels of this axis. As a consequence, the changes in the pattern and levels of adipokines in the bloodstream can be differently associated with activity of the hypothalamic, pituitary and testicular components of the HPG axis, since in this case it is necessary to take into account the functional state of autonomous adipokine systems. The ratio of different adipokines in the blood and in the tissues, the components of the HPG axis, contributes significantly to the resulting effects of adipokines on the reproductive system, since their effects on the male HPG axis, including the testicular steroidogenesis system, may be synergistic or antagonistic.
\nThe study of the role of adipokines in the regulation of the male HPG axis is of great interest, since it will allow in the future to develop the effective approaches for monitoring functional activity of the male reproductive system and correcting the dysfunctions in this system in metabolic and endocrine disorders, including obesity and DM2. The adipokines and their analogues, as well as regulators and modulators of their signaling cascades in the hypothalamic neurons and testes, can be used as potential drugs to improve the reproductive functions and to normalize the steroidogenesis in men. It is also important how the treatment of men with GnRH analogous, gonadotropins with LH-like activity and androgens will affect the systemic and autonomic regulation of the GPH axis by adipokines. This should be taken into account when developing the approaches to improve metabolic status in obese and diabetic patients and in elderly men with an androgen deficiency using the activators of the HPG axis and androgens. The study of the interaction between the male HPG axis and the adipokine system will allow us to decipher the fundamental mechanisms that determine the relationships between the eating behavior, hunger and satiety, on the one hand, and the sexual behavior and aggression, on the other.
\nThis work was supported by the Russian Foundation of Basic Investigations (project No 18-515-45004 IND-a).
\nConflicts of interest are absent.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. 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