Parameters registered in the experiments.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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She aims to develop new techniques and approaches in cognitive science and social neuroscience. She is an expert in experimental neuroscience, neuroeconomics, psychophysiology, and cognitive and social neuroscience. She performs neuroimaging studies in social contexts in order to investigate neural correlates involved during social interactions, such as, social exclusion, social support, empathy, communicative intention, social decision-making, in-group and out-group settings, etc. She currently works at Università della Svizzera italiana, Lugano, Switzerland.\n\nFor more information: http://usi.to/xuj",institutionString:"Faculty of Biomedical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Universita della Svizzera Italiana",institutionURL:null,country:{name:"Switzerland"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo",profilePictureURL:"https://mts.intechopen.com/storage/users/233998/images/system/233998.png",biography:"Sara Palermo has an MSc in clinical psychology and a PhD in experimental neuroscience. 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In this chapter, it is defined as a possible ability of an individual or a group to face, manage, and anticipate a possible problem. This concept of vulnerability is associated with that of risk factor for social isolation, and therefore to situations that can also lead to illness and lack of mental and physical health. It can have its roots in poverty, in social exclusion, in ethnicity, in disability or simply in disease or specific developmental phases in life. All these aspects reflect very important vulnerability factors among biological, psychological, social, and behavioral variables. To date, no one has highlighted together two critical moments in life in which this brain area undergoes important variations: adolescence, in which its development occurs, and old age, in which this area goes into cognitive decline with the relative loss of many higher cognitive functions. This knowledge can help to better understand the forms of exclusion due to vulnerability in order to develop new forms of social inclusion.",signatures:"Rosalba Morese, Sara Palermo, Matteo Defedele, Juri Nervo and Alberto Borraccino",downloadPdfUrl:"/chapter/pdf-download/66422",previewPdfUrl:"/chapter/pdf-preview/66422",authors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"},{id:"233998",title:"Ph.D.",name:"Sara",surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"},{id:"218983",title:"BSc.",name:"Juri",surname:"Nervo",slug:"juri-nervo",fullName:"Juri Nervo"},{id:"218984",title:"MSc.",name:"Matteo",surname:"Defedele",slug:"matteo-defedele",fullName:"Matteo Defedele"},{id:"266453",title:"Prof.",name:"Alberto",surname:"Borraccino",slug:"alberto-borraccino",fullName:"Alberto Borraccino"}],corrections:null},{id:"63833",title:"Living in Italy in an Anti-Immigrant Scenario: New Challenges for Muslim Second Generations",doi:"10.5772/intechopen.81280",slug:"living-in-italy-in-an-anti-immigrant-scenario-new-challenges-for-muslim-second-generations",totalDownloads:852,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Analysing whether and how the transition from the first to the second generation transforms adherence to Islam in Italy, a Catholic country which is undergoing a Lively immigration and Muslim-welcoming debate, is extremely interesting. The growing presence of Muslims in Italy stresses relations with ‘diversity’, especially in those areas where the incidence of migrants coming from Maghreb is higher and where there is an Arabic presence visible through ethnic shops, women wearing the chador and men wearing long robes. In these areas, the issues of control and safety have been on the agenda for many years. On the other hand, according to Muslim organizations there is a common interest in presenting a ‘moderate Islam’. 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Avila Bernal",coverURL:"https://cdn.intechopen.com/books/images_new/7253.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193020",title:"Dr.",name:"Jaime Andres",middleName:null,surname:"Perez Taborda",slug:"jaime-andres-perez-taborda",fullName:"Jaime Andres Perez Taborda"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11483",leadTitle:null,title:"Magnetic Materials - Recent Advances and Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tMagnetic materials acquired a very important position in several high-tech areas and technological developments. Such materials are being classified not only based on their origin but also on the nature of their processing, properties, functions, and applications. Magnetic materials present the basics of magnetism, magnetic materials, magnetic structures, and their applications in device technologies. Recently, new magnetic materials and hybrid structures have been developed using different synthesis and fabrication techniques. Different phenomena and interesting properties are studied theoretically and experimentally using advanced characterization techniques. Magnetic materials are now the building block of all technological innovation.
\r\n\r\n\tThis book aims to present an overview of different magnetic materials including theoretical study, synthesis, characterization, and application of magnetic materials. The chapter and different topics of the book hope to provide a key understudying on different magnetic materials. It will be very much helpful to students, researchers, academicians, and professionals. This book hopes to give the readers new ideas and insights into scientific advances and technology related to magnetic materials. Novelties on magnetic materials development will display attractive properties for a wide range of applications in advanced technologies.
",isbn:"978-1-80356-771-6",printIsbn:"978-1-80356-770-9",pdfIsbn:"978-1-80356-772-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"9df995499c9e30ad3bc64368cde49ef4",bookSignature:"Prof. Dipti Ranjan Sahu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11483.jpg",keywords:"Magnets, Magnetic Losses, Magnetic Alloys, Magnetic Thin Film, Magnetic Multilayers, Colossal Magnetoresistance (CMR) Manganites, Spintronics, Magnetic Recording, Magnetic Excitation, Frustrated Magnets, Magnetic Scattering, Low-Field Microwave Absorption",numberOfDownloads:98,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 25th 2022",dateEndSecondStepPublish:"June 3rd 2022",dateEndThirdStepPublish:"August 2nd 2022",dateEndFourthStepPublish:"October 21st 2022",dateEndFifthStepPublish:"December 20th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Sahu is a pioneering researcher in nanotechnology and advanced materials. He has worked as a postdoctoral researcher and visiting scientist at several institutions, including National Taiwan University, National Cheng Kung University, Taiwan, and the University of Witwatersrand, South Africa. He has published more than 112 peer-reviewed articles and more than 110 research articles in conference proceedings and meetings. He has also published four books and five book chapters.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"251855",title:"Prof.",name:"Dipti Ranjan",middleName:null,surname:"Sahu",slug:"dipti-ranjan-sahu",fullName:"Dipti Ranjan Sahu",profilePictureURL:"https://mts.intechopen.com/storage/users/251855/images/system/251855.png",biography:"Prof. (Dr.) Dipti Ranjan Sahu is a Professor of Physics in Department of Natural and Applied Sciences, Namibia University of Science and Technology (NUST),Namibia. He received a Ph.D. in Physics from Utkal University, India. He has worked as a postdoctoral researcher and visiting scientist at several institutions, including National Taiwan University, National Cheng Kung University, Taiwan, and the University of Witwatersrand, South Africa. His research focuses on multifunctional materials including nanomaterials, ceramics, composites, spintronics, ferroelectrics, and magnetic materials, and the application of these functional materials in devices. He has published more than 112 peer-reviewed articles and more than 110 research articles in conference proceedings and meetings. 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In this regard, the role of protection from external influences, especially from lightning, is growing steadily. The numerous experts’ statements noted that the ground wires of high voltage line (HVL) supports of stations and cable ways on power plants do not provide the required reliability of the electric grids for the highest voltage classes. Statistics of accidents and breakdowns in the operation of equipment energy indicates a high rate of lightning outages. They ranged from 20 to 50% of the total number of disconnections. The lightning storm outages have negative effect on the station operation, lines, and substation equipment, reducing the switch operational life and causing overvoltage switching on the equipment. Lightning also causes interference in chains of secondary commutation and devices of microprocessor technology, by means of induced electromagnetic fields. Because a lightning refers under the category of natural phenomena which is difficult to study, there is a great interest in full scale modeling effects of lightning. Full simulation of the effects of lightning in some cases is the only source of reliable information on the grounds that it affects on multiple related objects HVL and power plants, as well as to cause nonlinear processes in soils and ground wires when spreading the lightning currents. Understanding of the mechanisms and effects of lightning basic parameters for modeling were taken from work [1].
In the first part of the chapter presents the results of a full scale simulation of lightning currents, affecting directly the grounding devices designed to ensure the safe operation of power facilities. For these purposes have been designed, manufactured, and tested the mobile test complex (MTC EMG). A feature of this complex was the use of a helical explosive magnetic generator (EMG) as a pulse current source. EMG can convert the energy of the explosive in the electromagnetic energy that issues the current pulse in the load. Physical principles of work of explosive magnetic generators are reflected in a lot of classical works. For example, [2] gives the base of physical effects and the methods of generation high level electromagnetic fields. In [3], much attention is paid to EMG with a metal armature, the processes of energy conversion of detonation products into electrical energy pulses, and their efficiency. In [4], various schemes used to connect EMG to loads are discussed. References [5, 6] present the experimental and theoretical work of the Sarov’s nuclear center in the direction of lightning simulation using EMG on large grounded objects. EMG using in the experiments to examine spark soil processes [7], allowed us to represent the level of energy and pulse values of generated currents. The ways of transition from theory to practical schemes that use EMG in mobile testing facility were reported by authors in [8] firstly. It demands the reduction of explosive weight that allows realization of EMG, as a consumable item of MTC EMG. The theory of energy transfer from the EMG to high impedance load [9] was used for efficiently transfer energy from the EMG with using transformer circuits. Mathematical modeling of the dynamics of the EMG in a circuit with concentrated parameters allowed choosing the law of inductance output in the operation of EMG to provide a given front of the current pulse in the load without the use of switches. The theoretical background and mathematical modeling of such scheme are described in [10, 11]. In [10], the good agreement of the results of mathematical modeling and experimental measurements is illustrated. This chapter provides more complete results of field tests of MTC EMG. The active inductive load of two types is considered. In the first case, this is the ground loop. In the second case, it is a special model load. The ground loop forms an active load resistance of 2–4 Ω. In the case of the model load, the resistivity is increased to 10 Ω. The results of field tests showed stable reproduction of pulse values of currents at reliability, safety, and mobility of the complex.
The second part of this chapter presents the results of modeling the effects of high power electromagnetic impulse (EMI), disturbing the stability of energy systems. Such impact is not only on the result of a natural disaster—a thunderstorm, but also occurs at the use of electromagnetic pulse weapons and nuclear explosions. The pulse effect of lightning is accompanied by a change in the induction of the magnetic field in time. In this work, the near field of EMI impact was experimentally modeled by means of a source made on the basis of an explosive magnetic generator. The objects of influence were electronic measuring devices used in the experiment and made in a protected design. The front of the pulse current of EMI source was sharpened by a fast key on the basis of electro-explosive conductors (EEС) placed in the load circuit. The regime of rapid explosion was provided by the intense short-term action of the pulse current on the EEC. Reports collected in the chapter [12] are the basis for understanding the physics of the phenomenon of explosion conductors. The theory of explosion of EEC together with similarity criterion reflecting the relationship of mode of energy release in a conductor during the explosion with its physical properties was used in the selection of parameters of EEC [13, 14, 15, 16, 17, 18, 19, 20]. As shown in [14, 15], input in EEC energy sufficient for sublimation of conductors was the main requirement. Criterion for the optimal explosion of conductors in the case of capacitive storage as a pulsed energy source was considered in [17]. We used this approach when we started to simulate the explosion of conductors with a pulse source according to the Marx-Arkadyev scheme. The results were reported at the previous conferences on lightning protection [20]. The use of EMG is reported in this chapter. Two experiments were conducted for the same sources. The first experiment was prepared on the basis of preliminary calculations and was a trial one for the second. The measuring and recording equipment includes: control and measuring equipment, including Rogowski coil, voltage divider, oscilloscopes, and high speed camera HX3 of Japanese production for registration of the rapid process of explosion of the EEC. Evidence of a powerful EMI impact on electronic equipment was the fact that none of the devices could not record the data due to the interference and failure except for a specially designed device. This device was designed for other tasks as a recorder of lightning current. In spite of the use of standard means of protection against electromagnetic interference (metal housing grounded at a common point, isolated power supplies, and shielding), the level of exposure was high.
The results of both experimental and theoretical studies of the models presented were presented at conferences on Interaction of Intense Energy Fluxes with Matter, Elbrus, Kabardino-Balkaria, Russia “Elbrus” and Lightning Protection, St. Petersburg, Russia from 2012 to 2018. One of the presentations of the authors can be found on the conference website [20].
The third part of this chapter is devoted to the importance of full scale lightning simulation for lightning protection systems of power plants in terms of technical and economic indicators. The effectiveness assessments are based on the theory set out in the report at the lightning protection conference held in St. Petersburg in April 2018, a reference to the report is in [21].
During the development of the MTC EMG, several technical solutions were tested. The necessary requirements for the complex are: stable reproduction of pulse values of currents, while in operation for high voltage source, mobility, reliability, and safety. In the circuitry of MTC EMG explosive current breaker in the EMG circuit and closer in the load circuit were excluded, as they have essentially nonlinear characteristics and do not allow reproducing pulses of similar energy. The absence of untriggered discharger in the load circuit relieved the voltage jump when the transformer was in no load operation. In the new circuit, the load is always connected to the secondary winding of the pulse transformer (PT), and the EMG is directly connected to the primary winding of the PT. It gives possible to control the voltage on the load, setting the desired mode of operation of the EMG.
The formation of the front of the current pulse was provided by the design of the EMG. Special attention was paid to the geometry of the final section of the generator. The use of conical geometry in comparison with cylindrical geometry leads to an increase in the liner sliding speed. It is important that in these generators, the increase in the speed of the liner sliding along the spiral is achieved not by using a more powerful explosive, but due to the optimal angle of the cone spiral. For matching the EMG and the load, losses in the primary circuit of the transformer and the inductive-ohmic nature of the load were taken into account. Estimates made with the help of an equivalent circuit of substitution [10, 11] made it possible to obtain a condition for minimizing losses in the primary circuit, depending on the parameters of the circuit. At the same time, the efficiency of the energy transfer of the EMG to the inductive-ohmic load began to depend not only on the coupling coefficient of the pulse transformer windings and the ratio of the load inductance and the inductance of the secondary transformer winding, but also on the ratio of the active resistances of the primary and second transformer windings. In such a scheme, shown in Figure 1, the energy is transferred into the load both during the operation of the EMG and after completion, and thus, the pulse transformer is actually the storage of electromagnetic energy. In this case, the dissipation of a part of the energy in the primary circuit after the termination of the work of the EMG occurs. Estimates showed that when the condition for minimizing losses in the primary circuit is fulfilled, the efficiency of the transfer of energy into the load may exceed 50%.
Schematic diagram of the generator of lightning currents with the connected load.
MTC EMG is located on two KAMAZ vehicles. The lightning current generator, where EMG is the main element and refers to the spiral type, is mounted on the first four-axle base vehicle. The control panel of the test complex is located on the second three-axle base vehicle. The main elements of the lightning current generator are shown in Figure 2.
The main elements of the lightning current generator: 1—EMG; 2—explosion protection chamber; 3—pulse transformer; 4—container body; 5—bushing insulator.
The most important elements of the lightning current generator are the EMG and the pulse transformer (PT). EMG is placed in an explosive protection chamber, which excludes the destruction of the equipment of the complex during the operation. The explosion chamber is capable of withstanding explosions, which correspond to 5 kg in TNT equivalent. Thus, the EMG is the only consumable element of the MTC EMG. To match the EMG with the load, a pulse transformer with a low inductance primary winding is used. The transformer provides a maximum voltage on the primary/secondary windings of 100/1500 kV and a maximum current in the primary/secondary windings of 5000/100 kA. The transformer ratio is 55. The winding coupling coefficient is not less than 0.95. The design takes into account the requirements for limiting weight and increase in strength. The total weight of the equipment does not exceed 80% of the carrying capacity of the vehicle to ensure cross-country capability. The primary and secondary windings are made on one cylinder. High voltage output is carried out through a bushing insulator with a height of about 3 m. The commands between the control panel and the lightning current generator are transferred via fiber-optic communication lines. The measuring complex consists of self-contained recorder oscillograph. Recorders have autonomous power supply and are in a shielded enclosure. The recorder can be placed under any potential.
Most technical solutions are patented. In this scheme, a capacitive storage of electric energy is used as an initial energy source for creating an initial magnetic field in the EMG with an energy of up to 100 kJ. The initialization system is designed to initiate an explosive charge in the generator. The system does not contain electric detonators, which significantly increases the safety of work with explosives.
Field tests for an active load of up to 4 Ω were carried out in the east of the Moscow region. The test stand was located on the territory of approximately 70 m × 70 m. The photo of the placement of the MIK VMG and the experimental diagram are shown in Figure 3. The load was the ground between two ground loops. Ground loops were made of an aluminum wire with a diameter of 10–12 mm, located at a depth of 0.5 m. The external ground loop was 55 m × 55 m square. The internal ground loop in the first experiment was 15 m × 15 m, which corresponded to a load resistance of 2 Ω, in the second—4 m × 4 m (load resistance—4 Ω). The current was transmitted from the MTC EMG insulator mast to the pulse input rod into the internal circuit via the current transmission line. The total inductance, taking into account the air transmission line, did not exceed 80 μH.
Photo of field tests (a) and experimental diagram (b). 1—lightning current generator; 2—control machine; 3—impulse current input rod; 4—internal input circuit (dashed for the 2nd experiment); 5—ground loop; 6–9—voltage dividers; 10 and 11—Rogowski coils.
During the tests, the following parameters were recorded: initial current (powering current) of the EMG, current of the EMG (current of the primary winding of the PT), current in the load (current in the secondary winding of the PT), voltage at the MTC EMG output, that is, on inductive-active load, and voltage on the active load.
Rogowski coils were designed to record the derivative of current. They were used without integrators. The current was calculated by software integration of the data, taking into account the sensitivity of each coil. Voltage dividers were used to measure the voltage. The first voltage divider was connected to the high voltage output of the MTC EMG. The second voltage divider was connected to the load. To improve the transient characteristics, low inductance carbon resistors with a total resistance of 20 kΩ were used, which were located in a fiberglass pipe filled with transformer oil. To reduce the effect of parasitic capacitance of the resistor to the ground, when measuring, a pulsed current transformer on a ferrite core with a transformation ratio of 1:55 was used in a divider. This gave a galvanic isolation between the secondary circuit with the oscillograph and the primary circuit with the measured signal. Output voltage ratio was 1:220,000 (~1 MV:5 V).
Measurement of the resistance of the load (ground) was carried out before the beginning of the experiments. It is assumed that the potential of the outer loop due to its low resistance is zero. This assumption is satisfied (with an accuracy of 0.5%) for the experiment with an internal contour of 4 m × 4 m (experiment no. 2) and about 7% for an internal contour of 15 m × 15 m (experiment no. 1). The main results of the two tests (experiments) are presented in the graphs of Figures 4 and 5 and in Table 1.
The measured values of the currents in the load for the 1st (dotted line) and 2nd experiments.
The measured values of the voltage on the load for the 1st (pale color) and the 2nd experiments.
Parameters/experiment no. | No. 1 | No. 2 |
---|---|---|
Initial resistance between current input circuits (active load), Ω | 2 | 4 |
Load inductance, μH | 75 | 86 |
Initial energy of EMG, kJ | 23 | 43 |
Maximum amplitude of the current in the load, kA | 50 | 63 |
Energy generated by EMG, kJ | 900 | 1500 |
The maximum amplitude of the output voltage of MTC EMG, kV | 220 | 450 |
Maximum amplitude of the active load voltage, kV | 100 | 250 |
Rise time of the current pulse, μs | 30 | 25 |
Half-amplitude duration of the current pulse, μs | 120 | 80 |
Energy dissipated in the active load, kJ | 500 | 800 |
The increase in energy (energy in the active load with respect to the initial energy of the EMG) | 21 | 20 |
Parameters registered in the experiments.
Tests of the MTC EMG on the ground loop in the configuration, when the current flowed in the ground between the outer and inner contours, showed a linear increase in the voltage on the load with a decrease in the dimensions of the inner contour. A further increase in the load resistance in the tests became possible when the experimental scheme was changed and the use of model resistance.
MTC EMG field testing on the terminal parameter of the load specified in the development was carried out on a model load with an active resistance of 10 Ω and an inductance of about 150 μH. The tests were carried out on the territory of JIHT RAS, Shatura, Moscow region. Scheme and photo of the experiment are presented in Figure 6.
Scheme (a) and the photo (b) of the experiment for model load. SIE—source of initial energy with a capacitive storage; PT—pulse transformer; RL—resistive (active) load; LL—inductive load; RC 1… RC 3—Rogowski coils; HVD 1, HVD2—high voltage resistive dividers (1000 kV).
Figure 6a shows a diagram of the connection of the model load to the lightning current generator via a pulse transformer, as well as the location of the Rogowski coils for measuring currents and voltage dividers for measuring the voltage in the circuit. A model load has been developed and manufactured specifically for testing. The active load was modeled by a 10-Ω noninduction resistance.
In the foreground of Figure 6b, there is a lightning current generator on the first vehicle, on the left—an active load (a noninduction resistor) and two voltage dividers: at the MTC EMG output and on the load. In the background, there is the second vehicle with the control panel.
Resistance was installed vertically. The inductive load was modeled by wires connecting the resistive load. To reduce the size, the high voltage connection of the wire for the active load was made in the form of a spiral.
The main results of tests for the model load are presented in Table 2 and in the graphs of Figures 7–9. In these experiments, the signals were recorded on single-channel autonomous oscilloscopes; recording was performed at a given level of the input signal, which explains the time shift of the graphs relative to zero.
Parameter | Value |
---|---|
Active load resistance, Ω | 10 |
Load inductance, μH | 150 |
Voltage of the source of initial energy, kV | 62 |
Amplitude value of the powering current, kA | 115 |
The initial energy of the EMG, kJ | 73 |
The maximum derivative of the EMG current, kA/μs | 310 |
The maximum amplitude of the EMG current, kA | 6010 |
Energy generated by EMG, kJ | 900 |
The maximum amplitude of the voltage at the MTC EMG output, kV | 810 |
Maximum amplitude of the voltage on the active load, kV | 495 |
Maximum amplitude of the current in the load, kA | 44 |
The energy produced by the MTC EMG, kJ | 1640 |
Energy dissipated in the active load, kJ | 550 |
The increase in energy (energy in the active load with respect to the initial energy of the EMG) | 7 |
Rise time of the current pulse, μs | 37 |
Half-amplitude duration of the current pulse, μs | 50 |
Basic parameters in the tests for model load.
Voltage at the MTC EMG output from the voltage divider no. 1 and on the active load from the voltage divider no. 2.
Load current.
Schematic diagram of an experimental model with a power source based on the EMG. СOL and LOL—are the capacitance and inductance of overhead line; RC1—Rogowsi coil in the EMG circuit; RC2—Rogowsi coil in the load circuit; CT—the current transformer as part of voltage divider.
As can be seen from Tables 1 and 2, the increase in the active load resistance leads to a decrease in the energy transfer efficiency of the load from 55 to 33%, which corresponds to the theory [10, 11]. Thus, the use of MIC HMG for high resistance loads is less effective.
The pulse effect of lightning is accompanied by a change in the induction of the magnetic field in electrically conductive objects in time. The induction effect of the lightning channel is significant at distances commensurate with the length of the lightning channel. Induced voltages arise as a result of such influence on various technical means, for example, overhead transmission lines, grounding devices, etc. Induced voltage leads to the appearance of parasitic currents in the secondary circuits and external power cables due to the conductive coupling. The experimental model based on the EMG is a laboratory setup producing EMI impact on a limited space of 2 m × 2 m × 4 m. The schematic diagram of the electrical control and measuring equipment is shown in Figure 9.
The source of the pulse current is a helical-type explosive generator—EMG also. Output of current to the load is carried out through a pulse transformer (PT) and overhead transmission line (OL). The direct and reverse branches of the overhead lines are located on the insulator supports and are common for all experiments. The electrical explosion conductors (EEC) are at the end of the overhead line. General view of an experimental model is represented in Figure 10, and the view of EMG assembly is represented in Figure 11.
General view of an experimental model with EMG.
EMG assembly, before installation in the explosion protection chamber.
EEC in the EMI models is the key element. The regime of fast explosion is provided by the intense short-term action of the pulse current generated by the source. The rapid increase in resistance in exploding conductors leads to arising of a strong electric field. Together with the emerging magnetic field, an electromagnetic disturbance is formed by the EMI effect. The EEC in our models was made from the copper. Copper has a relatively low boiling point and low heat of vaporization. The current reaches the maximum by the end of evaporation if sufficient energy is supplied to the conductor [11]. The selection of EEC parameters, as the number, cross section, and length of the EEC, was carried out taking into account the similarity criteria reflecting the relationship of the character of the energy release in the explosion in the conductor with its physical properties. At the initial stage, the estimates were performed according to the criterion for capacitive energy sources set out in [16], but due to the difference in the pulse current fronts, they were overestimated in terms of the energy required for the explosion of conductors. The main criterion is the ratio of the transmitted EEC energy to the mass of the explosive conductor, which characterizes the initial stage of the explosion. From the balance of the inputted energy and the minimum specific energy required for the explosion, it is possible to estimate the limit mass of the conductors m = (W0/
We use the initial energy source for powering the EMG, it was about 15 kJ (a capacitor bank of 90 μF was charged to 18 kV). An overhead line inductance was 5.5 μH.
In the first experiment, 25 conductors of 120 μm diameter were taken. The full cross-sectional area of the conductors is 28⋅10−8 m2. The total mass of all conductors amounted to about 2.5 g. The number of conductors was determined by the requirement to obtain an explosion of conductors at the stage of current growth in the load. The specific energy obtained by the conductors is 12.5/2.4–5.2 kJ/g; it is roughly equal to the energy of the sublimation of copper. The experiment showed, see Figure 12, that the current was cut off (and the voltage increased abruptly) at the initial phase of the current rise. The current pause mode does not occur, and the further increase in the current is associated with the transition of the EEС into an electrically conductive plasma state. To achieve higher voltage amplitudes, we need to input more energy. This meant that we need to climb higher along the current curve to the time of the explosion of the EEC. To do this, we need to take more conductors, for input more energy, with a smaller diameter of each to increase the speed of energy input.
Impulse current and voltage values obtained with the explosion of conductors in the 1st experiment.
In accordance with the described reasoning, in the second experiment, 96 copper conductors with a diameter of 80 μm were taken. The total area of the cross sections of the conductors is 48⋅10−8 m2. The total mass of all conductors was about 4.3 g. The initial charging voltage was chosen as in the previous experiment, ~18 kV, respectively, the initial energy was about 15 kJ, as in the previous experiment. The explosion of the EEC occurred at 92 μs, which corresponds to the current drop and voltage peak, as illustrated in Figure 13. The maximum value of the current in the explosion was about 70 kA. In the current distribution, see Figure 13, we see again a nonpause mode of EEC transition into an electrically conductive plasma state. Further, the current increases again after several periods of high frequency oscillations to a maximum value of 127 kA, Figure 13. Then the plasma conductivity decreases due to the expansion of the plasma column, and the current begins to fall. Voltage amplitude at the moment of explosion was about 550 kV, and the electric field strength was about 550 kV/m. Voltage peak occurred approximately 0.5 μs after the explosion of conductors. The front of the voltage pulse was estimated to be approximately 100 ns. Estimates of the current density in the explosion gave a value of about 3⋅1011 A/m2. The resistance growth rate was about 16 Ω/μs. The energy inputted in the EVP during the explosion is about 60 kJ. Specific energy was 60/4.3–14 kJ/g, approximately 2.7 times more of sublimation energy of a copper.
Experimentally obtained impulse current and voltage at the load (EEC).
Characteristics of high speed camera Memrecam HX-3 (16 Gb, exposition time—200 ns, frame rate of 750,000 frame per second at working special resolution 320 × 24) allowed to fix the time of the explosion. Three frames, shot one after another, include: the first frame—before the explosion, the middle frame clearly illustrates the locally glowing area of the exploded conductor, and the next frame—a glowing plasma column formed by the products of the explosion of the EEC. The column has a radius much exceeding the initial radius of the wire, Figure 14. The split of the image is connected with the re-reflection from the neighboring conductors. Displayed glow significant attenuated on one-hundredth the frame that corresponds to time over 130 μs after the explosion (~220 μs). At this time, the current almost disappears.
Average frame illustrates of EEC explosion. The top frame is before the explosion and the bottom after the explosion.
The change of magnetic induction occurring around the EEP at the moment of break was estimated from the Ampere law in the approximation of a single turn solenoid, (N = 1),
Photo of the device for registration of current derivative from the source of powerful EMI action in the near field based on the 4th generation lightning current recorder.
There is not a ready-made model of techno economic analysis of the creation project of commercial samples of testing complexes for lightning protection tasks. We took as a basis of the economic expediency of the introduction of system of lightning protection from the point of view of minimizing outages caused by lightning. The analysis is based on the idea of calculating the internal rate of return (IRR) of the protection method, as well as the data on lightning outage presented in the report [21], University of S. Paulo, Brazil. The main numerical indicators for economic calculations and the list of lightning protection services are close to the Russian market. The methodology is based on an analysis of the cost of lightning protection and the benefits of lightning protection. The benefit was regarded as an opportunity to save on the damage caused by the emergency situation both at the power plant itself and the damage caused by the delay in the supply of electricity to consumers, including the payment of fines for regulated direct and indirect losses. It was taken into account what can be represented in monetary terms, excluding social and moral aspects. The simplified calculation did not take into account such aspects as: loss of communication, information, Internet access, reduced mobility of the population, damage to frozen products, disruption of banks, state institutions, etc. The main costs are the measures used to increase the lightning resistance of power plants. These include the improvement of insulation resistance, the use of earthed shielded cables, the installation of arresters in distribution networks, as well as the installation of grounding devices that carry out the removal of lightning currents into the ground. The volume of storm shutdowns was considered as a total number of cases and also with respect to areas with different population densities. Different protection systems with different degrees of complexity were considered. The average costs and benefits for each system were reduced to a unit of time. The obtained input data allowed estimating the values of cash flows and calculating the IRR for each protection system. This rate is equal to the ratio of profit (the amount of losses that can be avoided) to the amount of costs (investments). The following conclusions are made:
The lightning protection project is effective and appropriate if the final IRR rate is higher than the minimum rate of return for long-term financing, and for Russia, it is about 7% per annum. That is, the energy distribution company should have a positive return on investment.
Developing countries, where the cost of capital is high, face great difficulties in investing in protection systems, especially in regions with low population density and low income.
If we continue the study of technical and economic analysis in accordance with the proposed methodology in relation to the effectiveness of the implementation of the development of testing systems for our project, we can add the following conclusions:
We get the amount of benefits for the development of integrated solutions. Each benefit from the selected protection measure can be tested separately. And most importantly, it is possible to get the best comprehensive solution in the application of several protection measures. In theory, such solutions are difficult to obtain because the overall protection solution is not simply the sum of individual measures. For example, for grounding devices that perform the removal of lightning currents, to minimize the resistance of multipath grounding, it must take into account the specific resistance of the soil.
Developed complex solutions based on the tests can be standardized according to the adopted standards of protection and reproduced in the form of ready-made solutions.
By using testing complexes in the construction of power plants or scheduled safety inspections, it is possible to reduce the safe level of overvoltage and, accordingly, the number of lightning outages.
The creation and use of such test complexes are of high importance for developed countries, which have a high level of requirements for the operation of power plants, namely, to the quality and continuity of the energy supplied by them.
The cost of MIC EMG, without the option of EMI impact analysis, is approximately $ 2.3 million per 1 MJ of energy, which is transferred to the load. The evaluation was performed in 2017. As a result of R & D, a sample of testing complex, laboratory test stands, and a set of design and technological documentation necessary for the transition to commercial samples were obtained.
It should be noted that the test complexes based on EMG are a means for testing the existing protection of power stations from lightning. Despite the fact that the basis of EMG work is the physic-chemical law of conversion of chemical energy explosives into electrical energy with an efficiency of not more than 10%, and this tool is able to generate pulsed currents of the mega-ampere level and the electric field intensity of MV/m per microsecond, not achievable by other methods. In the transition from R & D to commercial facility, it requires a detailed calculation, first of all, of the technical and economic effect of the use of testing complex. The powerful impact of lightning is a probabilistic process for the power plant, but the level of destruction is much higher than any other losses. To calculate this effect, it is necessary to take specific parameters to improve lightning protection, applying to the technique described in work [22, 23], and calculate energy and exergy efficiencies. The return on investment in such complexes is likely to be correctly compared with the level of return on capital from long-term investments. There is a direct connection with the economic development of the country, which can afford high tech equipment.
Field tests of MIC EMG demonstrated stable reproduction of pulse values of currents during operation: its mobility, reliability, and safety. For the range of loads with active resistance from 1 to 10 Ω and inductance of 70–150 μH, the amplitude values of the currents ranged from 70 to 40 kA. Thus, the efficiency of application of MIC EMG for modeling lightning currents at low resistance loads such as grounding at electrical substations and power plants has been confirmed. The practical application of MIC EMG will allow increasing the level of lightning protection of strategically important energy facilities both at the stage of their building construction and during preventive inspections.
Laboratory testing of the generator of powerful EMI impacts on the basis of the EMG and electro explosive conductors in the load circuit confidently registered voltage pulses with the front of about 100 ns and the amplitude of the electric field strength of about 500 kV/m. The growth rate of the magnetic field intensity in the near field reached 0.2 T/μs. In practice, the use of such a facility will allow to solve the problem of optimizing the location of the elements of grounding devices in order to equalize the potentials in the grounding systems and to identify parasitic connections in electrical circuits, including those induced in the secondary circuits of underground utilities.
The tests of the described system samples showed the readiness of the development for the transition to commercial development. This chapter of the techno economic analysis of the development provides an approach to assess the profitability of the complex depending on the location of the power plant and the required level of lightning protection.
The interactions of proteins with chemicals have prompted increasing research interest in recent years. Proteins are remarkable biomolecules presenting different functions and roles. Some are specific to their biological actions whereas some are selective toward the binding site [1, 2]. Conformational changes of protein may influence its transportation, function, assembly, potential cytotoxicity, and tendency to aggregate [3, 4]. Furthermore, it has been indicated that the serum albumin conformation will be changed upon binding with ligands or molecules, and the change shows its influence on the secondary and tertiary structures of albumins and their biological function as a carrier protein [5, 6]. Some diseases (such as Alzheimer’s disease, Parkinson’s disease, and amyloid disease) are related to protein misfolding [6]. The thermodynamic and kinetic study of proteins plays an important role in understanding biological functions ranging from genetic information to molecular diagnostics [7, 8]. The functions and structure of a protein are strongly related to each other and due to this, protein folding/unfolding has protruded as an important property in biochemistry and biophysics [9, 10]. Therefore, the studies of such chemicals and their bindings with proteins are of fundamental and imperative importance.
The binding of nanoscale materials with proteins has become the most common with the availability of organic polymers, inorganic nanoparticles, carbon nanotubes, etc.. Recently, the nanoparticle studies have opened new avenues to study biomolecular interactions with their applications as drug delivery, biocompatibility, diagnostics, and smart materials. The binding of nanocolloidal particles to proteins has also been formed, since the study of immunoprobes in the early 1970s [11]. Moreover, various studies of peptide or protein including lysozyme binding with nanoparticles of different sizes have been conducted. In the process, the proteins, generally, suffer a significant loss in enzyme activity and a partial loss of structure [12, 13]. Thus, it should be expected that the size of the particle plays a major role in changing protein structure and function [13]. However, no systematic study has been performed to date on the effect of Roxatidine acetate–Chitosan nanoparticles on the structure and function of Lysozyme. For this reason, we embarked on a study of protein binding with Roxatidine acetate–Chitosan nanoparticles.
Lysozyme (Lyz) (Figure 1A) is one of the important proteins that is found in the blood and has various functions but is similar in its tendency to bind ligands/drugs. Lyz is an antibacterial and antiviral protein found in various biological tissues and fluids, such as skin, liver, lymphatic tissues, tears, saliva, and blood of human and other animals [13, 14]. Lyz is unique in its ability to hydrolyze the β-1,4 glycoside bond between N-acetylglucosamine and N-acetylmumaric acid of the gram-positive bacteria, thus protecting the body against the bacterial invasion [15]. Some of its important biological roles also include antihistaminic, anti-inflammatory, and antineoplastic activity [15, 16, 17, 18]. Lyz consists of 129 amino acid residues and contains six tryptophan (Trp) and three tyrosine (Tyr) residues [4, 15]. Three residues of Trp are placed at the binding sites, two sites in the hydrophobic cavity, while the last site is located independently from others [4, 15, 19, 20, 21], and the effectiveness of drugs depends on both pharmacokinetic and pharmacodynamic factors. Therefore, the studies on the interactions of drugs and Lyz are of importance in understanding the release disposition, transportation, and metabolism of drug as well as the efficacy process involving drug and Lyz. Lyz has been preferentially used as a model protein to study the protein folding/unfolding, dynamics, and ligand interaction due to its small size, abundance, high stability, and ability to bind and drug carrying capacity [22, 23, 24].
(A) Three dimensional structure of Lyz, (B) chemical structure of Roxatidine acetate.
Roxatidine acetate (RxAc) (Figure 1B) is an antagonist of a histamine H:z-receptor, which rapidly turns into Roxatidine through esterases in the plasma, small intestine, and liver (its active metabolite) [25, 26]. Roxatidine is an active inhibitor of gastric acid secretion in humans and animals [3, 25] and does not overlap with other drugs in the hepatic metabolism and has no antiandrogenic influences as most other H:z-receptor antagonists [27]. Wide-scale experiments have illustrated that 150 mg of Roxatidine acetate per day is recommended as typical dosages of ranitidine and cimetidine in the patients for treatment of gastric ulcer or duodenal ulcer [25, 27] and that 75 mg of Roxatidine acetate as dosage in the evening is probably a standard amount for the prohibition of peptic ulcer recurrence [25, 28]. Primary studies also mention that Roxatidine acetate is perhaps useful in the treatment of stomach ulcer and reflux esophagitis and in the protection of pulmonary acid aspiration [25].
Spectroscopic techniques are mostly used to detect the accessibility of quenchers to fluorophore groups of albumin and help to understand the binding mechanism of albumin to small molecules and clarify the nature of the binding phenomenon [11, 29].
In the present study, the RxAc and RxAcNPs interactions with Lyz were methodically investigated and analyzed using diverse spectroscopic techniques to reveal the binding types and properties of RxAc and RxAcNPs with Lyz. The influences of RxAc and RxAcNPs on the conformation and microenvironment of Lyz were explored.
The aim of this study was the synthesis and characterization of Roxatidine acetate–loaded Chitosan in the presence of Tween80 (Tw80) surfactant (RxAcNPs) and to clarify the binding mechanism of RxAc and RxAcNPs with Lyz using multi-spectroscopic and molecular docking techniques and provide useful information for understanding the toxicological actions of RxAc and RxAcNPs at the molecular level.
Lysozyme (from hen egg white) (Catalog number: L6876) was purchased from Sigma and was used as such. The Lysozyme solution was prepared in the 0.1 M phosphate buffer of pH = 7.40. The concentration of Lyz was determined using the extinction coefficient ϵ280 = 37,750 mol−1 L cm−1 [30]. Chitosan, Sodium tripolyphosphate (TPP), and Tween80 (Tw80) were also purchased from Sigma (India). NaCl (0.15 M) has been added to buffer solutions to control the ionic strength, as required. Roxatidine acetate HCl (RxAc) (≥ 98%) was purchased from Tokyo Chemical Industry Co., Ltd. (TCI), India. The stock solution of RxAc (0.3 mM) was prepared in ethanol and the final concentration of ethanol was below 2.3%, and the stock solution of RxAcNPs (0.3 mM) was also prepared in ethanol and this concentration was used for all the spectroscopic measurements. RxAc and RxAcNPs were accurately weighed on Shimadzu AUY-220 microbalance of resolution 0.1 mg. All the reagents were of analytical grade. For all experiments, double-distilled water was used.
Roxatidine acetate drug-loaded Tween80-Chitosan nanoparticles (RxAcNPs) were prepared through the ionotropic gelation technique. The principle of this method is interaction of the positive charge of Chitosan amino groups with the negative charge of TPP groups [31, 32]. As listed in Table 1, the solution of Chitosan was prepared by dissolving 0.5 g Chitosan (0.5%) in 100 ml of acetic acid (1% v/v). TPP solution (0.1%) was prepared through dissolving 100 mg of TPP in 100 ml of deionized water. 30 mg of Roxatidine acetate was added to the solution of TPP. The solution was stirred at 1500 rpm for 30 min using an ultrasonicator (vibronics), and the solution of TPP was added gradually with continuous stirring for 3 hours on a homogenizer. The mixture of Roxatidine acetate, 0.1% TPP, and 0.1% Tween80 was added gradually to Chitosan solution. Tween80 was added to make the prepared solution stabilized and to limit the nanoparticle growth and thus to obtain particles of reduced mean sizes [31, 32, 33]. The precipitate was stirred at 9000 rpm for 3 hours using an ultrasonicator (vibronics). After the addition of a drug–Tween80–TPP solution to the solution of Chitosan, the suspended solution of nanoparticles was centrifuged for 15 min at 10,000 rpm, and the Roxatidine acetate nanoparticles were obtained.
Components | Ratio (5:1:1) |
---|---|
Roxatidine acetate (mg)/100 ml | 30 |
Chitosan (g)/100 ml | 0.5 |
Sodium Tripolyphosphate (g)/100 ml | 0.1 |
Tween 80 0.1 % (ml) | 20 |
Acetic acid ml/100 ml | 2 |
Formula for preparation of Roxatidine acetate loaded Tween80-Chitosan nanoparticles.
To confirm the drug content, encapsulation efficiency, and release of RxAc, the conventional method and dialysis method were used for testing RxAc-loaded Tween80-CsNPs. The encapsulation efficiency and drug content were estimated according to the procedure reported by Cevher et al. [34]. After drug loading, the RxAcNPs were isolated from the suspension using centrifugation at 10000 rpm for 15 min. The quantity of free Roxatidine acetate in the supernatant was measured using the UV–Vis spectrophotometer (double beam Perkin Elmer λ-45) at 275 nm. RxAc release was investigated in vitro by dialysis using phosphate buffer (PBS) at different pH (3.5, 6.6, 7.4, and 8.4) and 298 K. 25 mg of Roxatidine acetate–loaded Tween80–Chitosan nanoparticles were added to 50 ml of each PBS buffer in different flasks and were shaken using a magnetic stirrer at 298 K. At various time intervals, 2 ml from the suspended solution of nanoparticles was taken and centrifuged at 10000 rpm for 15 min and the standard curve for RxAc was acquired by UV spectrophotometry. At 275 nm, the RxAcNPs entrapment efficient (EE), drug content, and accumulated release percentage (%) at different pH were determined spectrophotometrically and were calculated using the following equations, as described previously [31, 32, 33, 34, 35]:
Characterization of RxAc-loaded Tween80–Chitosan nanoparticles comprised Fourier transform infrared spectroscopy using PerkinElmer Frontier equipment with a resolution of 4 cm−1 and a wavenumber range of 400–4000 cm−1. The particle size was measured by Zetasizer Nano ZS (Malvern, UK), and scanning electron microscope (SEM) in a JEOL JSM-6510 with an accelerating voltage of 15 kV was used to visualize the shape of RxAcNPs. Powder XRD scanning (Lab-X, Shimadzu-XRD 6100 instrument, Japan) was performed to analyze the crystalline nature of RxAcNPs within the range of diffraction angle 2θ from 5° to 60.
The spectra of fluorescence emission were collected on Hitachi F-2700 Spectrofluorimeter with a Xenon lamp, and the quartz cuvette of 1 cm path length was used. The slit widths of excitation and emission were set at 5 nm. The rate of scanning was set to 300 nm/min. The wavelength of excitation was set at 280 nm and emission wavelength at 290–500 nm. The synchronous fluorescence spectra were scanned from 260 to 330 nm (Δλ = 15 nm) and from 220 to 330 nm (Δλ = 60 nm). A buffer blank spectrum was subtracted from the measured spectra for fluorescence background correction. The concentration of Lyz was kept constant at 10 μM, while the concentrations of RxAc and RxAcNPs were varied. All the measurements were performed at pH 7.4.
Tween80 was utilized to improve the stability of the therapeutic molecule and its safety at its target site. The influence of Tw80 inclusion on the interaction of the Lyz– RxAc system was studied by keeping the concentration of Lyz at 10 μM and changing the concentration of RxAc (2–16 μM), while the concentrations of Tw80 were maintained at 2 and 4 μM.
The UV–Vis absorption spectra were recorded using a double-beam PerkinElmer λ-45 spectrophotometer. For the whole experiment, the quartz cuvette of 1 cm path length was used. The concentration of Lyz was kept at 10 μM while the RxAc and RxAcNPs concentrations were varied. All the readings were recorded at room temperature.
Circular Dichroism (CD) spectra were carried out using a Jasco J-815 spectropolarimeter and using a quartz cell of 0.1 cm path length. Response time and data pitch were fixed at 1 s and 1 nm, respectively. CD spectra were measured in the far-UV region (200–250 nm) with a scan speed of 100 nm/min and two scans for each spectrum under constant nitrogen flow. For all the measured spectra, Phosphate buffer baseline subtraction (pH 7.4) was used. Concentration of Lyz for all runs was fixed at 10 μM, while the RxAc and RxAcNPs concentrations were 0, 40, and 80 μM. All the measurements were carried out at room temperature.
Molecular docking study used software Autodock 4.2 and Autodock tools (ADT) using the Lamarckian genetic algorithm [29]. The crystal structure of Lyz (PDB ID: 2LYZ) was obtained from Brookhaven Protein Data Bank and three-dimensional structure of Roxatidine acetate (CID = 5105) was obtained from PubChem. All the ions and water molecules were removed, hydrogen atoms were added, and partial Kollman charges were assigned. The Autodock run was carried out through the following parameters: GA population size, 150; maximum number of energy evolutions, 2.5 × 106, and Grid box size 86 Å × 80 Å × 96 Å along x-, y-, and z axes covering the whole protein with a grid-point spacing of 0.375 Å. Discovery Studio 3.5 was utilized for identification and visualization of the residues involved.
In order to obtain insight into the binding interaction of RxAcNPs with Lyz, the drug content, encapsulation efficiency (EE), and releasing percentage of RxAc were determined utilizing spectrophotometric techniques, with the mole ratio 5:1:1 of Cs, TPP, and Tween80, respectively. The maximum absorption wavelength was found to be 275 nm for RxAc. The drug content and encapsulation efficiency of RxAc in CsNPs based on the preparation of formulation are represented in Table 2. As listed in Table 2, the results displayed high encapsulation efficiency, which was 88.25 ± 0.26%, and the total content of drug in the nanoform was 26.48 ± 0.17 mg, which was nearly the total content of drug used in the preparation of the formulation matrix. These results revealed that the developed method is reliable and accurate to estimate the content of drug without interference of the formulation matrix or excipients. Additionally, it has the possibility to estimate the content of drug in the complex nanocarriers-based formulation.
The total quantity of Roxatidine acetate used in formulation (mg) | 30.00 |
---|---|
The cumulative quantity of RxAc (mg ± SD*) | 26.48 ± 0.17 |
Encapsulation efficiency ( % ± SD*) | 88.25 ± 0.26 |
Particle Size (nm ± SD*) | 220 ± 5 |
Nanoparticle sizes and mass balance of the Roxatidine acetate used in nanoparticles formulation.
Standard deviation (N = 3)
The RxAc release profile from RxAc-loaded Tween80–Chitosan nanoparticles at different values of pH is illustrated in Figure 2. The drug released from the nanoparticles was little during the initial 2 hours (less than 25%). After 2 hours, the quantity of the released drug increased with time. The RxAc percentages released at the end of 24 hours. were 90.21 ± 0.73, 85.83 ± 0.54, 82.79 ± 0.34, and 75.01 ± 0.57% for pH 3.5, 6.6, 7.4, and 8.4, respectively (Table 3 and Figure 2). Furthermore, as the pH decreased, the amount of released drug increased, showing that the drug release depends upon the pH of the media, as well as the nature of the polymer matrix [33, 34], which means that the developed method is suitable and effective for preparing the antiulcer drugs in nanoform.
In vitro of RxAcNPs release profile at different pH values.
pH Amount (mg) ± SD* | 3.5 | 6.6 | 7.4 | 8.4 |
---|---|---|---|---|
The total amount of Roxatidine acetate used for release study | 25 | 25 | 25 | 25 |
The cumulative amount of drug released | 20.32 ± 0.11 | 18.49 ± 0.39 | 16.82 ± 0.29 | 14.49 ± 0.46 |
Amount of drug unreleased | 2.23 ± 0.24 | 2.97 ± 0.41 | 3.88 ± 0.18 | 4.26 ± 0.27 |
The total amount of drug recovered | 22.55 ± 0.49 | 21.46 ± 0.05 | 20.70 ± 0.16 | 18.75 ± 0.21 |
Percentage amount of drug recovered (%) | 90.21 ± 0.73 | 85.83 ± 0.54 | 82.79 ± 0.34 | 75.01 ± 0.57 |
Mass balance of Roxatidine acetate used in vitro release study at deferent pH.
Standard deviation (N = 3).
The nanoparticles resulting from this developed method were used to investigate the applicability in simulation of studies of drug nanoparticles–protein interaction. The known concentrations (0–16 μM) of the RxAcNPs solution were added to the fixed concentration of Lyz (10 μM) to examine the binding interaction under physiological conditions.
Fourier transform infrared (FTIR) spectra of the CsNPs and RxAcNPs are shown in Figure 3A. Chitosan is known to possess amine groups on the glucosamine moiety whereas Roxatidine acetate is an amphoteric drug having hydrophobic and hydrophilic moieties (▬OH, CO, and ▬NH groups). The characteristic absorption bands for Chitosan were observed at 1650, 1545 and 1420 cm−1 were corresponding to amide I, amide II and amide III, respectively. 1095 cm−1 was corresponding to C▬N stretching, and 2936 cm−1 was corresponding to the asymmetric stretching vibration of methylene and 3350 cm−1 was due to the stretching vibration of N▬H. The FTIR spectra of RxAcNPs were compared with the FTIR spectra of CsNPs. The spectra did not show any new band for characteristic peaks of RxAc in RxAcNPs spectra and the existing shift of bands indicating entrapment of RxAc within the chitosan matrix, suggesting no new chemical bond formation between RxAc and CsNPs. Consequently, this observation excluded the possibility of an interaction between the polymer and drug indicating that RxAc was physically dispersed in the polymer [33, 34, 35, 36, 37, 38]. As shown in Figure 3B, RxAc-loaded Tween80–Chitosan nanoparticles were examined using the PXRD technique. The peak at 11.72° represents the presence of Cs and at 17.65°, the presence of TPP is indicated. A synthesized nanoform was specified, illustrating the semicrystalline nature of RxAcNPs after the available analysis, which depends on the little sharp pattern of XRD; hence, the drug was just encapsulated in Tween80–Cs nanoparticles without any interaction. The peaks at 24.18° and 27.21° indicated the presence of RxAc [39, 40, 41, 42, 43, 44, 45]. As shown in Figure 4A and Table 2, the data of DLS showed that the particle size of RxAcNPs was 220 ± 5 nm, which was almost in conformity with the data of SEM as shown in Figure 4B. The SEM micrograph of RxAcNPs clearly illustrates the presence of RxAc on the Chitosan surface, which clarifies the drug encapsulation in the nanoparticle surface. The data of SEM of Tw80–CsNPs before and after loading RxAc illustrated that the spherical shape of the nanoparticles of Tw80–CsNPs is slightly deformed because of the loading of RxAc, as shown in Figure 4B.
(a) FTIR spectra for Roxatidine acetate (RxAc), Chitosan nanoparticles (CsNPs), Roxatidine acetate loaded Chitosan nanoparticles (RxAcNPs), (b) PXRD spectra for Roxatidine acetate (RxAc), Chitosan nanoparticles (CsNPs), Roxatidine acetate loaded Chitosan nanoparticles (RxAcNPs).
(a) Particle size distribution of RxAcNPs, (b) SEM image of RxAc-loaded Chitosan nanoparticles (RxAcNPs).
Fluorescence quenching of lysozyme is broadly used in measuring the binding affinity of protein and drug. Lyz has three main Trp residues located at its active binding site, i.e., Trp-62, Trp-63, and Trp-108. The intrinsic fluorescence of Lyz comes from tryptophan residues (Trp-62, Trp-63, and Trp-108) and to study the conformational changes of Lyz in the binding process of Lyz with drugs used to be a fluorescent probe [4, 46]. The effects of RxAc and RxAcNPs on Lyz fluorescence intensity are shown in Figure 5A and B, respectively. After being excited with a wavelength of 280 nm, Lyz has a fluorescence emission with a peak at 337 nm; the fluorescent intensity of Lyz decreased regularly with increasing concentrations of RxAc and RxAcNPs. Interestingly, a red shift of about 6 nm and 4 nm in the λmax were observed in Lyz-RxAc and Lyz-RxAcNPs systems, respectively. Moreover, 78% of the fluorescence emission was quenched by RxAc in case of the Lyz–RxAc system whereas 77% quenching of the emission was observed in case of the Lyz–RxAcNPs system, which sketches a picture as to how the quencher RxAc and RxAcNPs ingress the fluorophore and bring about the quenching. Further, it suggests a change in the surrounding environment of the fluorophores due to interaction with RxAc and RxAcNPs and that the binding regions of RxAc and RxAcNPs are in the vicinity of Trp residues. Considering the above observations, it could be adjudged that RxAc and RxAcNPs bind to Lyz and quench its intrinsic fluorescence. The red shift in the λmax in Lyz–RxAc and Lyz–RxAcNPs systems indicated an increase in polarity and a decrease in hydrophobicity [47, 48, 49].
Fluorescence emission spectra of Lyz in the presence of (a) RxAc and (b) RxAcNPs at 298 K. CLyz : 10μM (a), CRxAc or RxAcNPs (b-i): 2, 4, 6, 8, 10, 12, 14 and 16 μM; native RxAc or RxAcNPs (j): 2 μM.
As we know well, the phenomena of fluorescence quenching are brought about by various intermolecular episodes, namely excited-state reactions, ground-state complex formation, energy-transfer molecular rearrangements, and collisional quenching [50, 51, 52]. There are two types of quenching that are Static quenching and dynamic quenching. In static quenching, a nonfluorescent fluorophore-quencher complex is formed, whereas in dynamic quenching, collision between the quencher and fluorophore during the lifetime of the excited state is established. The two types of quenching can be distinguished from each other by taking viscosity and temperature-dependent measurements [53]. In the present systems, the fluorescence-quenching mechanism has been studied using the well-known Stern–Volmer (S–V) Equation [48, 53, 54]:
where F0 and F are the protein fluorescence intensities in the absence and in the presence of the drug molecule (quencher), respectively, Ksv is the constant of Stern–Volmer quenching, [Q] is the concentration of the quencher, Kq is the quenching rate constant of the biomolecule, and τ0 is the biomolecule average lifetime in absence of the quencher. A single type of quenching mechanism, either static or dynamic quenching mechanism, is included, when the plot of F0/F vs. [Q] is linear, whereas deviation from linearity suggests the presence of both quenching mechanisms. The value of Ksv is estimated from the plot of F0/F vs. [Q]. Considering the well-known connection between the quenching constant and the Kq quenching rate constant, and taking into account the fluorescence lifetime of the biopolymer as 10−8 s, the Kq values can be calculated [9, 19, 55]:
Figure 6A and B show the plots of F0/F for Lyz versus [Q] of RxAc and RxAcNPs at 298, 304, and 310 K and pH 7.4, where [Q] ranges from 2 to 16 μM of RxAc and RxAcNPs. Plots in Figure 6A and B show that the results of Lyz–RxAc and Lyz–RxAcNPs systems agree very well with the Stern–Volmer equation, which indicates that a single type of quenching mechanism is involved, either static or dynamic [56, 57, 58, 59]. The results listed in Table 4 showed that KSV and Kq values of Lyz–RxAc and Lyz–RxAcNPs decreased upon increasing temperature and that the quenching of both systems follows the static quenching mechanism [53, 60]. The maximum scatter collision quenching constant (Kq) with the biopolymer is 2 × 1010 L mol−1 s−1. The values of Kq of the protein quenching initiated by RxAc and RxAcNPs are greater than the constant of maximum scatter collision quenching, thus indicating that quenching is initiated from the formation of complex and not the dynamic collision [53].
Stern-Volmer plots for quenching of Lyz fluorescence by (A) RxAc (B) RxAcNPs at different temperatures.
System | pH | T(K) | KSV × 104 (L mol−1) | SD* | R* | Kq × 1012 (L mol−1 s−1) |
---|---|---|---|---|---|---|
Lyz-RxAc | 7.4 | 298 | 1.86 | 0.04 | 0.999 | 1.86 |
304 | 1.54 | 0.12 | 0.999 | 1.54 | ||
310 | 1.17 | 0.28 | 0.999 | 1.17 | ||
Lyz-RxAcNPs | 7.4 | 298 | 1.76 | 0.17 | 0.996 | 1.76 |
304 | 1.49 | 0.13 | 0.994 | 1.49 | ||
310 | 1.22 | 0.07 | 0.994 | 1.22 | ||
Lyz-RxAc-Tw80 (2μM) | 7.4 | 298 | 1.47 | 0.06 | 0.999 | 1.46 |
Lyz-RxAc-Tw80 (4μM) | 7.4 | 298 | 1.33 | 0.08 | 0.998 | 1.33 |
Quenching parameters of Lyz-RxAc and Lyz-RxAcNPs systems at different temperatures.
S.D* is standard deviation (N = 3)
R** is the correlation coefficient of KSV
The constant of binding (Ka) and the number of binding sites (n) of the interaction between RxAc/RxAcNPs and Lyz could be investigated from the logarithmic form of the Stern–Volmer equation: [48, 52, 53]
From the plot of Log[(F0 – F)/F] vs. log [Q], the binding constant (Ka) and the number of binding sites (n) could be obtained, where the intercept yields the value of the binding constant (Ka) and the slope gives the number of binding sites (n) (listed in Table 5). The values of Ka were 104 L mol−1 for Lyz–RxAc (Figure 7A) indicating a high affinity of the Lyz molecule for RxAc besides binding number up to 0.96; however, the binding affinity of Lyz for RxAcNPs (Figure 7B) was found lower, ranging up to the order of 103 L mol−1 and binding number up to 0.91. All these results lead to the conclusion that binding is stronger between Lyz and RxAc than that between Lyz and RxAcNPs, which will definitely affect its free concentration and its bound concentration in the blood plasma [61, 62].
Plots of log [(Fo-F)/F] versus log [Q] for (A) Lyz-RxAc and (B) Lyz RxAcNPs systems at different temperatures.
System | pH | Temp. (K) | Ka (L mol−1) | R* | n | ∆G (kJ mol−1) | ∆H (kJ mol−1) | ∆S (J mol−1 K−1) |
---|---|---|---|---|---|---|---|---|
Lyz-RxAc | 7.4 | 298 | 1.14 × 104 | 0.998 | 0.96 | −22.25 | −71.80 | −166.28 |
304 | 0.84 × 104 | 0.999 | 0.95 | −21.24 | ||||
310 | 0.37 × 104 | 0.999 | 0.89 | −20.25 | ||||
Lyz-RxAcNPs | 7.4 | 298 | 1.24 × 103 | 0.999 | 0.91 | −17.73 | −86.61 | −231.13 |
304 | 0.69 × 103 | 0.999 | 0.88 | −16.34 | ||||
310 | 0.32 × 103 | 0.999 | 0.84 | −14.96 | ||||
Lyz-RxAc-Tw80(2 μM) | 7.4 | 298 | 2.33 × 103 | 0.999 | 0.90 | - | - | - |
Lyz-RxAc-Tw80(4 μM) | 7.4 | 298 | 1.07 × 103 | 0.997 | 0.85 | - | - | - |
Binding constant, number of binding sites and Thermodynamic parameters of Lyz-RxAc and Lyz-RxAcNPs systems at different temperatures.
*R is the correlation coefficient of Ka
The drug bioavailabilities could be estimated from the binding affinity values. The nanoform of drug (RxAcNPs) has shown less binding affinity to Lyz, which indicates that the distribution and absorption of drug nanoparticles to various tissues will be higher, as the stability of the Lyz–RxAcNPs complex is lower compared to Lyz–RxAc complex [63, 64].
The influence of Tween80 inclusion onto the interaction of Lyz–RxAc systems was studied by introducing Tween80 to the Lyz–RxAc system at room temperature (Figure 8A and B). The results of the Stern–Volmer constant (KSV) and binding constant (Ka) are shown in Figures 9A,B and 10A,B and listed in Tables 4 and 5. We observed that the results of KSV and Ka in the presence of Tw80 were smaller than in its absence. These results indicated that the Tw80 helps to release RxAc from the Chitosan nanoparticles, due to a fraction of RxAc binding to it by weak bonds; hence, Tw80 helps to release more drug to the tissues as compared to the drug released from plasma [65]. Furthermore, Tw80 encloses the RxAc molecule and obstructs it from colliding directly with the amino acid residues found in the binding sites of Lyz [66].
A,B: Fluorescence emission spectra of Lyz in the presence of RxAc and Tw80 at 298 K. CLyz: 10 μM (a), CTw80: 2 and 4 μM (b), CRxAc (c–k): 2, 4, 6, 8, 10, 12, 14 and 16 μM.
A,B: Stern-Volmer plots for quenching of Lyz fluorescence by RxAc in the presence of Tw80 (2 and 4 μM) at 298 K.
A,B: Plots of log [(Fo-F)/F] versus log[Q] for Lyz-RxAc-Tw80 systems.
The driving force of binding could be assessed from the thermodynamic law summarized by Ross and Subramanian. The stability of the protein–drug complex and the binding of drug onto protein are influenced by various types of noncovalent forces such as hydrophobic interactions, hydrogen binding, Van der Waals, and electrostatic forces. To get the thermodynamic parameters, the Van’t Hoff equation has been used:
where Ka is the constant of binding at the corresponding temperature T, T is the absolute temperature, and R is the universal gas constant. The plot of lnKa versus 1/T allows the estimation of the enthalpy change (ΔH) and the entropy change (ΔS) [9, 67, 68, 69]. The enthalpy change (ΔH) and the entropy change (ΔS) can be obtained from the slope and the intercept of the Van’t Hoff plots, respectively. From the thermodynamic viewpoint, Ross and Subramanian recommended that ΔH < 0 and ΔS < 0 suggest the van der Waals force and hydrogen bond formation, ΔH > 0 and ΔS > 0 show a hydrophobic interaction, and ΔH < 0 and ΔS > 0 propose electrostatic forces of interaction [53, 62, 63, 64].
As shown in Figure 11A and B, there is a good linear relationship between lnKa and 1/T, suggesting that ΔH is constant in the current temperature range. From Table 5, it could be seen that ΔH = − 71.80 kJ mol−1 and ΔS = − 166.28 J mol−1 K−1 for the Lyz–RxAc system and ΔH = − 86.61 kJ mol−1 K−1 and ΔS = − 231.13 J mol−1 K−1 for the Lyz–RxAcNPs system. The negative values of ∆H and ∆S for interaction of Lyz with RxAc and Lyz with RxAcNPs indicate that hydrogen bonds and Van der Waals forces play a major role in the interaction of Lyz–RxAc and Lyz–RxAcNPs systems, and the binding reaction is exothermic and enthalpically driven. The negative values of ∆G for both systems at different temperatures (298, 304, and 310 K) mean that the binding processes are spontaneous in both systems.
Vant-Huff Plot for (A) Lyz-RxAc and (B) Lyz-RxAcNPs systems at different temperatures.
Fluorescence resonance energy transfer is a nondestructive spectroscopic method and an investigatory tool that can monitor the proximity and relative angular orientation to study energy transfer from donor to acceptor. A transfer of energy could be carried out through direct electrodynamic interaction between the primarily excited molecule and its neighbors [70, 71]. The fluorophores of donor and acceptor can be entirely nonattached or attached to the same macromolecule [72]. In the present case, Lyz is the donor and RxAc and RxAcNPs are the acceptors. According to this theory, the efficiency (E) of energy transfer from Lyz to RxAc or RxAcNPs and the distance (r) of binding between Lyz and RxAc or RxAcNPs could be calculated by Eq. (8) [70, 73]:
where E could be determined experimentally from the donor emission in the absence (F0) and presence of the acceptor (F), normalized to the same donor concentration, r is the actual distance between the donor (Lyz) and the acceptor (RxAc/RxAcNPs), R0 is the critical distance when the efficiency of transfer is 50%, which depends on the quantum yield of the donor, the extinction coefficient of the acceptor, the overlap of donor emission and acceptor absorption spectra, and the mutual orientation of the chromophores. R0 can be defined by Eq. (9) [70, 74]:
where K2 is the spatial factor of orientation related to the geometry of the donor and acceptor of dipoles, N is the refractive index of the medium, Φ is the fluorescence quantum yield of the donor, and J is the effect of spectral overlap between the donor emission spectrum and the acceptor absorption spectrum, which could be calculated by Eq. (10)
where F(λ) is the donor fluorescence intensity at wavelength λ and ε(λ) is the molar absorption coefficient of the acceptor at wavelength λ. The efficiency of transfer (E) could be obtained using Eq.8, where F and F0 are the relative fluorescence intensities in the presence and absence of acceptor [56]. For Lyz, K2 = 2/3, N = 1.36, and Φ = 0.15 [62, 75].
The overlap of the absorption spectrum of RxAc and RxAcNPs with the fluorescence emission spectrum of Lyz are shown in Figure 12A and B, in the wavelength range of 280–310 nm and 280–308 nm, respectively. The fluorescence emission from both systems at an excitation wavelength of 280 nm is mainly from the Lyz molecule as both RxAc and RxAcNPs are nonfluorescent at the excitation wavelength. However, at this excitation wavelength, RxAc and RxAcNPs do show weak absorption, which suggests the probability of energy transfer from Lyz to RxAc/RxAcNPs. Using Eqs. (8)–(10), the parameters related to energy transfer from Lys to RxAc or RxAcNPs are calculated and are presented in Table 6. The values of R0, r, J, and E were found to be 3.40 nm and 4.66 nm, 6.67 × 10−14 cm3 L mol−1 and 0.23 for Lyz–RxAc, whereas the corresponding values were 3.44 nm, 4.53 nm, 7.18 × 10−14 cm3 L mol−1 and 0.24 for Lyz–RxAcNPs, respectively. The obtained result indicates that RxAc and RxAcNPs are strong quenchers and these may situate in the close proximity of Lyz. The values of binding distance (r) between the donor and acceptor for all the systems are in the range of 2–7 nm, denoting that the energy transfer is possible between Lys and RxAc or RxAcNPs. The values of R0 and r are also in the academic range, which proves that nonradiative energy transfer occurs between Lyz and RxAc/RxAcNPs. Furthermore, the results also suggest that static quenching is responsible for the quenching of fluorescence emission as the binding involved energy transfer from Lyz to RxAc/RxAcNPs [48, 59, 76, 77].
Spectral overlap between fluorescence emission spectrum of Lyz and absorption spectrum of (A) RxAc and (B) RxAcNPs when the molar ratio of Lyz and RxAc or RxAcNPs is 1:1. [Lyz]: 10 μM, [RxAc or RxAcNPs]: 2 μM at 298 K.
System | R0 (nm) | |||
---|---|---|---|---|
Lyz-RxAc | 3.40 | 4.66 | 0.23 | 6.67 × 10−14 |
Lyz-RxAcNPs | 3.44 | 4.53 | 0.24 | 7.18 × 10−14 |
Energy transfer parameters for Lyz-RxAc and Lyz-RxAcNPs interactions at 298 K.
Synchronous fluorescence spectroscopy is a kind of important method and a proficient technique, which is utilized to evaluate the conformational changes and provides the information regarding the molecular environment in the vicinage of the chromophore molecule [78, 79]. Because of its sensitivity, spectral simplification, spectral bandwidth reduction, and shunning of different perturbing effects, it can be used as an ideal and a very useful method to study the microenvironment of Trp residues by measuring the possible shift in wavelength emission maximum (λem) [48, 80]. The polarity changes around the chromophore molecule, i.e., the Lyz conformation, may be due to the shift in the position of emission maximum. As is well-known, the spectra of synchronous fluorescence show Trp residues of Lyz at the wavelength interval (∆λ) of 60 nm, while at the wavelength interval (∆λ) of 15 nm, the spectra of synchronous fluorescence show Tyr residues of Lyz [81].
At Δλ = 15 nm, in the Lyz–RxAc and Lyz–RxAcNPs systems in the investigated concentration range, the maximum emission wavelength keeps its position without any shift (Figure 13A and B), which indicates that there is no change in the microenvironment of the Tyrosine residues in both systems, whereas over the investigated concentration range at Δλ = 60 nm, it can be seen that the maximum emission wavelength moderately shifts from 279 to 274 nm in the Lyz–RxAc system and from 279 to 275 nm in the Lyz–RxAcNPs system toward blue wavelengths. On looking through the synchronous spectra for the Lyz–RxAc and Lyz–RxAcNPs systems (Figure 14A and B), the shift effect shows that the conformation of Lyz has changed. The blue-shift effect indicates that the microenvironment around the Tryptophan residues is disturbed and shows a decrease in the polarity and an increase in the hydrophobicity around Tryptophan residues.
Synchronous fluorescence spectrum of (A) Lyz-RxAc and (B) Lyz-RxAcNPs systems at 298 K : (∆λ = 15 nm), C(Lyz) = 10 μM; C(RxAc or RxAcNPs) (b-j): 2, 4, 6, 8, 10, 12, 14 and 16 μM.
Synchronous fluorescence spectrum of (A) Lyz-RxAc and (B) Lyz-RxAcNPs systems at 298 K : (∆λ = 60 nm), C(Lyz) = 10 μM; C(RxAc or RxAcNPs) (b-j): 2, 4, 6, 8, 10, 12, 14 and 16 μM.
UV–Vis spectroscopy is a simple technique and an effective method that can help to know the structural changes in the system and to explore the formation of complex and the change in hydrophobicity [82].
In the present study, we have observed the change in the UV absorption spectra of Lyz–RxAc and Lyz–RxAcNPs systems (Figure 15A and B), which indicated that the interaction between Lyz and RxAc/RxAcNP molecules may lead to change in the conformation of Lyz. It was evident that the UV absorption intensity of Lyz increased regularly with the variation of RxAc and RxAcNP concentrations. The maximum peak positions of Lyz–RxAc and Lyz–RxAcNPs were shifted slightly toward a longer wavelength region (279–284 nm and 279–283 nm, respectively). The change in λmax is observed possibly due to complex formation between Lyz and RxAc/RxAcNPs. The red shift in the absorbance spectra also indicated that the polarity of amino acid microenvironments increased with the addition of RxAc or RxAcNPs [83, 84, 85, 86], which is in good agreement with the quenching and Synchronous fluorescence spectroscopy and thermodynamic analysis results.
UV–Vis spectra of Lyz in the presence of (A) RxAc and (B) RxAcNPs at 298 K. CLyz: 10 μM (a), CRxAc or RxAcNPs (b-j): 2, 4, 6, 8, 10, 12, 14 and 16 μM.
The technique of far-UV Circular dichroism spectroscopy (CD) is an important and powerful technology technique utilized to probe the secondary and tertiary structures of the protein/biopolymer [87, 88, 89]. The method is used to explore the biopolymer conformational changes upon binding of RxAc and RxAcNPs to Lyz, due to its simplicity and reliability. The CD spectra of Lyz with various concentrations of RxAc and RxAcNPs have been shown in Figure 16A and B at room temperature. The results of CD spectra of Lyz show two negative bands at 208 nm (π → π* transition) and 229 nm (n → π* transition), which are attributed to the α-helical structure of protein [67] whose magnitude reveals the amount of α-helicity in Lysozyme and they arise due to π–π* and n–π* transitions of the peptide bond of α-helix [84, 89, 90, 91]. The CD data have been observed in terms of mean residue ellipticity (MRE) in deg cm−2 dmol−1 according to the following Equation [92, 93, 94, 95, 96, 97]:
The CD spectra of (A) Lyz-RxAc and (B) Lyz-RxAcNPs systems. Lyz concentration was kept fixed at 10 μM (a). In Lyz-RxAc and Lyz-RxAcNPs systems, RxAc or RxAcNPs concentration was fixed at 40 (b) and 80 μM (c).
where Cp is the molar concentration of protein, n is the number of amino acid residues of the protein (129 for Lyz), and l is the path length in cm. The α-helical content of Lyz is calculated from the MRE value at 208 nm, using the following Equation [92, 93, 94, 95, 96, 97]:
where MRE208 is the observed mean residue ellipticity (MRE) value at 208 nm, 4000 is the MRE of the β-form and random coil conformation cross at 208 nm, and 33,000 is the MRE value of a pure α-helix at 208 nm.
In order to study the influence of RxAc and RxAcNPs on the secondary structure of the Lyz, the CD measurements of Lyz in the absence and presence of RxAc and RxAcNPs were performed. From Figure 16A,B and Table 7, the α-helicity for free Lyz was 43.34%, while the addition of RxAc and RxAcNPs to the Lyz solution caused an increase in the negative peak ellipticities, probably as a consequence of the formation of complex between Lyz and RxAc/RxAcNPs. The CD data in the wavelength range of 200–250 nm are used to evaluate the change of the secondary structure in Lyz. The results showed that interaction with RxAc and RxAcNPs caused only an increase in the band intensity of Lyz without any significant shift of the peaks and the helical content decreased to 38.73% and 31.23%, respectively. The decrease in the α-helical content of lysozyme represents the unfolding of protein due to interaction with RxAc or RxAcNPs. The unfolding of protein changes the absorbance value, which in turn alters the ellipticity value. The results showed that Lyz was induced to adopt a more loose conformation of the extended polypeptide. The conformational transition probably resulted in the exposure of the hydrophobic cavities to more hydrophilic environment, which is favorable for the interaction between Lyz and RxAc or RxAcNPs. The CD results also corroborate the conclusion of fluorescence and UV studies [77, 98].
System | α-helix % | ||
---|---|---|---|
[Lyz] (μM) | Drug | [Drug] | |
0 | 43.34 | ||
10 | RxAc | 40 | 41.12 |
80 | 38.73 | ||
0 | 43.34 | ||
10 | RxAcNPs | 40 | 35.82 |
80 | 31.23 |
α-helicity (%) of Lyz at different concentrations of RxAc and RxAcNPs at 298 K.
The molecular docking is an excellent and an efficient computational technique, which is used to predict the probable binding site of interaction of protein with the ligand/drug molecule and also the preferred binding site of the ligand through the 3-D graphics [4, 11, 47, 99]. Moreover, it also displays the amino acid residues encircling the ligand/drug molecule and also assists to validate the results and highlights the interaction types operating in the protein–ligand/drug system [4, 99, 100]. To study the interaction in the Lyz–RxAc system, molecular docking studies were carried out with Autodock Vina software to clarify the mode of binding between lysozyme and Roxatidine acetate and illustrate the underlying mechanism. For further study, the lowest energy was chosen that was found to be −5.5 kcal/mol (−23.01 kj/mol), which is near to the experimental data of ∆G° in thermodynamic analysis (−22.25 kj/mol). In the Lyz–RxAc system (Figure 17A and B), the molecular docking showed the site of binding of RxAc along the long large pocket between the two domains of Lyz, which is also its site of active binding [101], and also showed that there were approximately three sites for binding of RxAc with lysozyme via hydrogen bonds at the lowest energy (Asn46 “two bonds” and Asp52 “one bond”) (Figure 18A and B). The three sites of binding were all located in the large pocket of lysozyme. There were two hydrogen bonds between Asn46 and RxAc that were formed; one bond was between the hydrogen atom of Asn46 and the oxygen atom (C〓O) of Roxatidine acetate, and another hydrogen bond was between the other hydrogen atom of Asn46 and the oxygen atom of Roxatidine acetate (C▬O▬C). The third hydrogen bond was between the oxygen atom of Asp52 and the hydrogen atom (NH) of Roxatidine acetate. The dominant fluorophores (Trp62 and Trp63) were involved in the binding sites through hydrophobic interaction via Pi–alkyl binding, which could illustrate the observed quenching of fluorescence, whereas the aliphatic amino acid (Ala107) also formed hydrophobic interaction through alkyl–alkyl binding; in addition, the oxygen atom of Asp52 formed electrostatic binding with the phenyl ring of Roxatidine acetate, as shown in Figures 17B and 18A,B. Molecular docking studies have explained that hydrogen bonding was the dominant driving force in the binding of RxAc to lysozyme, and these results were in accordance with the results of thermodynamic analysis and UV spectroscopy.
Docking interaction of Lyz-RxAc binding, (A) The lysozyme pocket when RxAc was added. (B) Gaussian contact maps superimposed with the RxAc ligand and the receptor lysozyme, hydrogen bonds preference was indicated.
(A) Amino acid residues surrounding RxAc. (B) 2-Dimentional representation of Lyz-RxAc system.
In the present study, the RxAc drug–loaded Tween80–Chitosan nanoparticles (RxAcNPs) have been characterized and probed through FTIR, PXRD, UV–Vis, DLS, and SEM techniques. The physicochemical properties of RxAcNPs have been employed and evaluated for drug formulation, determination of external morphology, particle size, drug content, entrapment efficiency, and in vitro release of drugs. In addition, the RxAc and RxAcNPs interactions with Lyz have been investigated utilizing spectroscopic methods such as fluorescence, UV–Vis, and CD spectroscopy. The results of Stern–Volmer plots illustrate that the interaction mechanism of Lyz–RxAc and Lyz–RxAcNPs systems was a static mechanism. In the presence of RxAc and RxAcNPs, the secondary construction of Lyz is reformed. The results of synchronous fluorescence and CD spectra confirm that the RxAc and RxAcNPs cause change in the secondary construction of Lyz. The thermodynamic results clarify that the main forces in both systems were hydrogen bonds and Van der Waals forces, also revealing that the reaction of binding in both systems is spontaneous, exothermic, and enthalpically driven. The molecular docking results were in accordance with the results of thermodynamic analysis, UV–Vis, and CD spectroscopy. The present study illustrates that the binding of RxAcNPs with Lyz is low as compared to RxAc, which confirms that the distribution and absorption of the RxAcNPs to various tissues would be higher. Therefore, the result of this study has a great importance in the clinical medicine and pharmacology area and provides important insight into the interaction of serum albumins with antiulcer drugs. The significance of this study is evident because the developed RxAc-loaded Tween80–Chitosan nanoparticles could be utilized as an efficient strategy using nanotechnology in applications of ulcer therapy.
The authors thank the Department of Chemistry and Interdisciplinary Biotechnology Unit, Aligarh Muslim University, India, for support to this work. They also thank the authorities of Aligarh Muslim University for extending the necessary facilities.
The authors declare no conflict of interest.
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\\n\\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\\n\\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\\n\\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\\n\\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\\n\\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\\n\\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\\n\\nCONFLICT OF INTEREST - REVIEWER
\\n\\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\\n\\nEXAMPLES OF CONFLICTS OF INTEREST:
\\n\\nFINANCIAL AND MATERIAL
\\n\\nNON-FINANCIAL
\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\\n\\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\\n\\nEXAMPLES:
\\n\\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\\n\\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\\n\\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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Morgan",coverURL:"https://cdn.intechopen.com/books/images_new/5599.jpg",editedByType:"Edited by",editors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",slug:"lee-roy-morgan",fullName:"Lee Roy Morgan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"53170",doi:"10.5772/66310",title:"Current Management of Brain Metastases: Overview and Teaching Cases",slug:"current-management-of-brain-metastases-overview-and-teaching-cases",totalDownloads:1687,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Over the past two decades, increased global incidence of malignancy, improved systemic disease treatment with prolonged survival, and increased central nervous system (CNS) surveillance in cancer patients have all contributed to a rise in cerebral metastatic disease. As many patients retain good neurologic function, the approach to their management has shifted markedly; a pre-terminal prognosis and palliative treatment have been replaced by individualized care plans to prolong functional survival. However, the rapid shifts in disease characteristics, treatment options and emerging evidence can be challenging to navigate, and a rational approach to brain metastases is needed. We discuss the changing epidemiology of brain metastases and consider approaches to prognostic classification. We review current treatment modalities and discuss the significant studies pertaining to each, with emphasis on Level 1 evidence when available and cooperative group trials, as well as studies on adverse effects. To integrate the information presented, we offer case scenarios that highlight pertinent decision-making factors. The shift in care goal for cerebral metastases from symptom palliation to prolongation of survival is not only feasible, but in many cases indicated. The appropriate application of various treatment modalities must be considered in the context of individual patients and their primary cancer.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Karolyn Au, Ying Meng, Suganth Suppiah, Anick Nater, Rakesh\nJalali and Gelareh Zadeh",authors:[{id:"194279",title:"M.D.",name:"Karolyn",middleName:null,surname:"Au",slug:"karolyn-au",fullName:"Karolyn Au"},{id:"197665",title:"Dr.",name:"Ying",middleName:null,surname:"Meng",slug:"ying-meng",fullName:"Ying Meng"},{id:"197666",title:"Dr.",name:"Suganth",middleName:null,surname:"Suppiah",slug:"suganth-suppiah",fullName:"Suganth Suppiah"},{id:"197667",title:"Dr.",name:"Anick",middleName:null,surname:"Nater",slug:"anick-nater",fullName:"Anick Nater"},{id:"197668",title:"Dr.",name:"Gelareh",middleName:null,surname:"Zadeh",slug:"gelareh-zadeh",fullName:"Gelareh Zadeh"},{id:"197669",title:"Dr.",name:"Rakesh",middleName:null,surname:"Jalali",slug:"rakesh-jalali",fullName:"Rakesh Jalali"}]},{id:"53003",doi:"10.5772/66131",title:"Managing CNS Tumors: The Nanomedicine Approach",slug:"managing-cns-tumors-the-nanomedicine-approach",totalDownloads:1188,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Albeit the rapidly evolving knowledge about tumor biochemistry enables various new drug molecules to be designed as treatments, malignant central nervous system (CNS) tumors remain untreatable due to the failure to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, drug delivery in CNS tumors must be properly addressed, as otherwise, novel therapies will continue to fail. In this regard, nanomedicine poses an appealing platform for efficient drug delivery to the CNS, since it may be targeted to improve the drug availability in the site of action, which would be translated into lower drug doses and fewer side effects. Hence, the accumulation of data about the CNS physiology and their relevant receptors, the widening therapeutic armamentarium of drugs potentially useful in CNS chemotherapy and the alternative routes for administration may envisage nanomedicines as a forthcoming routine approach. Indeed, on the basis of the promising results gathered from preclinical studies of nanomedicine-based therapy both systemically and locally administered, some nanomedicines have already been approved for clinical trials in a variety of CNS tumor conditions to serve as the first steps in the translation of nanotherapy to clinic. Their outcome will steer research directions for further improvements.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Juan Aparicio-Blanco and Ana-Isabel Torres-Suárez",authors:[{id:"193558",title:"Prof.",name:"Ana Isabel",middleName:null,surname:"Torres-Suárez",slug:"ana-isabel-torres-suarez",fullName:"Ana Isabel Torres-Suárez"},{id:"195630",title:"MSc.",name:"Juan",middleName:null,surname:"Aparicio-Blanco",slug:"juan-aparicio-blanco",fullName:"Juan Aparicio-Blanco"}]},{id:"54440",doi:"10.5772/67591",title:"NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents",slug:"neuropharmacology-as-applied-to-designing-new-chemotherapeutic-agents",totalDownloads:1245,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Neurooncology anticancer drugs are no exception—their distribution and tissue interactions follow the general rules of classical pharmacology. In an attempt to assist with the new therapeutic approaches to manage cancers involving the central nervous system, classical chemobiodynamic compartment and pharmacokinetic models are discussed and illustrated. In addition, strategies and approaches for penetrating the blood brain barrier (BBB) are reviewed and modeled. Finally, in support of classical pharmacology, a new anticancer agent in clinical trial for brain tumors is reviewed as an example of clinical onco-neuropharmacology.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Andrew H. Rodgers and Lee Roy Morgan",authors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",slug:"lee-roy-morgan",fullName:"Lee Roy Morgan"},{id:"193557",title:"Ph.D.",name:"Andrew",middleName:null,surname:"Rodgers",slug:"andrew-rodgers",fullName:"Andrew Rodgers"}]},{id:"54453",doi:"10.5772/65869",title:"A Review of Current Radiation Therapies for the Treatment of Metastatic Brain Tumors",slug:"a-review-of-current-radiation-therapies-for-the-treatment-of-metastatic-brain-tumors",totalDownloads:1255,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The treatment of brain tumors has evolved over the past few decades. While whole brain radiation therapy was the standard of care in the management of tumors for years, stereotactic radiation has for the most part replaced the technique in the management of metastatic tumors of the brain. In this review, the current indications are reviewed for both whole brain and stereotactic radiation therapy in the management of metastatic cancers involving the central nervous system, the most common types of malignancies diagnosed in the brain.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Jonathan S. Hayman",authors:[{id:"194386",title:"Dr.",name:"Michael",middleName:null,surname:"Hayman",slug:"michael-hayman",fullName:"Michael Hayman"},{id:"194430",title:"Dr.",name:"Jonathan",middleName:null,surname:"Hayman",slug:"jonathan-hayman",fullName:"Jonathan Hayman"}]},{id:"53032",doi:"10.5772/65911",title:"Role of Pathologist in Driver of Treatment of CNS Tumors",slug:"role-of-pathologist-in-driver-of-treatment-of-cns-tumors",totalDownloads:1648,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The incidence of Central Nervous System (CNS) tumors is gradually increasing. Furthermore, metastatic neoplasms are frequently seen in neuropathology practice as a major cause of mortality and morbidity. Pathologists try to reach a more accurate diagnosis by mentally filtering a synthesis, comprising age, radiological characteristics and microscopic findings in the sample sent, starting already from the intraoperative diagnosis process. By displaying their skills, they unveil whether a lesion in the brain parenchyma is a normal or reactive tumor and if this is a tumor, is it primary or metastatic, and if it is primary, what is the tumor type or if it is metastatic, which organ could it be associated with. Pathologists use diagnostic, prognostic and predictive markers in order to enable the patient receive the most effective and sufficient treatment. They ensure that an individualized treatment is provided via these tools, by making a histological diagnosis of the lesion according to the WHO classification, identifying the course of the disease and preventing undesired and dangerous complications. This chapter will focus on answering these questions and share the value of a multidisciplinary approach in the management of brain tumors in neurosciences, which is gradually increasing in importance, and how pathologists execute this art.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Serdar Altınay",authors:[{id:"185324",title:"Associate Prof.",name:"Serdar",middleName:null,surname:"Altınay",slug:"serdar-altinay",fullName:"Serdar Altınay"}]}],mostDownloadedChaptersLast30Days:[{id:"53170",title:"Current Management of Brain Metastases: Overview and Teaching Cases",slug:"current-management-of-brain-metastases-overview-and-teaching-cases",totalDownloads:1690,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Over the past two decades, increased global incidence of malignancy, improved systemic disease treatment with prolonged survival, and increased central nervous system (CNS) surveillance in cancer patients have all contributed to a rise in cerebral metastatic disease. As many patients retain good neurologic function, the approach to their management has shifted markedly; a pre-terminal prognosis and palliative treatment have been replaced by individualized care plans to prolong functional survival. However, the rapid shifts in disease characteristics, treatment options and emerging evidence can be challenging to navigate, and a rational approach to brain metastases is needed. We discuss the changing epidemiology of brain metastases and consider approaches to prognostic classification. We review current treatment modalities and discuss the significant studies pertaining to each, with emphasis on Level 1 evidence when available and cooperative group trials, as well as studies on adverse effects. To integrate the information presented, we offer case scenarios that highlight pertinent decision-making factors. 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The appropriate application of various treatment modalities must be considered in the context of individual patients and their primary cancer.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Karolyn Au, Ying Meng, Suganth Suppiah, Anick Nater, Rakesh\nJalali and Gelareh Zadeh",authors:[{id:"194279",title:"M.D.",name:"Karolyn",middleName:null,surname:"Au",slug:"karolyn-au",fullName:"Karolyn Au"},{id:"197665",title:"Dr.",name:"Ying",middleName:null,surname:"Meng",slug:"ying-meng",fullName:"Ying Meng"},{id:"197666",title:"Dr.",name:"Suganth",middleName:null,surname:"Suppiah",slug:"suganth-suppiah",fullName:"Suganth Suppiah"},{id:"197667",title:"Dr.",name:"Anick",middleName:null,surname:"Nater",slug:"anick-nater",fullName:"Anick Nater"},{id:"197668",title:"Dr.",name:"Gelareh",middleName:null,surname:"Zadeh",slug:"gelareh-zadeh",fullName:"Gelareh Zadeh"},{id:"197669",title:"Dr.",name:"Rakesh",middleName:null,surname:"Jalali",slug:"rakesh-jalali",fullName:"Rakesh Jalali"}]},{id:"53032",title:"Role of Pathologist in Driver of Treatment of CNS Tumors",slug:"role-of-pathologist-in-driver-of-treatment-of-cns-tumors",totalDownloads:1650,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The incidence of Central Nervous System (CNS) tumors is gradually increasing. Furthermore, metastatic neoplasms are frequently seen in neuropathology practice as a major cause of mortality and morbidity. Pathologists try to reach a more accurate diagnosis by mentally filtering a synthesis, comprising age, radiological characteristics and microscopic findings in the sample sent, starting already from the intraoperative diagnosis process. By displaying their skills, they unveil whether a lesion in the brain parenchyma is a normal or reactive tumor and if this is a tumor, is it primary or metastatic, and if it is primary, what is the tumor type or if it is metastatic, which organ could it be associated with. Pathologists use diagnostic, prognostic and predictive markers in order to enable the patient receive the most effective and sufficient treatment. They ensure that an individualized treatment is provided via these tools, by making a histological diagnosis of the lesion according to the WHO classification, identifying the course of the disease and preventing undesired and dangerous complications. This chapter will focus on answering these questions and share the value of a multidisciplinary approach in the management of brain tumors in neurosciences, which is gradually increasing in importance, and how pathologists execute this art.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Serdar Altınay",authors:[{id:"185324",title:"Associate Prof.",name:"Serdar",middleName:null,surname:"Altınay",slug:"serdar-altinay",fullName:"Serdar Altınay"}]},{id:"53873",title:"Primary Central Nervous System Lymphoma",slug:"primary-central-nervous-system-lymphoma-2017-03",totalDownloads:1716,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Although non-Hodgkin’s lymphoma (NHL) is a frequent cancer worldwide, primary central nervous system (CNS) lymphoma (PCNSL) is a rare presentation, with an incidence of less than 0.5 per 100,000 persons-years in the western world. In the vast majority of cases, it has the histology of a diffuse large B-cell lymphoma (DLBCL) and is a hardly curable disease with high relapse risk. Therapeutic options are limited by blood-brain barrier penetration of drugs and because of its low-incidence high-grade evidence from large studies is lacking, current management being based on reports on rather small cohorts. The current standard first-line treatment for PCNSL consists of high-dose methotrexate (HD-MTX) in combination with a variety of drugs and consolidation whole-brain radiotherapy, the latter being progressively replaced by chemotherapy. For patients relapsing after first-line treatment, intensive chemotherapy with autologous stem cell support is a feasible and relatively safe salvage therapy. In the present chapter, we briefly discuss primary central nervous system lymphoma management and review current therapeutic options and evidence-based recommendations. We discuss the role of whole-brain radiotherapy (WBRT) and new prospects to avoid this side effect-ridden approach. Also, we will look at new therapeutic approaches currently under investigation, including immunotherapy.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Mihnea Zdrenghea, Delia Dima, Ciprian Tomuleasa, Horia Bumbea\nand Cristina Bagacean",authors:[{id:"73222",title:"Dr.",name:"Delia",middleName:null,surname:"Dima",slug:"delia-dima",fullName:"Delia Dima"},{id:"193180",title:"Dr.",name:"Mihnea",middleName:null,surname:"Zdrenghea",slug:"mihnea-zdrenghea",fullName:"Mihnea Zdrenghea"},{id:"198423",title:"Dr.",name:"Cristina",middleName:null,surname:"Bagacean",slug:"cristina-bagacean",fullName:"Cristina Bagacean"}]},{id:"53003",title:"Managing CNS Tumors: The Nanomedicine Approach",slug:"managing-cns-tumors-the-nanomedicine-approach",totalDownloads:1189,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Albeit the rapidly evolving knowledge about tumor biochemistry enables various new drug molecules to be designed as treatments, malignant central nervous system (CNS) tumors remain untreatable due to the failure to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, drug delivery in CNS tumors must be properly addressed, as otherwise, novel therapies will continue to fail. In this regard, nanomedicine poses an appealing platform for efficient drug delivery to the CNS, since it may be targeted to improve the drug availability in the site of action, which would be translated into lower drug doses and fewer side effects. Hence, the accumulation of data about the CNS physiology and their relevant receptors, the widening therapeutic armamentarium of drugs potentially useful in CNS chemotherapy and the alternative routes for administration may envisage nanomedicines as a forthcoming routine approach. Indeed, on the basis of the promising results gathered from preclinical studies of nanomedicine-based therapy both systemically and locally administered, some nanomedicines have already been approved for clinical trials in a variety of CNS tumor conditions to serve as the first steps in the translation of nanotherapy to clinic. Their outcome will steer research directions for further improvements.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Juan Aparicio-Blanco and Ana-Isabel Torres-Suárez",authors:[{id:"193558",title:"Prof.",name:"Ana Isabel",middleName:null,surname:"Torres-Suárez",slug:"ana-isabel-torres-suarez",fullName:"Ana Isabel Torres-Suárez"},{id:"195630",title:"MSc.",name:"Juan",middleName:null,surname:"Aparicio-Blanco",slug:"juan-aparicio-blanco",fullName:"Juan Aparicio-Blanco"}]},{id:"54440",title:"NeuroPharmacology: As Applied to Designing New Chemotherapeutic Agents",slug:"neuropharmacology-as-applied-to-designing-new-chemotherapeutic-agents",totalDownloads:1248,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Neurooncology anticancer drugs are no exception—their distribution and tissue interactions follow the general rules of classical pharmacology. In an attempt to assist with the new therapeutic approaches to manage cancers involving the central nervous system, classical chemobiodynamic compartment and pharmacokinetic models are discussed and illustrated. In addition, strategies and approaches for penetrating the blood brain barrier (BBB) are reviewed and modeled. Finally, in support of classical pharmacology, a new anticancer agent in clinical trial for brain tumors is reviewed as an example of clinical onco-neuropharmacology.",book:{id:"5599",slug:"new-approaches-to-the-management-of-primary-and-secondary-cns-tumors",title:"New Approaches to the Management of Primary and Secondary CNS Tumors",fullTitle:"New Approaches to the Management of Primary and Secondary CNS Tumors"},signatures:"Andrew H. Rodgers and Lee Roy Morgan",authors:[{id:"158053",title:"Dr.",name:"Lee Roy",middleName:null,surname:"Morgan",slug:"lee-roy-morgan",fullName:"Lee Roy Morgan"},{id:"193557",title:"Ph.D.",name:"Andrew",middleName:null,surname:"Rodgers",slug:"andrew-rodgers",fullName:"Andrew Rodgers"}]}],onlineFirstChaptersFilter:{topicId:"1086",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. 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