Xenobiotic metabolizing enzymes genes regulate via AhR pathway.
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"3477",leadTitle:null,fullTitle:"Herbicides - Current Research and Case Studies in Use",title:"Herbicides",subtitle:"Current Research and Case Studies in Use",reviewType:"peer-reviewed",abstract:"Herbicide use is a common component of many weed management strategies in both agricultural and non-crop settings. However, herbicide use practices and recommendations are continuously updated and revised to provide control of ever-changing weed compositions and to preserve efficacy of current weed control options. Herbicides - Current Research and Case Studies in Use provides information about current trends in herbicide use and weed control in different land and aquatic settings as well as case studies in particular weed control situations.",isbn:null,printIsbn:"978-953-51-1112-2",pdfIsbn:"978-953-51-5378-8",doi:"10.5772/56743",price:159,priceEur:175,priceUsd:205,slug:"herbicides-current-research-and-case-studies-in-use",numberOfPages:664,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"793817029a616fa096c3ffb2d68d04ff",bookSignature:"Andrew J. Price and Jessica A. 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Dr. Price is a native of East Tennessee, USA, and has received both B.S. and M.S. degrees from the University of Tennessee majoring in plant and soil sciences and a Ph.D. from North Carolina State University majoring in crop science. Dr. Price’s primary responsibilities in the Conservation Systems Research Group are to conduct research addressing the impact of integrated weed management strategies on weed populations/competitiveness in conservation systems as well as to develop cost-effective and environmentally friendly weed management systems integrating conservation tillage, crop rotations, cover crops, and weed management systems.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"Agricultural Research Service",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"13748",title:"Prof.",name:"Jessica",middleName:null,surname:"Kelton",slug:"jessica-kelton",fullName:"Jessica Kelton",profilePictureURL:"https://mts.intechopen.com/storage/users/13748/images/5418_n.jpg",biography:"Jessica Kelton is a Research Associate with Auburn University at the Wiregrass Research and Extension Center in Headland, Alabama, U.S.A. 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Therefore, surgical removal of HCC is feasible only in 15–20% of cases and non-surgical modalities play a relatively important role in HCC management. There are several non-surgical methods; however, ablation therapy has become a mainstay in particular for early-stage HCC because of its superb local control capability and high safety profile [1].
Ablation modalities currently available include percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, laser ablation (LA), and irreversible electroporation.
PEI was one of the first effective ablative techniques to be widely adopted for the treatment of small HCC. Ethanol causes dehydration and subsequently necrosis [2]. As far as PEIs are concerned, the 5-year survival rates in patients with HCCs measuring less than 3 cm range from 47% to 65% and in a recent study of 685 Japanese patients, the 5-, 10-, and 20-year survival rates—49%, 18%, and 7.2%, respectively, were similar to those observed in patients with cirrhosis who did not have HCC [3]. PEI maintains the advantage of allowing the treatment of tumors near sensitive organs and tissues; however the applicability of PEI in larger HCC has been shown to produce incomplete necrosis mainly due to the heterogeneous consistency of these tumors [4]. Moreover, PEI is of little benefit in infiltrating HCC or in metastases.
Current limitations of PEI can be overcome with RFA. Radiofrequency current induces ionic agitation that in turn results in heating. The superiority of RFA to PEI in prolonging patient survival has been shown in a randomized controlled trial [5]. The 3-year survival rates were 48%–67% following PEI and 63%–81% following RFA. Moreover, Chen et al. performed a randomized control trial between RFA and hepatectomy in patients who had HCC ≤ 5 cm and found the same overall and recurrence-free survival between the two patient groups [6]. A major disadvantage of RFA is mainly the difficulty to target HCC located in “problem” areas of the liver, for instance tumors adjacent to blood vessels, settings in which the diffusion of heat is less advisable [7]. This phenomenon is also known as the heat-sink effect.
In the last two years, MWA has gained acceptance as a favorable alternative and in some cases a preferred choice of ablation alternative. In MWA, the mechanism of heat generation is based on rapid frictional movement of water molecules in high-frequency (900–2500 MHz) electromagnetic field. The tissue\'s polar molecules are forced to continuously realign with the oscillating electric field, increasing their kinetic energy, and hence the temperature of the tissue [8]. Unlike RFA, microwaves are capable of effectively heating and propagating through many types of tissue, even those with low electrical conductivity, high impedance, or low thermal conductivity. Moreover, they can readily penetrate through the charred or desiccated tissues that tend to build up around all hyperthermic ablation applicators, resulting in limited power delivery for non-microwave energy systems [9].
MWA has several theoretical advantages, including greater penetration of energy into tissues resulting in a larger area of ablation, higher intratumoral temperatures, faster ablation times, less susceptibility to the heat-sink effect, no need for grounding pads, and low sensitivity to local variation in tissue physiological properties [10]. In some studies, MWA has been compared with RFA for the treatment of HCCs of different sizes (< 3 cm and < 5 cm) and despite the theoretical advantages of MWA, no significant differences have been observed in either setting with regard to the completeness of tumor necrosis, disease recurrence, survival, or complication rates [11, 12].
Laser thermal ablation is another technique that has been associated with high rates of complete necrosis (an average of 95%) in HCCs measuring less than 3 cm [13]. Unfortunately, there are only a few centers that use this type of ablation and therefore the amount of data is limited. Moreover, it is based on sophisticated technology, requires much more substantial operator experience, and involves placement of multiple optical fibers within the neoplastic lesion according to a programmed spatial distribution scheme [14]. Although more expensive to set up and support than RF, LAs are a little more predictable.
To date, there are only a few studies comparing LA with RFA in hepatocellular carcinoma. In their randomized controlled prospective study, Ferrary et al. [15] treated 81 cirrhotic patients with 95 biopsy proven ≤ 4 cm HCCs comparing LA with RF ablation. Two matched groups were randomized to US-guided RF or LA under general anesthesia. The authors adopted multiple fiber techniques using 5 W per fiber delivering a maximum of 1800 J per fiber per single illumination. They reported no significant overall differences in survival rates between the two methods with cumulative rates of 91.8%, 59%, and 28.4% at 1, 3, and 5 years, respectively. However, they demonstrated a statistically significant higher survival rate for RF over LA for Child A patients (p=0.9966) and nodules ≤ 2.5 cm (p=0.01181). In a randomized prospective trial in a single center with three years of follow-up, the authors treated 140 patients with 157 biopsy-proven HCCs to compare LA and RFA (70 patients with 77 nodules and 70 patients with 80 nodules, respectively). Median follow-up in RFA and LA groups was 21 and 22.5 months, respectively. Complete response was observed in 97.2% and in 95.8% of RFA and LA group patients, respectively. Median time to tumor recurrence was 25.6 and 37.8 months in RFA and in LA groups, respectively (P = 0.129). Estimated probability of survival at 1, 2, and 3 years was 94%, 88%, and 66% in the RFA group and 94%, 81%, and 59% in the LA group, respectively (p = 0.693). No major complications or significant treatment-related morbidity were observed in both groups. The authors concluded that LA was non-inferior to RFA either in obtaining the complete ablation of HCC nodules or in the long-term outcome [16].
Another type of percutaneous tumor ablation is represented by cryoablation (CRYO). Percutaneous CRYO is a promising local ablation technique, which is believed to ablate cancer cells by several mechanisms including intracellular ice formation, solute-solvent shifts that cause cell dehydration and rupture, and small-vessel obliteration with resulting hypoxia. Perhaps, the main advantage of CRYO relative to RFA is its precise intraprocedural monitoring of iceball formation via various imaging techniques [17]. There are a few studies comparing CRYO with other types of tumor ablation techniques; however Wang C et al. report the results of a randomized, controlled multicenter trial comparing percutaneous CRYO and RFA in patients with cirrhosis, Child-Pugh class A or B liver function, and 1-2 HCC nodules measuring ≤ 4 cm. The primary endpoints were local tumor progression at 3 years and safety. As for the former, CRYO proved to be significantly superior to RFA in patients with larger tumors (i.e., those that were 3.1 to 4 cm in diameter). The two methods were not significantly different in terms of complication rates, which were less than 4% in both groups, or survival (overall and tumor-free) at 1, 3, and 5 years [18]. The superiority of CRYO over RFA in the larger tumors suggests that CRYO has the ability to necrotize larger volumes of tissue, hence increasing the chances of ablating microsatellite lesions that are always possible with lesions of this size.
Irreversible electroporation (IRE) is a new treatment method with certain advantages over the existing ablative techniques that have gained widespread attention. With IRE, cell death is induced with electric energy. Under image guidance electrodes are placed around the tumor and through multiple and short high-voltage electric pulses, the existing cell membrane potential is disturbed. As a consequence, nanoscale defects appear in the lipid bilayer of the cell membrane. Although IRE is believed to destroy all cells within the ablation zone effectively, the non-thermal nature of IRE results in relative preservation of the extracellular matrix. Hence, the structural integrity of vessels and bile ducts remain intact. Moreover, IRE is not affected by the heat-sink effect [19]. All these advantages suggest that IRE may be more suitable for the treatment of HCCs ineligible for surgical resections or thermal ablation because of unfavorable location.
Currently, there are no published clinical trials for the treatment of hepatic tumors using IRE. In a recent review, Scheffer J. et al. included 221 patients with 325 lesions in different organs: 227 hepatic tumors, 70 unresectable pancreatic adenocarcinoma, 17 renal tumors, 8 pulmonary tumors, 1 presacral tumor, and 2 lymph nodes. Most of the patients were treated by IRE owing to tumor proximity to bile ducts, bronchi, renal pelvis, presacral neural plexus or large vessels, making the tumor unsuitable for surgery or thermal ablation. They concluded that IRE is a safe procedure with a promising early efficacy on smaller hepatic tumors near vascular structures and portal triads, with reported ablation success reaching 90%, but rapidly decreasing with increasing tumor size [20].
Tremendous efforts have been made in the last decades to improve the currently available techniques. However, given that there is not a single method available that meets all the requirements of an ideal ablation system, based on what has been discussed above and on data from the vast literature available, we can reasonably draw some conclusions.
Firstly, all differences between the techniques in terms of results are modest. Secondly, one technique may be more difficult than another and more rapid than another. Thirdly, each technique has its own major advantages and disadvantages. Finally, the rate of recurrence is still high after tumor ablation despite the major advances in tumor ablation devices, optic fibers, and improved imaging guidance. A major limitation in its overall effectiveness is due to the difficulties of heating large tumors. Small regions of viable tumor may still remain even after apparently good tumor ablation. Moreover, simple heating techniques have trouble discriminating between tumors and surrounding healthy tissues leading to many side effects. In order to overcome these major limitations, numerous groups are investigating the use of different types of nanoparticles, including carbon nanotubes, gold nanoparticles, and magnetic nanoparticles, placed/ introduced within tumor tissues to facilitate localized heating.
A better understanding of the molecular mechanism of nanoparticle mediated tumor ablation is of great importance in order to improve the current available ablation techniques and also to increase the synergies between specific drugs and tumor ablation. There are several ways in which nanoparticles (NPs) alone can affect biological processes.
Several studies have shown that NPs can increase the production of reactive oxygen species (ROS). Cancer cells are generally deficient in antioxidative enzymes present in normal cells, making them more vulnerable to an oxidative assault. Iron oxide nanoparticles via direct uptake in cancer cells result in acutely elevated intracellular iron concentrations and subsequent ROS generation by Fenton reaction [21]. Moreover, silver nanoparticles have also been linked to ROS generation via a mechanism affecting calcium homeostasis. Silver ions can act on the same sites as calcium ions that could perturbate calcium influx in and out of the mitochondria. As a consequence, mitochondrial membrane damage results in ROS production, inhibition of ATP synthesis, and initiation of apoptotic signaling pathways [22].
From a biological and molecular point of view, NPs can affect different structures of the cancer cells. For instance, cellular uptake of NPs results in changes to the cytoskeleton and further affects many biological processes including cell spreading and adhesion, cell growth, viability, and ECM production [23]. Moreover, the accumulation of NPs in the cytoplasm may lead to physical interactions with the cytoskeleton, an increase in size and/or number of endosomes leading to the rearrangement of the cytoskeleton components in order to form new trafficking routes [24]. We consider that by altering the intracellular trafficking routes many other fundamental processes, including intracellular signaling pathways, different types of cross-talks with other cells and proliferation may also be affected. Furthermore, NPs can be engineered to accumulate preferentially in the nucleus of cancer cells. One study used gold nanoparticles (AuNPs) coated with polyethylene glycocol, bioconjugated with an arginine-gyicine-aspartic acid peptide and a nuclear localization signal peptide in order to transport the nanoparticles into the cancer cell nucleus. The results showed that nuclear targeting of AuNPs in cancer cells cause cytokinesis arrest, leading to the failure of complete cell division and thereby resulting in apoptosis [25].
In the past, cancer was considered an isolated self-sufficient ball of aberrant cells. However nowadays, tumors are viewed as “organs” composed of multiple and highly interactive cell types. Thus, the tumor is made up of primary cancer cells and of a court of stromal cells including mesenchymal derived cells, inflammatory cells, and vascular cells. Each of these cell types can be found in normal stroma, but in a tumorigenic setting, the cancer has appropriated, modified, and corrupted these cells to do its bidding [26]. NPs can also be used to target the tumor stroma changing the tumor microenvironment from its pro-tumorigenic state to an anti-tumorigenic state. One study demonstrated the ability of nanoparticles to target the tumor endothelium and improve the anti-tumoral efficacy of paclitaxel, both
Understanding how nanomaterials affect live cell function, controlling such effects, and using them in therapy (for example In tumor ablation), is now the most challenging aspects of nanobiotechnology. An ideal NP would be a multifunctional one, targeting both the tumor cells and tumor microenvironment with low toxicity, which is easy to engineer, and has low costs. However, there is still a long way and a great deal of research has to be performed in order to develop what we consider the ideal nanoparticle.
Near-infrared (NIR) laser light is ideal for
The efficacy of PTA can be significantly enhanced by using different types of nanoparticles that are applied to the target tissue to mediate selective photothermal effects. For instance, AuNPs including gold nanorods, gold nanocages, gold nanostars, and gold nanopopcorns with unique optical proprieties have been developed [30].
In order to treat a tumor, AuNPs are systemically administered to the subject and allowed to passively localize in the tumor. The tumor is then exposed to an excitation source such as the NIR laser light. The AuNPs absorb the incident energy and convert it into heat, which raises the temperature of the tissue and ablates the cancerous cells by disrupting the cell membrane [31]. AuNPs have unique optical-electronic proprieties as a result of surface plasmon resonances (SPRs). SPR is a phenomenon in which free electrons oscillate collectively at the interface of metal and surrounding medium in resonance with external electromagnetic fields [30].
Nanoparticles in the tissues produce heat strong enough for thermal ablation in both tumors and surrounding cells. Therefore, it is crucial to increase the intratumoral localization of the nanoparticles on the one hand and to protect the surrounding tissue on the other hand. Selective accumulation of AuNPs in the target tumor tissue can be achieved by surface conjugation of targeting agents, such as antibodies and peptides that can recognize specific cell types. For instance Liu et al. reported that gold nanoshells functionalized with the small peptide A54 can significantly increase the efficiency of cancer cell death in the NIR photothermal treatment due to the specific binding (targeting) between the A54-nanoshells and the liver cancer cells, BEL-7404 and BEL-7402 [32].
AuNP can also be functionalized to load various cargoes such as different types of anticancer drugs. As an example in this setting, You et al. investigated DOX-loaded hollow gold nanospheres (DOX@HAuNSs) and conjugated them with a peptide sequence that targets EPHB4, a tyrosine kinase receptor that is often overexpressed in many tumor cell membranes including HCC. NIR laser irradiation after treatment with targeted DOX@HAuNSs resulted in significantly suppressed tumor growth when compared with the control treatment with nontargeted DOX@HAuNSs or HAuNSs [33]. Moreover, another study conducted by the same authors, evaluated the triggered release of paclitaxel via NIR laser irradiation and its antitumor efficacy by hepatic arterial administration of HAuNS and paclitaxel loaded microspheres into rabbits with liver carcinoma in situ [34]. The results showed statistically significant increases in necrosis and apoptosis percentage in the MS-HAuNS-PTX-plus-NIR treatment group compared with the other two treatment groups.
A different approach in the field of NPs, mediated NIR thermal ablation has been developed in the last two years mainly due to the development of therenostic agents, which combine diagnostic and therapeutic modalities. This approach offers tremendous potential for the management of chronic liver injury or HCC. In a recent article, multifunctional nanoprobe based on Glypican-3 anti-body-mediated HCC-targeting Prussian blue nanoparticles (antiGPR-PBNPs) was developed as a novel theranostic agent for the targeted PTT and MR imaging of HCC treatments [35]. They concluded that antiGPC3-PBNPs could be used as a promising nanoprobe for further treating and early diagnosis of HCC.
A major limitation of nanoparticle-assisted drug delivery is represented by their uptake in the reticuloendothelial system leading to undesirable systemic toxicity and reduced efficacy. Hence many researchers have investigated the use of different cell types for drug delivery. Zhao J et al. in their study used adipose-derived mesenchymal cells (AD-MSCs) to deliver superparamagnetic iron oxide (SPIO)-loaded gold nanoparticles (SPIO@AuNP) into HCC tumors [36]. They demonstrated that AD-MSC is an effective carrier for the specific delivery of theranostic agents to liver injuries or HCC and SPIO@AuNP is a host-compatible cargo that enables both MRI enhancement and laser induced thermal ablation.
Besides the different types of gold nanoparticles described above, carbon nanotubes (CNT) also have the ability to efficiently convert NIR into heat. The role on CNT-mediated thermal therapy for the treatment of a wide variety of cancer types both
It is worth to mentioning that there is a massive amount of research in the field of nanoparticles-mediated PTA therapy. We only provided a few examples that we considered most suitable. Describing all the possible applications of nanoparticles mediated thermal therapy is beyond the purpose of this chapter.
Thermotherapy represents a physical treatment induced by hyperthermia. Nowadays, macroscopic thermotherapy (ablative methods: microwave or radiofrequency, optical laser irradiation via fibers, focused ultrasound) is widely used to destroy focal tumors. The mechanism of tumoral damage is the result of an irreparable destruction of molecular constituents of cells (mainly protein denaturation) that appears after an exposure of a few minutes at temperatures higher than 48°C. Even if it has lower side effects when compared to conventional therapy (chemo/radiotherapy) and although it has proved to be a reliable alternative to surgery, this therapy has several limits: the relative higher rate of incomplete destruction for tumors larger than 3 cm and a higher risk of destruction of the proximate healthy tissue. These deficiencies seem to disappear by using a new thermal method known as magnetic termic hyperthermia [38]. This approach uses an external alternating magnetic field applied to a target tumor where magnetic metallic particles (MNPs) have been infiltrated or injected. MNPs show distinguishing phenomena such as superparamagnetism, high field irreversibility, high saturation field, extra anisotropy contributions, or shifted loops after field cooling [39]. According to Reference [40], the distinguished phenomena noticed in MNPs are the result of the interaction between the intrinsic properties (size, distribution, and finite-size effects) and the interparticle interactions. The MNPs have the ability to absorb the energy of the alternating magnetic field energy and transform it into heat. Two factors are implicated in producing hyperthermia, the size of the magnetic material and the strength of the applied magnetic field. Larger implants (seeds) generate heat by resistance to circumferential eddy currents induced on the surface of the seeds by an alternative magnetic field [41]. Multidomain particles produce heat by hysteresis loss effects. On the contrary, nanoparticle, particularly subdomain particle, suspensions generate heat mainly by Brownian relaxation (heat is the result of friction arising from the total particle oscillations) and Neel relaxation (heat is the result of friction arising from the rotation of the magnetic moment with each field oscillation) [42, 43].
Superparamagnetic particles are particles that have sufficient high thermal motion after the magnetic field is removed, which can be randomly reoriented so as not to leave a residual magnetization [43].
Due to their properties, these particles may have several applications in clinical practice such as hyperthermia (HT), drug delivery and diagnosis (s.a nuclear magnetic resonance imaging).
HT represents a therapeutic procedure used to destroy a tumoral tissue at temperatures over 43°C [38]. It has been observed that tumoral cells have an increased thermal sensitivity in comparison to healthy cells; this feature is the result of an increased metabolism [44, 45]. Apoptosis is the result of cytotoxic effects that depend on physiological cell parameters (hypoxia or acidity) at temperatures over 43°C. 43°C is the temperature limit over which the expression of HSPs is stimulated, which leads to antitumor immunity and apoptosis [46]. The antitumor immunity increases as a result of an enhanced presentation of tumoral antigenic peptide to a major histocompatibility complex (MHC). HSP70 expression reaches its maximum 24 h after heating. The increased MHC class I surface expression is slower, so it starts 24 h after applied hyperthermia and the peak is after 48 h [38]. Two mechanisms have been suggested. One of the possible mechanisms is that the heat induces the enhancement of antigenic peptide presentation through MHC class I antigens of tumor cells. Another possible mechanism is the cross-presentation of antigenic peptides by dedicated antigen-presenting cells (APCs) [46].
The advantage of magnetic hyperthermia is that it restricts the heating to the tumoral area, which presents both grand opportunities and challenges for the non-invasive treatment of tumors. Therefore, by combining this characteristic of the tumoral tissue with the MNPs property, it is obvious that the administration of MNPs (with the purpose of delivering toxic amounts of thermal energy to the tumoral tissue) will produce a more effective destruction of the tumoral tissue.
For clinical practice, MNPs must meet several criteria: they must be small enough to remain in the circulation after injection and pass through the capillary; they must not be an embolic agent; they must be non-toxic and non-immunogenic; they must maintain the initial structure; and they must be biodegradable. Another important property of these particles is to be highly magnetized in order for their movement to be controlled with a magnetic field so that they can be immobilized near the targeted tumoral area [47]. The most important factors, which determine the biocompatibility and toxicity of these materials, are the nature of the magnetically responsive component, the final size of the particles, their core, and their coatings [39]. The most utilized MNPs are magnetite (Fe3O4) or its oxidized form, maghemite (γ-Fe2O3). Magnetite is easier to obtain than maghemite; therefore, most of the studies utilized magnetite [38]. In order to avoid the constitution of large aggregates, the modification from the original form and biodegradation, the MNPs are coated with a biocompatible polymer during or after the synthesis [39]. The particles’ size influence the stability, tissular diffusion, effective surface areas (easier attachment of ligands), and the power of absorption at tolerable altering current magnetic fields. Therefore, only subdomain magnetic particles (nanometer-sized), especially particles smaller than 100 nm (so-called nanoparticles), can be utilized [48, 49]. Also, it is important to highlight that the heating potential is dependent on particle size and shape, and thus the use of uniform particles is essential for a rigorous control in temperature [39]. Therefore, the magnetic particles used may modify the energy, absorption rate, mode of energy deposition, application, and focusing. For this technique, the sizes of the particles are as follows: seeds (rods of several millimeter size), multidomain particles (1–300 mm), nanoparticles (1–100 nm), and subdomain particles (below 20 nm) [41].
Gilchrist was the first author that showed promising results obtained after selective heating that followed the direct injection of a suspension of magnetic particles into draining lymph nodes from colon cancer [50]. In 2001, Moroz showed that hepatic arterial infusion of lipiodol containing ferromagnetic particles could result in an excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field [51]. The following years, encouraged by the results of the use of MNPs in animal studies (on mouse mammary carcinoma, glioblastoma, and prostate cancer), some authors focused on the improvement of HT techniques for clinical applications [52–56]. For in vivo delivery, the authors used thermosensitive liposomes, direct injection into the tumor, or the intravenous route.
An important progress has been made in improving the quality of the MNPs; therefore, for construction, high temperature crystallization or different coatings were used, such as dextran, polyethylene glycol (PEG), dopamine, silanes and gold [43].
Several authors introduced MNPs either in the core or in between the lipid bilayer of thermosensitive liposomes and, on alternating magnetic field AMF heating, the encapsulated drugs were released [43]. Shinkai utilized liposomes where he introduced magnetite nanoparticles (with a diameter of 10 nm). After administration, these nanoparticles increased the temperature of the tissue [57]. In another study, Ito injected magnetite cationic liposomes (MCLs) into the tumor tissue. They heated the tissue above 43°C and obtained a complete regression of mammary carcinomas in all mice [58]. Also, Jimbow [52] developed a particle with N-propionylcysteaminylphenol (NPrCAP) conjugated onto the surface of magnetite nanoparticles (NPrCAP/M). The result was the inhibition of melanoma cells growth as a result of the production of cytotoxic free radicals. In another study, a thermosensitive polymer was layered onto MNPs covalently coupled to doxorubicin with an acid-labile hydrazine bond that showed release on heating with AMF and a pH of 5.3 (the pH of endosomes) [59]. The authors combined via emulsification MNPs with a polyvinyl alcohol polymer and encapsulated hydrophobic/ hydrophilic drugs. The drugs were released after the heating with an alternative magnetic field [60].
Direct intratumoral injection was used in the first MNP HT clinical trial treating a patient with a recurrent prostatic tumor [61]. Through the use of transrectal ultrasound and fluoroscopy guidance, the authors performed a transperineal injection of the MNPs into the prostate. After the administration of MNPs, the particles were selectively heated in an externally applied alternative magnetic field. The conclusions of these trials were encouraging. Due to the low clearance of MNPs from tumors, serial heat treatments were possible after a single magnetic fluid injection. Another positive aspect was the fact that a low magnetic field was used to produce the necessary temperatures. Furthermore, this treatment does not cause discomfort or serious side effects. In these studies, the CT exam had an accuracy rate of 85% in evaluating the treatment-related parameters. The same good results were obtained later in human glioma trials [62, 63].
In 2008, Takamatsu et al. combined the intra-arterial selective HT with the transcatheter arterial embolization technique in a rabbit model for renal carcinoma [64]. For injection, they utilized a mixture of commercially available nano-sized magnetic particles (Ferucarbotran) and lipiodol as embolic material. The mixture was injected into the renal artery under fluoroscopic guidance. The intratumoral temperatures of 45ºC were obtained after the area was exposed to an external alternating-current magnetic field. Even the result was not spectacular (the treated tumor was hypovascular) the authors speculated that this method can be used only in hypervascular tumors. In another study, Huang HS injected IV MNPs (1.9 mg Fe/g tumor) in a subcutaneous squamous cell carcinoma mouse model. After the injection, they applied a field of 38 kA/m at 980 kHz; therefore, the tumors could be heated to 60°C in 2 min. The results were encouraging, showing an ablating with millimeter (mm) precision and a surrounding tissue intact [43].
Intravenous administration has several advantages compared to sowing such as: it assures a more precise cover even for an irregular tumor and small tumors; it can be used for the treatment of metastasis (after one injection more than one tumor can be treated simultaneously); the distribution is more overall (rather than the dotted distribution from sowing); and it is minimally invasive [43, 48].
The evaluation of the iron concentrations can be mapped with high accuracy by MRI, computed tomography or magnetorelaxometry [43, 65, 66].
The science of MNPs is still in its early stages. The recent results of magnetic HT in cancer therapy are very encouraging; but it is necessary to traverse the experimental stages into clinical practice to see the real applicability of this new technique.
Standard RFA is an invasive procedure that requires the insertion of electrodes within the tumor. Tumor destruction occurs as a result of vibrations of ions within tumor tissue induced by radio waves, which give rise to friction and lethal heat. Although it is possible to achieve local control in liver tumors < 2.5 cm, in larger lesions local tumor recurrence is common [67, 68].
Initially, in order to increase the efficacy of RFA, the ablation guidance methods were improved (contrast-enhanced ultrasound, fusion imaging, etc.), but this led only to a slight efficacy improvement. Because of the changes that occur after RFA (increased vascular and cellular membrane permeability), the periphery of the tumor becomes more susceptible to chemotherapy. Thus, the combination of thermal ablation and chemotherapy seemed to lead to promising results. The results of these methods did increase the efficacy of RFA, but it was not enough. Therefore, new treatments that will augment cytotoxicity at the margin of the ablation zone have been developed.
The efficiency of RFA can be significantly enhanced by administration of special thermal absorbing agents such as NPs, which are targeted into a tumor area (actively or passively) with the purpose to release locally the retained heat and thus enhance tumoral destruction.
The NPs in free form or those containing various anti-cancer agents may be administrated before, at the time, or after RFA [68, 69]. Administering CYT-6091, a TNF-labeled NP, 4 h prior to RFA yielded a significantly larger zone of central necrosis and a 23% increase in ablation volume in comparison to RFA alone [69]. Using this NP enhanced ablation, the partially ablated tissue at the periphery was replaced by completely ablated tissue [69].
The administration of NPs containing free doxorubicine at the time of RFA or after leads to an increased diameter of coagulated tumor tissue (and increased concentration of doxorubicine in the ablated tumor) [68]. The NPs accumulate in the region of ablation both in the treated tumor (as result of an increased leakage) and in the peripheral region with thermal induced inflammation. This is known as the enhanced permeability and retention (EPR) effect [70].
The liposomes were the first NPs that have been utilized in combination with RFA. The studies of Ahmed and Goldberg demonstrated that the use of lipid NPs as carriers of a drug combined with ARF was associated with an increased accumulation of doxorubicin in the tumor, while non-encapsulated free doxorubicin did not have increased tumor uptake following RFA [71]. Since then, an important number of investigators improved the lipid layer of liposomes that has contributed to enhanced tumor damage secondary to formation of lipid hydro-peroxide leading to enhanced oxidative stress. Also, the investigators demonstrated that NPs size could influence the intratumoral drug accumulation and tissue coagulation [68].
As a negative relationship between the frequency of the waves and the depth of penetration exists, radio waves may be used as an alternative to heat tumors that are deeply located. The heating rate of a certain tissue is described by the formula HR = SAR/69.77 CH where SAR is the specific absorption rate and CH the specific heat capacity of the tissue (kcal/kg °C). As SAR (W/kg) depends on the dielectric conductivity of the tissue, an enhanced conductivity provided by AuNPs or carbon nanotubes may increase the heat delivered to the tissue [72].
These low-frequency electromagnetic waves have the advantage to penetrate human tissues and pass through the entire body with minimal perturbations until the RF fields interact with metal. The metal particles absorb RF energy and release heat to the adjacent region. Several reports suggested that tumoral hyperthermia may be improved through the use of targeted nanomaterials, which produce an intracellular hyperthermia and act as RF-thermal transducers, leaving the surrounding healthy tissue intact [68].
The delivery of RF generated heat in deep structures may be achieved either by RF needle inserted into the tumor (standard RFA) or by an external device that generates an RF field [68, 72].
If standard RF ablation produces a hyperthermic region of 2–4 cm diameter around the probe\'s tip, the nanoparticle-mediated RF field induces a hyperthermic area of approximately 100 μm. The heating mechanism of NPs in an RF field is a complex phenomenon that is still under debate [73]. Most of the RF field devices produce shortwave RF fields (13.56 MHz), allowing them to be used in the medical field. Several reports have shown that Joule heating of the background ionic suspension where the NPs are suspended can be the main source of RF heat production [74]. A relative high variety of NPs as AuNPs, carbon nanotubes (SWNTs), quantum dots (cadmium-selenide and indium-gallium-phosphide), silicon nanoparticles (Si NPs), and La0.7Sr0.3MnO3 (Dex-LSMO) have been associated with RF field [74, 75]. The use of NPs seems to improve the standard RFA by increasing the specificity of tumor destructions and affording a relative target therapy. Between these NPs are several differences, such as the SWNTs are heated faster than AuNPs unlike quantum dots that are heated in a similar manner to AuNPs [73].
SWNTs showed that they can be activated from a distance by RF field to produce thermal cytotoxicity [75]. The SWNTs have been injected in Vx2 tumors and induced the necrosis of all tumors within 5 min of RF field exposure. Regions of necrosis were identified with 2–5 mm borders. It is important to highlight that SWNTs alone or RF field exposure alone did not induce any measurable tumor necrosis or liver injury. In another study, the authors demonstrated that SWNTs injected into malignant cells may allow noninvasive RF field treatments to produce lethal thermal injury to the malignant cells. In a similar study conducted by Raoof, Hep3B and HepG2 cells were injected to kentera modified SWNT and were exposed to an 800 W RF field. Significant thermal cytotoxicity was demonstrated with 2 min of RF exposure in a concentration-dependent manner [75]. Also the group conducted by Cardinal obtained similar results after they exposed a rat model (with HepG2 cells) into an RFA field following the administration of AuNPs [76]. In a study conducted by Glazer ES, AuNPs utilized cetuximab-conjugated AuNPs in nonionizing RF radiation to investigate human pancreatic xenograft destruction in a murine model [73]. The result showed an increased apoptosis with decreased viability of tumoral cells after treatment with cetuximab-conjugated AuNPs and RF field exposure. Another important observation was the lack of injury to other organs.
It becomes a reality the fact that nanotechnologies will play a major role in new antitumoral therapies. In the last years, the thermal approach using nanoparticles, nanoemulsion, pH responsive nanoparticles, nanoparticles combined with radiation, and nanovectors for drug delivery have been the most evaluated nanoparticle-based cancer treatment methods. The ability of SWNTs to convert NIR laser radiation into heat, due to the photon–phonon and electron interactions, provides the opportunity to create a new generation of immunoconjugates for cancer phototherapy. In 2011, Iancu et al. demonstrated that the HepG2 cells treated with multi-walled carbon nanotubes (HSA–MWCNTs) following laser irradiation had a higher necrotic rate compared with normal cells [77].
Discovered in 1964 by Alec Bangham, liposomes are self-assembling, biocompatible, biodegradable, and nonimmunogenic nanovesicles consisting of a lipid bilayer enclosing an aqueous phase [78]. The features of liposomes allow for a wide range of drug delivery; consequently, hydrophilic drugs can be trapped in the liposome’s aqueous compartments while the lipid bilayer can be utilized to incorporate hydrophobic drugs. Due to the discontinuous endothelial lining and the lack of efficient lymphatic drainage of the tumor, the extravasations of liposomes into the interstitial space is increased and the liposomes can accumulate in the tumoral tissue; therefore, they will function as a sustained drug-release formula [79]. Immordino mentioned for the first time this process and named it as EPR effect [80]. Moreover, the combination (liposome–chemotherapy) changes drug pharmacokinetic properties and minimizes its systemic toxicity. Furthermore, the drug prevents the entrapped drug from premature inactivation in the circulation. The main issue of liposomes is that they are rapidly phagocytized by the mononuclear phagocyte (MP) and removed from the blood circulation after intravenous injection. To avoid this inconvenience, the authors developed a grafting poly-(ethylene glycol) (PEG) or oligoglycerol-moieties on the surface of the liposomal carrier. By reducing MP system uptake [80], long-circulating PEGylated liposomes can passively accumulate into solid tumors undergoing angiogenesis. Another improvement was the incorporation of additional lipid compounds that further enhance membrane permeability at the phase transition temperature of the lipid membrane (lysolipid or oligoglycerol-polyglycol) [79, 81–84]. The result was a long blood circulation time
The main limit of this type of therapy remains the intimate relation between the biodisponibility of liposomes and the vascular permeability. It is important to underline that vascular permeability between different tumor types and even within tumors can be highly variable, resulting in unpredictable liposome extravasation into the tumor tissue [85, 86]. Due to the combination of sub-optimal drug release kinetics and unpredictable vascular permeability, only modest results in the therapeutic index of chemotherapy have been obtained using liposomes for target drug delivery [87].
An important progress in the use of liposomes was the invention of small, 100 nm-long circulating liposomes that have a long blood-residence time as their main characteristic. These favorable circulation properties resulted in an enhanced accumulation of liposomal drugs in the tumor area.
To date, several liposomal products have been approved for clinical use: liposomes with doxorubicin (Doxil/Caelyx, Myocet, and Lipo-Dox) for treatment of Kaposi’s sarcoma, ovarian cancer, breast cancer, and multiple myeloma; liposomes with daunorubicin (DaunoXome) for treatment of Kaposi’s sarcoma; and liposomes encapsulating vincristine (Marqibo) for acute lymphoblastic leukemia [88].
Hyperthermia represents the heating of tumors to temperatures of up to 43°C. The main effect consists of an increased tissue perfusion, oxygenation and blood flow velocity, and microvessel permeability contributing to increased antibodies, drug, or nanoparticles levels in tumors at clinically tolerated temperatures [89–92]. Nowadays, hyperthermia for triggering TSLs is applied locally and in a noninvasive way from an external source to a targeted area using focused ultrasound technology (FUS) and high-intensity focused ultrasound (HIFU), or invasively using ARF or MWA [93, 94]. For superficial tumors, the authors used regional HT and external antennas or applicators that emit microwaves or radio waves. Localized HT is used to destroy deeply located tumors. The antennas (microwave antennas, radiofrequency electrodes) are inserted directly within the tumor. The major limit of this heating method is the tumor diameter (less than 5 cm). Focused ultrasound is used to heat small lesions (mm). In a recent study Dromi et al. combined LTSLs with hyperthermia from FUS [95]. They obtained an increased drug discharge at the tumoral area and the most important tumor had a delayed growth.
The newest heating method is magnetic resonance guided focused ultrasound technology (MRgFUS). These combinations allow simultaneous treatments, imaging to guide the treatment and MR thermometry to noninvasively monitor temperature changes and assure feedback in real-time [87]. In two recent studies, the authors used MRgFUS and drug-loaded liposome in rat [96] and rabbit [97] models. The results showed that the combination MRgFUS with drug loaded liposome assured the greatest uptake of the drug when compared to controls (liposome only and/or free drug). Several studies have analyzed the combination of RFA and the non-thermally sensitive liposomal doxorubicin, showing larger ablation zones compared with RFA alone, both at the preclinical and clinical levels. The suggested mechanisms for the synergistic effect of liposomal doxorubicine and RFA are as follows: increased markers of DNA breakage, oxidative stress and apoptosis, increased heat-shock protein 70 in the areas surrounding the ablation zone after combination treatment [98, 99]. In addition, Ahmed and colleagues observed that after combining RFA with Doxil, the intratumoral drug uptake increased, while the dose of doxorubicin necessary for tumor destruction decreased [100].
In order to optimize the effects of liposomes, the use of TSLs that trigger the release of the drug at the edge of the heated zone was suggested [101–103]. These TSLs contain thermosensitive lipids in their bilayer, undergoing a gel-to-liquid phase transition at the desired temperature (usually between 41°C and 43°C), after which the drug enters tumor cells in free form. This conversion is the consequence of a conformational change in the alkyl chains of the lipids, which leads to an increase in the volume occupied by the hydrocarbon chains in the membrane and thus an increase in the permeability of the lipid bilayer [79]. Common TSLs have been composed from 1, 2-dipalimitoyl-sn -glycero-3-phosphocholine (DPPC) as the primary lipid, because its phase transition temperature (Tm) occurs at 41.5°C.
In 2009, TSLs containing Dox known as ThermoDox®, became the first heat-triggered release formula of the anthracycline doxorubicin that reached pharmaceutical development (Celsion Corporation, Columbia, Maryland, USA) and clinical application [104–105]. Thermodox® is composed of DPPC:MSPC:DSPE-PEG2000 (86:10:4 molar ratio) and in combination with mild was used in the Phase III clinical trial to treat hepatocellular carcinoma and the Phase II trial in combination with local mild for patients with recurrent breast cancer of the chest wall and colorectal liver. After intravenous administration, Thermodox® concentrates in the liver where it rapidly permeates HCC lesions and their vasculature. Regarding safety and tolerability, in Phase I ThermoDox® was associated with low side effects and the maximum tolerated dose was established at 50 mg/m2. According to the Phase I trial, RFA and ThermoDox® may be used as a front-line therapy for HCC > 3 cm [106]. Unfortunately, in 2013 Celsion Corp. was unable to demonstrate the effectiveness of ThermoDox® in the improvement of free survival [79]. It seemed that the temperature of drug release is different between
Fine tunings in drug release kinetics of LTSLs was demanded to assure an improved dug release [109]. In 2014, Chen J evaluated [79] high temperature triggered TSLs (HTSLs) composed of DPPC and hydrogenated soy phosphatidylcholine (HSPC). For these types of liposomes, the theoretical temperature of discharge of HTSLs was set at 44°C; thus, the body temperature had less influence on the drug release from the vesicles. The result of this study was encouraging. Compared to conventional LTSLs, the new formula of HTSLs was associated with higher stability and less content discharge to the heated tumor area.
Several authors recommended the attaching of targeting ligands to the nanoparticles to assure a more specific localization and retention of the liposomal drug in tumors. Another reason to utilize these ligands is the capacity of promoting active cellular uptake of the drug-containing nanoparticles through binding to targeted internalizing receptors [110-112].
The cationic TSLs, called CTSLs (cationic thermosensitive liposome) is a new class of LTSL that contains a cationic lipid in its membrane. The CTSLs are absorbed by vascular endothelium and tumor cells; afterwards, they release their contents upon applying a temperature trigger [113]. It seems that, once accumulated, rapid drug release by intracellular cationic liposomes may achieve high intracellular concentrations of drug, thereby maximizing damage to both the endothelial cell and tumor cell compartments [113]. To evaluate tumoral accumulation of liposomes, radionuclides and nuclear imaging may be used. Even if the authors have obtained good results, in the future these types of treatment will have to demonstrate their therapeutic potential in clinical practice.
As we have already seen, there are several types of thermal-based therapies that have shown modest efficacy in HCC treatment. Unfortunately, simple heating techniques have trouble discriminating between tumors and surrounding healthy tissues. Moreover, the use of thermal therapies in large HCC is of limited value. In order to overcome these limitations many groups have investigated the use of NPs to increase the tumor ablation zone.
There are many types of NPs, each type with its own major advantages and disadvantages. Based on currently available literature, we could not say which of the above-described NPs is better for the long-term management of HCC. Unfortunately, there are no studies comparing AuNPs with carbon nanoparticles or magnetic nanoparticle. The use of NPs such as AuNPs, carbon nanoparticles, and magnetic nanoparticles have shown great promise as light absorbers for cancer therapy, demonstrating an ability to destroy cancerous lesions both in vivo and in vitro [31].
We believe that an ideal NP should be a good light absorber in order to achieve complete ablation of the tumor tissues. To avoid systemic toxicity, the NPs should show selective accumulation in target tissue with minimal nonspecific distribution. Not at least, they should be rapidly cleared from the body after their mission to prevent redistribution into off-target sites [38].
Future research should focus on the development of multifunctional NP. For instance, theranostic agents could improve both the diagnostic accuracy and therapy of HCC. Small HCC means better outcomes. The majority of NPs are functionalized to target the tumor cells, leaving the tumor stroma unaffected. A pro-tumorigenic stroma or better said a pro-tumorigenic microenvironment could lead to tumor recurrence, therefore dual targeting of both tumor cells and tumor stroma could overcome these limitations.
Specific targeting in HCC is still a major problem. There are many molecular pathways involved in HCC development. Moreover, not all HCC express the same receptors on the cell surface. In order to specifically deliver NP in the tumor area, immunohistological staining must be performed. This is hard to perform, particularly in HCC, since liver biopsy is no longer recommended for HCC diagnosis. Maybe it is time to go back where we started and reconsider the role of liver biopsy in HCC management.
In the last 50 years, despite tremendous advances in our knowledge of the molecular mechanism of cancer, there has been no change in the age-adjusted mortality from cancer [39]. This data clearly suggests that what we are doing now is wrong and an individualized treatment could bring new hopes for HCC patients.
This material was financed by the partnership program in priority areas – PN II, implemented with support from the National Authority of Scientific Research (ANCS), CNDI – UEFISCDI, project nr. 2011-3.1-0252 (NANO- ABLATION).
Six decades ago, researchers made extensive studies to answer a puzzling question. That was how administrating exogenous substances such as polycyclic aromatic hydrocarbons (PAHs) had a potent induction on xenobiotic-metabolizing enzymes in rats’ livers [1, 2]. It was finally Alan Poland and his colleagues who finally answered this question in the early 1970s. Poland discovered a novel hepatic protein in complex with the polycyclic aromatic hydrocarbons compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [2]. The new protein was bound to TCDD in a potent affinity and was isolated from hepatic cytosolic fractions of mice C57BL/6, a mice model strain for studying aromatic hydrocarbon responsiveness. This protein was later termed as the aryl hydrocarbon receptor (AhR) [2] and was identified as a ligand-activated transcription factor.
Later studies showed that AhR is expressed in several tissues including but not limited to; liver, lung, placenta, and heart and different cell types throughout the developmental periods of organ growth [3]. Further knockout studies in mice revealed essential functions for AhR in multiple physiological and pathophysiological pathways [4, 5, 6]. This accumulated knowledge over the last decades defined AhR as an environmental sensor for air pollutants and as a ligand-activated transcriptional factor, which regulates the expression of various genes, including enzymes responsible for xenobiotic metabolism [7].
AhR-mediates the toxicity of uncountable xenobiotics, and their triggered toxicity is accompanied by an overexpression and overactivation of AhR in cells. Thus, it increases the pathophysiological functions of AhR and could develop cancer in different organs such as the breast and liver. In addition, it can also lead to cardiovascular diseases, among other diseases [8, 9]. Thus, targeting AhR with a small molecule agonist/antagonist could efficiently inhibit several of the important hallmarks of various cancers [10].
Computational modeling and computer simulations continue to be an important tool for studying various biological mechanisms and for analyzing the interactions between biomolecular entities (
AhR is a member of the basic helix–loop–helix (bHLH)-PER- ARNT-SIM (PAS) family of transcription factors. The “PAS” term is an abbreviation for three proteins, namely, the Drosophila circadian rhythm protein period (Per), the mammalian AhR nuclear translocator (ARNT), and Drosophila neurogenic protein single-minded (Sim) [7, 14, 15]. Human AhR is a 848 amino acid with a molecular weight of ~96 kDa [16]. It includes two PAS domains, namely PAS A and PAS B, and interacts with the Aryl hydrocarbon nuclear tranlocator (ARNT) protein. Moreover, the PAS B domain involves two interactions sites: a ligand-binding site in which a bound ligand can modulate the AhR activity; and a direct binding interface for the HSP 90-chaperone protein. Additionally, AhR includes a basic helix loop helix motif located near its N-terminal domain, which is responsible for DNA binding as well as contributing to other protein–protein interactions. Finally, the transactivation (
AhR domain structure and sub-domains’ functions.
The AhR PAS B domain can interact with both exogenous and endogenous chemicals from various origins. These interactions can induce different effects on AhR activity, leading to a wide range of physiological and toxicological downstream consequences. For example, several studies showed that environmental pollutants have been associated with developing cardiovascular diseases, cancer, and other diseases through AhR modulation [7, 17, 18]. Exogenous AhR ligands include various aromatic hydrocarbon molecules such as dioxins. One can be exposed to such ligands through contaminated food or environmental pollutants. Following exposure, their interaction with AhR can lead to several toxic effects, including organ dysfunctions, immunotoxicity, and carcinogenicity. On the other hand, endogenous AhR ligands are usually metabolic derivatives derived from cellular processes such as 6-Formylindolo (3,2- b) carbazole (FICZ). The interaction of these ligands with AhR is part of a normal functional response through AhR modulation [7, 19, 20].
AhR is an essential protein that contributes to countless biological pathways to establish its physiological role in developing the immune system and regulating xenobiotic enzymes [7, 15, 21]. AhR knockout mice models showed abnormal female reproductive functions and impairment in managing blood pressure [7]. The overactivation and constitutive activation of AhR have been associated with the initiation, promotion, progression, and invasion of cancer cells. For example, activating AhR by exogenous AhR ligands can have several effects, which includes inducing cell proliferation in the G1-S phase, silencing tumor suppressor genes, and activating proto-oncogenes in cancer cell lines.
Earlier findings showed that the exogenous AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD promoted the degradation of cell–cell adhesion and expansion of cancer cells’ motility by separating the Src kinase from the AhR protein complex. Furthermore, the activation of AhR via environmental pollutants can lead to a significant induction of xenobiotic-metabolizing enzymes, including CYP1A, which produces reactive intermediate metabolites and reactive oxygen species to promote tumor growth [14, 22]. In a nutshell, AhR resembles a machinery of genes, which controls xenobiotic-metabolizing enzymes in phases I and II, as shown in Table 1. Also, known AhR agonists such as TCDD and β -naphthoflavone have been shown to induce cellular hypertrophic actions on H9c2 cardiomyoblast cells. This was correlated with an increase in the levels of numerous cytochrome P450 genes, which could overcome by using an AhR antagonist [31].
Metabolism phase | Gene | Reference |
---|---|---|
Phase I | CYP1A1 | [23] |
Phase I | CYP1A2 | [24] |
Phase I | CYP1B1 | [25] |
Phase I | CYP2S1 | [26] |
Phase II | NQO1 NAD(P)H: Quinine oxidoreductase 1 | [27] |
Phase II | GSTA1 Glutathione transferase A1/2 | [28] |
Phase II | UGT1A6 Uridine diphosphate glucuronosyltransferase 1A6 | [29] |
Phase II | ALDH3A1 Aldehyde dehydrogenase 3A1 | [30] |
Xenobiotic metabolizing enzymes genes regulate via AhR pathway.
On the positive side, experiments on a mouse model of induced colitis showed that the endogenous AhR agonist (FICZ), which has a strong binding affinity towards AhR, could block IL-6 and claudin-2 expression, and prevent any induced disorders in the intestinal barrier function through AhR activation [32]. Further protein knockout studies showed that AhR ligands play a fundamental role in autoimmune diseases through regulating Tregs and TH17 cell differentiation in the immune system. For example, FICZ inhibited Treg and TH17 cell development, accelerating experimental autoimmune encephalomyelitis in mice models [21, 33].
AhR is generally expressed in its inactive form in the cytoplasm as part of a protein complex encompassing a dimer heat shock protein, co-chaperone p23, an AhR-interacting protein, called AIP, and the protein kinase SRC (see Figure 2). The PAS B domain within AhR binds to one monomer of the HSP90 dimer and the second HSP90 monomer interacts with the AhR basic helix–loop–helix domain (bHLH) as well as with the PAS A domain [34]. As shown in Figure 2, the bHLH domain within AhR is also crucial for DNA binding in a process initiated by the binding of an AhR ligand within the PAS B domain and its interaction with the co-chaperone P23. Binding to P23 stabilizes AhR in the cytoplasm, protecting it from proteasomal degrading, and also maintains the PAS B domain of AhR in a unique conformation, suitable for strong ligand binding [35, 36].
Canonical pathway of aryl hydrocarbon receptor.
Once an AhR ligand binds to the PAS B domain, it forms an AhR-ligand complex, including p23, SRC, and AIP (see Figure 2). This complex is transformed into an active state and then translocated inside the nucleus. Then in the nucleus, all complex components dissociate from the AhR-ligand complex, excluding an agonist and AhR protein. Subsequently, AhR forms an active heterodimer with ARNT and creates an AhR–ARNT complex. This complex is then recruited to the DNA via the Dioxin response element (DRE), exhibiting a common DNA compromise motif (5′-TNGCGTG-3). This canonical AhR pathway increases the expression of various genes, including the principal ones in xenobiotic metabolism, AhR repressor (AHRR), and other genes [36].
Resolving the full-length three-dimensional structure of AhR has been a challenging exercise for the last two decades. Unfortunately, despite the many efforts towards this goal, there is no complete structure for the whole AhR protein. However, as discussed below, there are a few structures, which describe the number AhR domains. Although these structures do not reveal the exact overall AhR architecture, they can still provide useful information on the function of these separate domains. Giving computational modeling a favorable vantage point to construct reliable hypotheses for the full-length AhR organization for rational drug development and drug screening campaigns.
The first AHR 3D structure was reported in 2013 for the mouse PAS A domain (residues 110 to 267) at a resolution of 2.55 Å (PDB ID: 4M4X) (see Figure 3). This X-ray diffraction-based PAS A homodimer structure was obtained from recombinant
The upper figure represents crystal structure of homodimer mouse AhR-PAS a obtained from protein databank [
Two more additional AhR structures were revealed in 2017 (see Figure 4). The two structures comprise multiple AhR domains and show a clear interaction between AhR and its dimerization partner, ARNT, as well as its interaction with two DNA strands. The two structures (PDB IDs: 5V0L and 5NJ8) [39, 40] were resolved at a resolution of 4.0 and 3.35 Å, respectively and revealed the complex formation among the bHLH and PAS A domains from human AhR and their interactions with ARNT and DNA. However, due to the observed high flexibility of the AhR PAS B domain and the transactive domain (C- terminal), none of these two subdomains were included in this architecture. However, both structures clearly explain the protein–protein interactions (PPI) and show clear interface regions for these interactions between the individual domains within AhR as well as their interactions with ARNET and DNA.
Crystal structure of human aryl hydrocarbon receptor in heterodimer with aryl hydrocarbon nuclear translocator and recruit on DNA in dioxin element response [
As shown in Figure 4, the first PPI interface is between the AhR-ARNT heterodimer with the two DNA strands. This interaction is mediated by DRE Ser36, His39, and Arg40 from the AhR bHLH domain and His79, Asp83, Arg86, and Arg87 from ARNT, as well as thymine and guanine from the DNA. The second PPI interface is between AhR and ARNT through different regions within the two proteins. These regions involve many hydrophobic interactions from both proteins and comprise residues Leu47, Leu50, Leu53, Val74, and Leu70 from the AhR bHLH domain and residues Ile109, Leu112, Val136, and Met139 in ARNT. The third PPI interface involves interactions between residues from the PAS A domain in both AhR and ARNT, mediated by residues Phe117, Leu118, Ala121, Leu122, Tyr137, Val126, Phe266, and Ile268 from AhR. The fourth, and final PPI interface encompasses the interdomain interactions between the AhR bHLH and AhR PAS A domains, through residues Phe136, Ser151, Ile154, and Leu246 from the PAS A domain and Phe56, Val60, Leu72, Ala79, and Phe82 from the bHLH domain.
The wealth of structural information described above on AhR provides an excellent opportunity to apply various computer-based simulations to study the dynamicity and structural organization of the various AhR domains. The applications of such computational tools not only can yield much needed insights on how these domains interact together within the AhR machinery, but can also offer detailed answers on their interactions with other AhR partners (
Most of the
In many AhR studies, the human hypoxia inducible factors (HIF-2α) crystal structures served as templates for AhR-PAS B domain because it has the highest sequence similarity towards the AhR-PAS B domain. Table 2 provides a list of the reported
PDB ID | Structure method | Year of study | Reference |
---|---|---|---|
3H82 | X-ray diffraction | 2014 | [41] |
4GHI | X-ray diffraction | 2014 | [43] |
3H3W | Electron microscopy | 2016 | [44] |
3F1O, 3H7W, 3H82 | X-ray diffraction | 2018, 2018 | [45, 46] |
4XT2 | X-ray diffraction | 2019 | [47] |
3F1N, 3F1O, 3F1P, 3H7W, 3H82, 4GHI, 4GS9, 4XT2, 4ZP4, 4ZQD | X-ray diffraction | 2019 | [12] |
3H82, 3H7W, 4ZQD | X-ray diffraction | 2020 | [48] |
Report studies that used different crystal structures of human hypoxia inducible factors (HIF-2α).
For example, Bisson and his group established an agonist-optimized model of the human AhR-PAS B domain, followed by docking around five thousand chemical structures, including AhR agonists and antagonists, within the PAS B domain. Docking results were then filtered and the top five systems were subjected to long MD simulations (~ 60 ns) to study the conformational and dynamical changes in these generated complexes. Findings from Bisson’s work revealed the importance of residues 307–329 in the PAS B domain, which were shown to be very flexible, acting as an access gate to the ligand-binding pocket. These residues can also adopt different conformations upon AhR ligands’ binding and play a primary function in controlling the structural changes and accessibility of the ligands to the AhR ligand binding pocket [41].
With the 3-dimensional structure of the PAS B domain in hand, many groups focused on studying its binding to different ligands (
Chemical structures of AhR ligands in this study obtained from pubchem database.
Mutations at outer residues (e.g., Arg282, Thr311, Glu339, and Lys350) into alanine did not impact TCDD binding to AhR [57]. In the human AHR-LBD a mutation at Ala375 to Val and Leu decreases the binding affinity of TCDD and makes indirubin a less potent endogenous AhR ligand [45, 58]. Additional site-directed mutagenesis within AhR-LBD residues has been used to identify key residues promoting for ligand selectivity in AhR. These developed models provided a clear basis towards understanding the mechanism of ligand-dependent activation of AHR via its PAS B domain. In particular, the above mentioned molecular docking and mutagenesis analyses helped in identifying and confirming the binding pocket of TCDD and other AhR modulators [52, 57, 59, 60].
Examples of these models include those developed by Kim and her team, who constructed 3D models from several avian species including, chicken, albatross, and cormorant, and studied the sensitivity of dioxin derivatives against multiple AhR isoforms. All models were subjected to docking simulations with TCDD followed by MD simulations. Kim’s results used the mean square displacement (MSD) of the MD trajectories as a stability indicator for the bound ligands. These findings revealed Ile324 and Ser380 from chicken AhR1 exhibited the least MSD values compared to all AhR-LBD residues in other avian species. The size of binding pocket was also shown to be variable among the different species. Moreover, stabilization of TCDD in the binding pocket of chicken AhR relied on the features of Ile324 and Ser380, which explained why chicken AhR is more sensitive to TCDD binding compared to other AhR isoforms [54, 61, 62, 63].
Further mutational and functional analysis studies were expanded to include additional AhR modulators other than TCCD. For example, the work of Faber and her team studied induribin binding to AhR in both mouse and human. This study revealed that a mutation in His326Tyr and Ala349Thr in mouse AhR, and Tyr332 and Thr355 in human AhR can increase the potency of indole compounds, particularly, indirubin. Also, although indirubin and vemurafenib can fit within the same binding pocket in AhR, the two compounds showed two different modes of binding [45, 47]. For example, flutamide efficiently binds to residues inside the AHR-LBD with a high affinity in both mouse and human AHR to activate the AhR pathway [64]. It is important to note that, the biological response of AhR is dependant on the type of the bound ligand and has been shown to change based on the interaction of a given ligand with the residues forming the LBD in the PAS B domain [48, 65].
Over the last few decades, virtual screening has been used as a major tool to in hit identification campaigns against numerous biological targets [66]. In this regard, AhR is no exception and various
Pharmacophore modeling maps the ligand-target interactions into a set of steric and electronic features structured in a specific 3D arrangement [70]. These pharmacophore models can be then used to screen millions of available chemical structural libraries for compounds that satisfy these pharmacophore features, which can be used for scaffold hopping and fragment-based drug design. On the other hand, structure–based methods require the knowledge of target protein crystal structure, or its 3D developed homology models. Ligands from a given database can be fitted into the active site of the target protein and can be ranked based on the predicted binding affinities. In this context, molecular docking and molecular dynamics simulations are among the many valuable tools that can be used to predict the most probable mode of binding of a given ligand within the target. Furthermore, structure-based pharmacophore models can provide more detailed insights on the interaction of ligand with the binding site [69, 71, 72].
As discussed below, several AhR screening studies combined both methods to enhance the search for possible AhR candidates [67, 73]. The plethora of accumulated physicochemical, chemical and structural data on AhR modulators augmented this hit identification search with great tools to build reliable machine learning models, which require large datasets of chemical structures along with their interaction kinetics with AhR [74].
An example of AhR
In a similar approach, Rath and his team built two human PAS B domain; a wild type and mutant (Val381 Ala, Val381Asn) models. Around 60 natural compounds from
Compound name | Induction of AhR transcription | Binding free energy (kcal/mol) | Reference |
---|---|---|---|
Withanolide A | + | −7.5 | [77] |
Pinocembrin (5,7-Dihydroxyflavanone, R-form) | + | −2.9 | [60] |
5-hydroxy-7-methoxyflavone | + | −4.3 | [60] |
IMA-06201 (N-ethyl- | + | Not report | [46] |
IMA-06504 (N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide) | + | Not report | [46] |
Activation of AhR transcription by chemical compounds that identified by in silico screening of different chemical libraries.
In another screening study, Mahiout, et al. identified IMA-06201 and IMA-06504 as two novel AhR agonists, with similar modes of binding to that of TCDD. Both compounds showed great stability in the central area of the AhR ligand-binding pocket. Furthermore, these AhR agonists were shown to be more efficient and more potent as selective AhR modulators than TCDD. To confirm that, Mahiout used CYP1A1 enzyme activity as a biomarker for AhR activation and compared the efficacy and potency of IMA-06201 and IMA-06504 (see Figure 5 and Table 3) to that of TCDD in the presence and absence of the AhR antagonist, CH-223191, at different concentrations in rat hepatoma cell lines. Their results showed that the new compounds, IMA-06201 and IMA-06504, were able to induce CYP1A1 activity in a similar efficacy to that of TCDD, where CH-223191 was shown to block their CYP1A1 induction. Also, in an Ames test to assess the genotoxicity of the new identified compounds, IMA-06201 and IMA-06504 did not show mutagenic effects at low concentrations [46].
Machine-learning algorithms combined with QSAR have been recently used to screen for new AhR ligands. For instance, Matsuzaka used deep learning (DL) to construct machine-learning models to predict AhR activators. These models showed advantages on enhanced input data based on the 3D chemical structures of the compounds into these models, and their performance was better than traditional machine learning models [78]. To enhance the screening process of AhR ligands, Zhu established a virtual screening protocol from combining ligand-based and structure-based screening with supervised machine learning to screen around eight thousand from the pesticide databases to identify an agonistic effect on AHR activity. Zhu’s results revealed sixteen compounds as AhR activators and these findings were validated in a zebrafish
Towards improving the prediction accuracy of his model, Yang, et al. used machine learning algorithms to construct two-dimensional quantitative structure–activity relationship (2D-QSAR) models from multiple linear regression (MLR) and artificial neural network (ANN) algorithms. He used the pEC50 values of 60 dioxins derivatives as AhR activators to build. These models predicted the toxicity of 162 new dioxin derivatives, showing a good correlation between compounds’ chemical structures and their IC50 and EC50 values.
Recently, Goya-Jorge employed various machine learning algorithms to build a set of QSAR models. These models adopted the adoboost (AdB), random forest (RF), gradient boosting (GB), support vector machine (SVM), and multilayer perceptron (MLP) as classifiers to examine around 1900 compounds from synthetic and natural sources on their AhR agonism. Around 40 compounds baring the benzothiazole scaffold were classified as AhR agonists. In vitro validation of these hits showed that indole derivatives can serve as AhR ligands, including the endogenous substances [80, 81]. Table 3 reports some of the top hits emerging from different
Identifying novel AhR modulators using in silico approaches require establishing more comprehensive computational models of this target. These models should describe the detailed organization of the different AhR domains as well is its interaction with other protein/DNA partners. While the available crystal structures provide a glimpse of these missing pieces of information, there are still more to be done in this regard. For example, all currently available AhR crystal structures deposited in the protein data bank are lacking two important AhR domains, namely the PAS B domain and the transactivation domain [39]. The transactivation domain is essential in AhR intercellular trafficking.
On the other hand, the PAS B domain interacts with an AhR ligand, which can modulate the AhR activity. While homology modeling has helped constructing acceptable models for this domain, the similarity of the templates used to build the PAS B domain is very low, leaving a lot of doubt about their accuracy. A crystal structure of the PAS B domain would be a great leap forward towards understanding the mode of action of AhR modulators and towards identifying better agonists/antagonists for this important target. Furthermore, there is a gap of knowledge on how AhR interact with other protein partners in the inactive state, including co-chaperone, AIP, and the protein kinase SRC. This builds an additional challenge to identify druggable pockets at their protein–protein interfaces [7, 82]. With the apparent advances in obtaining 3D experimental structures of protein (e.g. Cryo-electron microscopy (cryo-EM)) one expects several of these structural challenges can be solved in the near future, opening new gates for the computational science to identify new AhR modulators and to help understand its functional, structural and biological characterizes more clearly.
The AhR is a ligand-activated transcriptional factor. It regulates various genes’ expression and plays a pathophysiological function in numerous diseases. Crystallography has been employed to resolve three crystal structures containing bHLH and PAS A domains from human and mouse origin and to identify four protein–protein interfaces. However, all these structures lacked the PAS B domain, which plays a fundamental role in ligands’ binding domain to AhR. Computational and mutational studies revealed important residues that constitute the binding pockets within the PAS B domain. Towards identifying novel AhR modulators, several virtual screening and machine learning algorithms were constructed based on the available structural and pharmacological properties of known AhR ligands. Computational methods are extremely fast and intensely reduce the cost and time in screening millions of compounds to find compounds that could interact with the AhR. Recent studies employing these methods against AhR have been reviewed and discussed in this chapter. We hope the literature presented here can help advance the development of novel, selective and potent AhR modulators.
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
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\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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which depolymerizes the cellulose into glucose. Cellulases are produced by a diverse array of microbes including fungi, bacteria, yeast and actinomycetes. Considerable research for understanding the mechanism of cellulases began in early 1950s because of the significant use of these enzymes in various industries. This review provides a general account structure and availability of lignocellulosic biomass, pretreatment strategies for effective digestion, cellulase producing organisms, cellulase activity assay, and enzymology of cellulose degradation. Cellulase production, optimization, purification and characterization studies in addition to the industrial application of cellulase have also been discussed. At last a brief account of present market scenario of cellulases and future prospects of the study are also taken into account.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Namita Singh, Anita Devi, Manju Bala Bishnoi, Rajneesh Jaryal, Avni Dahiya, Oleksandr Tashyrev and Vira Hovorukha",authors:[{id:"278205",title:"Prof.",name:"Namita",middleName:null,surname:"Singh",slug:"namita-singh",fullName:"Namita Singh"},{id:"282352",title:"Dr.",name:"Anita",middleName:null,surname:"Devi",slug:"anita-devi",fullName:"Anita Devi"},{id:"282353",title:"MSc.",name:"Avni",middleName:null,surname:"Dahiya",slug:"avni-dahiya",fullName:"Avni Dahiya"},{id:"282354",title:"MSc.",name:"Manju Bala",middleName:null,surname:"Bishnoi",slug:"manju-bala-bishnoi",fullName:"Manju Bala Bishnoi"},{id:"282355",title:"Dr.",name:"Oleksandr",middleName:null,surname:"Tashyrev",slug:"oleksandr-tashyrev",fullName:"Oleksandr Tashyrev"},{id:"282356",title:"Dr.",name:"Rajneesh",middleName:null,surname:"Jaryal",slug:"rajneesh-jaryal",fullName:"Rajneesh Jaryal"},{id:"282939",title:"Dr.",name:"Vira",middleName:null,surname:"Hovorukha",slug:"vira-hovorukha",fullName:"Vira Hovorukha"}]},{id:"56708",doi:"10.5772/intechopen.69096",title:"Human Development and Research-Development-Extension Relationships",slug:"human-development-and-research-development-extension-relationships",totalDownloads:1733,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"Human capital is the most important strategic factor for development; as new technologies emerge, the market demand for better and healthier products and consumer demand in terms of quality and delivery time are changing. In today’s world, it becomes increasingly important to know how information can be accessed, how it is adopted, and how it can be assimilated. In this respect, each country allocates budget for training, education, and extension according to its own conditions. This budget may be intended for rural community-based social assistance, but the economic and welfare effect is essential. In this way, it is aimed to increase the living standards of the families living in the rural areas. This will naturally contribute to national income and to the prosperity of society. The subject has been discussed generally in the world, especially in the case of Turkey. According to this, all over the world, particularly in developing countries, research and extension (R&E) is very important and should be considered at least as much as research and development (R&D). However, it will be ensured that societies meet with the technology produced. For this, the development of human resources should be emphasized and a suitable atmosphere should be prepared for this widespread prosperity.",book:{id:"5819",slug:"research-and-development-evolving-trends-and-practices-towards-human-institutional-and-economic-sectors-growth",title:"Research and Development Evolving Trends and Practices",fullTitle:"Research and Development Evolving Trends and Practices - Towards Human, Institutional and Economic Sectors Growth"},signatures:"Orhan Özçatalbaş",authors:[{id:"170206",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Özçatalbaş",slug:"dr.-orhan-ozcatalbas",fullName:"Dr. Orhan Özçatalbaş"}]},{id:"66110",doi:"10.5772/intechopen.84770",title:"Gold Recovery Process from Primary and Secondary Resources Using Bioadsorbents",slug:"gold-recovery-process-from-primary-and-secondary-resources-using-bioadsorbents",totalDownloads:1996,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Bioadsorbents were prepared in a simple manner only by treating in boiling concentrated sulfuric acid from various biomass materials such as various polysaccharides, persimmon tannin, cotton, paper and biomass wastes such as orange juice residue and microalgae residue after extracting biofuel. These bioadsorbents exhibited high selectivity only to gold over other metals and extraordinary high loading capacity for gold(III), which were elucidated to be attributable to the selective reduction of gold(III) ion to elemental gold due to its highest oxidation-reduction potential of gold(III) of metal ions, catalyzed by the surface of bioadsorbents prepared in boiling sulfuric acid. By using these biosorbents, recovery of gold from actual samples of printed circuit boards of spent mobile phones and Mongolian gold ore was investigated. Recovery of trace concentration of gold(I) from simulated spent alkaline cyanide solution was also investigated using the bioadsorbent. Application of bioadsorbents to some recovery processes of gold from cyanide solutions was proposed.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Katsutoshi Inoue, Durga Parajuli, Manju Gurung, Bimala Pangeni, Kanjana Khunathai, Keisuke Ohto and Hidetaka Kawakita",authors:[{id:"198951",title:"Prof.",name:"Keisuke",middleName:null,surname:"Ohto",slug:"keisuke-ohto",fullName:"Keisuke Ohto"},{id:"259238",title:"Dr.",name:"Hidetaka",middleName:null,surname:"Kawakita",slug:"hidetaka-kawakita",fullName:"Hidetaka Kawakita"},{id:"289372",title:"Dr.",name:"Katsutoshi",middleName:null,surname:"Inoue",slug:"katsutoshi-inoue",fullName:"Katsutoshi Inoue"},{id:"298633",title:"Dr.",name:"Bimala",middleName:null,surname:"Pangeni",slug:"bimala-pangeni",fullName:"Bimala Pangeni"},{id:"298634",title:"Dr.",name:"Manju",middleName:null,surname:"Gurung",slug:"manju-gurung",fullName:"Manju Gurung"},{id:"298635",title:"Dr.",name:"Kanjana",middleName:null,surname:"Khunathai",slug:"kanjana-khunathai",fullName:"Kanjana Khunathai"},{id:"298636",title:"Dr.",name:"Durga",middleName:null,surname:"Parajuli",slug:"durga-parajuli",fullName:"Durga Parajuli"}]},{id:"66428",doi:"10.5772/intechopen.84833",title:"Review of Biofuel Technologies in WtL and WtE",slug:"review-of-biofuel-technologies-in-wtl-and-wte",totalDownloads:1177,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Processing of biomass feedstocks to produce energy, fuels, and chemicals via a combination of different applied technologies is considered a promising pathway to achieve sustainable waste management, with many environmental and economic benefits. In this chapter, we review the current state of the main processes associated with energy recovery and biofuel production under the concept of waste biorefineries. The reviewed technologies are classified into thermochemical, biological, and chemical, including combustion, gasification, steam explosion, pyrolysis, hydrothermal liquefaction, and torrefaction; anaerobic digestion, fermentation, enzymatic treatment, and microbial electrolysis; and hydrolysis, solvent extraction, transesterification, and supercritical conversion. Their brief history, current status, and future developments are discussed within a perspective of valorization and managing of current waste streams with no solution.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Bruno B. Garcia, Gonçalo Lourinho, Paulo Brito and Pedro Romano",authors:[{id:"261653",title:"Prof.",name:"Paulo",middleName:null,surname:"Brito",slug:"paulo-brito",fullName:"Paulo Brito"},{id:"261654",title:"Prof.",name:"Pedro",middleName:null,surname:"Romano",slug:"pedro-romano",fullName:"Pedro Romano"},{id:"291751",title:"B.Sc.",name:"Bruno B.",middleName:"B",surname:"Garcia",slug:"bruno-b.-garcia",fullName:"Bruno B. 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This chapter shows how these issues can be addressed starting with measuring and modeling energy consumption patterns by collecting an energy consumption dataset at device level. The open dataset allows to extract typical usage patterns and subsequently to model test scenarios for energy management algorithms. Section 3 discusses means for analyzing measured data and for providing detailed feedback about energy consumption to increase customers’ energy awareness. Section 4 shows how renewable energy sources can be integrated in a smart microgrid and how energy production can be accurately predicted. Section 5 introduces a self-organizing local energy system that autonomously coordinates production and consumption via an agent-based energy auction system. The final section discusses how the proposed methods contribute to sustainable growth and gives an outlook to future research.",book:{id:"5819",slug:"research-and-development-evolving-trends-and-practices-towards-human-institutional-and-economic-sectors-growth",title:"Research and Development Evolving Trends and Practices",fullTitle:"Research and Development Evolving Trends and Practices - Towards Human, Institutional and Economic Sectors Growth"},signatures:"Wilfried Elmenreich, Tamer Khatib and Andrea Monacchi",authors:[{id:"163771",title:"Dr.",name:"Wilfried",middleName:null,surname:"Elmenreich",slug:"wilfried-elmenreich",fullName:"Wilfried Elmenreich"},{id:"197214",title:"Dr.",name:"Andrea",middleName:null,surname:"Monacchi",slug:"andrea-monacchi",fullName:"Andrea Monacchi"}]}],mostDownloadedChaptersLast30Days:[{id:"66110",title:"Gold Recovery Process from Primary and Secondary Resources Using Bioadsorbents",slug:"gold-recovery-process-from-primary-and-secondary-resources-using-bioadsorbents",totalDownloads:1996,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Bioadsorbents were prepared in a simple manner only by treating in boiling concentrated sulfuric acid from various biomass materials such as various polysaccharides, persimmon tannin, cotton, paper and biomass wastes such as orange juice residue and microalgae residue after extracting biofuel. These bioadsorbents exhibited high selectivity only to gold over other metals and extraordinary high loading capacity for gold(III), which were elucidated to be attributable to the selective reduction of gold(III) ion to elemental gold due to its highest oxidation-reduction potential of gold(III) of metal ions, catalyzed by the surface of bioadsorbents prepared in boiling sulfuric acid. By using these biosorbents, recovery of gold from actual samples of printed circuit boards of spent mobile phones and Mongolian gold ore was investigated. Recovery of trace concentration of gold(I) from simulated spent alkaline cyanide solution was also investigated using the bioadsorbent. Application of bioadsorbents to some recovery processes of gold from cyanide solutions was proposed.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Katsutoshi Inoue, Durga Parajuli, Manju Gurung, Bimala Pangeni, Kanjana Khunathai, Keisuke Ohto and Hidetaka Kawakita",authors:[{id:"198951",title:"Prof.",name:"Keisuke",middleName:null,surname:"Ohto",slug:"keisuke-ohto",fullName:"Keisuke Ohto"},{id:"259238",title:"Dr.",name:"Hidetaka",middleName:null,surname:"Kawakita",slug:"hidetaka-kawakita",fullName:"Hidetaka Kawakita"},{id:"289372",title:"Dr.",name:"Katsutoshi",middleName:null,surname:"Inoue",slug:"katsutoshi-inoue",fullName:"Katsutoshi Inoue"},{id:"298633",title:"Dr.",name:"Bimala",middleName:null,surname:"Pangeni",slug:"bimala-pangeni",fullName:"Bimala Pangeni"},{id:"298634",title:"Dr.",name:"Manju",middleName:null,surname:"Gurung",slug:"manju-gurung",fullName:"Manju Gurung"},{id:"298635",title:"Dr.",name:"Kanjana",middleName:null,surname:"Khunathai",slug:"kanjana-khunathai",fullName:"Kanjana Khunathai"},{id:"298636",title:"Dr.",name:"Durga",middleName:null,surname:"Parajuli",slug:"durga-parajuli",fullName:"Durga Parajuli"}]},{id:"56708",title:"Human Development and Research-Development-Extension Relationships",slug:"human-development-and-research-development-extension-relationships",totalDownloads:1733,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"Human capital is the most important strategic factor for development; as new technologies emerge, the market demand for better and healthier products and consumer demand in terms of quality and delivery time are changing. In today’s world, it becomes increasingly important to know how information can be accessed, how it is adopted, and how it can be assimilated. In this respect, each country allocates budget for training, education, and extension according to its own conditions. This budget may be intended for rural community-based social assistance, but the economic and welfare effect is essential. In this way, it is aimed to increase the living standards of the families living in the rural areas. This will naturally contribute to national income and to the prosperity of society. The subject has been discussed generally in the world, especially in the case of Turkey. According to this, all over the world, particularly in developing countries, research and extension (R&E) is very important and should be considered at least as much as research and development (R&D). However, it will be ensured that societies meet with the technology produced. For this, the development of human resources should be emphasized and a suitable atmosphere should be prepared for this widespread prosperity.",book:{id:"5819",slug:"research-and-development-evolving-trends-and-practices-towards-human-institutional-and-economic-sectors-growth",title:"Research and Development Evolving Trends and Practices",fullTitle:"Research and Development Evolving Trends and Practices - Towards Human, Institutional and Economic Sectors Growth"},signatures:"Orhan Özçatalbaş",authors:[{id:"170206",title:"Prof.",name:"Dr. Orhan",middleName:null,surname:"Özçatalbaş",slug:"dr.-orhan-ozcatalbas",fullName:"Dr. Orhan Özçatalbaş"}]},{id:"68851",title:"Introductory Chapter: Objectives and Scope of Bioeconomy",slug:"introductory-chapter-objectives-and-scope-of-bioeconomy",totalDownloads:970,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Krzysztof Biernat",authors:[{id:"155009",title:"Prof.",name:"Krzysztof",middleName:null,surname:"Biernat",slug:"krzysztof-biernat",fullName:"Krzysztof Biernat"}]},{id:"68007",title:"Overview of the Process of Enzymatic Transformation of Biomass",slug:"overview-of-the-process-of-enzymatic-transformation-of-biomass",totalDownloads:1378,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"Cellulase is an enzyme which depolymerizes the cellulose into glucose. Cellulases are produced by a diverse array of microbes including fungi, bacteria, yeast and actinomycetes. Considerable research for understanding the mechanism of cellulases began in early 1950s because of the significant use of these enzymes in various industries. This review provides a general account structure and availability of lignocellulosic biomass, pretreatment strategies for effective digestion, cellulase producing organisms, cellulase activity assay, and enzymology of cellulose degradation. Cellulase production, optimization, purification and characterization studies in addition to the industrial application of cellulase have also been discussed. At last a brief account of present market scenario of cellulases and future prospects of the study are also taken into account.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Namita Singh, Anita Devi, Manju Bala Bishnoi, Rajneesh Jaryal, Avni Dahiya, Oleksandr Tashyrev and Vira Hovorukha",authors:[{id:"278205",title:"Prof.",name:"Namita",middleName:null,surname:"Singh",slug:"namita-singh",fullName:"Namita Singh"},{id:"282352",title:"Dr.",name:"Anita",middleName:null,surname:"Devi",slug:"anita-devi",fullName:"Anita Devi"},{id:"282353",title:"MSc.",name:"Avni",middleName:null,surname:"Dahiya",slug:"avni-dahiya",fullName:"Avni Dahiya"},{id:"282354",title:"MSc.",name:"Manju Bala",middleName:null,surname:"Bishnoi",slug:"manju-bala-bishnoi",fullName:"Manju Bala Bishnoi"},{id:"282355",title:"Dr.",name:"Oleksandr",middleName:null,surname:"Tashyrev",slug:"oleksandr-tashyrev",fullName:"Oleksandr Tashyrev"},{id:"282356",title:"Dr.",name:"Rajneesh",middleName:null,surname:"Jaryal",slug:"rajneesh-jaryal",fullName:"Rajneesh Jaryal"},{id:"282939",title:"Dr.",name:"Vira",middleName:null,surname:"Hovorukha",slug:"vira-hovorukha",fullName:"Vira Hovorukha"}]},{id:"67691",title:"The Use of Waste Management Techniques to Enhance Household Income and Reduce Urban Water Pollution",slug:"the-use-of-waste-management-techniques-to-enhance-household-income-and-reduce-urban-water-pollution",totalDownloads:1013,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Appropriate waste management options are major concerns in the developing world. Current methods include incineration in the open and accumulation of wastes in designated places where they constitute nuisance to the environment. Apart from air pollution from the incinerators, leachates from decomposed wastes are either washed off where they serve as source of pollutants to the adjourning streams and rivers or contaminate groundwater through deep percolation. We present viable options for managing agricultural wastes in this chapter. The options presented are so simple and sustainable such that it can be managed by individuals. Hence, they are independent of the government bureaucratic bottlenecks that have been the bane of the previous government interventions. If embraced, it will also serve as sources of income for the concerned household, hence enhance their livelihood.",book:{id:"8150",slug:"elements-of-bioeconomy",title:"Elements of Bioeconomy",fullTitle:"Elements of Bioeconomy"},signatures:"Olayiwola A. Akintola, Olufunmilayo O. Idowu, Suraju A. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,annualVolume:11407,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}}},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,annualVolume:11409,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:17,paginationItems:[{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"79345",title:"Application of Jump Diffusion Models in Insurance Claim Estimation",doi:"10.5772/intechopen.99853",signatures:"Leonard Mushunje, Chiedza Elvina Mashiri, Edina Chandiwana and Maxwell Mashasha",slug:"application-of-jump-diffusion-models-in-insurance-claim-estimation-1",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81557",title:"Object Tracking Using Adapted Optical Flow",doi:"10.5772/intechopen.102863",signatures:"Ronaldo Ferreira, Joaquim José de Castro Ferreira and António José Ribeiro Neves",slug:"object-tracking-using-adapted-optical-flow",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg",subseries:{id:"24",title:"Computer Vision"}}},{id:"81558",title:"Thresholding Image Techniques for Plant Segmentation",doi:"10.5772/intechopen.104587",signatures:"Miguel Ángel Castillo-Martínez, Francisco Javier Gallegos-Funes, Blanca E. Carvajal-Gámez, Guillermo Urriolagoitia-Sosa and Alberto J. 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