The producing states of
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",isbn:"978-1-80356-303-9",printIsbn:"978-1-80356-302-2",pdfIsbn:"978-1-80356-304-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"dd28db91ac081287c5204f82e219d67e",bookSignature:"Prof. Xiaoyan Dong and Prof. Nanbert Zhong",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11722.jpg",keywords:"Asthma, Th1/Th2 Balance, Airway Inflammation, miRNA, lncRNA, Cytokines, Signaling Pathways, Steroid Resistance, Severe Asthma, Therapeutic Targets, Biomarker, Bacterial",numberOfDownloads:3,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 15th 2022",dateEndSecondStepPublish:"April 19th 2022",dateEndThirdStepPublish:"June 18th 2022",dateEndFourthStepPublish:"September 6th 2022",dateEndFifthStepPublish:"November 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Dong is a medical doctor director of respiratory in the Shanghai children's hospital. She has served as the pediatric branch of Chinese medical association respiratory group members, pediatric respiratory group of chronic cough in children's lung function, as well as China's maternal and child health association, deputy director of children's allergy branch committee member, breathing group leader.",coeditorOneBiosketch:"Dr. Zhong is the Founder Director of Peking University Center of Medical Genetics as well as the Founder Chairman of Dept. Medical Genetics of Peking University Health Science Center. His research studies have been founded by the NIH (USA), March of Dimes Foundation (USA), Batten Disease Support and Research Association (USA), New York State Research Foundation for Mental Hygiene (USA), Chinese Ministry of Science and Technology, Chinese Ministry of Education, Chinese Natural Science Foundation, and Shangha",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"344976",title:"Prof.",name:"Xiaoyan",middleName:null,surname:"Dong",slug:"xiaoyan-dong",fullName:"Xiaoyan Dong",profilePictureURL:"https://mts.intechopen.com/storage/users/344976/images/system/344976.jpg",biography:"A medical doctor, graduate student tutor, the Shanghai children's hospital, director of respiratory, graduated from Shanghai second medical university, served as the member of Chinese Medical Association, pediatric respiratory group, the member of a collaborative group of Chinese children chronic cough, the member of the collaborative group of lung function of children, and the member of the Professional Committee of Shanghai antibiotics,vice director of shanghai the collaborative group of lung function of children, the younger member of shanghai allergy group. as well as the members of China's maternal and child health association, deputy director of children's allergy branch committee member, leader of the respiratory group.",institutionString:"Shanghai Children's Hospital",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Shanghai Children's Hospital",institutionURL:null,country:{name:"China"}}}],coeditorOne:{id:"191541",title:"Prof.",name:"Nanbert",middleName:null,surname:"Zhong",slug:"nanbert-zhong",fullName:"Nanbert Zhong",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"As a tenured faculty member, I am currently directing the Molecular Neurogenetic Diagnostic Laboratory and Heading the Developmental Genetics Laboratory at the New York State Institute for Basic Research in Developmental Disabilities. I am also the Founder Director of Peking University Center of Medical Genetics as well as the Founder Chairman of Dept. Medical Genetics of Peking University Health Science Center. I have a broad research interest in perinatal health, including maternal-fetal medicine with a focus on prematurity, children development, mental retardation, and developmental disabilities, and birth defects with a focus on brain developmental-relevant disorders. I have published 140+ articles in peer-reviewed journals, including Lancet, Nature Genetics, American Journal of Human Genetics, American Journal of Medical Genetics, Clinical Genetics, Human Genetics, Genetics in Medicine, Journal of Medical Genetics, Neurogenetics, Molecular Genetics, and Metabolism, Advanced Genetics, Genetic Testing, Neurology, Neurological Science, Biochimica et Biophysica Acta - Proteins & Proteomics, Biochemical and Biophysical Research Communications, Behavior and Brain Function, Encyclopedia, J Community Genetics, J Chromatogr B, J Mol Neurosci, BMC Preg Childbirth, and Epidemiology and Infection, etc. I have been the peer reviewer for the American Journal of Human Genetics, American Journal of Medical Genetics, Clinical Genetics, Nucleic Acid Research, Human Biology, FEBS Lett, Biochimica et Biophysica Acta, Encyclopedia of Medical Genomics and Proteomics, Genet Testing, Mol Biol Report, African J. Pathology, Fertility and Sterility, BMC Public Health, Clinical and Experimental Dermatology, PLoS One, Reproductive BioMedicine (Online) and Reproductive Biology. My research studies have been founded by the NIH (USA), March of Dimes Foundation (USA), Batten Disease Support and Research Association (USA), New York State Research Foundation for Mental Hygiene (USA), Chinese Ministry of Science and Technology (Oversea Chinese Outstanding Young Investigator Award, and 973 High Tech project), Chinese Ministry of Education (211, 985 Projects), Chinese Natural Science Foundation, and Shanghai Municipal Government. My current research is focusing on the genetic and genomic study of prematurity including preterm birth and stillbirth, as well as the outcome of pregnancy, with an integrated “-omics” approach. I am also exploring rational strategies for the prevention and intervention of preterm birth with a longitudinal approach. I have initiated China Human Placenta Project (CHPP) in 2015.",institutionString:"New York State Institute for Basic Research in Developmental Disabilities",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:[{id:"82455",title:"Effect of Family Education on Clinical Outcomes in Children with Asthma: A Review",slug:"effect-of-family-education-on-clinical-outcomes-in-children-with-asthma-a-review",totalDownloads:3,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444318",firstName:"Nika",lastName:"Karamatic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444318/images/20011_n.jpg",email:"nika@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Proper selection of trees and crop species helps meet wood demand, increase yield, soil fertility, promote sustainability and adequate efficiency of natural resources [2]. The cultivation of cocoa interspersed with tree species and high-density short rotation can be the best option to meet the growing requirements of raw materials for food and industry through the sustainability of natural resources [3].
The agroforestry systems of cacao in Tabasco (Mexico) is an ecological agricultural alternative, economically feasible, sustainable, and conservation of natural resources in the simultaneous preservation of forests and jungles. Given that
The
Based on the morphological characteristics and geographical origins, three main genetic groups have traditionally been defined within cocoa: Criollo, Forastero, and Trinitario. Trinitario has been recognized as a hybrid “Criollo × Forastero.” Recently, molecular markers and chromosome analysis have been used to classify cocoa germplasm into 10 main groups: Amelonado, Contamana, Curaray, Guayana, Iquitos, Marañón, Nanay, Purús, Criollo, and Nacional [5]. The genomes of Criollo and Amelonado have been sequenced and cover 76 and 92% of the estimated genome size, respectively [5, 6].
These genomes are important for research in genetic characterization, phylogenetics, and viability. Tabasco is a state of the Mexican Republic located in the southeastern part of the country (Mexico), with 17 municipalities of which three are the largest producers of cocoa with the agroforestry system: Comalcalco, Cunduacán, and Cárdenas (Figure 1). It has a tropical humidity climate, with temperatures ranging from a minimum of 17°C to a maximum of 42°C, with a rainfall of 2000 mm per year and a relative humidity of 90%. The topography is generally flat and low and is covered to a large extent with lakes, lagoons, and wetlands [4]. These biotic and abiotic conditions have favored the agroforestry systems in the production of cocoa of the three groups Criollo, Forastero, and Trinitario, at the same time, an increase in the fertility of the soil, micro- and macroorganisms, conservation and together with the sustainability.
The cacao agroforestry systems in Tabasco (México).
Diversification, efficiency in land use, climate change, sustainability, and permanent vegetation cover are important elements of agroforestry systems, which play an important role in adapting to climate change [7, 8, 9, 10]. Agrosystem has been recognized as a process in agriculture as an innovative and promising way to reduce the concentration of atmospheric CO2 by replacing fossil fuels in the Kyoto Protocol [11].
Tabasco is the first producer of cocoa under agroforestry systems, Mexico. It is mentioned as a green and economically viable alternative with the concurrent conservation of forest remains and economic services (Table 1). In this state, two typical systems of cocoa production are managed: (1) traditional farming system, where cocoa plantations are implanted under forests or natural forests, and herbaceous, shrubby, and upper canopy individuals are eliminated to provide greater light input [13, 14, 15]; and (2) cocoa plantations are established in areas where the entire forest or native has been removed and replaced by a single forest species and the cocoa plants are shaded with banana and other crops such as cassava and corn as a provisional shade until forest species provide sufficient shade [13, 16, 17].
State | Surfaces (Ha−1) | Production (T−1) | Performance (T/H−1) | |
---|---|---|---|---|
Seeded | Harvested | |||
Tabasco | 40,887 | 40,668 | 6995 | 0.172 |
Chiapas | 16,782 | 15,280 | 3947 | 0.259 |
Guerrero | 250 | 79 | 24 | 0.307 |
The producing states of
Source: https://www.gob.mx/siap [12].
Environmental performance in cocoa production as monoculture and agroforestry through life cycle assessment based on ISO 14040 and 14044, with adaptation for local impact indicators. The analysis considered cocoa production at the farm level, from field establishment to the limit of the cocoa crop. The results showed that agroforestry has the smallest contribution to the categories of global impact of global warming, acidification, and eutrophication, which represent carbon dioxide (3.67E+01 kg CO2−), sulfur dioxide (4.31E−02 kg SO2−), and phosphate (2.25E−05 kg PO4−), respectively [18].
Agroforestry with cacao and monoculture of cocoa also had the highest amount of organic carbon and organic matter in the soil, conditions that favor the growth and activity of beneficial microorganisms for the soil rhizosphere (
Agroforestry is increasingly considered as an important adaptation and mitigation strategy against climate change. In particular, the use of fruit trees, trees, and shrubs has been promoted as a practice that contributes to improving soil fertility through nitrogen fixation and the use of macro- and beneficial microorganisms, by increasing the supply of nutrients for the production of crops. While much of the evidence on the impact of tree diversity is based on ranch experiments and correlation analysis, there is a paucity of rigorous evidence under the real conditions of small farmers. Research on the impacts of the adoption and the change of arboreal vegetation such as
The producers in Malawi adopted the agroforestry system with cocoa and the changes of trees or shrubs of the legume type showed the increase in value to the different crops by 35%. It also had an impact on the disaggregation through stratification by land ownership revealing that farmers with smaller farms of up to 2 acres obtain the greatest benefits. In addition, the use of legume-type shrubs along with corn also significantly increased the value of food crops. This study offers preliminary ideas that contribute to an emerging field of research on the quantitative assessment of agricultural interventions, such as agroforestry practices using new analytical approaches. We provide some policy ideas and recommend the need to design future research on development initiatives that consider small-scale variation in the social, economic, and ecological context of farmers to improve their absorption and adaptation in order to take advantage of the full potential of the agroforestry to improve soil fertility and family food security [20].
Chocolate has been attributed to attainment of optimal human health and development due to its high content of flavonoids that are crucial in reducing the risk or delaying the development of cardiovascular disease, cancer, and other age-related diseases [21].
The production of chocolate had a great impact with the appearance of the diseases of “
The healthy and diseased “
The surface area and production of cocoa in the state of Tabasco [
Climate change can create serious problems for farmers by increasing the variability of rainfall, droughts, and floods. Understanding how to build the resilience of livelihoods for these purposes is a hallucinatory necessity. Agroforestry can be considered as a potential solution, although many people intuitively link agrosystems with livelihoods against floods and drought, there is little comprehensive empirical evidence. Agrosystems for small farmers can develop livelihood capacities for floods and drought: it is possible to adapt various strategies to climate change, but is crucial for small farmers, and agroecosystem can be a promising option to balance the main production of cocoa, which is mainly chocolate grains [23].
The soil of the agroforestry systems is enriched with the addition of litter in large quantities by the different plant species, which ultimately improves fertility in terms of organic carbon available from the soil to the plant and the participation of macro- and microorganisms in the soil. The processes of crushing, degrading, and transforming the available nutrients (N, P, and K) provide alternative sources of income and employment to the population of the rural areas that help in the economic systems [13, 24].
The fall of litter is an important input for the replacement of microbial substances in the soil and is one of the most essential ways to maintain soil fertility and quality of vegetable production with free of agrochemicals. The agroforestry system is a proven system of land use to vertically improve the health, quality, and microbial stability against unsuitable climatic conditions. This system contributes to increase the nutritional balance in the soil compared to the open system, that is, pH (7.9), EC (0.43 dSm−1), available nitrogen (253.48 kg/ha), potassium (219.63 kg/ha), organic carbon (1.07%), and available soil phosphorus (22.72 kg/ha) [13, 24].
The spatial integration of land use for the management of soil fertility, soil health, economic services, crop quality, and the key factors that influence the integration of land conservation based on multipurpose agrosystems such as outputs and inputs in the process of agroforestry-cocoa integration and the use of agroforestry space lands have been discussed [13, 25, 26, 27, 28].
Rheumatoid arthritis (RA) is an autoimmune-mediated systemic, chronic inflammatory disorder characterized by progressive inflammation of joints, cell infiltration, pannus formation, synovial dysplasia resulting in cartilage destruction and bone erosion [1]. The worldwide prevalence rate of RA in adult population has been predicted between 0.5–1% and 0.92% in India [2]. Generally, prevalent in women when compared to men (3,1) at any age group. According to recent statistics given in 2019 by the Global RA network and WHO, 23 million people are affected by RA, globally [3]. RA etiology is implicated to be linked to metabolic, genetic, environmental factors, and life style of the patient [4]. While it is considered non-lethal, RA is debilitating and severely compromises the quality of life, further reducing life expectancy in patients.
Despite tremendous progress in evolving efficient pharmacological molecules for RA therapy, their efficacious delivery at the diseased joint remains a long-lasting challenge. Over the last two decades, disease-modifying anti-rheumatic drugs (DMARDs: such as methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide (LFM), have attracted attention for effective attenuation of disease progression. Patient compliance is the primary treatment goal with glucocorticoids(GCs); e.g., prednisolone, dexamethasone, hydrocortisone, triamcinolone acetonide, and NASAID (such as ibuprofen, diclofenac, indomethacin etc) result in reducing pain and curbing disease progression [5]. Unfortunately, the associated toxicity caused by dose-escalation and long-term use with undesirable side-effects are limiting the therapeutic success. Continued medication of NSAIDs causes gastro-intestinal and renal toxicity; glucocorticoids cause hypertension, hyperglycemia, muscle wasting, osteoporosis, etc.; nausea and vomiting are common side-effects of conventional DMARDs, including gastro-intestinal irritations, headaches, insomnia, cytopenia, skin and hair damage, etc.; giving biologicals run the risk of anaphylaxis, infections, malignancy, psoriasis and other autoimmune disorders [6, 7]. Biosimilars/biologicals/Biological response modifiers like infliximab, adalimumab, rituximab etc. that have approval of Food and Drug Administration (FDA), were considered for their selective site-specific action, achieved extensive success in clinics for RA treatment. Prior reports suggest combination therapy with biologics, and synthetic DMARDs were found to be highly effective [8].
To circumvent the off-target drug induced systemic toxicity, direct drug delivery
Nanotherapeutics has emerged as an innovative approach enabling efficient delivery of drug for mitigating several diseases. The past decade, has seen an avalanche of publications that have increased our understanding of the patho-physiology of the affected synovial tissue in RA and equivalent progress in nanotechnology and material chemistry, generating tremendous interest in developing Smart drug delivery system (SDDS). Entrapping the anti-inflammatory drugs in SDDS strategically has potential to overcome all the barriers of normal delivery, projecting it as a promising option for site-specific delivery. Currently, RA targeting nanotherapeutics has progressed rapidly because the inflammatory microenvironments of arthritic joints mimic the tumor environment that has typical angiogenic features of neo-vessels coupled with impaired peripheral lymphatic drainage [9, 10]. This review comprehensively deliberates upon the understanding the pathophysiology of RA and role of SDDSs, highlighting the emerging trends for RA nanotherapeutics.
Chronic inflammation is the hallmark of RA that advances to destructive synovitis [11]. It develops in a genetically susceptible person largely due to environmental factors and related epigenetic mechanisms [12]. It predominantly indicates leukocyte infiltration, dysregulated angiogenesis, proliferation of lining layer, that alters the synovial tissue into an invasive pannus. The microvasculature of synovium is dysregulated, hence, in spite of enhanced flow of blood, the increased metabolic needs outdo the vascular blood supply, thereby creating an intense hypoxic microenvironment. However, rheumatoid factor (RF) and anticitrullinated peptide antibodies(ACPA) are induced and must exist before the onset of this disease. The heterogeneous nature of the disease manifests in different clinical forms, hence treatment of RA still remains obscure. It is well documented that synovial microenvironment has abundance of macrophages, multifaceted crosslink of immune cells secreting granulocyte colony-stimulating factor, pro-inflammatory cytokines, tumor necrosis factor(TNF-α), interleukin (IL-1), IL-6, chemokines, and degrading like MMPs that are particularly responsible for RA pathogenesis [13, 14]. Figure 1 illustrates the network of cytokines secreted by multitude of cells involved in RA development that can be useful for assessment of disease progression along with biomarkers present on these cells.
Schematic illustration indicating the key events and signaling cascades involved in RA pathophysiology. Leukocytes infiltrate synovium and stimulate the inflammatory cascade, characterized by cross-talk of SF and macrophages, monocytes, mast cells, dendritic cells, as well as B and T cells. Endothelial cells facilitate angiogenesis. The advanced stage includes hyperplastic synovium, cartilage damage, bone erosion, and systemic consequence. Bone resorption by osteoclasts practically creates bone erosions. The obliteration of the subchondral bone can ultimately lead to the degeneration of the articular cartilage that is a result of reduced osteoblasts and an increase in the number of osteoclasts and synoviocytes.
Proliferation and infiltration of SF is the key trigger for disease progression in RA. Under normal conditions fibroblasts are responsible for maintaining tissue homeostasis by modulating the inflammatory response [15]. Transcription factors like activator protein-1 and NF-κB, responsible for proliferation, activation, differentiation of fibroblasts, expression of MMPs, other matrix-degrading enzymes like cysteine proteases and aggrecanases have been observed in the synovium [5]. The genetic analysis of synovium would be useful for biological therapy as synovial tissue has a robust immune-inflammatory gene expression [16].
B cells contribute to antibody production
Activated T cells comprise ≥50% of RA synovial cells, and majority are memory CD4 T cells. In terms of T cell subsets, the Th1(T helper 1) and Th17(T regulatory) are predominant, but lack Th2 subsets [5]. T cells release cytokines as their effector functions; Th1 release interferon gamma(IFN-γ), that further activate macrophages and increases its phagocytic activity. Likewise, effector cytokines of Th17 cells are IL-17A, IL-17F, IL-21, and IL-22, responsible for cell recruitment, secretion of pro-inflammatory cytokines, initiation of differentiation of B-cell, and activate NK cells [19]. IL-17 may emerge as a beneficial target for RA therapies.
Macrophages are tightly regulated by microenvironment signals including presence of injured cells, microbial debris, pro/anti-inflammatory cytokine or mechanical forces [19]. Depending on the cues, macrophages tend to polarize into characterized phenotypes like pro-inflammatory or immunomodulatory [20]. Taking advantage of the fundamental homing capability of macrophages to migrate to the injured/inflamed arthritic synovium, macrophages can be exploited as delivery vehicles to target specific macrophage populations to carry payloads.
Enhanced osteoclast activity triggered by disproportionate ratio of Osteoprotegerin (OPG) and receptor activator of nuclear-factor kappa-beta ligand (RANKL) are critical factors for RA progression. When RANKL is overexpressed by activated macrophages, osteoblasts and lymphocytes, it stimulates an imbalance between osteoclast multiplication and anomalous activation triggered by the binding of RANKL to RANK on the mature osteoclasts and on the cell-membranes of precursor cells of osteoclast [21]. In addition, MMP-9 and MMP-14 secreted by the osteoblasts, triggers matrix degradation in cartilage, formation of pannus, and osteoclast migration to surface of the bone. Osteoclasts significantly cause erosion of subchondral bone, articular cartilage, and the synovium.
MMPs are the enzymes that irreversibly cause extracellular matrix (ECM) degradation, and slow-destruction of cartilage and bone in diseased joints. MMPs are zinc-dependent endopeptidases that are categorized into five sub-classes: i) gelatinases (MMP-2 and 9), ii) collagenases (MMP-1, −8 and 13), iii) stromelysins (MMP-3, −10 and − 11), iv) matrilysins (MMP-7 and -26) and v) membrane-type MMPs (MMP-14 to −17, −24 and − 25) [22, 23]. MMP-1, 2, 3, and 9 have been directly implicated in RA progression [24]. MMPs, in combination with lipases and esterases, accelerate degradation of ECM, articular cartilage and surface of the subchondral bone [25]. Ever-increasing emerging targets including these enzymes provide more options for anti-arthritic therapy with the help of targeted SDDS for RA.
Enhancement of therapeutic efficiency by ‘intelligent/smart’ carriers that release drugs in a controlled manner at the site of action to achieve minimal side effects are categorized as “Smart Drug delivery system” (SDDS). Maintaining optimum size and surface properties, the materials can be engineered to create nanoparticles that can maneuver the microenvironment and respond to endogenous stimuli, like increased concentration of some enzymes, redox gradient-enhanced level of glutathione, or variations in interstitial pH [26] and/ or exogenous stimuli that include temperature changes, applying magnetic field or light, and giving high energy radiation.
pH, an important parameter linked to pathophysiological conditions, like inflammation can be exploited for enhanced therapeutic efficiency [27]. Reports priori give clarity that pH in normal tissue and blood is maintained around 7.4, but in arthritic microenvironment, extracellular pH values are intrinsically acidic, usually pH 6.8 [28]. The acidic pH can be attributed to the excess infiltration and activation of proinflammatory cells in the synovium, causing increased demand for oxygen and energy. Augmented consumption of glucose
Two strategies are rationally used to design of pH-sensitive SDDS, one using materials with acid-sensitive bonds, that can be cleaved by low pH conditions allowing the release of encapsulated molecules from the nanoparticles; and secondly, using polymers (polyacids or polybases) that have ionizable groups, that undergo pH-dependent transformation and change in solubility [33]. Researchers have engineered a dual-strategy by attributing targeting abilities by surface functionalization and simultaneously using pH responsiveness to enhance therapeutic selectivity in RA.
Intracellular microenvironment can be exploited using redox responsive NPs. Reactive oxygen species (ROS) is generated primarily during oxidative phosphorylation(OXPHOS), but can further be produced by oxidative burst of activated phagocytic cells [34]. Polymers with ROS-sensitive thioketal moiety, or selenium (Se), tellurium (Te), B-based linkers in their monomeric backbone can be utilized as building blocks for the synthesis of stimuli- responsive nanoparticles. Hence, ROS can easily be monitored as an intracellular indicator [35] as chronic inflammation induces continuous production of ROS [36]. ROS concentrations in inflammatory tissues ranges 10- to 100- fold higher than normal tissues [36], thus, promising accuracy and specificity to develop the redox stimuli-responsive DDSs.
Temperature is another crucial factor essential for release of drug [38], as the normal physiological conditions have lower temperatures compared to the inflamed RA microenvironment [39]. Therefore temperature-responsive functionalized NPs can be used to trigger the release of drug at the inflammatory site. They are designed and fabricated to retain their payloads at physiological temperature (37°C), and quick release it when the temperature is increased around 40–45°C, attributing a more efficient targeted SDDS [40]. Phase-transition behavior of the materials that are thermosensitive are used to design NPs, based on the lower critical solution temperature (LCST) of polymers/lipids whose solubility varies with changes in temperature. All excipients in a mixture are totally miscible in all amounts in LCST. In materials with transitional behavior, increased solubility is observed below LCST; and polymeric constituents are prone to swelling due to the hydrogen bonds being formed between the polymer functional groups with water molecules enabling drug loaded molecules. When temperature is raised above the LCST, a hydrophobic-hydrophilic conversion takes place, that leads to a morphological transformation from a random coil-to-globular form. Because of alterations in temperature, the hydrogen bonds breaks causing the network to collapse, and the polymer becomes insoluble, causing shrinkage in the volume and oozing-out of water molecules from inside. This transition initiates release of the entrapped payload of drugs. The application of thermo-responsive SDDS is based on the concept of exploiting the temperature difference between healthy and diseased tissues [40]. Thermal energy can be given directly, or external utilizing heat sources like NIR that may be indirectly applied in RA, that elicits a thermo-responsive behavior based on the thermo-sensitivity of nanomaterials. Typically, the requisite range of temperature fluctuates from 38–43°C [37]. The temperature-stimuli can originate from within the body, or by localized hypothermia, or hyperthermia, may provoke a response based entirely on the thermo-sensitivity of used nanomaterials. Additional advantages of thermo-sensitive NPs may be attributed to reduction in use of toxic organic solvents during fabrication, the capacity to entrap both lipophilic and hydrophilic molecules, controlled and sustained release properties. A plethora of reports using several polymers have been established for the synthesis of temperature-responsive systems, that include derivatives of poly(N-isopropylacrylamide (PNIPAAm), pluronics (poly(ethylene oxide)- poly(propylene oxide) (PEO-PPO)), poly(N vinyl caprolactam), polysaccharide spinoffs, and derivatives of phosphazene [41, 42, 43]. Researchers are making concerted efforts on achieving temperature-responsive NPs stimulated by magnetic action coupled with thermo-responsive effect by light absorption instead of temperature alone.
Light-responsive systems rely on an external stimulus to activate the drug release preferably at the target site using light irradiation. NPs respond to ‘on–off drug’ release, as it may close/open when stimulated using light radiation. Also termed as photodynamic therapy, SDDS based on magnetic stimuli represents another external way to trigger drug release at the target site under programmable exposure of magnetic field [37]. Iron-oxide NPs have excellent potential for smart drug delivery, as it exhibits a significant response to both light and magnetic stimuli, it can be exploited for triggering a burst release of drug at the inflamed sites of RA termed as the magneto-calorific effect and photothermal effects. Thermal properties of magnetic NPs might be conveniently modulated by modifying their own viscosity in the endo-cellular environment. Photodynamic therapy (PDT) and photothermal therapy (PTT) use photosensitizers as therapeutic molecules. Moreover, near infrared(NIR) light can efficiently infiltrate the inflamed RA joints. Cu7.2S4 nanoparticles triggered with NIR irradiation (808 nm, 1 W cm−2) was suggested to accomplish improved bone mineral density (BMD) and bone structure and volume. It further impedes invasion to synovial tissue, erosion of cartilage and bone
Huo et al. have prepared optical nanoparticles induced PTT and PDT and documented probable pathways for cell toxicity [44]. During PTT cell necrosis can be induced by NIR laser light irradiation (wavelength:1064 nm), however when given as combination therapies (PTT + PDT), evidence of both necrosis and apoptosis pathways are indicated. Furthermore, PTT-PDT combination given simultaneously, can account for immunogenic cell-death, while fluorophores can be used for optical imaging as a diagnostic tool that can be applied for RA too.
Specific enzymes like phospholipases, proteases, or glycoside are often overexpressed in different pathological conditions, like inflammation, and can be exploited for enzyme triggered release and accumulation of drugs at the targeted site of interest [37]. Nevertheless, nature of cleavable units, the sensitivity of the delivery system can significantly influence the pharmacokinetics of entrapped payload. Further, it must be ensured that the metabolites or the degraded moieties are non-toxic and biocompatible and are cautiously eliminated from the body. Therefore, in future, enzyme-responsive nanoparticles offer tailor-made therapy according to variations in levels of disease expression. Redox- and enzyme-responsive nanoparticles are coming up as promising therapies in RA treatment.
Nanomaterials with exceptional physico-chemical properties targeting the lesions can be supplemented with precise external stimuli, such as light, microwave, ultrasound, and radiation. Upconversion nanoparticles (UCNPs) synthesized from rare-earth elements that are capable of translating NIR photons that have low-energy to high-energy ultraviolet or visible photons [45]. These extraordinary NIR excitation based optical properties of UCNPs allows penetration to deep tissues with minimum auto-fluorescence background, reinforcing a wide array of diagnostic applications alongwith biomedical imaging system [46, 47]. SDDS can translate the external stimuli and equivalent energy input into beneficial effects or release the payload
Schematic representation of stimuli-responsive polymers for nanotherapeutics of rheumatoid arthritis (RA).
Stimuli category | Stimulus | Description of the system | Drug | References |
---|---|---|---|---|
Chemical | pH | PLGA-PK3-lipid-polymer hybrid nanoparticles decorated with stearic acid-octa-arginine and folic acid (Sta-R8-FA-PPLPNs/MTX) [PK3, Folate-PEG-PLGA, egg PC, and Sta-R8] | MTX | [51] |
pH | Polymeric nanoparticles surface modified with Hyaluronic acid (HA)- (HAPNPs) consisting of polyethylenimine, egg phosphatidyl-choline, and PCADK | Dex | [52] | |
pH | PEGylated hyaluronic acid(P-HA) mineralized nanoparticles having a hydrophilic shell, 5β-cholanic acid as the hydrophobic core and CaP as the pH-responsive mineral | MTX | [53] | |
pH | Lipid nanocarriers formed by PEG-PLGA hydrophilic shell, functionalized with folic acid (FA) ligand for targeting FA-receptor, poly (cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK) & PLGA as the hydrophobic core. PCADK was used as pH-responsive material | MTX | [54] | |
pH | Spherical self-assembled micelles of poly (β-amino ester)-graft-poly(ethylene glycol) (PAE-g-PEG) encapsulating MTX into the hydrophobic core. | MTX | [55] | |
pH | Acetone-ketal-linked pro-drugs (AKP-dexs) pH-sensitive of dexamethasone nanoparticles | Dex | [56] | |
ROS | Folate conjugated to PEC 100 monostearate as film-forming material, and methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes (FOL-MTX&CAT-L) | MTX | [57] | |
Physical | NIR | Gold half-shell nanoparticles functionalized with RGD to target the inflammation, encapsulating methotrexate (MTX). | MTX | [58] |
PDT/PTT | Copper (Cu)-based nanomaterials with assistance of L-cystein termed as Cu7.2S4 nanoparticles (NPs) | __ | [59] | |
Magnetic | Magnetic iron oxide nanoparticles (IONPs) | __ | [60] | |
Multimodal Imaging | Light | Nanoparticles composed of PLGA co-encapsulating Au/Fe/Au- half-shell nanoparticles | MTX | [61] |
Biological | Enzyme (MMP) | Lipid nanoparticles with PEG coating, composed of triglycerol monostearate (TGMS) and 1,2-distearoyl- | Dex | [62] |
Cytokines | Nanoparticle system based on two natural polymers-N-trimethyl chitosan (TMC) and polysialic acid (PSA) encapsulated methotrexate | MTX | [63] | |
Combina- torial | Temp & pH | MTX loaded Gold nanoparticles and encapsulated in pegylated-poly (DL-lactic-co-glycolic acid) nanospheres | MTX | [64] |
NIR & Magnetic field | MTX-encapsulated poly(lactic-co-glycolic acid) (PLGA) (Au)/iron, (Fe)/gold (Au) half-shell nanoparticles coupled with arginine–glycine–aspartic acid (RGD) | MTX | [61] | |
pH & enzyme | Micelles of polyethylene-glycol-phenyl boric acid- triglycerol-monostearate (PEG–PBA–TGMS conjugated PPT) encapsulating Dex | Dex | [65] |
List of stimuli-responsive nanoparticles for the treatment of RA.
Presently, the conventional treatments exhibit escalation in dose and systemic toxicity upon administration of drug. Most anti-inflammatory therapeutic drugs are equitoxic to both the normal cells and inflamed cells. SDDS has been well recognized in the past few decades owing to its potential for site-specific and targeted delivery [66]. Encapsulation of anti-inflammatory drugs in nanoparticles can enhance the site-specificity, reduce the dose, curtail the systemic toxicity and improve the biodistribution to targeted disease site [67]. To overcome the disadvantage of conventional delivery of drugs, selective delivery whether passive or active can be used for targeting drug to the site of action as SDDS in RA therapy.
Passive targeting can be accomplished by targeting the physiological and anatomical changes in inflamed tissues, that occurred due to RA. For passive targeting, NPs do not require any surface modification, either by conjugation or by attaching a surface ligand. Various studies have shown the enhanced permeability and retention (EPR) mechanism for passive accumulation in inflamed tissues [68]. In the inflammatory RA milieu, there is evidence of angiogenesis but no evidence of displaying an abnormal lymphatic drainage [69]. The long-circulating delivery vehicles have been evidenced to specifically accumulate within the pannus of the inflamed synovium [70]. The hyperplasia in pannus exhibits a leaky vasculature due to high vascular permeability comparable to solid tumors. Consequently, taking advantage of leaky vasculature may for passive targeting is a promising option [71]. EPR allows NPs in size range from 20 to 200 nm to selectively accumulate in pannus and display on the surface of inflamed tissue. In addition to the EPR effect, hypoxic and acidic environment of inflamed joint also favors passive targeting [70]. Arthritic inflamed joint has poor oxygen delivery and increased metabolic rate due to meager perfusion into the diseased synovial joint. Therefore, the two conditions can easily be used as method of passive drug targeting in less oxygen and acidic microenvironment of RA affected inflamed tissue. NPs administrated in blood stream with hydrophobic surface are easily recognized by reticuloendothelial system (RES) such as spleen and liver, and engulfed by macrophages, consequently quickly eliminated from systemic circulation.
Targeted delivery involves active targeting to specific cells in the microenvironment of arthritic joints. Overexpressed receptors on particular immune cells can be targeted with its complimentary ligand that is decorated on nanoparticle surface. Several receptors are expressed by different cells, we shall be discussing a few including CD44, folate and beta-3 integrins. Targeting angiogenic vascular endothelial cells are also under investigation, with E-selectin as a promising target molecule [72]. Receptor mediated endocytosis is responsible for efficient uptake of the ligand decorated carrier molecule (ligand-receptor interaction) (Figure 3).
Outline of the targeting strategies for nanoparticulate drug delivery systems used in RA.
Activated macrophages overexpress folate receptor β(FR-β) in the arthritic joints [73]. Owing to post-translational modifications, the folate expressed on neutrophils are incapable of binding to FR-β [74]. Alternatively, a functional FR-β has been identified on the activated macrophages having nanomolar affinity for folate. Hence, the FR-β receptor emerges as a useful target in various diseases including RA, osteoarthritis [75], systemic lupus erythematosus [76], atherosclerosis [77] and Crohn’s disease [78]. Macrophages are key players of RA pathogenesis, as they secrete pro-inflammatory cytokines, metalloproteinases, ROS and prostaglandins. Folate is an attractive option for ease of surface modification, hydrophilicity, and stability in different solvents. Methotrexate (MTX) encapsulated folate-conjugated glycol chitosan (MFGCN) have been targeted to inflamed joint in adjuvant-induced arthritic rat model [79]. Likewise, surface of MTX-loaded liposomes was decorated with folate and were evaluated both
CD44 is a glycoprotein, overexpressed on the surface of activated macrophages, present in the inflamed joints of RA. CD44 can be exploited as a prospective target in RA treatment. HA, a biocompatible natural polymer has ben explored as a ligand that effectively binds to CD44 receptor. HA coated hydroxyapatite NPs (HA-NPs) encapsulating methotrexate (MTX) and teriflunomide (TEF) - (HYA-HAMT-NP) were reported for RA treatment [83]. Results suggested that HYA-HAMT-NP could emerge as an effective delivery vehicle to circumvent hepatotoxicity caused by drugs in RA.
Hypoxia in a critical factor in inflamed synovium that triggers neo-vascularization from existing vessels termed as angiogenesis [84]. The neo-vascularization preserves the chronic inflammatory state by engaging cells to the inflammatory site, provides nutrition and oxygen to the multiplying cells. Additionally, the enlarged surface of endothelium triggers secretion of adhesion molecules, cytokines and stimulates neutrophil infiltration as well as synovial membrane into the cartilage, causing cartilage destruction and bone erosion [85]. Promising therapies based on angiogenesis are emerging for RA therapy, where VEGF and integrins are the therapeutic targets.
Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor principally secreted by SFs in the pannus. In angiogenesis, VEGF triggers multiplication and migration of endothelial cells. Further, it enhanced blood vascular permeability, stimulates maturation and maintenance of the neo-vessels [86]. TNF-α and IL-1, the pro-inflammatory cytokines induce the SFs and other cells to secrete VEGF, and VEGF is overexpressed at the inflamed joint owing to angiogenesis [87]. Therefore, VEGF and VEGF receptor inhibition can be an attractive strategy for RA treatment as it may effectively decrease inflammation by inhibiting angiogenesis.
Vasoactive intestinal peptide (VIP) is a neuropeptide of the central and peripheral nervous system that has vasodilatory, anti-proliferative, anti-inflammatory, cell protective agent and broncho-dilatory role. The activity of VIP binds to high affinity VIP receptors, that are overexpressed on T-lymphocytes and several inflammatory cells. VIP inhibits the secretion of pro-inflammatory cytokines to act as anti-inflammatory molecule. It also promotes the secretion of anti-inflammatory molecules by stimulated innate cells [88]. Proliferating synoviocytes and activated macrophages overexpress VIP receptors in inflamed RA. Therefore, VIP receptor specific ligands can be conjugates to nanoparticles to specifically target the diseased site. Therefore, VIP can be exploited as a therapeutic agent for active targeting to RA joint.
Integrins are the biogenic markers of endothelium undergoing angiogenesis and play a vital effector role in it. Integrin alpha-V-beta 3 (αvβ3 integrin), also referred to as vitronectin receptor are overexpressed on osteoclasts and activated macrophages of the inflamed synovium. Integrin receptor promotes angiogenesis, helps in osteoclast-mediated bone resorption, and induces pathological neo-vascularization [89]. Inhibition of αvβ3 integrin activity stimulates endothelial cell apoptosis, thereby inhibiting angiogenesis [90]. Hence, αvβ3 is considered a reliable maker for targeted delivery to RA patients.
E- Selectin is a glycoprotein that is associated with leukocyte rolling and adhesion and is expressed on vascular endothelium of the inflamed synovium, and promotes angiogenesis [91]. The inflammatory cytokines maintain its upregulated expression in the inflamed tissue. Therefore, expression of e-selectin can be a useful molecular target for RA therapy. Therefore, e-selectin serves as yet another attractive strategy for active targeting of the chosen delivery of drug to the diseased RA joint [92].
The assembly of stimuli-sensitive nanoparticles necessities the usage of biocompatible constituents, that can undergo supra-molecular changes in conformation, a hydrolytic cleavage, and precise protonation, etc. Polymers have maximum suitability and has been widely explored class of materials that have incredible potential. Polymers may be of natural or synthetic origin. The flexibility of the polymer sources and its ability for synthesis of various combinations of polymers has facilitated manipulation of the polymer sensitivity to specific stimuli within a narrow range [93]. Nanoparticles could be synthesized by lipid, metals and polymers. NPs decoy pro-inflammatory molecules like cytokines and ROS and sometimes osteoclast differentiation factors. Moreover, surface modification of NPs with target moiety is a extensive application in site specific drug delivery by enhancing the bioavailability of drug and reducing non-target side effects [94].
PDC based DDS has been proposed by Ringsdrof in 1975 [95], in which a low molecular weight drug, targeting moiety and solubilizer are attached to polymeric backbone covalently
Nanoparticles are solid colloidal particles with unique physico-chemical properties such as ultra-small size, surface charge, large surface area to mass ratio Unlike polymer-drug conjugates, NPs allow encapsulation/absorption/entrapment of drug without modification. The high reactivity, diffusivity, solubility, toxicity, immunogenicity and drug release characteristics can be manipulated to make efficient delivery system. Polymeric, liposomes, micelles and metallic nanoparticles are the most commonly used nanoparticles [101].
The biodegradable backbone in biopolymeric NPs protects the drug from
Glycol chitosan has enhanced water solubility and functional groups for further chemical modifications making it better suited as a potent drug carrier [102]. Glycol-chitosan nanoparticles(GCNPs) are biocompatible, pH responsive and biodegradable. Methotrexate (MTX) encapsulated folate-conjugated glycol chitosan (MFGCN) have been reported to target the overexpressed folate receptors β (FR-β) on activated macrophages in the inflamed joint in adjuvant-induced arthritic rat model. Figure 4 gives a pictorial description of MFGCN that reduced the arthritic index, improved the antioxidant response and decreases pro-inflammatory cytokines and suggesting its potential in targeting activated macrophages of synovium [79].
Pictorial representation of utilization of folate functionalized methotrexate loaded glycol chitosan nanoparticles (MFGCN) in treating CIA rats targeting inflammation and ROS in rat serum post 21 days of treatment (n = 6). [A] MFGCN development and active targeting of M1 macrophages in the inflammatory synovium. [B] LPO and LDH activity [C] panel showing antioxidant potential (activity quantification of GST, GSH, GP and GR) [D] quantification of TNF-α, IL-4, IL-1β, IL-10 and IL-17 [E] Representative H&E staining images of study groups comparing healthy and arthritic control groups with the treatment groups(n = 6). Data was analyzed by one-way ANOVA *p < 0.05, **p < 0.01, ***p < 0.001.
GNPs can be surface functionalized through covalent bonding, by cationic polymers or physical or ionic absorption [103], functional groups like e.g. thiol, amine, and carboxyl groups that are reactive [104]. GNPs were strategically planted in macrophages to target thioredoxin reductase to evaluate its antiangiogenic impact by binding to the vascular endothelial growth factor (VEGF) [105]. Lee et al. suggested MTX encapsulated RGD-attached gold half-shell NP system for RA treatment [106]. On irradiation with near-infrared (NIR), these GNPs delivered MTX to the inflamed joints, maximizing its efficacy with minimal side effects. GNPs were modified physically with Tocilizumab(TCZ) and chemically altered with an end-group thiolated hyaluronate(HA). This complex of HA-GNP-TCZ indicated a synergistic effect for its dual-functional effect on VEGF and IL-6R (receptors for IL-6) in RA treatment [107]. GNPs may block the RANKL induced osteoclast formation which leads to cartilage and bone destruction [108].
Liposomes are bilayered lipids with an aqueous core. Both hydrophobic as well as hydrophilic drugs can be encapsulated within phospholipids and the water phase cavity, making them SDDS [109]. Particle size determines the extent of accumulation at the synovium, with maximum accumulation of liposomes reported with size <100 nm diameter [110]. Therapeutic efficacy is limited due to rapid clearance from circulation
Micelles can be synthesized in small size with narrow size distribution from amphiphilic molecules that self-assemble into NPs in aqueous solution with a distinct hydrophobic cavity and an exterior hydrophilic surface. This makes them apt for intravenous injection and targeted delivery into the inflamed synovium as a consequence of extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (ELVIS) [114]. Wang et al. reported self-assembled micelles with an amphiphilic copolymer PEG-poly-e-caprolactone (PEG-PCL), which displayed ELVIS in inflamed joints [115], but the non-biodegradable backbone of synthetic polymers caused non-specific accumulation in liver. Bader et al. [116] developed micelles from polysialic acid (PSA)-the hydrophilic polymer and synthesized micelles by altering it with N-decylamine (DA) and PCL, that formed the hydrophobic fragment. Prolonged circulation was observed with these micelles that accumulated passively at the inflamed tissue. PSA-DA micelles exhibited
Multifactorial pathogenesis is the hallmark in RA causing bone fragility and functional erosion linked disability in extreme conditions. Although, conventional therapeutic formulations alone or in combination may relieve the symptoms, these are associated with complex adverse reactions. Dose-escalation, immunogenicity, systemic toxicity, and non-specific biodistribution in tissues warrant SDDS development. Stimuli-responsive NPs target specific inflammatory intermediaries, thereby suppressing the pathophysiological cascade, that may alleviate RA symptoms and delay joint destruction. Therefore, both the approaches may be exploited for achieving dose reduction coupled with drug accumulation at the targeted inflamed joint.
LB is thankful to UGC, and VS is thankful to ICMR, Govt of India for Senior Research Fellowship. VK is thankful to Individual Fellowship from European Union’s Research and Innovation program, Marie Skłodowska-Curie grant agreement No. 890507.
The authors declare no conflict of interest.
Writing—original draft preparation, AKV, LB, VS and VK; visualization, AKV; conceptualization, writing—review and editing, supervision and project administration, AKV. All authors have read and agreed to the published version of the manuscript.
This research received no external funding.
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He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón",slug:"juan-carlos-gardon",fullName:"Juan Carlos Gardón",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:"Catholic University of Valencia San Vicente Mártir, Spain",institution:null},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain. She is a Full Professor at the Department of Medicine and Animal Surgery at the same University. She developed her research activity in the field of Endocrinology, Hematology, Biochemistry and Immunology of horses. She is a scientific reviewer of several international journals : American Journal of Obstetrics and Gynecology, Comparative Clinical Pathology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology. Since 2014, she has been the Head of the Clinical Analysis Laboratory of the Hospital Clínico Veterinario from the Faculty of Veterinary, CEU-Cardenal Herrera University.",institutionString:"CEU-Cardenal Herrera University",institution:{name:"CEU Cardinal Herrera University",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,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",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. 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After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". 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