Several intermolecular forces known to occur between analyte and polysaccharide CSPs. Adapted from ref. [8].
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"8738",leadTitle:null,fullTitle:"Asthma - Biological Evidences",title:"Asthma",subtitle:"Biological Evidences",reviewType:"peer-reviewed",abstract:"Asthma is a prevalent disease in all age groups that results from different pathogenic mechanisms, cells, and mediators engaged in innumerous clinical phenotypes and endotypes. This book exhaustively and didactically explores the biological expression of numerous cells and mediators involved in bronchial inflammation. The information provided aims at identifying the diversity and complexity of the interrelationships between the different players, drawing attention to critical mechanisms in asthma. It also highlights the requirement of new tools to identify strong biomarkers absolutely critical for managing asthma.",isbn:"978-1-78984-316-3",printIsbn:"978-1-78984-315-6",pdfIsbn:"978-1-83962-246-5",doi:"10.5772/intechopen.80155",price:119,priceEur:129,priceUsd:155,slug:"asthma-biological-evidences",numberOfPages:144,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b0af4d7a29f41b1408f487f13af4216d",bookSignature:"Celso Pereira",publishedDate:"October 2nd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8738.jpg",numberOfDownloads:9614,numberOfWosCitations:8,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:17,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:31,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 10th 2018",dateEndSecondStepPublish:"November 21st 2018",dateEndThirdStepPublish:"January 20th 2019",dateEndFourthStepPublish:"April 10th 2019",dateEndFifthStepPublish:"June 9th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"66336",title:"Prof.",name:"Celso",middleName:null,surname:"Pereira",slug:"celso-pereira",fullName:"Celso Pereira",profilePictureURL:"https://mts.intechopen.com/storage/users/66336/images/system/66336.png",biography:"Prof. Celso Pereira, MD, Ph.D., is head-chief of the Clinical Immunology Unit and Clinical Herbal Medicine in Clinical Practice, Medicine Faculty, Coimbra University, Portugal. He is also a graduated specialist in immuno-allergy and has developed clinical activity at Coimbra Surgical Center. His main activities include clinical practice, education (pre and postgraduate), and clinical and laboratory research. He was president of the Immuno-Allergy Board of the Portuguese Medical Association. He is the coordinator of some Portuguese clinical guidelines and a member of the national committee for the diagnostic procedures for allergy and clinical immunology and the national committee for COVID vaccination. His scientific interests include research in the mechanisms of respiratory allergy, specific immunotherapy, and medicinal plant applications.",institutionString:"Faculty of Medicine University of Coimbra",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"University of Coimbra",institutionURL:null,country:{name:"Portugal"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1047",title:"Pulmonology",slug:"pulmonology"}],chapters:[{id:"66788",title:"Childhood and Adult Asthma: Phenotype- and Endotype-Based Biomarkers",doi:"10.5772/intechopen.86006",slug:"childhood-and-adult-asthma-phenotype-and-endotype-based-biomarkers",totalDownloads:880,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The concept of asthma has changed from that of a single disease entity to that of a heterogeneous disease comprising several phenotypes linked to specific endotypes. Recently, significant progress has been made in disease classification into phenotypes and biologically distinct variants (endotypes). Classification of patients into endotypes has led to precision medicine in which specific biomarkers and appropriate individualized treatments have now been identified. Despite the ongoing classification of disease endotypes, the presence or absence of a T-helper 2 (Th2) molecular signature has resulted in the association of asthma endotypes with phenotypes so as to establish responders and non-responders to inhaled corticosteroid therapy. More importantly, biologic therapies predicated on disease endotypes may in future constitute a paradigm shift from the traditional pharmacologic treatments and lead to better prognosis in moderate-to-severe forms of the disease (in which they are presently used). This book chapter aims to discuss the current concepts on asthma classification and biomarker-based diagnosis.",signatures:"Joy N. Eze and Samuel N. Uwaezuoke",downloadPdfUrl:"/chapter/pdf-download/66788",previewPdfUrl:"/chapter/pdf-preview/66788",authors:[null],corrections:null},{id:"67151",title:"Clinical Applications of Impulse Oscillometry",doi:"10.5772/intechopen.85890",slug:"clinical-applications-of-impulse-oscillometry",totalDownloads:1307,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Impulse oscillometry is a noninvasive procedure that can be performed within few minutes. The purpose of the procedure is to measure the resistance of the small and large airways, as well as the reactants of the airways. It is gradually gaining popularity in evaluating lung function, particularly in patients with asthma and COPD. In contrast to spirometry, the test performs measurement during tidal breathing. In other words, forced exhalation is not required. Other advantages include, but are not limited to, evaluating COPD patients’ reversibility which is rarely noted on spirometry. IOS also is tool for chronic management of patients with asthma and COPD while on treatment. It can evaluate children with asthma even as young as 2 years old. Spirometry requires the child to cooperate and usually is of meaningful use beginning at the age of 5 years old. Other potential applications include early evaluation of transplant rejection, cystic fibrosis, and vocal cord disorder. In this chapter, we will explore the procedure itself, the settings, advantages and disadvantages, and comparative data with spirometry.",signatures:"Constantine Saadeh and Nicole Davey-Ranasinghe",downloadPdfUrl:"/chapter/pdf-download/67151",previewPdfUrl:"/chapter/pdf-preview/67151",authors:[null],corrections:null},{id:"65641",title:"Role of Airway Smooth Muscle Cells in Asthma Pathology",doi:"10.5772/intechopen.84363",slug:"role-of-airway-smooth-muscle-cells-in-asthma-pathology",totalDownloads:1081,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Airway smooth muscle (ASM) cells have been shown to play an important role in bronchial asthma. As the research progresses, the mechanism becomes more and more complex. This chapter reviews the role of ASM in asthma pathological mechanisms including inflammatory reaction, extracellular matrix proteins, cell contraction, cell structure, neuromodulation, airway remodeling, apoptosis, autophagy, miRNA, mitochondria, etc. In brief, ASM is similar to a “processing station.” It is not only affected by various signals in the body to produce biological effects and secrete various signals to act on downstream target cells but also feeds back to the upstream pathways or receives feedback from downstream pathways to form a complex network. The results summarized in this chapter are expected to provide new targets for the clinical treatment of asthma.",signatures:"Wenchao Tang",downloadPdfUrl:"/chapter/pdf-download/65641",previewPdfUrl:"/chapter/pdf-preview/65641",authors:[null],corrections:null},{id:"66011",title:"Endothelial Cells in Asthma",doi:"10.5772/intechopen.85110",slug:"endothelial-cells-in-asthma",totalDownloads:1038,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The occurrence of new blood vessel formation in the airway wall of asthma patients was reported more than a century ago. It was long thought that angiogenesis in asthma was an epiphenomenon of airway inflammation. Therefore, little research has been performed on the role of endothelial cells in this disease. We are moving away from this misconception as an increasing number of clinical studies and findings in murine models of asthma demonstrate a causal link between angiogenesis in the airway and genesis of allergic asthma. In this chapter, we review the evidence supporting key roles for the endothelium and other angiogenic cells in the pathogenesis of asthma.",signatures:"Andrew Reichard and Kewal Asosingh",downloadPdfUrl:"/chapter/pdf-download/66011",previewPdfUrl:"/chapter/pdf-preview/66011",authors:[null],corrections:null},{id:"66128",title:"The Role of Platelets in Allergic Inflammation and Asthma",doi:"10.5772/intechopen.85114",slug:"the-role-of-platelets-in-allergic-inflammation-and-asthma",totalDownloads:1021,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Platelets are a kind of blood cells derived from bone marrow megakaryocytes and play essential roles in thrombosis, hemostasis, and tissue repair. Platelets have been found to be crucially involved in various immune responses and actively involved in the pathogenesis of allergic diseases such as allergic asthma. Patients with allergic asthma have lower platelet counts and increased levels of markers of platelet activation after allergen exposure. Platelets have been found extravascularly in the airways, and platelet products have been measured in bronchoalveolar lavage (BAL) fluid of asthmatic patients. Platelets are also crucially involved in the development of allergic diseases, including the development of allergic asthma via the regulation of allergic inflammation, especially type 2 inflammation mediated by active platelet-derived IL-33 protein activation. Both platelets and IL-33 are activated by tissue damage and involved in biological defense mechanisms and initiation of tissue repair. Therefore, platelets may be involved in the development of steroid-refractory asthma, including irreversible airway remodeling phenotypes.",signatures:"Mirjana Turkalj and Ivana Banic",downloadPdfUrl:"/chapter/pdf-download/66128",previewPdfUrl:"/chapter/pdf-preview/66128",authors:[null],corrections:null},{id:"67117",title:"Eosinophilic Asthma",doi:"10.5772/intechopen.84297",slug:"eosinophilic-asthma",totalDownloads:1269,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Eosinophilic asthma is known as a main phenotype of asthma classified on the basis of immune cells involved in inflammatory response in the respiratory airway. Eosinophilic asthma can be related to increased severity of asthma, allergic sensitization, adult onset, and increased resistance to corticosteroids. The prevalence of eosinophilic asthma is 32–40% among asthmatic patients. Different cells and cytokines are involved in its pathogenesis including eosinophil, mast cells, type 2 helper T cells, innate lymphoid cells, IL-4, IL-5, and IL-13. Eosinophil count in induced sputum and bronchoalveolar lavage is the yardstick for recognizing and distinguishing eosinophilic asthma from non-eosinophilic asthma, while various tests which are noninvasive such as fractional exhaled nitric oxide and periostin are arising as possible substitutes. Novel and advanced therapies new and advanced therapies and more convenient biological drugs, Leads to high requirement for particular endotype- and phenotype-related treatment plans. Identification and knowledge of the specific pathophysiology of eosinophilic asthma have great association with disease management and chances for better patient prognosis.",signatures:"Bushra Mubarak, Huma Shakoor and Fozia Masood",downloadPdfUrl:"/chapter/pdf-download/67117",previewPdfUrl:"/chapter/pdf-preview/67117",authors:[null],corrections:null},{id:"66708",title:"Role of Various Mediators in Inflammation of Asthmatic Airways",doi:"10.5772/intechopen.84357",slug:"role-of-various-mediators-in-inflammation-of-asthmatic-airways",totalDownloads:1209,totalCrossrefCites:2,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The degree of airway inflammation is directly related to asthma severity and associated hyper-responsiveness. Airway inflammation is categorized into three types: (a) acute asthmatic inflammation featured by early recruitment of cells into the airways, (b) subacute asthmatic inflammation involving activation of recruited cells in continual inflammation, and (c) chronic inflammation characterized by cellular damage. T-helper lymphocytes, the key factor in the pathogenesis of bronchial asthma, induce B cells to synthesize and secrete IgE through production of IL-4 and induce eosinophil-mediated inflammation. Mediators such as histamine, PG, leukotrienes, and kinins contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells into airway epithelia that initiate mucociliary clearance signaling pathways through special Toll-like receptor 4 expressed on epithelial cells activated by allergic and infectious triggers. These cells form barrier against mechanical stress, oxidant stress, allergens, pollutants, infectious agents, and leakage of endogenous solutes. Various adhesion molecules and costimulatory factors also promote infiltration of inflammatory cells at the site of inflammation.",signatures:"Poonam Arora and S.H. Ansari",downloadPdfUrl:"/chapter/pdf-download/66708",previewPdfUrl:"/chapter/pdf-preview/66708",authors:[null],corrections:null},{id:"66690",title:"Pathogenic Roles of MicroRNA in the Development of Asthma",doi:"10.5772/intechopen.85922",slug:"pathogenic-roles-of-microrna-in-the-development-of-asthma",totalDownloads:949,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Asthma is a common and chronic inflammatory disease. Pathogenic mechanism underlying asthma is complicated. The inflammatory reactions in asthma have been recognized to involve mast cells, eosinophils, lymphocytes (T cells, B cells), macrophages, and dendritic cells. MicroRNA (miRNA, miR) is a group of small noncoding RNAs with 21–25 nucleotides (nt) in length, which impact biologic responses through the regulation of mRNA transcription and/or translation. MicroRNAs are related to developmental processes of many immunologic diseases. Most studies showed that regulation of miRNAs to their targeting genes appears to play an important role in the development of asthma. This chapter has discussed altered expression of miRNAs in cells and tissues from patients with asthma, in order to better understand the mechanics of pathogenesis of asthma. In addition, the regulation of miRNAs as a novel therapeutic approach will require a deeper understanding of their function and mechanism of action.",signatures:"Xiaoyan Dong and Nanbert Zhong",downloadPdfUrl:"/chapter/pdf-download/66690",previewPdfUrl:"/chapter/pdf-preview/66690",authors:[null],corrections:null},{id:"67683",title:"Nutritional Recommendations in Asthmatic Patients",doi:"10.5772/intechopen.86259",slug:"nutritional-recommendations-in-asthmatic-patients",totalDownloads:861,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Asthma is a heterogeneous disease, and airway inflammation has an important role in its pathogenesis. Some nutritional factors can influence the process of asthma. It is reported that saffron has anti-inflammatory, antioxidant, and muscle relaxant effects, and some animal and human studies showed that saffron and its active components (safranal and crocin) improved the asthma biomarkers and clinical symptoms. Some other nutritional factors also affect asthma; for example, magnesium can relax the muscles and thus has bronchodilatory effects. Curcumin is the major active component of turmeric which has a potent antioxidant, anti-inflammatory, and anti-allergic effects. Because some researchers suggested that intestinal microbial flora has an important role in allergy, probiotics can be a complementary supplement for asthmatic patients. Generally nutritional factors could be advised for asthmatic patients with the goal of reducing the needs for chemical drugs.",signatures:"Marzie Zilaee and Seyed Ahmad Hosseini",downloadPdfUrl:"/chapter/pdf-download/67683",previewPdfUrl:"/chapter/pdf-preview/67683",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"934",title:"Allergic Diseases",subtitle:"Highlights in the Clinic, Mechanisms and Treatment",isOpenForSubmission:!1,hash:"0d8961a0f59ba85124b525aee52a4d8c",slug:"allergic-diseases-highlights-in-the-clinic-mechanisms-and-treatment",bookSignature:"Celso Pereira",coverURL:"https://cdn.intechopen.com/books/images_new/934.jpg",editedByType:"Edited by",editors:[{id:"66336",title:"Prof.",name:"Celso",surname:"Pereira",slug:"celso-pereira",fullName:"Celso 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Awareness of the complexity of the renin-angiotensin system (RAS) has increased exponentially since it was initially considered relevant only to hypertension and has led to an explosion of understanding in biochemistry, molecular biology, cell physiology, anatomy, pharmacology, and pathophysiology. I have been involved in studies at all these levels in a wide variety of experimental models in animals and humans for over 50 years. This chapter is a review of what my colleagues and I have learned over the course of this half-century. This is not meant to be an update on all features of the RAS but rather the advances over the years in my personal research journey. It represents almost half of my total research publications.
This has included studies on the effects of angiotensin on the adrenal medulla in intact cat adrenal glands and cultured bovine chromaffin cells, renin storage and release in the rat kidney and secretory granules, properties of isolated proteins, hormonal and second messenger control of prorenin presence and secretion from human utero-placental tissues and renin/prorenin in a variety of tumors. These studies have implicated the RAS in a rodent model of pulmonary fat embolism syndrome (PFE) and showed that drugs acting at different steps in the RAS provided protection, suggesting that this approach could be useful in treating/preventing this potentially fatal condition. Investigating the RAS in many models in animals and humans should increase our understanding of normal and pathological processes and thus improve therapy/prevention of a variety of diseases. For the sake simplicity the term renin will be understood to mean total renin (renin + prorenin) unless specified otherwise. In extrarenal sites, prorenin may be the only one present and it can have some catalytic activity even without processing to the smaller protein renin, especially when bound to its membrane receptor.
In the early 1960s, evidence was presented that angiotensin II (Ang) could evoke the release of aldosterone from the adrenal cortex and catecholamines from the adrenal medulla, but the cellular mechanisms had not been completely identified. Since my colleagues and I had been mining the role of calcium in adrenal medullary secretion in response to acetylcholine [1], we decided to examine peptides in our studies and found that extracellular calcium was required for the stimulant effect of Ang [2]. Interestingly, one of the earliest demonstrations of the direct effect of Ang on adrenomedullary hormone secretion was carried out in 1963 in the laboratory of Wilhelm Feldberg at the National Institute for Medical Research in London [3] at which time I was working in the same lab on a different project during my postdoctoral training. Their study and our later one were carried out on the isolated perfused adrenal glands of cats. This is when I gained experience and insight into the value of using intact tissues in experimental studies without disruption of their cellular connections and revealed the immediate effect of treatment with peptides and amines. We could also stimulate the splanchnic nerve in these preparations to more closely simulate the natural signaling condition. Further studies on the role of calcium in stimulus-secretion coupling revealed its fundamental importance in exocytosis in exocrine secretion and neurosecretion [4, 5, 6]. This was summarized in several review papers [7, 8, 9].
The next time that I had occasion to study the effects of Ang was over 20 years later when I was working on sabbatical in the laboratory of my former student, Dr. J.S. Hong, at the National Institute of Environmental and Health Sciences. His lab was interested in the long-term effects of agents on the adrenal medulla (as a surrogate for postganglionic sympathetic nerves) and the potential feedback on enzymes and peptides. In a series of experiments on isolated chromaffin cells, our group found that a stable Ang peptide (S-Ang) increased the secretion and expression of catecholamines and met-enkephalin as well as the mRNA expression of several catecholamine synthetic genes (tyrosine hydroxylase and phenylethanolamine N-methyltransferase) [10, 11]. The time course of the response to S-Ang showed both short-term and long-term effects and revealed the increased expression of the oncogene c-fos [12] and its role in nuclear stimulation. These changes were mimicked by in vivo stimulation in rats by insulin [12]. These experiments directly implicated intracellular calcium as a second messenger leading to nuclear mRNA synthesis that required a lag time that followed catecholamine release [11].
We found evidence that endogenously released Ang from chromaffin cells could initiate the secretion of catecholamines and met-enkephalin from bovine chromaffin cells [13, 14]. It is likely that the enzyme responsible for this is renin since renin has been found in the adrenal medulla and in chromaffin cells [15]. Prorenin was not found in these cells in control animals. These results suggest that there may be some autocrine regulation of adrenomedullary secretion mediated by the RAS.
In the 1970s, we turned our attention to studies on renin and the analytical method of the day was to measure the generation of angiotensin I using a protein or polypeptide substrate. The literature indicated that renin activity from various sources was not inhibited by the usual SH-targeting agents but was potentiated in some cases by the SH-protecting agent dithiothreitol (DTT). Since we intended to find a useful substrate, we first studied the interaction of DTT with renin and/or several renin substrates (angiotensinogen). The commercially substrate available at the time was hog renin substrate but we also prepared a semi-purified bovine substrate. We found that the potentiating effect of DTT was exerted on the substrate (bovine or porcine) and not on renin [16].
Using our sensitive enzymatic assay and radioimmunoassay (RIA) for angiotensin I, we were able to initiate a number of studies on the storage of renin in the kidney using knowledge gained from our previous studies on secretory granules from the adrenal medulla [17] and the posterior pituitary [18]. The goal was to understand secretory mechanism for renin utilizing the secretory granules from the juxtaglomerular cells of the renal cortex. There had been a few studies on storage of renin but no systematic studies to understand their physical properties and the effect of isolation techniques. In our initial study we took into consideration what we had learned about the influence of temperature and pH on other secretory granules and found that crude rat kidney renin secretory granules were more stable when isolated at room temperature (22–25°) than at 0° and were most stable at pH 6.0 [19]. They were also somewhat stabilized by MgATP unlike adrenal chromaffin granules [20]. Later studies with more purified granules confirmed that the granules were more stable at room temperature but were labile if transferred from hyperosmotic density gradient media back to physiological tonicity [21]. When these purified granules were incubated at 37° instead of room temperature they again showed lability when they were subsequently incubated at 0° [22]. In order to avoid the problems with isolation in hypertonic media, we employed density gradients with lower osmotic properties and at room temperature. These granules were stable as long as there were not transferred to 0° media and kept not far from pH 6.0 [23]. Granules prepared in isotonic density gradient media showed two peaks with short term centrifugation that was resolved with longer term preparation, suggesting that renin granules are of two sizes with the same density [23].
When we began to study renal granules, we became aware of a study of another angiotensin I-generating enzyme that had a lower pH optimum and preferred the tetradecapeptide substrate rather than the protein substrate. They called it pseudorenin [24]. It was found in rat plasma and a wide variety of tissues and in much higher concentrations in the salivary gland and the spleen than in the kidney. Since we could not find any physiological studies of pseudorenin in intact animals, we examined the changes in plasma pseudorenin and renin in rats after nephrectomy and in response to converting enzyme inhibition and beta-adrenergic receptor blockade. We found that, unlike renin, plasma pseudorenin increased after nephrectomy and treatment with propranolol but did change after angiotensin converting enzyme treatment [25]. Later we examined bovine spleen and provided evidence that pseudorenin is cathepsin D [26].
Although there had been several reports of increased renin activity in serum or tissues of patients with renal tumors using bioassays for analysis [27, 28], none had followed the clinical course and biochemical evaluation of the patients and utilized agents interfering with angiotensin to modulate the course of the disease. We reported on a patient with bilateral Wilms tumor (nephroblastoma) who exhibited congestive heart failure, hypertension and elevated serum renin using a more contemporary radioimmunoassay and an international standard [29]. We found the patient’s clinical course and tumor size in response to surgery and chemotherapy were paralleled by serum renin concentrations (PRC) and his hypertension was ameliorated by saralasin, a peptide angiotensin receptor antagonist (this was before non-peptide ARBs were available). We were able to assay samples with exceedingly high renin concentrations that would not be possible with simple plasma renin activity (PRA) assays since these high dilutions would reduce the available endogenous substrate to suboptimal levels. For our assays, we used substrate from nephrectomized sheep that was known to be a better substrate for human renin. Plasma renin concentration was over 4600 μU/ml before therapy (normal 30–90 in our lab) and fell to 69 after chemotherapy and surgery. A few months later the tumor size increased and so did the renin concentration [29] A partially resected tumor mass was found to contain renin by immunohistochemical and biochemical analysis (1245 μU/g).
To utilize a non-enzymatic method to localize renin, we utilized a specific antirenin antiserum and examined several non-renal tumors. In preliminary studies we found renin and prorenin in complete and incomplete hydatidiform moles [30, 31]. By 1990, prorenin was a widely accepted name for what had one time been called “inactive renin” and we reported on its presence in cyst fluid and ascites in patients with ovarian tumors [32].
When considering the possibility of alternative forms of renin, we noted the report of high concentrations of renin in human amniotic fluid [33] and sought to purify the enzyme from this source. We noted that the original description of renin in amniotic fluid included a step of acidification and that it was subsequently found that this caused an activation of “inactive renin”. We compared chromatographic and kinetic properties of endogenous renin, acid- and pepsin-activated renin using bovine and hog substrate and found differences between acid- and pepsin-activated renin [34]. Further purification of the inactive renin allowed separation from the pseudorenin mentioned above that was similarly inhibited by pepstatin [35, 36]. We developed an assay utilizing a single tube for renin-generated angiotensin I and the subsequent radioimmunoassay which greatly facilitated these studies [37]. We also showed that both prorenin and active renin were inactivated by ethyl diazoacetylglycinate, a compound known to inactivate aspartyl proteases but not pepsinogen [38].
We initially demonstrated the presence of the renin and prorenin with both acid and trypsin activation using nephrectomized sheep plasma substrate. This showed, like amniotic fluid, that the bulk of the potential angiotensin-generating activity was in the inactive (IR)-prorenin form (about 70% in these samples) [39]. Our immunofluorescence study, using antiserum to human kidney renin, showed that the positive cells were the amniotic epithelial cells and not contaminating chorionic cells [39]. We noted at the time that early initial attempts to show synthesis by cultured amniotic cells were negative [40]. Those studies included bioassays of samples that had initially been treated at pH 3.0 so some prorenin would have been activated and recorded as renin [40]. In our study where we did not expose samples to low pH and used trypsin activation to assay IR, we found no IR or R in medium from cultured amniotic cells although similarly cultured chorionic cells produced enormous quantities of IR/prorenin that sometimes required a dilution of 1000× to bring the samples into the assay range [41].
In another model, to assess the potential synthesis of IR from the amnion, we superfused separately the amnion and the chorion from a clamped fetal membrane in a Ussing chamber device. We found that there was a dramatic and increasing release from the chorion side but a low and decreasing amount from the amnion side [41]. Furthermore, when a high concentration of IR previously released on the chorion side, was superfused on the chorion side, there was no increase on the amnion side, thus excluding leakage or transport [41]. Since there are many sources of prorenin in the human uteroplacental complex at term pregnancy [42], there could be more than one source of its presence in amniotic fluid. That could include uptake from fetal urine since prorenin has been found in urine [43] and an uptake system in amnion has been reported [44]. The latter group used amnion explants and found very low levels of renin mRNA and extremely low levels of prorenin protein release but considered that the decidua could be the source of amniotic prorenin. There was no evidence of
After determining that the amnion was not a likely source of prorenin in the amniotic fluid, we turned our attention to the other major fetal membrane, the chorion, and more specifically the chorion leave (free chorion). In our initial report [45], we noted the early work that suggested that Hofbauer cells (fetal macrophages) and not trophoblasts or fibroblasts were the renin-containing cells, using the Bowie stain that showed renin in the kidney We used an immunofluorescence technique and employed an antiserum to a highly purified renin preparation from human kidney that we subsequently realized recognized both renin and prorenin. We found that the renin immunoreactivity in the chorion was strictly localized to the cytotrophoblast layer [45]. Subsequent biochemical studies showed that the “inactive renin” from chorion and culture medium from chorionic cells is definitely prorenin [46]. In addition, we found that this same cell layer was positive for hCG [47] and there was a relatively constant ratio of renin/hCG in purified chorionic cells: 5.14 μU renin/mIU hCG. Here and elsewhere the terms renin and prorenin and IR are used interchangeably except where noted since all or almost all the renin is present as prorenin.
We used our superfused membrane, preparation to show that both prorenin and hCG were released at a constant or increasing rate even after 80 minutes [47]. An interesting finding from our studies on the superfused chorion was the short term release of prorenin by angiotensin II [48]. We also found that angiotensin induced the release of LHRH (GnRH)-like activity from this preparation [49]. In parallel experiments we demonstrated specific binding of angiotensin II to these cells [49].
Since the purified chorionic cells could be grown in tissue cultures for many days, we were able to examine factors that might modify synthesis and release in the short or long term. We could even grow these cells for periods up to 3 months without them losing their capacity to synthesize and release prorenin [41, 48]. When we examined these cells for the steroid hormone progesterone that had been reported to be present in the chorion, we found they indeed did contain progesterone and its synthesis and release could be promoted by various precursor steroids. (pregnenolone and 25HC) [50]. The amount of progesterone released greatly exceed the amount initially found in these cells and the synthesis and secretion were both promoted by agents acting to raise cyclic AMP (cAMP) [50]. These included dibutyryl cAMP, methyl isobutyl-xanthine (MIX), forskolin and cholera toxin. Prorenin secretion by these cultured cells was also promoted by MIX and cholera toxin and especially by cholera toxin in the presence of phorbol myristate acetate (PMA), a protein kinase C agonist. In some cases, the concentration after 72 hours of incubation with these agents reached 700,000 IU/ml. This was not due to an increase in cell numbers since these were confluent monolayers [48]. The dramatic potential for term chorion to synthesis and release prorenin clearly differentiates the secretory process from the renal secretion of renin where it is stored primarily in dense secretory granules and is presumably released by conventional regulated exocytosis. We have found prorenin in the chorion to be mostly in the cytoplasmic fraction of the tissue and not in particulate fractions [49].
After a report in 1989 that decidual cells have the capacity to synthesize and release active and total renin from decidua [51], we turned our attention to the maternal portion of the feto-placental unit. The first potential hormonal/primary messenger that we examined was relaxin [52]. This hormonal messenger was known to be present in chorion and decidua [53]. We found that renin released from cultured purified decidual cells was 95% prorenin when we did not expose the samples to acidification as was done in the earlier report [51] and that relaxin caused a dose-dependent increase in release that was paralleled by an increase in tissue prorenin and was inhibited by cycloheximide [52]. This was consistent with new protein synthesis. We cited the views at the time on relaxin’s potential effects on uterine ripening and decidual prolactin release. This was one of many pieces of our studies on the utero-placental complex that pointed to paracrine or autocrine effects in supporting local autonomy.
The next potential positive regulator of prorenin release that we examined was endothelin since it was known to be present in the placenta and had been found to modify renin release from the kidney. We found that several endothelin peptides caused a dose-dependent release of prorenin that was associated with an increase in renin mRNA [54]. The release was greater than the control content and was not associated with the release of cellular prolactin. This was another clear example of prorenin secretion by the protein synthesis-dependent constitutive secretion. Further studies on the effect of endothelin (ET-1) on prorenin release showed a clear difference from the control of prolactin (PRL) release The calcium ionophore A-23187 stimulated basal prorenin release and potentiated ET-1 stimulated release while having no effect on PRL release; and the calcium channel blocker nifedipine blocked the effect of ET-1 on prorenin but had no effect on PRL [55]. The protein kinase C agonist PMA stimulated basal and potentiated ET-1 induced prorenin release but inhibited basal PRL release and potentiated the inhibitory effect of ET-1 [55]. Finally, the PKC inhibitor staurosporine increased basal PRL release and reversed the inhibitory effect of ET-1 on PRL release. These results indicate that prorenin and PRL release from decidua are affected in different directions by protein kinase C and that prorenin release is dependent on extracellular calcium but PRL release is not [55]. In addition to protein kinase C and calcium, we also studied the influence of cyclic AMP (cAMP). We found that agents which elevated cAMP in decidual cells also stimulate Pro release. These included forskolin, cholera toxin (CT) and dibutyryl-cAMP [56]. Ninety-eight percent of the renin was in the form of Pro. PMA potentiated the effects of CT and dibutyryl cAMP. These studies had therefore implicated cAMP as well as protein kinase C as second messengers in Pro release from decidua.
After a report that lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF) stimulated prostaglandin production by decidua [57], we examined the effects of these agents on prorenin release from our semi-purified decidual cells. We found that LPS inhibited the synthesis and release of both Pro and PRL from the decidual cells in a time and dose-dependent manner [58]. We noted at the time that the inhibitory effect of LPS might be mediated by the release of cytokines from macrophages and then a paracrine effect on stromal cells could ensue. We also indicated that it could also be due to a direct effect on the stromal cells. We followed up this study by an examination of the effects of two other cytokines, TNF and interleukin-1β (IL-1β). We reported that these cytokines inhibited synthesis and release of renin from cultured decidual cells in a dose-dependent manner [59] and noted that the cells that were initially plated were composed of 22% macrophages (CD-68-staining) and 78% PRL positive (the other major cell type in decidual cells). We therefore concluded that the effects of these two cytokines could have been mediated by their known actions on macrophages. There was no inhibition of DNA synthesis or cell number. It was of interest that the effects of these cytokines was opposite to those on the rat renal tissues where there was an increase in renin release which occurred in minutes [60] unlike the decidual release that took days [59]. The third cytokine that we examined was interferon-ϒ (IFNϒ) which was known to have receptors on placental cells. We found that IFNϒ inhibited Pro release and its mRNA expression in decidual cells. When we employed an additional step of purification using immunomagnetic beads to separate the macrophages, we found that renin release from both populations of cells was inhibited by IFNϒ and TNF and the combination of these two cytokines was even more effective in producing inhibition of release. Since IFNϒ mRNA was found only in the macrophage population, while the IFNϒ receptor was found on both, it suggested that the effect of locally produced IFNϒ on renin release from macrophages could result from both autocrine and paracrine mechanisms while effects on stromal cells would be paracrine in nature [59].
Since we knew that macrophages represented a significant portion of decidual cells at term pregnancy and represented about 22% of our decidual cell preparation, we decided to examine directly whether these cells could also could be a source of prorenin. We utilized a method employing immunomagnetic beads after coating the macrophages with HLA-DR antibody to separate the macrophages from stromal cells. This increased the portion of HLA-DR (+) cells from 22 to 93%. The purified cells no longer showed mRNA for prolactin which was abundantly expressed in the non-macrophage population [61]. These cells stained for renin with a specific antibody, expressed renin mRNA and released prorenin into culture medium during 3 days of culture. They did not release prolactin. Importantly, the non-macrophage cells also stained positively for renin and released the same amount of renin per ug DNA per cell as the HLA-DR (+) cells. They also did not stain for a cytokine receptor that was present in the macrophage fraction [61]. These results indicated that both types of decidual sells had the capacity to synthesize and release prorenin and strengthened the case for possible autocrine/paracrine signaling. In addition, we collected some peripheral blood monocytes and demonstrated that they also showed mRNA for renin and speculated on some potential functions of the RAS within the uteroplacental complex [61].
To study the expression and regulation of renin in a pure cell line, we employed the well-studied U-937 cells which can be differentiated into a terminal macrophage/monocyte phenotype using phorbol dibutyrate (PDBU). We found that the treatment did cause a morphological change that was identical to those reported in the literature [62, 63]. The differentiated cells expressed renin mRNA and released prorenin into culture media [64]. We first looked at the potential regulation by cAMP, which we had found to be important in prorenin release from decidual and placental cells [56, 65] and others had found important in renal juxtaglomerular cells [66]. Renin mRNA and prorenin release were increased by dibutyryl-cAMP, and forskolin. In addition, terbutaline, a β2-adrenergic agonist known to increase c-AMP, also increased expression and release of prorenin [64]. The stimulation by terbutaline was potentiated by a type IV c-AMP-phosphodiesterase (PDE) inhibitor. It was known that these cells possess β2-adrenergic receptors and the type IV PDE. The stimulatory effect of terbutaline on renin secretion was inhibited by an angiotensin receptor agonist and also by TNF and LPS+ IFNϒ [64]. Taken together with our studies on isolated decidual macrophages [61], these results reinforced the potential importance of some components of the RAS in the function of macrophages and other bone marrow-derived cells. They also highlight the possible positive and negative autocrine actions of local mediators.
The villous placenta at term has very low concentrations of renin with higher concentrations in decidua and chorion [67, 68]. We hypothesized that the renin concentration might be influenced by gestational age as influenced by alterations in hormonal milieu and found that this was indeed the case [69]. We found that there were dramatically high levels of prorenin and active renin in first-trimester pregnancies: prorenin was 1130 μU/mg protein in the first trimester vs. 5.9 at term; the corresponding values for active renin were 330 vs. 0.15. As might be expected, the values for hCG in the first trimester were also greater than at term (2396 vs. 38.6ng/mg protein). However the levels of hCG and prolactin in decidua did not change much during gestation and there was no detectable prolactin at any stage in placenta [69]. Placental prorenin correlated with chorionic gonadotropin but not prolactin in both groups. and could reflect similar cellular origins.
An early preparation that we used was a superfused placental mince that allowed investigations of mostly intact cells with normal cellular contacts over a period of many hours. With this preparation we showed that there was a dramatic increase in prorenin release beginning after 12 hours, reaching levels of 16 μU/ml at 26 hours from a basal level about 0.5 or less [70, 71]. This spontaneous increase was blocked by cycloheximide and actinomycin D, supporting the conclusion that it required new mRNA and protein synthesis, like our results on decidua and chorion. We also showed that the spontaneous release could be amplified by treatment with relaxin [72]. Further evidence of the increase in synthesis of prorenin was found when we measured the tissue content of superfused placental minces after superfusion for 24 hours with or without the adenyl-cyclase stimulator forskolin. This model was useful for rapid kinetic measurements, but the disadvantage was interruption of much cellular connections.
Another model that we used was the dually perfused human cotyledon which allowed nutrients and drugs to reach cells through vascular channels and permitted assessment of vascular reactivity. It was known that AI and AII produced dose-dependent pressor responses which were blocked by the angiotensin antagonist saralasin and the response to AI was blocked by captopril [73]. We showed in this preparation that there was no renin released into the fetal circulation but there was consistent release into the maternal circuit [74]. It was all prorenin. This preparation suggested that renin in fetal circulation
The most useful model that we employed retained much cellular connections and could be used over longer periods of time. That was based on an early model of placental explants, sometimes called organ culture [75]. We found the optimal conditions by putting the explants on top of wire-mesh platforms and keeping the fluid level at the surface of the tissue. With this model we examined potential primary and secondary signals in regulation of the placental RAS.
It was known in humans that renal renin secretion was stimulated by catecholamines and selectively by β-1 adrenergic agonists [76] and that the villous placenta had both β-1 and β-2 adrenergic receptors [77]. When we studied the effects of epinephrine and beta-adrenergic agonists on placental renin secretion from placental explants, we found that both β-1 and β-2 adrenergic agonists elicited renin secretion, associated with an increase in synthesis [78]. Again, this was about 95% trypsin activatable and presumably prorenin. This is consistent with the view that extrarenal renin in the human reproductive track is almost exclusively prorenin [54, 79]. We discussed the likelihood that beta-agonist-induced renin secretion would be regulated by activators produced by the fetus [78]. At the same time, we found that hCG secretion was selectively stimulated by the β-2 adrenergic agonist terbutaline and that its stimulant action was blocked by a selective antagonist. We showed that the stimulant effects of beta-adrenergic agonists on both renin and hCG secretion were potentiated by selective inhibitors of phosphodiesterase types III and IV [78]. The differences in agonist selectivity between renin and hCG secretion was consistent with findings on their respective localization in term placenta, with renin in cytotrophoblasts and hCG in syncytiotrophoblasts [80].
The likelihood that renin and hCG are released in close proximity to one another suggests that there might be some paracrine regulation involved. With this model system we provided evidence that hCG stimulates renin secretion and tissue levels [81]. Furthermore, the stimulation was potentiated by phosphodiesterase inhibitors, just like renin secretion, and was accompanied by an increase in media cAMP. The effect of hCG was markedly attenuated by the protein kinase A inhibitor H-89. These results suggested that placental renin secretion may be regulated in part by hCG and mediated by cAMP transduction mechanisms [81]. Further support for the influence of cAMP on renin secretion is presented in Section 8.4.
A possible negative regulator on renin release, based on what has been found in studies on cultured juxtaglomerular cells (JG), is angiotensin II, where a purported negative feedback loop reveals an inhibitory action [82]. We found that a stable analog of angiotensin II inhibited the spontaneous release of renin from placental explants during the 72 hour incubation [71, 83]. This paralleled a study where transfected JG cells released prorenin and not renin [82].
Other negative regulators of placental renin secretion that we identified included LPS and the glucocorticoid dexamethasone. They both inhibited spontaneous and stimulated renin release [71]. These agents act at many different sites, including macrophages, so their influence on renin secretion is complicated.
We had already identified cAMP as a second messenger for chorion and decidual renin release and we examined if similar mechanisms existed in placental prorenin secretion. Evidence for cAMP mediation was supported by our finding that renin release from explants was stimulated by several orders of magnitude by forskolin and by cholera toxin (CTX) [83]. The effects were potentiated by a cAMP phosphodiesterase inhibitor. The enhanced release of renin was accompanied by an increase in hCG found in the media. It is important to note that prolactin was not detected in the media, thus excluding decidual contamination. This was also supported by the fact that the phosphodiesterase inhibitor did not cause an increase in renin release from similarly-treated decidual explants [84]. Not only did the tissue levels of renin increase indicating new synthesis, but there was a decrease in LDH leakage demonstrating cellular integrity [83]. An interesting finding was that an angiotensin II agonist inhibited both the spontaneous and the CTX-enhanced release of renin. This effect was blocked by an angiotensin receptor antagonist. Further evidence on the role of cAMP came from our studies on cAMP-dependent protein kinase (cAPK) [85]. We found that the dobutamine-stimulated secretion of renin and cAMP was accompanied by an increase in tissue cAPK. We used substituted analogues of cAMP, selective for binding sites on cAPK, and found that site B analogues which bound to catalytic or regulatory sites were stimulants of renin secretion but that site A analogs were not [85]. Strengthening the case for the role of cAPK in dobutamine-induced renin secretion, we found that the specific cAPK inhibitor H-89 blocked secretion and an activator SP-cAMPS stimulated secretion [85]. We then used molecular biology techniques to assess the role of mRNA synthesis in the stimulation of renin secretion, using the β-1 agonist dobutamine and the β-2 adrenergic agonist terbutaline. These agents both increased renin mRNA in a dose-dependent manner which paralleled their effects on renin secretion and tissue levels [86]. The effects on renin secretion and tissue levels were blocked by cycloheximide (a translational inhibitor in protein synthesis) and actinomycin D (a transcriptional inhibitor which acts directly on DNA). Actinomycin D blocked the increase in renin mRNA but cycloheximide did not, thus showing the specificity of these agents and the importance of gene regulation in adrenergic stimulation of placental prorenin secretion [86].
Other second messengers that have been studied in a wide variety of tissues including the placenta include eicosanoids, protein kinase C and calcium. Prostaglandins have been known to influence renal secretion of renin and are actively secreted by utero-placental tissues. We reported that meclofenamate, a relatively selective inhibitor of cyclooxygenase, inhibited the release of renin from placental cells and (unpublished studies) that it also inhibited the ET-1 induced renin release from decidua [71]. As with the decidua, the protein kinase C agonist PMA increased renin release from placental explants and the enzyme inhibitor staurosporine was inhibitory [71]. The influence of calcium was contrary to many, but not all, studies on the kidney where calcium is considered an inhibitory messenger on renin secretion. Extracellular calcium caused a dose-dependent increase in short-term renin release between 1.0 and 3.6 mM in contrast to the kidney. It should be noted that there are some studies on renal tissues in special situations where calcium is a positive regulator [87, 88, 89] and other studies on extra-renal renin secretion where calcium also has a positive influence on renin secretion [90, 91]. Similarly, angiotensin was shown to have inhibitory effects on the synthesis and release of renin from placental explants but was stimulatory during short term exposure of superfused chorion [48].
These studies on different anatomical portions of the utero-placental complex suggest that local conditions and times of gestation can modulate the regulation of the RAS and that studies on single cells may be missing the complex interactions that exist in vivo.
After 40 years in academia and an enormous expansion of information in the RAS field, I retired. It was short lived because I still wanted to see new developments and help in obtaining information. That is why I was eager to join (and help revitalize) a project on fat embolism that had been dormant for 40 years. Dr. Federico Adler, a retired orthopedic surgeon, asked for my help in restarting a study of fat embolism in rats that he had worked on in the 1960s. My focus was gaining evidence on the potential role of the RAS in fat embolism syndrome, a sometime fatal consequence of long bone fracture (and some other conditions). This brought me back to
Since there were reports that some RAS drugs had beneficial effects in other types of pulmonary injury, we examined the effects of the angiotensin converting enzyme inhibitor (ACEI) captopril and the type 1 antagonist (AT1) losartan when given 1 hour after the triolein. Both agents provided significant protection against the histopathological effects when viewed at 48 hours [93] and provided strong evidence that the acute effects of fat embolism involved the production of angiotensin II and actions on the AT1 receptor. In a later study we found that the pulmonary injury was also ameliorated by the renin inhibitor aliskiren [94].
We subsequently determined that the initial acute phase after fat embolism was followed by a slowly developing smaller inflammatory response and this was associated with an increase in the presence of angiotensin peptides [95]. Since there were still some fat particles present at this later time period, we suggested that one mechanism could be the continued activation of macrophages that were engulfing the fat and signaling mast cells (and perhaps other cells) to release renin and then local angiotensin release. Some support for this view came from two further studies. In one, we gave the AT1 blocker losartan 6 weeks after the triolein injection and examined the rats 4 weeks later. In this experiment the protective effect of losartan was still demonstrated at this late stage, supporting the view of continued activation of the RAS [96]. In another study we found that 24 and 48 hours after triolein there was an increase in renin staining in lungs that diminished but was still present at 3 and 6 weeks [97]. The renin staining increased again at this late stage when the rats were treated with lipopolysaccharide (LPS) [97] which was known to interact with the RAS [98]. Since we had suggested that some of this renin could be in mast cells, we examined the presence of mast cells in triolein-treated rats and the influence of losartan. We found that 10 weeks after triolein there was an increase of mast cells and this was attenuated by losartan [99]. Addition of LPS at 6 weeks caused slightly more mast cells and this was also blocked by losartan. We also considered that macrophages could be a source of renin.
In several of our papers, we have suggested that the RAS drugs could be useful in the treatment or prevention of fat embolism syndrome and there are some other findings of potential clinical interest. The lungs from a pregnant patient who had succumbed to a pulmonary fat embolism were examined at our affiliated hospital and showed the same kind of histopathological changes that we had observed on our rat experiments [100]. Another point of possible clinical interest was our finding that 6 weeks after fat embolism when the animals appeared normal and had grown as well as the saline-treated controls, they were especially sensitive to a “second hit” with LPS [101]. The potential clinical relevance of these findings is that patients who have severe respiratory distress more than would be expected from their presenting diagnosis could be suffering from a “second hit” a long time after a forgotten trauma which has left a smoldering low-grade inflammatory process continuing in the lung. A recent review of our studies on fat embolism syndrome has been published online [102] that implicates the RAS as a key component of this condition.
The latest part of my journey related to the RAS (which is still ongoing) comes 53 years after my first paper mentioning angiotensin [2] and 59 years after my first scientific paper as a medical student [103]. Although I have enjoyed working in many areas of biomedical research, it has been very gratifying to see this major part of my career get closer to the long-range goal of improving health care for people in need. An ironic and maybe not surprising development is that my early and long-standing studies on chromaffin granules and their ATPase [17, 20, 104, 105, 106, 107] have come full circle with the finding that the granules contain renin and prorenin [15] and their membranes contain the prorenin receptor [108, 109]; and it is now known, but not in the 1960s, that there is a receptor for renin/prorenin (P)RR that can act on second messengers independent of the RAS [110, 111] It was also not appreciated that there was an opposing arm of the RAS that could antagonize many of the deleterious effects of the angiotensin-ACE-AT1 receptor axis. and it is ubiquitous in distribution outside and inside the cell [112, 113, 114, 115]. My studies and the current literature suggest that it will be difficult to find any extra-renal system that does not have some components of an endogenous RAS.
I will conclude with my views on ways of approaching biomedical research based on my experience and lessons that I have learned.
Many of these lessons were not appreciated when I was a medical student.
Low doses of drugs may have opposite effects of higher doses, the hormetic effect. Sometimes this is because receptors of different sensitivity are activated as the dose is increased. Other times this may be due to non-receptor mediated effects, such as enzyme inhibition. An example in the RAS is the activation of AT2 receptors by angiotensin II opposing the actions on AT1 receptors and the activation of Ang (1–7) receptors as angiotensin II is converted. This is further discussed below under moonlighting (10.2.d.).
Species differences: It has long been clear that other species may have differences in metabolism, pharmacokinetics, morphology and a host of features that make direct extrapolation to humans problematic. Also, mice and rats are not equivalent when compared to human biology.
Short term vs. long term experiments: Many experiments have shown biphasic response to drugs with opposite effects seen depending on when the observations were made. This is an argument for examining time-response curves in addition to dose-response curves. This has led in the past to some studies missing a response by looking at a single time-point.
Response of young animals (organs) may not be the same as that of older ones. This has been obvious for a long time since the changes during maturation in animal biology has long been appreciated. A striking change during development in a single organ has been found in the human placenta as we have noted in our studies on the RAS. Of course, the placenta is a unique organ and has features of many other organ systems, including the liver, kidney and endocrine and nervous systems among others.
Another lesson that was not appreciated is that of moonlighting. This is the area pioneered by the ground-breaking research of Constance Jeffery from 1999 [116] and still expanding in 2018 [117]. It appears that prorenin and the prorenin receptor are archetypes of multi-functional proteins. Prorenin (a) serves as the zymogen precursor of renin that follows cleavage of the prosegment; (b) becomes a catalytically active enzyme without cleavage when bound to its receptor, (c) activates a surface membrane receptor coupled to the generation of intracellular kinases, and (d) likely serves in several capacities intracellularly [118]. This complexity was not imagined at the time we were calling this ‘inactive renin’. The prorenin receptor ((P)RR) also has multiple functions, some not related to angiotensin peptides [119].
I have carried out experiments using extreme reductionist approaches, such as studies on isolated proteins and on gene expression. Some of our studies were on isolated organelles and on isolated cells. These types of experiments removed many cells from their natural environment and from potential neuronal, paracrine, or endocrine modulation. The next step up in complexity were studies on isolated perfused glands or tissue slices where there was some contact between different cells as in the intact animal but still not complete signaling from the entire organism. Finally, I have studied the effects of drugs on whole animals
Finally, I have been fortunate to have chosen to study the RAS for much of my research career since this system seems to be ubiquitous throughout biology and has only in the past five decades begun to reveal the many ways we depend upon its proper regulation to maintain our health and suffer when it is out of control.
I wish to acknowledge the many colleagues who have accompanied (and often educated) me along the way. Their names are cited in the list of references and described in more detail below.
Major contributors include the late Edward Walaszek who helped me start my research career as a medical student at the University of Kansas Medical Center (KUMC); the late William Douglas who was my first research mentor and then colleague at the Albert Einstein College of Medicine; the late Stuart Handwerger at Duke University and the Cincinnati Children’s Hospital; my students and colleagues Jau-Shyong Hong at KUMC and NIEHS and Gregory Downing at KUMC; and Agostino Molteni at KUMC and Univ. Missouri Kansas City (UMKC) who continues to be my research colleague in studies on fat embolism. My deepest gratitude goes to my late wife Roselle Burstein Poisner who helped me in the laboratory for more than 30 years and provided the ideal partner for family and career.
Polysaccharide-based chiral stationary phases (CSPs) have been reported in the literature for nearly 50 years as of the writing of this chapter. Hesse and Hagel made the first practical reports in 1973 using microcrystalline triacetylcellulose (MCTA) as a chiral separation medium, with a simple chiral model [1]. From this initial report, the applications have grown thanks to the advancements made by Prof. Yoshio Okamoto and many others, to include applications in the production of commercialized pharmaceuticals, polypeptides and biologics, natural products, and more recently, cannabis.
As a natural product, cannabis contains a wide range of compounds including, but not limited to, cannabinoids, terpenes, and other plant-based compounds [2]. These compounds typically exist as a single isomer as a requirement for further downstream processes. That is, many biological processes are enzymatically controlled, and require specific molecule confirmation for proper interaction and recognition. Therefore, biological systems have evolved to produce said single isomer that matches this confirmation. Common achiral phases like octadecylsilyl (ODS or C18) and other non-polar analogs have therefore been successfully used for the separation and analysis of cannabis and cannabis-related products, as they are capable of separating achiral mixtures exclusively ([3, 4, 5, 6, 7] as examples). CSPs have been underutilized as a solution for the separation of such compounds and mixtures, as their cost and specialization have been seen as prohibitive or unnecessary. However, it is well established that polysaccharide CSPs are capable of performing both chiral and achiral separations, so they represent a unique opportunity for investigators to perform two types of separations at the same time. The nature of polysaccharide CSPs is unlike that of typical achiral phases. The polymeric structure of the CSPs, either cellulose or amylose-based, along with their functionalization with small molecule chiral selectors, creates an environment that can recognize the subtle structural differences that exist between enantiomers.
What exactly are enantiomers? The most effective way to envision this is to hold up one’s left and right hand – the hands are mirror images of each other (excluding the minor differences in jewelry, fingernail length, cuts/bruises, etc.), but are not superimposable. When you try to overlap them, there is clearly a difference in the structure, i.e. the geometry, of the hands. Compounds that are enantiomers are the same – they have the same combination of atoms or chemical groups connected (bonded) to a single atomic center (also referred to as a stereogenic center or chiral center – usually it is carbon, but can also be nitrogen, phosphorus, or sulfur). Enantiomers differ from each other in the configuration of said atoms or chemical groups around the chiral center. They can also arise from other elements of symmetry like a plane and/or axis where two distinct confirmations can exist. An example of the latter would be atropisomers. Atropisomers contain a rotatable single bond, but because of steric hindrance (a blockage caused by large/bulky groups), are locked into two distinct confirmations. These geometric differences are not exploitable by achiral SPs, but they are by polysaccharide CSPs.
This chapter will begin with a discussion on the mechanism by which polysaccharide CSPs are capable of separating achiral and chiral analytes. This is important to understand why CSPs are so effective in their function, and why they play an important role moving forward in the separation and analysis of cannabis and cannabinoids. This will be followed by a brief sharing of established and practical examples of CSP applications in a range of mature fields (pharmaceutical and agricultural for example). The chapter will conclude with numerous examples in the literature for the separation of cannabinoids on polysaccharide-based CSPs, under various mobile phase modes including normal phase and reversed phase high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC).
Traditional achiral separations on widely available phases like ODS or silica are governed primarily by polarity. That is, the difference in polarity between the analytes (compounds) and the polarity of the stationary phase (SP). With a simple enough model, one can easily predict elution order based simply on the chemical structure (or polarity) of the analyte and the polarity of the SP. As a simple example, for the separation of phenol and toluene on a C18 column with a mixture of acetronitrile/water, one would expect that phenol should elute first as it is more polar than toluene, which will be more strongly attracted/retained on the non-polar C18 SP. The same modeling cannot be performed for chiral separations however, as enantiomers are equal in their polarity. As described above in the Introduction, enantiomers differ only by the geometry in which their atoms or functional groups are arranged around the chiral center. This geometric difference can only be exploited by a medium that can create an environment that facilitates chiral recognition, which is why CSPs are a critical tool for enantiomeric separations. A well-established (yet highly unpredictable) series of intermolecular interactions helps CSPs to distinguish these subtle differences to elicit a chiral separation.
At the core of polysaccharide CSPs are three components: the silica gel support material, the polysaccharide backbone (either cellulose or amylose), and the chiral selector (see Figures 1 and 2 for examples). The support material does not have too much of a role to play in the separation of enantiomers, but is important to provide CSPs with a rigidity and robustness to be used under high-pressure applications. The chiral selector and polysaccharide backbone are responsible for creating an environment that is able to distinguish the two enantiomers via a series of well-documented intermolecular (between two molecules) interactions that arise from it (see Table 1). When contained within in an enclosed system like a packed, chromatographic column, the potential combination of interactions is capable of producing a separation of the enantiomers. The chiral selector is key to creating these interactions - hydrogen bonding, π-π stacking, dipole forces, inclusion, and repulsion can exploit the subtle differences between the enantiomer geometries [8].
Examples of structures of chiral selectors and names of coated polysaccharide-based CSPs.
Examples of structures of chiral selectors and names of immobilized polysaccharide-based CSPs.
Type of interaction | Strength | Direction | Working distance |
---|---|---|---|
Hydrogen bonding | Very strong | Attractive | Long range |
Steric hindrance | Weak to very strong | Repulsive | Short range |
π-π Interaction | Strong | Attractive | Medium range |
Dipole–dipole | Intermediate | Attractive | Short range |
Several intermolecular forces known to occur between analyte and polysaccharide CSPs. Adapted from ref. [8].
Polysaccharide CSPs are unique in their ability to combine all of the above-mentioned differentiating interactions (Table 1) into a macromolecule that is capable of interaction with the racemic (chiral) mixture. The type and frequency of these interactions is highly dependent on several factors: (1) the type of polysaccharide backbone (e.g., cellulose or amylose), (2) the functionalization of the chiral selectors (e.g., carbamates, benzoates and their respective substituents), and (3) the combined 3D-structure created by supporting on silica. Furthermore, the solvation, swelling, or shrinking of the derivatized polymer backbone in the presence of certain solvents or additives plays an important role. Because of these factors, the interactions that take place on polysaccharide CSPs are much more unpredictable and a systematic screening becomes an essential tool for their effective application.
After Hesse and Hagel published their first work using MCTA [1], the continued development of such phases lagged for more than a decade, because of structural and chromatographic inefficiencies. Professor Yoshio Okamoto in Japan made a breakthrough in 1984 by stabilizing the polysaccharide polymer (cellulose in that case), onto a solid silica gel support [9, 10, 11]. This allowed for HPLC or high pressure applications, and improved chromatographic efficiency. The first chiral selectors utilized were coated cellulose tribenzoate and coated cellulose triacetate, later commercialized by Daicel Corporation as CHIRALCEL OA and CHIRALCEL OB respectively [12, 13, 14].
In these early examples, simple models like
Further advancements in the production of the CSPs added robustness and increased solvent compatibility, via the incorporation of an immobilization step. This immobilization step both cross-links the polysaccharide backbone and bonds it to the silica gel surface, leading to the insolubilization of the polymer [23, 24, 25, 26, 27, 28, 29, 30, 31, 32]. This resulted in a new generation of immobilized CSPs, providing access to selectors that were previously not accessible and an expanded range of compatible solvents for expanded selectivity (see Figure 2 for full list of immobilized CSP selectors as of the time of this publication).
This diversification of selectors allowed for an expansion of selectivity that corresponded with a widening utilization in more application areas. β-blockers [33, 34, 35] and non-steroidal anti-inflammatory drugs (NSAIDs) [36, 37, 38] were two of the first classes of compounds to be screened for chiral recognition. Relevant examples included, but were not limited to, acebutolol and propranolol (β-blockers), ibuprofen and naproxen (NSAIDs). Other classes of compounds included proton-pump inhibitors like omeprazole [39, 40, 41], anti-histamines like cetirizine and meclizine [42, 43, 44], selective serotonin reuptake inhibitors (SSRIs) like sertraline and citalopram [45, 46, 47], and commercialized pharmaceuticals like Modafinil [48], Keppra [49], and Bicalutamide [50].
Agrochemicals have also become an important application area, as many pesticides, herbicides, and insecticides contain a chiral center. This application area historically received minimal attention, as there was no requirement to assess biological activity of these compounds, like there is/was for pharmaceuticals. However government regulations have changed over the last few decades, and polysaccharide CSPs have been critical for these analyses as well. There have been many papers published covering the separation of compounds like malathion, fipronil, metalaxyl, dichlorodiphenyltrichloroethane (DDT), bromuconazole, and etoxazole (as examples) [51, 52, 53]. The analysis of food has been an important application, as composition analysis is important for nutritional integrity and quality assurance. Many examples for the analysis and separation of flavanone, diketopiperizine, and naringenin-based compounds have been reported [54, 55, 56].
As mentioned in the introduction, CSPs have historically been overlooked for the analysis and separation of cannabinoids. This came primarily from the belief that cannabis did not contain any racemic pairs of compounds, or at least not any that were of particular interest. This has of course changed with the identification of cannabichromene (CBC) and cannabicyclol (CBL), as well as the rise of synthetic sources of cannabinoids, which have the potential to produce non-naturally occurring opposite enantiomers. This has also been affected by the understanding that polysaccharide CSPs are just as capable of separating achiral mixtures as they are chiral mixtures. CSPs were initially designed to exploit the subtle geometric differences that exist between enantiomers, but they are also capable of distinguishing between more pronounces achiral differences is structure.
One of the earliest reports for the use of polysaccharide-based CSP for the separation of cannabinoids came from Levin
In 1995, Levin
Jumping back briefly to 1994, Yan
Thakar
Tarbox
Umstead published a paper in 2021 for the separation of several cannabinoids, including cannabicyclol, cannabichromene, Δ6, and Δ10 THC enantiomers [65]. There were several columns used for this work, including CHIRALPAK IB N-3, CHIRALPAK IG-3 (see Figure 3), CHIRALPAK IA-3, and CHIRALPAK IC-3. Normal phase HPLC was used including hexane-ethanol and hexane-isopropanol mobile phases ranging from 90–10 (v/v) to 98–2 (v/v) (see ref. [65] for full method details).
Separation of cannabicyclol, Δ6, and Δ10 THC under normal phase conditions of hexane-ethanol = 95–5 (v/v) on CHIRALPAK IG-3 [
So far, only normal phase conditions have been reported, however aqueous mobile phases (containing water – also referred to as reversed-phase) have also been used for the separation of numerous cannabinoids. A particular advantage of using a reversed-phase (RP) mobile phase over normal phase is the MS compatibility, which assists in the analysis of complex cannabinoid mixtures. Onishi and Umstead published a paper in 2021 focused on the separation of a 10 cannabinoid mixture (which contained Tetrahydrocannabinolic Acid A (THCA-A), Cannabidiolic Acid (CBDA), delta-8 Tetrahydrocannabinol (Δ8-THC), Cannabidiol (CBD), (±)-Cannabichromene (CBC), Cannabinol (CBN), delta-9 Tetrahydrocannabinol (Δ9-THC), and Cannabigerol (CBG)) [66]. A particularly novel feature of this work was the use of ultra-high performance liquid chromatography (UHPLC) and Daicel Corporation’s sub-2 μm immobilized polysaccharide CSPs for the separation.
Figure 4 shows a comparison of Van Deemter plots for the performance of 5 μm, 3 μm, and sub-2 μm CHIRALPAK IA. A Van Deemter plot is a graphical representation of three competing terms that describe the chromatographic separation of an analyte by a chromatographic column. The A term (Eddy-diffusion), B term (diffusion coefficient), and C term (resistance to mass transfer) play different roles in the overall chromatographic separation efficiency. The A term is a constant, as it is assumes the pathway length through a packed particle is more or less the same (although the actual pathway is random). The B term is also more or less constant at functional chromatographic flow rates (although it sharply decreases at very low flow, significantly less than what you would use for a separation). The C term linearly increases from zero to infinity, with the slope being less shallow for smaller particles compared to larger particles (i.e. the plate height (H) decreases much less for small particles as flow rate increases). When combined, you see curves like in Figure 4.
Van Deemter plot for different particles sizes of CHIRALPAK IA immobilized CSP showing column efficiency related to linear velocity (flow rate) [adapted from ref.
The y-axis represents the theoretical plate height (H in μm), and the x-axis linear velocity (in mm/s). Intrinsically larger particle sizes like 5 and 3 μm (in green and red respectively) have a higher theoretical plate-height due to decreased packing efficiency when packing into a column i.e. the constant A term is larger for these particle sizes. However when the linear velocity is increased, they also lose efficiency more quickly than a smaller particle (due to the C term). For this reason, faster nominal flow rates can be achieved with the smaller particles, allowing for fast/ultra-fast separations with minimal loss of resolution, or the analysis of complex samples with higher resolution.
Circling back from the short tangent on chromatographic theory, Onishi and Umstead looked at both normal phase and reversed phase HPLC, and found a number of very efficient separations. For normal phase CHIRALPAK IB-U (Figure 5) and CHIRALPAK IH-U were found to be the best CSPs for the separation, which used n-hexane-isopropanol-ethanol-trifluoroacetic acid = 96-3-1-0.1 (v/v) as a mobile phase.
10 cannabinoid mixture separation under normal phase conditions with CHIRALPAK IB-U [adapted from ref.
For reversed phase, CHIRALPAK IG-U (Figure 6) and CHIRALPAK ID-U were found to be the best CSPs for the separation, which utilized water/acetonitrile/trifluoroacetic acid = 45-55-0.1 (v/v) or 55-45-0.1 (v/v) respectively.
10 cannabinoid mixture separation under reversed phase conditions with CHIRALPAK IG-U [adapted from ref.
De Luca
Reversed phase separation of CBDA, CBD, THC, CBC, and THCA with CHIRALPAK IC (in blue) and IF (in red). Adapted from ref. [
Umstead published a paper in 2022 covering the separation of CBD enantiomers under both reversed phase and normal phase HPLC [68]. For reversed phase, CHIRALPAK IA and CHIRALPAK IG were found to be the most effective CSPs for separation, using water-acetonitrile = 45–55 (v/v) or 30–70 (v/v) respectively. For normal phase HPLC, IA and IG were again found to be very effective CSPs, with the addition of CHIRALPAK ID and CHIRALPAK IE yielding good baseline resolutions as well. For the normal phase HPLC separation on IG (which used hexane-ethanol = 95–5 (v/v)), the separation was also performed on the sub-2 μm version, CHIRALPAK IG-U. This resulted in a sub-15 second separation (Figure 8). Similarly, the reversed phase HPLC separation on IG was repeated on IG-U, resulting in a sub-20 sec separation.
Separation of (+) and (−) CBD on CHIRALPAK IG-U with Hex-EtOH = 95–5 (v/v).
On a preparative scale, the separation of (+) and (−) Δ9 THC was patented by Gutman
The mechanism for chiral separation on polysaccharide CSPs is the same for SFC as it is for HPLC, i.e., a series of intermolecular interactions between chiral analyte and chiral selector. The main difference is the composition of the mobile phase. Rather than 100% organic solvent as is the case for HPLC, SFC uses super-critical carbon dioxide (CO2) as its primary mobile phase component. There are numerous advantages to using SFC, including the reduction of waste and associated disposal cost, overall lower viscosity mobile phases, which allows for faster flow rates i.e. faster analyses, and the ability to use methanol as a modifier, which cannot be done under normal phase HPLC (miscibility of methanol and hexane is very poor).
Toyo’oka and Kikura-Hanajiri published a paper in 2015 on the SFC separation of several synthetic cannabinoids [70]. While the work contained mostly achiral separations, there was also a reported separation of enantiomers of cis and trans cannabicyclohexanol (CCH) on coated amylose
Runco
Breitenbach
Denicola and Barendt presented a poster in 2018 that covered the analytical separation of a series of cannabinoid mixtures ranging from 9 to 16 cannabinoids, using CHIRALPAK IB N-5 and a methanol gradient from 11 to 14% [73]. Although some partial co-elution was observed, the use of peak deconvulsion software assisted in the baseline quantification of the more complex mixtures. The method was applied to a real hemp oil sample, demonstrating the effective quantification of THC to ensure compliance with the 2018 Farm Bill requirements of less than 3% THC in CBD containing products.
Later that year, Denicola and Barendt presented a second poster that focused on the preparative separation/removal of THC from the same hemp oil sample [74]. Using the method established in the previous poster, the authors showed the isolation of 1.2 kilograms of CBD/day was possible with this new method, which at the time, was about 1.5× more productive than the achiral C18 flash chromatography method that was being used.
Polysaccharide CSPs have a rich and storied history for the separation and analysis of chiral pharmaceuticals and agrochemicals, as well as important applications in the food and cosmetic industries. Although not traditionally used for achiral separations, their unique separations mechanism allows for the exploitation of small differences in energy and molecular geometry, meaning a broader range of applicability when compared to achiral SPs. As this awareness has grown, the applications in the field of cannabis separation and analysis have grown with it, particularly over the last decade. Their ability to separate diastereomers, structural isomers, and other positional isomers present in cannabis make them well suited for these applications.
As demonstrated in the chapter their ability to be used in a wide range of mobile phases makes them suitable for numerous applications, ranging from analytical and preparative scale, and with great flexibility in detection technique (mass-assisted or ultra-violet detection for instance). No doubt as the library of natural and synthetic cannabinoids continues to grow, the need for enantiomeric resolution will grow with it. As all application areas continue to expand, particularly for medicinal use, polysaccharide-based CSPs are and will be well suited to meet the needs for chiral purity testing.
The author declare no conflict of interest.
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His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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Although their expected number is more than 2.2–3.8 million, only 120,000 taxa have been identified so far. Basidiomycetes are very large group of fungi including mushrooms, toad stools, puff balls, earth stars, polypores, and rust and smut fungi. Previously, these fungi were identified only by morphological characters that have been considered as variable due to environmental factors. Literature shows that many fungi are misidentified due to phenotypic changes. Molecular methods including phylogenetics prove to be successful aids along with traditional methods for correct identification of these fungi and these have revolutionized fungal reclassification. Many fungal taxa have been shifted to other groups of fungi after their phylogenetic analysis. 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The classification proposed by Aristotle today seems naïve and unnatural, but it lasted from ancient Greece until the publication of the Linnaeus Systema Naturae in 1758. Although quite accurate, the taxonomic classification proposed by naturalist Carl Linnaeus did not consider the evolutionary relationships between living beings. This view, although prior to Charles Darwin, only gained deserved prominence after On the Origin of Species. Only in the twentieth century, a new area founded by Hennig, phylogenetic systematics was implemented, and with this, a series of useful methods in the construction of phylogenetic trees arose, as maximum parsimony, neighbor joining, UPGMA, maximum likelihood, and Bayesian inference. With the advancement of information technology, phylogenetic analyses have become more sophisticated and faster. The algorithms used in the analysis programs have become more complex and realistic, favoring the addition of substitution models. The application of these data and the greater facility in generating nucleotide and amino acid sequences allowed the comparison previously unimaginable, for example, between bacteria and eukaryotes. In this way, the history of the advances of phylogenetic knowledge is confused with the greater knowledge about the origin of life.",book:{id:"6880",slug:"recent-advances-in-phylogenetics",title:"Recent Advances in Phylogenetics",fullTitle:"Recent Advances in Phylogenetics"},signatures:"Eliane Barbosa Evanovich dos Santos",authors:[{id:"250217",title:"M.Sc.",name:"Eliane",middleName:null,surname:"Evanovich",slug:"eliane-evanovich",fullName:"Eliane Evanovich"}]},{id:"39794",title:"Missense Mutations in GDF-5 Signaling: Molecular Mechanisms Behind Skeletal Malformation",slug:"missense-mutations-in-gdf-5-signaling-molecular-mechanisms-behind-skeletal-malformation",totalDownloads:2622,totalCrossrefCites:0,totalDimensionsCites:8,abstract:null,book:{id:"2535",slug:"mutations-in-human-genetic-disease",title:"Mutations in Human Genetic Disease",fullTitle:"Mutations in Human Genetic Disease"},signatures:"Tina V. Hellmann, Joachim Nickel and Thomas D. 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Pyhlogenetic trees constructed showed polyphyletic relationships in C. ethanolica whereas close relatives of S. cerevisiae and P. kudriavzevii showed little divergence. Sequence data for both Elaeis sp. and Raphia sp. palm trees showed that highest number of palm wine yeasts relatives sequence submissions to the Genbank were from China and beverages were mainly the sources of close relatives of S. cerevisiae and P. kudriavzevii whereas C. ethanolica closest relatives were from various non-food sources. Overall relatives of palm wine yeasts were not specific to any particular food or fermentation mix. The guanine-cytosine (G+C) content in P. kudriavzevii (57–58%) and C. ethanolica (56–57%) was higher than that of S. cerevisiae (47.3–51%). This suggests that the P. kudriavzevii and C. ethanolica have a higher recombination rate than S. cerevisiae strains analyzed. 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