Values of affinity (pD2) and intrinsic activities (α) for parasympatholytics inhibiting the Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The intrinsic activity of atropine was found to be equal to 1.0.
\\n\\n
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\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:"9522",leadTitle:null,fullTitle:"Tibia Pathology and Fractures",title:"Tibia Pathology and Fractures",subtitle:null,reviewType:"peer-reviewed",abstract:"The tibia is the larger, stronger, and anterior (frontal) of the two bones in the leg, which connects the knee with the ankle bones. The tibia, or shinbone, is the most fractured long bone in the body. In recent years, high-energy accidents result in comminuted tibia fractures or intraarticular fractures of the knee (plateau) or ankle (platform) that need immediate open reduction and internal fixation with anatomical plates or intramedullary nails. Intraarticular fractures with comminution or fractures with non-appropriate internal fixation predispose to post-traumatic knee or ankle arthritis. Conservative current therapies (injections of plate-rich plasma or stems cells) or high tibia osteotomies may delay the need of total knee arthroplasty. Tibia Pathology and Fractures analyzes all the up-to-date internal fixation or other operative or conservative therapies.",isbn:"978-1-83962-407-0",printIsbn:"978-1-83962-406-3",pdfIsbn:"978-1-83962-408-7",doi:"10.5772/intechopen.87317",price:119,priceEur:129,priceUsd:155,slug:"tibia-pathology-and-fractures",numberOfPages:144,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"a458a39d8281ed7fda0548fbb75927a2",bookSignature:"Dimitrios D. Nikolopoulos, George K. Safos and John Michos",publishedDate:"September 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9522.jpg",numberOfDownloads:5653,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 26th 2019",dateEndSecondStepPublish:"March 6th 2020",dateEndThirdStepPublish:"May 5th 2020",dateEndFourthStepPublish:"July 24th 2020",dateEndFifthStepPublish:"September 22nd 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"228477",title:"Dr.",name:"Dimitrios D.",middleName:null,surname:"Nikolopoulos",slug:"dimitrios-d.-nikolopoulos",fullName:"Dimitrios D. Nikolopoulos",profilePictureURL:"https://mts.intechopen.com/storage/users/228477/images/system/228477.jpg",biography:"Dr. Dimitrios D. Nikolopoulos (MD, PhD) is a sports medicine-specialized orthopedic surgeon and arthroscopist. He focuses on sports injuries, mainly in shoulder, hip, knee, foot, and ankle pathology. He has performed arthroscopic restoration of hip, knee, and ankle cartilage, as well as treatment and surgical correction of foot disorders. He has published 42 original scientific articles in prestigious scientific journals in the United States, Europe, and Greece referring to knee (valgus knee) and shoulder (arthroscopic and minimally invasive new techniques) surgery, osteoporotic spine and hip fractures, and research into the in vitro environment of bone and cartilage metabolism. He has more than 180 citations in research projects on valgus knee and cartilage ankle restoration. He has also presented over 180 oral and poster presentations internationally.",institutionString:"Central Clinic of Athens",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"228550",title:"Dr.",name:"John",middleName:null,surname:"Michos",slug:"john-michos",fullName:"John Michos",profilePictureURL:"https://mts.intechopen.com/storage/users/228550/images/system/228550.jpg",biography:"Dr. John Michos has been Director of the 4th Orthopaedic Department in Asklepion Voulas Hospital since 2004. He studied in\nAthens University Medical School and qualified as an orthopedic\nsurgeon in 1985. He worked in UK hospitals from 1985 to 1989\nand thereafter in the Asklepion Voulas Hospital in Athens. His\nspecial interest is knee surgery, including arthroplasty and ligament reconstruction surgery. He established the Sports Medicine\nClinic of Asklepion Voulas Hospital. He also served as President of the Hellenic\nOrthopaedic Association in 2011.",institutionString:'Orthopaedic Clinic of "Asklepieio Voulas" General Hospital',position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"228551",title:"Dr.",name:"George K.",middleName:null,surname:"Safos",slug:"george-k.-safos",fullName:"George K. Safos",profilePictureURL:"https://mts.intechopen.com/storage/users/228551/images/system/228551.jpg",biography:"Dr. George K. Safos is a graduate of Athens University Medical School. He completed his residency in Orthopaedic Surgery and Traumatology at General Hospital of Asklepeion Voulas. He then completed two fellowships in the USA, namely at the National Institutes of Health (NIH) in Bethesda, Maryland as well as at The University of Miami-Orthopaedic Department. A post-graduate degree in Tissue Banking at The National University of Singapore with a United Nations scholarship soon followed. Additionally, he completed a prestigious Foot and Ankle course at the Academic Centre of Amsterdam University and many more internationally-renowned post-graduate courses. Past work experience includes Doctor of Basketball Team Olympiacos B.C. for five years, orthopaedic surgeon in State, Military and Private Hospitals alike. Currently, he specializes in orthopaedic surgery and traumatology with particular interest in sports medicine (knee, hip, ankle, elbow and shoulder arthroscopic surgery) as well as total hip and knee replacement surgery. As a well-published doctor, he now serves as a medical orthopaedic consultant and primary doctor to various athletic teams, dance groups as well as foreign diplomatic missions.",institutionString:"Central Clinic of Athens",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1150",title:"Orthopedics",slug:"orthopedics"}],chapters:[{id:"72475",title:"Tibial Plateau Fracture",doi:"10.5772/intechopen.92684",slug:"tibial-plateau-fracture",totalDownloads:1259,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Tibial plateau fractures are a common orthopedic injury. These fractures involve the articular surface of the tibia that is part of the knee joint. Plateau fractures can range from low energy injuries with little or no displacement to complex fractures with significant associated injuries. Stability of these injuries depends on a combination of bony and associated ligamentous injuries. Treatment consists of a wide spectrum of therapies which have been discussed in this chapter. Complications such as compartment syndrome, post-traumatic arthritis, chronic pain, malunion, and wound problems (in addition to other complications) can develop.",signatures:"Christian M. Schmidt II, Jan P. Szatkowski and John T. Riehl",downloadPdfUrl:"/chapter/pdf-download/72475",previewPdfUrl:"/chapter/pdf-preview/72475",authors:[null],corrections:null},{id:"71800",title:"Surgical Approaches and Leg Positions for Tibial Plateau Fractures",doi:"10.5772/intechopen.92126",slug:"surgical-approaches-and-leg-positions-for-tibial-plateau-fractures",totalDownloads:1219,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Tibial plateau fractures are a common orthopedic injury. Epidemiological studies have shown that these injuries appear in younger or older patients with different mechanisms of injury. For better long-term results, it is crucial to achieve successful fracture reduction, thus avoiding the main complication, which is post-traumatic arthritis. Reduction can be achieved by choosing the proper surgical approach. Many approaches that address the fractures of the tibial plateau have been described in international literature. In the past, the direct anterior midline approach was used, which required a large detachment of the soft tissues. Nowadays, the percutaneous approach, the anterolateral approach, the medial approach, the posteromedial approach, the posterolateral approach, and the direct posterior approach are used by orthopedic surgeons to treat these kinds of fractures. In this chapter, we will describe the surgical approaches available for tibial plateau fractures and the possible positions of the affected leg.",signatures:"Katsimentzas Triantafyllos, Tryfon Ditsios and Kostantinos Ditsios",downloadPdfUrl:"/chapter/pdf-download/71800",previewPdfUrl:"/chapter/pdf-preview/71800",authors:[null],corrections:null},{id:"72081",title:"Midterm Results of Quality of Life after Surgical Treatment of Tibial Plateau Fractures of Type Moore V",doi:"10.5772/intechopen.92062",slug:"midterm-results-of-quality-of-life-after-surgical-treatment-of-tibial-plateau-fractures-of-type-moor",totalDownloads:729,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The midterm restriction of the quality of life should be evaluated and correlated with the objective radiological results in patients with the special tibial plateau fracture of type Moore V. From 2003 to 2012, 36 patients with 38 fractures were registered in a retrospective cohort study. Injury mechanism, surgical treatment, complication rate, and radiological results after a mean follow-up of 37 months and the quality of life (NRS, IKDC-form, and EQ-5D-score) after 68 months were analyzed. There were 27 men and 9 women (mean age 50.8 years) in 30 cases with high impact injury. External fixator was used in 24 cases primarily, single plate fixation was used in 12 cases, and double plate fixation was used in 25 cases. All early complication (21%) could be cured. Mean NRS was 4.53, IKDC-score was 50.46, and the EQ-5D was 7.47. The quality of life was quoted to 44% of the output value before the injury. Osteoarthritis was seen in 36 cases; severe in 19 cases and 4 requiring endoprostheses. Loss of reduction and deviation of axis were seen in 13 and 3 patients, respectively. The tibial plateau of type Moore V is a severe injury resulting in the midterm reduction of the quality of life. There is a correlation of subjective and objective results.",signatures:"Reiner Wirbel",downloadPdfUrl:"/chapter/pdf-download/72081",previewPdfUrl:"/chapter/pdf-preview/72081",authors:[null],corrections:null},{id:"70800",title:"Far Proximal and Far Distal Tibial Fractures: Management with Intramedullary Nails",doi:"10.5772/intechopen.90915",slug:"far-proximal-and-far-distal-tibial-fractures-management-with-intramedullary-nails",totalDownloads:848,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Operative treatment of tibial fractures located at the proximal metaphyseal-epiphyseal and distal metaphyseal-epiphyseal areas, including those with articular extensions, is a technical challenge. Common methods for surgical management include plates (locking and nonlocking), external fixation devices, and intramedullary nails. All these methods have shown satisfactory results in terms of quality of reduction and clinical and radiological outcomes. The authors present some technical methods and strategies that have been useful for the surgical approach, reduction, and fixation of these lesions with the use of locked nails.",signatures:"Luis Bahamonde, Alvaro Zamorano and Pierluca Zecchetto",downloadPdfUrl:"/chapter/pdf-download/70800",previewPdfUrl:"/chapter/pdf-preview/70800",authors:[null],corrections:null},{id:"68387",title:"The Regenerative Effect of Intra-Articular Injection of Autologous Fat Micro-Graft in Treatment of Chronic Knee Osteoarthritis",doi:"10.5772/intechopen.88220",slug:"the-regenerative-effect-of-intra-articular-injection-of-autologous-fat-micro-graft-in-treatment-of-c",totalDownloads:961,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The study started in 2010 to find the effect of autologous fat micrograft for osteoarthritis (OA); the result was published on normal animal’s model, in 10 patients, then in 80 patients with knee osteoarthritis, and the current study in 205 patients. The study was conducted at King Abdulaziz University Hospital (January 2012–October 2015); 80 adult patients were suffering from moderate to severe knee osteoarthritis. About 10–20 mL fat micrograft was prepared with liposuction and injected intra-articularly into the affected knee/s. The results revealed that pain improvement after the fat injection during rest and with activity with the visual analogue scale. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) indicated improvement, both in the three domains (pain, stiffness, and physical function) and in total. The use of intra-articular autologous fat micrograft is simple, safe, and effective for degenerative knee osteoarthritis.",signatures:"Sabah S. Moshref, Yasir S. Jamal, Amro M. Al-Hibshi and Abdullah M. Kaki",downloadPdfUrl:"/chapter/pdf-download/68387",previewPdfUrl:"/chapter/pdf-preview/68387",authors:[null],corrections:null},{id:"72867",title:"High Tibial Osteotomy",doi:"10.5772/intechopen.92887",slug:"high-tibial-osteotomy-1",totalDownloads:638,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"To address lower limb malalignment with concomitant medial compartment osteoarthritis, meniscal deficiency, focal chondral defects, and ligamentous instability, high tibia osteotomy (HTO) is a reliable treatment option. In order to achieve a good long-term outcome with HTO, a comprehensive history and physical examination, together with a meticulous patient selection and careful pre-operative planning, and selection of the appropriate fixation technique and rehabilitation protocol are paramount.",signatures:"Tuna Pehlivanoglu, Kerem Yildirim and Tahsin Beyzadeoglu",downloadPdfUrl:"/chapter/pdf-download/72867",previewPdfUrl:"/chapter/pdf-preview/72867",authors:[null],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7898",title:"Cartilage Tissue Engineering and Regeneration Techniques",subtitle:null,isOpenForSubmission:!1,hash:"cb87bdbe93f1269aae5c6c678c598ce7",slug:"cartilage-tissue-engineering-and-regeneration-techniques",bookSignature:"Dimitrios D. Nikolopoulos, George K. 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\r\n\tElectric field is a fundamental nature phenomenon and one of the most important physical parameters. It had significant effects on the last century's science, technology, economy, society, and human lives. After a long development, the electric field appears to take quite different roles in the recently developing science and technology. Its effect is much more refined and stronger. It is thus necessary to take a reviewing look at the development of the electric field in the advancing science and technology in recent years and to see how it would develop in the future. This book is intended to focus on the most important aspects: new materials, novel and sophisticated devices, molecule-level biology and medicine, highly developed instruments, and metrology. We will intend to show in this book that the electric field is taking more and more deterministic roles in newly advancing materials including nanomaterials, two-dimensional materials, new structure catalysts, meta-materials, etc. Devices are becoming tinier and tinier and multi-functioned, so the electric field design and function are getting precise, complicated, sophisticated but strong and multiplied. Biology and medicine are getting into molecule level, so the studies of electric field stimulation effect, electric field cue, and other electric-field related behaviors are growing very fast and will be widely practiced in the near future. Electrical field measurement is becoming an important tool for other physical behaviors such as weak magnetism, and the measurement is getting into the atomic scale so that instruments related to the electric field are stepping greatly forward. The electrical field appears more significant also in the fields of climate, environment, space science, etc., so we intend to present it in this book also as it would contribute remarkably to the future science and high technology.
\r\n\t
The forthcoming biochemical observations were from the resecates of the patients who underwent surgical intervention because of peptic ulcer disease. These observations were done during 1969–1976, when only the parasympatholytics were used in the medical treatment of patients with peptic ulcer.
The resecates of the gastrointestinal tract were divided into two parts: one was used for classical histopathological examinations (with the permission from Professor György Romhányi, Head of the Department of Pathology and of Professor Tihamer Gy. Karlinger, Head of First Department of Surgery, Pécs University, Hungary),, awhile the other part was used for biochemical examinations. Different parts from the mucosa and musculature were separated from each other immediately after the surgical resection of the GI tract, and these parts were put immediately into liquid nitrogen.
All biochemical parameters of the GI tissue samples (normal and ulcerated antral, duodenal and jejunal mucosa and three gastric fundic mucosa and musculature, if we received fundic tissues) were maintained in the same time in all the received tissue samples.
It is very important to emphasize that, on the one hand, all biochemical parameters maintained from the same tissue samples, and on the other hand, all tissue samples were biochemically examined. It is also important to note that the weight of these tissue samples was about 0.25–0.5 g wet tissue (these examinations cannot be carried out from biopsy materials).
The methodologies were detailed in the original published papers.
These patients had typical ulcer histories and endoscopic pictures. These patients received medical treatment (by dominant internists) for about 4 weeks before surgery. The patients who were suspected to have malignant ulcers did not receive any tissue samples from the resecates (because of necessary histopathological examinations).
In the gastric basal acid output (BAO) and maximal acid output (MAO), there are different associations with cations and protein secretion from the serosa to the mucosa: the H+, chloride, K+, Mg2+, Ca2+ and albumin increase significantly, while the Na indicates a decrease (Myren, 1968; Semb and Myren, 1968; Wright and Hirschowitz, 1976). These called for attention to study the correlations between the classical membrane-bound ATP-dependent energy systems and gastric BAO and MAO.
There was no doubt that after the administration of pentagastrin or histamine (given in doses) to produce gastric MAO values, the changes in the contents of the gastric juice cations became much higher than those in gastric BAO. These data also suggested that there is some correlation between the membrane-bound ATP-dependent energy systems and the gastric BAO and MAO values.
In 45 patients with peptic ulcer (20 patients with gastric and 25 patients with duodenal ulcer), the gastric H+ was measured without the administration of any drug (basal acid output, BAO), and its value was expressed in mEq/L. These patients underwent resection of the stomach for peptic ulcer. During the surgery, a piece was cut from the fundic part of the stomach. The gastric mucosa and the muscular layer were separated from each other, and the membrane ATPase was prepared from fundic gastric mucosa with differential centrifugation (20.000 × g and 40.000 × g) and treatment with 2.0 M NaI solution as per our method (Mózsik and Øye, 1969). The membrane ATPase activity was measured in an incubation system at 37 oC by the liberation of inorganic phosphorus (Mózsik, 1969b). The Na+–K+-dependent ATPase activity was calculated as the difference between the total (obtained in the presence of Mg2+, Na+ and K+) and Mg2+-dependent system (obtained in the presence of Mg2+) (Figure 45).
Correlation between the Na+–K+-dependent ATPase activity from human fundic mucosa (ordinate) and basal acid output (BAO) (abscissa) in 45 patients with peptic ulcer. The enzyme activities are expressed as
The Na+–K+-dependent ATPase differs from the H+–K+-dependent ATPase, independently from the similarities of protein structures (see Sections 5.1, 5.2), and the mitochondrial ATP is a common substrate for both these enzymes. Our enzyme was prepared from the whole gastric fundic mucosa; H+–K+–ATPase is located only in the parietal cells, which are highly specialized epithelial cells in the inner cell lining of the stomach. H+–K+–ATPase can be separated from the Na+–K+-pump enzyme based on specific immunological studies (Saccomani et al., 1979b; Yao and Forte, 2004; Dunbar and Caplan, 2001; Sachs et al., 1995; https.//www.nlm.nil.gov/cgi/mesh/2011/MB_cgi?&term=Potassium+Hydrogen+ATPase).
There is no doubt that both the active transport of Na+ and K+ (Na pump) and the gastric acid secretion are energy-dependent processes (obtained from the ATP transformation into ADP); however, the sodium pump is a general function of all cells, while the H+–K+–ATPase is responsible only for gastric acid secretion.
We never participated in the study of H+–K+–ATPase; however, it is true that the presence of Na+–K+–ATPase was proved earlier in the rat and human gastrointestinal (gastric) mucosa (Mózsik and Øye, 1969).
We used the Na+–K+-dependent ATPase system as a key enzyme participating in the regulation of cell functions, of course, in the gastric mucosal cells. The function of Na+–K+–ATPase represents only one side of the ATP splitting process (as energy source), while the actual level of tissue ATP indicates the other side of energy source system (namely, the ATP resynthesis). These processes occur together in all cells and tissues. Both Na+ and K+ are involved in both the classical sodium pump and the gastric acid secretion.
Our results presented here are related dominantly to the function of the classical sodium pump in the human gastric mucosa. It is interesting and important to note that the activity of Na+–K+-dependent ATPase is closely associated with the gastric acid secretion.
This section deals with the effects of some cholinergic and anticholinergic drugs on the membrane-bound ATPase enzyme (Mózsik et al., 1974c).
Effects of acetylcholine (Ach), carbamylcholine (Carb.ch.) and neostigmine (Neostig.) on the total ATPase activity in the human gastric fundic mucosa. The enzyme activity is expressed in percentage of total ATPase activity (=100%) without any drug [Mózsik, Nagy, Kutas, Tárnok: Scand. J. Gastroenterol. 9: 741–745, 1974 (with kind permission).]
Effects of acetylcholine on Mg2+-dependent, total and Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The results are presented in percentage of total ATPase (=100%) activity without the administration of any drugs. [Mózsik, Nagy, Kutas, Tárnok: Scand. J. Gastroenterol. 9: 741–745, 1974 (with kind permission).]
Effects of atropine on Mg2+-dependent, total and Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The results are presented in percentage of total ATPase (=100%) activity without the administration of any drugs. [Mózsik, Nagy, Kutas, Tárnok: Scand. J. Gastroenterol. 9: 741–745, 1974 (with kind permission).]
Comparative inhibitory effect of different parasympatholytics on the total membrane ATPase prepared from the human gastric fundic mucosa. The results are presented in percentage of total ATPase (=100%) activity without the administration of any drugs. [Mózsik, Nagy, Kutas, Tárnok: Scand. J. Gastroenterol. 9: 741–745, 1974 (with kind permission).]
Comparative inhibitory effect of different parasympatholytics on the total membrane ATPase activity prepared from the human gastric fundic mucosa. The results are presented in per cent of total ATPase (= 100 per cent) activity without application of any drugs. (Mózsik, Nagy, Kutas, Tárnok: Scand. J. Gastroenterol. 9: 741-745, 1974) (with kind permission).
Cumulative dose–response curves for parasympatholytics inhibiting the Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The intrinsic activity (α) of atropine was found to be equal to 1.0 on Na+–K+-dependent ATPase activity. Each point represents the average of 10 measurements (chemical structures: isopropamide, 2,2-diphenyl-4-diiso-propylamino-methyliodide; GastrixonR, methyl-tropinium-bromide-xanthene-9-carboxylate). [Mózsik, Kutas, Nagy, Tárnok, Vizi: Acta Physiol. Sand. Special Suppl. 199–208, 1978 (with kind permission).]
\n\t\t\t\t | \n\t\t
Values of affinity (pD2) and intrinsic activities (α) for parasympatholytics inhibiting the Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The intrinsic activity of atropine was found to be equal to 1.0.
The results presented above indicate clearly the following:
During the cholinergic activation, the enzyme system of sodium pump (the transformation of ATP into ADP by membrane ATPase) is in working state (acetylcholine, carbamylcholine, neostigmine);
The parasympatholytics inhibit the function of membrane ATPase prepared from the human gastric fundic mucosa;
The different parasympatholytics produced different extents on the inhibition of membrane ATPase activity.
The gastric acid secretory responses are characterized by the so-called basal acid secretory responses (e.g., without the administration of any drug to stimulate the gastric acid secretion) (basal acid output, BAO) and maximal gastric acid secretory responses (maximal acid output, MAO). The MAO can be produced by the administration of histamine (0.04 mg/kg body weight, given subcutaneously) (Kay’s test) or pentagastrin (6 µg/kg given subcutaneously).
Histamine (10-7 M) effects on only Mg2+-dependent ATPase and on Na+-K+-dependent ATPase activity. The results (means±SEM) are presented as per cent of control values. (Mózsik, Nagy, Tárnok, Jávor, Kutas: Pharmacology 12: 193-200, 1974) (with kind permission).
The effect of histamine was studied on the typical membrane ATPase prepared from the gastric fundic mucosa of patients with gastric (8 patients) and duodenal (6 patients) ulcer, before resection of their stomach: BAO value = 3.86 ± 1.14 mEg/h and MAO = 16.30 ± 2.25 mEg/h.
Histamine was used in 10−7 M concentration to test its effect only on Mg2+--dependent part and Na+–K+-dependent part (Figure 52).
Inhibition of total ATPase from the human gastric fundic mucosa by histamine. The results of 14 patients are expressed in means ± SEM. The left ordinate shows the enzyme activity (µmol P
The inhibition of total membrane ATPase activity was caused by histamine in a concentration of 10−7 to 10−3 M.
Similar observations were noted in pentagastrin, and the same type of inhibition of membrane ATPase was obtained as that of histamine.
The effects of prostaglandin E1 and E2 were studied on the Mg2+- dependent and Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa (Figures 54, 55), and significant inhibitory actions were produced by PGE1 and PGE2 in concentrations of 10−10 to 10−6 M.
Inhibitory effects of prostaglandin E1 (top) and E2 (bottom) on Mg2+-dependent ATPase prepared from the human gastric fundic mucosa. The results are expressed as percentage value of total ATPase activity (=100%). The abscissa indicates the concentrations of prostaglandins (M). Each point represents the means ± SEM of 10 observations. [Mózsik, Kutas, Nagy, Németh: Eur. J. Pharmacol. 29: 133–137, 1974 (with kind permission).]
Inhibitory effects of prostaglandin E1 (top) and E2 (bottom) on Na+–K+-dependent ATPase prepared from the human gastric fundic mucosa. The results are expressed as percentage value of total ATPase activity (=100%). The abscissa indicates the concentrations of prostaglandins (M). Each point represents the means ± SEM of 10 observations. [Mózsik, Kutas, Nagy, Németh: Eur. J. Pharmacol. 29: 133–137, 1974 (with kind permission).]
It was clear to conclude that the magnitudes of drugs actions depend on the membrane enzyme activity. Because the membrane ATPase activity significantly changes on the activity of target organ, the drug actions depend on the activity of the target organ (Nagy et al., 1976, 1981 a, b).
\n\t\t\t\t | \n\t\t
Correlations between the magnitudes of drug actions and the magnitudes of Na+–K+–ATPase prepared from the human gastric fundic mucosa.
We prepared the membrane ATPase from the human gastric fundic mucosa and, simultaneously, directly measured the tissue level of ATP, ADP, lipid phosphates, ribonucleic acid and deoxyribonucleic acid. The tissue levels of ATP, ADP, lipid phosphates and ribonucleic acid were expressed in accordance to 1.0 mg deoxyribonucleic acid (DNA). The membrane ATPase activity was assayed (Mózsik and Øye, 1969) by
Biochemical regulatory pathways between Na+–K+-dependent ATPase, tissue levels of ATP, ADP in the human gastric fundic mucosa dependent on the gastric BAO values (means ± SEM). [Mózsik, Tárnok, Kutas (1981) in Gáti, Szollár, Ungváry (eds.) Advances in Physiological Sciences Vol. 12. Nutrition, Digestion, Metabolism. pp. 117–128. 1981 (with kind permission).]
Correlation between the gastric basal acid output (BAO) versus gastric maximal acid output (MAO) in patients examined biochemically. [Mózsik, Vizi, Nagy, Bero, Tárnok, Kutas (1976): Na+–K+-dependent ATPase system and the H+ secretion by the human gastric mucosa. In: Mozsik Gy., Javor T. (eds). Progress in Peptic Ulcer. Budapest, Akadémiai Kiadó, pp. 37–72 (with kind permission).]
Figure 58 indicates the results of different correlation calculations versus MAO values.
We found positive and significant correlations between the following parameters:
MAO versus Na+–K+-dependent ATPase;
MAO versus tissue level of ATP;
Na+–K+-dependent ATPase versus ATP;
ATP versus ADP;
MAO versus ADP. (Andrási, 1997; Bódis et al., 1977 a, b; Levine, 1971; Mózsik et al., 1978b).
Biochemical regulatory pathways between Na+–K+-dependent ATPase, tissue levels of ATP, ADP in the human gastric fundic mucosa dependent on the gastric maximal acid output (MAO) values. For further explanation, see Figure 56 (with kind permission).
The contradictory effects of drugs on Na+–K+-dependent ATPase and adenylate cyclase were demonstrated earlier (Mózsik, 1969 a, b, 1970, 1974 a, b, 1979 b, c, e).
Table 33 indicates affinity (pD2) and intrinsic activity (pA2) curves for the actions of acetylcholine, histamine and pentagastrin. The table also indicates the contradictory actions of these agents on Na+–K+-dependent and adenyl cyclase systems.
We hypothesized a feedback system between the membrane ATPase and adenylate cyclase in the development of gastric BAO and MAO (Figure 59).
\n\t\t\t\t | \n\t\t
Actions of acetylcholine, histamine and pentagastrin in human beings.
Our suggestion to demonstrate the correlations between the ATP-dependent membrane-bound energy systems and the gastric BAO and MAO values regulated by acetylcholine, pentagastrin and histamine. [Mózsik, Debreceni, Juricskay, Karádi, Nagy (1997) In: Gaginella T.S., MózsikGy., Rainsford K.D. (eds) Biochemical Pharmacology as an Approach to Gastrointestinal Disorders, Kluwer Academic Publishers, Dordrecht, Boston, London. pp. 199–222 (with kind permission).]
The biochemical examinations were carried out in resecates of stomach (fundus, antrum) and small intestine (duodenum, jejunum) in patients with chronic peptic ulcer, who underwent surgical intervention.
The gastric BAO and MAO (subcutaneously given 6 µg/kg body weight of pentagastrin) were measured before the surgical intervention.
The examined patients were divided into three groups, according to the BAO values (Table 34). These patients underwent resection of stomach (and some part from duodenum; in patients with jejunal ulcer, who underwent surgery previously, Billroth II-type gastric resection was carried out, and jejunal ulcer appeared later). Immediately after resection, different tissue samples were separated from the obtained tissues, and they were put into liquid nitrogen.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
BAO < 2.0 mEq/ h | \n\t\t\t0.27 ± 0.0.1 (n = 12) | \n\t\t\t7.95 ± 1.38 (n = 12 ) | \n\t\t
BAO 2.00 to 4.0 mEq/h | \n\t\t\t2.81 ± 0.10 (n = 9 ) | \n\t\t\t15.69 ± 0.76 (n=9) | \n\t\t
BAO > 4.0 mEq/h | \n\t5.33 ± 0.24 (n = 11) | \n\t18.76 ± 2.15 (n=11 ) | \n
Gastric secretory responses in patients in whom the biochemical examinations were carried out. The gastric acid secretory responses are presented in mEq/h (means ± SEM),
The following biochemical examinations were carried out from different tissue samples:
Determination of membrane (Mg2+–Na+–K+-dependent) ATPase;
Separation and determination of adenine–adenosine, adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP);
Separation and determination of lipid phosphates;
Separation and determination of nucleic acids.
The details of these methodological problems are presented in a paper (Mózsik et al., 1976b).
It is important to note and emphasize the following:
The number of biochemically evaluated tissue samples in different figures is different (e.g., in case of gastric fundic mucosa vs. musculature), which is dependent on the
We had no possibility for direct measurement of cyclic AMP from these tissue samples in these series of observations;
All biochemical examinations (including the preparative works) were carried out in all tissue samples obtained in one patient.
Tissue levels of adenosine triphosphate (ATP) in the gastric fundic mucosa and musculature prepared from patients with peptic ulcer depending on the gastric acid secretory responses. The results are presented in nmol/mg DNA (means ± SEM). The results are based on the results published in a paper (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 11: 205–211, 1976) (with some modification).
Tissue levels of ribonucleic acid (RNA) in the gastric fundic mucosa and musculature prepared from patients with peptic ulcer depending on the gastric acid secretory responses. The results are presented in mg RNA/mg DNA (means ± SEM).The results are based on the results published in a paper (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 11: 205–211, 1976) (with some modification). The numbers in parenthesis indicate the number of patients.
ATP–membrane ATPase–ADP system in the human gastric fundic mucosa and musculature prepared in the stomach resecates obtained from patients with peptic ulcer. The results are based on the results published in a paper (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 11: 205–211, 1976 and Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977) (with some modification). The numbers in parenthesis indicate the number of patients.
Correlations between the membrane ATPase activity, tissue levels of ATP and ADP in the human gastric fundic mucosa and musculature in patients with different gastric (hypacid, normacid and hyperacid) secretory responses depending on the gastric basal acid output (BAO) (means ± SEM). The results are based on the results published in a paper (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 11: 205–211, 1976 and Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977) (with some modification).
The changes in the biochemistry of gastric fundic mucosa and musculature in patients with different gastric BAO values. The results are expressed as means ± SEM/1.0 mg deoxyribonucleic acid (DNA) (means ± SEM). The results are based on the results published in a paper (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 11: 205–211, 1976 and Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977) (with some modification). The numbers in parenthesis indicate the number of patients.
There was an energy gradient in the corpus, antrum and duodenum mucosa depending on the gastric basal and maximal acid secretory activities (Mózsik et al., 1976 a, b, c, 1979 b, 1981a) (Figures 65–66; Tables 35–37).
Biochemical parameters in the corpus, antrum and duodenum in patients with gastric hypacidity (BAO, MAO) (means ± SEM) (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1976) (with some modification).
Biochemical gradients in the gastric fundic, antral and duodenal mucosa in patients with hyperacidity (means ± SEM). (Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1976) (with some modification).
\n\t\t\t | \n\t
Substrate levels in the gastric mucosa of the corpus, antrum and duodenum of patients with BAO values <2.0 mEq/h (BAO = 0.27 ± 0.27; MAO = 9.75 ± 1.38)a. [Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977 (with kind permission).]
\n\t\t\t | \n\t
Substrate levels in the gastric mucosa of the corpus, antrum and duodenum of patients with 2.0<BAO<4.0 mEq/h (BAO = 2.81 ± 0.10; MAO = 15.69 ± 0.76)a. [Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977 (with kind permission).]
\n\t\t\t | \n\t
Substrate levels in the gastric mucosa of the corpus, antrum and duodenum of patients with BAO values >4.0 mEq/h (BAO = 5.33 ± 0.24; MAO = 18.76 ± 2.15)a. [(Mózsik, Vizi, Kutas: Scand. J. Gastroenterol. 12: 461–464, 1977 (with kind permission).]
The membrane ATPase activity and tissue levels of ATP and ADP were measured around the gastric antral, duodenal and jejunal ulcer patients (after partial gastrectomy).
The ATPase activity and tissue levels of ATP and ADP were significantly higher around the gastric antral, duodenal and jejunal mucosa than those obtained in the non-ulcerated (control) mucosa (Mózsik et al., 1976 d, f, 1981 a, c, 1987 a, b, 2000) (Figures 65, 66; Tables 35–37).
Changes in the extents of ATP–ADP transformation in the antral mucosa of patients with chronic antral ulcer in the ulcerated and non-ulcerated (control) mucosa (means ± SEM). [Mózsik, Kutas, Nagy, Tárnok, 1979; Mózsik, Kutas, Nagy, Tárnok, Acta Medica Acad. Sci. Hung. 36: 1–29, 1979 and Acta Medica Acad. Sci. Hung. 38: 129–134, 1984 (with kind permission).]
Changes in the extent of ATP–ADP transformation in the duodenal mucosa of patients with chronic duodenal ulcer, in the ulcerated and non-ulcerated duodenal mucosa (means ± SEM). [Mózsik, Kutas, Nagy, Tárnok: Acta Medica Acad. Sci. Hung. 37: 39–49, 1979 (with kind permission).]
It was clear to conclude that the magnitudes of drugs actions depend on the membrane enzyme activity. Because the membrane ATPase activity significantly changes on the activity of target organ, the drug actions depend on the activity of the target organ (Nagy et al.,1976, 1981 a, b).
Changes in the extent of ATP–ADP transformation in the jejunal mucosa of patients who underwent partial gastrectomy (according to the method of Billroth II) around the jejunal ulcerated mucosa and non-ulcerated jejunal mucosa (means ± SEM). [Mózsik, Nagy, Tárnok, Kutas: Acta Medica Acad. Sci. Hung. 38, 129–134, 1981 (with kind permission).]
Figures 70 and 71 clearly indicate that the tissue levels of mucosal levels of ATP and ADP are significantly higher in the ulcerated antral, duodenal and jejunal mucosa than those obtained in the control (non-ulcerated) mucosa specimen (the measurements were done simultaneously in patients).
As we indicated earlier, the membrane ATPase activity was also significantly higher in these ulcerated mucosa specimens than that in the control (non-ulcerated) mucosa. Against these biochemical changes, the values of “energy charge” remained the same (Figure 72).
Comparative demonstration in the changes of the tissue levels of ATP in the ulcerated versus non-ulcerated antral, duodenal and jejunal mucosa (the musculature is located under the examined mucosa tissues) (means ± SEM). [Mózsik el al., in Mózsik, Hänninen, Jávor (eds.) Advances in Physiological Sciences. Vol. 29. Gastrointestinal Defence Mechanism, Pergamon Press, Oxford-Akadémiai Kiadó, Budapest. pp. 213–288, 1981 (with kind permission).]
Comparative demonstration in the changes of tissue levels of ADP in the ulcerated and non-ulcerated antral, duodenal and jejunal mucosa (the musculature is located under the examined mucosa tissues). (Mózsik et al., In: Mózsik, Hänninen, Jávor (eds.) Advances in Physiological Sciences. Vol. 29. Gastrointestinal Defence Mechanism, Pergamon Press, Oxford- Akadémiai Kiadó, Budapest. pp. 213–288, 1981). For further explanation, see Figure 70.
Critical evaluation of the “energy charge” in the mucosa around the chronic antral, duodenal and jejunal mucosa versus Non-ulcerated mucosa (the musculature located under the studies mucosa tissues). [Mózsik el al., in Mózsik, Hänninen, Jávor (eds.) Advances in Physiological Sciences. Vol.29. Gastrointestinal Defence Mechanism, Pergamon Press, Oxford- Akadémiai Kiadó, Budapest. pp. 213–288, 1981 (with kind permission).] For further explanation, see Figure 70.
These results demonstrated earlier in Figures 70–72 clearly indicate the following:
The extent of ATP–ADP breakdown is significantly higher in the ulcerated antral, duodenal and jejunal mucosa specimens than that in the control (non-ulcerated) mucosa specimens. This fact can be proven by the increased membrane ATPase activity and by increased level of ADP;
No impaired phosphorylation can be found in the ulcerated mucosa specimens, which can be proven by increased tissue levels of ATP in time when the ATP–ADP breakdown was significantly increased (significantly higher membrane ATPase activity and increased level of ADP);
The extent of ATP–cAMP transformation was significantly higher in the ulcerated antral, duodenal and jejunal mucosa around the chronic ulcer;
The tissue levels of ATP were significantly higher in the mucosa – around the chronic antral, duodenal and jejunal ulcer – that those in the control (non-ulcerated) mucosa, while the extents of both ATP–ADP and ATP–cAMP transformations were increased in the ulcerated antral mucosa specimens;
The higher ATP tissue levels (in time when the ATP breakdown was increased in both directions) can be obtained by the intact oxidative phosphorylation pathway;
The biochemical components of gastric mucosal tissue were expressed in accordance to 1.0 mg DNA, which represents the same number of cells (Figure 297). The values of adenine–adenosine, ATP, ADP and AMP were increased in the gastric fundic mucosa in patients with increased gastric secretory responses (BAO, MAO) and in the mucosa around chronic antral, duodenal and jejunal ulcers.
No physiological data are available in the literature to prove the presence of decreased GMBF in the gastric fundic mucosa in patients with gastric hyperacidity, and nobody found an increased tissue level of lactate. All experts accept the increased energy turnover (increased extents of ATP–ADP and ATP–cAMP transformation) in these gastric fundic mucosa specimens.
The results of animal experiments clearly indicated that the biochemical components differ significantly in the glandular stomach in comparison with the values in the forestomach. When we analyzed the time -sequence of biochemical changes, development of gastric hyperacidity and ulcer development, we first obtained the gastric hyperacidity and then the ulcer development. The same tendency was obtained in the changes of gastric mucosal biochemistry in both parts of the stomach, and these changes appeared before the development of gastric hyperacidity in 24-hour pylorus-ligated rats (Mózsik and Vizi, 1976 a, b).
A significant biochemical gradient was biochemically proved in the gastric fundic, antral, duodenal and jejunal mucosa depending on the gastric secretory responses (BAO, MAO).
Extracellular vesicles (EVs) are a collective term for tiny vesicles with a phospholipid bilayer structure that are actively secreted by cells. Almost all known cell types can be secreted. The two main categories of EVs are exosomes and microvesicles (Table 1). Exosomes (30-150 nm in diameter) are intraluminal vesicles, formed by the invagination of the multivesicular endosome membrane, and are released into the extracellular space after the multivesicular endosomes fuse with the cell membrane [1]. Microvesicles (50–1,000 nm in diameter) are a group of highly heterogeneous EVs characterized in that their origin and secretion are budding through the plasma membrane [1]. Considering the complexity of identifying its biogenesis, the size of the vesicle is the most widely used parameter for classifying EV types, and on this basis they are described as small EVs or medium and large EVs. In this article, unless otherwise specified, the term “EVs” generally refers to small EVs.
Vesicle | Size (nm) | Density (g/mL) | Origin | Markers |
---|---|---|---|---|
Exosomes | 30-150 | 1.13-1.18 | Endosomes | Tetraspanins, Alix, TSG101 |
Microvesicles | 50-1000 | 1.16-1.19 | Plasma membrane | Intergrins, Selectins, CD40 |
In recent years, people’s understanding of the biogenesis, composition, function and mechanism of EVs has continued to deepen [3, 4, 5]. Their application in clinical treatment has also attracted more and more attention. One of the most useful properties of EVs is their ability to cross barriers, such as the plasma membrane and blood/brain barrier. This makes them very suitable for delivering therapeutic molecules. With their natural source material transport properties, inherent long-term blood circulation capabilities and excellent biocompatibility, EVs can deliver a variety of chemical drugs, proteins, nucleic acids, gene drugs and other drugs. They have great potential in the field of drug carriers. CD47 is the ligand for signal regulatory protein alpha (SIRPα), and CD47-SIRPα binding initiates the ‘don’t eat me’ signal that inhibits phagocytosis. Therefore, CD47 on EVs prevents them from being engulfed by immune cells [6]. EVs are more efficient than their synthetic analog liposomes. The application of EVs as drug delivery carriers is like putting a “stealth coat” on the drug molecules, which can maximize the stability of the drugs, reduce the immune system’s clearance of them, and make “precise delivery” possible. Therefore, EVs can be described as “stealth transport aircrafts” for drugs. EVs therapy has shown great application prospects from oncology to regenerative medicine.
A number of studies have shown that EVs derived from mesenchymal stem cells (MSCs) can be used for stem cell replacement therapy [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. In most cases, it is not clear which component of the unmodified EVs exerts curative effects. The researchers’ operations are only the separation and purification of EVs produced by therapeutic cells. The curative effects are based on the biological functions of the donor cells, such as the regulation of the immune environment, the repair of damaged cells and the promotion of angiogenesis.
At present, the most extensive research is the attempt to use stem cell-derived EVs for disease treatment. The main application ranges are to repair and regenerate tissues and organs. Such researches involve central nervous system diseases [7, 8], cardiovascular diseases [9, 10, 11, 12] and other organ damage repair and regeneration [13, 14, 15, 16, 17, 18, 19, 20, 21].
In the treatment of central nervous system disease, there is a blood-brain barrier, which often results in that drugs can not reach the diseased site and work well. Stem cells have been gradually used in the treatment of central nervous system diseases in recent years. A large number of research results have been obtained [22, 23]. However, there are still potential risks faced by direct stem cell transplantation, such as tumorigenicity, infection, transplant failure, graft versus host disease, hemorrhagic cystitis, and long-term complications [24].
The application of stem cell EVs avoids a variety of potential risks of direct stem cell transplantation. EVs have low immunogenicity and are easy to preserve and transport, showing unique advantages as a “cell-free stem cell therapy technology”. Spinal cord injury (SCI) is one of the deadliest diseases. The complex inhibitory microenvironment needs to be fully mitigated. EVs derived from MSCs have the function of microenvironmental regulation. Studies have established innovative implantation strategies using human MSC-derived EVs immobilized in peptide-modified adhesive hydrogels (Exo-pGel) [7]. Exo-pGel plays an important role in nerve recovery and urinary tissue protection by effectively reducing inflammation and oxidation [7]. In addition, small extracellular vesiclesderived from embryonic stem cells (ESC-sEVs) can significantly reduce the time-related aging of hippocampal neural stem cells (H-NSCs) through intravenous injection into vascular dementia (VD) rats. ESC-sEVs can restore the damaged proliferation and neuronal differentiation ability, and reverse cognitive impairment. The application of ESC-sEVs may be a new cell-free treatment tool for VD and other diseases related to aging [8].
Stem cells can be induced to differentiate into cardiomyocytes. Early studies believed that the transplanted stem cells can differentiate into heart cells and necrotic cells in the body to repair damaged myocardium and maintain heart function [25]. At present, a large number of preclinical studies have found that EVs derived from transplanted stem cells also have the function of myocardial repair [26, 27]. EVs mainly promote myocardial regeneration by activating cardiac precursor cells, promoting the survival and proliferation of cardiomyocytes, inhibiting their apoptosis, promoting cardiac angiogenesis, reducing infarct size and tissue fibrosis, and regulating inflammation. Extracellular vesicles secreted by cardiovascular precursor cells (hCVPC-EVs) derived from human pluripotent stem cells (hPSCs) play a role in protecting the heart in myocardial infarction by improving cardiomyocyte survival and angiogenesis [9]. Mouse ESC-derived EVs promote angiogenesis, cardiomyocyte survival and proliferation, reduce cardiac fibrosis, and improve cardiac function by carrying miR-294-3p [10]. IPSC-derived EVs inhibit cardiomyocyte apoptosis through miR-21 and miR-210 loaded, and also have a cardioprotective effect [11]. Exosomes produced by immature bone marrow-derived macrophages (BMDM-exo) contain anti-inflammatory microRNA-99a/146b/378a. They can reduce the necrotic lesions of atherosclerosis [12].
With the continuous discovery of the repair and regeneration effects of stem cell EVs in brain tissue and cardiovascular tissues and organs, the application of stem cell EVs in the repair and regeneration of other tissues has also made a lot of progresses.
MSC-derived EVs reduce radiation-induced lung injury through miRNA-214-3p [13]. Replacing autologous cells with EVs derived from hair follicle papillary cell spheres can promote hair growth [14]. Human umbilical cord mesenchymal stem cell-derived exosomes (UMSC-Exo) can inhibit pyrolysis and repair muscle ischemic injury by releasing circular RNA circHIPK3 [15]. Hertwig’s EVs derived from epithelial root sheath cells promote the regeneration of dentin plasma tissue [16]. Exosomes from neural progenitor cells retain photoreceptor cells during retinal degeneration (RD) by inactivating microglia. This suggests that NPC-exos and its contents may be the mechanism of stem cell therapy to treat RD [17].
Aging is the process of cell and tissue dysfunction. Small extracellular vesicles (sEVs) isolated from primary fibroblasts from young human donors can improve certain biomarkers of cellular senescence from elderly and Hutchinson-Gilford progeria donors. Studies have shown that sEVs have GST activity to improve aging-related tissue damage [18]. In obesity diseases, EVs derived from adipocytes, as new adipokines, are related to the body’s metabolic homeostasis. EVs released from brown adipose tissue or adipose stem cells can help control the remodeling of white adipose tissue, making it brown and maintaining metabolic homeostasis. EVs have been considered as new regulators of diseases such as insulin resistance, diabetes and non-alcoholic fatty liver. The results provide new treatment strategies for obesity and metabolic diseases [19].
In addition, some reports suggest that some EVs derived from mesenchymal stem cells contain some tumor suppressor molecules. For example, it has been reported that miR-206 in exosomes derived from bone marrow mesenchymal stem cells could inhibit the progression of osteosarcoma by targeting TRA2B [20]. The exosomes derived from human umbilical cord mesenchymal stem cells deliver miRNA-375 to delay the progression of esophageal squamous cell carcinoma [21]. However, although EVs contain these small RNAs that have been reported to exert anti-cancer effects, they also contain a large number of growth factors and pro-angiogenesis factors. When these substances are transported to tumor cells by EVs, can EVs derived from MSCs still exert a tumor suppressor effect? This needs more research to prove.
At present, cell replacement therapy based on the characteristics of donor cells has been studied earlier and more frequently in the field of EVs. There is also a clearer understanding of the components that play a major role. With the continuous increase of clinical needs, people began to try to modify the surfaces and contents of EVs to adapt to more disease treatments.
Although natural EVs have been used for cell replacement therapy based on their source and achieved good results, their therapeutic range is far from meeting the current treatment needs. One of the most important therapeutic areas is the treatment of malignant tumors. The secretion ability of EVs in malignant tumor itself is enhanced and contributes to tumor progression. Considering that MSC-derived EVs generally contain high levels of growth factors and pro-angiogenic factors, most natural EVs are not suitable for tumor therapy, except that EVs derived from antigen-presenting cells can be used as tumor vaccines to activate anti-tumor immune responses [28]. Based on the biological characteristics of EVs, it has become the focus of researchers and biopharmaceutical companies to transform EVs as carriers of multiple drugs.
Most diseases have characteristic down-regulation of small RNA expression. Small RNA is the main content of extracellular vesicles, the most abundant and the most easily carried component. Therefore, EVs can be used to carry and deliver small RNA and other gene therapy systems. This section will discuss the progress of engineered EVs to deliver nucleic acid drugs and the strategies of drug loading and targeting.
There are three main problems in the development of nucleic acid drugs: the instability of nucleic acid molecules in the body, potential side effects and difficulties in drug delivery systems. The most important one is the development of delivery systems. Because a good drug delivery system can improve drug stability and target cell absorption efficiency, and can reduce its side effects. At present, the commonly used delivery vehicles in the field of nucleic acid drugs are mainly adeno-associated virus (AAV) and liposomal nanoparticles (LNPs). A small number of companies also use lentivirus (LV) and exosomes as delivery vehicles.
The packaging capacity of AAV is small (≤5kb). AAV will be used more than once in patients for therapeutic purposes and the second use will cause the body to produce a strong immune response. The safety of LNPs is relatively high, and the carrier capacity and delivery efficiency can meet the current demand for drug carriers. However, the organ selectivity of LNPs is still relatively limited. The main delivery area is concentrated in the liver, and the delivery efficiency to other tissues and organs is relatively low.
EVs are now candidate carriers for nucleic acid drugs by virtue of their advantages. The red blood cell extracellular vesicles (RBCEVs) have a large loading capacity (≤11kb), can be loaded with many types (including DNA, mRNA, antisense oligonucleotides, siRNA and other nucleic acid types), and contain very little nucleic acid. The advantages make them high-quality natural blank nucleic acid carriers. RBCEVs can be delivered to many different organs and tissues. In mouse experiments, the delivery effects of lung, liver, kidney, bone tissue, immune cells, etc. are all obvious [29]. Moreover, the raw materials used to produce RBCEVs are mainly blood from type O blood donors. This means large quantities of raw materials are readily available, and costs are controllable. Carmine Therapeutics focuses on the research and development of nucleic acid delivery technology using RBCEVs as carriers.
In addition, researchers are also committed to modifying the surfaces of EVs to improve their targeting. Many results show that this strategy can indeed improve the therapeutic effect of engineered EVs [30, 31, 32, 33].
The researchers combined ligand-coupled superparamagnetic nanoparticles with specific membrane proteins of blood exosomes to achieve the separation, purification and tumor targeting of exosomes [30]. The chemotherapy drug doxorubicin (Dox) and the cholesterol-modified single-stranded miRNA-21 inhibitor (chol-miR21i) were co-loaded onto the exosomes. Then the cationic endolysin peptide was absorbed on the negatively charged membrane surface of exosomes to promote the cytoplasmic release of the packaged cargo (Figure 1). The research results showed that these effectively released drugs and RNA simultaneously interfered with nuclear DNA activity and down-regulated the expression of oncogenes, thereby significantly inhibiting tumor growth and reducing side effects [30].
Schematic representation of engineered blood exosomes for effective gene/chemo combined antitumor therapy [
Chimeric antigen receptors (CAR) are cell surface receptors that recognize specific proteins (antigens). Tumor cells express their specific antigens. Modification of EVs surfaces with CAR targeting tumor antigens enables EVs to target tumors for drug delivery. Modified EVs with CAR can serve as a biosafety delivery platform for the CRISPR/Cas9 system to improve their tumor selectivity. Compared with unmodified EVs, CAR-EVs accumulate rapidly in tumors and effectively release the CRISPR/Cas9 system targeting MYC oncogenes in vitro and in vivo [31].
Rabies virus glycoprotein (RVG) is neurogenic. At present, it has become the most active guide molecule for brain targeted drugs. Lysosomal-associated membrane glycoprotein 2b (Lamp2b) is the membrane surface protein of EVs. RVG fused with Lamp2b is located on the surface of the EV to achieve brain targeting. Engineered Lamp2b-RVG-circSCMH1-extracellular vesicles (Lamp2b-RVG-circSCMH1-EVs) can selectively deliver circSCMH1 to the brain. The treatment can improve the functional recovery of mice and monkeys after stroke [32].
In addition, EVs without modification for targeting have also shown certain curative effects. The miR-214 inhibitor was transfected into HEK293T cells. Their exosomes Exo-anti-214 can reverse the resistance of gastric cancer to DDP [33]. HEK293T cells were transfected with HGF siRNA and their exosomes were harvested. In vivo and in vitro experiments have shown that exosomes loaded with HGF siRNA can inhibit the proliferation and migration of cancer cells and vascular cells [33].
Methods of loading nucleic acids into EVs include: chemical reagent transfection, electroporation transfection, transfection of donor cells, protein and characteristic sequence targeting methods. The application scope and advantages and disadvantages of different methods are shown in Table 2.
Methods | Application scope | Merit and demerit | References |
---|---|---|---|
Chemical reagent transfection | Broad-spectrum. | Easy to operate, but EVs should be purified before and after transfection. | [34] |
Electroporation transfection | The most commonly used method, but not for miRNA, shRNA, mRNA containing chemical modification. | Easy to operate, but EVs should be purified before and after transfection. | [35] |
Transfection of donor cells | Broad spectrum, but not for biotoxic molecules. | Purify EVs after transfection, but the effect of the transfected molecule on the donor cell should be taken into account (e.g. biotoxicity). | [33, 36, 37] |
Protein and characteristic sequence targeting | mRNA and miRNA. | High specificity of loading, but the therapeutic molecules will be modified. Whether this will affect the efficacy remains to be determined. | [38, 39] |
Methods of loading nucleic acid drugs into engineered EVs.
The use of proteins that can bind to specific RNA sequences (Figure 2) or the conservative sequences of Exosome-enriched RNAs (eRNAs) to achieve active packaging is a promising direction. The researchers used the specificity of protein binding to the RNA sequence to develop EXOtic devices for mRNA delivery [38]. Archaeal ribosomal protein L7Ae specifically binds to the C/Dbox RNA structure [40, 41, 42]. Based on this, L7Ae was conjugated to the C-terminus of CD63. C/D box was inserted into the 3′-untranslated region (3′-UTR) of the reporter gene. Therefore, the mRNA encoding the reporter protein could be well incorporated into exosomes via the interaction between L7Ae and the C/D box in the 3′-UTR. Exosomes containing the RNA packaging device (CD63-L7Ae), targeting module (RVG-Lamp2b to target CHRNA7), cytosolic delivery helper (Cx43 S368A) and mRNA (nluc-C/Dbox) were efficiently produced from exosome producer cells by the exosome production booster. The engineered exosomes were delivered to target cells and the mRNA was delivered into the target cell cytosol with the help of the cytosolic delivery helper. Finally, protein encoded in the mRNA was expressed in the target cells [38] (Figure 2). In the future, researchers need to obtain more specific RNA sequence binding proteins and conserved sequences of eRNAs through bioinformatics analysis.
EXOtic devices for mRNA delivery. A schematic illustration of the EXOtic devices [
The lack of protein and malfunction are important causes of many diseases. For example, the occurrence of malignant tumors is related to the lack of certain tumor suppressor factors and malfunctions. Therefore, increasing the corresponding protein level is one of the ways to treat diseases. Considering the risk of genome changes, researchers aim to deliver therapeutic protein molecules to the lesion through effective drug delivery vehicles. This section will introduce the use of EVs to transport protein molecules for the prevention and treatment of tumors, immune diseases, cardiovascular diseases, atherosclerosis, myocardial infarction and other diseases.
Compared with the previous small molecule compound drugs, protein drugs have the characteristics of high activity, strong specificity, low toxicity, clear biological functions, and are beneficial to clinical application. However, protein drugs are unstable in the internal and external environments, and may undergo a variety of complex chemical degradation and physical changes, such as aggregation, precipitation, racemization, hydrolysis, and deamidation. Protein drugs have short half-life, high clearance rate, large molecular weight, poor permeability, susceptibility to the destruction of enzymes, bacteria and body fluids in the receptor, and low bioavailability of non-injection administration. These problems greatly limit the use of protein drugs. Although researchers have improved the stability and absorption efficiency of protein drugs through methods such as PEG modification, microsphere sustained release, and liposome embedding, they still look forward to the emergence of better drug carriers. The application of EVs has brought dawn to this field.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent. Delivery of TRAIL through EVs can efficiently induce cancer cell apoptosis. When combined with dinaciclib, they inhibit the growth of drug-resistant tumors [43]. Immunosuppressive drugs must be taken after organ transplantation, but long-term use of these drugs increases the risk of infection and other serious diseases. Using bioengineering methods, researchers prepared exosome-like nanovesicles (NV) displaying the dual target cargo of PD-L1/CTLA-4. These NVs enhanced the PD-L1/PD-1 and CTLA-4/CD80 immunosuppressive pathways and could be used as prospective immunosuppressive agents in organ transplantation [44]. Using extracellular nanovesicles to package CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping can avoid off-target mutagenesis and immunogenicity. And this method can achieve effective genome editing in a variety of cell types that are difficult to transfect, including human induced pluripotent stem cells (iPS), neurons and myoblasts [45]. Catalase could be loaded into exosomes by incubating at room temperature, saponins penetrating the membrane, repeated freezing and thawing and mechanical extrusion for the treatment of Parkinson’s disease (PD) [46].
Surface modification of EVs carrying protein drugs can greatly improve their targeting. In the study of stroke, nerve growth factor (NGF) exerts various neuroprotective functions after ischemia. NGF was loaded into EVs with RVG peptide modification on the surface. Through systemic administration, NGF was effectively delivered to the ischemic cortex. The delivered NGF reduced inflammation by remodeling microglia polarization, promoted cell survival, and increased the number of neuroblast marker doublecortin-positive cells. The results of the study indicated the potential therapeutic effect of NGF@Exo (RVG) on stroke [47]. In addition, integrin αVβ5 exhibits tropism for the liver while integrin α6Vβ4 and integrin α6β1 target lung [48, 49]. The iRGD specifically recognizes αV integrins on the surface of tumor cells [50]. RVG and c(RGDyK) peptides target brain tissue [51]. Klotho protein has the property of binding to circulating endothelial progenitor cells (EPCs) [52]. And chimeric antigen receptor (CAR) targeting specific tumor antigens and so on. These guiding molecules are utilized either by fusion with EVs membrane surface proteins (such as Lamp2b, VSVG, CD63, and other transmembrane proteins, etc.), or by chemical cross-linking on the surface of EVs to achieve the EVs targeting modification. Liu et al. summarized the surface modification strategies to improve the targeting of EVs (Figure 3) [53]. In addition, EVs derived from antigen-presenting cells with tumor antigens can be used as tumor vaccines to activate anti-tumor immune responses.
Design strategies for therapeutic exosome targeting [
How to load protein drugs into EVs? There are currently the following strategies:
Transfect donor cells with plasmids carrying the gene of interest. The cell will synthesize the target protein. These proteins are then secreted into EVs through a natural packaging process. Subsequent separation and purification of EVs in the cell culture supernatant is sufficient [54]. Although this method seems simple and easy to implement, cytotoxicity, mixed interactions and impaired biological responses will provide great obstacles to the production of EVs. And the loading efficiency of the target protein is relatively low. Therefore, researchers have carried out various attempts to specifically load target proteins into EVs. For example, the fusion of therapeutic proteins with the constituent proteins of EVs and the specific modification of therapeutic proteins.
The therapeutic proteins are fused with the constituent proteins of EVs. Then they will be distributed into EVs mediated by the constituent proteins. This method can improve the specificity of protein loading into EVs. The fused constituent proteins of EVs that have been tried include: CD63, Nef [55], vesicular stomatitis virus glycoprotein (VSVG) [56], apolipoprotein E (ApoE) [57], lysosome-associated membrane glycoprotein 2 (LAMP2B) [58], etc.
In addition, based on the idea of fusion proteins, researchers have developed a conditional loading method called “exosomes for protein loading via optically reversible protein-protein interaction (EXPLORs)” [59]. The principle is to couple the exosomal membrane protein CD9 with CIBN, and CRY 2 with the therapeutic protein. After light excitation, CIBN and CRY2 interact, and the therapeutic protein can be loaded into EVs through “photoreversible protein-protein interaction” [59].
All in all, the fusion expression of therapeutic proteins with the constituent proteins of EVs can indeed increase the enrichment level of therapeutic proteins in EVs. However, whether the fusion protein affects the uptake and function of the therapeutic protein by the recipient cells needs to be verified. Therefore, exploring the fusion of peptides that can play a sorting role with therapeutic proteins and minimize the impact on protein functions will become one of the research hotspots in the field of engineered EVs.
Currently, known protein modifications that can target therapeutic proteins into EVs mainly include two types. One is ubiquitination modification. The fusion of ubiquitin to the C-terminus of therapeutic protein can make the concentration of the fused therapeutic protein in EVs increased by nearly 10 times [60]. The other is to fuse the N-terminus of the therapeutic protein with a palmitoylated or myristoylated peptide, which can further increase the therapeutic protein in EVs [61]. However, it is still unknown whether the modification of proteins, especially ubiquitination, will cause the degradation of the therapeutic protein by the proteasome and affect its function in the recipient cell.
Expression of therapeutic protein in donor cells, combined with mechanical methods that pass through different pores, can produce small vesicles containing the therapeutic proteins [46, 62]. In addition, there are methods such as incubation at room temperature, permeabilization with saponin, freeze-thaw cycles and sonication, [46]. There are two main problems with engineered EVs obtained by mechanical methods. One is that the technical requirements for the separation and purification of EVs are relatively high. The second is the maintenance of the integrity and biological activity of EVs. The composition of EVs actively produced by cells is different from the composition of mechanically produced EVs. The difference may affect the efficacy of engineered EVs. In the future application research of EVs, these two problems need to be solved and proved urgently.
So, what are the possible development directions for the existing cytotoxicity and the interaction of biological functions? The expression of tumor suppressor protein molecules may cause cytotoxicity to donor cells, which is not conducive to the production of EVs. If an inducible expression system is established, the coding DNA containing the inducible promoter is introduced into the donor cell to make the donor cell produce EVs containing the coding DNA, which will avoid cytotoxicity to the donor cell. Then prepare EVs containing small molecules that induce DNA expression. The two types of EVs can be used in combination to express tumor suppressor molecules in target cells. It can play a therapeutic role without affecting the production efficiency of EVs. The dual targeting of the two EVs will greatly reduce the impact of engineered EVs on non-targeted tissues. Because single-component EVs are randomly engulfed by cells and will not affect the cells. This may become one of the follow-up development directions in this field.
Chemotherapeutics and traditional Chinese medicine ingredients with anticancer effects are often used in the clinical treatment of a variety of malignant tumors. However, their toxic, side effects and short half-life limit their efficacy. The packaging and transportation with EVs will improve the targeting of chemotherapeutic drugs, increase the uptake efficiency of tumor cells, promote drug stability, reduce the use concentration, and reduce toxic side effects on other organs and normal tissues [63].
The hydrophobic drug curcumin could be packaged into exosomes by direct mixing for tumor treatment [64]. Paclitaxel (PTX) was loaded into EVs secreted by macrophages by different methods such as room temperature incubation, electroporation and sonication. Studies have found that ultrasound treatment increases the load of EVs on drug molecules and the sustained release [65]. Small compounds can also be naturally secreted into EVs by incubating with donor cells. Incubation with paclitaxel make mesenchymal stromal cells produce microvesicles containing paclitaxel [66]. Injecting methotrexate-containing plasma membrane microvesicles (MTX-TMP) from apoptotic human tumor cells into the bile duct lumen of extrahepatic CCA patients could mobilize and activate neutrophils, and relieve the bile duct obstruction in 25% of patients, almost no adverse reactions [67].
At present, small molecule drugs are often loaded into EVs by passive loading methods, such as direct mixing, incubation, ultrasonic treatment, vortexing, saponin permeation, repeated freezing and thawing, and mechanical extrusion. The disadvantages of these methods have always existed, that is, the loss and quality reduction of EVs caused by multiple purifications. In addition, long-term in vitro processing and the physical and chemical properties of drug molecules will also affect the biological activity and stability of EVs. Therefore, before EVs can be widely used in treatment, the storage methods and stability factors of EVs are also worthy of research.
Why are EVs a “stealth cap” for drugs? Because we know viruses to use them exactly like this. In nature, viruses “hijack” EVs to secrete and infect other cells. This method helps to provide a “cover” for the virus to prevent the virus from being cleared by the immune system or neutralized by antibodies, such as the infection process of HAV, HBV and HCV.
In gene therapy, currently widely used adeno-associated virus (AAV), oncolytic adenovirus (OAV) and lentivirus (LV) mediated gene therapy can cause the body’s immune response. After the same kind of AAV is used once, the body will produce a strong immune response, making the second injection ineffective. If EVs encapsulate viral particles to mediate their delivery, perhaps the therapeutic effect will be better.
Studies have shown that AAV isolated from conditioned media could bind to exosomes (exo-AAV) [68]. Compared with conventional AAV, exo-AAV was more resistant to neutralizing antibodies. After systemic injection in mice, compared with conventional AAV, exo-AAV delivered genes to the brain more efficiently at low vector doses. Importantly, no cytotoxicity was found in exo-AAV transduced cells. This may make exo-AAV widely used as a neuroscience research tool [68]. Compared with non-targeted modified EV-AAV, the expression of brain-targeting peptides on the surfaces of EVs can significantly enhance transduction [69].
In gene therapy of ophthalmic diseases, transferring genes to the retina is challenging. Because it requires a carrier system to overcome physical and biochemical barriers to enter and spread throughout the retinal tissue. After the exo-AAV was injected into the vitreous cavity (IVT), it was found that the expression of exo-AAV was better than the traditional AAV. Exo-AAV exhibited a deeper penetration in the retina, effectively reaching the inner core and outer plexus, and to a lesser extent the outer nuclear layer. Exo-AAV is a reliable mouse retina gene delivery tool. Its simplicity of production and isolation makes it widely used in basic eye research [70].
Due to the low efficiency of gene delivery to the inner ear sensory hair cells. AAV is not so advanced in the field of gene therapy for hearing impairment. Studies have shown that Exo-AAV1-GFP is more effective than traditional AAV1-GFP, whether injected in mouse cochlear explants in vitro or directly injected into the cochlea in vivo. Exo-AAV was not toxic in the body. Exo-AAV1 gene therapy partially rescued the hearing in a mouse model of hereditary deafness. It was a powerful hair cell gene delivery system that could be used for gene therapy of deafness [71].
Oncolytic viruses show unique anti-cancer mechanisms in cancer treatment. Chemotherapeutic drugs combined with oncolytic viruses showed stronger cytotoxicity and oncolytic effects. Someone has studied the systemic delivery of oncolytic adenovirus and paclitaxel encapsulated by EVs. The results have shown that this combination therapy enhanced anticancer effects in lung cancer models both in vitro and in vivo. EVs play a key role in the effective transmission of oncolytic viruses and chemotherapeutic drugs [72].
EVs currently used for therapeutic research are mainly derived from the following sources: mesenchymal stem cells (MSCs), dendritic cells (DCs), tumor cells, red blood cells, macrophages and plants. EVs from different sources have different biological characteristics. Materials should be selected according to the purpose of treatment. The characteristics, advantages and disadvantages of EVs from different sources will be described below.
The MSCs involved in the study of EVs include adipose-derived MSCs, bone marrow MSCs, progenitor cells from different tissues, and so on. MSCs can be extracted from the patient’s bone marrow, fat, or other tissues. EVs derived from MSCs are very attractive. Because they have anti-inflammatory, anti-apoptotic and anti-microbial capability, and promote angiogenesis and the repair and regeneration of damaged tissues. As mentioned above, EVs derived from MSCs have been widely used in the treatment of central nervous system diseases, cardiovascular diseases, bone and cartilage damage repair and regeneration, wound repair, and other organ damage repair and regeneration [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21].
One potential source of therapeutic EVs is immature dendritic cells (imDCs). EVs secreted by imDCs lack surface markers such as CD40, CD86, MHC-I and MHC-II. Therefore, they have low immunogenicity. They can be isolated from CD34+ cells from the patient’s peripheral blood. It is one of the preferred sources of therapeutic EVs.
The use of EVs derived from tumor cells to deliver drugs and vaccines for immunotherapy is very promising. Tumor EVs can deliver antigens to dendritic cells, thereby inducing T cell-mediated immune responses to tumor cells [73]. As tumor-derived EVs specifically express Tetraspanins, they can target different tissues. This makes it possible to use tumor-derived EVs for tumor-targeting and selective drug delivery [74]. However, tumor-derived EVs also have many potential risks. Due to the presence of Tetraspanins, Urokinase plasminogen activator, Cathepsin D, Vimentin and other molecules derived from the surface of tumor cells [75, 76], they may promote tumor proliferation and metastasis, and Immunosuppressive effect [77, 78, 79].
Blood EVs mainly secreted by reticulocytes (RTC) are a potential source of safe and sufficient EVs. Because they integrate various membrane proteins including Transferrin (Tf) receptors, but they do not have any immune and cancer stimulating activity [30]. Red blood cell EVs (RBCEV) also have the following advantages: large load; low self-nucleic acid content (red blood cells without nucleus and mitochondria); they can be delivered to a variety of different organs and tissues; large quantities of raw materials and easily available (the raw materials for producing RBCEVs are mainly O-type Blood of blood donors). Using blood EVs as carriers can efficiently target tumors to co-deliver chemotherapeutics and nucleic acid drugs. Significant tumor growth inhibitory effects were observed in tumor-bearing mice. There were no obvious side effects [30].
Macrophages are an important immune cell in the antigen-presenting cell family. EVs derived from immune cells can mimic immune cells to target tumor cells. Macrophage EVs can transfer miRNAs or proteins to tumor cells, mediate tumor cell resistance to chemotherapy, promote cell invasion and other regulatory effects. Therefore, in the study of tumor treatment of EVs, in addition to using the targeting properties of macrophages-derived EVs, the influence of their contents must also be considered. It has been reported that the contents of EVs derived from macrophages can be removed. Then the EVs were used to carry chemotherapeutic drugs to achieve targeted therapy of triple-negative breast cancer [80].
Based on reliable sources and safety, fruits and plants have been used as alternative sources for the isolation of EVs for clinical use [81]. Plant-derived EVs have similar structural characteristics to animal cell-derived EVs. EVs from different plant sources have the physiological functions of the plant from which they are derived. For example, lemon-derived EVs have certain anti-cancer effects. Some researchers have tried to isolate lemon-derived EVs (LDEVs) for the treatment of gastric cancer. LDEVs caused s-phase arrest of gastric cancer cell cycle and induced cell apoptosis. LDEVs could be retained in the organs of the gastrointestinal tract and had strong anti-tumor activity against gastric cancer [82]. The isolated plant EVs can also be used after being engineered. Some researchers isolated EVs from grapefruit, modified the EVs in a targeted manner, and then loaded the anti-tumor drugs doxorubicin and curcumin. These modified EVs could target inflammatory tumors and have anti-inflammatory effects in mouse models [83].
Plant-derived EVs have a wide range of sources, are safe and non-toxic, have low immunogenicity, low cost, and are edible. They have great clinical application potential as edible chemotherapeutic drug carriers.
So far, no EVs drugs have entered the clinic. Codiak BioSciences, a leading company in the development of engineered EVs as a new type of biopharmaceutical, uses its proprietary engEx platform to engineer EVs with different characteristics, load them with various types of therapeutic molecules and change their orientation, so that they can reach specific cellular targets. Recently, Evox Therapeutics Ltd. and Eli Lilly and Co. reached a cooperation agreement to apply its exosome technology to the system to deliver RNA interference and antisense oligonucleotide drugs to the central nervous system, treating five unspecified Neurological diseases. Carmine Therapeutics is also a gene therapy company based on EVs, established in 2019. Carmine’s REGENT technology platform focuses on using red blood cell extracellular vesicles (RBCEV) as drug delivery vehicles. Mantra Bio also joined the emerging group of exosome drug development companies. With the deepening of research, more and more companies will join the field of EVs treatment.
The Severe Acute Respiratory Syndrome (which first appeared in December 2019) related to the new coronavirus (COVID-19) has rapidly developed into a pandemic, and the morbidity and mortality rates are increasing worldwide. COVID-19 respiratory tract infection is characterized by an imbalanced immune response, leading to an increased possibility of severe respiratory disease and multiple organ disease.
Because EVs derived from MSCs have anti-inflammatory, anti-apoptotic and anti-microbial capability, promote angiogenesis and the repair and regeneration of damaged tissues. In related lung disease models, including acute lung injury and sepsis, systemic administration of MSC-EVs preparations can modulate immune responses. In a mouse model of pneumonia induced by Escherichia coli, it was found that MSC-EVs administration could enhance the phagocytosis of bacteria. In the pig model, MSC-EVs could reduce influenza virus-induced acute lung injury by inhibiting influenza virus replication. In other disease models, the disease alleviation effect of MSC-EVs on the inflammatory immune response has also been observed. It is speculated that they may also have anti-COVID-19 efficacy. In cell therapy research for COVID-19, some registered clinical trials have turned their targets to EVs in the conditioned medium of MSCs. MSC-EVs can be administered intravenously (ChiCTR2000030484) or by inhalation (NCT04276987, ChiCTR2000030261).
However, before using MSC-EVs for COVID-19 patients, many other issues should be considered, such as the huge heterogeneity of MSC-EVs composition and source. In fact, comparing MSC-EVs harvested from the conditioned medium of bone marrow MSCs derived from different donors, there are significant differences in cytokine content and different therapeutic effects. In addition to immune regulation, MSC-EVs can also control other biological processes and may cause unpredictable side effects. For example, increasing the risk of thrombosis.
In short, in order to reduce the risk of potential life-threatening side effects, International Society for Extracellular Vesicles (ISEV) and International Society for Cell and Gene Therapy (ISCT) strongly require that the clinical data from reasonable clinical trial should be carefully weighed. The EV preparations with good characteristics and produced under strict GMP conditions and appropriate regulatory supervision could be used. Any application of EVs should be carefully evaluated [84].
The potential application of EVs in new diagnostic and therapeutic strategies has attracted increasing attention. However, due to the inherent complex biogenesis of EVs and their huge heterogeneity in size, composition and source, the research of EVs still faces huge challenges. It is necessary to establish a standardized method to solve the heterogeneity of EVs and the analysis of pre-processing and analysis of sources of variability in the study of EVs. The quality standards, extraction specifications and especially the stability of preparation conditions for therapeutic EVs also need to be clarified.
In addition, the diversity and uncertainty of EVs content are also issues that need to be considered in the application. Before metastasis, malignant tumor cells use EVs to modify the microenvironment of the organ targeted by cancer metastasis, making it a suitable “soil” for tumor cell growth. The contents of EVs secreted by most tumor cells play a role in promoting tumor metastasis and progression. As mentioned earlier in this article, macrophage EVs can transfer miRNAs and proteins to tumor cells, mediate tumor cell resistance to chemotherapy, promote cell invasion and other regulatory effects. Therefore, if EVs from such sources are used as drug carriers, it is particularly important to first remove the adverse effects of their contents.
As an important medium of intercellular communication, EVs play an important physiological function and are also involved in the occurrence and development of a variety of diseases. In recent years, there have been numerous studies on the treatment of related diseases with EVs from different cell sources, and EV has shown its unique advantages in drug transportation. EVs are similar to natural liposomes, which can enhance the function of EVs to treat specific diseases through targeting modification and delivery of functional active substances and other technical modifications according to the characteristics of different diseases. EVs with improved function have shown obvious advantages in the treatment of tumors and difficult diseases of central nervous system. However, the clinical application of EVs technology is still in its infancy, and the challenges it faces are accompanied by the possibility of numerous new discoveries and new technologies. We expect that with the continuous in-depth research, EVs as a new drug carrier in the treatment of a variety of diseases will bring more and greater surprises.
This work was supported by the National Key R&D Program of China (2018YFA0900900), and the National Natural Science Foundation of China (81773251 and 81702735).
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All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
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\n\nIn line with publication ethics practices recommended by COPE, ICMJE, and other similar organizations, IntechOpen's contributing Authors, Academic Editors, and Peer Reviewers are required to declare fully all possible conflicts of interest.
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\n\n\n\nThe Internet has changed the dynamics of scholarly communication and publishing which is why we find it necessary to clearly indicate our stance on what we consider to be a published scientific work. A significant number of working papers, early drafts, and similar works in progress are shared openly online between members of the scientific community. It has become common practice for researchers to announce their work on a personal website or a blog in order to gather comments and suggestions from other researchers. Such works and online postings are ‘published’ in the sense that they are made publicly available, but this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\n\n\nTo identify instances of fraud and misconduct during the publishing process, IntechOpen implements a robust policy governing such occurrences. In line with our general commitment to openness, and in order to maintain the highest scientific standards, we are committed to transparency about our editorial policy regarding retractions and corrections.
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\n\nIntechOpen publishes books in the English language. If you are interested in the translation of Book Chapters, please check IntechOpen's Translation Policy.
\n\n\n\nIn line with the Principles of Transparency and Best Practice in Scholarly Publishing, you can access a more detailed description of IntechOpen's Advertising Policy.
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\n\n\n\nAll chapters will be published via IntechOpen's 'Online First' service meaning chapters will be published individually, immediately after review and before the entire book is ready for publication, allowing content to be shared, searched and cited straightaway, thereby generating early stage interest and momentum for your research
\n\nOnline First Chapters are considered published on the day they are posted and are citable from that date.
\n\nChapters will remain listed as Online First until the final versions of the books are published online. Following publication of the full monograph, Chapters will be redirected from the Online First version and will be available only through the final link of the official published page.
\n\nYou are invited to download, use, reproduce, make derivative works of, display, distribute and cite the Online First works. You can find "How to Cite and Reference" by following the link at the end of each online book chapter. Please be aware that it is possible that further editing and changes might be made before the final release of the book.
\n\nIf there are supplemental materials to the chapter, these will be published at the time the final book is published online.
\n\nReaders and Authors can notify us if they find any errors in the works published under Online First. All major errors will be accompanied by a separate correction notice, erratum or corrigendum (Retraction and Correction Policy.)
\n\nIntechOpen books are available online by accessing all published content on a chapter level.
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Community- and research-based conservation mechanisms could be an appropriate approach for mitigating the problems pertinent to the loss of medicinal plants and their habitats and for documenting medicinal plants. Chromatography; electrophoretic, macroscopic, and microscopic techniques; and pharmaceutical practice are mainly used for quality control of herbal medicines.",book:{id:"8502",slug:"plant-science-structure-anatomy-and-physiology-in-plants-cultured-in-vivo-and-in-vitro",title:"Plant Science",fullTitle:"Plant Science - Structure, Anatomy and Physiology in Plants Cultured in Vivo and in Vitro"},signatures:"Admasu Moges and Yohannes Moges",authors:[{id:"249746",title:"Ph.D.",name:"Admasu",middleName:null,surname:"Moges",slug:"admasu-moges",fullName:"Admasu Moges"},{id:"297761",title:"MSc.",name:"Yohannes",middleName:null,surname:"Moges",slug:"yohannes-moges",fullName:"Yohannes Moges"}]},{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:193348,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. 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Due to its profound qualities, nanocellulose extracted from cotton fibers have tremendous application potential and have been intensively studied particularly in the generation of nanofillers and as reinforcement components in polymer matrixes. Deposition of inorganic nanoparticles on cotton fabric result in antimicrobial textiles with multifunctional use particularly in manufacture of PPE and as filtration devices against environmental pollutants and pathogens. This chapter compiles three main sections. The first section gives an overview of the extent of work done in the creation and application potential of cotton-based nanocomposites. The second section describes the in situ and ex situ methods of nanoparticle deposition and self assembly on cotton fabrics to generate multifunctional cotton-based nanocomposites with antimicrobial potential while the final section describes the incorporation of cotton nanofibers in polymer matrices, their reinforcing properties, as well as surface modification to assist their incorporation. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. 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