\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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This book presents recent applications of MIR for content-based image retrieval, bioinformation analysis and processing, forensic multimedia retrieval techniques, and audio and music classification.",isbn:"978-1-83880-060-4",printIsbn:"978-1-83880-059-8",pdfIsbn:"978-1-83880-540-1",doi:"10.5772/intechopen.83217",price:119,priceEur:129,priceUsd:155,slug:"multimedia-information-retrieval",numberOfPages:136,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"d44f176ab7139d4d3d6fc65309c77c69",bookSignature:"Eduardo Quevedo",publishedDate:"June 2nd 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9221.jpg",keywords:null,numberOfDownloads:2552,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:2,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 22nd 2020",dateEndSecondStepPublish:"May 13th 2020",dateEndThirdStepPublish:"July 12th 2020",dateEndFourthStepPublish:"September 30th 2020",dateEndFifthStepPublish:"November 29th 2020",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:"With broad industry experience, Dr. Quevedo is an expert in image and video enhancement and has received several awards, including the Outstanding Doctoral Thesis Award at the University of Las Palmas de Gran Canaria.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"186525",title:"Dr.",name:"Eduardo",middleName:null,surname:"Quevedo",slug:"eduardo-quevedo",fullName:"Eduardo Quevedo",profilePictureURL:"https://mts.intechopen.com/storage/users/186525/images/system/186525.png",biography:"Eduardo Quevedo is Assistant Professor of Biostatics and Research Methodology, Mathematics Department, University of Las Palmas de Gran Canaria (ULPGC), Spain. He is also a researcher at the Institute for Applied Microelectronics (IUMA) at the same university. Dr. Quevedo received his Ph.D. from ULPGC in 2015 and received the ULPGC Outstanding Doctoral Thesis Award in 2016. He also holds degrees in Communications Engineering (2007) and Electronics Engineering (2009) from ULPGC. He was granted a national award for the best master’s thesis from the Official National Telecommunications Engineering Association in 2008. 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Drug metabolism can either lead to detoxification, bio-inactivation and/or elimination of the drug from the body. Metabolism can be broadly categorized into phases I and II. Phase I drug metabolizing enzymes (DMEs) primarily comprise of the Cytochrome (CYP) 450 family of enzymes. CYP3A4 is the most common isoform expressed in human liver and intestine accounting for ~30-60% of CYPs (Nebert & Russell, 2002) More than 50% of the currently marketed drugs are metabolized by CYP3A4 in humans (Guengerich, 1999). Phase II metabolism consists of conjugation reactions forming polar metabolites leading to enhanced excretion. Phase II reactions include glucuronidation (Uridine 5\'-diphospho-glucuronosyltransferase, UGT) sulfation (Sulfotransferase, SULT), methylation (Methyltransferase), glutathione conjugation (Glutathione S-transferase, GST), etc. (Jancova et al., 2010, Meyer, 1996).
\n\t\t\t\tDrug transporters play a central role in the absorption, distribution, metabolism and elimination (ADME) processes of xenobiotics across the cellular barriers. They are broadly classified into uptake and efflux transporters which facilitate drug disposition in or out of the cells (Mizuno et al., 2003). Major transporters include, but are not limited to: multidrug resistant gene/P-glycoprotein (MDR/P-gp), multidrug resistance associated protein (MRP1-3), breast cancer resistance protein (BCRP), organic anion transporting peptides (OATPs) and organic cationic transporters (OCTs) (Mizuno et al., 2003, Mizuno & Sugiyama, 2002).
\n\t\t\tSeveral studies have shown that drug metabolism and transport is disrupted during diseases and altered pathophysiological conditions primarily due to reductions in gene expression of these enzymes and transporters (Aitken et al., 2006, Kato, 1977). The transcription factors such as nuclear factor-κB (NF-κB), CAAT enhancer-binding protein (C/EBP) or nuclear transcription factor E2-related factor 2 (Nrf2) have been shown to regulate DME and transporter gene expression
Altered drug metabolism can lead to adverse drug reactions which account for ~10% of hospitalized cases (Deng et al., 2009, Maddox et al., 2010). However, due to underreporting, the actual incidences may be much higher (Lazarou et al., 1998., Pirmohamed et al., 2004). As early as 1960s, variations in drug metabolism were observed in patients or animals with diabetes (Dixon et al., 1961), cancer (Kato et al., 1963), hepatitis (Klotz et al., 1974, McHorse et al., 1974) or influenza (Kraemer et al., 1982). Changes in drug metabolism were also associated with a corresponding change in the pharmacodynamics (PD) of drugs (Dixon et al., 1961; Kato et al., 1968). These early studies prompted the researchers to study the alterations in DME and transporter gene expression and activity in pathophysiological conditions such as cancer, diabetes/obesity, rheumatoid arthritis (RA), non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs) such as hypertension, heart failure, or stroke, etc. (Alkayed et al., 2002, Charles et al., 2006, Fisher et al., 2008, 2009a; 2009b, Thum & Borlak, 2002). Overall, the readers of this chapter will benefit from the discussions of the changes in expression of DMEs and transporters, and pharmacokinetics/pharmacodynamics (PK/PD) of clinically relevant medications in different pathophysiological conditions.
\n\t\t\tMost of the studies on regulation on DMEs have been documented with gram-negative bacteria. Of clinical relevance, sepsis induced by cecal ligation and puncture (CLP) is the most frequently used model owing to its close resemblance in the progression and characteristics of human sepsis (Wichterman et al., 1980). In a CLP rat model, total hepatic microsomal CYP content and activities were significantly reduced (Godellas et al., 1995). Infection of pigs with the gram-negative respiratory pathogen,
Although, gram-positive infections account for more than 50% of the total community acquired infections (Martin et al., 2003), very few studies have linked the effects of gram-positive bacteria on regulation of DMEs. It was shown that in patients suffering from gram-positive bacteremia such as
The gram-negative bacterial component, lipopolysaccharide (LPS), and the gram-positive bacterial component, lipoteichoic acid (LTA), serve as sterile infection models by inducing inflammatory responses in animals (Ginsburg, 2002, Leemans et al., 2002). LPS can down-regulate the expression and activity of key hepatic, intestinal and renal DMEs in several animal species such as mice, rats or rabbits (Ghose et al., 2008, Sewer et al., 1996). Interestingly, studies have that changes in CYP expression and activity is dependent on the route of administrate at same dose of LPS (Shimamoto et al., 1998). We recently showed that LTA significantly down-regulated the gene expression of several phase I and phase II DMEs in mice (Ghose et al., 2009).
\n\t\t\t\tChanges in expression of drug transporters can have significant impact on the safety and efficacy of the drugs. LPS treatment of mice significantly down-regulated P-gp and Mrp2, major transporters involved in disposition of clinically relevant drugs such as colchicine, verapamil, daunorubicin, cyclosporin A and the abundant food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-
As early as 1980’s, it was shown that vaccination with the bacillus Calmette-Guerin (BCG) decreased clearance of theophylline in human volunteers (Gray et al., 1983). Altered PK was observed in other bacterial infections induced by
Viral infections can also stimulate the immune system releasing various inflammatory mediators from the immune cells (Mannering & Deloria, 1986). A survey of the literature reveals numerous studies on the effect of viral infections such as mouse-adapted influenza virus (Corbett & Nettesheim, 1973), Newcastle disease virus (Singh & Renton, 1981), encephalomyocarditis virus (Renton, 1981), chronic active hepatitis and cirrhosis (Schoene et al., 1972; Wilkinson, 1997) and HIV infection (Lee et al., 1993) on alteration of gene expression and activity of DMEs and oxidative pathways in animals and humans. Decreased levels of hepatic CYP1A2 were detected in children suffering from upper respiratory tract viral infections during an influenza outbreak (Chang et al., 1978; Kraemer et al., 1982). With exceptions of CYP2D6 mRNA and CYP1A2 activity, other major CYPs such as CYP2C9, 2C19, and 3A4 in HCV-infected PXB mice (chimeric mouse with human hepatocytes) were comparable to the non-infected controls (Kikuchi et al., 2010). Recombinant adenovirus injections in Sprague-Dawley rats led to significant down-regulation of renal CYP2E1 and hepatic CYP3A2 and CYP2C11 expression and activity, and induction of CYP4A protein expression (Callahan et al., 2005; Le et al., 2006).
\n\t\t\t\tA recent study showed that HIV-type 1 viral envelope glycoprotein gp120 decreased P-gp and Mrp expression levels in rat astrocytes (Ronaldson & Bendayan, 2006). However, due to the fact that HIV infected patients are on highly active antiretroviral therapy (HAART) consisting of numerous drugs, both, induction and suppression of drug transporters in HIV infection are reported (Giraud et al., 2010). Polyinosinic/polycytidylic acid [poly (I:C)] is widely used as a model of
During the 1982 influenza B outbreak in King County, Washington, 11 children whose asthma had previously been controlled with a stable theophylline dose, developed theophylline toxicity on this same dose (Kraemer et al., 1982). These children had a significant decrease in CL and increase in T1/2 of theophylline. HIV infections could also lead to altered PK of levofloxacin and fluconazole (Goodwin et al., 1994, Tett et al., 1995). End-stage liver disease, which is largely the result of HCV infection, now accounts for up to 50% of deaths among persons with HIV-1 infection (Bica et al., 2001). A clinical study in HIV-HCV-coinfected patients showed significantly lower nelfinavir oral clearances in HIV+ and HCV+ patients with and without cirrhosis compared to HIV+ and HCV-negative patients (Regazzi et al., 2005). This presses the need for therapeutic drug monitoring in individualizing nelfinavir dosage in HIV-HCV-coinfected patients. In addition, an increase in AUC and Cmax of several anti-retrovirals are reported in HCV-infected patients with moderate liver impairment (Veronese et al., 2000, Wyles & Gerber, 2005). Other studies have also shown significantly higher AUC of docetaxel and reduced glomerular filtration rate, suggesting changes in renal CYP in rats injected with the recombinant adenovirus expressing β-galactosidase (Le et al., 2006, Wonganan et al., 2009). On the contrary, significantly reduced Cmax and AUC of ceftiofur hydrochloride were observed in pigs infected with porcine reproductive and respiratory syndrome virus compared to the uninfected pigs (Tantituvanont et al., 2009).
\n\t\t\t\tBacterial or viral infections lead to activation of Toll-like receptor (TLR) signaling pathway, which leads to the induction of pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α in the immune cells. In the liver, TLRs are present on the cell surface of various immune cells (the resident macrophages or Kupffer cells) as well as the hepatocytes (Scott et al., 2009). Out of the 13 TLRs identified in mammals, TLR4 is activated by the gram-negative component, LPS, and TLR2 is activated by the gram-positive component, LTA (Aliprantis et al., 1999, Takeuchi et al., 1999). We and others have shown down-regulation of Cyp3a11 and P-gp in LPS sensitive TLR4
Cytokines are involved in alteration of DMEs and transporters
However, recent evidence suggests cytokines may not be playing a major role in regulation of DMEs. Earlier studies in TNF-α-/- and IL-6-/- knockout mice revealed that DMEs were still down-regulated (Warren et al., 1999, 2001). A recent study by
Nitric oxide (NO), released from macrophages and hepatocytes during inflammation is also known to regulate DMEs (Morris & Billiar, 1994). However, contrasting results have been reported for the role of NO in regulation of DMEs in cytokine-treated primary rat hepatocytes (Carlson & Billings, 1996, Sewer & Morgan, 1997). IL-1β and TNF-α-mediated down-regulation of CYP protein was NO dependent, but not in IL-6 mediated down-regulation (Carlson & Billings, 1996). NO was also shown to regulate the suppression of UGT activities in cytokine-treated hepatocytes (Monshouwer et al., 1996).
\n\t\t\t\tSeveral studies have shown that inflammation-mediated activation of NF-κB plays a significant role in down-regulation of DMEs (Abdulla et al., 2005, Gilmore, 2006, Ke et al., 2001). NF-κB can either indirectly regulate CYP gene expression through mutual repression between NF-κB and nuclear receptors, or can directly regulate CYP gene expression through binding to NF-κB response element in the promoter region of CYP genes (Pascussi et al., 2003). Interaction of NF-κB with nuclear receptors during pathophysiological conditions can alter expression of DMEs (Gu et al., 2006). Inflammation-mediated activation of mitogen activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK), also regulates nuclear receptors and DMEs (Adam-Stitah et al., 1999, Yu et al., 1999). Recent experiments in human gastric carcinoma and pancreatic carcinoma cell lines suggested a prominent role of JNK activation in down-regulation of P-gp protein expression (Zhou et al., 2006). However, further detailed studies using
We speculate that down-regulation of nuclear receptors during inflammation might be involved in regulating the gene expression of DMEs and transporters in animal models (Ghose et al., 2004, 2008, 2009, Synold et al., 2001). We also showed that down-regulation of nuclear receptors by LPS in TLR4+/+ or by LTA in TLR2+/+ mice was blocked in TLR4 mutant or TLR2-/- mice (Ghose et al., 2008, 2009, 2011a). On the contrary, mRNA and protein expression of several CYPs did not differ in PXR-/- or PPAR-/- mice treated with LPS (Richardson & Morgan, 2005). Similarly, it was shown that PXR was least important in regulating several efflux and uptake drug transporters using PXR
Owing to the fact that, most anticancer drugs have a very low or narrow therapeutic index, alteration of DMEs can lead to life-threatening adverse drug reactions or increased risk of treatment failure in patients undergoing chemotherapy. Decreased hepatic microsomal DME activity was detected in tumor bearing rats with Walker carcinosarcoma 256, where impaired metabolism of hexobarbital, strychnine and meprobamate was observed (Kato et al., 1963). Due to difficulties in obtaining human liver tissue from cancer patients, an Engelbreth-Holm-Swarm (EHS) sarcoma mouse model bearing transgenic CYP3A4/lacZ gene was developed (Charles et al., 2006). Reduced hepatic levels of the transgene-derived β-galactosidase, as quantified by o-nitrophenyl-β-D-galactopyranoside assay, and
Changes in the genetic variability in clinical specimens as well as over expression of ABC transporter family in tumors have been shown to play a critical role in multidrug resistance to several anticancer drugs (Hoffmeyer et al., 2000, Robinson et al., 1997, Yoh et al., 2004, Young et al., 1999). A recent study showed significant reductions in the mRNA levels of Mdr2, Mrp2, Mrp3, Ntcp, Oatp 2, bile salt export pump (Bsep), Bcrp, whereas Mdr1a and Oatp1 remained unchanged (Sharma et al., 2008).
\n\t\t\tCancer-induced changes in the PK and PD profiles of several drugs have been documented since the late 1960s (Kato et al., 1968, Rosso et al., 1968, 1971). In a clinical study, the absorption rate constant, apparent Vd and serum CL of penbutolol (antihypertensive drug) were significantly reduced in the cancer group (Aguirre et al., 1996). PD effect (reduction in heart rate) of penbutolol did not vary statistically in respect to baseline values in cancer patients (Aguirre et al., 1996). Reduction in the metabolism of omeprazole (CYP2C19 substrate) has also been observed in patients with advanced cancer (Williams et al., 2000). Reduced CYP3A expression resulted in >2 fold increase in the sleep time in tumor bearing mice receiving the widely used sedative-hypnotic, midazolam, (CYP3A specific substrate) (Charles et al., 2006).
\n\t\t\tSince the 1800s, it was observed that chronic inflammation is frequently associated with the onset and progression of various cancers (Balkwill & Mantovani, 2001). A strong association between cancer progression and induction of cytokines or acute phase reactive proteins in tumors is documented (Burke & Balkwill, 1996, Burke et al., 1996, Naylor et al., 1993). E.g. EHS tumor-bearing mice had significantly higher circulating plasma levels of IL-6 (25 pg/ml) compared to the control mice (below detection limit). IL-6 mediated activation of JNK was also evident in EHS tumor-bearing mice, which again prompts the important role of JNK in regulation of DMEs. Studies have shown that TLR expression is enhanced in tumor cells lines (Yu & Chen, 2008). However, the role of TLRs in alteration of DMEs and transporters in cancer has never been investigated.
\n\t\t\t\tThe role of NF-κB activation in acute inflammation has been suggested in carcinogenesis (Karin et al., 2002, Lind et al., 2001). Cancer-mediated alteration of DMEs and transporters may possibly be regulated by over-expression of NF-κB. A recent study highlighted the role of extra hepatic malignancies in down-regulation of PXR and CAR in tumor-bearing mice (Kacevska et al., 2011). This study prompts to link the reduction in nuclear receptors with altered drug metabolism in cancer. However, additional studies with nuclear receptor knockout animal models with tumors will help identify their direct role in regulation of DMEs and transporters. Overall, all these studies imply that tumor-mediated inflammation may play an integral role in drug response and toxicity of various anticancer agents.
\n\t\t\tAnother prevalent pathophysiological condition affecting millions of people in the world is the occurrence of diabetes and obesity. As per the latest statistical report, 366 million people in the world will have diabetes by 2030 (Wild et al., 2004).
Streptozotocin treatment in rats increased hepatic levels of
Obesity-associated alterations in phase II metabolism were reported in 1980’s. E.g. clearances of oxazepam and lorazepam, widely used benzodiazepines and excreted as glucuronide conjugates, were significantly increased in obese patients (Abernethy et al., 1983). Similarly, increased metabolism of chlorzoxazone (CYP2E1 substrate) to 6-hydroxychlorzoxazone was observed in obese individuals. This was attributed to increased CYP2E1 activity associated with obesity (O\'Shea et al., 1994). Animal studies performed using a diabetes mellitus rat model (induced by alloxan or streptozotocin treatment) have reported altered PK of drugs such as acetaminophen, chlorzoxazone, theophylline, clarithromycin, furosemide, and methotrexate (Baek et al., 2006, Kim et al., 2005a, 2005b, Park et al., 1996, 1998, Watkins & Sherman, 1992). Although, no changes in PD of atracurium were reported in obese animals compared to lean control (Varin et al., 1990), triazolam-induced sedation in obese humans increased significantly compared to normal weight men (Derry et al., 1995). We also observed similar disparities in the PD of midazolam, CYP3A substrate, (increased sleep time) and zoxazolamine, CYP2E1 substrate (no change) in DIO mice (Ghose et al., 2011b). This can be attributed to decrease in CYP3A and no change in CYP2E1 expression. Thus, the differential effects of obesity on PD of drugs may depend on the DME, or the drug or the target organ itself.
\n\t\t\tThe major pathophysiological manifestation in diabetes/obesity is characterized by low-level chronic and local inflammation, such as release or over expression of TNF-α and C-reactive protein in adipose tissue (Hotamisligil et al., 1993, Wellen & Hotamisligil, 2005). However, the role of inflammation in regulation of DMEs and transporters in diabetes/obesity remains unclear. Hormonal regulation of DMEs in diabetes/obesity has also been addressed before (Thummel & Schenkman, 1990). Although an increase in mRNA or protein levels of CYP2E1 have been observed in obese patients (Lucas et al., 1998),
Interestingly, lower expression of CAR and CYP2B in obese Zucker rats and ~2 fold induction in obese and genetically diabetic mice (
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent with an estimated world population between 14% and 24% being affected. NAFLD comprises of symptoms ranging from simple steatosis (fatty liver) to the more severe non-alcoholic steatohepatitis (NASH, fatty liver with infiltration of inflammatory cells) to progressive hepatic fibrosis and to cirrhosis (Reynaert et al., 2005). Alteration of hepatic CYP2E1 was first noted in humans with NASH (Weltman et al., 1998). Later studies have shown significant contribution of NAFLD (comprising of both, simple stage fatty liver as well as NASH) on expression and activity of DMEs in animals (Fisher et al., 2008, 2009a, 2009b). Similarly,
Decreased mRNA and protein expression of uptake transporters such as NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 were observed in NAFLD (Fisher et al., 2009a).
\n\t\t\tStudies have shown interesting results with acetaminophen (APAP) PK in rats and humans with NAFLD. Children with NAFLD had significantly higher concentrations of APAP-glucuronide (APAP-G) in serum and urine compared with controls, with no significant differences in PK of APAP among the 2 groups (Barshop et al., 2011). Another study showed that biliary concentrations of APAP-sulfate (APAP-S), APAP-G, and APAP-glutathione were reduced in MCD (methionine- and choline-deficient) rats (Lickteig et al., 2007a). However, plasma levels of APAP-G were also elevated in MCD rats, similar to that observed in children (Barshop et al., 2011). A clinical study evaluated the effect of NAFLD on PK of silymarin (Schrieber et al., 2008). The AUC0-24h for the sum of total silymarin flavonolignans was ~3-4 fold higher in patients with NAFLD (p<0.03), compared with healthy volunteers.
\n\t\t\tSeveral mechanisms have been proposed for the effect of NAFLD on altered drug metabolism. Deposition of fat in human hepatocytes can lead to a marked impairment in CYP mRNA and activity (Donato et al., 2006).
CYPs in humans are responsible for metabolizing a large number of cardiovascular medications, including β-blockers, calcium channel blockers and angiotensin receptor antagonists (Abernethy & Flockhart, 2000). Alteration in DMEs could be of particular clinical relevance in patients with heart failure because these patients take more than 10 medications on average. Although, not detected in the normal human heart, failing hearts expressed CYP11B1 and 11B2 (Young et al., 2001). Surprisingly, an up-regulation in CYP2J2, 1B1, 2E1, 4A10 and 2F2 gene expression was reported in the failing heart (Tan et al., 2002). Increased cardiac CYP11B2 mRNA was associated with increased myocardial fibrosis and the severity of left ventricular dysfunction in patients with heart failure (Satoh et al., 2002). It was shown that the production of testosterone metabolites, including dihydrotestosterone and androstenedione, was significantly increased in hypertrophic human hearts (Thum & Borlak, 2002). Transient ischemic attacks (TIA) are risk factors for strokes. A recent study showed that cerebral infarct size was reduced in TIA-preconditioned animals and CYP2C11 mRNA and protein were coincidentally increased in the brain after experimentally induced TIA (Johnston, 2004). Genetic polymorphisms of DMEs are commonly associated with heart failure and hypertension (Kivisto et al., 2005). E.g. a study in Japanese subjects reported that CYP2C9
A recent study demonstrated a selective disease-dependent regulation of the high-affinity carnitine transporter, OCTN2, in patients with dilated cardiomyopathy, whereas the other OCT(N)s were unaffected (Grube et al., 2011).
\n\t\t\tIt was shown that lidocaine plasma clearance was significantly decreased in patients with cardiac failure and this was associated with decreased liver blood flow (Thomson et al., 1971). Another group also observed reduced plasma clearance of lignocaine in patients suffering from myocardial infarction without cardiac failure (Prescott et al., 1976). Thus, the mounting evidence for the effect of CVDs on DMEs and transporters needs to be extended for further PK/PD studies.
\n\t\t\tFailing or hypertensive hearts are susceptible to infiltration by pro-inflammatory cytokines and reactive oxygen species induced by stress (Fliser et al., 2004). Studies have shown that increased circulating levels of TNF-α and IL-6 in patients with congestive heart failure were inversely proportional to CYP2C19 and CYP1A2 activity (Frye et al., 2002). Similarly, down-regulation of OCTN2 expression in patients with dilated cardiomyopathy inversely correlated with cardiac CD3+ T-cell count (Grube et al., 2011). In addition, cardiac cytokine release may affect OCTN2 expression during cardiomyopathy associated with inflammation.
\n\t\t\tRheumatic diseases are estimated to affect up to 1.1% of the world’s population (Harris, 1980). Various studies have shown that gene expressions of DMEs are altered in adjuvant arthritis (AA) rats (Achira et al., 2002b, 2002c, Projean et al., 2005). Similarly, activities of CYP3A were significantly decreased in AA rats compared to control rats (Uno et al., 2007).
\n\t\t\tDecreased activity of hepatic P-gp in the isolated perfused liver of AA rats was reported (Achira et al., 2002c, Uno et al., 2007). Decrease in P-gp activity corresponded with the decreased levels of Mdr1a mRNA and P-gp protein in AA rats.
\n\t\t\tPK/PD changes such as elevated plasma levels of acebutolol, cyclosporin A, propranolol and prolongation of sleep time with pentobarbital were observed in AA rats compared to normal rats (Dipasquale et al., 1974, Piquette-Miller & Jamali, 1992, 1993, Shibata et al., 1993). Based on these early observations, recent studies have also shown altered PK of methotrexate, T-5557 (novel anti-inflammatory agent) and doxorubicin in AA animals (Achira et al., 2002a, 2002b, 2002d). Although, a significant increase in the plasma concentrations of verapamil in rats and humans with underlying arthritis were reported, there were no changes in the PD of verapamil (prolongation of PR interval) (Mayo et al., 2000, Sattari et al., 2003). This discrepancy was then attributed to a decrease in the receptor-ligand affinity in inflammation (Laporte et al., 1998, Shore et al., 1997).
\n\t\t\tAA animal models represent a systemic inflammatory disease with bone and cartilage changes similar to those observed in RA (Williams et al., 1992). Down-regulation of hepatic P-gp in AA rats was attributed to elevated levels of cytokines such as TNF-α and IL-6 but not IL-1β (Philippe et al., 1997). Similarly, increased plasma concentrations of drugs in AA rats correlated with increased serum TNF-α level (Sattari et al., 2003). Several
A common theme of this chapter is that a multiplex of mechanisms are responsible for alterations of DMEs, transporters and PK/PD of drugs in different pathophysiological conditions. It is well-established that changes in gene expression of enzymes and transporters can lead to disruption in drug disposition in altered pathophysiological conditions including infection/inflammation, cancer, obesity, CVD, rheumatoid arthritis, etc. Studies show that induction of inflammatory mediators is an underlying factor common to all these pathophysiological conditions and may contribute to altered drug disposition in disease states. In addition, the generally accepted role of cytokines in alterations of DMEs and transporters needs further evaluation. We have established the involvement of Toll-like receptor signaling pathway in the regulation of DMEs and transporters, and our studies point to the role of cytokine-independent pathways in the liver. The role of transcription factors and nuclear receptors in the regulation of DMEs and transporters in disease states need further investigation. There is an urgent need to develop models for delineating the roles of individual inflammatory mediators or nuclear receptors in altered drug disposition in disease states. Understanding alterations of drug disposition in disease states is critical in predicting and preventing undesirable effects of clinically-relevant medications.
\n\t\tp53 is a multifunctional transcription factor that induces cell cycle arrest, DNA repair, and apoptosis, thereby suppressing cell cancerization [1, 2]. It is referred to as a guardian of the genome that determines cell fate. When p53 is activated by various stress factors, it searches for and binds to target DNA sequences and regulates the expression of downstream genes. p53 is composed of an N-terminal (NT) domain, core domain, linker, tetramerization (Tet) domain, and C-terminal (CT) domain. The core and Tet domains possess specifically folded structures, while other domains are intrinsically disordered [3, 4, 5]. p53 forms a tetramer via Tet domains [5]. Core and CT domains are involved in its binding to DNA sequences in a specific and nonspecific manner, respectively [6]. Fifty percent of gene mutations in tumor cells were found in p53, and many of the identified mutations were located in structured domains, which inhibited target DNA binding [3]. Comprehensive mutagenesis analysis supports the correlation between the structured domains of p53 and its function [7]. Since p53 possesses common properties frequently observed in DNA-binding proteins, including oligomerization, disordered regions, and multiple DNA-binding domains [8], it is used as a model protein in the target search study described below [9, 10, 11].
\nThe target DNAs for p53 were ~ 20 bp, while the genomic DNA was ~109 bp. Accordingly, p53 was required to search for small targets efficiently from within vast lengths of non-target DNAs. This is known as a target search problem for sequence-specific DNA-binding proteins. To solve this problem, a facilitated diffusion mechanism has been proposed for DNA-binding proteins. The facilitated diffusion is the integration of three-dimensional (3D) diffusion in solution, one-dimensional (1D) diffusion along DNA, hopping/jumping along DNA, and intersegmental transfer between two DNAs (Figure 1a). In 3D diffusion, p53 diffuses in solution, altering the search sites on genomic DNA. In 1D sliding, it moves along the DNA, while maintaining continuous contact. In addition, p53 hops or jumps along DNA (within 100 bp of jump). Intersegmental transfer enables p53 to move from one DNA to another without dissociation. Theoretical studies suggest that the integration of multiple search dynamics, while not requiring all dynamics, can facilitate the target search [14, 15, 16, 17]. The facilitation factor depends on various physical parameters, such as diffusion coefficient along DNA, residence time on DNA, dissociation time in solution, and frequency of transfer and jump.
\nTarget search dynamics of DNA-binding proteins and visualization of p53 dynamics on DNA by single-molecule fluorescence microscopy. (a) Schematic diagram of four target search dynamics. (b) Schematic diagram of single-molecule fluorescence microscope and flow cell. In the flow cell, one end of the DNA is tethered to the surface and it is stretched by buffer flow. p53 molecule labeled to a fluorescence dye is illuminated by TIRF and the fluorescence is detected by EM-CCD through an objective lens. Panels (a) and (b) are adapted from ref. [
How does p53 solve the target search problem using facilitated diffusion? How is the target search and binding of p53 regulated? In this chapter, I explain the facilitated diffusion and regulation of p53 based on recently accumulated single-molecule data.
\nSingle-molecule fluorescence microscopy enables the differentiation and characterization of individual search dynamics of DNA-binding proteins, including p53, as reported previously [18, 19, 20, 21, 22, 23, 24]. In general, the system combines a fluorescence microscope and a flow cell (Figure 1b). In the flow cell, one end of the DNA is tethered to the surface, and it is stretched by buffer flow. Several methods have been proposed for tethering DNAs [18, 25, 26, 27, 28, 29]. For example, a DNA garden is a simple method for producing DNA arrays, in which neutravidin molecules are printed in a line on polymer-coated coverslips, and biotinylated DNAs are tethered to the printed neutravidin [29]. p53 molecules labeled with a fluorescence dye are introduced into the flow cell using a syringe pump. The fluorescent p53 bound to DNA is selectively illuminated by total internal reflection fluorescence (TIRF). p53 molecules on DNA are detected as fluorescent spots on the sequential images of an electron-multiplying charge-coupled device (EM-CCD). The positions of molecules were tracked using an appropriate analysis program to visualize the search dynamics of p53.
\nIn 2008, 1D sliding of p53 along DNA was observed for the first time using single-molecule fluorescence microscopy [30]. This observation was consistent with a reported indirect evidence that p53 dissociated rapidly from short DNA in the absence of blocks at ends by sliding off from DNA [31]. In 2011, a study of p53 mutants deleting either of two DNA-binding proteins revealed that p53 can slide along DNA using disordered CT domains [32]. This is consistent with the fact that a designed peptide targeting CT domains suppressed the 1D sliding of p53 [33]. Furthermore, 1D sliding of p53 was supported by molecular dynamics simulations [34, 35]. In 2012, it was shown that 1D sliding dynamics of p53 depends slightly on DNA sequence, suggesting that p53 feels the energy landscape based on DNA sequence through interactions between core domains and DNA [36]. In 2015, a detailed analysis of 1D sliding dynamics demonstrated that p53 possesses two sliding modes on non-target DNA [37, 38]. In the fast mode, it interacts with DNA loosely using CT domains. In contrast, in the slow mode, it binds tightly to DNA using core and CT domains (Figure 2a). In 2017, the disordered linker was identified to trigger the switch between the two modes (Figure 2a) [41]. In 2016, the target recognition process of p53 was characterized in detail [42]. The results demonstrated that target recognition occurs mainly via 1D sliding. The target recognition of p53 was quite low (the successful recognition probability was 7%), but it was enhanced two-fold upon a post-translational modification. Accordingly, 1D sliding is considered as one of the important dynamics in the target search and binding of p53.
\nTarget search dynamics of p53. (a) Schematic diagram of two modes for 1D sliding p53 along DNA. p53 is composed of the NT (purple), Core (green), linker (black), Tet (yellow), and CT (pink) domains. The switch between two modes is triggered by the linker. (b) Typical single-molecule data showing intersegmental transfer of p53 between crisscrossing DNAs. (c) Schematic diagram of intersegmental transfer of p53 between two DNAs. p53 uses CT domains (pink) for the transfer. (d) Typical single-molecule data showing jumping of p53 along DNA (white traces). Arrows denote the jumping events. (e) Schematic diagram of encounter complex formation of p53 and conversion from the encounter complex to long-lived complex. Panel (b) is adapted from ref. [
In 2018, intersegmental transfer of p53 was examined using ensemble kinetic and single-molecule fluorescence measurements [39]. After the solutions of p53 bound to fluorescently labeled DNA and non-labeled DNA were mixed, the transfer reaction of p53 was monitored between the two DNAs. The observed reactions included the dissociation of p53 from one DNA and its transfer to the other. Actually, as the concentration of non-labeled DNA increased, the observed rate constant increased, suggesting intersegmental transfer. The rate constant of the transfer was ~108 M−1 s−1, which is close to the diffusion limit. Furthermore, single-molecule tracking of p53 on crisscrossed DNAs demonstrated that p53 moves along the first DNA and then moves along the second DNA through the transfer at the intersection (Figure 2b). A study of p53 mutants deleting either of two DNA-binding domains identified that p53 binds to the first DNA and then to the second DNA using disordered CT domains at the same time; it then releases the first DNA, resulting in a transfer between the two DNAs (Figure 2c). This mechanism is supported by molecular dynamics simulations of p53 [43].
\nIn 2020, the hopping/jumping of p53 on DNA was investigated [40]. Hopping/jumping was expected to occur at a time scale that is faster than the time resolution of the microscope (ex. 33 ms). To detect these events, the time resolution of the microscope was improved to 500 μs by optimizing the fluorescence excitation based on critical angle TIRF illumination and by utilizing the time delay integration mode of the EM-CCD [40]. Using the sub-millisecond-resolved microscope, jumping events of p53 along DNA were directly detected (arrows in Figure 2d). The jump frequency of p53 was ~6 s−1, and the jump time was 2.2 ms. Based on the study of p53 mutants deleting either of two DNA-binding domains, disordered CT domains were identified to be indispensable for the jumping of p53 along DNA [13]. Furthermore, 1D diffusion along DNA was enhanced upon increasing the salt concentration, suggesting that p53 moves along DNA by hopping DNA-binding domains. Thus, it was revealed that p53 possesses hopping and jumping dynamics along DNA.
\nIn 2016, 3D diffusion of p53 was characterized using ensemble kinetic measurements [42]. Association rate constants for target and non-target DNAs were determined to be ~109 M−1 s−1, comparable to the diffusion limits. The difference in affinity for target and non-target DNAs was attributed to the dissociation rate constants. In 2020, the association process of p53 with non-target DNA was further investigated at the single-molecule level using a sub-millisecond resolved fluorescence microscope [40]. Kymographs demonstrated that short-lived traces of p53 with an average residence time of 2.8 ms were detected in addition to long-lived traces moving along DNA. The short-lived complex was interpreted as an encounter complex. Disordered CT domains of p53 were identified to participate in the transient complex formation and in the conversion from the transient complex to the long-lived complex [13] (Figure 2e). The long-lived complex was further stabilized by core domains [13].
\nOverall, single-molecule fluorescence microscopy revealed that p53 possesses all four search dynamics proposed theoretically: 3D diffusion, 1D sliding, hopping/jumping, and intersegmental transfer. The unique structure of p53, which is a tetramer of two DNA-binding domains, enables these search dynamics. This is the first study to examine all search possibilities for a single model protein.
\nTarget search and binding of p53 might be regulated by a liquid-like assembly of p53 molecules. In a liquid–liquid phase separation (LLPS), p53 molecules, which disperse in the bulk phase, assemble and form a condensed phase called liquid droplets. In the droplet phase, p53 can move fluidly while maintaining a high concentration. This fluid property in the condensed phase differs from the solid aggregation that causes malfunction of p53. Early
In 2020, this possibility was extensively examined using
Liquid droplet formation of p53 regulates its function. (a) Time course of a typical fusion event of three p53 droplets into a single droplet using DIC microscopy. (b) DIC and fluorescence images of the droplets of Alexa488-labeled p53 and non-labeled p53. Scale bars in panels (a) and (b) represent 10 μm. (c) Schematic diagram of p53 conformation in the droplet. p53 is composed of the NT (purple), Core (orange), Tet (yellow), and CT (red) domains. In the droplets, the NT and CT domains interact electrostatically. Arrows denote the structural changes on the different domains of p53 that are induced by the intermolecular interactions in a droplet. The dimer structure is displayed for clarity. (d) Functional switch model of p53. The panels (a)-(d) are adapted from ref. [
The structural properties of p53 in solution and in droplet form were investigated using fluorescence resonance energy transfer (FRET) between two fluorophores labeled at two residues of p53. Since FRET depends on the distance between the two fluorophores, it was used to measure the conformational changes. The distance between the core domains of p53 was slightly longer in the droplets, while the distance between the CT domains became slightly shorter (Figure 3c). Accordingly, p53 adopted a new tertiary structure, forming interactions with the adjacent molecules in the droplets.
\nDoes p53 maintain binding to the target DNA after experiencing the droplet formation? The reactions of p53 binding to the target DNA were similar before and after the droplet formation. These results indicate that droplet formation of p53 is reversible, and p53 dispersed in solution from the droplets retains its DNA binding ability.
\nDroplet formation of p53 was found to be regulated by molecular crowding, endogenous molecules, and post-translational modification. Molecular crowding agents, mimicking the cellular crowding condition, promoted droplet formation. In contrast, ssDNA, dsDNA, and ATP suppressed it. The p53 mutant mimicking post-translational phosphorylation did not form droplets. Based on these results, a functional switch model was proposed (Figure 3d). Under normal cell conditions, the compartmentalization of p53 into the droplets suppresses its function as a transcriptional regulator. Under stress conditions, the activation of p53, triggered by posttranslational phosphorylation, releases p53 from the droplets and promotes target search and binding.
\nIn this section, the current model of p53 is described in terms of target search and regulation. p53 functions as a transcription factor that responds to various emergency situations in cells. Under normal cell conditions, p53 turns off through the following mechanisms. First, the copy number of p53 is maintained at a low level, allowing dimers with a low affinity to target DNAs in an oligomeric state [48, 49]. Second, post-translational modifications for activating p53 are not added, for example, suppressing the target recognition of p53 [42]. Third, p53 is stored in liquid droplets [47]. These actions of p53 prevent its malfunction under normal conditions.
\nUnder cellular stress, p53 is activated by post-translational modifications [1, 2, 50, 51, 52, 53, 54, 55, 56] and by a change in its oligomeric state from dimers to tetramers, with a high affinity for target DNAs [48, 57, 58, 59]. Phosphorylation of the CT domain of p53 triggers its release from the droplets, allowing it to engage in target search [47]. The increase in the copy number of p53 also facilitates the target search [60]. As explained above, p53 utilizes facilitated diffusion combining four search dynamics. Using 3D diffusion, p53 associates randomly with nonspecific sites of DNA, followed by dissociation. Until p53 associates with the target sequence by chance, it repeats such association and dissociation motions. If the search motion of p53 is limited to 3D diffusion, it would be a time-consuming endeavor. After p53 associates with the nonspecific site of DNA by 3D diffusion, it can search for the target sequence along DNA near the bound site using 1D sliding and hopping/jumping. The search distance of p53 per association event is estimated to be 700 bp [40], corresponding to approximately 35-fold facilitation of the target search.
\nIn cells, genomic DNAs are covered by many DNA-binding proteins, including histones and other nucleoid proteins. These DNA-binding proteins may act as obstacles in the target search of p53. For example, when the sliding p53 collides with other DNA-binding proteins on DNA, it may not be able to bypass these obstacles due to steric hindrance, thereby limiting the search distance on DNA. However, p53 possesses two bypass mechanisms: the jumping along DNA [40] and the intersegmental transfer between two DNAs [39]. Using these motions, it can overcome such obstacles and continue its search for targets in cells. Overall, the search and regulation strategies of p53 could satisfy various cellular requirements.
\nThe target search and binding of p53 and its regulation have been characterized using single-molecule fluorescence microscopy and relevant biophysical methods. The accumulated data demonstrate that p53 searches for target DNAs utilizing four search dynamics: 3D diffusion in solution, 1D sliding along DNA, hopping/jumping along DNA, and intersegmental transfer between two DNAs (Figure 4). Especially, hopping/jumping and intersegmental transfer between two DNAs are required to bypass obstacles bound to DNA. It was reported that other DNA-binding protein with a disordered DNA-binding domain bypasses obstacles through obstacle-unbound region of DNA [24]. Since p53 possesses a similar disordered DNA-binding domain, it is not surprising that p53 possesses this bypass mechanism. Target search and binding are regulated by copy number, post-translational modifications, and liquid droplet formation. Considering that p53 can interact with many partner proteins, the partner proteins may affect the target search. Complexity in the target search and regulation of p53 would enable a response to various emergency situations in cells and be required to satisfy various cellular requirements.
\nSchematic diagram of target search of p53. Pink and gray circles are p53 and obstacle bound to DNA, respectively. Four search mechanisms are illustrated.
I thank the corroborators for their helpful discussions on our studies of target search by p53.
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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:303,paginationItems:[{id:"280338",title:"Dr.",name:"Yutaka",middleName:null,surname:"Tsutsumi",slug:"yutaka-tsutsumi",fullName:"Yutaka Tsutsumi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/280338/images/7961_n.jpg",biography:null,institutionString:null,institution:{name:"Fujita Health University",country:{name:"Japan"}}},{id:"116250",title:"Dr.",name:"Nima",middleName:null,surname:"Rezaei",slug:"nima-rezaei",fullName:"Nima Rezaei",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/116250/images/system/116250.jpg",biography:"Professor Nima Rezaei obtained an MD from Tehran University of Medical Sciences, Iran. He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"117248",title:"Dr.",name:"Andrew",middleName:null,surname:"Macnab",slug:"andrew-macnab",fullName:"Andrew Macnab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. Gonzalez-Sanchez",slug:"juan-a.-gonzalez-sanchez",fullName:"Juan A. 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Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
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