Classification of drug-induced cutaneous toxicity.
\r\n\t
",isbn:"978-1-83768-165-5",printIsbn:"978-1-83768-164-8",pdfIsbn:"978-1-83768-166-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"681a60ff84a29b9f72de9b662bab9c38",bookSignature:"Prof. Shailendra K. 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Dr. Saxena is a fellow of various prestigious international societies/academies, including the Royal College of Pathologists, United Kingdom; Royal Society of MedProf. He is the vice dean and Professor at King George\\'s Medical University, Lucknow.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",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. 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Among hospitalized patients, the incidence of adverse drug reactions concerning the skin ranges from 1% to 3%; however, the actual prevalence is much higher, as many mild forms of cutaneous adverse reactions are not reported [1]. We are constantly exposed to external stimuli, such as chemical and environmental substances, resulting in various skin symptoms. This article focuses on (1) the function and structure of the skin and (2) characteristics of cutaneous toxicity of pharmaceutical products and chemical substances in humans and animals.
\nSkin is the largest organ of the body, covering the surface and accounting for approximately 15–20% of body mass. In addition to its constant barrier role, protecting the living body against external stimuli, skin is important for maintaining the body health (e.g., through regulation of body temperature, storage of fluids and electrolytes, and the synthesis of vitamin D) and also acts as an important component of the immune system. As a sensory organ, the skin can sense pain, touch, pressure, and temperature [2]. Histologically, the skin consists of the epidermis, dermis, and subcutaneous tissue. The epidermis is formed by keratinized squamous epithelia, stratified from the surface into the cornified layer, clear layer (only on the palms and soles), granular layer, spinous layer, and basal layer [3]. The epidermis also contains antigen-presenting Langerhans cells (mainly in the spinous layer); melanocytes (mainly in the basal layer), which produce melanin to protect epidermal cells against damage induced by ultraviolet light; and Merkel cells (mainly on the palms and soles), which are neuroendocrine cells. The dermis is composed of fibrous connective tissue with elastic and reticular fibers intermingled with collagen bundles, containing mast cells that are involved in allergic reactions, sweat glands, sebaceous glands, hair follicles, blood vessels, lymphatic vessels, and nerve fibers. Subcutaneous tissue is composed of loose connective tissue and subcutaneous adipose tissue. Adipose tissue is especially prominent in the footpads where it functions as a “shock absorber” and as an insulating layer [4]. Skin appendages are skin-associated structures that serve a particular function, including sensation, contractility, lubrication, and heat loss. They contain hairs (sensation, heat loss, filter for breathing, protection), sebaceous glands (secrete sebum onto hair follicles, which oils the hair), sweat glands (can produce sweat secreted with strong odor (apocrine) or with a faint odor (eccrine), and nails (protection). Hair growth occurs in three stages: anagen (growth phase), catagen (involution period), and telogen (resting phase during which hair shedding occurs) [5, 6]. The rate of hair growth and duration of the growth cycle vary in different areas of the body and are influenced by sex hormones and growth factors. Sebaceous glands are most often associated with hair follicles and produce sebum by holocrine secretion. Zymbal’s gland is a specialized sebaceous gland in rodents located at the base of the external ear canal; the gland cells contain cytochrome P450 isoenzyme and peroxidases and are capable of chemical metabolism [7, 8]. Apocrine glands are distributed throughout the skin of most laboratory animals, whereas in humans they are located in axillary, pubic, and perianal areas, while they are only present in the plantar areas in rodents. There are a number of specialized apocrine glands, such as the anal sac gland of dogs, the ceruminous glands of the external ear canal, and the glands of Moll in the eyelids. Eccrine glands are found throughout the body in humans; however, these glands are limited to the footpads of carnivores and rodents.
\nIn preclinical studies, cutaneous toxicity is rarely encountered, except in cutaneous application, intradermal administration, and subcutaneous administration. Cutaneous toxicity primarily involves either a direct local inflammatory reaction to the drug without involvement of an immunological mechanism or an indirect inflammatory reaction associated with a systemic manifestation [6]. In cutaneous application studies, both epidermis and skin appendages are important factors in transdermal drug absorption [9]. Experimental animals such as guinea pigs, monkeys, and swine exhibit similar absorption characteristics to humans [5]. Of all laboratory animals, swine skin is most structurally comparable to human skin [4]. Swine and humans have comparable stratum corneum, epidermal thickness, and hair follicle density, as well as similar chemical composition of the stratum corneum. Rodents have much thinner skin (especially the epidermis) with greater permeation compared to humans [4]. In general, skin is thicker over the dorsal and lateral surfaces and thinnest on the ventral and medial surfaces. Areas of skin that contact the ground, such as footpad and heels, have the thickest epidermis (Figure 1). The extent of transdermal drug absorption differs according to skin location. Sites in order of favorable absorption, due to the skin thickness, are the abdomen, forehead, palms, and soles of feet [5]. It should be noted that skin thickness varies considerably during the hair cycle (Figure 2). Skin thickness during the anagen stage is thickest and is thinnest during the catagen stage in rodents and rabbits. If the skin is damaged, the biological protective barrier function decreases, leading to a significant increase in drug absorption, which results in intensified systemic toxicity [10]. Microsomal enzymes in keratinocytes are capable of metabolizing topically applied chemicals, thus rendering them inactive or active. Dimethylbenz(a)anthracene (DMBA) becomes a potent skin carcinogen after metabolic activation by keratinocytes [11].
\nComparative histology of different skin locations in rats. (a) Scalp region at the vertex. (b) Nose region. (c) Inguinal region. (d) Back region. (e) Abdominal region. (f) Footpad region. (g) Eccrine sweat gland in the footpad. Note that scalp, inguinal, and abdominal skin are thin. In contrast, back and footpad skin are thicker. Footpad skin is the thickest, especially the stratum corneum and epidermis. Eccrine sweat glands are located only in the footpad of rodents; however, these glands are found throughout the human body.
Comparative histology of back skin during different hair cycle stages. (a) Anagen stage in the mouse. (b) Catagen stage in the mouse. (c) Anagen stage in the rat. (d) Catagen stage in the rat. (e) Anagen stage in the rabbit. (f) Catagen stage in the rabbit. Note that skin thickness is thickest at the anagen stage and thinnest at the catagen stage in rodents.
Cutaneous toxicity can be classified according to the mechanism of onset into the following: (1) contact dermatitis, i.e., damage resulting from contact of the skin with a drug (irritant dermatitis, allergic contact dermatitis, and chemical burns); (2) photosensitivity, caused by the combined effect of a chemical substance and ultraviolet light (phototoxic dermatitis and photoallergic contact dermatitis); (3) contact urticaria; (4) chemical-induced acne; (5) pigmentary disturbance; (6) drug rash; (7) hair disturbance; (8) nail disturbance; and (9) tumor-induced. Cutaneous toxicity can also be classified according to the route of exposure, i.e., either due to systemic effects or local irritation of the skin (local toxicity) [5, 6].
\nContact dermatitis is skin inflammation occurring as a result of direct contact of the skin with a drug that can be classified into the following three types, according to the mechanism of onset.
\nIrritant dermatitis is an inflammatory change caused by direct irritation of the skin that can be either acute or cumulative. Activation of mast cells, complement or prostaglandin synthesis results in reversible damage to the skin, observed as irritation within 4 hours following topical application of the chemicals. Irritant dermatitis is characterized by inflammatory cell infiltration, acanthosis, epidermal hyperkeratosis, and hyperplasia associated with other epidermal changes such as erosion/ulcer, necrosis, or vesicle formation [11]. Irritant dermatitis depends on the severity of the irritants and duration of their exposures [5, 6] (Figure 3). If the damage to the skin is irreversible, the lesion is clinically referred to as corrosion, which is characterized by full thickness necrosis of the epidermis penetrating into the underlying dermis [11]. In preclinical studies of topical application agents, skin irritation testing is conducted using rabbits or guinea pigs to evaluate drug-induced irritation using the Draize method (with a 5-grade score based on macroscopic assessment of the severity of erythema, crusting, and edema) (Figure 4 and Table 2). The Draize test consists of application of the chemical to the test site on shaved dorsal skin. The test sites undergo gross evaluation at 6, 24, and 72 postapplication.
\nClassification | \nType | \nDefinition and characteristics | \n
---|---|---|
A. Classification according to the route of exposure to the drug | \nCutaneous toxicity due to systemic effect Local irritation of skin (local toxicity) | \n|
B. Classification according to the mechanism of onset | \n\n | \n |
1. Contact dermatitis | \nIrritant dermatitis | \nSkin inflammation occurring as a result of direct contact of the skin with a drug, without involvement of an immune mechanism | \n
Allergic dermatitis | \nSkin inflammation upon re-exposure to a drug that had been previously administered and bound as a hapten to a protein in the skin to become immunogenic (type IV allergic reaction) | \n|
2. Photosensitivity | \nPhototoxic dermatitis | \nA condition caused by a drug with covalent binding as a result of a photochemical reaction with ultraviolet light | \n
Photoallergic dermatitis | \nSkin inflammation upon re-exposure to a previously administered drug that absorbed ultraviolet light and was transformed to act as a hapten to bind with a protein in the skin to become immunogenic (type IV allergic reaction) | \n|
3. Contact urticaria | \n\n | Acute erythema with involvement of histamine release from mast cells (increased vascular permeability), occurring soon after contact with the drug | \n
4. Chemical acne | \n\n | Inflammation of hair follicles due to excessive keratin and sebum in hair follicles | \n
5. Pigmentary disturbance | \nHyperpigmentation | \nA condition occurring in association with increased melanin production due to activation of melanocytes, hemosiderin deposition due to hemorrhage, or deposition of the drug itself | \n
Hypopigmentation | \nA condition occurring in association with loss of melanin or selective damage to melanocytes | \n|
6. Drug rash (cutaneous reaction) | \nToxic epidermal necrolysis, oculomucocutaneous syndrome | \nThe mechanism remains unknown, although an allergic reaction has been speculated. Reported for greater than 1100 drugs, including sulfa drugs | \n
7. Hair disturbance | \nAlopecia | \nA condition due to drugs with an androgenic effect acting on hair follicles to shorten the hair cycle, or drugs with an antimitotic effect inducing atrophy of hair follicles and prolongation of the resting phase of the hair cycle | \n
Hypertrichosis | \nA condition due to prolongation of the anagen phase of hair follicles induced by certain immunosuppressants, antihypertensives (minoxidil), or drugs for benign prostatic hyperplasia (finasteride) | \n|
8. Nail disturbance | \nNail transverse ridges, onycholysis, discoloration | \nA condition arising from damage to the nail matrix cells due to drugs with an antimitotic effect or deposition of the drugs themselves | \n
9. Tumors | \n\n | \n |
Sequential stages of inflammatory changes in irritant contact dermatitis following a single exposure to sodium lauryl sulfate (SLS) in the guinea pig. (a) Epidermal necrosis and slight infiltration of neutrophils in dermis are observed 24 hours after exposure. (b) Epidermal necrosis and severe infiltration of neutrophils in epidermis and dermis are observed 24 hours after exposure. (c) Epidermal abscess (pustule) and acanthosis (epidermal regeneration) are observed 48 hours after exposure. Owing to its emulsifying properties, SLS is an anionic surfactant used in many hygienic and cleaning products, including shampoos, toothpastes, and shaving foams.
Macroscopic photos from a cumulative dermal irritation study in animals. (a) After the hair on the back of the rat is shaved, the drug is continually applied to the same area. The rat wears the Elizabethan collar to prevent the animal from biting or licking the exposure site. (b) Cumulative dermal irritation study in a rabbit (left: vehicle application, right: drug application). The site of drug application is observed with erythema, redness, swelling, and moistness. The change spreads beyond the site of application, indicating a strong irritant property of the drug.
Skin reaction | \nGrading value | \n
---|---|
Erythema and eschar formation | \n|
No erythema | \n0 | \n
Very slight erythema (barely perceptible) | \n1 | \n
Well-defined erythema | \n2 | \n
Moderate-to-severe erythema | \n3 | \n
Severe erythema to slight eschar formation | \n4 | \n
Edema formation | \n|
No edema | \n0 | \n
Very slight edema (barely perceptible) | \n1 | \n
Slight edema (raised edges of area well defined) | \n2 | \n
Moderate edema (raised more than 1 mm) | \n3 | \n
Severe edema (raised more than a mm and extending beyond the area of exposure) | \n4 | \n
Skin irritation test (Draize scale).
Eschar is scab or crust formation.
This table has been modified from [4].
Allergic contact dermatitis is a condition caused by a delayed (type IV) allergic reaction. A low molecular weight drug binds as hapten to a protein in the body to act as a complete antigen. Characteristically, inflammation is induced approximately 12 hours following recontact of a sensitized animal with the drug. Known sensitizing substances include preservatives contained in topical application agents, nickel sulfate, potassium dichromate, neomycin, aroma chemicals, formaldehyde, rubber/latex medical supplies, and plants (e.g., rhus lacquer).
\nChemical burns are an injury caused by a chemical substance that is extremely corrosive or irritating (e.g., strong acid or strong alkali), often involving itching and/or ulceration due to local coagulative necrosis (Figure 5). No currently available pharmaceutical products cause this type of injury. Accidental exposure to skin or oral ingestion of these chemicals represents a pediatric emergency problem and these chemicals have a history of being common agents used for suicide [12, 13]. Cement burn is well known in the developed world. The majority of patients are either workers in the construction industry or do-it-yourself enthusiasts, commonly kneeling or standing in cement. The mechanism of injury is a combination of the effects of cement alkalinity and mechanical abrasion. Besides denaturing protein, alkalis saponify fat-producing liquefactive necrosis [14].
\nSodium hydroxide-induced burn in the back skin of a rat. Severe coagulative necrosis is observed in all cutaneous layers. Insert is a higher magnification image of the same photo.
Macroscopic photo from a phototoxic study of 8-methoxypsoralen in guinea pigs. After the hair on the back of the guinea pig was shaved, the drug was applied to the same area and irradiated with ultraviolet light, and the reaction was subsequently evaluated. (a) The site on the left was irradiated with ultraviolet light (UVA) after drug application, while the site on the right was not irradiation after drug application. Erythema is observed at the site with ultraviolet light irradiation. This reaction to 8-methoxypsoralen with ultraviolet light has been utilized in ultraviolet light therapy (PUVA) for psoriasis in humans. (b) Apoptotic epidermal cells (sunburn cells) are observed at the site with ultraviolet light irradiation.
Photosensitive dermatitis (photosensitivity) is a general term that refers to skin inflammation caused by the combined effect of a drug and light. It can be classified into two types, either with or without involvement of an immunological mechanism. Numerous systemic and topical drugs, aroma chemicals, plants, and cosmetics have been reported to induce this condition. Some examples of photosensitizing drugs are phenothiazine, tetracyclines, sulfonamides, chlorpromazine, nalidixic acid, and fluorocoumarins (psoralens).
\nPhototoxic dermatitis is skin damage caused by a drug that is sensitive to light (ultraviolet light), not by the drug alone, but after absorption of photon energy, without involvement of an immune mechanism. Free radicals and peroxidative injuries have been reported to be involved in this reaction. In preclinical studies of topical application agents, phototoxicity testing is conducted using guinea pigs for evaluation of drug phototoxicity (Figure 6).
\nPhotoallergic contact dermatitis is a condition caused by a delayed (type IV) allergic reaction. A drug sensitive to light (ultraviolet light) absorbs photon energy and is transformed into a substance (i.e., hapten) that combines with a protein in the body to act as a complete antigen. Characteristically, inflammation is induced approximately 12 hours following recontact of a sensitized animal with the drug.
\nContact urticaria is acute redness or rash that occurs within several minutes to one hour following exposure to a drug. It can be caused by a direct effect of the drug on vascular walls, by an indirect effect on vascular walls via histamine release from mast cells (without involvement of an immune mechanism), or by an IgE-mediated immediate (type I) allergic reaction with involvement of an immune mechanism. For immune contact urticaria, known conditions include systemic reactions to penicillin or food, as well as urticaria due to natural rubber products (latex allergy), but it is generally difficult to reproduce such conditions in preclinical studies using experimental animals.
\nChemical-induced acne is a disease of hair follicles caused by a chemical substance and is characterized by keratin plugs in hair follicles due to excessive proliferation of keratinocytes in hair follicles (comedo), sebum retention and inflammation [11]. Known examples of chemical-induced acne include occupational skin disorders of oil acne, caused by frequent exposure of the skin to cutting oils, as well as chloracne, induced by dioxins such as TCDD and PCB [15]. Clinically, the lesions are located around the eyes, ears, back, and genitalia; and other symptoms include hyperpigmentation, conjunctivitis, and ocular discharge. A notorious event occurred when Ukraine President Viktor Yushchenko was stricken with facial chloracne resulting from deliberate poisoning with TCDD during his presidential campaign [16].
\nPigmentary disturbance is only observed in animals with scarce hair or animals that have been shaved, thus is difficult to detect in preclinical studies. Altered pigmentation is a condition that sometimes follows skin inflammation and is characterized histopathologically by an increase or decrease in the number of melanocytes as well as melanin production. Hyperpigmentation can occur in association with increased melanin production due to drug-induced activation of melanocytes, hemosiderin deposition due to hemorrhage, or deposition of a heavy metal or drug itself (Figures 7 and 8). Melanin production is increased by busulfan, cyclophosphamide, long-term high-dose ACTH, and inorganic arsenic. In addition, chlorpromazine or minocycline can form a complex with melanin or hemosiderin with deposition in the skin, leading to blue-gray discoloration of the skin. In contrast, hypopigmentation results from loss of melanin due to damage to melanocytes. Depigmenting agents such as phenols, catechols, and hydroquinone have a similar structure to tyrosine, thus can inhibit melanin synthesis and induce hypopigmentation (Figure 8). Recently, an unexpected outbreak of patients with leukoderma occurred in Japan with use of brightening/lightening cosmetics containing rhododendrol, which is a competitive tyrosinase inhibitor, thereby inhibiting melanin synthesis [17]. This type of leukoderma is induced by not only apoptosis of melanocytes but also subsequent immune reactions with CD8-positive T cell infiltration toward melanocytes [18, 19].
\nHyperpigmentation due to melanin deposition in dermis at a drug injection site in the monkey. (a) Crust and epidermal hyperplasia are observed in the epidermis, and black pigment is observed in the dermis. (b) High power field of (a). Note that the black pigment is scattered throughout the dermis.
Macroscopic photo from a dermal application study of two drugs in mini-pigs (dark Yucatan pigs). The normal skin of Yucatan pigs appears black, because the skin contains a large amount of melanin pigment. With one drug applied to the left regions of the image, darkening of the skin is shown compared to the normal portion of skin, indicating excessive pigmentation due to drug application. With another drug applied to the right side of the image, lightening of the skin is shown with decreased pigmentation.
Drug rash (cutaneous reaction) is the most common adverse drug reaction reported to occur with antibiotics. The most serious forms of drug rash are toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, which are known to occur with the use of various drugs, including penicillin derivative or cephem derivative antibiotics, antipyretic analgesics (particularly NSAIDs), allopurinol, amine antiepileptic drugs (phenytoin and carbamazepine), and sulfa drugs. The Ministry of Health, Labour and Welfare of Japan announced that of 110,023 cases of adverse drug reactions reported from 2005 to 2009, approximately 2.2% of the cases (2370) were toxic epidermal necrolysis or Steven-Johnson syndrome [20]. Although the mechanism of onset remains unknown in many instances, a type III allergic reaction is often speculated.
\nMany new antitumor drugs with specific molecular targets have been approved in recent years (the so-called “targeted therapies”), and their adverse effects are highly specific with respect to the skin. Cutaneous reactions to these therapies are among the most frequently observed and, when severe or protracted, can result in significant morbidity, requiring dose modification or drug discontinuation [21, 22]. Hyperplastic changes of the epidermis can be attributed to numerous causes, including response to stimulation from growth factors, such as epidermal growth factor (EGF). The repeated administration of EGF to cynomolgus monkeys results in cutaneous desquamation and epidermal hyperplasia [23]. Epidermal growth factor receptor (EGFR), multikinase, c-Kit, BRAF, or MEK inhibitors induce papulopustular rash, maculopapular rash, and hand-foot syndrome in humans [24, 25]. EGFR inhibitor-induced lesions are associated with the inhibition of EGFR in undifferentiated, proliferating keratinocytes in the basal and suprabasal layers of the epidermis [26]. Other inhibitor-related rashes appear to be associated with the inhibition of vascular endothelial growth factor (VEGF) receptors in the skin [24].
\nMany drugs induce hair disorders, such as hair loss, stimulated hair growth, or, more rarely, changes in the hair shape and color [27]. Hair loss (hypotrichosis or alopecia) is a common problem that affects approximately 60 million men, women, and children in the United States, with a total cost for medical consultation and treatment of US$1.3 billion per year [28]. The onset of alopecia (toxic alopecia) often depends on the hair cycle at the time of drug administration. Drugs with an androgenic effect can cause alopecia by acting on the resting phase of the hair cycle to shorten the cycle. In addition, drugs with an antimitotic effect (e.g., anticancer drugs) or irradiation can cause alopecia by inducing apoptosis of hair follicles during the anagen phase of the hair follicle, thereby causing atrophy of hair follicles and prolongation of the resting phase of the hair cycle (chemotherapy or radiation-induced follicular dystrophy) [29, 30] (Figure 9). Hypertrichosis refers to drug-induced promotion of hair growth or induction of the anagen phase [31] Figure 10, and has been reported in organ transplant recipients and animal models treated with cyclosporine [32], as well as an antihypertensive (minoxidil) and a drug for treating benign prostatic hyperplasia (finasteride) [33]. Minoxidil and finasteride have been approved for clinical use as drugs to stimulate hair growth [34]. Hypertrichosis is observed as an increase in the length, thickness, and number of eyelashes in glaucoma patients treated with prostaglandin F2α agonists [35]. Bimatoprost has been used as a therapy for eyelash insufficiency or as eyelash restorer. As in the cases of the pigmentary disturbances described above, these changes can only be observed in animals with scarce hair or animals with shaved hair and are thus difficult to detect in typical preclinical studies.
\nImmunosuppressant drug-induced hypertrichosis in a mouse follicular dystrophy model. (a) Compared to
Nail changes that reflect a previous general condition are a barometer of health that can be used to predict the presence or absence of an abnormality several weeks before its presentation [6]. Transverse ridges (Beau’s line), washboard nail plates, and onycholysis are known to occur with use of metoprolol, retinoids, anticancer drugs, or irradiation [5]. Adverse effects of targeted molecular therapies, such as EGFR inhibitors, are also highly specific with respect to nails in human patients [22, 36]. In addition, yellow nail discoloration is known to occur with penicillamine, and black nail discoloration with Futraful (tegafur), anticancer drugs, or gold drugs. Administration of nucleoside analogs to dogs results in nail loss and footpad erosions with associated radiomimetic defects in the stratum germinativum [4]. In general, onycholysis can be induced by anticancer drugs or irradiation in experimental animals, while other changes are difficult to detect in preclinical studies.
\nA 2-year dermal application study of a drug in CD1 mice. (a) Macroscopically, multiple reddish skin tumors are observed on the back. (b) Histological findings are consistent with squamous cell papilloma.
Some photoirritants, such as 8-methoxypsoralen, have been associated with UV-induced skin carcinogenesis. Treatment of psoriasis by photochemotherapy (PUVA) with oral methoxsalen, a psoralen, in conjunction with UVA radiation, is associated with an increased risk of irregular pigmented skin lesions, squamous cell carcinoma, and malignant melanoma [37, 38]. Chemically induced skin tumors have been associated with numerous topically applied and systemically administered compounds in rodents; however, there appear to be few clinically used drugs that are suspected of being involved in skin carcinogenesis in humans. Rodent models of skin carcinogenesis are widely used for studies of carcinogenic mechanisms and the evaluation of carcinogenesis associated with chemical substances. Huff et al. performed a retrospective investigation of carcinogenicity tests on 379 chemical compounds conducted by the US National Toxicology Program (NTP) and reported that increased skin carcinogenesis was observed with 19 chemical compounds [39] (Table 3). Currently used methods used to determine skin carcinogenesis of drugs/chemical substances or methods to clarify carcinogenic mechanisms include: 2-year dermal application carcinogenicity studies (Figure 11); DMBA/TPA two-stage skin carcinogenesis models using 12-O-tetradecanoylphorbol-13-acetate (TPA) and 7,12-dimethylbenzanthracene (DMBA) (DMBA as an initiator, TPA as a promoter) [40]; studies in Tg.AC transgenic mice with expression of the v-Ha-ras gene in the epidermis [41]; and studies in SENCAR (SENsitivity to CARcinogen) mice [42]. Two-stage skin carcinogenesis models using metallothionein-I/II knockout mice have shown significant increases in skin carcinogenesis, thereby indicating an important role of metallothionein as an inhibitory factor of carcinogenesis in skin [43]. p53 is a protein that causes cell cycle arrest, apoptosis, or senescence that is crucial in the process of tumor suppression in several cell types [44]. In the DMBA/TPA two-stage skin carcinogenesis model, the absence of p53 in stratified epithelia leads to the appearance of a higher number of tumors that grow faster and become malignant more frequently than tumors arising in mice with the wild type p53 genotype [45]. The carcinogenic risk of a chemical after topical application is traditionally investigated in rats; however, in recent years, Tg.AC mice have become a popular alternative. The skin of Tg.AC mice is genetically initiated, thus the induction of epidermal papilloma in response to dermal or oral exposure to a chemical agent acts as a reporter phenotype for the carcinogenicity of the test chemical [11, 46]. The SENCAR mouse is an outbred strain (not genetically engineered) that was selected specifically for increased skin tumor multiplicity and decreased tumor latency in response to known dermal carcinogens [41]. A recent report described a possible animal model for human keratoacanthoma involving a single intraperitoneal injection of 50 or 75 mg/kg
Animal model for human keratoacanthoma following a single intraperitoneal injection of
This is a common clinical adverse reaction to NSAIDs or steroids and involves proliferation of acne bacteria leading to worsening of inflammation (steroid acne). In preclinical studies, spontaneous interdigit inflammation may worsen in beagle dogs following NSAID administration, eventually leading to skin ulcers in all extremities in severe cases (Figure 13).
\nName of chemical compound | \nRoute | \nAny skin carcinogenesis (2-year carcinogenesis study) | \nMutagenicity (Ames) | \nTR No. | \n|||
---|---|---|---|---|---|---|---|
F344 rats | \nB6C3F1 mice | \n||||||
Male | \nFemale | \nMale | \nFemale | \n||||
3-Amino-9-ethylcarbazole | \nDietary | \n+ | \n+ | \n+ | \n+ | \n+ | \n093 | \n
Benzene | \nOral | \nCE | \nCE | \nCE | \nCE | \n– | \n289 | \n
Chloroethane | \nInhalation | \n? | \n? | \n? | \nCE | \n+ | \n346 | \n
C.I. acid red 114 | \nDrinking water | \nCE | \nCE | \n\n | \n | + | \n405 | \n
C.I. basic red 9 monohydrochloride | \nDietary | \nCE | \nCE | \nCE | \nCE | \n+ | \n285 | \n
C.I. Direct Blue 15 | \nDrinking water | \nCE | \nCE | \n\n | \n | – | \n397 | \n
2,4-Diaminoanisole sulfate | \nDietary | \n+ | \n+ | \n+ | \n+ | \n+ | \n084 | \n
3,3′-Dimethoxybenzidine dihydrochloride | \nDrinking water | \nCE | \nCE | \n\n | \n | + | \n372 | \n
3,3′-Dimethoxybenzidine-4,4′-diisocyanate | \nDietary | \n+ | \n+ | \n– | \n– | \n+ | \n128 | \n
3,3′-Dimethoxybenzidine dihydrochloride | \nDrinking water | \nCE | \nCE | \n\n | \n | + | \n390 | \n
2,4-Dinitrotoluene | \nDietary | \n+ | \n+ | \n– | \n– | \n+ | \n054 | \n
Fenthion | \nDietary | \n– | \n– | \n? | \n– | \n+/− | \n103 | \n
Glycidol | \nOral | \nCE | \nCE | \nCE | \nCE | \n+ | \n374 | \n
Nithiazide | \nDietary | \n– | \n+ | \n+ | \n? | \n+ | \n146 | \n
5-Nitro-O-anisidine | \nDietary | \n+ | \n+ | \n? | \n+ | \n+ | \n127 | \n
Nitrofurazone | \nDietary | \n? | \nCE | \n– | \nCE | \n+ | \n337 | \n
Rhodamine 6G | \nDietary | \n? | \n? | \n– | \n– | \n– | \n364 | \n
Tris(aziridinyl)-phosphine sulfide | \nSubcutaneous | \n+ | \n+ | \n+ | \n+ | \n+ | \n058 | \n
4-Vinyl-1-cyclohexene diepoxide | \nDermal application | \nCE | \nCE | \nCE | \nCE | \n+ | \n362 | \n
Chemical compounds reported to produce skin carcinogenesis from systemic exposure (US NTP study).
+: Positive, CE: apparent increase in incidence, ?: increased incidence but not significantly, −: negative, +/−: positive or negative, TR No.: National Toxicology Program (NTP) study number.
This table has been modified from [39].
Nonsteroidal anti-inflammatory analgesic drug (NSAID)-induced skin lesion in a subacute toxicity study using beagle dogs. (a) Macroscopic observation of an interdigit lesion in the foot pad. Severe swelling and ulceration due to inflammation with local bacterial infection are observed. (b) In severe cases, the local lesions progress to skin ulcers on all extremities (subcutaneous phlegmon).
Skin atrophy can be observed with long-term, repeated use of corticosteroids due to inhibitory effects on cell proliferation and/or fiber production, leading to decreases throughout the epidermis, skin appendages (hair follicles, sweat glands, and sebaceous glands) and subcutaneous adipose tissue [50] (Figure 14). Skin atrophy is also commonly observed with systemic exposure to anticancer drugs in preclinical studies.
\nCorticosteroid-induced cutaneous atrophy in the rat. (a) In normal rat skin, the skin is thick with large hair shafts, sebaceous glands, and subcutaneous adipose tissue. (b) In the drug-exposed skin, the skin is thin with a severe decrease in all cutaneous layers, skin appendages (hair follicles and sebaceous glands), and subcutaneous adipose tissue.
A lesion similar to cutaneous gangrene seen in diabetic patients can be induced in monkeys with certain drugs, and is speculated as a consequence of peripheral circulatory insufficiency due to the involvement of a vascular disorder [5].
\nHypodermic injections of certain drugs induce granulomatous inflammation located at the injection site, which is highly painful for the patients (Figure 15). Granulomas induced by luteinizing hormone-releasing hormone analogues have been reported in some patients for the treatment of prostatic cancers [51]. Histopathologically, epithelioid granulomatous inflammation with small vacuoles derived from the constituent ingredients of drug microcapsules has been observed [52]. In some patient cases, vaccinations induce granulomatous reactions at the injection site due to specific inflammation and irritation [53]. Recently, treatment with interferon has been associated with cutaneous granulomatous reactions and sarcoid reactions [54].
\nDrug-induced granuloma in subcutaneous tissue of the rat. (a) Granuloma is observed in the subcutaneous tissue. (b) Many foreign body giant cells that phagocytose lipoid materials are observed. Lipoid materials are derived from the contents of the drug. (c) Dystrophic calcification is observed in the obsolete lesions.
This review has outlined the types and characteristics of drug-induced cutaneous toxicity, as well as providing descriptions of the methods of cutaneous toxicity testing required for safety evaluation. It should be emphasized that cutaneous toxicity of drugs or chemical substances may appear in various forms. In recent years, advances have been made in the development of pharmaceutical products targeting specific molecules, genes, or nanotechnology-based pharmaceutical products. Due to the potential onset of cutaneous toxicity involving novel mechanisms with new pharmaceutical products, it will continue to be important to understand the basic toxic changes described here.
\nAll authors have read and approved the final manuscript. The authors declare no competing financial interests. This project was supported by a grant from MEXT-Supported Programs for the Strategic Research Foundations at Private Universities (Kansai Medical University).
\nCatalases are one of the most studied groups of enzymes. The term catalase was first identified by Loew as hydrogen peroxide (H2O2) degrading enzyme in 1901, and the protein has been the focus of study for biochemists and molecular biologists ever since. The overall reaction for catalase can simply be described as the degradation of two molecules of hydrogen peroxide to water and oxygen (reaction 1). This catalytic reaction occurs in two distinct stages, but what each of the stages includes is mainly based on the kind of catalase [1]. The first stage involves oxidation of the heme using first hydrogen peroxide molecule to form an oxyferryl species in which one oxidation equivalent is taken off from the iron and one from the porphyrin ring to make a porphyrin cation radical (reaction 2). In the second stage, this radical intermediate, known as compound I, is reduced by a second hydrogen peroxide to regenerate the resting state enzyme, water and oxygen (reaction 3) [2, 3]. Catalases can also function as peroxidases, in which suitable organic compound is used as an electron donor. During peroxidase reaction, compound I is converted to compound II (reaction 4), which can be oxidized by another hydrogen peroxide to produce the inactive compound III (reaction 5). For NADPH-binding catalases, it has been suggested that enzyme inhibition through the appearance of compound III can be prevented by the NADPH blocking or releasing compound II generation [4, 5, 6].
Catalases have been classified into three groups: monofunctional heme-containing catalases, heme-containing catalase-peroxidases, and manganese-containing catalases [7]. Among them, monofunctional catalases constitute the largest and most extensively studied group of catalases [1, 2]. They all possess two-step mechanism for dismutation of hydrogen peroxide. Members of this largest class of catalases can be biochemically subdivided based on having large (75–84 kDa) subunits with heme
Although monofunctional catalases are described as such due to the prolonged-agreed belief that their only role is hydrogen peroxide removal, this rather limited catalytic role has recently been questioned. Vetrano et al. expressed a novel oxidase activity in the absence of hydrogen peroxide [14]. Later, a catalase from
The study of the bacterial response to oxidative stress has given insights into how catalase synthesis is controlled in different cells. Studies with
The regulatory mechanism of the katE gene, encoding HPII, is quite different and requires a functional katF gene as a positive effector [22]. HPII levels are expressed at high levels when cells enter stationary phase and are unaffected by hydrogen peroxide and/or anaerobiosis [9, 22]. The most important factor for HPII induction seems to be σS, as concluded from studies related with the involvement of additional transcription factors [22, 23].
The prosthetic group of horse liver catalase enzyme was first isolated by Stern in 1935 [24]. This non-covalently bound component was identified as protoheme (also called hematin), consisting of an iron atom and a porphyrin ring.
The heme prosthetic group has been found to be buried inside the protein, approximately 20 Å from the surface in almost all hem-containing catalases whose structures have been dissolved [25, 26, 27, 28]. Despite the similarities in heme-binding pocket, catalases from different sources contain different prosthetic groups [29]. All small subunit size catalases have been shown to include a non-covalently bound iron protoporphyrin IX (heme
Structures of heme
The γ-spirolactone ring and additional hydroxyl group make heme
The residues in a contact with heme in the active center are shown to be different for protoheme and heme d enzymes. Such residues for BLC include Met60, Ser216, Leu298, and Met349, whereas analogous residues for PVC involve Ile41, Val209, Pro291, and Leu342 and for HPII contain Ile114, Ile279, Pro356, and Leu407 [29, 35].
Small subunit size catalases have the ability to bind NADP(H) cofactor which is not essential for the activity of catalase [36], but it is believed to have a role in protecting the enzyme from the formation of catalytically inactive intermediate (cpd II) by promoting its reduction to resting state (Fe3+) during catalytic cycle [37, 38]. According to this hypothesis, large subunit enzymes, whose catalytic cycle lacks compound II formation, do not require to bind NADP(H) [38]. It has also been found that NADP(H) is essential for the dismutation of small peroxides, other than hydrogen peroxide [37]. Instead, large subunit size catalases possess the extra C-terminal domain with a flavodoxin-like topology [29, 30]. Despite this difference, residues defining the NADPH pocket in the bovine liver catalase appear to be well preserved in HPII. Only two residues that interact ionically with NADP(H) in the bovine catalase (Asp212 and His304) differ in HPII (Glu270 and Glu362), but it has been proven that their mutation to the bovine sequence does not promote nucleotide binding [4].
As described previously, catalytic reaction occurs in two steps [1, 2, 3]. The first phase of catalytic cycle involves reaction of ferric enzyme and hydrogen peroxide molecule to generate compound I and water. In the second stage, compound I combines with a second molecule of hydrogen peroxide molecule to regenerate the ferric enzyme, molecular oxygen, and water [2].
Paulos and Kraut firstly proposed the formation of compound I using crystal structure of cytochrome c peroxidase in 1980 [39]. According to this mechanism, proton transfer takes places from hydrogen peroxide to distal imidazole group, and iron-oxygen bond is generated [40]. The studies of water release or rebinding to the coproduct formation site have shown that compound I intermediate might exist in two forms either in a wet form in which a water molecule is present at or near the site of coproduct water formation or dry form where the coproduct water formation site is dry. It is assumed that the presence of water may play a significant role in both substrate selectivity and the variety of redox pathways available in the donor oxidation phase of the catalytic cycles [40, 41].
Compound I intermediate is also perceived in the presence of organic peroxides as substrate, and the reaction rate of compound I production decreases with an increase in the molecular size of the leaving group such as H▬ > CH3▬ > HOCH2▬ > CH3CH2▬ > CH3C(〓O) ▬ > CH3(CH2)2▬ > CH3(CH2)3OOH▬ [42]. At low hydrogen peroxide concentrations and in the presence of suitable organic electron donors, compound I can be reduced by one-electron addition leading to the formation of compound II (a formal Fe4+ state) which can cause enzyme inactivation. In this reaction, the porphyrin accepts one electron, therefore losing its radical character [43, 44].
The proposed catalytic mechanism supports that catalase enzyme is never saturated with its substrate, H2O2, and that turnover of enzyme increases indefinitely as substrate concentration increases [2]. Apparently, catalases have been recognized with a rapid turnover rate and the maximum observed velocities ranging between 54,000 and 833,000 reactions per second [3].
The classical kinetic parameters, Vmax, kcat, and Km, cannot be directly applied to the observed data as catalases do not follow Michaelis-Menten kinetics except at very low substrate concentrations. However, at concentrations below 200 mM, all small subunit size catalases show Michaelis-Menten-like dependence of velocity. At concentrations above 300–500 mM, most small subunit size catalases suffer inactivation. Conversely, large subunit size catalases begin to suffer inhibition above 3 M hydrogen peroxide concentrations [1, 3].
All catalases, whose structure have been dissolved, exhibit highly conserved β-barrel core structure [45]. Their structure is composed of four domains (Figure 2) [26, 30, 46, 47]:
An amino-terminal arm
An anti-parallel eight-stranded β-barrel domain
Wrapping domain
α-helical domain
Schematic drawing of the polypeptide chain and elements of secondary structure in a
The amino-terminal domain is an extended arm and is quite variable in length ranging from 53 residues in
The second domain, referred to as β-barrel domain, is the central feature of catalase. Most of the residues involved in forming the cavity on the distal side of the heme are placed in the first half of the β-barrel. On the other hand, the second half corresponds to the NADP(H)-binding pocket in small subunit catalases. This domain also involves at least six helices situated in two long insertions between β-strands along the polypeptide chain [30, 47].
The wrapping loop is an extended region of almost 110 residues that link the β-barrel and α-helical parts. This region, residues from 366 to 420, does not have any secondary structure except the essential helix (α9) stating the proximal side of heme with tyrosine residue. This part of the polypeptide chain is involved in different interdomain and intersubunit interactions especially with residues from the amino-terminal arm region from another subunit [30, 47].
The α-helical region contains four anti-parallel helices that are close to some of the helices from the β-barrel domain [30, 47].
Unlike BLC, the structures of PVC and HPII present an extra carboxy-terminal domain including roughly 150 residues with a high content of secondary structure elements organized with a “flavodoxin-like” topology [30, 46, 47]. The possible role of this extra domain in PVC remains unknown [30]. In BLC, prior to the flavodoxin-like domain is occupied by an NADP(H) molecule [48].
Although PVC and HPII share common structural similarities, HPII differs in the existence of 60 residues at N-terminal end that increase the contact area between subunits [25].
In all catalases, the heme group is deeply buried in the core structure, and its distance from the nearest part of the molecular surface is about 20 Å [9, 30]. Three residues, tyrosine on the proximal side of the heme (Tyr415 in HPII) and histidine and asparagine on the distal side (His128 and Asn201 in HPII), are believed to be essential for catalysis [30]. The oxygen of phenolic hydroxyl group in tyrosine residue is the proximal ligand of heme iron and is probably deprotonated with negative charge, so that it can lead to the stabilization of iron’s high oxidation states. The imidazole ring of distal histidine is placed almost parallel to the heme at a mean distance of about 3.5 Å above either pyrrole ring III in PMC or pyrrole ring IV in PVC and HPII [9]. The histidine and asparagine residues on the distal side of the heme make the environment strongly hydrophobic [30]. A conserved serine residue (Ser167 in HPII) is also found to be hydrogen bonded to the Nδ of the essential histidine and might facilitate the enzymatic mechanism [46].
Despite possessing the same type of heme in active site, PVC and HPII differ in the presence of covalent bond between tyrosine and histidine residues. HPII contains a novel type of covalent bond joining the Cβ of the essential Tyr415 and the Nδ of His392 but not in PVC [33, 44, 46, 49].
The limited accessibility to heme grouping catalases requires the presence of channels [30]. The heme of the enzyme is connected to the exterior surface by three channels, namely, the main channel, the lateral channel, and the central channel. Among them, the main channel is placed perpendicular to the surface of the heme. The lateral channel approaches horizontal to the heme and the central one heading from the distal side [34, 45].
The main channel is considered to be the primary route for substrate movement to the active site [1, 3]. It is funnel-shaped with 30 Å long in small catalases [30, 48], while in large catalases that channel is replaced by an elongated, constricted, and possibly bifurcated channel that includes the C-terminal domain of adjacent subunit [3, 30].
The conserved residues in the main channel are shown in Figure 3 including the essential histidine, a valine, and an aspartate (His82, Val123, and Asp135 in CATPO) situated 4, 8, and 12 Å from the heme, respectively [17]. The histidine residue is essential for catalysis in HPII, and the side chain of valine residue makes the channel narrower to a diameter of about 3 Å that prevents any molecule larger than H2O and H2O2 from gaining access to the active site. The role of aspartate has not been investigated in any catalase, but the presence of negatively charged side chain has been found to be critical for catalysis [45].
Channels in CATPO of
The lateral or minor channel approaches heme above and below the essential asparagine and emerges in the molecular surface at location corresponding to the NADP(H)-binding pocket in catalases that bind a cofactor (Figure 4) [30, 50]. The function of this channel remains unknown [34]. Molecular dynamics analysis indicates that water can exit the protein through this channel [4].
View of chain A of CATPO complex with 3TR (PDB 5ZZ1, gray) superposed onto human catalase (PDB 1DGH7, blue). CATPO loop 533–537 lies across the top of the NADPH-binding pocket, clashing with the position of the NADPH in the human enzyme [
The main channel is a preferred route for substrate entry, but it might be too long and narrow for the release of reaction products (water and molecular oxygen). As the central channel is mainly hydrophilic and leads to the central cavity that is contiguous to the bulk water, this could be a way out for O2. However, substitutions of amino acid residues extending the major channel in large catalases might allow the exit of oxygen through the main channel. In fact, oxygen preferentially exits through the main channel instead of central one in all catalases having b-type heme in the active site. Thus, the presence of minor channels might be an alternative mechanism for a fast release of products under the condition of high H2O2 stress. These results indicate that O2 can exit the enzyme through different channels although the main exit in large catalases might be through the central channel and in small catalases through the major channel [34, 51].
Many reports on catalase and phenol oxidase enzymes suggest that the activities may flap in some way that catalases exhibit additional oxidase activity and phenol oxidases present further catalase activity. This relationship can be explained by the release of H2O2 due to polyphenol oxidation [52]. Hydrogen peroxide generation by phenol oxidation was also reported by Aoshima and Ayebe [53]. They observed high concentrations of H2O2 in beverages like tea or coffee directly after opening caps as a result of oxygen.
Jolley et al. first developed mushroom tyrosinase with catalase activity in the presence of hydrogen peroxide [54]. Garcia-Molina et al. [55] and Yamazaki et al. [56] also studied this bifunctional behavior of tyrosinase. In addition to this novel tyrosinase, a catalase-like process was found to have one isozyme of catechol oxidase from sweet potatoes (
In literature, the first report on catalase known as a monofunctional enzyme but possessing secondary activity (oxidase) was introduced for mammalian catalase. This enzyme has been reported to present oxidase activity when hydrogen peroxide is absent or levels of H2O2 are low. As mentioned previously, the main function of catalase is the decomposition of hydrogen peroxide into water and oxygen (catalytic activity). Moreover, it is known that catalases can oxidize low molecular weight alcohols in the presence of low concentrations of H2O2 (peroxidatic activity). The catalytic mechanism of catalases is a two-step process in which catalase heme Fe3+ reduces one hydrogen peroxide molecule to water and generates a porphyrin cation radical called compound I, which is then oxidized by a second hydrogen peroxide to give molecular oxygen and water. The peroxidase activity stems from the oxidation of alcohols by compound I through single-electron transfer. Vetrano et al. expressed a novel oxidase activity in the absence of hydrogen peroxide. This oxidase reaction involves the interaction of catalase heme with a strong reducing agent like benzidine (HB) and molecular oxygen leading to the formation of a compound II-like intermediate. The subsequent electron transfer causes substrate oxidation and regeneration of resting enzyme. An incomplete reaction may result in the formation of radical centered intermediates and the production of superoxide [14].
Later, catalase from the thermophilic fungus
There are a great number of reports available describing the structural and biochemical characterization of catalases. However, basic questions related to substrate and product flow remain unanswered, particularly related to the oxidase activity. Therefore researchers have recently focused on the investigation of the region of CATPO that corresponds to the NADPH-binding region of bovine liver catalase (BLC) and the lateral channel. A number of mutations were introduced into this region, and the properties of these mutant variants, including their specific activities and sensitivities to various inhibitors, are interpreted in terms of a role for the lateral channel in CATPO. The structural, mutation, and kinetic evidences suggested that this pocket at the entrance to the lateral channel, captured by NADPH’s nicotinamide moiety in mammalian catalases, should be the site of both oxidase substrate and 3TR binding. The promiscuous nature of CATPO oxidase is clarified by the presence of numerous ordered water molecules which facilitate substrate binding through hydrogen bond formation and can be transferred to accommodate various size and shaped substrates. Peroxide-independent phenolic substrate oxidation is then likely to happen in a similar manner to NADPH oxidation, by electron transfer from the substrate to a high-valent iron-oxo intermediate, apparently arisen through reaction with oxygen [50].
Catalases have been studied for over 100 years, with examples of the enzyme isolated, purified, and characterized from many different organisms. The crystal structures of 16 monofunctional catalases have been solved at high resolution. These structures show that they are tetramers, and each of the four active sites consists of a pentacoordinated-iron protoporphyrin IX prosthetic group with a tyrosinate axial ligand. Some also contain a NADPH cofactor tightly bound at the periphery of each subunit. Recently, it has been found that these enzymes exhibit an oxidase activity in addition to their H2O2 degrading activity. Although they are old enzymes, a peroxide-independent oxidase activity of catalases is new in the literature. Such studies have led to the proposal that this secondary oxidative activity may be a general characteristic of catalases.
The author is grateful to the Department of Biotechnology, Middle East Technical University, Turkey, for providing the necessary facilities during PhD program and many thanks to the Department of Biology, Kocaeli University and TUBİTAK (grant No. 113Z744) for financial support. The author is also grateful to the EU COST Action CM1306 “Movement and Mechanism in Molecular Machines” for STSM support.
The authors declare no conflict of interest.
bovine liver catalase catalase-phenol oxidase compound 3-amino-1,2,4-triazole hydrogen peroxide benzidine hydroperoxidase I hydroperoxidase II L-3,4-dihydroxy-phenylalanine nicotinamide adenine dinucleotide phosphate porphyrin
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\\n\\nAll Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\\n\\nAny use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\\n\\nUnless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\\n\\nWe employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\\n\\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\\n\\nIntechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\\n\\nIntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\\n\\nWe reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\\n\\nIf you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\\n\\nWithout prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\\n\\nIntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\\n\\nThese Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\\n\\nCroatian version of Terms and Conditions available here
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\n\nThe following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\n\n“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\n\n“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\n\n“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\n\nAll Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\n\nAny use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\n\nUnless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\n\nWe employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\n\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\n\nIntechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\n\nIntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\n\nWe reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\n\nIf you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\n\nWithout prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\n\nIntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\n\nThese Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\n\nCroatian version of Terms and Conditions available here
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Morrow, Makoto Kunieda, Yunfeng Liang and Toshifumi Matsuoka",authors:[{id:"112525",title:"Dr.",name:"Norman",middleName:null,surname:"Morrow",slug:"norman-morrow",fullName:"Norman Morrow"},{id:"112695",title:"Dr.",name:"Koichi",middleName:null,surname:"Takamura",slug:"koichi-takamura",fullName:"Koichi Takamura"},{id:"112889",title:"Dr.",name:"Nina",middleName:null,surname:"Loahardjo",slug:"nina-loahardjo",fullName:"Nina Loahardjo"},{id:"112890",title:"Dr.",name:"Winoto",middleName:null,surname:"Winoto",slug:"winoto-winoto",fullName:"Winoto Winoto"},{id:"112891",title:"Dr.",name:"Jill",middleName:null,surname:"Buckley",slug:"jill-buckley",fullName:"Jill Buckley"},{id:"114293",title:"Mr.",name:"Makoto",middleName:null,surname:"Kunieda",slug:"makoto-kunieda",fullName:"Makoto Kunieda"},{id:"114294",title:"Dr.",name:"Yunfeng",middleName:null,surname:"Liang",slug:"yunfeng-liang",fullName:"Yunfeng Liang"},{id:"114296",title:"Dr.",name:"Toshifumi",middleName:null,surname:"Matsuoka",slug:"toshifumi-matsuoka",fullName:"Toshifumi Matsuoka"}]}],mostDownloadedChaptersLast30Days:[{id:"66537",title:"Gases Reservoirs Fluid Phase Behavior",slug:"gases-reservoirs-fluid-phase-behavior",totalDownloads:1275,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter discusses the fundamentals of the phase behavior of hydrocarbon fluids. Real reservoir fluids contain many more than two, three, or four components; therefore, phase-composition data can no longer be represented with two, three or four coordinates. Instead, phase diagrams that give more limited information are used. The behavior of reservoir of a reservoir fluid during producing is determined by the shape of its phase diagram and the position of its critical point. Many of producing characteristic of each type of fluid will be discussed. Ensuing chapters will address the physical properties of these three natural gas reservoir fluids, with emphasis on retrograde gas condensate gas, dry gas, and wet gas.",book:{id:"8229",slug:"oil-and-gas-wells",title:"Oil and Gas Wells",fullTitle:"Oil and Gas Wells"},signatures:"Eman Mohamed Mansour, Mohamed El Aily and Saad Eldin Mohamed Desouky",authors:[{id:"277274",title:"Dr.",name:"Eman M.",middleName:null,surname:"Mansour",slug:"eman-m.-mansour",fullName:"Eman M. 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Subsequently, the alteration in the shape or composition of the fine particles such as clay (water-wet solids), as a result of the stress on it, in the flow path of the second phase can lead to the permeability decline of reservoir. Consequently, the solvents such as surfactants (as demulsifiers) to lower the surface tension as a phenomenon associated with intermolecular forces (known as capillary action) during flowback are consumed to avoid the emulsions and sludge mostly in the near-wellbore zone or undertreatment and under-injection radius of the reservoir. However, in addition to surging or swabbing the wells to lower the surface tension, using solvents as the wettability changing agent along with base fluid is a common method in the water block elimination from the wellbore, especially in the low permeability porous media or the reservoirs latter its average pressure declined below bubble point. For more profitability, after using solvents in various reservoir characterizations, the trend of their behavior variations in the different lithologies is required to decide on the removed damage percentage. The investigations on this subject involve many experimental studies and have not been presented any mathematical formulas for the damage of water block in the water, oil, and gas reservoirs. These formulas determine selection criteria for the applied materials and increase variable performance. An integrated set of procedures and guidelines for one or more phases in a porous media is necessary to carry out the step-by-step approach at wellhead. Erroneous decisions and difficult situations can also be addressed in the injection wells or saltwater disposal wells, in which water block is a formation damage type. Misconceptions and difficult situations resulting from these injuries can increase water saturation in borehole and affect the fluid transmissibility power in reaching far and near distances of the wellbore, which results in injection rate loss at the wellhead. Accordingly, for the equations of water block here, a set of variables, of a particular domain, for defining relationships between rock- and fluid-based parameters are required. For these equations, at first, the structural classifications of fracture and grain in the layers (d1, d2, and d3) are defined. Afterward, the equations of overburden pressure (Pob) for a definite sectional area surrounding the wellbore for any lithology (in the three categories relative to porosity) are obtained by these structural classifications and other characteristics of rock and fluid. Naturally, prior to equations of overburden pressure in a definite layer or a definite sectional area around the wellbore, the overburden pressure of a point in a layer in the first four equations is expressed. In the second, the estimated overburden pressure equations are applied in driving the equations of removed water block (Bk). The equations of removed water block, themselves, are divided into two groups of equations, i.e., equations of oil wells and equations of saltwater disposal wells, and each group of equations is again classified based on the wettability of reservoir rock (oil-wet or water-wet) in the two ranges of porosity. In the third, after describing these equations (i.e., equations of Bk), the other new variable included in the equations of removed water block, that is, the acid expanding ability (Ik) for a definite oil layer around the wellbore, is presented, which is extracted from (1) the full characteristics of reservoir (including experimental and empirical equations of overburden pressure), (2) the history of producing well, (3) core flooding displacement experiments at laboratory, and (4) the acidic and alkaline solvent properties. Finally, the rate of forming water block (q) is calculated using the value calculated for the removed water block, and, additionally, the trend of using solvents is determined for different rocks using these sets of equations. The acceptance criteria are the nature of rock and fluid in the reservoir circumstances. Equations as a quick and cost-efficient method are also introduced, providing computational methods to determine how much and how the blocked fluid in the reservoir layers is removed from the definite strata around the wellbore after injection operation of acids and solvents, with various degrees of acidity, to the types of lithology during acidizing operations. Moreover, these equations can calculate the removed water block (Bk) after injecting solvents to the different acidic properties in the acidizing, for two categories of porosity which cover all lithologies. The equations also ascertain in the current reservoir conditions how much solvent for a type of lithology is to be mixed with other base fluids.",book:{id:"8229",slug:"oil-and-gas-wells",title:"Oil and Gas Wells",fullTitle:"Oil and Gas Wells"},signatures:"Mohammad Karimi, Mohammad Reza Adelzadeh, Mojtaba Mosleh Tehrani, Maryam Mohammadipour, Ruhangiz Mohammadian and Abbas Helalizade",authors:[{id:"298820",title:"Mr.",name:"M.",middleName:null,surname:"Karimi",slug:"m.-karimi",fullName:"M. 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",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"July 6th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA. Dr. Stavropoulos received her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. She is the Assistant Director of the SEARCH Center at UCR and is a Faculty member in the Graduate Program in Neuroscience.",institutionString:null,institution:{name:"University of California, Riverside",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"22",title:"Applied Intelligence",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",isOpenForSubmission:!0,annualVolume:11418,editor:{id:"27170",title:"Prof.",name:"Carlos",middleName:"M.",surname:"Travieso-Gonzalez",slug:"carlos-travieso-gonzalez",fullName:"Carlos Travieso-Gonzalez",profilePictureURL:"https://mts.intechopen.com/storage/users/27170/images/system/27170.jpeg",biography:"Carlos M. Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. 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His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. 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Badria",profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",institutionString:"Mansoura University",institution:{name:"Mansoura University",institutionURL:null,country:{name:"Egypt"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9659",title:"Fibroblasts",subtitle:"Advances in Inflammation, Autoimmunity and Cancer",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",slug:"fibroblasts-advances-in-inflammation-autoimmunity-and-cancer",publishedDate:"December 22nd 2021",editedByType:"Edited by",bookSignature:"Mojca Frank Bertoncelj and Katja Lakota",hash:"926fa6446f6befbd363fc74971a56de2",volumeInSeries:25,fullTitle:"Fibroblasts - Advances in Inflammation, Autoimmunity and Cancer",editors:[{id:"328755",title:"Ph.D.",name:"Mojca",middleName:null,surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj",profilePictureURL:"https://mts.intechopen.com/storage/users/328755/images/system/328755.jpg",institutionString:"BioMed X Institute",institution:{name:"University Hospital of Zurich",institutionURL:null,country:{name:"Switzerland"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8977",title:"Protein Kinases",subtitle:"Promising Targets for Anticancer Drug Research",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",slug:"protein-kinases-promising-targets-for-anticancer-drug-research",publishedDate:"December 8th 2021",editedByType:"Edited by",bookSignature:"Rajesh Kumar Singh",hash:"6d200cc031706a565b554fdb1c478901",volumeInSeries:24,fullTitle:"Protein Kinases - Promising Targets for Anticancer Drug Research",editors:[{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"8018",title:"Extracellular Matrix",subtitle:"Developments and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/8018.jpg",slug:"extracellular-matrix-developments-and-therapeutics",publishedDate:"October 27th 2021",editedByType:"Edited by",bookSignature:"Rama Sashank Madhurapantula, Joseph Orgel P.R.O. and Zvi Loewy",hash:"c85e82851e80b40282ff9be99ddf2046",volumeInSeries:23,fullTitle:"Extracellular Matrix - Developments and Therapeutics",editors:[{id:"212416",title:"Dr.",name:"Rama Sashank",middleName:null,surname:"Madhurapantula",slug:"rama-sashank-madhurapantula",fullName:"Rama Sashank Madhurapantula",profilePictureURL:"https://mts.intechopen.com/storage/users/212416/images/system/212416.jpg",institutionString:"Illinois Institute of Technology",institution:{name:"Illinois Institute of Technology",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{type:"book",id:"9759",title:"Vitamin E in Health and Disease",subtitle:"Interactions, Diseases and Health Aspects",coverURL:"https://cdn.intechopen.com/books/images_new/9759.jpg",slug:"vitamin-e-in-health-and-disease-interactions-diseases-and-health-aspects",publishedDate:"October 6th 2021",editedByType:"Edited by",bookSignature:"Pınar Erkekoglu and Júlia Scherer Santos",hash:"6c3ddcc13626110de289b57f2516ac8f",volumeInSeries:22,fullTitle:"Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoğlu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoğlu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.jpg",institutionString:"Hacettepe University",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Proteomics",value:18,count:4},{group:"subseries",caption:"Metabolism",value:17,count:6},{group:"subseries",caption:"Cell and Molecular Biology",value:14,count:9},{group:"subseries",caption:"Chemical Biology",value:15,count:13}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:8},{group:"publicationYear",caption:"2021",value:2021,count:7},{group:"publicationYear",caption:"2020",value:2020,count:12},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:2}],authors:{paginationCount:303,paginationItems:[{id:"313921",title:"Dr.",name:"Hassan M.",middleName:null,surname:"Heshmati",slug:"hassan-m.-heshmati",fullName:"Hassan M. Heshmati",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313921/images/system/313921.jpg",biography:"Dr. Hassan Massoud Heshmati is an endocrinologist with 46 years of experience in clinical research in academia (university-affiliated hospitals, Paris, France; Mayo Foundation, Rochester, MN, USA) and pharmaceutical companies (Sanofi, Malvern, PA, USA; Essentialis, Carlsbad, CA, USA; Gelesis, Boston, MA, USA). His research activity focuses on pituitary tumors, hyperthyroidism, thyroid cancers, osteoporosis, diabetes, and obesity. He has extensive knowledge in the development of anti-obesity products. Dr. Heshmati is the author of 299 abstracts, chapters, and articles related to endocrinology and metabolism. He is currently a consultant at Endocrinology Metabolism Consulting, LLC, Anthem, AZ, USA.",institutionString:"Endocrinology Metabolism Consulting, LLC",institution:null},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. in Chemistry in July 2000, and his Ph.D. in Physical Chemistry in 2007 from the University of Khartoum, Sudan. In 2009 he joined the Dr. Ron Clarke research group at the School of Chemistry, Faculty of Science, University of Sydney, Australia as a postdoctoral fellow where he worked on the Interaction of ATP with the phosphoenzyme of the Na+, K+-ATPase, and Dual mechanisms of allosteric acceleration of the Na+, K+-ATPase by ATP. He then worked as Assistant Professor at the Department of Chemistry, University of Khartoum, and in 2014 was promoted to Associate Professor ranking. In 2011 he joined the staff of the Chemistry Department at Taif University, Saudi Arabia, where he is currently active as an Assistant Professor. His research interests include:\r\n(1) P-type ATPase Enzyme Kinetics and Mechanisms; (2) Kinetics and Mechanism of Redox Reactions; (3) Autocatalytic reactions; (4) Computational enzyme kinetics; (5) Allosteric acceleration of P-type ATPases by ATP; (6) Exploring of allosteric sites of ATPases and interaction of ATP with ATPases located in the cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/198499/images/system/198499.jpeg",biography:"Dr. Daniel Glossman-Mitnik is currently a Titular Researcher at the Centro de Investigación en Materiales Avanzados (CIMAV), Chihuahua, Mexico, as well as a National Researcher of Level III at the Consejo Nacional de Ciencia y Tecnología, México. His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 270 peer-reviewed papers, 32 book chapters, and 4 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:null,institution:null},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"428313",title:"Dr.",name:"Sambangi",middleName:null,surname:"Pratyusha",slug:"sambangi-pratyusha",fullName:"Sambangi Pratyusha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"CGIAR",country:{name:"France"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}}]}},subseries:{item:{id:"15",type:"subseries",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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