Glimpse of phytochemical and pharmacological endorsement of both the species.
\r\n\t
",isbn:"978-1-80356-357-2",printIsbn:"978-1-80356-356-5",pdfIsbn:"978-1-80356-358-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"3aba1eb3600a8c9ff880c628f70b3298",bookSignature:"Ph.D. Delfín Ortega-Sánchez",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11481.jpg",keywords:"Integrated Curriculum, Transdisciplinarity, Integrated Active Learning, Educational Programs, Contemporary Social Problems, Critical Thinking, Creative Thinking, Social Thinking, Agenda 2030, Sustainable Development Goals, Educational Paradigm, Social Reality",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2022",dateEndSecondStepPublish:"March 18th 2022",dateEndThirdStepPublish:"May 17th 2022",dateEndFourthStepPublish:"August 5th 2022",dateEndFifthStepPublish:"October 4th 2022",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Internationally recognized researcher in the field of historical and social science education. Author of more than 100 publications, awarded three Doctorate degrees and the National End of Degree Award, granted by the Ministry of Education to the best academic records of Bachelor's degrees in Spain. Dr. Ortega-Sánchez has been Vice-Rector for Social Responsibility, Culture, and Sports at the University of Burgos since 2021.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"302925",title:"Ph.D.",name:"Delfín",middleName:null,surname:"Ortega-Sánchez",slug:"delfin-ortega-sanchez",fullName:"Delfín Ortega-Sánchez",profilePictureURL:"https://mts.intechopen.com/storage/users/302925/images/system/302925.jpg",biography:"I hold a PhD in Didactics of Social Sciences from the Autonomous University of Barcelona, a PhD in Educational Sciences from the University of Burgos, and a PhD in History from the University of Extremadura. My research interests focus on the construction of identities in the History and Geography teaching, gender mainstreaming in initial education and training for teachers, the didactic treatment of relevant social problems and controversial issues in the teaching of the social and human sciences, and the application of educational technology in the specific field of social sciences. I am currently a Social Sciences teacher and researcher at University of Burgos (Spain).",institutionString:"University of Burgos",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Burgos",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"429339",firstName:"Jelena",lastName:"Vrdoljak",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/429339/images/20012_n.jpg",email:"jelena.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"78065",title:"Meticulous Endorsement of Black Seed and Jambolana: A Scientific Review",doi:"10.5772/intechopen.99225",slug:"meticulous-endorsement-of-black-seed-and-jambolana-a-scientific-review",body:'Historical evidences indicates that, herbs and spices have beneficial consequences as medicine to treat different disease and its ailments, primarily they are having food valve, apart from this the composition comprised in different herbs and spices to get rid from major and minor disorder associated with the complex organic physiological system, demonstrating benefits as food by scientific mean is challenging, specially, when standards applied to assess the pharmaceutical agents. Pharmaceutical agents are special molecules which were isolated and purified in concentrated forms, whereas food is having in combination, literally in large quantity [1]. The real challenge not here to prove whether herbs and spices as food have healthy benefits but rather figuring out, one of the greatest saying by
NS belonging to the family
NS plant germinate, flower, set seed and die all in one. Ultimately reproduce themselves to set of seeds. Grow up to height of 20–30 cm (7.10–11.9 inches) with linear lanceolate leaves. The flowers are very much dedicated bearing 10 to 5 petals with remarkable white, yellow, pale blue. Pink, pale violet in colors. NS plants fruits are large & inflated capsules bearing with 3 to 7 united follicles having enormous number of seeds, whereas seeds containing black color with flattened, angular oblong with 0.2 cm long and 0.1 cm wide funnel shaped [5].
Domine: Plantae
Sub-domine: Tracheobionta
Division: Spermatophyta
Phylum: Magnoliophyta
Class Magnoliopsida
Order: Ranunculales
Family: Ranunculacese
Genus: Nigella
Species: Sativa
Wild onion seeds, Funnel flower, Black cumin, Nutmeg flower, Black caraway, black seeds, Devil in the bush, Roman coriander, Roman coriander, Damascene etc.
Chinese: Pei hei zhong cao
French: Cheveux de Vénus, Nigelle
Hindi: Kalonji.
Marathi: Kalonji Jire
Persian: Siah Dana
Punjabi: Kalvanji
Urdu: Kalonji
Moreover, the NS meticulously endorsed by above mentioned taxonomical and botanical descriptions. Indeed, much uncertainty about particular name of NS seed. NS seed is called black cumin, black caraway and black onion seed in particular regions of the continent, such as Central Asia and Northern India, with different botanical and taxonomical description, NS seed or any such seed, apparently, are often the part of the stock, that is commercially available and used as adulterants [6].
NS herb mostly grown during the winter season. It is annually grown on light and heavy soil. The scattering period of seeds in between October–November and get harvest in between April and May. The yield is about 350 kg/acre to 450 kg/acre.
The germination processes of the plant would be delay, if scattering of seeds on upper soil or deep inside but it should be optimal. It need not be irrigated frequently. When the fruit / capsule turns yellowish, the crop is harvested.
It can be threshed by trampling with a tractor or proper thresher after harvesting and proper drying. The seeds are stored properly in bags or containers after threshing [6].
As mentioned in above point-2, NS bearing ultimately important and valuable amount of phytoconstituent which were extracted, separated, identified and reported and updated up to the limit of extent but still needs to be explored, where in contemplation to retrieve the relevant documentary evidence leads to figure out the following valuable constituents, such TQ (48%) in 25 gm, thymo-hydroquinone, dithymoquinone, p-cymene (15%), carvacrol (12%), 4-terpineol (7%), tanethol (5%), sesquiterpene longifolene (1 to 8%), thymol & α-pinene etc. Seeds contain dual different types of alkaloids called iso-quinoline alkaloids (indazole ring bearing alkaloids are nigellicinine, nigellicimine-N-Oxide & pyrazole alkaloids). NS seeds are also contain α-hederin which is water soluble pentacyclic triterpene and saponin (potential anticancer agent). The potential pharmacological activity of NS seeds is mainly due to Quinine constituents, whereas thymoquinone is most abundant one. NS seeds also contains micro & macromolecules that are, carbohydrates-28%, protines 27%, fats-25%, crude fibers-9%, total ash-5%, Vitamins &, minerals like Cu, P, Zn and Fe++ etc.:
a- NS seeds b- NS flowers c- EJ leaves and fruits.
Some important steroidal monomers also reported from NS seed are nigellone, avenasterol-5-ene, avenasterol-7-ene, campesterol, cholesterol, sitrostadienol, obtusfoliol, lophenol, stigasterol, stigmasterol-7-ene, β-amirn, butyrospermol, cycloartenol, 24-methylene-cycloartenol, taraxerol, tirucallol, 3-O-[β-D-xylopyranosyl(1 → 3)-α-L-rhamnopyranosyl(1 → 2)-α-L-arabino-pyranosyl]-28-O-[α-L-rhamnopyranosy](1 → 4)-β-D-glucopyranosyl(1 → 6)-β-D-glucopyranosyl]-hedera- genin, up to 1.6%-Volatile oil, fatty oil-41.6%, olic acid, C15 esters of unsaturated fatty acid with higher terpenoids, esters of dehydrostericacid & linolic acid, aliphatic alcohols like melanthin, melanthigenin etc, moreover to endorsed it also contain bitter constituents with tannin, resin, protein, reducing sugars like saponine, 3-O-[β-D-xylopyranosyl, (1 → 2)-α-L-rhambopyranosyl, (1 → 2)-β-D-glucopyranosyl]-11-methoxy-16, 23-dihydroxy-28-methyl-olean-12-enoate, stigma-5, 22-diene-3-β-D-glucopyranoside, cycloart-23-methyl-7,20,22-triene-3β, 25-diol, negellidine-4-O-sulfite, N-amines A3, A4, A5, C & A1, A2, B1 & B2 were found in seeds of NS. Hence it was assumed that, because of presence of above-mentioned bioactive constituents, NS stands apart with special category of medicinal specie, with infinite number of medicinal properties to manage bronchitis, diarrhea, rheumatism, asthma, skin disorders, it also acts as liver tonic, anti-diarrheal, appetite stimulant, digestive disorders. It also beneficial to increase milk production in nursing mothers, it also utilized to fight with parasitic infections, immunity system will be strengthened by regular utilization of NS seeds. In addition to above NS seeds are also used in food as additives, especially flavoring agent in bread and pickles coz low level of toxicity value. The NS seeds and oil also preferred in treatment of worm infestation, skin eruption, antiseptic, eternal anesthetics & roosted seeds of NS given internally to stop vomiting (Figure 2) [8].
Reported bioactive components of NS.
Next to NS another herbs which is bearing identical pharmacological properties with extra ordinary source of natural remedies and therapeutic application to treat different disease and its aliment, mid-nineteenth century was the era, which came up, with its first scientific evidence, as antidiabetic properties, apart from this the medicinal values endorsed in the ayurvedic, Unani, siddha and other folklore system of medicine [9].
Kingdom: Plantae.
Subkingdom: Viridaeplantae.
Infrakingdom: Streptophyta.
Division: Tracheophyta.
Subdivision: Spermatophytina.
Infradivision: Angiospermae.
Class: Magnliopsida.
Superorder: Rosanae.
Order: Myrtales.
Family: Myrtaceae.
Genus: Syzygium.
Species: Cumini.
Scientific Name: Syzigium cumini (L) Skeel.
Hindi: Jamuna, Sanskrit: Mahajambu, Ksudrajambu, Assam: Jam, Bengali: Jaam, Kalajam, English: Jambul tree, Gujarat: Gambu Jamun,Tamil: Naval, Urdu: Jamun, Telegu: Neredu [11].
Brazil - Azeitona,Pakistan – Jaman, West Indies-Jambol, Nepal-Java plum, Thailand – Lukwa, Japan - Madan Madagascar – Rotra.
EJ was tropical & subtropical plant grows up to 2,000 meters in the region where annual day time temperature ranges from 20 to 32°C & it tolerate 12 to 48°C, mature growth of the plant will be affected at -2°C lower, whist youngest growth is affected at -1°C. The plant grows well at annual rainfall in the range 1500 to 6,000 mm but tolerates 800–9900 mm. EJ can withstand a dry season of up to 7 months, where it prefers a sunny position, the pH prefer to range 5.5 to 7. The plants are moderately shade-tolerant, especially when young [12]. The versatile plant will grow on wide range of soils, even in shallow rocky soils where provided rainfall is maximum to tolerate prolonged flooding, once established, it tolerates drought in dry sites, the plant confine itself to the vicinity of watercourses & it tolerates quite strong winds, it sow-self freely and become serious pests in pasture.
In Florida EJ plant is listed as undesirable fast-growing plant, seedlings may reach up to 4 meter in 2 Years. This tree coppices remarkably well, with vigorous shoots, in large number, with minor and major stumps alike, the coppice which were stands in streams, will grew up to 4.6 meter in 4 years, and the raw material of the plant can be collected in rainy seasons to get good amount of bioactive constituents [13].
EJ is found to be rich in tannins, alkaloids, carbohydrates, flavonoids, sterols, glycosides, and among other phytoconstituents in different parts of the tree. There are many families of phytochemicals and they help the human body in a variety of ways. Phytochemicals can protect (Figure 3) human from diseases. Phytochemicals are nonnutritive plant chemicals that have protective or disease preventive properties. The fruits produce and determine the physical–chemical and sensory characteristics of light jambolan jelly. This fruit has intense purple color, which gave the jellies - both standard and light - a quite attractive visual aspect. The phytochemical analysis of ethanol extract of Jamun stem bark, leaf, seed and fruit pulp showed the presence of alkaloids, anthraquinone glycosides, flavonoids, tannins, saponins, phenols, cardiac glycosides, terpenoids, phytosterols, steroids and amino acids in all extracts. Terpenoids and phytosterols were absent in the leaf extract. The seeds are rich in protein and calcium. The seeds contain both micro & macromolecules as in NS. EJ also contines fats and oil such as tannins-19%, ellagic acid-2%, glycoside, jamboline, starch, myricyl alcohol in un-saponified fraction in small quantity that is 0.05% of pale yellow oil with specific gravity 20:0.926, [α] D- 5.420. The essential oils isolated from the freshly collected leaf (accounting for 82% of the oil), stem, seed, fruits contain α-Pinene, camphene, β-Pinene, myrcene, limonene, cis-ocimeme, trans-ocimeme, sterculic and vernolic acid, literature reported that huge quantity of malic acid present in fruits, i.e. thrice the weight of the fruit (0.59% wt of fruit), whereas oxalic acid present in minor amount but Gallic acid and tannin accountable for astringent taste of the fruit. The purple color of fruit is due to Cyanidin diglycosides, fruits are reach source of suger-9%, non-reducing sugars-10%. The fruits also contain monomeric sugar units such as glucose, fructose, mannose, galactose & mineral constituents were also reported to be present (mg/100 g of edible pulp) are Ca, Mg, Fe, Na, K, and Cu,. The vitamins present (in 100 g. edible pulp) are vit. A, 80 IU; thiamine, 0.03 mg, riboflavin, 0.01 mg; nicotinic acid,0.2 mg; vit. C, 18 mg; choline, 7 mg; folic acid, 3 μg. The stem bark contain friedelin, kaempferol, ellagic acid, gallotannin, betulinic acid, βsitosterol, eugenin. The leaves contain phenolic content like ferullic acid, catechin, also, n-dotricontanol, myrcetin, mycaminose, quercetin, annic acid, tocopherol and acetylated flavonol glycoside. The flowers contain oleanolic acid and other triterpenoids also acetyl oleanolin acid (0.3%) melting point (260–262°C), Eugenia- triterpenoid A (0.5%) and Eugenia triterpenoid B (0.3%). The roots contain myricetin 3-O-glucoside and myricetin 3-O-robinoside. Reported constituents (Figure 4) structures from different part of plant [14].
Major bioactive constituents of jamun and its benefits.
Constituents from eugenia jambolana.
NS seeds and oil has been broadly utilized to cure different disease & its aliments associated with, leaving physiological system, which was proved by adopting modern scientific methodology. The collected research repository from different sources with regardless of time, focusing the activity done on NS, worldwide form the centuries NS seeds and oil traditionally utilized as therapeutic medicine, in Indian system of medicine (Unani & ayurvedic) the pharmacological applications are endorsed [15], further more to say our Prophet Muhammed
The efficacy of NS seeds and TQ are variable and depend on target species. And other study reported the use of seeds and oil to control the symptoms of COVID-19 in combination with crude extract of EJ [18].
The second herbs which is having similar pharmacological properties was
The entire plant is used in various traditional system of medicine in India and other parts of the continent around the globe. However, the leaves and bark are regarded as most significant part. In Ayurveda, the bark is acrid, sweet, digestive and astringent to the bowels, anti-helminths. Besides it is used to cure sore throat, bronchitis, asthma, thirst, biliousness, dysentery, blood purifier in ulcer treatment. In Unani system of medicine EJ Leaf ash is used to strengthen teeth gums, EJ seeds are used as astringent, diuretic and also used to stop urinary discharges. The bark of EJ having strong antidiabetic properties. The siddha system of Indian medicine utilizes Jambolana seeds for hematinic, thermo-regulate, the traditional medicine of Madagascar’s the Jambolana seeds are utilized to regenerate the β-cells of pancreas and leaves are used by women to contract vagina after delivery, reduce mucus and odors [20].
The uniform resemblances of pharmacological application both the species have been extensively analyzed with regardless of time, and tabulated in Table 1, the aim of the study, to put the researcher to focus on the beneficiary effect of bioactive constituents present in both the medicinal plants.
S.N | Uniform resemblances of both species | |||||
---|---|---|---|---|---|---|
Parts of BS | Composition of constituent | Activity | Chechanism | Parts of BP | Composition of constitutent | |
1. | Seeds | α-Hedrin, Steryl-glucosides, Acetylsteryl-glucoside | Anti-inflammatory | Anti-inflammatory activity is attributed to inhibition of cytokine, eicosanoids generation and measure lipid peroxidation through inhibition of cyclo-oxygenaseand 5-lipoxygenase pathway of archidonate metabolism. In addition, T cell- and natural killer cell-mediated immune responses are also accountable to its immune-modulatory activity. | Leaves | Ellagic acid, gallotannin betullinic acid, β sitosterol, eugenin, kaempferol triterpenoids, saponins and tannins phenolic compounds and flavonoids |
2. | Oil | Nigellicimine, Nigellidine, Nigellimine-N-oxide | Cardiovascular actions | Cardiovascular depressant effects are mediated centrally via indirect and direct mechanisms that involved both 5-hydroxytryptaminergic and muscarinic mechanisms. Direct mechanism is virtue of volatile oild (TQ) which processes potent antihypertensive potential. | Seeds | Flavonoids, phenolic content-caffeic acid, ellagic acid, ferulic acid, tannins, terpenes |
3. | Seeds | Arginine, Glutamic acid, Leucine, Lysine, Methionine, Tyrosine, Proline And Threonine | Anti-hyperlipidemic | Anti-hyperlipdemic effect is owing to significant reduction in hepatic HMG-COA reductase activity. In addition, this effect is attributed to blockage of the ex-vivo basal and in-vitro maximal formation of conjugated diene and malondialdehyde, and lengthened the lag times of low density lipoprotein, small dense low density lipoprotein and large buoyant low density lipoprotein. Methanolic extract possessing ω-6 linoleic acid along with palmitic acid is more effective that volatile extract containing thymol and isothymol phenolic antioxidant compounds. Thymoquinone has anti1hyperlipidemic as well as antioxidant activity | Plant pulp Seed | Triton X-100 induced hyperlipidemia |
4. | Seeds | Palmitic acid (12.5%), Stearic and Myristic acid (30%). | Hypoglycemic effects | N. sativa and | Leave | Vit. C, gallic acid, tannins, anthocyanins including cyanidin, petunidin, Lupeol, β-sitosterol |
5. | Seeds | Esters Of Linoleic1 5a Caindd, N Tiann Ngilny,C | Antinociceptive effects | Antinociceptive effects of | Seeds | Flavonoids, alkaloids, steroids |
6. | Seeds | Enoate, Stigma-5, 22-Dien- 3-B-D-Gluco. | Anti-oxytocic potential | The volatile oil of | Roots | Flavonoids, alkaloids, steroids |
7. | Seeds | 6-Methoxy-Coumarin, Hydroxy-Coumarin, 7-Oxy-Coumarin | Gastro-protective effects | Leaves | Amylase | |
8. | Seeds | Cycloeucalenol, Cycloartenol, Sterol Esters | Neuroprotective action | Neuro-protective action of NSO is correlated to its ability to inhibit not only excessive reactive oxygen species (ROS) formation but also seizure generation | Seeds | Anthocyanins, volatile oils, terpenes |
9. | Seeds | Arginine, Glutamic Lysine, Methionine, Nephro-protective effect | NSO acts in the kidney as a potent scavenger of free radicals | Crude extract | Flavonoids, glycosides | |
10. | Seeds | Almitoleic acid, β-Sitosterol, α1Sitosterols (44–54%), | Anti-schistosomiasis | TQ were considered as protective agents against the chromosomal aberrations induced as a result of schistosomiasis | Crude extract of pulp | phenolic content and acetylated flavonol glycosides |
11. | Seeds | Tyrosine, Proline and Threonine | Anxiolytic effect | Seeds | Flavonoids, alkaloids, steroids | |
12. | Seeds | Almitoleic acid, β-Sitosterol, α1Sitosterols (44–54%), Cycloartenol, Sterol | Anti-malarial Effects | N. sativa oil can possibly be utilized as both supplements and as adjuvant. It has great importance when combine with chloroquine because the rate of loss and failure becomes less that’s why it is safer for utilization. This will lessen the side effects of CQ. Total charge of treatment of malaria through chloroquine being the least expensive and mostly accessible | Methanolic extract of leaves | Polyphenols including Flavonoids, alkaloids, glycosides & phenolic compound, fatty oils |
13. | Seeds | Almitoleic acid, β-Sitosterol, α1Sitosterols (44–54%), Cycloeucalenol, | Anti-parastic Effects | Leaves | glycosides & phenolic compound, fatty oils | |
14. | Seeds | Cycloartenol, Sterol Esters and Sterol Glucosides | Influence on blood | In an ongoing report it was seen that menthol dissolvable parts of | Seeds | glycosides & phenolic compound, fatty oils |
15. | Seeds | Cycloeucalenol, Cycloartenol, Sterol Esters and Sterol Glucosides | Treatment of Acne | The | Leaves and fruit pulp extract | Triterpenoids, Resin, Resin, Phytosterol |
17. | Seeds and oil | Almitoleic acid β-Sitosterol, α1Sitosterols (44–54%) | Effect on reproductive system | The uptake of 1 ml/kg/day of black cumin oil enhances the release of sexual hormones that stimulated the increase protein production of liver enzymes, platelets number and in the blood it diminishing the level of cholesterol present in serum. | Flavonoids, phenolic content – caffeic acid, ellagic acid, ferulic acid, tannins, terpenes | |
18. | Seeds | Almitoleic acid, β-Sitosterol, α1Sitosterols (44–54%) | Effect on respiratory system | In Saudi Arab and neighboring nations Kalonji seeds and oils are commonly utilized for the cure o asthma. Carbonyl polymer of thymoquinone (nigellone) ends up being an incredible preventive agent for both bronchial asthma and asthmatic bronchitis. Essential oil can be utilized as probable respiratory energizer if thymoquinone is eliminated | Seeds | glycosides & phenolic compound, fatty oils |
19. | Seeds | Sterol Esters and Sterol Glucosides | Anti-bacterial Activity | Crude extract of leaves and bark | Phenols and flavonoids | |
20. | Seeds and oil | Cycloartenol | Anti-fungal Effects | The essential oil of Kalnoji of various backgrounds has accounted for to have adequate inhibitory activity against disease causing strains of: yeasts, dermatophytes and Non-dermatophytic filamentous parasites alongside aflatoxin-creating organisms. | Roots | Flavonoids, phenolic content – caffeic acid, ellagic acid, ferulic acid, tannins, terpenes |
21. | Seeds and oil | Cycloeucalenol, Cycloartenol Sterol | Antiallergic effect | Act on H1 and H2 receptors | Crude Extract | Flavonoids, alkaloids, steroids |
22. | Seeds and oil | Thymoquinone, dithmoquinone, thymohydroquinone, nigellone, thymol | Anti-cancer | Act to dissolve the unwanted cells in the body by dissolving them and have significant cytotoxic effect against the majority of tumor cell lines | Crude extracts of roots | Phenols and flavonoids |
23. |
Glimpse of phytochemical and pharmacological endorsement of both the species.
In a nutshell, both the species having identical pharmacological properties, bearing with different and rich source of phytoconstituents, currently, todays era getting conscious about the utilization of herbal medicaments, hence it was the preliminary choice of consumer world-wide. Otherwise, the traditional medicines are still occupying remedy-kingdom in particular area of research. Inherent and varied activities with meticulously indorsed phytoconstituents from both the species is triggering zone to the drug research, whereas this chapter is entirely dedicated to bring out the best from research crafted by different scholars. NS is one of the most important medicinal herbs with considerable commercial value, the valuable Phytoconstituents bearing by these herbs is commendable and also the gap in research to fucose on, merely the principal constituents responsible for activity are the derivatives of thymoquinone (TQ), as evident by various scientific studies support its safe use for the long-term traditional food and medicinal purposes.
To date, number of studies showed that, EJ is evergreen tree, having food value, which provide remarkably diversified therapeutic application, to treat different disease and its disorder associated with physiological system. The studies suggested that the major constituents responsible for the activity are flavonoids, anthocyanins, carotenoids, essential oil, terpenes, tannins and phenolic compounds.
To jot down, NS and EJ having wider safety margin and praiseworthy therapeutic activity, against sustainably cure to different bacteria and virus, this era of treatment require the molecules isolated from natural sources, whereas the worldwide ban of antibiotic, steroidal hormones and outbreak of covid-19, this candidate will prove its effectiveness.
Author immensely grateful to the management of AIKTC and the book publishing family for giving me the opportunity to become a part of this novelty work. Last but not least my heartfelt thanks to Librarian of AIKTC for guidance support. I never deny the support and love of my children and family for providing me the quality time to draft this chapter.
The author declared no conflict of interest.
Thanks to publishing house for giving me the opportunity to contribute.
NS | Nigella sativa |
EJ | Eugenia jambolana |
TQ | Thymoquinone |
NSO | Nigella sativa oil |
DPPH | 2,2-diphenyl- 1-1picryhydrazyl hydrate |
LOO | lipid peroxyl radicals |
FRAP | Ferric reducing antioxidant power |
GAE | Gallic acid equivalent |
CE | Catechin equivalent |
TAE | Tannic acid equivalent |
AGEs | Acute gastroenteritis |
CVD | Cardio Vascular Disease |
AMD | Age Related Macular Degeneration |
Systemic sclerosis (SSc), characterised by autoimmune inflammation, vasculopathy and fibrotic tissue deposition as the main pathophysiological features, can affect any organ system. In fact, the aetiology and pathophysiology of SSc are still not completely elucidated [1]. Gastrointestinal tract (GIT) is one of the most commonly involved organ systems in SSc.
\nUp to 90% of SSc patients are affected by some degree of GIT fibrosis, with no difference in frequency in limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc) subsets. However, more severe involvement and increased mortality occur rather in dcSSc than lcSSc [2, 3]. Dysmotility is the cardinal pathological abnormality, which can affect any part of GIT and contributes to the majority of symptoms [4], which are mostly non-specific and overlapping for a particular anatomical site. GIT involvement varies in extent, severity and course and can manifest even in the absence of cutaneous disease [5].
\nThe pathophysiology of GIT involvement in general corresponds to the skin and other organ involvement in SSc, with the main characteristic pathologic features: vascular abnormalities, immune cell infiltration in tissue, autoantibodies and typical extensive deposition of collagen fibres. This process leads to specific early myenteric neural dysfunction caused by autoantibodies and collagen deposition, vasculopathy in myointimal layer mainly in capillaries preceding the muscle changes, smooth muscle cell infiltration with mononuclear cells with consequent atrophy and fibrosis of enteric connective tissue [1, 6]. Regarding the aetiology, genetic component is supposed to play a significant role in GIT involvement. In the Canadian population study, in which SSc patents were classified according to the ethnicity, population of white patients had less severe GIT involvement compared to North American native population (including American Indians and others), suggesting a predisposition for severity and progression of the disease [7]. Another study identified some haplotypes in an American native population (Choctaw Indians) strongly associated with SSc and more severe progression of this disease (HLA-DRB1*1602, DQB1*0301 and DQA1*0501) [8]. Some studies have also reported high prevalence of
GIT involvement significantly impacts quality of life and contributes to depression, sleep disturbance and pain [11, 12, 13]. It also negatively influences the prognosis with up to 12% of mortality due to fibrosis of GIT and accompanying malnutrition [1]. Up to 8% of SSc patients can develop severe GIT symptoms, which lead to increased mortality with only 15% survival at 9 years [5].
\nThe pathophysiology of GIT involvement in SSc is a complex process. Unfortunately, it is still poorly understood due to many reasons: heterogeneity of clinical manifestations, the lack of appropriate animal models and the paucity of studies examining the pathophysiology. The key pathogenic mechanisms of GIT involvement, similarly to SSc in general, include fibro-proliferative vasculopathy, immune dysfunction with the participation of various components of immune system and fibrosis [14].
\nEndothelial injury as the crucial event in SSc results in increased production of reactive oxygen species (ROS) and release of chemokines and growth factors. Recruited immune cells (B- and T-cells and pro-fibrotic macrophages) contribute to further release of ROS, cytokines and pro-fibrotic mediators [15]. These mechanisms lead to reduced blood flow in mucosa, endothelial cell apoptosis, perivascular infiltrates and thickening of the basement membrane [16, 17, 18].
\nThe initial step in pathophysiology of GIT dysmotility is neuropathy, followed by myopathy and later by progress to fibrosis [19]. Specific autoantibodies isolated from serum of SSc patients (SSc-IgGs) were described to cause significant smooth muscle dysfunction [20]. The mechanism lies in inhibition of acetylcholine binding on the M3 receptors (M3-Rs) [21, 22]. The action of SSc-IgGs seems to be dependent on the disease stage: in early SSc there is higher affinity of SSc-IgGs to the M3-Rs of myenteric neurons, which represents the neuropathic damage. During the course of the disease, the affinity increases to both smooth muscle cells and myenteric neurons, representing the myopathic phase. This temporal increase of SSc-IgGs affinity could elucidate the progressive character of GIT involvement [14, 19, 23]. Presence and action of M3-R autoantibodies can explain the impaired GIT function explored by manometry before the occurrence of histological changes [14].
\nNeutralisation of M3-R antibodies by human intravenous immunoglobulins (IVIGs) and its antigen-binding fragment F(ab)2 might reverse the intestinal dysfunction and is considered as a potential therapy [19]. The ultimate smooth muscle cell atrophy and tissue fibrosis lead to the loss of GIT contractile function and disability to respond to any external stimuli; thus any treatment of dysmotility is futile [14].
\nAlterations in cell-mediated immunity have a significant role in SSc GIT involvement [24, 25]. Interleukin (IL)-4 stimulates type 2 helper (Th2) polarisation of CD4+ T-cells, which is predominant in SSc. Th2 cells further upregulate humoral immunity [15, 26]. CD4+ T-cells in immune cell infiltrates in gastric biopsy specimens with typically increased CD4+/CD8+ T-cell ratio can be responsible for pathogenic autoantibody production and fibrosis of GIT [14, 27]. Generalised fibrosis with increased deposition of collagens I and III in most layers (muscularis mucosae, submucosa and muscularis propria) was described in gastric wall biopsies, together with strong expression of fibrogenic cytokines (transforming growth factor-β and connective tissue growth factor) and α-smooth muscle actin [28]. Other factors contributing to fibrosis are reduction of matrix metalloproteinase-1 expression and damage and reduction of telocytes—specific stromal cells essential for extracellular matrix scaffolding [29, 30]. Moreover, consequent increased stiffness of GIT wall is an additional potential stimulus for further fibrosis [31].
\nIn addition, differentially expressed microRNAs (miRNAs) targeting both inflammation and fibrotic pathways have a probable role in SSc pathogenesis [32, 33]. Depletion of the miR-29 family, which targets collagen gene expression and regulates fibrosis, probably leads to increased collagen deposition in tissues [34].
\nAs mentioned, any part of GIT can be affected, so the clinical manifestations vary according to the involved organ. Large proportion of patients are asymptomatic, or symptoms may be unspecific and overlapping [1]. Fibrosis and dysfunction of GIT lead to many complications, such as gastro-oesophageal reflux disease (GERD) with complications (oesophageal strictures, Barrett’s oesophagus), dilation and non-compliance of the stomach (gastroparesis), small intestinal bacterial overgrowth (SIBO), colonic dilation and dysfunction of internal anal sphincter. The vasculopathic manifestations are gastric antral vascular ectasia (GAVE), small intestine vascular ectasia and diverticula in the oesophagus, small intestine and colon, resulting in malabsorption and faecal incontinence [14]. Clinical features are divided according to individual organ involvement.
\nThere are numerous SSc-related alterations of the oral cavity [35]. Pathognomic fibrosis results in characteristically reduced oral aperture (microstomia), thickening of the sublingual fraenulum and widening of periodontal ligaments [36]. In addition, secondary Sjögren’s syndrome, reported in about one fifth of SSc patients, can lead to tooth loss along with above-mentioned pathologies. All these factors complicate dental hygiene and food intake and contribute to malnutrition [37]. Up to 20% of SSc patients can develop mandibular resorption predisposing to pathological fractures, osteomyelitis and trigeminal neuralgia [38]. Oropharyngeal dysphagia manifests in 25% of SSc patients and is caused both by dysmotility and GER as a reflex mechanism [39]. Apart from malnutrition, dysphagia is also a risk factor for aspiration pneumonia [40]. With regard to malignancy, risk of tongue cancer (squamous cell carcinoma) has been reported in dcSSc 25-fold higher compared to general population [41].
\nOesophageal dysfunction appears to be the most common GIT manifestation in SSc affecting up to 90% SSc patients with higher prevalence and tendency to deteriorate over time in dcSSc compared to lcSSc [42, 43]. Up to 30% of SSc patients may suffer from asymptomatic oesophageal involvement [44]. The main feature of oesophageal involvement is dysphagia due to smooth muscle cell atrophy and destruction of neuronal complexes. Drug-induced dysphagia and
Long-standing GERD results in development of distal reflux oesophagitis and eventually progresses to peptic strictures and Barrett’s oesophagus (BE) formation. The prevalence of BE is reported to be 12.7% in SSc patients treated with proton-pump inhibitors (PPIs) [45]. Approximately 20% of these patients develop dysplasia and are at higher risk of adenocarcinoma compared to SSc patients with BE and without dysplasia. However, this risk seems not to be increased in SSc compared to general population with GERD [45, 46].
\nThe recent high-resolution manometry study reported positive correlation of severe oesophageal dysmotility with the duration of SSc and presence of interstitial lung disease (ILD) [47]. GERD can contribute to the emergence of ILD and worsen the ILD in SSc by microaspiration of gastric content; therefore, early diagnosis and administration of high-dose PPI therapy are needed [48, 49].
\nGastric involvement leads mainly to gastroparesis and GAVE [50]. Gastroparesis manifests clinically by early satiety, nausea and vomiting, epigastric discomfort and bloating and may progress to complete food intolerance [51, 52]. GAVE, also called “watermelon stomach”, is considered a macroscopic manifestation of SSc vasculopathy, corresponds with skin telangiectasias and is associated with Raynaud’s phenomenon [53, 54]. The prevalence of GAVE in SSc ranges from 6 to 22% [53, 54, 55, 56]. It usually occurs within the first few years from the onset of the disease. Nevertheless, it can also be the first SSc manifestation in the absence of cutaneous involvement, clinically expressed as anaemia of combined aetiology: iron deficiency (sideropenia) and chronic bleeding (occult bleeding, melena or haematemesis) [56]. The presence of GAVE correlated negatively with the positivity of anti-topoisomerase I antibodies, but, in one study, was not associated with anti-RNA polymerase III autoantibodies (anti-RNAP3) [54]. However, on contrary, an association was confirmed in the recent study of EUSTAR population, where 48% of patients with GAVE had anti-RNAP3 positivity compared to 16% of SSc patients without GAVE. Of note, the autoantibody profile was not available for the whole cohort of SSc patients included [57]. A more recent study of EUSTAR population including almost 5000 SSc patients assessing the association of anti-RNAP3 autoantibodies with clinical features and risk of malignancies reported, among other results, a negative association of anti-RNAP3 with GERD and a positive association of anti-RNAP3 with GAVE (more than eight times increased risk of GAVE in anti-RNAP3-positive patients than in anti-RNAP3-negative SSc patients) [58]. The association with specific antibodies and its potential clinical use is a quest for further studies.
\nThe small intestine belongs to the most commonly affected organ of GIT involvement in SSc, after the oesophagus and anorectum. Decreased motility results in typical complications, which participate in malabsorption and malnutrition: local small bowel dilation, intestinal pseudo-obstruction and SIBO, development of pneumatosis cystoides intestinalis (PCI) and jejunal diverticula [59]. The range of symptoms is wide, from dyspeptic symptoms to systemic symptoms resulting from malabsorption [14].
\nPredisposing factors for pseudo-obstruction, either acute or chronic, are both SSc related—dilation, atony and delayed transit—and treatment related, especially the use of opiates [51, 60]. The stasis due to dysmotility of intestinal content predisposes to SIBO that was detected in up to 40–50% of SSc patients [51, 61]. This can, along with the failure of recurrent antibiotics therapy, cause the vulnerability to severe malabsorption [62].
\nPCI is a rare complication of SSc characterised by multiple gas-filled cysts in submucosa or subserosa [63] as an incidental radiographic (RDG) finding. Contributing factors involve dysmotility with consequent SIBO, ischemic damage and muscular atrophy [64]. Rarely, the rupture can cause benign spontaneous pneumoperitoneum or more severe complications as bowel ischaemia, perforation and peritonitis [63]. The treatment of benign pneumoperitoneum consists of conservative approach (oxygen, antibiotics and bowel rest) or surgery intervention in more severe cases [14].
\nColonic involvement, including hypomotility, telangiectasia and diverticula, affects up to 50% of SSc patients and is often asymptomatic or can typically manifest by chronic constipation and abdominal distension [1]. Dysmotility and the resulting constipation can in extreme cases lead to faecal impaction or perforation requiring surgery. The colon can be dilated with the loss of haustration [14]. SSc patients can also suffer from diarrhoea and severe malabsorption caused by SIBO [65].
\nColon and anorectal involvement can manifest by rectal prolapse and diverticula typically described as “wide mouth”, which are mostly asymptomatic and not complicated by diverticulitis. Anorectal involvement is regarded as the second most common with a prevalence of 50–70% [14]. Symptoms include incontinence, tenesmus and painful defaecation. Faecal incontinence, present in 40% SSc patients, is generally attributable to several factors: diarrhoea, internal and external anal sphincter dysfunction, reduced rectal compliance and capacity with impaired recto-anal inhibitory reflex, rectal prolapse and also constipation with overflow [66, 67]. Dysfunction of smooth muscles in internal anal sphincter (neuropathic or myopathic) is supposed to be the initial cause of faecal incontinence [68]. The main cause of sphincter involvement seems to be the vasculopathy and resulting tissue atrophy described in endo-anal ultrasound imaging as a hyperechoic thinned sphincter. On the other hand, thick hypoechoic sphincter due to tissue fibrosis is found in some cases [69].
\nInvolvement of the liver is less frequent compared to GIT organs mentioned above. Nodular regenerative hyperplasia (NRH), benign liver involvement in SSc, can precede primary biliary cirrhosis (PBC) and can progress to non-cirrhotic portal hypertension [70, 71]. The pathogenesis lies in obliterative changes in portal veins and corresponds with the microvascular damage in SSc. Although NRH is mostly asymptomatic, it can develop into portal hypertension [72].
\nPrimary biliary cirrhosis is the most common liver disorder associated with SSc with a prevalence of about 2%, higher in lcSSc [73]. It can precede the diagnosis of SSc, for example, as a Reynolds syndrome comprising PBC with Raynaud’s phenomenon [74]. PBC is associated with anti-centromere antibody positivity [73]. Nevertheless, PBC screening antibodies (anti-mitochondrial, anti-gp21, anti-sp100) are detectable also in 20% of SSc patients with no liver disease [75]. The rate of progression of SSc-related PBC to end-stage liver disease and transplantation is lower compared to non-SSc PBC, but the reason is still unknown [76]. PBC contributes via cholestasis and decreased bile acid secretion to malabsorption and malnutrition [1].
\nOther rare liver infections in SSc include autoimmune hepatitis, idiopathic portal hypertension and primary sclerosing cholangitis [77, 78]. Specific anti-liver kidney microsomal (anti-LKM) or anti-smooth muscle (anti-SMA) antibodies detected in SSc without liver involvement are attributable to the autoimmune character of SSc [79].
\nThe involvement of the pancreas seems to be rare and the symptoms can overlap with SIBO. The exocrine pancreatic insufficiency can take part in malabsorption [80]. Case reports describe occlusion of medium-sized pancreatic arteries in SSc resulting in haemorrhagic pancreatitis and fatal pancreatic infarction [81].
\nPrevalence of malnutrition in SSc patients is estimated to be 15–58% [51, 82, 83]. Mortality is significantly increased in underfed SSc patients compared to patients with adequate nutritional intakes, whereas about 4% deaths are attributable to consequences of malnutrition [14, 83]. Both GIT involvement and cachexia from chronic inflammation play a key role in malnutrition [51]. However, there are other additional risk factors for malnutrition worth mentioning, e.g. depression and anxiety, although their significance is uncertain [1, 84].
\nAccording to the data from the Canadian Scleroderma Research Group database on almost 600 SSc patients, malnutrition correlates with disease duration and severity, severity of anaemia, abdominal distension and the rate of subjective complains [51]. The American Society of Parenteral and Enteral Nutrition (ASPEN) recommends early screening for malnutrition in every patient with newly diagnosed SSc and then annually [85]. Screening is performed by examination of blood samples for chosen parameters: haemoglobin, iron and vitamin B12, serum levels of fat-soluble vitamins, prealbumin, albumin and additional test for micro- and macronutrient deficiency, particularly in suspected SIBO [86].
\nPatients at risk are indicated to rigorous monitoring and prompt treatment optimally in cooperation with dietitian and gastroenterologist [85]. At the advanced stage, nasoenteral feeding should be tried, eventually a percutaneous endoscopic gastrostomy or jejunostomy in case of severe gastroparesis. The last-mentioned approach carries the advantage of reduction of pulmonary aspiration risk. The most severe refractory intestinal involvement is indicated to parenteral nutrition (PN) [14].
\nNegative changes of bone mineral density (BMD), weight loss and muscle atrophy are associated with the nutrition insufficiency, but can also be related to reduced ability of physical activities, and severity of the disease. There are only few studies investigating alterations of body composition (BC) in SSc. Up to date, no large study or meta-analysis is available. Studies mostly used dual-energy X-ray absorptiometry, which is a suitable method for measuring BMD, lean body mass (LBM) and fat mass (FM) [87].
\nStudies have reported reduced BMD, which is determined by many factors: malnutrition and vitamin D deficiency, decreased physical activity, corticosteroid and immunosuppressive treatment and the disease-specific features [88, 89]. Low circulating levels of vitamin D may be related to the extent of skin involvement [90].
\nStudies on BC including body mass index (BMI) and other methods are scarce and their results differ. One study describes no alterations of FM or LBM in SSc patients compared to control population [90]. On the contrary, another study reported significantly lower BMI, LBM and FM as well as lower BMD in SSc women compared to healthy women, whereas more significant alterations of BC were expressed in dcSSc [91]. BMI significantly negatively correlated with duration of the disease in SSc patients, which was also the only risk factor associated with low LBM (sarcopenia). Of interest, reported negative changes of BC were not associated with current dietary customs [91].
\nOne study reported decreased left ventricular mass (LVM) evaluated by echocardiography as a potential marker of malnutrition, whereas LVM correlated positively with BMI and severity of vascular involvement but negatively with skin thickening [92]. Another study reported the correlation of visceral abdominal fat with the main cardiovascular risk factors [93]. Both these studies are lacking a control group.
\nThere is a strong need for large, well-designed studies including complex methods for evaluation of BC and disease-specific features and an adequate control group, so that the consequences of BC alterations could be properly elucidated and managed.
\nEvery patient diagnosed with SSc should be referred to a gastroenterologist, even if asymptomatic regarding GIT involvement [14]. Problematic swallowing and oral pathology should be examined by other specialists (dentists, speech pathologists and eventually an oral surgeon) [1]. Social and psychosocial factors have certain impacts on some GIT symptoms and hence should be taken into consideration too.
\nA wide spectrum of investigation methods is available for detection of GIT involvement, including laboratory and imaging methods [14]. Endoscopy has a key role in evaluation of oesophageal and gastric involvement and is used for therapeutic interventions as well. Except for video endoscopy, manometry and pH test are also useful in testing dysmotility and reflux (especially refractory GERD) [86, 94]. Barium oesophagogram is indicated for detection of suspect strictures [95]. Barrett’s oesophagus requires regular screening by endoscopic biopsies with frequency depending on the baseline finding: no initial dysplasia should be screened every 3–5 years, and low-grade or high-grade dysplasia is recommended for control screening every 3–6 months. Endoscopy is also indicated in anaemia due to suspected GAVE [86]. Gastroparesis should be confirmed by RDG (delayed gastric emptying), before administration of prokinetics [96]. Endoscopy in small intestinal involvement (e.g. capsule endoscopy) is restricted and difficult, particularly if dysmotility is the main symptom.
\nDiagnosis of SIBO is based on subjective complains and objective signs of malabsorption—weight loss and nutrient deficiency—confirmed by results of blood test showing low serum carotene level (marker of vitamin A absorption), low vitamin B12, 25-hydroxyvitamin D, iron, pathologic prothrombin time, etc. [86]. Though breath test has good specificity, the sensitivity is poor (65–70%) and is not able to detect bacterial overgrowth in more distal parts of the small intestine [97, 98]. Invention of appropriate diagnostic tools for evaluation of SIBO is still an unmet need.
\nValidation and measurement of the consequences and outcomes related to certain disease and involvement can be challenging. Construction of appropriate questionnaires for evaluating SSc patients’ symptoms and correlating them to objective disease features was the task in the last decade [14]. The first questionnaire assessing the overall severity and quality of life in the context of GIT involvement was the Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0), validated in 2009 [99]. Later it was revised, shortened and adapted into final version called University of California, Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA SCTC GIT 2.0) [100]. This revised questionnaire consists of 33 items taken from SSC-GIT 1.0 and 1 new item evaluating rectal incontinence (faecal soilage). Total GIT score correlates with the overall burden of GIT disease in SSc patients [100].
\nAnother instrument developed by the National Institutes of Health is called Patient-Reported Outcome Measurement Information System (PROMIS) GI symptom item [101]. Compared to UCLA SCTC GIT 2.0, PROMIS contains more items and has additional scales for disrupted swallowing, nausea and vomiting. There is large correlation and satisfactory reliability between this two instruments, but PROMIS seems to be more easily comprehensible for general and low-literacy population, usable across diverse populations and less demanding for respondents to fulfil [102]. The only validated tool for evaluating the malnutrition in SSc patients is Malnutrition Universal Screening Tool (MUST) [103]. MUST is one of screening tools recommended by North American expert panel for initial screening of malnutrition in SSc patients, as it is easy to administer [85]. MUST reflects the weight change and acute dietary intake and can be less sensitive to nutritional status and GIT involvement than another tool Subject’s Global Assessment (SGA) [104]. Although MUST can identify the severity of malnutrition in SSs, it does not reflect the symptomatology contributing to this problem [105]. MUST is generally recommended as the screening tool for nutritional status by several groups (
To date, no specific disease-modifying drugs exist to stop the progress of the disease. Early diagnosis of SSc organ involvement is essential for symptomatic organ-specific treatment, until the irreversible fibrotic and hardly treatable damage develops [14]. Currently, treatment of SSc-related gastrointestinal involvement is based on symptomatic therapy and includes acid-reducing therapy and administration of antibiotics and prokinetics. Octreotide is prescribed in refractory small intestinal pseudo-obstruction and bacterial overgrowth [40, 107] (Table 1).
\nManifestation of GIT involvement | \nInitial therapy/examination | \nOther therapeutic approaches and lifestyle modifications | \n
---|---|---|
GERD | \nModification of diet and lifestyle PPI (daily administration) | \n1) Take PPI at least 30 minutes prior to eating; control the right intake 2) Consider increasing the dose of PPI—twice a day—or change the PPI drug 3) Add an H2 blocker at night 4) If symptoms are still present, perform pH-metry or endoscopy Lifestyle and diet modification: Small meals more frequently during the day, more food in the first half of the day; take a walk after eating; restrict from aggravating foods; sleep with the upper half of the body elevated or lay on the left side | \n
Barrett’s oesophagus | \nOptimal therapy of GERD, monitoring by a gastroenterologist, regular upper endoscopy | \nRadiofrequency ablation (RFA)—consider in low- or moderate-grade dysplasia, always indicated in high-grade dysplasia | \n
Stricture | \nOptimal therapy of GERD | \nConsider endoscopic dilation, in case of persistent dysplasia | \n
Gastroparesis | \nProkinetics (after gastric emptying study to confirm delayed gastric emptying) | \n1) Modification of diet (small meals, walking after meal), adequate liquid intake 2) Metoclopramide (ECG monitoring due to risk of prolonged QT interval) 3) Domperidone or erythromycin (if QT interval is normal) 4) Treatment of nausea | \n
GAVE | \nFirstly, upper endoscopy to verify the diagnosis; argon plasma therapy in case of active bleeding; support therapy in case of bleeding (red blood cell transfusion, etc.) | \n1) Repeated sessions of argon plasma therapy 2) Laser therapy as an alternative approach 3) Immunosuppressive therapy in indicated cases | \n
SIBO | \nBreath test (poor sensitivity) Examination of malabsorption (laboratory tests, body composition) Therapeutic trial with antibiotics (metronidazole, ciprofloxacin, neomycin, rifaximin, amoxicillin, doxycycline) | \n1) Administration of antibiotics for 2 weeks—in recurrent cases repeat cyclic antibiotics therapy 2) Probiotics 3) Enteral or parenteral nutritional support 4) FODMAP diet* | \n
Intestinal pseudo-obstruction | \nClinical assessment Imaging examination to exclude the mechanical cause of obstruction (X-ray, CT) Initial therapy and nutritional support during the hospitalisation | \n1) Nutritional support 2) Prokinetics (subcutaneous octreotide) 3) Broad-spectrum antibiotics 4) Surgery (in resistant cases, to provide decompression) | \n
Malnutrition | \nRegular screening, BMI examination, recommended screening tools (MUST) Laboratory markers of malnutrition | \n1) Nutritional support 2) (Total) parenteral nutrition 3) Percutaneous feeding tubes (endoscopy gastrostomy) | \n
Constipation | \n“Bowel hygiene” (adequate liquid and fibre intake), defaecation in timely manner, taking regular exercise or other physical activity | \nOsmotic laxatives, stool softeners | \n
Diarrhoea | \nFirstly, identify the cause of diarrhoea (other than SSc or multifactorial) | \nManagement of the cause of diarrhoea (dysmotility, SIBO, fat malabsorption, etc.) | \n
Faecal incontinence | \nManagement of diarrhoea and SIBO, biofeedback, pelvic-floor exercises | \nSacral nerve stimulation in resistant cases | \n
Therapeutic intervention and follow-up of SSc patients with GIT involvement.
FODMAP foods: inappropriate and irritating ingredients in patients with irritable bowel syndrome or chronic bowel disease (idiopathic bowel inflammation, celiac disease, etc.); FODMAP diet consists of eliminating the intake of these foods: fermentable oligosaccharides (gluten, onion, garlic, etc.), disaccharides (lactose), monosaccharides (fructose) and polyols (alcohol sugars)—these are poorly absorbable carbohydrates in the small intestine.
Adapted from Ref. [86];
Firstly, non-pharmacological treatment—lifestyle modification—should be applied to improve symptoms: elevation of the head or upper half of the body in the bed, sleeping on the left side, modification of eating regimen (indigestion of multiple small meals during the day, avoidance of eating meal less than 3 or 4 hours before bedtime), loss of weight if obesity, cessation of smoking and minimalizing alcohol intake, avoidance of drinking beverages and taking food or drugs decreasing the LES pressure (caffeine drinks, chocolate, calcium channel blockers, nitrates) and appropriate education about using risk drugs (bisphosphonates, tetracycline, iron, NSAIDs) [86].
\nThe last update of EULAR recommendations published in 2017 has summarised the up-to-date treatment management into three points: (1) PPI for treatment of SSc-related GERD and prevention of oesophageal ulcers, strictures and other adverse consequences, (2) prokinetics for control of the GIT dysmotility and (3) intermittent or rotating cycles of antibiotics for treatment of symptomatic SIBO. However, large randomised control trial (RCT) studies evaluating the above-mentioned medication in SSc are lacking [108].
\nA small RCT reported favourable effect of PPI on improvement of upper GIT symptoms in SSc [109]. Moreover, omeprazole potentially reduces or regresses the oesophageal fibrosis [110, 111]. On the other hand, long-term therapy with PPI potentially decreases the intestinal absorption and thus causes nutritional deficiency. It is associated with the risk of bacterial overgrowth and infections (
Treatment by prokinetics is based on individual symptoms of GIT dysmotility and potential benefit to risk [108]. Several non-randomised or uncontrolled studies reported improvement of GI symptoms in SSc [107, 114, 115, 116]. Prokinetics improve refractory GERD symptoms via supporting the gastric emptying in cases of gastroparesis in patients treated adequately for GERD. Combination with antiemetics is favourable [86]. Inclusion of prokinetics in combination therapy may have benefits in the early disease stage. Nevertheless, there is only a little or no profit from using prokinetics in later stages with dominant smooth muscle atrophy [96]. Choice of a certain drug from this group depends on individual benefit for each patient [86]. Small studies in patients with SSc and other connective tissue diseases reported a beneficial effect of cisapride [117, 118, 119, 120, 121]. However, cisapride can cause long QT syndrome predisposing to severe arrhythmias; thus it is not commonly available in some countries [122]. Metoclopramide is the first-line therapy in gastroparesis, followed by domperidone, erythromycin, or eventually pyridostigmine. Using these medicaments also requires monitoring for adverse effects [86].
\nIn patients suspected for SIBO, intermittent or rotating administration of antibiotics is indicated. The current approach is based on empirical courses of one or more broad-spectrum antibiotics [123]. A therapeutic trial is performed for 2 weeks, without any testing. After these courses of antibiotics, gastrointestinal symptoms are assessed and if there is no improvement, cyclical courses of antibiotics continue every 2 weeks altered by 2 weeks off [86]. Therapy duration and regimen depend on the severity and recurrence of symptoms and clinical response [86]. Two small studies reported favourable effect of antibiotics in SSc-related SIBO [61, 124]. Nutritional status should not be omitted, and the supplementation should be eventually started at the same time as antibiotics [86]. Probiotics have favourable effect on symptoms and are suitable also in combination with antibiotics [125, 126].
\nThere are more aspects of GIT involvement treatment. Regarding GERD, some studies reported favourable effect of GABA-B (gamma-aminobutyric acid receptor type B) agonists or metabotropic glutamate receptor antagonists (mGluR), which slow the decrease of basal LES pressure [127]. However, the beneficial effect has yet to be studied in SSc [86]. New pharmacological targets are still investigated, e.g. nitrous oxide synthase, cannabinoid, muscarinic or opioid receptors, etc., which reduce the transient LES relaxation. Surgical intervention is not generally recommended in SSc, because of association with increased risk of complications compared to general population, especially worsening of dysphagia [86].
\nInterventional endoscopy is the method of choice in indicated patients, e.g. endoscopic dilation of confirmed strictures should not be performed empirically due to the risk of perforation [128, 129, 130]. Laser or argon plasma coagulation is performed in GAVE, after adequate supplementation therapy of anaemia. Surgery should be the last solution after all strategies fail [86, 131].
\nIntestinal pseudo-obstruction requires exclusion of mechanical obstruction (RDG or computer tomography). Basal therapeutic approach lies in bowel rest, nutritional support, correcting electrolyte imbalance and use of prokinetics and antibiotics for coexisting SIBO [86]. In most cases (70%), this conservative treatment leads to spontaneous resolution. Some patients are indicated for surgery (9%) [132]. Subcutaneous octreotide at doses 50–200 micrograms per day is also recommended [86].
\nTreatment of large bowel symptoms is mainly symptomatic, including dietary measure and administration of laxatives or antidiarrhoeal drugs according to the dominant symptomatology [86]. Before the treatment of constipation, obstruction has to be excluded and current medication should be revised to avoid constipating drugs [133]. Aetiology of diarrhoea should be evaluated to exclude other aetiology, e.g. infections or other autoimmune disorders (celiac disease, microscopic colitis, amyloidosis). Antidiarrhoeal drugs (loperamide) have to be used with caution, because of the risk of pseudo-obstruction [86]. Bile acid sequestrants can be used to improve fat malabsorption in case of SIBO [133]. Incontinence is difficult to treat and requires complex approach consisting of management of diarrhoea, behavioural therapy (anorectal biofeedback), pelvic-floor exercise and eventually neuronal stimulation of sacral nerve—a microsurgery intervention [86].
\nEnteral and sometimes long-term parenteral nutrition is often needed in progressive and advanced disease [1]. There are no studies available on enteral nutrition in SSc patients [83]. The North American expert panel recommends dietary supplementation in similar manner to treatment in patients with chronic diseases. In case of gastroparesis, dietary measures are recommended (low-fibre, low-fat, frequent small meals and higher content of liquid) along with regular monthly monitoring of body weight [83]. Alternative ways of enteral nutrition in case of insufficient oral alimentation are gastric or jejunal feeding [1]: percutaneous endoscopic gastrostomy (PEG) tube feeding, nasojejunal tube, or percutaneous or surgically placed enteral tube feeding in case of refractory gastroparesis and preserved normal small bowel function, or by PN [134, 135].
\nPN is an emerging option of treatment for patients with refractory malnutrition, where the EN is not sufficient (e.g. SIBO) or where surgical enteral nutrition may be difficult to provide (severe cutaneous fibrosis and thickening) [1]. The main disadvantages of PN are in general the cost and PN-related complications: catheter-related bloodstream infections; liver function abnormalities (e.g. cholestasis); metabolic bone disease; fluid overload, especially in patients with ILD and pulmonary arterial hypertension; electrolyte imbalances; and risk of central vein thrombosis in predisposed patients [136, 137, 138, 139, 140]. Moreover, specific problems with PN in SSc are caused by skin involvement, poor quality of veins due to vasculopathy and hand deformities requiring assistance with PN infusion [1].
\nData on long-term PN in SSc patients are lacking. However, based on studies on PN in patients with chronic intestinal pathology and the data from retrospective studies on PN nutrition in SSc patients, which reported the improvement of quality of life and patients’ profit from this therapy, this therapeutic approach is considered as effective in SSc patients [136, 141, 142, 143, 144]. Regular monitoring for complications, control of body weight and adequate altering of nutrient supplements are recommended, along with the establishment of a team for patients’ education, prevention of the catheter-related complications and optimising the nutrition intake. The optimal duration of PN needs to be determined [1].
\nNovel therapeutic options of SSc GIT involvement are investigated, particularly immunosuppressive drugs targeting pro-fibrotic cytokines and IVIGs. Effect of IVIG therapy is multiple: anti-idiotypic-mediated neutralisation of muscarinic, anti-fibroblast or anti-endothelial cell circulating autoantibodies and reduction of pro-fibrotic cytokines. IVIG has a better safety profile compared to immunosuppressive drugs [14]. Observational studies confirmed its potential to improve GIT symptoms and reverse cholinergic dysfunction induced by M3-R autoantibodies in vivo [145, 146, 147]. Another therapeutic approach is targeting miRNA-29 by anti-miRNA chemically modified oligonucleotides [148]. However, future large-scale controlled studies are needed to confirm the beneficial effects of these promising approaches in SSc patients.
\nGastrointestinal involvement is highly prevalent in systemic sclerosis, affects the majority of patients and can be hidden or can precede the obvious skin manifestation. Therefore, overall screening is recommended for early management of the gastrointestinal involvement until the ultimate damage develops. The pathophysiology and specific therapy are still the focus of research, with some promising prospects. To date, the cornerstone of the treatment is mainly symptomatic therapy and adequate nutritional support, best managed in cooperation with other specialists. The general impact of this involvement on patients’ health status and quality of life should not be omitted. Large studies are required to examine aetiopathology and treatment options, including new therapeutic agents, and also complex impact of gastrointestinal involvement on patients’ status (Table 2).
\nField of research | \n\n | To do | \n
---|---|---|
Aetiology | \nGenetic predisposition Infectious aetiology Environmental factors | \nIdentify special haplotypes Identify pathoorganisms triggering the disease (e.g. Identify the insult/toxin triggering the disease (smoking, exposition to toxic substances, etc.) | \n
Pathogenesis Pathology | \nAutoantibodies Cytokines/chemokines | \nAssociation of well-known autoantibodies with the disease features and their role in pathogenesis (anti-topoisomerase I, anti-polymerase III, etc.) Identify new autoantibodies and their role in pathogenesis (e.g. IgG antibodies binding the M3 receptor for acetylcholine) Elucidate the role of cytokines/chemokines and cell immunity | \n
Clinical features/manifestation/phenotype | \nOnset of the disease Extent and severity of involvement Progression | \nFactors determining the course of the disease and clinical manifestation | \n
Comorbidities | \nMalignancy Cardiovascular risk | \nIdentify the factors/disease characteristics increasing the risk of malignancy Determine the risk compared to general population; identify the aetiology and type of specific manifestation | \n
Nutrition Body composition | \nMarkers of malnutrition Prevalence and character of negative changes of body composition | \nComposition of a sensitive and specific tool for evaluation of nutrition and complications leading to malnutrition (e.g. SIBO) Recommendation of an appropriate tool for examination of body composition and frequency of such testing | \n
Therapy | \nFuture specific therapy, targeted at specific mechanisms (molecules, antibodies, etc.) implicated in pathogenesis of the disease | \nIVIG (evidence of anti-idiotypic-mediated neutralisation of muscarinic, anti-fibroblast or anti-endothelial cell circulating autoantibodies and reduction of pro-fibrotic cytokines) Targeting RNA with small molecules; anti-miRNA chemically modified oligonucleotides Conventional synthetic/targeted synthetic/biologic/biosimilar DMARDs Stem-cell transplantation | \n
Brief list of unmet needs and tasks for future research.
This chapter is supported by NV18-01-00161 A, MHCR 023728 and GAUK 312218.
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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 255 peer-reviewed papers, 32 book chapters, and 2 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:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{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. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke 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; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in 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:"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:"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"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. 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His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. 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