\r\n\tNearly 25% - 30% of the world population is affected by neurological diseases exerting a hard financial strain on the healthcare system. The costs are estimated at around $800 billion annualy, expected to exponentially increase as the elders, at high risk of debilitating neurological diseases, will double by 2050. A varied spectrum of neuroprotective strategies has been suggested, including combined antioxidative-anti-inflammatory treatments, ozone autohemotherapy, hypothermia, cell therapy, the administration of neurotrophic factors, hemofiltration, and others. Distressingly, none of the currently available neuroprotective approaches has so far proven to prolong either life span or the cardinal symptoms of the patients suffering from brain injury. Last but not least, translational studies are still lacking.
\r\n\r\n\tThe book aims to revisit, discuss, and compile some promising current approaches in neuroprotection along with the current goals and prospects.
",isbn:"978-1-83880-440-4",printIsbn:"978-1-83880-439-8",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"10acd587ca2c942616bfc09c4b79df39",bookSignature:"Dr. Matilde Otero-Losada, Dr. Francisco Capani and Dr. Santiago Perez Lloret",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8087.jpg",keywords:"IKKβ/NF-κB pathway, neuroendocrine studies, anti-inflammatory agents, Bipolar disorder, oxidative metabolism, metabolic syndrome, Parkinson's disease, Alzheimer's disease, neurotrophins, growth factors, ATP-mediated calcium signalling, glutathione peroxidase",numberOfDownloads:162,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 10th 2019",dateEndSecondStepPublish:"October 1st 2019",dateEndThirdStepPublish:"November 30th 2019",dateEndFourthStepPublish:"February 18th 2020",dateEndFifthStepPublish:"April 18th 2020",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,editors:[{id:"193560",title:"Dr.",name:"Matilde",middleName:null,surname:"Otero-Losada",slug:"matilde-otero-losada",fullName:"Matilde Otero-Losada",profilePictureURL:"https://mts.intechopen.com/storage/users/193560/images/system/193560.jpeg",biography:"Dr. Matilde Otero-Losada graduated at the School of Pharmacy and Biochemistry, University of Buenos Aires (UBA) Argentina; pursued her studies in Neuropharmacology getting her Sci.D. in Neuropharmacology (UBA, Argentina); and completing her Ph.D. in Psychiatry at the Wolverhampton University, WLV, UK. \r\nHer following studies in Psychometrics and Statistical Methods, Radioisotopes and Radiochemistry, Signal Processing and Microcomputers, took her to the University of California San Diego (UCSD) for training in human Psychophysics. \r\nBack in Argentina, she carried on studying smell, taste and trigeminal perception at the Hospital de Clínicas, UBA. \r\nShe focused on the study of metabolic syndrome, soft drinks and cardiovascular-renal morbidity for the last ten years, and in the last two years she is back to her roots: Neurosciences. \r\nWith over 90 papers published in prestigious journals indexed in PubMed, Embase and Scopus and book chapters authored, as Senior Researcher of the National Research Council (Argentina), she customarily reviews manuscripts and is acknowledged for her scientific writing, and editing capacities.",institutionString:"University of Buenos Aires",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:{id:"120703",title:"Dr.",name:"Francisco",middleName:null,surname:"Capani",slug:"francisco-capani",fullName:"Francisco Capani",profilePictureURL:"https://mts.intechopen.com/storage/users/120703/images/system/120703.jpeg",biography:"Dr. Francisco Capani graduated at the School of Medicine, University of Buenos Aires, (UBA) Argentina and completed his doctoral studies in Neurosciences at the Institute of Cell Biology and Neuroscience Prof E. De Robertis, School of Medicine (UBA), Argentina. Then he moved abroad to perform his postdoctoral studies at the University of California San Diego (UCSD-NCMIR) and the Karolinska Institute, Department of Neuroscience. Over an eight-year period, his research focused on synaptic organization, combining electron tomography, 3-D reconstruction, and correlative light and electron microscopy techniques. Upon his return to Argentina in 2006, he devoted to study the mechanisms involved in the pathophysiology of the perinatal asphyxia supported by his broad experience in electron microscopy. 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After obtaining his MD and PhD, he pursued master courses in pharmacoepidemiology, clinical pharmacology and biostatistics at the Universities of Bordeaux and Paris. Dr. Perez Lloret is Assistant professor of Neurophysiology at the Medicine School of the Buenos Aires University and Associate Researcher at the Cardiology Research Institute, University of Buenos Aires, National Research Council. He is member of the International Parkinson’s Disease and Movement Disorder Society (MDS), where he is Co-editor of the Webpage and collaborates in several committees, including the Educational and the Evidence-based Medicine Committees.",institutionString:"University of Buenos Aires",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Buenos Aires",institutionURL:null,country:{name:"Argentina"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:[{id:"69122",title:"Lifestyle Factors, Mitochondrial Dynamics, and Neuroprotection",slug:"lifestyle-factors-mitochondrial-dynamics-and-neuroprotection",totalDownloads:83,totalCrossrefCites:0,authors:[null]},{id:"69463",title:"Polyphenols as Potential Therapeutic Drugs in Neurodegeneration",slug:"polyphenols-as-potential-therapeutic-drugs-in-neurodegeneration",totalDownloads:36,totalCrossrefCites:0,authors:[null]},{id:"69376",title:"Trends in Neuroprotective Strategies after Spinal Cord Injury: State of the Art",slug:"trends-in-neuroprotective-strategies-after-spinal-cord-injury-state-of-the-art",totalDownloads:35,totalCrossrefCites:0,authors:[null]},{id:"70228",title:"Aptamers and Possible Effects on Neurodegeneration",slug:"aptamers-and-possible-effects-on-neurodegeneration",totalDownloads:10,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. 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Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"62373",title:"Chemistry of South African Lamiaceae: Structures and Biological Activity of Terpenoids",doi:"10.5772/intechopen.77399",slug:"chemistry-of-south-african-lamiaceae-structures-and-biological-activity-of-terpenoids",body:'This work is dedicated to Prof. Benjamin Rodriguez (Instituto de Quimica Organic General, CSIC, Spain) for his contributions in the field of natural products and specially in the chemistry of Lamiaceae family.
The Green economy concept has been driven as an urgent need for addressing global challenges in vital fields like energy, environment, and health. Green economy is expected to play a very important role in changing the way that society manages the interaction of the environmental and economic domains. Consequently, a new paradigm has been established and shifted toward green economy or green growth. Natural products represent one of the most important elements required to build safe and effective economy especially in health sector. South Africa (SA) is recognized as one of the most biodiverse country in the world with 20,456 indigenous vascular plant taxa recorded where 13,265 (65%) are endemic [1, 2].
The Lamiaceae (formerly Labiateae, mint family) is a cosmopolitan family with ~7136 species in 236 genera. Most species are shrubby or herbaceous and trees are extremely rare [3]. The Lamiaceae family has great economic value, as it contains several horticultural species, most of which are used as culinary herbs like salvia, rosemary, ocimum, mint, Leonotis, etc. Lamiaceae species are known to contain pharmacologically active terpenoids with a wide spectrum of bioactivity and expected to play more important roles in the process of drug discovery as well as cosmetic, food, and pesticides industries [4, 5, 6]. In the Sub-Saharan region, ~60 genera with ±980 species were reported [7]. SA considers as a diversity spot of Lamiaceae with ±308 species in 41 genera [8]. The species occur predominantly in the summer and/or winter rainfall areas. The habitats are different and vary to a great extent [9].
However, the South African flora is one of the most important mega floras for its unique diversity and endemism, it receives low attention in terms of bioprospecting, and the number of research paper every year dealing with chemical/biological profiling is still beyond the required level. This review serves as a background for the chemistry of all species belonging to the family Lamiaceae growing in SA and it covers publications till 2017. The articles information’s abstracted from Sci-finder database [10] and includes all species growing in SA as well as other places. This chapter doesn’t cover the essential oils and Plectranthus barbatus, which recently reviewed by others [11, 12].
Different classes of secondary metabolites have been identified from Lamiaceae, the majority of the isolated compounds are terpenoids (~71%), and additionally other classes of compounds like flavonoids, α-pyrone derivatives, phenolic acids, and alkaloids were reported. Mono-, sesqui-, and tri-terpenoids are relatively small in number (~15%) when compared to diterpenoids and it was reported that more than 100 of different diterpene skeletons were identified which indicate the high evolutionary index of Lamiaceae [13]. According to the literature, the genera Leonotis (known as wild dagga) and Plectranthus have received the highest attention where 70 (Leonotis) and 94 (Plectranthus) compounds were identified so far, the majority of the isolated compounds are labdane diterpenes. In this chapter, the different genera have been listed alphabetically and the trivial names have been retained in the cases where they were given by authors and/or chemical abstracts.
Aeollanthus genus represented by 43 species globally and 7 in SA. From A. buchnerianus, an abie-tane diterpene, [(rel)-14α-acetoxyabiet-7-en-18-oic acid] (1) [14], 3β-acetoxy-7,15-isopimaradiene (2), 3β-acetoxy-7,15-isopimaradien-19-ol (3) and 19-acetoxy-7,15-isopimaradien-3β-ol (4), 7,15-isopimaradien-19-ol (5, akhdarenol) and 7,15-isopimaradien-3β,19-diol (6, virescenol), a mixture of 19-isobutyryloxy- and 19-butyryloxy-8β-hydroxy-15-isopimarene (7), and a 3:1 mixture of 5-stigmasten-3β-ol and β-sitosterol were isolated from the aerial parts of A. rydingianus. 5 and 6 showed activity against S. aureus and Enterococcus hirae [15].
Ballota is represented by one species in SA vizB africana. Hispanolone (8) was isolated from the aerial parts [16].
Cedronella genus is represented by only one species in SA viz C. canariensis. The phytochemical studies of the aerial parts resulted in isolation of a dimer of d-pinocarvone (9), cedronellone (10), and ursolic acid (11) [17].
Seven species were recorded in SA and clerodendrumic acid (12) was isolated from C. glabrum var. glabrum and showed weak antifungal, antibacterial, and cytotoxic activities [18].
Hoslundia genus is represented by one species in SA vizH. opposite. The phytochemical studies of the aerial parts yielded an interesting and rare pyrano and furanoflavonoid derivatives in addition to euscaphic and (13) ursolic acid (11) [19, 20]; four abietane-type esters, 3-O-cinnamoylhosloppone (14), 3-O-benzoylhosloppone (15), 3-O-benzoylhosloquin-one (16), and 3-O-benzoylhinokiol (17); 13 was found to exhibit MIC of 50 μg/mL against M. tuberculosis, while 14 inhibits the growth of the MDR strain K1 of Plasmodium falciparum in vitro with an IC50-value of 0.4 μg/mL [21].
Three species were recorded in SA. The triterpenes 3α,19α-dihydroxyurs-12-en-28-oic acid (18) and 3β-acetoxyoleanan-13β,28-olide (19), Me betulinate (20), oleanolic acid/acetate (21/22), and ursolic (11) and maslinic acids (23) were isolated from H. mutabilis [22].
From H. spicigera, seven labdane diterpenes; 19-acetoxy-2α,7α,15-trihydroxylabda-8(17),(13Z)-diene (24); 15,19-diacetoxy-2α,7α-dihydroxylabda-8(17),(13Z)-diene (25); 7α,15,19-triacetoxy-2α-hydroxylabda-8(17),(13Z)-diene (26); 19-acetoxy-2α,7α-dihydroxylabda-8(17),(13Z)-dien-15-al (27); 19-acetoxy-7α,15-dihydroxylabda-8(17),(13Z)-dien-2-one (28); 2α,7α,15,19-tetrahydroxy-ent-labda-8(17), (13Z)-diene (29); and 19-acetoxy-2R,7R-dihydroxylabda-14,15-dinorlabd-8(17)-en-13-one (30) were isolated from the aerial parts [23].
Seven species were recorded in SA and two of them were extensively studied. Traditionally, this genus is used to substitute hemp and called as wild dagga; however, there is no much scientific biological evidences supporting such claim. The chemistry was started in early 60s of the last century by South African researchers. Many labdane diterpenes have been isolated. The chemistry of the genus was covered previously by a review published by Piozzi et al.[24].
The chemistry of Leonotis was commenced in 1962 and some compounds were identified; marrubiin (31) compounds, X (32) and Y (33), the stereoisomers of premarrubiin (34) and (35) (the C-13 epimeric forms of premarrubiin). Leonurun (36) has been isolated and the relative stereochemistry was determined using single-crystal X-ray diffraction analysis [24, 25]. After two years, labdane (13S)-9α,13α-epoxylabda-6β(19),15(14)-dioldilactone (37) was isolated, this compound caused significant changes in blood pressure of anesthetized normotensive rats, and also was found to exhibit a negative chronotropic effect [26].
The organic extract of L. leonurus showed 99% growth inhibition against M. tuberculosis at 1.0 mg/mL, subsequent phytochemical studies resulted in the identification of three labdane-type diterpenoids: 9,13:15,16-diepoxy-6,16-labdanediol (38), 6-acetoxy-9,13-epoxy-15-methoxy-labdan-16,15-olide (39), and 9,13-epoxy-6-hydroxylabdan-16,15-olide (40). None of the isolated compounds were active against M. tuberculosis [27].
Recently, Fang et al. [28] identified leonurenones A–C (41–43), in addition to 9,13:15,16-diepoxy-6,16-labdanediol (38) and nepetifolin (44). The leonurenones contain an uncommon α,β-unsaturated enone moiety in ring B. Compound 38 was isolated as epimeric form, (at C-16, ratio 3:1). Compound 41 was isolated from aqueous extract of the leaves and the authors proposed the possible formation of 43 as an artefact via oxidation and lactonization of the more polar intermediate (41) during the isolation process. The total aqueous extract, at concentration of 1.0 g/mL, showed an 81% inhibition in a binding assay at the GABAA site. Compounds 41 and 43 did not show activity (<50% inhibition) in this assay [28].
In the following year, Wu and co-workers (2013) were successful to isolate and identify eleven labdanoides, viz leoleorins D–J (41–43, 45–48) and 16-epi-leoleorin F (49), leoleorin A [corresponding to compound Y (33)], leoleorin B (50) (anhydro derivative of compound Y), and leoleorin C [9,13-epoxy-6-hydroxylabdan-15,16-olide (40)]. The absolute configurations of leoleorin A (33) and D (41) were established by X-ray crystallographic analyses. It is important to indicate that new compounds “leoleorins G-I”, which were isolated in this study, were reported in the previous work under the names of leonurenones A–C (41–43) (13C data showed exchange positions C12 and C14 for leonurenones C/leoleorin H between the two references) [29].
From L. leonurus’ flowers, an acyclic diterpene ester, 1,2,3-trihydroxy-3,7,11,15-tetramethylhexadecan-1-yl-palmitate (51), along with geniposidic acid (52) were isolated, the compounds exhibited neither cytotoxicity on mammalian kidney fibroblasts (Vero cells) nor antimicrobial activities [30].
The chemistry of L. nepetaefolia started almost simultaneously with L. leonurus. Leonotin (53), nepetaefuran (54), nepetaefuranol (55), nepetaefolin (44) methoxynepetaefolin (56), nepetaefolinol (57) and leonotinin (58) the dilactone (8β,17,9,13-diepoxylabdane-16,15,19,6β-diolactone, 59) were characterized [31, 32, 33, 34, 35, 36].
From the species collected from India, nepetaefolinol (57), dehydrated nepetaefolinol (60) and isomeric tetrol (61) (15,16-epoxy-labda-13(16),14-diene-6β,9,17,19-tetrol: the reduction product of leonotinin) were identified [37]. Leonitinic acid (62) with free C-17 carboxyl group was also isolated [38].
From a commercially material, originally collected from Peru, five inseparable epimeric mixtures of bis-spirolabdane diterpenoids, resulted from biosynthetic epimerization of three different structures around C-13 and C-15, have been isolated and identified as leonepetaefolin A (63) and its epimeric isomer 15-epi-leonepetaefolin A (64) (ratio 1:1), leonepetaefolin B(65)/15-epi-leonepetaefolin B (66) (2:3), leonepetaefolin C(67)/15-epi-leonepetaefolin C (68) (1,1), leonepetaefolin D (69)/15-epi-leonepetaefolin D (70) (7,10), leonepetaefolin E (71)/15-epi-leonepetaefolin E (72) (2,3) [39]. Additionally, methoxynepataefolin (56), nepetaefolin (44), nepetaefuran (54), dubiin (73), 19 chlroro derivative of nepetaefolin (74), leonotinin (58), leonotin (53), and LS-1 (75) were isolated. The absolute configuration of the epimeric mixture 63 and 64 was determined by X-ray crystallographic analysis [39].
The isolated compounds were evaluated for their binding activities to a panel of CNS G-protein-coupled receptors including adrenergic, dopaminergic, histaminic, muscarinic, opioid, and serotonergic receptors and neurotransmitter transporters and showed no interesting activity.[39]. From the material collected from Japan, five iridoid glycosides: 10-O-(trans-3,4-dimethoxycinnamoyl) geniposidic acid (76), 10-O-(p-hydroxybenzoyl) geniposidic acid (77), geniposidic acid (52), mussaenoside (78), and ixoside (79) were isolated [40].
L. ocymifolia was studied under different synonyms viz; L. dubia (L. ocymifolia, var. ocymifolia),L. leonitis; L. leonitis var. hirtfolia (L. ocymifolia, var. ocymifolia) and L. dysophylla Benth. (L. ocymifolia var. raineriana) and L. ocymifolia var. raineriana (Burm f) Iwarsson var. raineriana (Visiani) Iwarsson. The chemical studies resulted in the isolation of dubiin (73), 9α,13(S)-epoxy-8β-hydroxylabdane-6β,19;16,15-diolide (80), and leonitin (81). 20-acetoxy-9α,l3-dihydroxy-15(16)-epoxylabd-14-en-6β(19)-lactone (82) and 6β-acetoxy-9α,l3α-epoxylabda-20(19),16(15)-diol-dilactone (83) are from the leaves, in addition to compound X (32)[24, 41] Finally, nepetaefolin (44), leonotinin (58), and leonotin (53) were identified from the material collected from Pretoria (South Africa) [42].
Neophyptis genus is represented by N paniculata in SA. Isoneocembrene-A (84), β-caryophyllene oxide(85), α-himachalene (86), the isolates showed weak to moderate antibacterial activity against five strains of S. aureus [43].
Ocimum genus comprises 65 aromatic species, distributed in tropical and subtropical regions worldwide. Species belonging to this genus are popularly used in Africa and Asia for treating diabetic symptoms. The genus is represented by 16 species in SA and the phytochemical study of O. amercanium afforded four compounds of the copane series (copan-3-ol (87), cop-l1(12)-en-3-o1 (88), cop-3(15)-en-11-ol (89), and cop-l0(ll)-en-3,12-diol(90)) [44].
Orthosiphon genus comprises 40 species recorded from the old world: in tropical and subtropical regions including Southern Africa and Madagascar. Three species were found in SA. Three labdanoids (+)-trans-ozic acid (91), labda-8(17),12E,14-trien-2α,18-diol (92), and 2α-hydroxylabda-8(17),12E,14-trien-18-oic acid (93) have been isolated from an ethanol extract. Compound 93 exhibited activity against M. tuberculosis, while 92 showed cytotoxic activity against MCF-7 and decreased the production of all the pro-inflammatory cytokines. From the same source, pheophytin a, the acidic degradation product of chlorophyll a, was isolated and showed inhibition of HIV-1 protease [45, 46].
Only one species was recorded in SA. From the ethyl acetate extract of P. rotundifolium, cassipourol (94), β-sitosterol, and α-amyrin were identified [47].
About 300 species distributed in tropical and warm regions of the old World, 45 species recorded in SA, from which 19 species were studied for their chemical and/or biological constituents. The genus is characterized by the presence of orange glands that distributed in the aerial parts and contain highly oxygenated (and modified) abietane-type diterpenoids. Others, e.g., kaurane, labdane, phyllocladane as well as the rare skeleton halimane diterpenoids were described.
Plectranthus ambiguus afforded a series of tetracyclic phyllocladane-type (= 13β-kaurane) diter-penoids: (16R)-2α-senecioyloxy-3α-acetoxyphyllocladan-16,17-diol (95), (16R)-2α-senecioyloxy-3α,17-diacetoxy-16-hydroxyphyllocladane (96), (16R)-2α-isovaleroyloxy-3α-acetoxyphyllocladan-16,17-diol (97), (16R)-2α-isovaleroyloxy-3α,17-diacetoxy-16-hydroxyphyllocladane (98), (16R)-3α-acetoxyphyllocladan-16,17-diol (99), (16R)-2α-senecioyloxy-16,17-dihydroxyphyllocladan-3-one (100), and (16R)-2α,3α-diacetoxyphyllocladan-16,17-diol (101). The authors discriminated between phyllocladane and ent-kaurane tetracyclic skeletons after extensive spectroscopic investigation as well as chemical transformations [48, 49].
Thymoquinone (105) was identified as an active nonpolar ingredient to suppress the expression of lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) [50]. The total extract showed cytotoxic activity against MCF-7, using HPLC-based metabolomics approach, and 7α-acetoxy-6β-hydroxyroyleanone (102) was identified as the main active constituent. Other minor compounds like coleon E (103) and royleanone (104) were also identified [51].
Plectranthus caninus afforded coleons M (106), N (107), P (108), Q(109), R (110), S (111), and T (112) and barbatusin (113) [52, 53].
Plectranthus ecklonii is traditionally used in South Africa for treating stomach aches, nausea, vomiting, and meningitis. Ecklonoquinone A (114) and B (115) and parviflorons D (116) and F (117) were isolated [54, 55]. Compound 117 showed potent activity against Listeria monocytogenes and M. tuberculosis and both 116 and 117 were found to be very toxic against vero cell lines. The potency of parvifloron D (116) was further confirmed and showed fast and potent apoptotic inducer in leukemia cells [56].
Two pimaranes rel-15(ζ),16-epoxy-7α-hydroxypimar-8,14-ene (118): rel-15(ζ),16-epoxy-7-oxopimar-8,14-ene (119) and a labdane 1R,11S-dihydroxy-8R,13R-epoxylabd-14-ene (120) were isolated. The three compounds showed activity against M. tuberculosis and different strains of S. aureus [57].
Plectranthus fruticosus cultivated in Porugal afforded 4 labdanes, ent-labda-8(17),12Z,14-trien-2β-ol (121),ent-2α-acetoxylabda-8(17),12Z,14-trien-3β-ol (122), ent-3β-acetoxylabda-8(17),12Z,14-trien-2α-ol (123),3β-acetoxylabda-8(17),12E,14-trien-2α-ol (124), 10 kauranes (ent-12β-acetoxy-15β,16β-epoxykauran-19-oic acid (125), ent-7β-hydroxy-15β,16β-epoxykauran-19-oic acid (126), ent-15β,16β-epoxykauran-19-oic acid (127), ent-15β,16β-epoxykauran-19-ol (128), ent-12β-acetoxy-15β-hydroxykaur-16-en-19-oic acid (129), ent-12β-acetoxy-7β-hydroxykaur-16-en-19-oic acid (130),methyl ent-12β-acetoxy-16-kauren-19-oate (131), ent-7β-hydroxykaur-15-en-19-oic acid (132), methyl ent-12β-acetoxy-7β-hydroxykaur-15-en-19-oate acid (133), ent-12β-acetoxy-17-oxokaur-15-en-19-oic acid (134), methyl ent-12β-acetoxy-15-kauren-19-oate (135), additionally, armendrance (136), caryophyllene α-oxide (137), ursolic/oleanolic acids (2,1 mixture) β-sitosterol, stigmasta-5,22E-dien-3β-ol, and β-amyrin. Some of the compounds showed moderate anti-staphylococcus activity [58, 59]. P. fruticosus growing in India showed abietane diterpene pattern and 7α-acetoxy-6β-hydroxyroyleanone (102), 6,7-dehydroroyleanone (138) and 7α,6β-dihydroxyroyleanone (139) were isolated [60].
In addition to 14-hydroxytaxodione (140), coleons U (141) and V (142), a series of abietane dimers namely grandidone A (143), B(145), and D(147) and their epimers 7-epigrandidone A(144), B(146), and D (148) and grandidone C (149) [61] were identified. Also, royleanone (103), 6,7-dehydroroyleanone (138), horminone (150), 6β-hydroxyroyleanone (151), and 7α-acetoxy-6β-hydroxyroyleanone (102) together with a mixture of fatty acid esters of 7α-acyloxy-6β,12-dihydroxy-abieta-8,12-diene-11,14-dione (152), 7α,6β,-dihydroxyroyleanone (139), and 9α-(2-oxopropyl)abietane derivative(156) were isolated [62, 63, 64, 65, 66, 67].
Fatty acid esters of 7α-acyloxy-6β-hydroxyroyleanone (152) showed moderate antibacterial activity [62]; coleon U exhibited potent cytotoxicity against a panel of human cancer cell lines [63, 65] also showed potent inhibition of mouse splenocyte proliferation induced by ConA or LPS mitogens [64]. Coleons U 141 is considered as a promising compound and deserves further evaluation as an anti-cancer drug [68]. Coleon U (141), 7α-acetoxy-6β-hydroxyroyleanone (102), and horminone (150) showed activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Recently, the biological activity of 102 was reported and showed selective cytotoxicity against MCF-7. Other derivatives of the same compound showed potent cytotoxic [69, 70] and antimicrobial [66] activities.
Plectranthus hereroensis horminone (150), 16-acetoxy-7α,12-dihydroxy-8,12-abietadiene-11,14-dione (153) and 7α-12-dihydroxy-17(15→16)-abieta-8,12,16-triene-11,14-dione (157);3β-acetoxy-6β,7α-12-trihydroxy-17(15→16)18(4→3)bisabeo-abieta-4(19)8,12,16-triene-11,14-dione (158) were isolated [13, 66, 71], on the other hand, the structure of an aristolane sesquiterpene aldehyde (159) have been revised [72], all compounds showed moderate antimicrobial activity [13, 66, 71, 72], while 158 showed antiviral activity [73].
Plectranthus madagascariensis is used as a traditional medicine in Southern Africa. Three constituents were isolated and identified as 6β,7β-dihydroxyroyleanone (154), 7β-acetoxy-6β-hydroxyroyleanone (155), and coleon U (141). The compounds exhibited inhibitory activity on α-glucosidase, S. aureus and Enterococcus faecalis [74].
Traditionally, the plants were used for treatment of stomach and liver diseases and as a substitute of P. barbatus. The phytochemical studies resulted in the isolation of 11 neoclerodanes (plec-trornatins A (160) [75], 11R*-acetoxykolavenic acid (161), 11R*-acetoxy-2-oxokolavenic acid (162), 11R*-acetoxy-3β-hydroxyneocleroda-4(18),13E-dien-15-oic acid (163) [76], ornatins A–E (164-168), 3β-hydroxyneocleroda-4(18),13E-dien-15-oic acid (169) [77]; 7 labdanes (plectrornatins B (170), C (171), [75],6-O-acetylforskolin (172); 1,6-di-O-acetylforskolin (173), 1,6-di-O-acetyl-9-deoxyforskolin (174) [76, 78], rhinocerotinoic acid (175) [66], 8β-hydroxylabd-13-en-15-oic acid (176) [77]); 2 abietanes (14-O-acetyl-coleon U (177), coleon R (110)) and a halimane derivative, (11R*-acetoxyhalima-5,13E-dien-15-oic acid (178) [79]) in addition to β-sitosterol and stigmasterol, 3β-acetyl-α-amyrin, and friedelin. Inversion at C-13 of 1,6-di-O-acetyl-9-deoxyforskolin (174) was carried out based on correlations between 13C NMR experimental data and HF/6-31G* calculation [80]. 160, 161 showed moderate antimicrobial. 178 exhibited growth inhibitory activity against five Staphylococcus and five Enterococcus strains [75]. Ornatin C, D, E and three related diterpenes displayed marginal bactericidal or bacteriostatic effects against the Gram-positive strains [77].
Plectranthus porcatus: (13S,15S)-6β,7α,12α,19-tetrahydroxy-13β,16-cyclo-8-abietene-11,14-dione (179) has been isolated and showed weak antibacterial activity against S. aureus [81].
Plectranthus Saccatus ent-7α-acetoxy-15-beyeren-18-oic acid (180), ent-3β-(3-methyl-2-butenoyl) oxy-15-beyeren-19-oic acid (181), and ent-3β-(3-methylbutanoyl) oxy-15-beyeren-19-oic acid (182). Both 181 and 182 showed insect antifeedant activity against Spodopteralittoralis, while 180 showed no antibacterial activity [81, 82].
Plectranthus strigosus: 9 abietanes (parviflorones A (183), B (184), C (185), D (114), E (186), F (115), G (187), and H (188) [83], and hinokiol (189)) [84]), 3 kauranes (ent-16-kauren-19-ol (190), ent-16-kauren-19-oic acid (191), xylopic acid (192), xylopinic acid (193)), and 2 sesquiterpens (4β,6β-dihydroxy-1α,5β(H)-guai-9-ene (194) 4β,6β-dihydroxy-1α,5β(H)-guai-10(14)-ene (195)), were isolated [84]. A bioactivity study revealed herpetic inhibitory properties for (190) and (191) [84].
The genus Salvia is known as sage and is the largest genus in Lamiaceae, comprising over 900 species distributed throughout the world. Salvia is represented by 30 species in SA, distributed mainly in great cape region. The chemistry of Salvia is rich in diterpenoids and different skeletons have been reported, also, many members of this genus is well known for its curative and medicinal properties like S. officinalis and S. miltiorrhiza.
Salvia africana-lutea: carnosol (196), rosmadial (197), and carnosic acid (198-characterized as its methyl ester) were isolated. Compound 198 exhibited potent activity against M. tuberculosis and cytotoxic activity against a breast (MCF-7) human cancer cell line [45].
Salvia chamelaeagnea: four compounds were isolated: carnosol (196), 7-O-methylepirosmanol (200), oleanolic and ursolic acids as the active principles against S. aureus [85].
Salvia coccinea: momordic acid, methyl ester (201) [86], salviacoccin (202) [87], dehydrouvaol (203), and uvaol (204) [88] were isolated.
Salvia disermas aerial parts afforded ocotillol II (205) [89].
Salvia radula: betulafolientriol oxide (206) was isolated [90].
Salvia reflexa: four neoclerodanes were isolated and identified as salviarin (207), 6β-hydroxysalviarin (208), 15,16-epoxy-8α-hydroxyneocleroda-2,13(16),14-triene-17,12R:18,19-diolide (209), and 5,6-secoclerodane, 7,8-didehydrorhyacophiline (210) [91].
S. repens whole plant extract yielded 12-methoxycarnosic acid (199) with antiprotozoal activity against Leishmania donovani amastigotes and cytotoxicity against the L6-cells [92].
Solenostemon genus is from S. rotundifolius; oleanolic acid was isolated as a major component [96].
Seven species were recorded in SA, one of them T. riparia is widely distributed in Africa and showed interesting chemical profile. Several compounds have been isolated from the leaves of this plant, including 8(14),15-sandaracopimaradiene-7α,18-diol (214) [97], 8(14),15-sandaracopimaradiene-2α,18-diol (215) [98], 9β,13β-epoxy-7-abietene (216), 6,7-dehydroroyleanone (136) [99], and ibozol (217) [100].
Compound (214) exhibited antimicrobial activity (213). Compound (215) showed papaverine-like antispasmodic activity on guinea pig ileum contracted by methacholine, histamine, or BaCl2 and on the noradrenaline-induced contractions of rabbit aorta [101]. It also showed activities against Trichomonasvulgaris with MIC of 20–40 μg/mL [102], wheat rootlets inhibition activity (MIC7.81 μg/mL) [103], and M. tuberculosis[104].
Three species were recorded in SA. From T. africanumtafricanins A (218) and B(219), teutrifidin (220) and 4α,18-epoxytafricanin A (221) were isolated [105].
Vitex genus is represented by 12 species in SA. The fraction responsible for antimicrobial activity of V. rehmannii was purified to give a labdane diterpene as an inseparable epimeric mixture of 12S,16S/R-dihydroxy-ent-labda-7,13-dien-15,16-olide (222). The extract and the labdane diterpene exhibited good antimalarial activity, with the labdane diterpene being the most active IC50: 2.39 ± 0.64 μg/mL [106].
South African flora characterized by high endemism and unique floral kingdom is only located in the great cape region. Lamiaceae is represented by ~308 species widely distributed all over the country. In general, the bioprospecting of SA flora including Lamiaceae is not reached; yet the required level and more attention are required to explore the potential of their chemical constituents. The present work shades the light on the isolated terpenoids of all listed species in updated SA flora checklist. It is interesting to indicate that Plectranthus genus contains mostly abietane diterpenes and shows potent activity as demonstrated by coleon U and parviflorons F and D. On the other hand, leoleorin C from L. Leonurus showed moderate binding affinity (Ki = 2.9 μM) to the Sigma 1 receptor. These compounds and others may be considered as a model for drug discovery for human benefits.
Cape Peninsula University of Technology and National Research Foundation, South Africa, (grant No. 106055).
The author declares no conflict of interest to disclose.
Vaccines are biologics that provide active adaptive immunity against specific diseases. Vaccines usually contain drugs that resemble the microorganisms responsible for the disease and are often made from one of the killed or attenuated microorganisms, their toxins, or their surface proteins, introduced by mouth, by injection, or by nasal spray to stimulate the immune system in us and recognize the foreign agents and destroy them.
\nThere are many success stories in vaccine. The first vaccine, against smallpox, a disease that had killed millions of people over the centuries by British physician Edward Jenner in 1796 [1], was derived from the benign cowpox virus, which provided immunity to small pox. In 1980, following an historic global campaign of surveillance and vaccination, the World Health Assembly declared smallpox eradicated. In the nineteenth and twentieth centuries, scientists following Jenner’s model developed new vaccines to fight numerous deadly diseases, including polio, whooping cough, measles, tetanus, yellow fever, typhus, rubella mumps, varicella, and hepatitis B and many others [2]. Rabies was the first virus attenuated in a lab to create a vaccine for humans.
\nThe vaccine exposes humans to very small and safe amounts of attenuated or killed viruses and bacteria. When you are exposed to it in later life, the immune system will learn to recognize and attack infections. So you will not get sick, or you may be infected lightly. During the process of immunity development, the body produces antibodies against specific microorganisms and creates defense. The next time the person encounters that microorganism, the antibody prevents him from causing disease or alleviates the severity of the disease, regardless of the way that a vaccine is made.
\nVaccines are the most cost-effective healthcare interventions known to prevent death and disease. A dollar spent on a childhood vaccination not only helps save a life but greatly reduces spending on future healthcare. According to a new study from the University of North Carolina at Chapel Hill, vaccination efforts made in the world’s poorest countries since 2001 will have prevented 20 million deaths and saved $350 billion in healthcare costs by 2020 [3]. There are still numerous diseases causing globally significant morbidity and mortality, for which no vaccines are available. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, diseases without effective vaccines. This chapter describes the vaccine types now in use and that may lead to the vaccines of the future.
\nThere are several different types of vaccines. Each type is designed to boost your immune system and prevent serious, life-threatening diseases. Four types of vaccines are currently available:
live attenuated vaccines;
inactivated vaccines;
subunit, recombinant, polysaccharide, and conjugate vaccines; and
toxoid vaccines.
Live attenuated vaccines contain a version of the living virus that has been weakened so that it does not cause serious disease in people with healthy immune systems. Live attenuated vaccines can be made in several different ways. The most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Viruses are often attenuated by growing them in cells that they do not normally grow in for many generations. With each passage, the virus becomes better at replicating in new cells but loses its ability to replicate in human cells. Eventually, the attenuated virus will be less able to live in human cells and can be used in a vaccine. This method selects mutants that are more suitable for growth under abnormal culture conditions and is therefore less suitable for growth in natural hosts. Therefore, when attenuated viruses are given to a human, they are not able to replicate enough to cause illness like they would naturally but will still provoke an immune response that can protect against future infection. Albert Sabin’s oral polio vaccine and measles, rubella, mumps, and varicella vaccines are all achieved by in vitro cell culture passage selection clones. The poliovirus used in the Sabin vaccine is attenuated by the growth of monkey kidney epithelial cells. The measles vaccine contains a strain of rubella virus that grows in duck embryo cells and later grows in human cell lines [4, 5, 6, 7, 8]. Another live vaccine that has so far only been used in the military to prevent epidemic pneumonia includes adenoviruses 4 and 7 grown in human diploid cell lines and orally administered for replication in the intestine [9]. Other live vaccines that are attenuated in cell culture passages are attenuated monovalent rotavirus vaccines in Vero cells [10] and Japanese encephalitis virus strain SA14-14-2 [11]. Some viral vaccines are grown in chicken eggs; live attenuated influenza vaccine and yellow fever vaccines are currently produced in embryonated hen’s eggs, a method developed in the late 1930s [12, 13].
\nLive attenuated vaccines have advantages and disadvantages. Live attenuated vaccines are ideal for teaching the immune system against specific viruses because they are closest to natural infections. They often require only a single immunization, eliminating the need for repeated boosters. And these vaccines are relatively easy to create for certain viruses.
\nThe Sabine polio vaccine consists of three attenuated poliovirus strains that are orally administered to children in sugar cube or sugar liquid. The attenuated virus colonizes the gut and produces protective immunity against all three virulent poliovirus strains. Unlike most other attenuated vaccines that require a single immunization dose, the Sabin polio vaccine requires a booster because the three attenuated polioviruses in the vaccine interfere with each other’s replication in the gut.
\nThe main disadvantage of attenuated vaccines is the possibility they will revert to a virulent form and cause disease. These vaccines cannot be administered to people with weakened immune systems due to cancer, HIV, or other immune system depressing diseases. Attenuated vaccines also may be associated with complications similar to those seen in the natural disease. Live attenuated vaccines usually have to be refrigerated and protected from light. It can be difficult to ship these vaccines overseas and use them in places where there is lack of refrigeration. This technique does not work well for bacteria; therefore there are few live bacterial vaccines. The virus is very simple, but for bacteria, which have thousands of gene, is at least a hundred times larger than a typical virus. This makes bacteria more difficult to control and manipulate than viruses. Currently, scientists are trying to remove key genes from certain bacteria in order to create a weakened version for vaccines.
\nImmunization using this strategy are [14]:
\nViral:
MMR vaccine;
Rotavirus vaccine;
oral polio vaccine (not used in the USA);
influenza vaccine (nasal spray) FluMist;
varicella (chickenpox) vaccine;
shingles vaccine;
yellow fever vaccine;
adenovirus oral vaccine (military); and
Vaccinia vaccine.
Another common method of vaccine production is inactivation of the pathogen by heat or by chemical treatment. This destroys the pathogen’s ability to replicate but keeps it “intact” so that the immune system can still recognize it. Maintaining the epitope structure on the epitope antigen during inactivation is critical. Heat inactivation is generally unsatisfactory because it results in extensive denaturation of the protein; therefore, any epitope that is dependent on higher levels of protein structure may change significantly. Chemical inactivation with formaldehyde or formalin has been successful. The Salk polio vaccine is produced by formaldehyde inactivation.
\nBecause killed or inactivated pathogens cannot replicate at all, they cannot revert to a more virulent form capable of causing disease (as discussed above with live attenuated vaccines). Attenuated vaccines generally require only one dose to induce long-lasting immunity. However, inactivated vaccine tends to provide a shorter length of protection than live vaccines and is more likely to require boosters to create long-term immunity.
\nA vaccine consisting of orally administered killed cholera bacteria with or without the B subunit of cholera toxin has been developed [15]. Formalin-inactivated whole-cell pertussis vaccine was tested by Madsen [16], and later it was shown to be relatively successful in controlling severe disease [17]. In 1923, Glenny and Hopkins reduced the toxicity of diphtheria toxin by formalin treatment [18]. Ramon has improved this finding and has shown that it is possible to inactivate the toxicity of these molecules while retaining their ability to induce toxin-neutralizing antibodies [19]. In the twentieth century, chemical inactivation was also applied to viruses. Influenza vaccine was the first successful inactivated virus vaccine [20].
\nInactivated whole bio vaccines still present certain risks, even if they contain killed pathogens. When formaldehyde failed to kill all viruses in both vaccine batches, serious complications of the first Salk vaccines occurred, which led to a high proportion of polio (poliomyelitis).
\nInactivated vaccines are used to protect against:
hepatitis A;
flu (shot only);
polio (shot only); and
rabies.
The first vaccine, the smallpox vaccine, consists of live attenuated viruses, but it does not cause disease in human hosts. Many of the vaccines used today, including measles vaccines, yellow fever vaccine, and some influenza vaccines, use live attenuated viruses. Others use inactivated forms of toxins made from killed form of virus, debris of bacteria, or bacteria. The killed virus, bacterial debris, and inactivated toxins will not cause disease but will still cause immune reactions and prevent future infections. However, new techniques are also being developed to make different types of vaccines.
\nSubunit, recombinant, polysaccharide, and conjugate vaccines are biosynthetic vaccines. Biosynthetic vaccines contain man-made substances that are very similar to pieces of the virus or bacteria. The hepatitis B vaccine is an example.
\nSince these vaccines use only specific pieces of the germ, they show a very strong immune response, which targets the main part of the germ. It can also be used by almost everyone who needs them, including people with weakened immune system and long-term health problems. Vaccines consisting of specific purified molecules derived from pathogens can avoid some of the risks associated with attenuated or killed organism vaccines.
\nOne limitation of these vaccines is that you may need booster shots to get ongoing protection against diseases.
\nSubunit vaccines use only a subset of target pathogens to stimulate the immune system’s response. This can be done by isolating a specific protein from the pathogen and presenting it separately as an antigen. Acellular pertussis vaccines and influenza vaccines (injected forms) are examples of subunit vaccines.
\nAnother subunit vaccine can be created by genetic engineering. The gene encoding the vaccine protein is inserted into another virus or inserted into a cultured production cell. Vaccine proteins are also produced when the vector virus is propagated. The result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. Many genes encoding surface antigens from viral, bacterial, and protozoal pathogens have been successfully cloned into bacterial, yeast, insect, or mammalian expression systems, and the expressed antigens are used for vaccine development. A hepatitis B vaccine that is approved for use in humans is a recombinant vaccine. The vaccine was developed by cloning the hepatitis B virus surface antigen (HBsAg) gene and expressing it in yeast cells. Recombinant yeast cells proliferate in large fermenters, and HBsAg accumulates in cells. At the end of the fermentation, recombinant HBsAg are harvested by disrupting yeast cells, which is then purified by biochemical techniques. This recombinant hepatitis B vaccine has been shown to induce the production of protective antibodies [21, 22].
\nHuman papillomavirus (HPV) vaccine is another vaccine made using genetic engineering. Two types of HPV vaccine are available, Gardasil (marketed by Merck and protecting against types 6, 11, 16, and 18 of the human papillomavirus) and Cervarix (marketed by GlaxoSmithKline and protecting against types 16 and 18 only). Both are made in the same way: for each strain, a single viral protein was isolated. When these proteins are expressed, viruslike particles (VLPs) are produced. These VLPs contain no genetic material that causes disease but promote immune responses and protect future HPV infection.
\nRecombinant vector vaccines use attenuated viruses (or bacterial strains) as vectors. A gene encoding a major antigen of a particularly virulent pathogen can be introduced into an attenuated virus or bacterium. The attenuated organism acts as a vector that replicates and expresses the gene product of the pathogen in the host.
\nBaculovirus which is a virus that infects only insects can be used as a vector, and genes for specific immunogenic surface proteins of influenza virus can be inserted. Once the modified virus is introduced into humans, the immunogen is expressed and displayed, producing an immune response against the immunogen and producing an immune response to the immunogen from which it is derived. In addition to insect viruses, human adenoviruses have been identified as potential carriers for recombinant vaccines, particularly against diseases such as AIDS. Vaccinia virus, the attenuated vaccine used to eradicate smallpox, was the first used in live recombinant vaccine approaches [23]. This large, complex virus, with a genome of about 200 genes, can be designed to carry dozens of foreign genes without compromising their ability to infect host cells and replicate. Experimental recombinant vaccinia strains have been designed to provide protection against influenza, rabies, and hepatitis B and other diseases.
\nDNA vaccines consist of plasmid DNA encoding antigenic proteins which are injected directly into the muscle of the recipient. The DNA itself inserts into the individual’s cells, which then produce the antigen from the infectious agent. DNA vaccines have advantages over many existing vaccines. For example, the encoded protein is a native form of the host and has no denaturation or alteration. Therefore, the immune response is identical to the antigen expressed by the pathogen. The handling and storage of plasmid DNA do not require refrigeration, a feature that greatly reduces the cost and complexity of delivery. At present, there are human trials underway with several different DNA vaccines, including those for malaria, AIDS, influenza, and herpesvirus. Researchers hope that DNA vaccines can produce immunity against parasitic diseases such as malaria; however, there is currently no human vaccine in use for fighting parasites [24].
\nConjugate vaccines are somewhat similar to recombinant vaccines: they are prepared using a combination of two different components. The conjugate vaccine was prepared using fragments from the coats of bacteria. These coatings are chemically linked to a carrier protein which is used as a vaccine. Conjugate vaccines are used to produce a more powerful co-immune response: in general, the presented “fragments” of the bacteria do not themselves produce a strong immune response, while the carrier protein produces a strong immune response. This fragment of bacterium does not cause disease, but when combined with carrier proteins, it can produce immunity against future infections. The vaccines currently in use for children against pneumococcal bacterial infections are made using this technique.
\nThese vaccines are used to protect against:
Haemophilus influenzae type b (Hib) disease;
hepatitis B;
human papillomavirus (HPV);
whooping cough (part of the DTaP combined vaccine);
pneumococcal disease;
meningococcal disease; and
shingles.
Toxoid vaccines are made from selected toxins that have been sufficiently attenuated and are able to induce a humoral immune response. These toxins produce many of the symptoms of the disease. For example, diphtheria and tetanus vaccines can be prepared by purifying bacterial toxins and then inactivating toxin with formaldehyde to form a toxoid. Inoculating with a toxoid induces an anti-toxoid antibody that is also capable of binding toxins and neutralizing their effects.
\nToxoid vaccines tend not to have a duration of immunity comparable to attenuated viral vaccines; therefore, toxid vaccines, like some other types of vaccines, may need booster shots to get ongoing protection against diseases. Revaccination (booster) may be required multiple times in a single year depending on individual patient risk factors.
\nToxoid vaccines are used to protect against:
diphtheria; and
tetanus.
There are still the needs for vaccines against other diseases. Millions of people worldwide die of malaria, tuberculosis, and AIDS every year, among which there are no effective disease vaccine. The road to successful development of vaccines that can be approved for human use, reasonably manufactured cost, and effective delivery to high-risk groups is expensive, long, and tedious.
\nResearchers continue to develop new vaccine types and improve current approaches.
\nThis work was supported by the National Natural Scientific Foundation of China (Grant Nos. 81673117 and 81573140).
\nWe have no conflict of interest.
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