\r\n\t a multi-pronged approach. The pervasive computing paradigm is at a crossroads where never before computing \r\n\t has been so much embedded within the user. Recent developments in sensor technologies, wireless protocols \r\n\tintegration, and AI have empowered the citizen towards a smart citizen with a high degree of autonomy and varying \r\n\tcomputing capabilities from one context to another. \r\n\t \r\n\tMoreover, software engineering has evolved too to allow lightweight programming and full-stack coding of those sensors. The network itself is today viewed as a programming platform, thus wearable devices are no more stand-alone and do not operate in a vacuum. This book aims at attracting authors from academia, the industry, research institutions, public and private agencies to provide the findings of their recent achievements in the field, but also visionaries who foresee the future of wearable technologies in the coming decades.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"20f07b48960c9e77c8b043adb00b555e",bookSignature:"Dr. Nawaz Mohamudally",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9917.jpg",keywords:"AI, IoT, Cloud computing, Embedded devices, cyborgs, wireless protocols, holograms, AR/VR, intelligent goggles, miniaturization, portability, code mobility",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 24th 2019",dateEndSecondStepPublish:"March 4th 2020",dateEndThirdStepPublish:"May 3rd 2020",dateEndFourthStepPublish:"July 22nd 2020",dateEndFifthStepPublish:"September 20th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"119486",title:"Dr.",name:"Nawaz",middleName:null,surname:"Mohamudally",slug:"nawaz-mohamudally",fullName:"Nawaz Mohamudally",profilePictureURL:"https://mts.intechopen.com/storage/users/119486/images/system/119486.jpeg",biography:"Dr. Nawaz Mohamudally graduated in telecommunications from the University of Science and Technology of Lille I in France. 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1. Introduction
Cultivated forage legumes and range legumes are contributing in sustainable agriculture production apart from nutritional security to the livestock population of India. Cultivated forage legumes and range legumes are also crucial for the nutritional security for mankind as they are integral component for increased availability of animal protein and product which has higher biological value than the plant proteins. The major fodder legumes crops cultivated in India are Medicago sativa, Trifolium alexandrinum, Vigna unguiculata, Mucuna pruriens, Vigna umbellate and range legumes are Stylosanthes spp., Desmanthus virgatus, Clitoria ternatea and others. Among these, Medicago sativa, Trifolium alexandrinum and Vigna unguiculata are more popular among cultivated legumes and Stylosanthes in range legumes because of easy availability of seeds of improved varieties and well developed technology to increase the forage yield and quality. To understand the current status and scope of tropical forage legumes of India for sustaining income through livestock sector, their importance in livestock production, soil health and ecosystem services and diversity among germplasms, evaluation and breeding for improved varieties are discussed in this chapter.
2. Forage legumes in livestock production
India has the largest livestock population in the world with more than 512 million heads. It supports 56.7% of the world’s buffaloes, 12.5% of the world’s cattle and 20.4% of the world’s small ruminants (sheep and goats) [1]. Besides, the country hosts 17% of the world human population [2]. India is also the leading milk producing country in the world but milk productivity per animal basis is very low. Deficiency in quality of fodder is one of the major reasons for the low animal productivity. Although India is very rich in varied flora and fauna but there is deficiency of quality green fodder to the tune of around 35%. The animals need proper feeding to meet their nutrient requirement to express their full genetic production potential.
In fact, the sustenance of Indian rural agricultural economy depends on crop and animal farming, the two key components of a mixed farming system. Although the contribution of agricultural sector in the Indian economy is steadily declining (from 36.4% in 1982–1983 to 14.1% in 2012–2013), it still contributes employment to over 50% of the work force [3]. The contribution of livestock sector to agriculture GDP has increased to more than 28% and is likely to increase further. In the recent past, the lifestyle of people has been changed with a marked shift in food habits towards milk, milk products and meat leading to increase in demand of livestock products. Economic scenario in animal husbandry is also changing with emergence of peri-urban livestock farming and fodder markets. This indicates the huge pressure on available land, most of which, is used for arable farming and food production.
Forages form the main stay of our animal farming to reduce the competition between human beings and animals due to increasing demand for land and other inputs. Sole feeding of green forages to dairy animals is much cheaper than feeding concentrates with crop residues and has the potential of higher level of milk production. Nearly 65% of the total expenditure of milk production in cows is attributed to the feeding of animals when both concentrates and green fodders are fed as mixed ration. When the milk production is primarily depend upon concentrate based feeding, the cost of feeding towards milk production reaches to 80%, however, in case of forage (legumes) based feeding, it is reduced to only 40% of the total expenditure [4]. Hence, any attempt towards enhancing availability of quality green fodder, and economizing the feed cost would result in better remuneration to livestock farmers/producers.
From an animal perspective, one of the largest benefits provided by legume forages is that they provide a better level of nutrition than cereal forages/grasses at a similar stage of growth, leading to greater forage intake by livestock and increased animal performance. The symbiosis between legumes and Rhizobia provides the plant with an ample supply of N and it is one of the reasons why crude protein (CP) concentrations of legumes are higher than cereals/grasses. In addition to higher concentrations of CP, forage legumes also provide a higher quality protein which may be of equal or greater importance in case of non-ruminant livestock species like equines. Legumes also contain more concentrations of digestible energy than grass/cereal forages due to the structure and development of the legume cell wall. Indeed, the cell wall of legume plants contains fewer hemicelluloses and more pectin compared to that of cereals, thus increasing their digestibility by livestock. However as the cell matures, a secondary cell wall consisting of cellulose and lignin is deposited on the interior of the primary cell wall and reduces the overall availability of the structural carbohydrates in the digestive system. In cereal forages, this phenomenon occurs in all tissues types (i.e. leaves, stems, etc.) while being primarily restricted to the vascular tissues of legume stems. The lignin of non-legumes is also more esterified to hemicelluloses and is more recalcitrant in composition (e.g. higher proportion of syringyl subunits) indicating a more suppressed degradability than in legume species.
3. Forage legumes in soil health and ecosystem services
Forage legumes is essential for providing a source of biological nitrogen fixation (BNF) for enriching soil fertility (15–40 kg fixed N/ha), reduction in land degradation, disease breaks and for mitigating climate change. Estimating biological N2 fixation of the forage and fodder legumes precisely is challenging because statistics on the areas and productivity of these legumes are highly difficult to obtain. Therefore, N2 fixation values of forage and fodder legumes will be less reliable and also estimates of %Ndfa (nitrogen derived from atmosphere) of fodder legumes in those lands. There are very few reports available on forage legumes—BNF in India. But, all works mainly focused on application of Rhizobium inoculants to fodder legumes and testing their potential for enhancing fodder production (fresh and dry weight, crude protein content, forage quality aspects, nodulation properties, etc.). Appreciable amount of atmospheric N (~60–100%) is fixed by forage legumes annually, fixing up to 380 kg N ha−1 [5]. Quantity of forage residues available for soil incorporation range from 80 to 143 kg N ha−1 and rice cultivated following forage legumes yields the same as rice with 24–50 kg fertilizer N ha−1 [6]. About 100–120 Mha of land is under fodder and forage legumes and green manure crops, with assumed average N2 fixation rates of 200 kg N/ha/year for alfalfa, 150 kg N/ha/year for clovers (Trifolium spp.), 100 kg N/ha/year for other forages and 50 kg N/ha/year for legume-grass pastures [7]. From this assumption, total nitrogen fixation by forage and fodder legumes was calculated at 12 Tg annually (average of about 110 kg N/ha/year). But fixation by legume-grass mixtures is much more variable, ranging from a just a few kilograms to more than 250 kg N ha−1.
In India, area under fodder legumes and grasses is about 8 Mha (Sorghum bicolor—2.6 Mha, Trifolium—1.9 Mha, Medicago—1 Mha, other legume forages—1.9 Mha). Mean N uptake by Trifolium alexandrinum (240–264 kg/ha), Medicago sativa (216–264 kg/ha), Vigna unguiculata (161–181 kg/ha), Sorghum bicolor (128–160 kg/ha), BN hybrid (Pennisetum glaucum × Pennisetum purpureum) and Megathyrsus maximus (288–360 kg/ha), Avena sativa (120–144 kg/ha). Percent nitrogen derived from atmosphere (%Ndfa) is about 0.7 for legumes and 0.1 for cereals/grasses. Annual contribution of BNF by forage and fodder crops in India is about 0.61 Tg/year which is nearly 5% of world BNF of forage and fodder [8]. However, majority of values available for legume N2 fixation were based on shoots and above ground parts only. They did not include the fixed N present in roots, nodules and rhizodeposition in general. Published values for below-ground N as a percentage of the total plant N are 22–68% for the pulse and oilseed legumes, Glycine max, Vicia faba, Cicer arietinum, Vigna radiata, Lupinus albus, Pisum sativum and Cajanus cajan and 34–68% for the pasture/fodder legumes, subterranean clover, white clover and alfalfa [9, 10, 11].
In addition to BNF, many forage legumes have soil-covering growth habit similar to most grasses and deep root system which can contribute to the mitigation of many soil problems, viz., soil conservation by legume cover crops such as Stylosanthes, Crotalaria, Sesbania, Arachis and Desmodium to prevent erosion; contour-hedges with leguminous trees such as Leucaena; rehabilitation of degraded soils by legumes such as Stylosanthes spp., which are deep-rooted and adapted to infertile soils, cycle minerals from deeper soil layers resulting in soil improvement and enhanced concentration of soil organic matter through litter production [12]; the potential of legumes like Stylosanthes hamata can be exploited to ameliorate compacted soil [13]. When used as cover crop forage legumes can also control weed growth, which can be exploited as an attractive alternative to the use of herbicides. They supplement part of N fertilizer application, thus reduce nitrate leaching and eutrophication of water bodies as a consequence of surface runoff as a result of N fertilization in tropical pasture production process. Tropical forage legumes have considerable potential to increase productivity of forage-based livestock systems, while providing benefits to the environment [14]. The environmental benefits, referred as ‘ecosystem services’, comprise positive effects on: soil conservation and soil chemical, physical and biological properties; mitigation of global warming and of groundwater contamination; saving of fossil energy; and rehabilitation of degraded lands [14]. These features make tropical forage legumes particularly valuable at all levels of the system because of their interaction with plants, soil, animals and the atmosphere.
4. Genetic resources of tropical forage legumes
Plant genetic resources (PGR) are the basic platform for screening, improving and developing fine cultivars, and the important materials for biodiversity studies including classification, evolution and origin. Therefore, maintenance of enormous genetic diversity is mandatory for broadening the genetic base of the present and future forage improvement programmes to achieve the national goals. Extensive collection, proper evaluation, in depth study of genetic attributes and cataloging of germplasm is prerequisite for its efficient utilization. According to an estimate there are about 650 genera, 18,000 species of legumes (Leguminosae) in the world. Out of these, only about 30 legumes are used to an appreciable extent for forage production [15]. Information regarding the centre of origin of different forage crops is furnished in Table 1.
Genus
Species
Centre of origin
Distribution
Atylosia
scarabaeoides
India
Centrosema
pubescens
South America
South east Asia, Indonesia and Africa
Clitoria
ternatea
Tropical America
Tropical and subtropical parts of the world
Desmanthus
virgatus
Argentina
Florida, throughout the India
Desmodium
intortum
Central and South America
Throughout the tropical areas of Africa, Australia and new world
Macroptilium
atropurpureum
Central and South America
Australia, South east Asia, Pacific Islands
Macroptilium
lathyroides
India
Tropical and subtropical world
Macrotyloma
spp.
Africa and Asia
Sri Lanka
Macrotyloma
uniflorum
India
Africa
Stylosanthes
guianensis
Brazil
West Indies, Africa and Pacific Islands
Stylosanthes
hamata
Islands of West Indies
Coastal regions of north and south America
Stylosanthes
humilis
North east Brazil and Venezuela
Tropical parts of world
Stylosanthes
scabra
Tropical America
Kenya, Brazil and Queensland
Stylosanthes
seabrana
Brazil
Lablab
purpureus
Asia or Africa
India, subtropical areas of Africa, south Asia
Cyamopsis
tetragonoloba
Africa
India (secondary centre of origin)
Trifolium
alexandrinum
Syria
Egypt
Medicago
sativa
Asia Minor
Near East and central Asia
Table 1.
Centre of origin of different tropical forage legumes.
World-wide, 1500 gene banks are registered in the WIEWS (World Information and Early Warning System on PGR) database [16] and conserve a total of 7.1 million accessions belonging to 53,109 species, including major crops, minor or neglected crop species, as well as trees and wild plants. Out of total germplasms stored, 651,024 accessions belonging to forage crops [17]. Among the international organizations major forage germplasm repositories are International Livestock Research Institute (ILRI), Nairobi, CIAT Columbia; ICARDA Syria; CSIRO-Australia, IGER-UK, USDA-Fort Collins. Forage germplasm diversity in these organizations is part of a Consultative Group of International Agricultural Research (CGIAR) coordinated activity in plant genetic resources. The ILRI Gene bank conserves more than 18 thousand accessions of forages from over 1000 species. This is one of the most diverse collections of forage grasses, legumes and fodder tree species held in any gene bank in the world [18]. CIAT gene bank keeps 35,898 accessions of beans, for 44 species of the genus Phaseolus from 109 countries, and 23,139 forage accessions belonging to 668 different species of grasses and legumes from 72 countries, that have been introduced over the past 30 years [19]. The IITA gene bank holds the world’s largest and most diverse collection of cowpeas, with 15,122 unique samples from 88 countries, representing 70% of African cultivars and nearly half of the global diversity.
Indian sub-continent being one of the world’s mega centres of crop origin and crop plant diversity, represents a wide spectrum of eco-climate and reported diversity of 21 forage legumes genera viz., Desmodium, Lablab, Stylosanthes, Vigna, Macroptelium, Centrosema and browse plants including Leucaena, Sesbania, Albizia, Bauhinia, Cassia, Grewia, etc. (Table 2). Diversity of cultivated and range legumes were collected in form of 3261 diverse germplasm accessions through different indigenous and exotic germplasm collection programme. Collected diversity of forage legumes were evaluated and sources for different biotic and abiotic stress tolerance were identified apart from >50 cultivars in different forage legumes for different geographic regions developed. Crop wild relatives (CWR) being the reservoirs of genes for stress tolerance and quality have been utilized for genetic enhancement of forage legumes. The main centre of diversity for tropical legumes viz., Dolichos, Desmodium, Vigna and Crotalaria is peninsular India and subtropical legumes viz. Teramnus, Atylosia, Pueraria and Mucuna are mainly confined to north eastern region. Likewise, rich genetic wealth for the temperate legumes namely Medicago, Melilotus, Trifolium and Hedysarum is distributed in western Himalayan region [20]. Besides, India possesses enormous diversity of minor and under-utilized fodder species such as Agrostis alba, Desmodium parvifolium, Leptochloa fusca, Potentilla fruticosa, Rhynchosia minima and Salvadora persica [21]. The forage genetic wealth of India distributed in 15 agro-climatic zones has been summarized in Table 2.
Sikkim, Arunachal Pradesh, Meghalaya, Nagaland, Manipur, Tripura, Mizoram, Assam, Jalpaiguri and Cooch Bihar district of West Bengal
Rice bean, maize, range grasses, Brachiaria, broom grass and lablab bean
3
Lower Gangetic Plains
Basin plains, central alluvial plains, alluvial coastal plains and Rarh plains
Rice bean, guinea grass, coix and range grasses
4
Middle Gangetic Plains
12 districts of eastern Uttar Pradesh and 27 districts of Bihar plains
Maize, cowpea, rice bean, Pennisetum pedicellatum and coix.
5
Upper Gangetic Plains
central, south-western and northern-western Uttar Pradesh
Maize, sorghum, cowpea Senji, Dichanthium, sehima and Heteropogon
6
Trans-Gangetic Plains
Punjab, Haryana, Delhi, Chandigarh and Sri Ganganagar district of Rajasthan
Guar, maize, bajra, berseem, lucerne, guinea grass, sorghum and cowpea
7
Eastern Plateau and Hills
(i) Sub region of Wainganga, Madhya Pradesh, eastern hills and Orissa inland; (ii)Orissa northern, Madhya Pradesh, eastern hills and plateau; (iii) north and eastern Chota Nagpur hills and plateau; (iv) Chota Nagpur south, West Bengal hills and plateau, and (v) Chhattisgarh and south-western Orissa hills.
46 districts of Uttar Pradesh, Madhya Pradesh and Rajasthan
Maize, cowpea, rice bean, P. pedicellatum, Coix, Atylosia, sorghum, bajra, guar, Cenchrus, range grasses and legumes
9
Western Plateau and Hills
Maharashtra, parts of Madhya Pradesh and one district of Rajasthan
Maize, sorghum, Dichanthium spp. pearl millet, Dichanthium carzacosum, Vicia, cowpea, rice bean, Cenchrus, range grasses and legumes
10
Southern Plateau and Hills
35 districts of Andhra Pradesh, Karnataka and Tamil Nadu
small millet, Heteropogon, Dichanthium sehima and Stylosanthes sp.
11
East Coast Plains and Hills
(i) Coastal Orissa (ii) North-Coastal Gujarat (iii) South-Coastal Andhra Pradesh, North-Coastal Tamil Nadu (v) Thanjavur and (vi) South Coastal Tamil Nadu.
cowpea, rice bean, guinea grass, coix, small millet, sorghum, Heteropogon, Dichanthium and Stylosanthes sp.
12
West Coast Plains and Hills
Western coast of Tamil Nadu, Kerala, Karnataka, Maharashtra and Goa
Congo, signal grass, Paspalum, panicum, Digitaria, Brachiaria, Iseilemalaxum, Isilemia and Vicia
13
Gujarat Plains and Hills
19 districts of Gujarat
Lucerne, sorghum, small millet, pearl millet, chioori, range grasses and legumes
14
Western Dry Region
Nine districts of Rajasthan
Guar, moth, cowpea, sorghum, pearl millet and Cenchrus spp.
15
Island Region
Territories of the Andaman and Nicobar Islands and Lakshadweep
Table 2.
List of prominent forage genetic resources distributed in 15 agro climatic zones of India.
The National Bureau of Plant Genetic Resources (NBPGR) is the nodal agency for characterization, evaluation, maintenance, conservation, documentation and distribution of germplasm resources in India. Currently a total of 4594 accessions of different forage crops including cereal forages (1167), grasses (11,160, range legumes (1443), forage millets (781) and others [85] are being maintained at long term storage (LTS) module of National Gene Bank at NBPGR, New Delhi [22]. Indian Grassland and Fodder Research Institute (IGFRI) is a unique R&D organization in South Asia for sustainable agriculture through quality forage production for improved animal productivity. IGFRI being the National Active Germplasm Sites (NAGS) on forages works with its three regional stations and All India Coordinated Research Project (AICRP) on forage crops with 18 coordinated centres. At present IGFRI maintains more than 8000 accessions of 19 major forage crops including cereal forages, forage legumes, grasses and fodder tree at midterm storage [23].
5. Problems associated with breeding of tropical forage legumes
Tropical forage legumes breeding programmes are associated with certain unique problems. Most of the tropical pasture legumes still possess traits of wild plants that include seed shattering, small seed size, seed dormancy, relatively slow germination rates, etc. In most of the cases we have very little knowledge about the basic biology of the species. Some of the problems include overlapping of vegetative and reproductive growth phases, uneven pod setting, non-synchronous maturity and seed shattering in forage legumes [24]. Inherent heterozygosity as most forage species are cross pollinated. Self-incompatibility limits the extent to which they may be inbred; small floral parts make artificial hybridization tedious; poor seed producers; or produce seed with low viability as well as inherently low seedling vigor and competitive ability. Many forage species produce weak seedlings and stands are not easily established. Strains may perform differently with different systems of grazing management. Persistence of perennial tropical forage legumes is not as a single trait, but rather as a complex of traits dependent on various factors, such as diseases, insects, abiotic stresses, or management stress. Fertility barriers of one sort or another are very common in tropical forage legume breeding viz., berseem [25], owing to the wild nature of the species and inadequate knowledge of inter- or intra-specific variation.
6. Major forage legumes of India
6.1. Egyptian clover (Trifolium alexandrinum L.)
The genus Trifolium from the tribe Trifolieae of the family Leguminosae (Fabaceae) is important for its agricultural value. A few of the 237 species of this large genus have actually been cultivated [26], out of which 25 species are important as cultivated and pasture crops [27]. Egyptian clover or berseem (T. alexandrinum 2n = 16) is commonly cultivated as winter annual in the tropical and subtropical regions. Berseem is popular due to its multicut [4, 5, 6, 7, 8] nature, providing fodder for a long duration (November to May), very high quantum of green fodder (85 t/ha) and better quality of fodder (20% crude protein), high digestibility (up to 65%) and palatability. Berseem was introduced in India from Egypt in 1904, and has been established as one of the best Rabi (winter season) fodder crop in entire North West Zone, Hill Zone and part of Central and Eastern Zone of the country, occupying more than two million hectare [28].
Berseem being an introduced crop in India, the most important drawback in genetic improvement has been the lack of genetic variability [29, 30]. Variability in the existing gene pool has been induced through mutation, polyploidization and inter-specific hybridization. High biomass production potential along with extended growth period and resistance to biotic stresses specially root rot and stem rot have been the main target traits that were to be improved genetically. Different genetic improvement programmes carried out in various research institutes/universities by utilizing breeding approaches like selection, polyploidy and mutation resulted in the development of >15 varieties for different berseem growing regions of India. Inter-specific hybridization have been used to improve resistance to biotic and abiotic stresses and extended length of the vegetative period because genes for wide scale adaptability are widely distributed in several wild species of Trifolium (Table 3). Interspecific hybrids of berseem with Trifolium apertum [31], T. constantinopolitanum [32], T. resupinatum [33] and T. vesiculosum [34] were successfully developed and progenies of interspecific hybrids showed introgression of various desirable traits, including late flowering and resistance to root rot and stem rot diseases.
Species
Chromosome number (2n)
Desirable characters
References
T. alexandrinum ecotype Mescavi
2n = 16
Annual, multicut, highly productive, crude protein, high digestibility and palatability, basal branching
Desirable characters in berseem ecotypes and wild Trifolium species.
A major breakthrough in berseem breeding in India was achieved through induction of polyploidy. The work on polyploidization of berseem genome was started with the aim to induce greater leaf and stem size [35, 36]. Autotetraploid induced by using colchicine treatment, and selection at tetraploid level resulted in the development of first polyploid variety ‘Pusa Giant’ with more fodder production and good regeneration capacity, uniform and higher yield throughout the season than diploid varieties released for general cultivation in India [37]. Another big achievement in polyploidy breeding was achieved at IGFRI, Jhansi by developing an autotetraploid variety namely ‘Bundel Berseem-3’ through colchiploidy followed by recurrent single plant selection followed with mass selection [28]. Major success in Berseem breeding was achieved by induction of longer duration mutant in Mescavi variety through gamma ray treatment which resulted in ‘BL-22’ a variety released in 1988 for temperate and north west zone; and ‘BL-180’ released in 2006 for cultivation in north-west zone of India [28]. Protocol for in vitro plant regeneration from meristematic tissue and the establishment of regenerable callus culture have been developed in Berseem and related species viz., Trifolium glomeratum, T. apertum, T. resupinatum [38, 39, 40]. Embryo rescue technique has been effectively utilized to overcome the problems of post fertilization barriers in interspecific crosses of berseem with Trifolium apertum, T. constantinopolitanum, T. resupinatum and T. vesiculosum [31, 32, 33, 34]. Recently, SSR based markers were developed for large scale utilization programme in Berseem [30]. Few studies on genetic diversity in Berseem and related Trifolium species were reported by using isozymes [29] and molecular markers [41].
6.2. Stylosanthes
The genus Stylosanthes comprises approximately 40 species, distributed in the tropical [42], subtropical and temperate regions areas of America, Africa, and Southeast Asia. It can be grouped into two subgeneric sections, Stylosanthes and Stylosanthes. Most species are diploid (2n = 20) but polyploid species (2n = 40 and 2n = 60) also exist. Six species, namely Stylosanthes scabra, S. seabrana, S. hamata, S. guianensis, S. humilis and S. viscosa, are predominantly used as fodder legume in humid to semi-arid tropics of India (Table 4). These are very popular and have been widely adapted due to their ability to restore soil fertility, improve soil physical properties, and provide permanent vegetation cover as well as to provide nutritious fodder. The most specific problems associated with Stylosanthes are the limited variations of available germplasm and the susceptibility to anthracnose disease caused by the fungus Colletotrichum gloeosporioides. In the past, mainly five species of Stylosanthes (S. hamata, S. scabra, S. humilis, S. viscosa and S. guianensis) have been introduced primarily from Australia and evaluated at different sites in India [43, 44, 45]. This was in addition to the native perennial S. fruticosa Alston, which is widely distributed throughout the southern peninsular regions [46].
Species
Chromosome
Specific features
S. scabra
2n = 4x = 40
Adapted in low rainfall areas (325 mm rainfall), suitable for semi-arid areas of Maharashtra, Andhra Pradesh, Karnataka and Tamil Nadu, S. seabrana and S. viscosa are known progenitor of S. scabra
S. hamata
2n = 2x = 20 2n = 4x = 40
Diploid S. hamata and S. humilis are the two progenitors of this species (Curtis et al., 1995), highly palatable, grazing tolerant
S. viscosa
2n = 2x = 20
Early emergence and highly stickiness of the leaves and stems, drought tolerant, grows on poor soils, some resistance to anthracnose, acaricidal properties
S. humilis
2n = 2x = 20
Tolerance for salinity, susceptible to anthracnose, hairs on stems and leaves are some of the important features helpful in identifying the species
S. guianensis
2n = 2x = 20
Suitable for humid and higher rainfall regions, adapted to acid infertile soils, tolerant of Al and Mn
S. fruticosa
2n = 4x = 40
Allotetraploid, drought tolerant
Table 4.
Important Stylosanthes spp. with specific features.
Testing and evaluation of wide germplasms carried out at IGFRI on acid and saline soil which contribute major part of the soils of India, indicated better adaptation of S. hamata and S. seabrana lines over other species in salinity. The potential of S. seabrana for tropical and subtropical regions of the country with clay and heavy soils, cool winters and distinct wet-dry seasonal conditions directed the use of this species in developing new breeding approach. The one could be based on the finding that it is the second progenitor of S. scabra which in turn elucidated the evolution of one of the most important Stylosanthes species, S. scabra may lead to important impacts on the efforts of improving S. scabra [47]. It may be possible to artificially synthesize S. scabra using pre-selected S. viscosa and S. seabrana accessions [48]. These artificial S. scabra genotypes could be used directly or more likely, be used in breeding programs. By doing so the genetic variation existing in the two diploid progenitor species would become available in improving the allotetraploid S. scabra. So far developed map and linked markers with anthracnose resistance also provide the opportunity to use them after converting them in sequence tagged sites (STS) or sequence characterized amplified region (SCAR) and then using them in direct breeding programs.
6.3. Alfalfa (Medicago sativa L.)
Genus Medicago is one of the oldest forage legume comprising 60 perennial and 35 annual species, distributed mainly around the Mediterranean basin, cultivated throughout the world in diverse environments ranging both temperate and tropical environments [49]. It is generally agreed that the basic chromosome number for the genus Medicago are x = 7 and x = 8. Its ploidy varies from diploid (2n = 16) to polyploid (2n = 32, 48, 64). Perennial species are mainly tetraploids (2n = 4x = 32) and allogamous, however diploid (2n = 2x = 16) and hexaploid (2n = 6x = 48) cytotypes have also been reported [50]. Medicago sativa (alfalfa or lucerne) is widely cultivated as the most important forage legume in the temperate areas of the world. Lucerne is native to South West Asia as indicated by occurrence of wild types in the Cancasus and in mountainous region of Afghanistan, Iran. M. sativa complex, comprises of several members at the same ploidy level e.g., M. falcata, M. media and M. glutinosa, which freely intercross, without any hybrid sterility in the F1 or later generations [51]. In India, it is grown in Maharashtra, Gujarat, Andhra Pradesh, Karnataka, Tamil Nadu, Haryana, Madhya Pradesh, Rajasthan, Punjab. The major breeding objectives in the crop include vigorous tall growing plants, better branching, quick regeneration, and balance between seed and forage yield and persistence.
Genetic resources for alfalfa improvement are limited and restricted to the M. sativa complex but tolerant sources for biotic and abiotic constraints are lacking in the complex [52]. The annual and perennial species of the genus Medicago are the reservoir of several useful agronomic traits, including disease and insect resistance and potential salt and drought tolerance having direct implication in cultivated alfalfa improvement (Table 5). Most of the lucerne cultivars grown in the country and worldwide are susceptible to many diseases and insect pests and the most serious constraint is the alfalfa weevil (Hypera postica Gyll.) [53]. Resistance to weevil has been reported in several annual species such as M. scutellata, M. prostrata, M. turbinata and M. intertexta [54, 55, 56, 57]. Genes conferring resistance to aphid have been identified in M. rugosa, M. scutellata and M. littoralis [58]. Similarly, three woody species viz. M. arborea, M. strasseri and M. citrine of the section Dendrotelis have been reported as excellent sources for incorporating drought and salt tolerance in M. sativa [59, 60, 61]. However, due to post fertilization barrier, interspecific hybridization is difficult, so we may need to use biotechnological tools like ovule-embryo culture and electroporation.
Species
Annual/perennial
Chromosome number (2n)
Distribution
Desirable traits
References
M. dzhawakhetica Bordz.
Perennial
32
Western Mediterranean region
Cold tolerance and resistance to Phoma medicaginis
Annual and perennial Medicago species and their desirable characters.
Inter specific hybrids of M. sativa with some of the perennial species viz. M. cancellata, M. glomerata, M. papillosa, M. prostrata, M. rhodopea and M. saxatilis have been recovered by conventional crosses [51]. However, pollen and embryological studies demonstrated that there exist strong post fertilization barriers for recovering hybrids between M. sativa and annual species [62]. Utilizing embryo culture and fertilized pod culture techniques interspecific hybrids were obtained between M. sativa and many other annual species however, no hybrids were produced between M. sativa and weevil resistant M. scutellata [63, 64]. Bauchan and Elgin [65] reported chromosomal incompatibility and presence of two SAT chromosomes in M. scutellata as the major barriers for getting interspecific hybrids between M. sativa and M. scutellata. Utilizing protoplast fusion technique S1 plants were obtained between M. sativa and M. rugosa and it was confirmed by genomic in situ hybridization (GISH) that small portions of M. rugosa chromosomes were present in the hybrid however, it is not clear that in which chromosome the resistance genes are present [50].
A lot of molecular information has been generated across species. However, information from M. truncatula on marker-trait association is unlikely to be exploitable in lucerne, considering the large differences between annual and perennial [66]; in addition to the differences due to the ploidy level which may further contribute to the inconsistent genetic control of some morpho-physiological traits between the two species [67]. Some breeding goals such as region-specific adaptation; drought-tolerance; improvement for forage quality should be considered [68]. Attempts have been made to produce transgenic alfalfa containing fungal chitinase gene for resistance against fungal pathogens [69], tolerance to abiotic stresses such as salt and cold [70, 71], improved forage quality [72], and sulfur-containing amino acids [73], value addition by making it an edible forage vaccine [74]. In recent years the breeding strategies for Lucerne are more towards utilizing potential of polycross methods followed with phenotypic selection. It has resulted in development of a few cultivars in recent years. The future strategies should include development of cold and drought hardy lucerne with degree of persistence for pasture and meadows, increasing genetic base, high seed production, stress tolerance, diseases and pest resistance etc.
6.4. Cowpea (Vigna unguiculata (L.) Walpers)
Cowpea (2n = 2x = 22, genome size = 620 Mb) also known as ‘black eye pea’ or ‘hungry-season crop’ is an annual food and forage crop mostly grown throughout the semi-arid tropics in parts of Asia, Africa, Southern Europe, Southern United States, and Central and South America (Singh 2005). It can be grown throughout the year due to its short duration and fast growing nature. It is suitable for inter, mixed and relay cropping system. Cultivated cowpea, which is in subspecies unguiculata, is divided into five cultivar groups namely Unguiculata, Sesquipedalis (yard-long-bean), Textilis, Biflora and Melanophthalmus [75]. The commonly cultivated cowpea belongs to cultivar group Unguiculata the most widespread and economically important group of the species. They are pulse and vegetable and forage types. Other cultivar group Biflora also known as ‘catjang cowpea’ mainly cultivated in South Asia (India, Sri Lanka) as a pulse or as forage for hay and silage, and as a green manure crop. In Australia and Asia cowpea is primarily a fodder crop, but is also used for green manure or as a cover crop [76]. In India, the crop is cultivated around 6.5 lakh ha with 3 lakh as fodder crop in Rajasthan, Gujarat, Maharashtra, Karnataka and Tamil Nadu [24].
Cowpea was first introduced to India 1000–1500 years ago and now Indian-subcontinent appears to be a secondary centre of diversity. In India a large numbers of varieties for vegetable, pulse and fodder purpose have been developed. The breeding objectives have focused around developing lines with terminal drought tolerance, early maturity, erect growth to fit in cropping systems and enabling improved radiation use efficiency, high harvest index and resistance to diseases. The desirable traits in forage cowpea varieties are leafiness with indeterminate growth to get green fodder for a longer period. International Institute of Tropical Agriculture (IITA) has developed several dual purpose cultivars of cowpea with high grain and biomass yields and erects habit for intercropping/mixed farming purposes. In future development of cowpea lines against various forms of root-knot nematode, cowpea aphids and Fusarium wilt, is required. Further, development of transgenic cowpea lines with resistance to major insect pests can also be a breakthrough in cowpea breeding.
7. Conclusion
Tropical forage legumes were promoted in the past with the major focus on livestock production in India. This has led to a substantial decrease in research on tropical forage legumes. In view of current climate change problems and environmental concerns, research on forage legumes should be resumed with adequate funding support at national and international levels. Newer biotic and abiotic stress tolerant varieties should be developed for the changing environmental conditions. Forage legumes have potential to contribute significantly to environment-friendly agricultural land use and sustainable livestock production in the tropics.
\n',keywords:"crop wild relatives, gene introgression, germplasm, range legumes, livestock production, N-fixation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/64176.pdf",chapterXML:"https://mts.intechopen.com/source/xml/64176.xml",downloadPdfUrl:"/chapter/pdf-download/64176",previewPdfUrl:"/chapter/pdf-preview/64176",totalDownloads:1125,totalViews:503,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"April 17th 2018",dateReviewed:"August 28th 2018",datePrePublished:"December 6th 2018",datePublished:"February 27th 2019",dateFinished:null,readingETA:"0",abstract:"Livestock contributes enormously in food and nutritional security apart from livelihood security to rural population all over the world. India has the largest number of livestock, representing over 17% of world population. Availability of forage legumes is essential for better animal health, production and increasing the nutritive value of forage-based rations, besides providing a source of biological nitrogen fixation for enriching soil, reducing land degradation and mitigating climate change. However, supply of quality green fodder in India is extremely precarious, and the gap is huge against demand. The major fodder legume crops cultivated in India are Medicago sativa, Trifolium alexandrinum, Vigna unguiculata, Vigna umbellate and range legumes are Stylosanthes spp., Desmanthus virgatus, and Clitoria ternatea. Indian subcontinent represents wide spectrum of eco-climates and reported diversity of 21 forage legumes genera viz., Desmodium, Lablab, Stylosanthes, Vigna, Macroptelium, Centrosema and browse plants Leucaena, Sesbania, Albizia, Bauhinia, Cassia, Grewia, etc. Diversity of forage legumes were collected (>3200 accessions), evaluated and sources for different biotic and abiotic stress tolerance were identified, apart from >50 cultivars developed. Considering these aspects, tropical legumes for livestock production, soil health and ecosystem services, diversity, evaluation and breeding for improved varieties are discussed in this chapter.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/64176",risUrl:"/chapter/ris/64176",book:{slug:"forage-groups"},signatures:"Tejveer Singh, Srinivasan Ramakrishnan, Sanat Kumar Mahanta,\nVikas C. Tyagi and Ajoy Kumar Roy",authors:[{id:"254954",title:"Dr.",name:"Srinivasan",middleName:null,surname:"Ramakrishnan",fullName:"Srinivasan Ramakrishnan",slug:"srinivasan-ramakrishnan",email:"srinivasmic@gmail.com",position:null,institution:null},{id:"254958",title:"Dr.",name:"Tejveer",middleName:null,surname:"Singh",fullName:"Tejveer Singh",slug:"tejveer-singh",email:"tejveersinghbhu@gmail.com",position:null,institution:null},{id:"254959",title:"Dr.",name:"Sanath Kumar",middleName:null,surname:"Mahanta",fullName:"Sanath Kumar Mahanta",slug:"sanath-kumar-mahanta",email:"mahantask@rediffmail.com",position:null,institution:null},{id:"254960",title:"Dr.",name:"Vikas",middleName:null,surname:"Tyagi",fullName:"Vikas Tyagi",slug:"vikas-tyagi",email:"tyagiv54@yahoo.in",position:null,institution:null},{id:"254961",title:"Dr.",name:"A.K.",middleName:null,surname:"Roy",fullName:"A.K. Roy",slug:"a.k.-roy",email:"royak333@rediffmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Forage legumes in livestock production",level:"1"},{id:"sec_3",title:"3. Forage legumes in soil health and ecosystem services",level:"1"},{id:"sec_4",title:"4. Genetic resources of tropical forage legumes",level:"1"},{id:"sec_5",title:"5. Problems associated with breeding of tropical forage legumes",level:"1"},{id:"sec_6",title:"6. Major forage legumes of India",level:"1"},{id:"sec_6_2",title:"6.1. Egyptian clover (Trifolium alexandrinum L.)",level:"2"},{id:"sec_7_2",title:"6.2. Stylosanthes",level:"2"},{id:"sec_8_2",title:"6.3. Alfalfa (Medicago sativa L.)",level:"2"},{id:"sec_9_2",title:"6.4. Cowpea (Vigna unguiculata (L.) Walpers)",level:"2"},{id:"sec_11",title:"7. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'BAHS. Basic Animal Husbandry Statistics. 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Euphytica. 2008;162(1):39-50'},{id:"B48",body:'Liu CJ, Musial JM. Stylosanthes sp. aff. S. scabra: A putative diploid progenitor of Stylosanthes scabra (Fabaceae). Plant Systematics and Evolution. 1997;208:99-105'},{id:"B49",body:'Small E, Jomphe M. A synopsis of the genus Medicago. Canadian Journal of Botany. 1989;67:3260-3294'},{id:"B50",body:'Mizukami Y, Kato M, Takamizo T, Kanbe M, Inami S, Hattori K. Interspecific hybrids between Medicago sativa L. and annual Medicago containing Alfalfa weevil resistance. Plant Cell Tissue and Organ Culture. 2006;84:79-88'},{id:"B51",body:'Lesins KA, Lesins I. Genus Medicago (Leguminosae) a Taxonomic Study. The Hague, The Netherlands: Junk bv Publishers; 1979. p. 228'},{id:"B52",body:'Barnes DK, Bingham ET, Murphy RP, Hunt OJ, Beard DF, Skrdla WH, et al. Alfalfa germplasm in the United States: Genetic vulnerability, use, and maintenance. In: USDA-ARS Tech. Bull. Hyattsville, MD: USDA-ARS; 1977. p. 1571'},{id:"B53",body:'Chandra A, Pandey KC. Assessment of genetic variation in lucerne (Medicago sativa L.) using protease inhibitor activities and RAPD markers. Journal of Environmental Biology. 2011;32:559-565'},{id:"B54",body:'Sorensen EL, Horber EK. Glandular trichomes on Medicago: Building self defense against insects. In: Rep. of the Twenty-Ninth Alfalfa Improvement Conf. 1984. p. 135'},{id:"B55",body:'Kleitner GL, Sorensen EL. Erect glandular trichomes of Medicago scutellata (L.) Mill: Gland deveropment and early secretion. Botanical Gazette. 1983;144(2):165-174'},{id:"B56",body:'Chandra A, Pandey KC, Singh UP. Medicago scutellata—A possible source of weevil resistance for lucerne improvement. Indian Journal of Plant Genetic Resources. 2006;19:291-293'},{id:"B57",body:'Chandra A, Pandey KC. Effect of proteinase inhibitors on Indian alfalfa weevil (Hypera postica Gyll.) growth and development. Acta Physiologiae Plantarum. 2008;30:501-505'},{id:"B58",body:'Verma JS, Mishra SN. Advances in forage plant improvement in upper Gangetic Plains. In: Hazra CR, Mishri B, editors. New Vistas in Forage Production. Jhansi-284003, India: Indian Grassland and Fodder Research Institute. 1995. pp. 83-96'},{id:"B59",body:'Olives G. La alfalfa arbórea. In: Pesca y Alimentación. Madrid: Ministerio de Agricultura; 1969'},{id:"B60",body:'Greuter W, Matthäs U, Risse H. Notes on Cardaegan plants. 3. Medicago strasseri, a new leguminous shrub from Kriti. Wild. 1982;12:201-206'},{id:"B61",body:'Rosato M, Castro M, Rosselló JA. Relationships of the Woody Medicago species (section Dendrotelis) assessed by molecular cytogenetic analyses. Annals of Botany. 2008;102(1):15-22'},{id:"B62",body:'MCCOY T. Interspecific hybridization of Medicago sativa L. and M. rupestris M.B. using ovule-embryo-culture. Canadian Journal of Genetics and Cytology. 1985;27(2):238-245'},{id:"B63",body:'Wang JW, Sorensen EL, Liang GH. In vitro culture of pods from annual and perennial Medicago species. Plant Cell Reports. 1984;3:146-148'},{id:"B64",body:'McCoy TJ, Smith LY. Interspecifi c hybridization of perennial Medicago species using ovule-embryo culture. Theoretical and Applied Genetics. 1986;71:772-783'},{id:"B65",body:'Bauchan GR, Elgin JH Jr. A new chromosome number for the genus Medicago. Crop Science. 1984;24:193-195'},{id:"B66",body:'Volenec JJ, Cunningham SM, Haagenson DM, Berg WK, BC J, Wiersma DW. Physiological genetics improvement: Past failures, future prospects. Field Crops Research. 2002;75:97-110'},{id:"B67",body:'Bingham ET, Groose RW, Woodfield DR, Kidwell KK. Complementary gene interactions in alfalfa are greater in autotetraploids than diploids. Crop Science. 1994;34:823-829'},{id:"B68",body:'Annicchiarico P, Scotti C, Carelli M, Pecetti L. Questions and avenues for lucerne improvement. Czech Journal of Genetics and Plant Breeding. 2010;46:1-13'},{id:"B69",body:'Hipskind JD, Paiva NL. Constitutive accumulation of a resveratrol-glucoside in transgenic alfalfa increases resistance to Phoma medicaginis. Molecular Plant-Microbe Interactions. 2000;13(5):551-562'},{id:"B70",body:'Winicov I. Alfin1 transcription factor over expression enhances plant root growth under normal and saline conditions and improves salt tolerance in alfalfa. Planta. 2000;210:416-422'},{id:"B71",body:'McKersie BD, Murnaghan J, Jones KS, Bowley SR. Iron-superoxide dismutase expression in transgenic alfalfa increases winter survival without a detectable increase in photosynthetic oxidative stress tolerance. Plant Physiology. 2000;1224:1427-1437'},{id:"B72",body:'Xie DY, Sharma SB, Paiva NL, Ferreira D, Dixon RA. Role of anthocyanidin reductase, encoded by BANYULS in plant flavonoid biosynthesis. Science. 2003;299:396-399'},{id:"B73",body:'Tabe LM, Wardley-Richardson T, Ceriotti A, Aryan A, McNabb W, Moore A, et al. A biotechnological approach to improving the nutritive value of alfalfa. Journal of Animal Science. 1995;73:2752-2759'},{id:"B74",body:'Carrillo C, Wigdorovitz A, Trono K, Dus Santos MJ, Castañón S, Sadir AM. Induction of a virus-specific antibody response to foot and mouth disease virus using the structural protein VP1 expressed in transgenic potato plants. Viral Immunology. 2001;14:49-57'},{id:"B75",body:'Pasquet RS. Cultivated cowpea (Vigna unguiculata): Genetic organization and domestication. In: Pickersgill B, Lock JM, editors. Advances in Legume Systematics 8: Legumes of Economic Importance. Kew, UK: Royal Botanic Gardens; 1996. pp. 101-108'},{id:"B76",body:'Tarawali SA, Singh BB, Peters M, Blade SF. Cowpea haulms as fodder. In: Singh BB, Mohan Raj DR, Dashiell KE, Jackai LEN, editors. Advances in Cowpea Research. Sayce, Devon, UK: Co-publication Intl Inst Tropical Agric (IITA) and Japan Intl Res Center Agric Sci (JIRCAS); 1997. pp. 313-325'},{id:"B77",body:'Singh AK, Varma N, Yadav SK, Mohanty A, Singh S, Singh S. Indian forage genetic resources: Perspectives and strategies. Progressive Agriculture. 2009;9(2):250-256'},{id:"B78",body:'Singh T, Malaviya DR, Kaushal P. Genetic analysis of some morphological traits in Egyptian clover (Trifolium alexandrinum L.) sustainable use of grassland resources for forage production, biodiversity and environmental protection. In: Roy AK, Kumar RV, Agrawal RK, Mahanta SK, Singh JB, Das MM, Dwivedi KK, Prabhu G, Shah NK, editors. Extended Abstracts 23rd International Grassland Congress. 2015. Paper ID: 1467'},{id:"B79",body:'Putiyevsky E, Katznelson J. Cytogenetic studies in Trifolium spp. related to berseem. I. Intra- and inter-specific hybrid seed formation. Theoretical and Applied Genetics. 1973;43:351-358'},{id:"B80",body:'Bhaskar RB, Malviya DR, Roy AK, Kaushal P. Evaluation of exotic Trifolium accessions for disease incidence and resistance. In: Abstr. Nat. Symp. on ‘Grassland and Fodder Research in the New Millennium’; IGFRI, Jhansi. 2002. pp. 31-32'},{id:"B81",body:'Renfro BL, Sprague EW. Reaction of Medicago species to eight alfalfa pathogens. Agronomy Journal. 1959;51:481-483'},{id:"B82",body:'Borges OL, Stanford EH, Webster RK. Selection for resistance to Stemphylium botryosum in alfalfa. Crop Science. 1976;16:456-458'},{id:"B83",body:'Chandra A. Screening global Medicago germplasm for weevil (Hypera postica Gyll.) tolerance and estimation of genetic variability using molecular markers. Euphytica. 2009;1693:363-374'},{id:"B84",body:'Boscaiu M, Riera J, Estrelles E, Güemes J. Números cromosomáticos de plantas occidentales 751-776. Anales del Jardín Botánico de Madrid. 1997;55:430-431'},{id:"B85",body:'Alomar G, Mus M, Rosselló JA. Flora endèmica de les Balears. Palma de Mallorca: Consell Insular de Mallorca; 1997'},{id:"B86",body:'Zhou C, Han L, Pislariu C, Nakashima J, Fu C, Jiang Q, et al. From model to crop: Functional analysis of a STAY-GREEN gene in the model legume Medicago truncatula and effective use of the gene for alfalfa improvement. Plant Physiology. 2011;157:1483-1496'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Tejveer Singh",address:null,affiliation:'
ICAR-Indian Grassland and Fodder Research Institute, Jhansi, India
ICAR-Indian Grassland and Fodder Research Institute, Jhansi, India
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Attia-Ismail",authors:[{id:"204190",title:"Emeritus Prof.",name:"Salah",middleName:"Abdelaty",surname:"Attia-Ismail",fullName:"Salah Attia-Ismail",slug:"salah-attia-ismail"}]},{id:"57721",title:"An Insight into Current and Future Production of Forage Crops in Zimbabwe",slug:"an-insight-into-current-and-future-production-of-forage-crops-in-zimbabwe",signatures:"Allan Sebata",authors:[{id:"143409",title:"Dr.",name:"Allan",middleName:null,surname:"Sebata",fullName:"Allan Sebata",slug:"allan-sebata"}]},{id:"56953",title:"Phosphorus in Forage Production",slug:"phosphorus-in-forage-production",signatures:"Ademar Pereira Serra, Marlene Estevão Marchetti, Elisângela Dupas,\nCarla Eloize Carducci, Eulene Francisco da Silva, Elaine Reis Pinheiro",authors:[{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",fullName:"Ademar Serra",slug:"ademar-serra"}]},{id:"57115",title:"Best Management Practices (BMPs) for Nitrogen Fertilizer in Forage Grasses",slug:"best-management-practices-bmps-for-nitrogen-fertilizer-in-forage-grasses",signatures:"Ademar Pereira Serra, Marlene Estevão Marchetti, Elisângela Dupas,\nSimone Candido Ensinas, Elaine Reis Pinheiro Lourente, Eulene\nFrancisco da Silva, Roberto Giolo de Almeida, Carla Eloize Carducci\nand Alessandra Mayumi Tokura Alovisi",authors:[{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",fullName:"Ademar Serra",slug:"ademar-serra"}]},{id:"56079",title:"Alfalfa and Its Symbiosis Responses to Osmotic Stress",slug:"alfalfa-and-its-symbiosis-responses-to-osmotic-stress",signatures:"Mohammed Mouradi, Mohamed Farissi, Abdelaziz Bouizgaren,\nYahya Lahrizi, Ahmed Qaddoury and Cherki Ghoulam",authors:[{id:"204044",title:"Dr.",name:"Mohammed",middleName:null,surname:"Mouradi",fullName:"Mohammed Mouradi",slug:"mohammed-mouradi"}]},{id:"56047",title:"Genetic Variability of US and Czech Phalaris Arundinacea L. 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\n
1. Introduction
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Photodynamic therapy (PDT) is a less-invasive treatment of cancer and other nonmalignant conditions [1, 2, 3]. This treatment is a medicinal application of photochemistry. Antimicrobial treatment, called as antimicrobial photodynamic therapy (aPDT) or photodynamic antimicrobial chemotherapy (PACT), is also important application [4, 5, 6, 7]. In the case of cancer treatment, less-toxic PDT reagents, photosensitizers, cause oxidative damage to biomolecules, including protein, nucleic acids, and/or other compounds, under visible-light irradiation. This photosensitized reaction results in necrosis or apoptosis of cancer cells [1, 2, 3]. As the PDT photosensitizers, porphyrins have been extensively studied and used [8, 9, 10, 11]. For example, porfimer sodium [12, 13] and talaporfin sodium [13], an oligomer and a monomer of a free-base anionic porphyrin, respectively, are well-known photosensitizers in clinical use. In general, the porphyrin photosensitizer (e.g., almost 60 mg/body for talaporfin sodium) is given for the target tissue, followed by irradiation of the visible light (e.g., 664 nm, 150 mW cm−2, and 10 J cm−2). To reduce the risk of adverse side effects, the development of efficient photosensitizers that work with harmless weak light is important. Furthermore, consideration of PDT mechanism is also important to develop effective photosensitizer. Most of porphyrins have relatively large quantum yield (ΦΔ) for singlet oxygen (1O2), a reactive oxygen species (ROS), generation [14]. 1O2 can be easily generated by relatively small energy photon of long wavelength visible light and/or near infrared radiation (wavelength ≳ 770 nm) through energy transfer from photoexcited photosensitizer to oxygen molecule [15, 16, 17]. Radiation in the long wavelength region called “optical window”, 600 ~ 1300 nm, can penetrate human tissue deeply [18]. Therefore, 1O2 is the important reactive species of porphyrin-based PDT. However, the phototoxic effect of 1O2 on PDT is restricted because of the hypoxic condition of tumors [19, 20, 21, 22]. Furthermore, in certain cases, PDT itself enhances hypoxia [23] via vascular damage [24]. This “hypoxia problem” of tumor is very important to improve the PDT effect.
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Oxidation is defined as the oxygenation, hydrogen extraction, and electron extraction. Electron extraction from biomolecules to photoexcited photosensitizer is also the mechanism of oxidative biomolecule damage. This electron transfer oxidation may be an important mechanism to resolve the “hypoxia problem” and to develop the effective PDT photosensitizers. Phosphorus(V) porphyrins [25, 26] and cationic free-base porphyrins [27] have relatively strong oxidative activity through electron transfer [28]. Furthermore, electron transfer process can be control by surroundings condition, for example pH of medium [29, 30].
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In this chapter, recent studies about the electron transfer-supported photosensitizer for PDT are reviewed. The examples of activity control of photosensitizer for the cancer-selective PDT are also introduced. In the last section, the role of electron transfer mechanism in aPDT is discussed.
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2. Electron transfer oxidation as a mechanism of photosensitized biomolecule damage
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In general, photosensitized biomolecule damage can be explained by oxygen-independent mechanism (Type I mechanism) and oxygen-mediated mechanism (Type II mechanism) (Figure 1) [31, 32, 33]. Because the electron transfer-mediated biomolecule oxidation does not absolutely require oxygen, this mechanism is categorized as Type I mechanism. On the other hand, biomolecule oxidation through 1O2 generation is defined as Type II mechanism (Type II, major). Another ROS-mediated process, superoxide (O2\n•−)-mediated biomolecule oxidation is also categorized as the Type II mechanism (Type II, minor). Although O2\n•− is produced through electron transfer from photoexcited photosensitizer, it’s not categorized as the Type I mechanism. The initial process of electron transfer-mediated biomolecule oxidation is an electron extraction from the targeting biomolecule, such as protein, to the photoexcited photosensitizer.
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Figure 1.
Relaxation process of photoexcited state of photosensitizer and the typical photosensitized biomolecule damaging mechanisms.
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2.1 Driving force dependence of electron transfer
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The driving force of electron transfer, Gibbs energy (ΔG), is determined by the excitation energy of photosensitizer (photon energy) and the redox potential of photosensitizer and targeting biomolecule. The electron transfer is a relaxation process of photoexcited photosensitizer. Fast electron transfer is advantageous for an efficient electron transfer. Due to the Marcus theory [34, 35], the rate constant of electron transfer (k\nET) is expressed using ΔG as follows:
where h is Plank constant, λ is the reorganization energy, K\nB is the Boltzmann constant, and V\nDA is the effective electronic Hamiltonian matrix element. The λ can be calculated from the following equation:
where e is the elementary charge, ε\n0 is the vacuum permeability (8.854 × 10−12 F m−1), r\nD and r\nA are the radius of the electron donor and that of acceptor, respectively, d is the distance between electron donor and acceptor, n is the refractive index, and ε is the static dielectric constant of surrounding material. Since the V\nDA is determined by the overlap between wavefunctions of electron donor and acceptor, the electron transfer rate strongly depends on the d, and decreased exponentially with an increase in d. Therefore, association between photosensitizer and targeting biomolecule is very important. The ΔG, driving force of electron transfer, is expressed as follows:
where E\nred is the redox potential of a one-electron reduction of photosensitizer, Eox is the redox potential of a one-electron oxidation of targeting biomolecule, and E0–0 is the 0–0 energy (singlet excited (S1) energy) of photosensitizer. The Eq. (1) indicates that k\nET becomes maximum at ΔG = λ. However, in general, large -ΔG is advantageous for fast electron transfer. Therefore, small (small absolute value) E\nred and/or large (large absolute value) E\nox is appropriate for effective electron transfer. To evaluate the electron transfer in the triplet excited (T1) state, the “E\n0–0” term in Eq. (3) is replaced with the T1 state energy. Because T1 state energy is smaller than E\n0–0, in general, electron transfer oxidation by T1 state photosensitizer becomes difficult.
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2.2 Excitation energy and electron transfer
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Excitation energy (photon energy) strongly affects the electron transfer rate and efficiency as the Eq. (3). Indeed, an ultraviolet photosensitizer can oxidize DNA, which is relatively resistant to the electron extraction, through photoinduced electron transfer [32, 33]. However, ultraviolet radiation is harmful for human tissue. Furthermore, long wavelength visible light or near infrared radiation can penetrate human tissue deeply as mentioned above as the optical window [18]. Therefore, visible light (or near infrared) photosensitizer, such as porphyrins and phthalocyanines, are important for PDT. To realize the electron transfer photosensitizer, which can be excited by long wavelength light, the design and synthesis of photosensitizer molecules with small E\nred value are required. However, a molecule with small E\nred has tend to decay through reduction by surrounding molecules, and small E\nred is not appropriate for stability of molecule.
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2.3 Kinetics of electron transfer
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In general, electron transfer can be demonstrated by a transient absorption spectrum measurement [36, 37] and a time-resolved electron paramagnetic resonance measurement [38, 39]. The k\nET values can be determined by the analysis of transient absorption spectra. Fluorescence lifetime measurement is also an important method [40]. Although fluorescence lifetime is affected by various factors other than electron transfer, it is sensitive and convenient method. If other factors can be excluded, this method is advantageous for the kinetic evaluation of electron transfer. The k\nET value can be obtained using fluorescence lifetime by the following equation:
where τ\nf is the observed fluorescence lifetime of photosensitizer with electron donor (targeting biomolecule) and τ\nf\n0 is that without electron donor. In general, k\nET becomes larger than 108 ~ 109 s−1 in the case of electron transfer in the S1 state, because lifetime of most of porphyrin S1 state is order of several nanosecond. In the case of T1 state, the lifetime is order of microsecond and the rate constant becomes relatively small. As mentioned above, the T1 state is not appropriate for electron transfer oxidation from the thermodynamic point of view.
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3. Phosphorus(V) porphyrin photosensitizer
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Porphyrin derivatives have been used as clinical photosensitizer for PDT [8, 9, 10, 11]. Porfimer sodium [12, 13] and Talaporfin sodium [13] are famous examples of clinically used photosensitizers. The PDT mechanism of these porphyrins is 1O2 generation. The photochemical property of porphyrin can be changed by the replacement of the central atom and substitution. It has been reported that phosphorus(V) porphyrin can oxidize biomolecules, such as nucleobase [41], protein [42, 43, 44, 45, 46, 47, 48], and other biomolecules [49, 50] through electron transfer.
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3.1 General property of phosphorus(V) porphyrin
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General procedure of synthesis method of phosphorus(V) porphyrin is a reflux of free base porphyrin with phosphoryl chloride in dry pyridine [51]. The photochemical property of phosphorus(V) porphyrin can be improved by the substitution of the meso- or β-positions and the axial ligand (Figure 2) [42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]. An example of phosphorus(V) porphyrin, diethoxyP(V)tetrakis(4-methoxyphenyl)porphyrin chloride, is shown in Figure 3. The calculation with density functional theory (DFT) at ωB97X-D/6-31G* level shows the distorted structure of phosphorus(V) porphyrin. Their distorted structures have been reported from the results of X-ray crystal analysis [54]. Phosphorus(V) porphyrins introduced in this chapter are listed in Table 1. Because phosphorus(V) porphyrin is a cationic porphyrin, its water solubility is relatively large. Furthermore, hydrophilic substitution markedly increases the water solubility [55]. One of the most important characteristics of phosphorus(V) porphyrin is relatively small E\nred value due to the positive charge of the central phosphorus atom, resulting in the strong oxidative activity in the photoexcited state. This character is very important as electron transfer-supported photosensitizer for PDT. Furthermore, in general, phosphorus(V) porphyrin has relatively large quantum yield of photosensitized 1O2 generation in an aqueous solution (ΦΔ is more than 0.5, Table 1) due to the effective intersystem crossing [42, 43, 44, 45, 46, 47]. In the presence of enough oxygen molecules, phosphorus(V) porphyrin can oxidize biomolecule through 1O2 generation, a traditional PDT mechanism.
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Figure 2.
Structures of phosphorus(V) porphyrins.
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Figure 3.
Optimized structure of Por10 by the DFT calculation at ωB97X-D/6-31G* level.
3.2 Photosensitized protein damage by phosphorus(V) porphyrin through electron transfer
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Isolated amino acids, a water-soluble protein, and enzymes have been used as the targeting biomacromolecules to examine photosensitizer activity of phosphorus(V) porphyrins [42]. For example, human serum albumin (HSA), a water-soluble protein, is a convenient target. The crystal structure and amino acid sequence of HSA have been clarified [56]. In addition, HSA has major drug specific binding sites identified as Sudlow’s site I and site II [57]. The mono-cationic phosphorus(V) porphyrins listed in Table 1 are well-soluble in organic solvents (e.g., alcohol) rather than water, indicating the hydrophobic character beside the hydrophilicity. Therefore, binding interaction between HSA and phosphorus(V) porphyrins is expected and their binding site can be speculated. Because the electron transfer-mediated oxidation strongly depends on the distance between photosensitizer and the target molecule, a binding interaction is very important. HSA has one tryptophan, which is easily oxidized by oxidative stress, including 1O2 and electron transfer reaction [42, 43, 44, 45, 46, 47, 58]. Tryptophan can emit relatively strong fluorescence and its damage can be detected by fluorescence measurement [45, 58]. Using these characteristics of HSA, the oxidative damage of tryptophan residue by photosensitized reaction can be easily examined by a fluorometry [45, 46, 47, 58].
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Qualitative study of HSA photodamage by phosphorus(V) porphyrins was reported using Por2 [43]. Por2 oxidized the tryptophan of HSA through 1O2 generation and electron transfer. It has been considered that damaged tryptophan is changed to N-formylkynurenine and other decomposed products [59, 60]. 1O2 can oxidize the tryptophan residue of HSA [61]. Using isolated amino acids, it has been demonstrated that tyrosine and tryptophan can be oxidized by photoexcited Por2 [42].
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Photosensitized HSA damage by Por5 and Por6 was quantitatively clarified [45]. Por5 and Por6 bound to HSA and damaged its tryptophan residue during photoirradiation. Por5 and Por6 photosensitized 1O2 generation, and the contribution of 1O2 was confirmed by the inhibitory effect of a 1O2 quencher, sodium azide (NaN3, [62]). From the kinetic analysis, the contribution of electron transfer mechanism to HSA damage was demonstrated [45]. Fluorescence lifetime measurement and the calculation of ΔG supported the electron transfer mechanism.
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To realize the effective PDT photosensitizer, response of photosensitizers to long wavelength visible light or near infrared region is important. To improve the abovementioned phosphorus(V) porphyrins, Por5 and Por6, meso-phenyl substituted derivatives were designed and synthesized [46]. Por8, Por9, and Por12 can be excited under the irradiation of long-wavelength visible light (> 630 nm). These phosphorus(V) porphyrins induced tryptophan oxidation in HSA under illumination with light-emitting diode (central wavelength: 659 nm), and this protein photodamage was barely inhibited by NaN3 [46]. Fluorescence lifetimes of phosphorus(V) porphyrins was decreased by HSA, suggesting the electron transfer quenching. The ΔG value of electron transfer from tryptophan to the S1 state of these porphyrins calculated from their redox potentials also supported the electron transfer-mediated oxidation.
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3.3 Cancer selective photodynamic action of phosphorus(V) porphyrin photosensitizers
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Above mentioned phosphorus(V) porphyrins, Por8, Por9, and Por12, exhibited the cancer cell selective toxicity under visible light irradiation [46]. Photocytotoxicity to HeLa cells by these porphyrins are the following order: Por9 > Por12 > Por8 in the condition of previous report (Figure 4) [46]. Although the half maximal inhibitory concentration (IC50) value for Por8 is largest (least phototoxicity) in the three phosphorus(V) porphyrins, its photocytotoxicity to cancer cells is sufficiently high. Furthermore, Por8 did not exhibit photocytotoxicity to HaCaT cells, cultured human skin cells (normal cell model). Por9 and Por12 exhibited phototoxicity to HaCaT cells, however, these IC50 value were significantly larger than those for HeLa cells and cellular DNA damage in HaCat cells were not observed. These three phosphorus(V) porphyrins demonstrated significant PDT effects on mice tumor models [46]. The observed PDT effects by these porphyrins are almost the same, and are comparable with that of talaporfin sodium. These results suggest the cancer selectivity of Por8, Por9, and Por12, and lower carcinogenic risk to normal cells. Specifically, Por8, of which the redox potential is most advantageous for the electron transfer-mediated biomolecule oxidation, demonstrated the highest cancer-selectivity and significant PDT effect under irradiation with long-wavelength visible light.
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Figure 4.
Structures of Por8, Por9, and Por12, and their IC50 values for HeLa cells under photoirradiation [46].
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3.4 Photoinduced electron transfer by phosphorus(V) porphyrin triggers the chain reaction for NADH decomposition
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The electron transfer mechanism can contribute to oxidation other various biomolecules. For example, nicotinamide adenine dinucleotide (NADH), an important endogenous reductant, becomes an important targeting molecule [50]. The S1 states of Por3 and Por4 easily extract electron from NADH, resulting in the formation of NAD•, a radical. Further oxidation leads to the irreversible decomposition of NADH to NAD+ (Figure 5). The total quantum yield of NADH decomposition (ΦD) is expressed as follows:
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Figure 5.
Structures of NADH and its oxidized form, and the electron transfer-triggered chain reaction of NADH decomposition.
where ΦET is the quantum yield of the initial process (electron transfer) and ΦFR is that of the further reaction to form NAD+. Analysis of the quantum yields, obtained values of ΦFR became much larger than unity. These findings suggest that the electron accepting by the photoexcited Por3 and Por4 triggers a chain reaction of NADH oxidation (Figure 5). The initial electron transfer to photoexcited Por3 or Por4 produces NAD•. The NAD• immediately reacts with molecular oxygen to produce O2\n•−:
The electron transfer-mediated reaction induces the chain reaction, resulting in the acceleration of NADH decomposition and secondary generation of reactive oxygen species. In the case of direct photosensitized reaction, ultraviolet photon is required to produce H2O2 [28]. The secondary formed H2O2 may produce hydroxyl radicals (•OH), very strong ROS. These results suggest that electron transfer reaction with visible light irradiation induces a severe toxic effect through a chain reaction and the formation of H2O2, similarly to the ultraviolet radiation.
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3.5 Photosensitized oxidation of folic acid by phosphorus(V) porphyrin through electron transfer
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Folic acid, a vitamin, is also oxidized through photoinduced electron transfer [64]. Because the fluorescence intensity of folic acid is significantly increased by the decomposition, a fluorometry of folic acid can be used as a convenient indicator to evaluate the photosensitizer activities [65, 66]. For example, photosensitized decomposition of folic acid by Por2 through electron transfer was reported [49]. Photoexcited porphyrin can produce 1O2, and folic acid is also oxidized by 1O2. The contribution of 1O2-mediated decomposition can be excluded by the effect of 1O2 quencher and the effect of electron transfer reaction can be evaluated.
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4. Contribution of the electron transfer mechanism in photosensitized reaction by cationic porphyrins
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Photooxidation activity through electron transfer depends on the redox potential. It has been demonstrated that photoexcited hematoporphyrin, a free base porphyrin, induces the oxidative electron transfer from the tryptophan residue of bovine serum albumin [67, 68]. Cationic porphyrins show relatively small E\nred values due to their positive charge. In this section, several examples of electron transfer-mediated oxidation of biomolecules by cationic porphyrins.
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4.1 Protein photooxidation through electron transfer by cationic porphyrins
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The photosensitized protein damage by tetrakis(N-methyl-p-pyridinio)porphyrin (H2TMPyP, Figure 6) and its zinc complex (ZnTMPyP, Figure 6) was reported [69]. Photosensitized reaction of H2TMPyP has been extensively studied [14, 70]. Water-solubility of H2TMPyP and its analogues is appropriate for biological study. Furthermore, electrostatic interaction between these cationic porphyrins and biomacromolecules is considered to enhance the electron transfer reaction with targeting biomolecules. The ΦΔ value of H2TMPyP is relatively large [14, 69, 71], and photosensitized biomolecule damage caused by H2TMPyP through 1O2 generation is generally accepted [70, 72]. However, E\nred of H2TMPyP is relatively small [27], and negative ΔG values for photosensitized oxidation of several amino acids through electron transfer are estimated. Therefore, electron transfer-mediated photooxidation of biomolecules is expected.
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Figure 6.
Structures of H2TMPyP and ZnTMPyP (A), their binding interaction with DNA (B), and the electron transfer reactions (C). ABG: Amino benzoyl-L-glutamic acid.
\n
H2TMPyP and ZnTMPyP bound to HSA and caused photosensitized oxidation of the tryptophan residue [69]. Three amino acids–tryptophan, phenylalanine, and tyrosine–were also used as target biomolecules, and tryptophan and tyrosine were photodamaged by these cationic porphyrins. However, H2TMPyP and ZnTMPyP could not photosensitize the damage of phenylalanine. The protein damage (oxidation of the tryptophan residue) was enhanced in deuterium oxide and inhibited by NaN3. Analysis of the scavenger effect showed that the absolute quantum yields of electron transfer-mediated oxidation are 5.3 × 10−3 and 4.0 × 10−3 for H2TMPyP and ZnTMPyP, respectively. The E\nred of H2TMPyP (−0.23 V vs. SCE) [27] is lower than that of ZnTMPyP (−0.85 V) [73]. The values of -ΔG for electron transfer from tryptophan to their S1 states suggest that H2TMPyP (−1.03 eV) is more oxidative than ZnTMPyP (−0.53 eV). The estimated value of k\nET estimated from the fluorescence lifetime for H2TMPyP was 1.0 × 108 s−1. On the other hand, the fluorescence lifetime of ZnTMPyP was not affected by the interaction with HSA in the presented experimental condition. Because of the relatively shorter fluorescence lifetime of ZnTMPyP (1.3 ns), the estimation of k\nET may be difficult by the fluorescence lifetime measurement. Furthermore, protein photodamage by the T1 states of H2TMPyP and ZnTMPyP were also discussed [69]. The lifetimes of their T1 states are relatively long: H2TMPyP (2.1 μs) and ZnTMPyP (2.7 μs), suggesting that the electron transfer in the T1 state is kinetically advantageous. The estimated -ΔG of the electron transfer from tryptophan to their T1 states (−0.65 eV for H2TMPyP and − 0.15 eV for ZnTMPyP) suggests that this electron transfer is also possible in terms of energy.
\n
\n
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4.2 Electron transfer from DNA to photoexcited cationic porphyrins and microenvironmental effect of DNA on photoinduced electron transfer
\n
Photoinduced electron transfer between DNA and the cationic porphyrins, H2TMPyP and ZnTMPyP, was analyzed by the fluorescence measurements (Figure 6) [74]. Absorption spectrum and circular dichroism measurements showed that H2TMPyP mainly intercalates to calf thymus DNA, whereas ZnTMPyP binds into a DNA groove. An electrostatic interaction with DNA raises their redox potentials of the binding cationic porphyrins. In the presence of DNA, the fluorescence intensity of these porphyrins was almost the same as that without DNA. The E\nox of H2TMPyP (>1.30 V vs. SCE in water) [27], ZnTMPyP (1.18 V vs. SCE in water) [73], and guanine (1.24 V vs. SCE in acetonitrile) [75, 76] suggested that electron transfer by the S1 state of H2TMPyP is possible in terms of energy. Furthermore, the electron donating character of guanines increased in the double-stranded structure [77, 78, 79]. However, the fluorescence measurements indicated that the S1 states of these porphyrins are barely quenched by DNA. These results could be explained by that an electrostatic interaction between cationic porphyrins and an anionic DNA strand should increase the redox potential of porphyrins, leading to the inhibition of the electron transfer. In the cases of their higher excited states, secondary excited singlet (S2) states, the electron transfer from DNA was observed. The lifetime of S2 state is significantly short (a few picoseconds). However, the E\nred value of their S2 states are large (larger E\nred value of the excited state indicates stronger oxidative activity); >2.14 V vs. SCE for H2TMPyP and 1.94 V vs. SCE for ZnTMPyP. Therefore, the S2 states of porphyrins are thermodynamically strong oxidants through electron transfer mechanism.
\n
Photoinduced electron transfer from these porphyrins to benzoquinones, electron acceptors, and that from N-(4-aminobenzoyl)-L-glutamic acid (ABG), an electron donor, to these porphyrins were also studied [74]. As mentioned above, the electrostatic interaction with DNA raises the redox potential of cationic porphyrins (i.e. decreases the oxidative property of cationic porphyrins). Therefore, the DNA microenvironment inhibited the electron transfer from ABG, an electron-donating quencher, to the binding porphyrins. On the other hand, the electron transfer from the binding porphyrins to benzoquinones, an electron-accepting quencher, was enhanced. A steric effect by the DNA strand was also important. A hydrophobic bulky electron acceptors forms stacking complex with porphyrins, resulting in the strong fluorescence quenching. The interaction with DNA strand cleaves this stacking interaction and inhibit the electron transfer to the benzoquinone. In summary, the DNA microenvironment significantly affects the electron transfer property of the binding cationic porphyrins through an electrostatic interaction and the steric effect.
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5. Activity control based on the electron transfer
\n
Electron transfer can be controlled by the surrounding environment. For example, pH is an important factor to control the photoinduced electron transfer [29, 30, 48, 80, 81]. Since it has been reported that cancer cells are slightly acidic (pH 6 ~ 7) against normal tissues (pH 7 ~ 7.4) [82, 83, 84, 85], control of the electron transfer of the photosensitizer by pH can be applied for the development of cancer-selective PDT. In the cases of pH-dependent 1O2 photosensitizers, the redox control [30, 86, 87, 88], the structure change [89], and the control of intersystem crossing [90] by pH have been reported as the important concepts. Several types of pH-activatable-porphyrin photosensitizers [30, 88], including a phosphorus(V) porphyrin [48, 81], have been reported. In addition, a self-quenching of the photoexcited molecules can be also used to control the activity [47]. In this section, several examples about the activity control of electron transfer-photosensitizers are introduced.
\n
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5.1 Electron transfer control by pH
\n
The biomolecule oxidation activity of photosensitizer through electron transfer can be controlled by using changeable electron donor. Por13 was designed and synthesized to control the photodynamic activity of phosphorus(V) porphyrin photosensitizer (Figure 7) [48]. As an electron-donor, 6-methylpyridine was used. The photoexcited Por13 is quenched through intramolecular electron transfer and this quenching is suppressed by protonation of the methylpyridine moiety, an electron donor. The pK\na of protonated methylpyridine moiety was about 7, and fluorescence lifetime of Por13 was lengthened under an acidic condition by suppression of the quenching through intramolecular electron transfer by methylpyridine. The quantum yields of photosensitized 1O2 generation and biomolecule oxidation through electron transfer mechanism were also increased under acidic condition. NADH oxidation by Por13 through photoinduced electron transfer was successfully enhanced under acidic conditions. However, photosensitized protein damage (oxidative damage of HSA) through electron transfer was decreased under an acidic condition, and relatively strong protein damage was observed under a neutral condition. It is explained by the fact that a relatively weak association between protein and Por13 under an acidic condition due to electrostatic repulsion. Protonated protein under acidic condition decreases the association with cationic porphyrin, resulting in the suppression of the electron transfer from the amino acids. Furthermore, the hydrophobic environment of protein inhibits the electron transfer-quenching of Por13. This study shows the difficulty of activity control of photosensitizers by pH, because other factors significantly affect the photoinduced electron transfer.
\n
Figure 7.
Scheme of the activity control of photosensitizer, Por13, by pH and the relaxation processes of photoexcited state.
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5.2 Activity control through the self-quenching of photosensitizers
\n
DiethoxyP(V)tetrakis(p-methoxyphenyl)porphyrins, Por10 and Por11, analogues of above mentioned Por9, were synthesized [47]. Their water-solubilities were smaller than that of Por9, and these porphyrins form self-aggregation complexes (Figure 8). Photoexcited states of Por10 and Por11 were effectively quenched through this aggregation (concentration quenching). These phosphorus(V) porphyrins can bind to the hydrophobic pocket of HSA, resulting in dissociation of their self-aggregation states (Figure 8). Calculating simulation showed the distance between the tryptophan residue and the porphyrin molecules as follows: 24.4 Å (Por10) and 23.5 Å (Por11). Fluorescence lifetime of these porphyrins were recovered by the dissociation of self-aggregation. Photoirradiation to these porphyrins binding to HSA induced the oxidation of tryptophan through 1O2 generation and electron transfer. The axial fluorination of ethoxy chain of central phosphorus atom reduced the E\nred of porphyrin ring. The electron transfer rate constant from the tryptophan residue of HSA to Por11 is larger than that of Por10, due to the effect of axial fluorination. The substitution by fluorine, the highest electronegative element, showed the improving effect on photooxidation of protein through electron transfer. However, the fluorination decreased the binding interaction with HSA. In the presence of same concentration of porphyrins, Por10 exhibits higher damaging activity to HSA under photoirradiation. These results suggest that selective interaction is important for electron transfer-mediated photodamage of biomolecules. These porphyrins demonstrated the photocytotoxicity to HaCaT cells. The IC50 value of Por11 was lower (stronger cytotoxicity) that Por10. Photooxidative activity of Por11 through electron transfer and enhanced cellular uptake by the fluorination may play the important role in this photocytotoxic effect. Furthermore, Por10 and Por11 barely induce cellular DNA damage to HaCaT cells, similarly to Por8, Por9, and Por12. Therefore, their carcinogenic risks are also small. The self-aggregation of photosensitizers can be used to suppress their photosensitizing activity. These results suggest that the PDT activity of self-aggregation photosensitizers can be reversed using association with targeting biomacromolecules, such as protein.
\n
Figure 8.
Scheme of the activity control of photosensitizers, Por10 and Por11, through the self-aggregation and interaction with HSA.
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6. Electron transfer mechanism and antimicrobial photodynamic therapy
\n
PDT can be applied for disinfection and sterilization [4, 5, 6, 7]. Microbial, including bacterium and viruses can be removed by photosensitized reaction. The physical treatment, such as PDT, is advantageous against antibiotic-resistant bacteria [91, 92]. PDT for microbial treatment is called as aPDT and/or PACT. Red light (relatively long wavelength visible light) is used for aPDT. Because 1O2 can be easily produced by relatively small energy photons, it is considered as the important reactive species for aPDT process. Phenothiazine dyes, such as Methylene Blue is used as the photosensitizer for aPDT [93], because Methylene Blue can absorb relatively long-wavelength visible light and its ΦΔ value is relatively large [94]. However, the aPDT mechanism has not been well-understand. Biological environments are under a hypoxic condition [95], the mechanism mediated by 1O2 generation mechanism may be restricted. Therefore, the electron transfer mechanism may play an important role in the aPDT mechanism.
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6.1 Photosensitized DNA damage through electron transfer
\n
DNA is a potentially important targeting biomacromolecules for PDT and aPDT [1, 2, 3, 28]. In the cases of DNA damage, the generation of reactive oxygen species, such as 1O2 (Type II mechanism), and the direct oxidation of nucleobases through photoinduced electron transfer (Type I mechanism) are important. In general, O2\n•− formation and following H2O2 and/or •OH production (Type II mechanism, minor) require relatively shorter wavelength radiation, such as ultraviolet ray [28, 32, 33]. Therefore, the contribution of the O2\n•− generation (Type II minor) mechanism is considered to be small in the aPDT mechanism. As mentioned above, photosensitized 1O2 generation is the important mechanism of aPDT. Guanine is the selective target of 1O2, and every guanine is oxidized by 1O2 in a DNA sequence [28, 33]. Similar to the 1O2 generation mechanism, guanine is also damaged through electron transfer selectively [28, 32, 33]. However, single guanines in double-stranded DNA and guanine residue in single-stranded DNA are resistant to electron transfer mechanism, in the contrary to the 1O2 mechanism [28, 33]. Since π-π interaction between consecutive guanines decrease the E\nox of guanine, the consecutive guanines, such as GG and GGG, are selectively oxidized through electron transfer mechanism [77, 78, 79]. Similar compounds are produced of guanine oxidation through the both mechanisms of 1O2 generation and electron transfer [72].
\n
The mechanism of DNA damage photosensitized by Nile Blue (Figure 9) has been studied as a potential photosensitizing reaction [96]. The reported value of ΦΔ by Nile Blue is very small (0.005) [66, 97]. Therefore, Nile Blue is an appropriate model to examine the oxygen-independent mechanism. Nile Blue bound to DNA strand through an electrostatic interaction and the fluorescence lifetime was decreased, supporting the electron transfer quenching. Using 32P-5′-end-labeled DNA fragments, DNA damaging mechanism of Nile Blue was examined and consecutive guanine damage was observed. From the analysis of DNA damaging pattern, the contribution of DNA damage through electron transfer mechanism was estimated to be 72% (the contribution of 1O2 mechanism is 28%). The ΔG of electron transfer from guanine to the S1 state of Nile Blue is negative (−0.15 eV) [96], and this value is considered to become smaller in the case of consecutive guanine, as mentioned above [77, 78, 79]. The estimated k\nET value is relatively large (1.0 × 1010 s−1). These values supported the electron transfer-mediated DNA oxidation. The mechanism of DNA damage photosensitized by Nile Blue is shown in Figure 9. Relevantly, rhodamine-6G, a fluorescence dye, induces the electron transfer-mediated oxidation of DNA [98] and folic acid [64] with photoirradiation. In general, fluorescence dyes hardly photosensitize 1O2 generation. On the other hand, photooxidative activity through electron transfer depends on the redox potential of molecules. These results suggest that the electron transfer-oxidation becomes important PDT mechanism for non-1O2 generating dyes.
\n
Figure 9.
Structure of Nile Blue and the proposed mechanism of guanine decomposition through photoinduced electron transfer.
\n
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6.2 Photosensitized protein damage through electron transfer
\n
Photosensitized protein damage by Methylene Blue and its analogues (Figure 10). were studied [99]. Similar to the cases of phosphorus(V) porphyrin photosensitizers, HSA was used as the targeting biomacromolecules. DNA binding through electrostatic force of these cationic compounds are well-known [40, 71, 74, 96, 100]. However, the interaction between these cationic dyes and HSA is small and a hydrophobic interaction (not electrostatic interaction) may be a driving force of the association with HSA [58]. The reported binding constant, which were estimated by the Benesi-Hildebrand Equation [101] are shown in Figure 10. Fluorometry of HSA tryptophan residue demonstrated the photosensitized oxidation through both mechanisms, electron transfer and 1O2 generation [99]. The analyzed quantum yields through these mechanisms are shown in Figure 10. Fluorescence decay of these dyes was complex. From the analysis of their observed fluorescence decay, the estimated k\nET values were order of 109 s−1, supporting the electron transfer mechanism. Furthermore, this result suggests the existence of markedly fast electron transfer species, much faster than the detection limit of this study (within ~50 ps) [99]. DFT calculation also supported the electron transfer mechanism. The energy gap between the highest occupied molecular orbital (HOMO) of amino acids and that of photosensitizers are important for the electron transfer mechanism. The plot between the HOMO values of these cationic dyes and the protein damaging quantum yield through electron transfer demonstrated a relatively good relationship. Furthermore, the relationship between the ΦΔ and the damaging quantum yield through 1O2 generation is also observed. These results shown that the electron transfer mechanism is also important for photosensitized protein oxidation by Methylene Blue and its analogues, as 1O2 generation mechanism does. The electron transfer mechanism is not completely independent of oxygen molecule, because oxygen support the electron transfer by removing the excess electron from the reduced photosensitizer. However, other endogenous oxidative agents, such as metal ions, may support the electron transfer mechanism, in vivo, the electron transfer mechanism may play an important role in the aPDT under hypoxic condition.
\n
Figure 10.
Structures of Methylene Blue and its analogues. Binding constants with HSA were examined in a 10 mM sodium phosphate buffer (pH 7.6). QET: The quantum yield of HSA oxidation through electron transfer mechanism. QSO: The quantum yield of HSA oxidation through 1O2 generation.
\n
\n
\n
\n
7. Conclusions
\n
This chapter reviewed the several topics about the photosensitizers, which play electron transfer-supported mechanism. 1O2 is the important reactive species in PDT and aPDT. However, hypoxic condition in biological environment is not appropriate for reactive oxygen-dependent mechanism. Electron transfer is not completely independent of oxygen; however, this mechanism does not absolutely require oxygen. Endogenous oxidative substances other than oxygen can support the electron transfer mechanism. In the study of PDT photosensitizer for cancer, phosphorus(V) porphyrins showed the selectivity for cancer cell and relatively strong PDT effects. Most important property of these photosensitizers is strong photooxidative activity through electron transfer under long-wavelength visible light irradiation. Furthermore, the photosensitizing activity of phosphorus(V) porphyrins through electron transfer mechanism can be controlled by surroundings, such as pH. In the processes of aPDT, the electron transfer mechanism may be important. For developing the effective drugs for aPDT, molecular design based on the electron transfer is also useful as well as that based on the 1O2 generating activity. The activity of electron transfer oxidation depends on the redox potential, and a long lifetime of photoexcited state is advantageous. For PDT photosensitizers, relatively strong response to long-wavelength radiation is required. In the molecular design of PDT photosensitizers including phosphorus(V) porphyrins, the calculations of HOMO energy level and the excitation energy are important as the initial steps.
\n
\n
Acknowledgments
\n
This work was supported in part by Grants-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (JSPS KAKENHI 17H03086) and Futaba Electronics Memorial Foundation (10407).
\n
Conflict of interest
The author declares no conflict of interest.
\n',keywords:"Photoinduced electron transfer, porphyrin phosphorus(V) complex, protein oxidation, cationic porphyrin, phenothiazine dyes",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73712.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73712.xml",downloadPdfUrl:"/chapter/pdf-download/73712",previewPdfUrl:"/chapter/pdf-preview/73712",totalDownloads:83,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 21st 2020",dateReviewed:"September 28th 2020",datePrePublished:"October 22nd 2020",datePublished:null,dateFinished:null,readingETA:"0",abstract:"Photodynamic therapy (PDT) is a less-invasive treatment of cancer and precancerous lesions. Porphyrin derivatives have been used and studied as the photosensitizers for PDT. In general, the biomacromolecules oxidation by singlet oxygen, which is produced through energy transfer from the photoexcited photosensitizers to oxygen molecules, is an important mechanism of PDT. However, the traditional PDT effect may be restricted, because tumors are in a hypoxic condition and in certain cases, PDT enhances hypoxia via vascular damage. To solve this problem, the electron transfer-mediated oxidation of biomolecules has been proposed as the PDT mechanism. Specifically, porphyrin phosphorus(V) complexes demonstrate relatively strong photooxidative activity in protein damage through electron transfer. Furthermore, other photosensitizers, e.g., cationic free-base porphyrins, can oxidize biomolecules through electron transfer. The electron transfer-supported PDT may play the important roles in hypoxia cancer therapy. Furthermore, the electron transfer-supported mechanism may contribute to antimicrobial PDT. In this chapter, recent topics about the biomolecules photooxidation by electron transfer-supported mechanism are reviewed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73712",risUrl:"/chapter/ris/73712",signatures:"Kazutaka Hirakawa",book:{id:"7886",title:"Photodynamic Therapy - from Basic Science to Clinical Research",subtitle:null,fullTitle:"Photodynamic Therapy - from Basic Science to Clinical Research",slug:null,publishedDate:null,bookSignature:"Dr. Natalia Mayumi Inada, Dr. Hilde Buzzá, Dr. Kate Cristina Blanco and Dr. Lucas D. Dias",coverURL:"https://cdn.intechopen.com/books/images_new/7886.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"90788",title:"Dr.",name:"Natalia",middleName:"Mayumi",surname:"Inada",slug:"natalia-inada",fullName:"Natalia Inada"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"97768",title:"Dr.",name:"Kazutaka",middleName:null,surname:"Hirakawa",fullName:"Kazutaka Hirakawa",slug:"kazutaka-hirakawa",email:"hirakawa.kazutaka@shizuoka.ac.jp",position:null,institution:{name:"Shizuoka University",institutionURL:null,country:{name:"Japan"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Electron transfer oxidation as a mechanism of photosensitized biomolecule damage",level:"1"},{id:"sec_2_2",title:"2.1 Driving force dependence of electron transfer",level:"2"},{id:"sec_3_2",title:"2.2 Excitation energy and electron transfer",level:"2"},{id:"sec_4_2",title:"2.3 Kinetics of electron transfer",level:"2"},{id:"sec_6",title:"3. Phosphorus(V) porphyrin photosensitizer",level:"1"},{id:"sec_6_2",title:"3.1 General property of phosphorus(V) porphyrin",level:"2"},{id:"sec_7_2",title:"3.2 Photosensitized protein damage by phosphorus(V) porphyrin through electron transfer",level:"2"},{id:"sec_8_2",title:"3.3 Cancer selective photodynamic action of phosphorus(V) porphyrin photosensitizers",level:"2"},{id:"sec_9_2",title:"3.4 Photoinduced electron transfer by phosphorus(V) porphyrin triggers the chain reaction for NADH decomposition",level:"2"},{id:"sec_10_2",title:"3.5 Photosensitized oxidation of folic acid by phosphorus(V) porphyrin through electron transfer",level:"2"},{id:"sec_12",title:"4. Contribution of the electron transfer mechanism in photosensitized reaction by cationic porphyrins",level:"1"},{id:"sec_12_2",title:"4.1 Protein photooxidation through electron transfer by cationic porphyrins",level:"2"},{id:"sec_13_2",title:"4.2 Electron transfer from DNA to photoexcited cationic porphyrins and microenvironmental effect of DNA on photoinduced electron transfer",level:"2"},{id:"sec_15",title:"5. Activity control based on the electron transfer",level:"1"},{id:"sec_15_2",title:"5.1 Electron transfer control by pH",level:"2"},{id:"sec_16_2",title:"5.2 Activity control through the self-quenching of photosensitizers",level:"2"},{id:"sec_18",title:"6. Electron transfer mechanism and antimicrobial photodynamic therapy",level:"1"},{id:"sec_18_2",title:"6.1 Photosensitized DNA damage through electron transfer",level:"2"},{id:"sec_19_2",title:"6.2 Photosensitized protein damage through electron transfer",level:"2"},{id:"sec_21",title:"7. Conclusions",level:"1"},{id:"sec_22",title:"Acknowledgments",level:"1"},{id:"sec_25",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nDolmans DEJGJ, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nature Reviews Cancer. 2003;3:380-387. DOI:10.1038/nrc1071\n'},{id:"B2",body:'\nCastano AP, Mroz P, Hamblin MR. Photodynamic therapy and anti-tumour immunity. Nature Reviews Cancer. 2006;6:535-545. DOI:10.1038/nrc1894\n'},{id:"B3",body:'\nAbrahamse H, Hamblin MR. New photosensitizers for photodynamic therapy. Biochemical Journal. 2016;473:347-364. DOI: 10.1042/BJ20150942\n'},{id:"B4",body:'\nSperandio FF, Huang YY, Hamblin MR. Antimicrobial photodynamic therapy to kill Gram-negative bacteria. Recent Patents on Anti-Infective Drug Discovery. 2013;8:108-120. DOI: 10.2174/1574891x113089990012\n'},{id:"B5",body:'\nAmos-Tautua BM, Songca SP, Oluwafemi OS. Application of porphyrins in antibacterial photodynamic therapy. Molecules. 2019;24:2456. 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DOI: 10.1007/s00259-018-4116-y\n'},{id:"B22",body:'\nKumari R, Sunil D, Ningthoujam RS. Naphthalimides in fluorescent imaging of tumor hypoxia - An up-to-date review. Bioorganic Chemistry. 2019;88:102979. DOI: 10.1016/j.bioorg.2019.102979\n'},{id:"B23",body:'\nLiu Y, Liu Y, Bu W, Cheng C, Zuo C, Xiao Q, Sun Y, Ni D, Zhang C, Liu J, Shi J. Hypoxia induced by upconversion-based photodynamic therapy: towards highly effective synergistic bioreductive therapy in tumors. Angewandte Chemie International Edition. 2015;54:8105-8109. DOI: 10.1002/anie.201500478\n'},{id:"B24",body:'\nVictor HF, Wieman TJ, Wiehle SA, Cerrito PB. The role of microvascular damage in photodynamic therapy: the effect of treatment on vessel constriction, permeability, and leukocyte adhesion. Cancer Research. 1992;52:4914-4921.\n'},{id:"B25",body:'\nMarrese CA, Carrano CJ. The synthesis, characterization and electrochemistry of 5,10,15,20-tetraphenylporphinatodichlorophosphorus(V) chloride. Inorganic Chemistry. 1983;22:1858-1862. DOI: 10.1021/ic00192a024\n'},{id:"B26",body:'\nTakeuchi Y, Hirakawa K, Susumu K, Segawa H. Electrochemical determination of charge transfer direction of “center-to-edge” phosphorus(V) porphyrin arrays. Electrochemistry. 2004;72:449-451. DOI: 10.5796/electrochemistry.72.449\n'},{id:"B27",body:'\nKalyanasundaram K, Neumann-Spallart M. Photophysical and redox properties of water-soluble porphyrins in aqueous media. The Journal of Physical Chemistry. 1982;86:5163-5169. DOI: 10.1021/j100223a022\n'},{id:"B28",body:'\nHirakawa K. DNA damage through photo-induced electron transfer and photosensitized generation of reactive oxygen species. In: Kimura H, Suzuki A, editors. New Research on DNA Damage. New York: Nova Science Publishers; 2008. p. 197-219. ISBN: 978-1-60456-581-2\n'},{id:"B29",body:'\nHirakawa K, Segawa H. Acid dissociation of the axial hydroxylgroup of hydroxy(1-pyrenebutoxy)phosphorus(v) porphyrin controls the intramolecular excitation energy transfer. Photochemical and Photobiological Sciences. 2010;9:704-709. DOI: 10.1039/B9PP00204A\n\n'},{id:"B30",body:'\nHoriuchi H, Kuribara R, Hirabara A, Okutsu T. pH-Response optimization of amino-substituted tetraphenylporphyrin derivatives as pH-activatable photosensitizers. The Journal of Physical Chemistry A. 2016;120:5554-5561. DOI: 10.1021/acs.jpca.6b05019\n'},{id:"B31",body:'\nFoote CS. Definition of type I and type II photosensitized oxidation. Photochemistry and Photobiology. 1991;54:659. DOI: 10.1111/j.1751-1097.1991.tb02071.x\n'},{id:"B32",body:'\nIto K, Kawanishi S. Site-specific DNA damage induced by UVA radiation in the presence of endogenous photosensitizer. Biological Chemistry. 1997;378:1307-1312.\n'},{id:"B33",body:'\nHiraku Y, Ito K, Hirakawa K, Kawanishi S. Photosensitized DNA damage and its protection via a novel mechanism. Photochemistry and Photobiology. 2007;83:205-512. DOI: 10.1562/2006-03-09-IR-840\n'},{id:"B34",body:'\nMarcus RA. On the theory of oxidation-reduction reactions involving electron transfer. I. The Journal of Chemical Physics. 1956;24:966-978. DOI: 10.1063/1.1742723\n'},{id:"B35",body:'\nMarcus RA, Sutin N. Electron transfers in chemistry and biology. Biochimica et Biophysica Acta. 1985;811:265-322. DOI: 10.1016/0304-4173(85)90014-X\n'},{id:"B36",body:'\nKeane PM, Kelly JM. Transient absorption and time-resolved vibrational studies of photophysical and photochemical processes in DNA-intercalating polypyridyl metal complexes or cationic porphyrins. Coordination Chemistry Reviews. 2018;364:137-154. DOI: 10.1016/j.ccr.2018.02.018\n'},{id:"B37",body:'\nFujitsuka M, Kim SS, Lu C, Tojo S, Majima T. Intermolecular and intramolecular electron transfer processes from excited naphthalene diimide radical anions. The Journal of Physical Chemistry B. 2015;119:7275-7282. DOI: 10.1021/jp510850z\n'},{id:"B38",body:'\nHigashino T, Yamada T, Yamamoto M, Furube A, Tkachenko NV, Miura T, Kobori Y, Jono R, Yamashita K, Imahori H. Remarkable dependence of the final charge separation efficiency on the donor-acceptor interaction in photoinduced electron transfer. Angewandte Chemie International Edition. 2016;55:629-633. DOI: 10.1002/anie.201509067\n'},{id:"B39",body:'\nHasegawa M, Nagashima H, Minobe R, Tachikawa T, Mino H, Kobori Y. Regulated electron tunneling of photoinduced primary charge-separated state in the photosystem II reaction center. The Journal of Physical Chemistry Letters. 2017;8:1179-1184. DOI: 10.1021/acs.jpclett.7b00044\n'},{id:"B40",body:'\nHirakawa K, Nishimura Y, Arai T, Okazaki S. Singlet oxygen generating activity of an electron donor-connecting porphyrin photosensitizer can be controlled by DNA. The Journal of the Physical Chemistry B. 2013;117:13490-13496. DOI: 10.1021/jp4072444\n'},{id:"B41",body:'\nHirakawa K, Kawanishi S, Hirano T, Segawa H. Guanine-specific DNA oxidation photosensitized by the tetraphenylporphyrin phosphorus(V) complex via singlet oxygen generation and electron transfer. Journal of Photochemistry and Photobiology B: Biology. 2007;87:209-217. DOI: 10.1016/j.jphotobiol.2007.04.001\n'},{id:"B42",body:'\nOuyang D, Hirakawa K. Photosensitized enzyme deactivation and protein oxidation by axialsubstituted phosphorus(V) tetraphenylporphyrins. Journal of Photochemistry and Photobiology B: Biology. 2017;175:125-131. DOI: 10.1016/j.jphotobiol.2017.08.036\n'},{id:"B43",body:'\nHirakawa K, Fukunaga N, Nishimura Y, Arai T, Okazaki S. Photosensitized protein damage by dimethoxyphosphorus(V) tetraphenylporphyrin. Bioorganic and Medicinal Chemistry Letters. 2013;23:2704-2707. DOI: 10.1016/j.bmcl.2013.02.081\n'},{id:"B44",body:'\nHirakawa K, Azumi K, Nishimura Y, Arai T, Nosaka Y, Okazaki S. Photosensitized damage of protein by fluorinated diethoxyphosphorus(V)porphyrin. Journal of Porphyrins and Phthalocyanines. 2013;17:56-62. DOI: 10.1142/S1088424612501258\n'},{id:"B45",body:'\nHirakawa K, Umemoto H, Kikuchi R, Yamaguchi H, Nishimura Y, Arai T, Okazaki S, Segawa H. Determination of singlet oxygen and electron transfer mediated mechanisms of photosensitized protein damage by phosphorus(V)porphyrins. Chemical Research in Toxicology. 2015;28:262-267. DOI: 10.1021/tx500492w\n'},{id:"B46",body:'\nHirakawa K, Ouyang D, Ibuki Y, Hirohara S, Okazaki S, Kono E, Kanayama N, Nakazaki J, Segawa H. Photosensitized protein-damaging activity, cytotoxicity, and antitumor effects of P(V)porphyrins using long-wavelength visible light through electron transfer. Chemical Research in Toxicology. 2018;31:371-379. DOI: 10.1021/acs.chemrestox.8b00059\n'},{id:"B47",body:'\nHirakawa K, Suzuki A, Ouyang D, Okazaki S, Ibuki Y, Nakazaki J, Segawa H. Controlled photodynamic action of axial fluorinated diethoxyP(V)tetrakis(p-methoxyphenyl)porphyrin through self-aggregation. Chemical Research in Toxicology. 2019;32:1638-1645. DOI: 10.1021/acs.chemrestox.9b00172\n'},{id:"B48",body:'\nHirakawa K, Ohnishi, Y, Ouyang D, Horiuchi H, Okazaki S. pH-Dependent photodynamic activity of bis(6-methyl-3-pyridylmethoxy)P(V)tetrakis(p-methoxyphenyl)porphyrin. Chemical Physics Letters. 2020;746:137315. DOI: 10.1016/j.cplett.2020.137315\n'},{id:"B49",body:'\nHirakawa K, Morimoto S. Electron transfer mediated decomposition of folic acid by photoexcited dimethoxophosphorus(V)porphyrin. Journal of Photochemistry and Photobiology A: Chemistry. 2016;318:1-6. DOI: 10.1016/j.jphotochem.2015.11.028\n'},{id:"B50",body:'\nHirakawa K, Murata A. Photosensitized oxidation of nicotinamide adenine dinucleotide by diethoxyphosphorus(V)tetraphenylporphyrin and its fluorinated derivative: Possibility of chain reaction. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2018;188:640-646. DOI: 10.1016/j.saa.2017.07.055\n'},{id:"B51",body:'\nSusumu K, Segawa H, Shimidzu T. Synthesis and photochemical properties of the orthogonal porphyrin triad composed of free-base and phosphorus(V) porphyrins. Chemistry Letters. 1995;24:929-930. DOI: 10.1246/cl.1995.929\n'},{id:"B52",body:'\nHirakawa K, Aoki S, Ueda Y, Ouyang D, Okazaki S. Photochemical property and photodynamic activity of tetrakis(2-naphthyl)porphyrin phosphorus(V) complex. Rapid Communication in Photoscience. 2015;4:37-40. DOI: 10.5857/RCP.2015.4.2.37\n'},{id:"B53",body:'\nMeshkov I, Bulach V, Gorbunova YG, Gostev FE, Nadtochenko VA, Tsivadzeb AU, Hosseini MW. Tuning photochemical properties of phosphorus(V) porphyrin photosensitizers. Chemical Communications. 2017;53:9918-9921. DOI: 10.1039/c7cc06052a\n'},{id:"B54",body:'\nBarbour T, Belcher WJ, Brothers PJ, Rickard CEF, Ware DC. Preparation of group 15 (phosphorus, antimony, and bismuth) complexes of meso-tetra-p-tolylporphyrin (TTP) and x-ray crystal structure of [Sb(TTP)(OCH(CH3)2)2]Cl. Inorganic Chemistry. 1992;31:746-754. DOI: 10.1021/ic00031a011\n'},{id:"B55",body:'\nMatsumoto J, Shiragami T, Hirakawa K, Yasuda M. Water-solubilization of P(V) and Sb(V) porphyrins and their photobiological application. International Journal of Photoenergy. 2015:148964. DOI: 10.1155/2015/148964\n'},{id:"B56",body:'\nHe XM, Carter DC. Atomic structure and chemistry of human serum albumin. Nature. 1992;358:209-215. DOI: 10.1038/358209a0\n'},{id:"B57",body:'\nSudlow G, Birkett DJ, Wade DN. The characterization of two specific drug binding sites on human serum albumin. Molecular Pharmacology. 1975;11:824-832.\n'},{id:"B58",body:'\nHirakawa K. Evaluation of photodynamic agent activity using human serum albumin. In: Cohen D, editor. Human Serum Albumin: Structure, Binding and Activity. New York: Nova Science Publishers; 2019. p. 1-33 (Chapter 3). ISBN: 978-1-53614-787-2\n'},{id:"B59",body:'\nThomas AH, Serrano MP, Rahal V, Vicendo P, Claparols C, Oliveros E, Lorente C. Tryptophan oxidation photosensitized by pterin. Free Radical Biology and Medicine. 2013;63:467-475. DOI: 10.1016/j.freeradbiomed.2013.05.044\n'},{id:"B60",body:'\nReid LO, Roman EA, Thomas AH, Dántola ML. Photooxidation of tryptophan and tyrosine residues in human serum albumin sensitized by pterin: a model for globular protein photodamage in skin. Biochemistry. 2016;55:4777-4786. DOI: 10.1021/acs.biochem.6b00420\n'},{id:"B61",body:'\nJensen RL, Arnbjerg J, Ogilby PR. Reaction of singlet oxygen with tryptophan in proteins: a pronounced effect of the local environment on the reaction rate. Journal of the American Chemical Society. 2012;134:9820-9826. DOI: 10.1021/ja303710m\n'},{id:"B62",body:'\nLi MY, Cline CS, Koker EB, Carmichael HH, Chignell CF, Bilski P. Quenching of singlet molecular oxygen (1O2) by azide anion in solvent mixtures. Photochemistry and Photobiology. 2001;74:760-764. DOI: 10.1562/0031-8655(2001)074<0760:qosmoo>2.0.co;2\n'},{id:"B63",body:'\nGoldstein S, Czapski G. Reactivity of peroxynitrite versus simultaneous generation of •NO and O2\n•− toward NADH, Chemical Research in Toxicology. 2000;13:736-741. DOI: 10.1021/tx000099n\n'},{id:"B64",body:'\nHirakawa K, Ito H. Rhodamine-6G can photosensitize folic acid decomposition through electron transfer. Chemical Physics Letters. 2015;627:26-29. DOI: 10.1016/j.cplett.2015.03.030\n'},{id:"B65",body:'\nHirakawa K. Using folic acids to detect reactive oxygen species. In: Taylor JC, editor. Advances in Chemistry Research. Volume 26. New York: Nova Science Publishers; 2015. p. 111-126. ISBN: 978-1-63463-630-8\n'},{id:"B66",body:'\nHirakawa K. Fluorometry of singlet oxygen generated via a photosensitized reaction using folic acid and methotrexate. Analytical and Bioanalytical Chemistry. 2009;393:999-1005. DOI: 10.1007/s00216-008-2522-x\n'},{id:"B67",body:'\nSilvester JA, Timmins GS, Davies MJ. Protein hydroperoxides and carbonyl groups generated by porphyrin-induced photo-oxidation of bovine serum albumin. Archives of Biochemistry and Biophysics. 1998;350:249-258. DOI: 10.1006/abbi.1997.0495\n'},{id:"B68",body:'\nSilvester JA, Timmins GS, Davies MJ. Photodynamically generated bovine serum albumin radicals: evidence for damage transfer and oxidation at cysteine and tryptophan residues. Free Radical Biology and Medicine. 1998;24:754-766. DOI: 10.1016/s0891-5849(97)00327-4\n'},{id:"B69",body:'\nOuyang D, Inoue S, Okazaki S, Hirakawa K. Tetrakis(N-methyl-p-pyridinio)porphyrin and its zinc complex can photosensitize damage of human serum albumin through electron transfer and singlet oxygen generation. Journal of Porphyrins and Phthalocyanines. 2016;20:813-821. DOI: 10.1142/S1088424616500991\n'},{id:"B70",body:'\nTada-Oikawa S, Oikawa S, Hirayama J, Hirakawa K, Kawanishi S. DNA damage and apoptosis induced by photosensitization of 5,10,15,20-tetrakis (N-methyl-4-pyridyl)-21H,23H-porphyrin via singlet oxygen generation. Photochemistry and Photobiology. 2009;85:1391-1399. DOI: 10.1111/j.1751-1097.2009.00600.x\n'},{id:"B71",body:'\nHirakawa K, Taguchi M, Okazaki S. Relaxation process of photoexcited meso-naphthylporphyrins while interacting with DNA and singlet oxygen generation. The Journal of Physical Chemistry B. 2015;119:13071-13078. DOI: 10.1021/acs.jpcb.5b08025\n'},{id:"B72",body:'\nBurrows CJ, Muller JG. Oxidative nucleobase modifications leading to strand scission. Chemical Reviews 1998;98:1109-1151. DOI: 10.1021/cr960421s\n'},{id:"B73",body:'\nNeumann-Spallart M, Kalyanasundaram KZ. On the one and two-electron oxidations of water-soluble zinc porphyrins in aqueous media. Z. Naturforsch. 1981;36b:596-600.\n'},{id:"B74",body:'\nHirakawa K, Nakajima S. Effect of DNA microenvironment on photosensitized reaction of water-soluble cationic porphyrins. Recent Advances in DNA and Gene Sequences. 2014;8:35-43. DOI: 10.2174/2352092208666141013231434\n'},{id:"B75",body:'\nLewis FD, Wu Y. Dynamics of superexchange photoinduced electron transfer in duplex DNA. Journal of the Photochemistry and Photobiology C: Photochemistry Reviews. 2001;2:1-16. DOI: 10.1016/S1389-5567(01)00008-9\n'},{id:"B76",body:'\nSeidel CAM, Schulz A, Sauer MHM. Nucleobase-specific quenching of fluorescent dyes. 1. nucleobase one-electron redox potentials and their correlation with static and dynamic quenching efficiencies. The Journal of Physical Chemistry. 1996;100:5541-5553. DOI: 10.1021/jp951507c\n'},{id:"B77",body:'\nSugiyama H, Saito I. Theoretical studies of GG-specific photocleavage of DNA via electron transfer: significant lowering of ionization potential and 5′-localization of HOMO of stacked GG bases in B-form DNA. Journal of the American Chemical Society. 1996;118:7063-7068. DOI: 10.1021/ja9609821\n'},{id:"B78",body:'\nYoshioka Y, Kitagawa Y, Takano Y, Yamaguchi K, Nakamura T, Saito I. Experimental and theoretical studies on the selectivity of GGG triplets toward one-electron oxidation in B-form DNA. Journal of the American Chemical Society. 1999;121:8712-8719. DOI: 10.1021/ja991032t\n'},{id:"B79",body:'\nYoshioka Y, Kawai H, Sato T, Yamaguchi K, Saito I. Ab initio molecular orbital study on the G-selectivity of GGG triplet in copper(I)-mediated one-electron oxidation. Journal of the American Chemical Society. 2003;125:1968-1974. DOI: 10.1021/ja028039m\n'},{id:"B80",body:'\nAigner D, Freunberger SA, Wilkening M, Saf R, Borisov SM, Klimant I. Enhancing photoinduced electron transfer efficiency of fluorescent pH-probes with halogenated phenols, Analytical Chemistry. 2014;86:9293-9300. DOI: 10.1021/ac502513g\n'},{id:"B81",body:'\nHoriuchi H, Isogai M, Hirakawa K, Okutsu T. Improvement of the ON/OFF switching performance of a pH-activatable porphyrin derivative by the introduction of phosphorus(V), ChemPhotoChem. 2019;3:138-144. DOI: 10.1002/cptc.201800248\n'},{id:"B82",body:'\nVaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review, Cancer Research. 1989;49:6449-6465.\n'},{id:"B83",body:'\nEstrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ. Acidity generated by the tumor microenvironment drives local invasion. Cancer Research. 2013;73:1524-1535. DOI: 10.1158/0008-5472.CAN-12-2796\n'},{id:"B84",body:'\nKorenchan DE, Bok R, Sriram R, Liu K, Santos RD, Qin H, Lobach I, Korn N, Wilson DM, Kurhanewicz J, Flavell RR. Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer. Oncotarget. 2019;10:6096-6110. DOI: 10.18632/oncotarget.27225\n'},{id:"B85",body:'\nVasquez-Montes V, Gerhart J, Thévenin D, Ladokhin AS. Divalent cations and lipid composition modulate membrane insertion and cancer-targeting action of pHLIP, Journal of Molecular Biology. 2019;431:5004-5018. DOI: 10.1016/j.jmb.2019.10.016\n'},{id:"B86",body:'\nZhu X, Lu W, Zhang Y, Reed A, Newton B, Fan Z, Yu H, Ray PC, Gao R. Imidazole-modified porphyrin as a pH-responsive sensitizer for cancer photodynamic therapy, Chemical Communications. 2011;47:10311-10313. DOI: 10.1039/c1cc13328d\n'},{id:"B87",body:'\nTian J, Zhou J, Shen Z, Ding L, Yu JS, Ju H. A pH-activatable and anilinesubstituted photosensitizer for near-infrared cancer theranostics. Chemical Science. 2015;6:5969-5977. DOI: 10.1039/c5sc01721a\n'},{id:"B88",body:'\nHoriuchi H, Hirabara A, Okutsu T. Importance of the orthogonal structure between porphyrin and aniline moieties on the pH-activatable porphyrin derivative for photodynamic therapy, Journal of the Photochemistry and Photobiology A: Chemistry. 2018;365:60-66. DOI: 10.1016/j.jphotochem.2018.07.034\n'},{id:"B89",body:'\nTørring T, Toftegaard R, Arnbjerg J, Ogilby PR, Gothelf KV. Reversible pH regulated control of photosensitized singlet oxygen production using a DNA i-motif. Angewandte Chemie International Edition. 2010;49:7923-7925. DOI: 10.1002/anie.201003612\n'},{id:"B90",body:'\nWang C, Qian Y. A novel BODIPY-based photosensitizer with pH-active singlet oxygen generation for photodynamic therapy in lysosomes. Organic and Biomolecular Chemistry. 2019;17:8001-8007. DOI: 10.1039/c9ob01242g\n'},{id:"B91",body:'\nTim M. Strategies to optimize photosensitizers for photodynamic inactivation of bacteria. Journal of the Photochemistry and Photobiology B: Biology. 2015;150:2-10. DOI: 10.1016/j.jphotobiol.2015.05.010\n'},{id:"B92",body:'\nMa W, Liu C, Li J, Hao M, Ji Y, Zeng X. The effects of aloe emodin-mediated antimicrobial photodynamic therapy on drug-sensitive and resistant Candida albicans. Photochemical and Photobiological Sciences. 2020;19:485-494. DOI: 10.1039/c9pp00352e\n'},{id:"B93",body:'\nTardivo JP, Del Giglio A, de Oliveira CS, Gabrielli DS, Junqueira HC, Tada DB, Severino D, de Fátima TR, Baptista MS. Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications. Photodiagnosis and Photodynamic Therapy. 2005;2:175-191. DOI: 10.1016/S1572-1000(05)00097-9\n'},{id:"B94",body:'\nUsui Y, Kamogawa K. A standard system to determine the quantum yield of singlet oxygen formation in aqueous solution. Photochemistry and Photobiology. 1974;19:245-247. DOI: /10.1111/j.1751-1097.1974.tb06506.x\n'},{id:"B95",body:'\nJørgensen E, Bay L, Bjarnsholt T, Bundgaard L, Sørensen MA, Jacobsen S. The occurrence of biofilm in an equine experimental wound model of healing by secondary intention. Veterinary Microbiology. 2017;204:90-95. DOI: 10.1016/j.vetmic.2017.03.011\n'},{id:"B96",body:'\nHirakawa K, Ota K, Hirayama J, Oikawa S, Kawanishi S. Nile blue can photosensitize DNA damage through electron transfer. Chemical Research in Toxicology. 2014;27:649-655. DOI: 10.1021/tx400475c\n'},{id:"B97",body:'\nWainwright M, Mohr H, Walker W.H. Phenothiazinium derivatives for pathogen inactivation in blood products. Journal of the Photochemistry and Photobiology B: Biology. 2007;86:45-58. DOI: 10.1016/j.jphotobiol.2006.07.005\n'},{id:"B98",body:'\nHirakawa K, Ochiai S, Oikawa S, Kawanishi S. Oxygen-independent DNA damage photosensitized by rhodamine-6G. Trends in Photochemistry and Photobiology. 2011;13:29-35.\n'},{id:"B99",body:'\nHirakawa K, Ishikawa T. Phenothiazine dyes photosensitize protein damage through electron transfer and singlet oxygen generation. Dyes and Pigments. 2017;142:183-188. DOI: 10.1016/j.dyepig.2017.03.035\n'},{id:"B100",body:'\nVardevanyan PO, Antonyan AP, Parsadanyan MA, Torosyan MA, Karapetian AT. Joint interaction of ethidium bromide and methylene blue with DNA. The effect of ionic strength on binding thermodynamic parameters. Journal of Biomolecular Structure and Dynamics. 2016;34:1377-1382. DOI: 10.1080/07391102.2015.1079557\n'},{id:"B101",body:'\nBenesi HA, Hildebrand JH. A spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons. Journal of the American Chemical Society. 1949;71:2703-2707. DOI: 10.1021/ja01176a030\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Kazutaka Hirakawa",address:"hirakawa.kazutaka@shizuoka.ac.jp",affiliation:'
Department of Engineering, Applied Chemistry and Biochemical Engineering Course, Graduate School of Integrated Science and Technology, Shizuoka University, Japan
Department of Optoelectronics and Nanostructure Science, Graduate School of Science and Technology, Shizuoka University, Japan
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