Composition of main substrates for
\r\n\tThe WHO classification in 2007; was based on the histogenesis and cell origin of the tumor. In the latest classification made in 2016; to better characterize the tumor and obtain better data on its prognosis; The combination of molecular and genetic biomarkers and histopathological features of the tumor was used. Despite all current treatment approaches, the median survival time is around 12 months in most GBM patients. Compared with the situation of some types of successfully treated cancers; the survival time of GBM patients is not at an acceptable level today. In the treatment of CNS tumors; surgery, chemotherapy, and radiation treatments (x-rays, gamma rays, electron and proton beams) are used. The therapeutic potential of chemotherapy; New strategies are needed to increase drug concentration at the diseased site, as this largely depends on the ability of the chemotherapeutic agent to achieve effective concentrations at tumor localization. Based on our better understanding of the genetic and molecular characteristics of CNS tumors; Targeted therapies, including vaccines, and treatment protocols such as immunotherapy are promising developments.
\r\n\r\n\tThis book supposes to be written by many authors who have an internationally honored place in their field to share their ideas about the treatment of CNS tumors. Surgery, Radiotherapy, Chemotherapy and Antiangiogenic Therapy Protocols, Immunotherapy, Molecular Therapy, Specific target-agents therapy with Nanoparticles and Gene Therapy for CNS tumors among the book chapters.
\r\n\tIn these sections; there are many practical pieces of information that can help the students who graduated from the Medicine Faculty and specialist doctors who are interested in Neurosurgery.
In recent years the interest for nonstandard function spaces has risen due to several considerations including their need in some fields of applied mathematics, differential equations, and simply the possibility to study extensions and generalizations of classical spaces.
\nOne of such type of spaces is the variable exponent Lebesgue spaces. A first introduction to them was due to Orlicz in 1931. He considered measurable functions \n
the usual exponent \n
for \n
Later generalizations consisted on considering real functions \n
where
\nis a suitable function. Such spaces are known nowadays as Musielak-Orlicz spaces. We are interested in the case
\nwhich corresponds to variable exponent Lebesgue spaces, with some adequate restrictions for the
The study of problems in spaces with nonstandard growth has been mainly related to Lebesgue spaces with variable order \n
Another known application is related to image restoration. Based on variable exponent spaces, the authors of [7] proposed a new model of image restoration combining the strength of the total variation approach and the isotropic diffusion approach. This model uses one value of \n
The theory of spaces of analytic functions on domains of the complex plane, or in general of \n
A Banach space \n
Vectorial operations are precisely the pointwise operations on \n
If \n
If \n
Evaluation functionals \n
Classical Hardy and Bergman spaces are examples of functional Banach spaces. In the case of spaces of analytic functions, the evaluation functionals \n
The setting of nonstandard spaces of analytic functions is a young area of research; a lot is yet to be explored. In this chapter, an introduction to the subject of variable exponent spaces of analytic functions will be given, making emphasis in the special place that evaluation functionals have in the theory.
\nPerhaps the most known function spaces in mathematical analysis are the
The basics on variable Lebesgue spaces may be found in the monographs [1, 17, 18]. For \n
For a complex-valued measurable function \n
and the
Given \n
Most of the research being done on variable exponent spaces makes use of a regularity condition in the variable exponent in order to have a “fruitful” theory.
\n\n
for all \n
for all \n
This condition has proven to be very useful in the theory since, among other things, it implies the boundedness of the Hardy-Littlewood maximal operator in \n
and represents an important tool in harmonic analysis. We used it in [19] to show that the Bergman projection is bounded on variable exponent Bergman spaces.
\nAnother consequence of the \n
that hold for all balls \n
One interesting point of the theory of variable exponents is that, in general, the classical approach to Bergman spaces seems to fail in the variable framework. For example, in [19] it is shown that the Bergman projection is bounded from \n
In this section we will give an introduction to the variable exponent Hardy spaces and the results and techniques that are usually found. We will follow the presentation as in [20].
\n\n
and the Poisson transform of a function \n
where \n
We will use the following result from [21]:
\n\n
is uniformly bounded on \n
We are now ready to define the harmonic Hardy spaces with variable exponents. Given \n
\n
Notice that, since \n
\n
\n
and moreover, the inclusions are continuous.
\n\n
In an analogous way to the classical setting \n
Recall that for all functions \n
For each \n
are called
\n
\n
The main tool for proving the previous theorem is following the version of a Forelli-Rudin inequality, adapted to the case of variable exponents. Here, the Log-Hölder continuity plays a key role.
\n\n
\n
The theory of Bergman spaces was introduced by S. Bergman in [22] and since the 1990s has gained a great deal of attention mainly due to some major breakthroughs at the time. For details on the theory of Bergman spaces, we refer to the books [5, 23].
\n\n
One of the first results proven in [19] about this theory was the boundedness of the evaluation functionals that, as we saw before, will allow us to conclude that convergence in \n
\n
Using different techniques, the following sharp estimate was obtained in [24]:
\n\n
The proof of this fact relies on the Log-Hölder condition and on the following version of a Jensen-type inequality for variable exponent spaces (see [17]).
\n\n
\n
for all \n
The additional term that appears in the previous inequality makes the boundedness of the domain a necessary condition to use such technique. One question to address in future investigations is how the situation is for Bergman spaces defined on unbounded domains. In such case, the error term accumulates despite the regularity condition on \n
One technique developed to study variable exponent Bergman spaces is a combination of mollifiers and dilations. Such concept was developed for studying the density of the set of polynomials in Bergman spaces. In the classical case, this is a consequence of the fact that convergence in \n
converge in norm to \n
One way of overcoming this problem in the case of variable exponent Lebesgue spaces is the use of a
where \n
and
\nMollified dilations allow us to approximate analytic functions in the variable exponent Bergman spaces by functions that are analytic on a neighborhood of the unit disk.
\n\n
\n
As a consequence of the previous theorem, we can approximate a function \n
Another classical problem that has a variable exponent equivalent consists on finding a geometrical characterization of Carleson measures in variable exponent Bergman spaces. Given a positive Borel measure \n
In other words, \n
Lennart Carleson gave a geometric characterization of Carleson measures on Hardy spaces \n
In the case of the classical Bergman spaces \n
\n
The main tool for the proof of the previous theorem is Eq. (2) that implies the following estimate for the reproducing kernels.
\n\n
An interesting area will be to study some analytic properties of functions belonging to variable exponent Bergman spaces. One starting point will be to study the structure of zero sets in the space.
\nA sequence of points \n
Although the problem of completely describing the zero sets in \n
This result depends on studying the radial growth of functions in the Bergman space and on Jensen’s formula for the sequence \n
This equation holds for every analytic function on \n
Another result involving zero sets is that if \n
Finding an extension of such result to variable exponents would include making sense of the right-hand side term that is not even clear in this context.
\nA related concept that we would like to address in variable exponent Bergman spaces is that of sampling sequences. A sequence of points \n
One difference that is expected to occur in the case of variable exponents is that sampling sequences will probably not be invariant under automorphism of the unit disk. This is true for a constant exponent, and it will be interesting to find counterexamples if the exponent varies. Sampling sequences are related to the concept of “frames” in Hilbert spaces and can be thought as sequences that contain great information of the space. It is expected that a sampling sequence is a somehow “big” and “spread out” subset of the unit disk. The notion is clearly related in \n
If we define a discrete measure \n
where \n
The characterization of Carleson measures obtained in [24] opens the possibility of studying the boundedness and compactness of certain operators acting on variable exponent Bergman spaces.
\nAmong those operators worth studying are multiplication operators. Those are formally defined on a functions space \n
where \n
Such question has been addressed in the case of weighted Bergman spaces in [23]. The proof relies on a geometric characterization of Carleson measures, a composition with a disk isomorphism, and a theorem of change of variables. Such tool is difficult to use in the setting of variable exponents since any change of variables will also affect the exponent and consequently the spaces are not necessarily invariant under composition with isomorphisms. This makes the situation different from the case of a constant exponent.
\nOther operators related to multiplication are Toeplitz operators. Those have already being studied in [30] for the case of weighted Bergman spaces with non-radial weights. Given a function \n
One natural question is to ask whether this operator can be extended boundedly to the space \n
The composition operators are another type of operators to be studied. Given an analytic self-map \n
A natural question is to find function-theoretic conditions on \n
where \n
\n
\n
This result allows, under certain conditions, to pass from the of studying operators defined on variable exponent spaces, to study operators defined on weighted constant exponent spaces, and therefore it is possible to use known results from the Muckenhoupt weights theory.
\nAnother type of spaces we are interested is the class of analytic Besov spaces \n
For each \n
One particular property of this space is that they are Möbius invariant in the sense that \n
One useful technique to study such spaces is a derivative-free characterization of functions in \n
A similar result in the case of variable exponents could serve as a starting point for investigating other properties of the space.
\nSeveral problems might arise when producing secondary metabolites using both spontaneous and cultivated plants or parts of plants. If the material for extraction is collected by spontaneous plants, the major risk is related to the impoverishment of resources and biodiversity, consequently. Although natural ecosystems are usually rich in officinal plants that can be used by humans, an excessive collection of spontaneous flora can act as a direct cause of biodiversity loss [1, 2]. Currently, it is estimated that at least 50,000 plant species are used, which in the majority of cases grow spontaneously, however, sometimes products come from specific cultivation. Based on what was reported by the 2020 edition of the State of the World’s Plants and Fungi [3], climate change is threatening two-fifths of the plants currently known; this value is doubled compared to what observed in 2016 and, among these, species are included many medicinal plants used both as a natural remedy and for drug production. According to such data collection that involved 210 scientists and 42 countries, over 140,000 plants should be classified as under extinction threat, including 730 medicinal plants. Among known species, 5500 medicinal plants can be found and approximately 13% of these are under extinction threat [4]. Concerning the most vulnerable plants, we can mention
A large number of species belonging to the plant kingdom have always coexisted on Earth, over the years they have created a great heritage of biodiversity. Plants have always been a primary source of sustenance for herbivorous and omnivorous animals including the human species, the latter, however, over time, has realized the possibility of using plant biomass to also obtain substances to be utilized in various effective ways, for example as medication or food supplements.
Western medical culture can be traced back to the Sumerian Nippur tablets of 3000 BC on which the names of medicinal herbs are reported. The first known writing on the subject is a papyrus (1552 BC), dating back to an Egyptian dynasty. It features numerous herbal formulas and, between magic and medicine, even invocations to ward off disease and a catalog of plants, minerals, magical amulets, and useful spells. It is based on more than 500 plants, nearly a third of which are still found in today’s Western pharmacopoeias.
The most famous Egyptian physician was Imhotep (Memphis around 2500 BC) whose “materia medica” included practices to reduce head and thoracic trauma, wound care, prevention, treatment of infections, and principles of hygiene.
The first Chinese manual of materia medica, Shennong Ben Cao Jing (Emperor Shennong’s classic Materia medica), written in the first century, describes 365 medicines, 252 derived from herbs.
Ancient literature also provided the manuscript “Recipes for fifty-two foods,” the longest medical text found in the Chinese tomb of Mawangdui, (168 BC), the Wushi’er Bingfang (9950 characters). It along with others shows the early development of Chinese medicine while subsequent generations have developed Yaoxing Lun, a “Treatise on the Nature of Medicinal Herbs.”
Ayurveda is the traditional medicine in India that emphasizes plant-based treatments, hygiene, and the balance of the state of the body. The Indian Materia Medica included knowledge of plants, the place of its growth, the methods of conservation, and the duration of the collected materials; includes also directions for extracting juices, powders, cold infusions, and extracts.
Later in Greece, it was Hippocrates, a philosopher known as the father of medicine, who in 460 BC founded a school focused on the necessity to discover the causes of disease to combat them. His treatises, aphorisms, and prognostics, in addition to describing 265 drugs, supported the importance of diet for the treatment of diseases.
Theophrastus (390–280 BC), a disciple of Aristotle’s, historically known as the “father of botany,” wrote the treatise Historia Plantarium, the first attempt to classify plants and botanical morphology in Greece with details of medicinal herbs and concoctions based on them.
Later Galen, philosopher, physician, pharmacist, and prolific writer of medical matters, collected the medical knowledge of his time in an extensive report and wrote on the structure of organs, the impulse and its association with respiration, arteries, and blood circulation, and the uses of the “Theriac” “In treatises such as on Theriac to Piso, on Theriac to Pamphilius, and on Antidotes, Galen identified in the Teriaca a compound of 64 ingredients, which can be defined as a polypharmaceutical, suitable for treating every known disease.” His work rediscovered in the fifteenth century became the authority on medicine and healing for the next two centuries.
The Greek physician Dioscorides treated medical questions in five volumes, entitled Περὶ ὕλης ἰατρικῆς in Greek and De Materia Medica in Latin; they include about 500 plants and direct observations of the plants and the effects that the various drugs have had on patients. De Materia Medica was the first extensive drug system comprising a 1000 natural drugs (products for most basic plants). The classification used by Dioscorides is of an elementary type even if he uses a botanical taxonomy. The books written by Dioscorides on medicinal herbs of history are considered the precursors of the modern pharmacopeia remaining in use until the 1600s.
Active principles synthesized through secondary metabolites act as a defense strategy, playing an active role in plant ecophysiology against herbivores, attacks by pathogens but also as a response to abiotic stress, and competition with other plants; at the same time, they play a crucial role in attracting beneficial organisms, such as symbionts and pollinators. Recently, several studies on “secondary metabolism” highlighted additional features related to these molecules, which make them essential for the organism that produces them as they provide useful information on quality and on specific features of a range of raw materials, both of animal and vegetal origin as well as on food produced with them [6, 7]. As a matter of fact, the secondary metabolites pool is often influenced by specific environmental conditions, for instance, in the case of essential oil profile; for this reason, secondary metabolite products in essential oils may provide important support in acquiring valuable information on their origin.
Unlike primary metabolites that are stable in concentration and chemical structure, ensuring cell structural and functional integrity, secondary metabolites show a “high degree of freedom” as far as these aspects are concerned [8, 9].
Due to an enormous diversity in structure and intraspecific variability, biosynthesis in secondary metabolites is limited to definite groups of plants and thus they are not ubiquitous. Synthesis in secondary metabolites was selected when during evolution such compounds managed to respond to specific needs by vegetal organisms [10]. This is the case, for instance, of the variation of scents and colors in flowers to attract pollinators and promote and increase efficiency in pollination [11].
Secondary metabolism-derived molecules are released in the environment through different mechanisms, among others we can mention volatilization that leads to a dispersion of substances such as ethylene and sesquiterpenes that can be absorbed by surrounding plants directly through the soil or atmosphere; lisciviation, instead, promotes the release of substances, such as sugar, amino acids, alkaloids, fatty acids, terpenoids, and phenolic acids, from the aerial part of the plant through hydrosolubility caused by rain or fog. Other mechanisms promoting dispersion are 40 exudation and decomposition.
The activity of substances released also depends on the physiological and nutritional status of plants and environmental abiotic factors, such as light, rain, and temperature [12].
During the nineteenth century, chemists showed interest in the study of secondary metabolism and metabolites, concerning especially drugs, poison, aromatizers, and industrial products, all representing as a whole the final products of metabolic pathways or networks of these; actually, more than 200,000 are known to date.
Recently, potential roles of secondary products at the cell level that have been identified are—plant growth regulation, gene expression modulation, and compounds involved in signal transduction [13, 14]. Hence, while for centuries secondary metabolites have been used in traditional medicine, nowadays, they act as valuable pharmaceutical, cosmetic, chemical compounds, and nutraceuticals in the recent past [15].
Active principles can be divided into three big molecule families based on the biosynthesis pathways from which they are originated—terpenoids and steroids, alkaloids and phenolics [15].
These are the most recurrent compounds; lipid molecules synthesized starting from acetyl CoA or from glycolysis intermediates reaching a total of 35,000, abundant in essential oils, resins, rubber, volatile molecules, scented, colorless, soluble in oil or highly lipophilic solutions, and inflammable. They function as protectors for wood tissues, exert antibacterial effects, are responsible for insect attraction and repulsion, as well as represent the base material for vegetal hormones or pigments (chlorophyll and carotenoids) synthesis; they also take part in the mitochondrial electron transport and plastoquinone.
These molecules, which accumulate nitrogen becoming an important source of it, are produced by approximately 20% of plants; more than 20,000 different alkaloids are known and are synthesized principally from amino acids.
They play an important role as an advanced chemical defense system of plants under predators’ pressure (larvae, insects, herbivores, mammals). They work as antibiotics and pesticides with a deterrent action to prevent plants from being ingested.
Alkaloids used as drugs, poison, with stimulating and narcotizing effects were used even by Greek and Romans, such as atropine (
Secondary plant metabolites belonging to the big family of polyphenols [16], having mostly hydrosoluble characteristics. They represent one of the main classes of secondary metabolites that includes a wide range of highly heterogeneous substances having all in common an aromatic ring. They are formed through the biosynthesis pathway of shikimic or mevalonic acids; a total of 15,000 are known and represent a group of substances easily occurring in superior plants; the most common cinnamic acid derivatives are caffeic, p-Coumaric, ferulic, gallic, and synaptic acids.
Compounds of different colors accumulate especially in aerial plant organs (stems, leaves, flowers, and fruits) rather than in roots; such a preferred location is related to a light-induced effect on phenolic metabolism; besides, phenolic compounds play a protective role against UV that are successfully absorbed and accumulated into leaves epidermis to avoid damage caused to cell DNA [16]. They influence the color, generally yellow, of flowers and fruits where they can be found as glycosides diluted in cell juice except for anthocyanidines and their glucosides (anthocyanins) that are red, purple, or blue depending on the pH of cell juice [17]. The flavonoids content in plants depends not only on the genotype but is also closely related to environmental conditions especially by light radiation such as UV; the latter, in fact, induces a significant increase of flavonoids in leaves [18, 19].
Flavonoids and phenolic acids are the most important antioxidants in the diet and can be found also in tea, wine, and beer [8].
They are considered pharmacologically active compounds having anti-inflammatory activity, active against liver injury due to hepatotoxicity, and acting as antitumoral, antimicrobials, antivirals, enzyme inhibitors, antioxidants, protect against capillary fragility, as well as playing a role as insect repellents and signaling in plant-organism interactions.
In the recent past, the most common use involving the antioxidant properties has been represented by the “scavenger” activity exerted by a series of enzymes, such as dismutase, superoxide, catalase, glutathione peroxidase; they play a role in halting the radical reaction cascade causing acceleration of cell senescence processes.
Among multiple biological activities exerted by these secondary metabolism molecules, we highlight the role of antioxidants against aging, such as in the case of cocoa (
The high variety of phenolic structures shows the same amount of function diversification—they can play a role as low molecular weight flower pigments, antibiotics, and anti-UV screens.
Likewise, elicitation on a secondary metabolic pathway by a pathogen can lead to
Antioxidants can be defined as any substance that is able to delay or significantly inhibit oxidation in a specific substrate even if it shows a really low concentration compared to the oxidable substrate [20]. Nutrition plays a crucial role in ensuring the efficacy of antioxidant enzyme defenses—many essential oligoelements, such as selenium, copper, manganese, and zinc, are involved in the molecular structure or in the catalytic activity of these enzymes. The main antioxidant compounds in food are—ascorbic acid (vitamin C), tocopherols (vitamin E), carotenoids, flavonoids.
Over the years, pharmaceutical companies have been focusing on antioxidant compounds from food to promote healthy properties of food as available data show that an increase in oxidant intake from natural sources, specifically from fruit and vegetables, may have a beneficial effect on disease prevention. Their production can be effectively achieved through
Secondary metabolites can be produced
Cultures of vegetal tissues (Figure 1) or isolated cells (Figure 2) are inoculated in sterile conditions starting from explants, such as leaves, stems, meristems, roots, buds, callus (Figure 3) both for multiplication and secondary metabolite production. Production can take place in more than one tissue.
Culture of shoots on liquid substrate.
Cell suspension culture.
Isolated callus on solidified medium.
Depending on the species, biomass production can be initiated from an undifferentiated callus or cell suspension. In other cases, sprouts, roots, and somatic embryos can be cultured. Using differentiated tissues or organs is crucial when the requested metabolite is produced in specific plant tissue or organ or also in specialized glands such as in the case of essential oils [24, 25]. Although different studies showed efficacy in secondary metabolite production through cultures of differentiated tissues and callus, the technique mostly used is cell suspension [22, 23, 26, 27]. The latter is a culture of cells isolated in a liquid medium that exploits cell totipotency for large-scale production. Each cell, in fact, keeps the biosynthesis ability of the plant and under the right conditions can produce metabolites identical to the ones produced by the mother plant. Furthermore, it can be noticed that cell cultures have greater and faster potential application to the market compared to other production methods [25, 28]. This technique ensures the continuous production of metabolites of interest while offering an elevated quality standard and product uniformity. In addition, it is possible through biotechnology applications to produce new metabolites not synthesized by the mother plant [29, 30]. Currently, different metabolites with an interesting market value are produced using cell suspension culture, such as taxol [31, 32], resveratrol [33], artemisinin [34], ginsenosides [35], raubasine [36].
Among differentiated tissues, hairy roots should be highlighted as they enable the production of secondary metabolites from a considerable number of plants.
Hairy roots are formed in nature on plants following an infection caused by
Agrobacterium can transfer genetic information to plants inducing transformations. Once the infection takes place, a plasmid fragment called T-DNA can be integrated into the plant nuclear DNA where genes are integrated. The composition and organization of T-DNA sequences vary considerably. As some cT-DNA genes show strong growth effects when expressed in other species, they can also influence the growth of natural transformants. However, there is still a need to fully identify the mechanisms through which these genes alter growth models and their regulation by promoters and plant transcription factors [38]. Among the advantages of such a technique, we can mention the high level of cell differentiation, rapid growth, relatively easy production, genetic, and biochemical stability. It should also be taken into consideration the potential accumulation of secondary metabolites in the aerial part of the plant. However, technical problems might arise in cultivation systems for the market [37].
The process can involve both cells and elicitors. They are bound inside a matrix through trapping, absorption, or covalent bonding. The system must be integrated with an adequate substrate as in the case of cultures of suspended cells, as well as regulating chemical and physical parameters, such as pH and temperature.
In a system of this kind, secondary metabolites must be released by cells in the culture media naturally or through induced secretion. One of the advantages of this methodology is the potential stabilization of a continuous production process through the adoption of a specific system of bioreactors.
Generally, the substrate contains mineral elements formed by macro and microelements and an organic component formed by vitamins, amino acids, and other nitrogen components as well as carbohydrates. There are different substrates that can play a specific role in achieving different objectives, as a consequence of the concentration of specific substances contained in them, such as those indicated, for example, in Table 1.
Macro and microelements | MS (mg/L) | WPM (mg/L) | B5 (mg/L) | NN (mg/L) |
---|---|---|---|---|
Ammonium nitrate | 1650.000 | 400.000 | 720.000 | |
Boric acid | 6.200 | 6.200 | 3.000 | 10.000 |
Anhydrous calcium chloride | 332.200 | 72.500 | 113.24 | |
Cobalt chloride hexahydrate 6H2O | 0.025 | 0.025 | ||
Tripotassium phosphate | 170.000 | 170.000 | 130.500 | 68.000 |
Potassium iodide | 0.830 | 0.750 | ||
Sodium molybdate 2H2O | 0.250 | 0.250 | 0.250 | 0.250 |
Calcium nitrate | 386.000 | |||
Potassium nitrate | 1900.000 | 2500.000 | 950.000 | |
Ammonium sulfate | 134.000 | |||
Iron sulfate·7H2O | 27.800 | 27.800 | 27.850 | 27.850 |
Anhydrous magnesium sulfate | 180.700 | 180.700 | 122.09 | 90.340 |
Manganese sulfate·H2O | 16.900 | 22.300 | 10.000 | 18.940 |
Potassium sulfate | 990.000 | |||
Copper sulfate 5H2O | 0.025 | 0.250 | 0.025 | 0.025 |
Zinc sulfate 7H2O | 8.600 | 8.600 | 2.000 | 10.000 |
VITAMINS | ||||
Folate | 0.500 | |||
Nicotinic acid | 0.500 | 0.500 | 1.000 | 5.000 |
Biotin | 0.050 | |||
Myo-inositol | 100.000 | 100.000 | 100.000 | 100.000 |
Pyridoxine·HCl | 0.500 | 0.500 | 1.000 | 0.500 |
Thiamine·HCl | 0.100 | 1.00 | 10.000 | 0.500 |
OTHER ADDITIVES | ||||
Disodium EDTA (·2H2O) | 37.260 | 37.300 | 37.250 | 37.250 |
Glycine | 2.000 | 2.000 | 2.000 |
The choice of an appropriate substrate should be based on the following [43]:
the type of ions contained
macroelements balance
total ionic concentration of medium
Microelements are used in small quantities; lack of such elements causes specific symptoms as they intervene in plant metabolism; they are integrated into enzymes. Some microelements can influence the production of secondary metabolites, acting as elicitors [44].
Hormones carry out an essential role as growth regulators in plants [45, 46]. The need to add growth regulators to substrates is based on the fact that normal tissues or small organs placed
Among known hormones mostly utilized we can find:
Auxin: Natural auxin is Indole-3-acetic acid (IAA, 3-IAA); in substrates for
IBA (Indole-3-butyric acid), the most commonly used;
NAA (1-Naphthaleneacetic acid);
2,4 D (2,4-Dichlorophenoxyacetic acid).
Natural auxins are added in variable quantities (0.01–10 mg/l) and the synthetic ones are added in quantities between 0.001 and 10 mg/l, determining—elongation and tissue distension, cell division, adventitious roots formation [47, 48].
Cytokines: Natural cytokinins are as follows:
Kinetin (N6-Furfuryladenine, 6-Furfurylaminopurine)
Zeatin [6-(4-Hydroxy-3-methylbut-2-enylamino)purine]
2Ip [N6-(2-Isopentenyl)adenine]
Cytokines are used in concentrations between 1 and 10 mg/l to stimulate cell division, stimulate adventitious buds production from tissues or from callus, and growth of somatic embryos, to induce the development of axillary buds. In addition, cytokines inhibit root development [49].
Gibberellins: Among gibberellins, the most used is GA3 (gibberellic acid) which promotes internode elongation, meristem, and bud development while inhibiting the formation of roots; thus, it is employed in subsequent phases after planting [50, 51].
pH: Another factor essential for a cultural substrate is pH as its value influences—salt solubility, elements absorption, and substrate solidification; for these reasons, the pH range is quite limited ranging from 5.2 to 5.8. As far as secondary metabolites are concerned, optimal ranges are established both for pH and temperature according to the cultured species.
To achieve secondary metabolite production, elicitation is one of the most important strategies and is used to increase productivity; it takes place through the addition of compounds called elicitors—they can be defined as stress-inducing compounds that induce or improve biosynthesis of specific compounds when a specific amount is applied to a living system [52, 53].
Elicitors can be biotic, such as jasmonic acid, hydrolyzed casein, cellulase, macerozyme, yeast extract, fungal extract, chitin; in addition, chemical compounds usually synthesized from pathogens; abiotic elicitors that include nonorganic substances and can be divided into physical, chemical, and hormonal factors (Figure 4) [53, 54].
Classification of elicitor based on different features.
In cell suspension, depending on environmental parameters and on bioreactor features, the development of cells cultured on the liquid substrate is based on specific phases illustrated in Figure 5. The graph shows time (horizontal axis) and cell number (vertical axis). At the beginning a slow-growth phase is shown, known as lag phase followed by a phase in which cell concentration grows based on a logarithmic scale, log phase; then a second slow-growth phase occurs followed by a phase in which the culture is numerically constant indicated as a plateau or steady state.
Growth curve of a cell suspension culture.
During the latency phase, reduced growth and an accumulation of substances useful for cell development occur, while during the exponential growth phase a considerable biomass increase can be observed. In a discontinue culture, in the case that cells accumulate metabolites in vacuoles, the biomass is removed at the end of the exponential phase; during the stationary phase a balance occurs between new cells and dead cells, then secondary metabolites are excreted in culture media. In this case, the collection is carried out by replacing from time to time or continuously the culture media.
In the production of high-value secondary metabolites, a good strategy is offered by the use of technologies that ensure elevated yield and stable over time. It should be underlined that the production of secondary metabolites from plants is genotype-dependent and this fact influences both metabolite type and quantity. Mother plants can be selected to a first selection to identify plants that ensure also
The output can also be increased through conventional systems or metabolic engineering methodologies [22, 55].
By using metabolic engineering, the biosynthesis pathways can be studied more efficiently [56, 57] through studying gene overexpression that alterates pathways. The study design includes analysis of enzyme reactions and biosynthesis processes at genetic, transcriptomic, and proteomic levels; in addition, it is also studied the manipulation of genes that encode critical enzymes and those that regulate the speed in the biosynthesis pathways [58, 59]. However, to date this system is limited to experimental settings and no method has been identified yet for industrial transfer of such methodology. Currently, the study of the biosynthesis pathway in phenylpropanol seems to be one of the most promising given that this substance is involved in the biosynthesis of different secondary metabolites in plants [60, 61].
Culture parameters are among the factors that mostly influence secondary metabolite production—substrate composition both in terms of mineral and organic compounds; pH; characteristics of cell inoculation; physical parameters, such as temperature, light intensity, duration, shaking, and aeration [22, 23, 27]. The substrate should be selected based on the requirements of plant species. Each substrate parameter can be modified to better adjust to the species and to metabolites to be obtained by it—salt type and concentration, carbon source, growth regulators. In nature, secondary metabolites production is in response to environmental stimuli, or for defensive purposes. This mechanism can be simulated in the laboratory through the modification of the culture parameters, for example, light, temperature, or through the use of substances called elicitors. To elicitors belong both organic and inorganic molecules, such as methyl jasmonate, salicylic acid, microbial cell wall extracts (e.g., yeast extract, chitosan), inorganic salts, heavy metals, physical agents (e.g., UV radiation) among others (Tables 2 and 3).
Elicitor | Plant species | Culture | Compound | References |
---|---|---|---|---|
Ozone (O3) | Shoot | Rosmarinic acid | [62] | |
Cell suspension | Hypericin | [63] | ||
Cell suspension | Puerarin | [64] | ||
pH | Shoot | Bacoside A | [65, 66] | |
Hairy root | Withanolide A | [67] | ||
Cell suspension | Withanolide A | [68] | ||
Sucrose | Seedling | Hypericin and pseudohypericin | [69] | |
Cell suspension | Paclitaxel | [70] | ||
Shoot | Bacoside A | [65, 66] | ||
Cell suspension | Withanolide A | [68] | ||
Ultraviolet C | Cell suspension | Stilbene | [71] | |
Proline | Callus and suspension | Steviol glycoside | [72] | |
Polyethylene glycol | Callus and suspension | Steviol glycoside | [72] | |
Seedling | Hypericin and pseudohypericin | [69] | ||
Jasmonic acid | Shoot | Bacoside A | [73] | |
Hairy root | Plumbagin | [74] | ||
Cell suspension | Plumbagin | [75] | ||
Methyl jasmonate | Hairy root | Tanshinone | [76] | |
Adventitious roots | Cryptotanshinone and tanshinone IIA | [77] | ||
Cell suspension | Stilbene | [71] | ||
Shoot | Bacoside | [73] | ||
Shoot | Diterpenoid | [78] | ||
Cell suspension | Silymarin | [79] | ||
Hairy root | Tanshinone | [80] | ||
Cell suspension | Gymnemic acid | [81] | ||
Hairy roots | Withanolide A, withanone, and withaferin A | [82] | ||
Cell suspension | Andrographolide | [83] | ||
Cell suspension | trans-Resveratrol | [84] | ||
Root | Glycyrrhizic acid | [85] | ||
Gibberellic acid | Hairy root | Tanshinones | [86] | |
Hairy root | Caffeic acid derivatives | [87] | ||
Salicylic acid | Hairy root | Tanshinone | [76] | |
Cell suspension | Stilbene | [71] | ||
Shoot | Digitoxin | [88] | ||
Shoot | Hypericin and pseudohypericin | [89] | ||
Cell suspension | Gymnemic acid | [81] | ||
Hairy root | Withanolide A, withanone, and withaferin A | [82] | ||
Root | Hyoscyamine and scopolamine | [90] | ||
Adventitious root | Glycyrrhizic acid | [91] | ||
Sodium salicylate | Shoot | Carnosol | [92] | |
Sodium chloride | Embryogenic tissues | Vinblastine and vincristine | [93] | |
Sorbitol | Adventitious roots | Cryptotanshinone and tanshinone IIA | [77] | |
Silver (Ag) | Adventitious roots | Cryptotanshinone and tanshinone IIA | [77] | |
Cell suspension | Resveratrol | [94] | ||
Hairy root | Tanshinone | [80] | ||
Hairy root | Atropine | [95] | ||
Cadmium (Cd) | Cell suspension | Resveratrol | [94] | |
Root | Sesquiterpenoid | [96] | ||
Cobalt (Co) | Cell suspension | Resveratrol | [94] | |
Copper (Cu) | Shoot | Xanthotoxin | [97] | |
Shoot | Bacoside | [73] | ||
Root | Sesquiterpenoid | [96] |
Abiotic elicitors.
Elicitor | Plant species | Culture | Compounds | References |
---|---|---|---|---|
Chitin | Shoot | Hypericin and pseudohypericin | [98] | |
Cell suspension | Phenylpropanoid and naphtodianthrone | [99] | ||
Cell suspension | trans-Resveratrol and viniferins | [83] | ||
Pectin | Shoot | Hypericin and pseudohypericin | [98] | |
Dextran | Shoot | Hypericin and pseudohypericin | [98] | |
Yeast extract | Adventitious roots | Cryptotanshinone and tanshinone IIA | [77] | |
Cell suspension | Plumbagin | [75] | ||
Cell suspension | Silymarin | [79] | ||
Hairy root | Tanshinone | [100] | ||
Hairy root | Thiarubrine A | [101] | ||
Hairy root | Azadirachtin | [102] | ||
Root | Glycyrrhizic acid | [85] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [99] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [99] | ||
Cell suspension | Phenylpropanoid and naphtodianthrone | [99] | ||
Cell suspension | Gymnemic acid | [55] | ||
Cell suspension | Gymnemic acid | [55] | ||
Cell suspension | Gymnemic acid | [55] | ||
Cell suspension | Gymnemic acid | [55] | ||
Cell suspension | Gymnemic acid | [55] | ||
Hairy root | Atropine | [95] | ||
Hairy root | Atropine | [95] | ||
Hairy root | Atropine | [95] | ||
Root | Gymnemic acid | [85] |
Biotic elicitors.
Aid to the production of new secondary metabolites, or increased production of those already known and used, can come from new technologies, such as transgenic cultures. Several works have demonstrated the safety of these technologies, and their effectiveness, at low cost, for the production of secondary metabolites for medicine and industry [103].
Focusing on biodiversity can be useful to strengthen food security and human nutrition aiming at promoting general sustainable development. Traditional crops represent an important biodiversity source and carry out a key role in preserving the identity of specific production areas as well the consumer behavior and transfer of cultural heritage to next generations. However, these cultures and foods require to be preserved from genetic erosion that can determine tragic effects on biodiversity, environmental sustainability, and rural economies.
As a matter of fact, this methodology based exclusively on a phenotypic evaluation does not allow to easily distinguish between genotype and effects on the environment. Recent methodologies based on gene markers enable us to identify species, cultivars, and autochthone varieties easily and rapidly.
Elevated costs and technical problems that might arise when the relationship between phenotype features and gene expression is studied, make the application of these methodologies often difficult. Recently, secondary metabolite analysis has been proposed as a crucial tool to identify a specific species; the metabolic profile, in fact, can lead to the identification of a huge quantity of local autochthone varieties, acting against globalization of agriculture production and being at the same time a tool to identify metabolites useful in traditional project characterization.
The parts of plants to be used for therapy, nutrition, and other activities can be obtained from spontaneous or cultivated plants; the choice of production method is mostly determined by economic factors is affordable to collect spontaneous plants when abundant and costs are relatively low, however, in case of high collection costs and lack of spontaneous plants, cultivation can be less expensive [17]. Furthermore, a lot of spontaneous plants are collected without any control and are currently under extinction threat; just a small percentage is cultivated [104]—all these factors are of concern due to the decrease and loss of gene diversity and environmental degradation. Advantages of open field cultivations are related not only to the fact that they give a solution to a lack of vegetal material available in nature, but also to the fact that the wild plant often offers a highly heterogeneous which might be at the same time inadequate in terms of continuous supply and quality standards. Production of secondary metabolites from cell cultures is a valuable option for molecules that have elevated extraction costs and low output from plant material coming from cultivation [105, 106].
For these reasons and due to the current increased demand for natural food products and drugs of natural origin, the employment of biotechnological artificial culture systems might be a good alternative to conventional cultivations for
On one hand,
Plant tissue culture is based on the principle that the same substances found in nature inside an organ, a fruit, or other plant tissues can be induced to accumulate in undifferentiated cells while keeping gene information and the ability to produce that range of active principles detected in the mother plant [108].
Multiple factors influencing
Plant cell cultures are defined also as “chemical factories for secondary metabolites” [25] and represent to date a viable alternative to the cultivation of pharmaceutical plants both from
The most important reason for pharmaceutical companies to obtain valuable secondary metabolites in this way is due to the fact that conventional cultivations in fields of pharmaceutical plants of some species are time-consuming, expensive, and generate a reduced output.
Some large-scale protocols of productions for the market have been set up for extractions of berberine, shikonin, and
Further research was performed on other secondary metabolites such as flavoring agents (i.e., vanillin produced in bioreactors from calluses explanted from
Although for the production of food from plants there is an increasing tendency toward natural agriculture, in the production of substances intended for industry, in particular the medicinal industry, a cultivated or spontaneous plant cannot always guarantee a constant and high-quality product. Pollution problems, climate change, and the political unsafe of some harvesting and cultivation areas also make production uncertain. In this situation, the production of secondary metabolites
New technologies, always evolving, can give an even greater push toward
The present work is co-financed by the RAS (Autonomous Region of Sardinia), under the Advanced Technologies for LANds management and Tools for Innovative Development of an EcoSustainable agriculture.
The authors declare no conflict of interest.
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He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. 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He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"3",type:"subseries",title:"Bacterial Infectious Diseases",keywords:"Antibiotics, Biofilm, Antibiotic Resistance, Host-microbiota Relationship, Treatment, Diagnostic Tools",scope:"