\r\n\tHealth and mental health issues of both children and adults and evidence-based treatments will be included. The types of sexual violence that occur and prevention efforts that have – or have not – been made to address the occurrence of these types of violence will be covered.
\r\n
\r\n\tCultural and governmental policies, as well as legal and jurisdiction issues to address victims of these crimes, will also be incorporated in the book. For instance, Meagan’s Law and its worthiness in protecting children will be incorporated as well as the Federal program to reimburse victims of online child pornography and the legal entanglements and ramifications of that program.
\r\n
\r\n\tThe typology of offenders and the effectiveness of treatment will also be addressed. \r\n\tFinally, the direction of prevention strategies, treatment needs for both victims and offenders, and policy issues to move the field forward, particularly in terms of research, will be presented. The field of sexual violence has made significant strides in the past 45 years in terms of understanding sexually deviant behavior, the impact on children who then experience the symptoms of that trauma in adulthood, how to effectively interview sexually victimized children, and finally, treatment and social mores that make disclosure possible and recovery hopeful.
",isbn:"978-1-83768-099-3",printIsbn:"978-1-83768-098-6",pdfIsbn:"978-1-83768-100-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d3d39a00095ec14f7f869ed5b5211527",bookSignature:"Dr. Kathleen Monahan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12202.jpg",keywords:"Childhood Sexual Abuse, Child Pornography, Sex Trafficking, Mental Health Issues, Intimate Partner Violence, Acquaintance Rape, Sexual Assault, Rape, Treatment Issues, PTSD, Meagan’s Law, Restitution to Online Victims",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 18th 2022",dateEndSecondStepPublish:"July 22nd 2022",dateEndThirdStepPublish:"September 20th 2022",dateEndFourthStepPublish:"December 9th 2022",dateEndFifthStepPublish:"February 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Monahan is a licensed clinical social worker in private practice since 1984 specializing in the Effects of Intimate Partner Violence and Brain Injury (IPV/BI), sexual abuse and women’s health issues, and trauma. 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1. Introduction
Ever since our ancestors, humanity has been dependent on the consumption of plants as a source of food, health, and for construction/ornamental. In addition, plants have developed a complex defense system against biotic and antibiotic stress: therefore, they can produce diverse secondary metabolites (SMt). The stress to which plants are submitted under natural conditions is caused by different factors, among which stand out: attack by diverse insects and/or microorganisms (viruses, bacteria, and fungi) competition for soil, light, and nutrients, and exposure to sunlight [1].
SMt are compounds that do not play a fundamental role in the vital processes of plants, but they are important as mechanisms of defense. They are responsible for organoleptic and protective properties, such as odor, flavor, color, and consistency. These SMt also act as chemoattractants or chemorepellents. In addition, they are of great interest in industry for the preparation of food additives, agrochemicals, essences, biodiesel, narcotics, insecticides, cosmetics, and aromatics, and one of the most important of these is for the production of substances with pharmaceutical interest. Frequently, the production of SMt wild-collected plant is very low (less than 1% of the plant’s Dry Weight -DW-), and this depends specifically on the plant’s physiological state, the geographic location, the climate, among other factors [2].
Due to the low yield of SMt in wild plants and considering its important biological activity, alternatives or tools are currently being sought to increase its yield. One of these alternatives is the application of several biotechnology processes, a discipline that is oriented toward the development and innovation of technologies that involve the management of biological material for the production of a good or service [3].
One of the advantages in the use of biotechnological processes is to increase the production of bioactive SMt and also reduce the production time, which favors their availability [4]. The purpose of this paper is to summarize all the information that exists on the use of biotechnological processes for the production of bioactive compounds from Mexican medicinal plants.
2. Products with pharmaceutical importance
Plants constitute a huge reservoir of chemical structures, the most economically important are medicinal plants, due to their diverse biological activities; which over the years have favored human survival thanks to their use in Traditional Medicine (TM) [5, 6, 7]. TM is widely used in some developing countries, where their health system is still growing and is of great economic importance. In Africa, up to 80% of the population employs TM to help satisfy its health needs. In Asia and in Latin America, the populations continue to use TM because of historical circumstances and cultural beliefs. In China, TM is of great importance due to the large percentage of population that utilizes it, being higher than 60%. In some developed countries, the percentage of the population that uses TM is 48% in Australia, 70% in Canada, 42% in the USA, 38% in Belgium and 75% in France [8].
Currently, Medicinal Plants (MP) are employed by 80% of the world population; therefore, these are overexploited not only because are source of active ingredients, also due to the high nutritional, wood, cosmetic, agricultural, and/or medicinal value that many of these have. For example, it is estimate that China exports 120,000 tons of MP and India, some 32,000 tons while Europe imports 400,000 tons of MP. This leads to overexploitation of the species and many of them are in danger of extinction [9, 10].
The World Conservation Union and the World Nature Fund report that there are between 350,000 and 550,000 species of MP in the world, of which only approximately 20% possess documented investigation of their biological potential, and nearly 15,000 species are in danger of extinction due to the overexploitation and destruction of habitats [10, 11].
Nowadays, scientific interest in MP has increased due to the high costs and adverse effects that allopathic drugs cause, in addition to the increasing appearance of strains of microorganisms that are resistant to current treatments [12, 13, 14]. It is noteworthy that almost 25% of the active principles of allopathic drugs currently used were isolated and/or semisynthesized from plants [9]. In modern medicine, digoxin is use as a cardiotonic and was isolated from Digitalis purpurea (purpura, its common name); escin is use as an anti-inflammatory and venotonic and was isolated from Aesculus hippocastanum (its common name, horse chestnut). Another compound utilized is ajmalicin, employed for circulatory disorders, and was isolated from Rauwolfia serpentina; paclitaxel (an anticancer drug) has been semisynthesized by Bristol-Myers Squibb since 2002, and was obtained from the compound 10-deacetylbacatin III, it was obtained from the cell suspension of the Taxus baccata. While diosgenin, a steroidal sapogenin, was obtained from the tubercules of several Dioscorea species, which was the raw material for the semisynthesis of progesterone [15].
Guanidine is a natural product with good hypoglycemic activity that was isolated from Galega officinalis (L); however, this compound has been reported to be toxic for human consumption. Therefore, this compound was semi-synthesized obtaining metformin (dimethylbiguanide), which is less toxic and has a pharmacologic effect similar to the original molecule and is widely used for the treatment of type II diabetes mellitus. It is worth noting, due to the high demand for SMt on the market; several companies have seen the need to discover novel sources of raw material from MP [16].
On the other hand, at present, the use of medicinal plants and/or phytodrugs is very frequent. The phytodrugs are elaborate with plant material and some derivatives of this. The main ingredient is the aerial or subterranean plant’s part; as well as extracts, tinctures, juices, resins, fatty acids, and essential oils presented in pharmaceutical form. The therapeutic effectiveness and safety have been confirmed scientifically [17]. Some examples of these include ginseng, it is obtained from Panax genus (Panax ginseng and P. quinquefolium) native from Asia and America, respectively. The main biological effect of ginseng “tonic” phytodrug is that it possesses the ability to increase the capacity to tolerate tensions, which leads to increased mental and physical yield. Another phytodrug obtained from St. John’s wort (Hypericum perforatum) is Hiperikan, which is standardized based on its content of hypericin; its principal pharmaceutical use is against depression. Ginkgo biloba (Ginkgo) belongs to the Ginkgoaceae family, the active compounds in the leaf’s extracts are gingolides (gingolides A-C, J, and M), along with a mix of sesquiterpene lactones and flavonoids which is used against depression. The majority of commercial preparations from Ginkgo are standardize with approximately 5–7% of terpenic lactones and 22–27% of flavonoids and they are employed mainly for the treatment of the cognitive deterioration associated with alterations in blood circulation in the brain, such as dementia. The phytodrug elaborated with Echinacea purpurea is commercially known as EchinaCold (Schwabe Pharma) or Immulone (ATOS Pharma). These are standardized on based of the echinacosides (caffeic acid derivative) content, whose main biological effect is as an immunostimulant [18]. In Oceania region, the extract from Piper methysticum (from root and rhizome) has the commercial name Kava-kava (with 30% of kava lactones), and is utilized for their neurotransmitter activity [19]. Another phytodrug is Vitango, obtained from Rhodiola rosea (with 3.5% rosavins and 1% salidrosides), and it is employed for reducing the stress associated with physical and mental tasks [20]. Plantival has extract mixture from Valeriana officinalis (160 mg) and Melissa officinalis (80 mg) and is use in the treatment of nervousness, restlessness and insomnia as an anxiolytic and antidepressive [21]. Another phytodrug, known as Prostasan, is the extract of Serenoa repens, standardized at 25% of fatty acids; the dose employed is 160 mg, and its principal effect is antiandrogenic and against benign prostatic hyperplasia [22].
Due to the acceptance and growing use of phytodrugs around the world, PM are raw materials of great attention due to high consumption. In addition, MP biosynthesize several bioactive compounds, which are classified as terpenoids, alkaloids, lactones, flavonoids, coumarin, lignans and phenols, among others; many of these have restrictive taxonomical distribution. Although the SMt functions are not directly associated with the plant’s basic function, these compounds carry out some interaction roles in the plant and its environments such as: protection against pathogens, protection against abiotic tensions (ultraviolet radiation radiation), they possess the function of attracting pollinating insects, and they are signaling molecules and active ingredients for drugs [23, 24, 25].
It is estimated that around 50% of the drugs approved by the Federal Drug Administration are products derived from natural sources or analogs deriving from plants or microorganisms [26]. However, raw material can be limited, and its exploitation is one of the main ecological concerns. One of the key objectives of plant biotechnology is the development of large-scale production methods of pharmacologically active products. Additionally, the massive biosynthetic potential of plants has not been completely exploited yet and biotechnology can be employed to generate new chemical compounds that possess unknown biological activities and/or with a different mechanism of action, or a better one, than those in existence [23].
3. Production of SMt by biotechnology tools
There are distinct strategies to optimize the production and modulation SMt in medicinal plants and food. The main strategies are by uses the elicitors (molecules capable of inducing defense in the plant) [1], which are classified as biotic and abiotic. Biotics are of biological origin, while abiotics can be physical or chemical. Some examples of physical abiotics are the weather, bacteria, and plagues, among others, while chemical abiotics possess an intense variety, with those most utilized being jasmonic acid and salicylic acid [27, 28]. One of the advantages of using elicitors treatment is that they function as signaling compounds for the mechanisms of defense; thus, they increase the production of SMt in an effective and rapid manner [29]. There is great specify in the interaction of plant-elicitor species which implies that the adequate one for each culture, the time of adding it, and the concentration for obtaining best response should be selected [30].
There is other technique very used to obtain SMt in vitro, it focuses on obtaining the roots, which is known as “hairy roots” or transformed roots; for this, the bacterium Agrobacterium rhizogenes is very used. This microorganism transfers the plasmid of the Transfer-DNA (T-DNA) of the T-DNA to the plant cell, to verify whether a root transformation was obtained, this can be confirmed by Southern hybridation analysis (this technique permits the detection of a specific DNA sequence in a complex mixture). A main advantage of these is that they have the capacity of rapid growth without the external administration of Plant Growth Regulators (PGR); the majority of these do not require a light supply, and their yield of metabolites is constant due to their genetic stability [1]. Another internal factor is the culture medium added with macro- and micronutrients, as well the external factors, such as light intensity, temperature, humidity, and stirring speed [31].
In general, formulation of the culture medium begins with the base medium, being the most utilized Muashige & Skoog (MS), B5 of Gamborg and Linsmaier and Skoog (LS), and Nitsch and Nitsch (NN) [32]. These culture mediums contain minerals, vitamins, and a carbon source, normally sucrose and sometimes fructose is used. Although plant cell cultures typically are initiate in solid medium, they require liquid medium for production on a large scale. The mineral content and/or the carbon source in culture medium have a profound impact on biosynthesis of SMt employed in the manufacturing of phytodrugs and/or compound-of-pharmaceutical-interest [33].
Other tools very used to obtain SMt by biotechnological process is through the use of BioCatalyzers; this method has been used to transform polyphenols compounds; for example, Bouvardia ternifolia is utilized for the production of a BioC denominated dehydrodiisoeugenol, which was obtained from the supernatant of cells suspension, demonstrating a yield of around 77%. The dehydrodiisoeugenol obtained from B. ternifolia allows the production of isoeugenol by biotransformation; it is known that plant peroxides transform phenols substituted for by a methyl group orto position to the corresponding O-radical, which, on establishing itself by resonance, produces a C-radical; the latter is that which leads to dimerization, producing a dimer. This biotransformation represents a clean and green alternative with respect to traditional chemical methods, in which oxidative bonding reactions are affected using catalysts such as FeCl3, K3(FeCN)6, and Cu(OH)Cl [34].
Figure 1.
Chemical structure of some polyphenols and other SMt with biological activity.
Recently, interest in research and development of in vitro plant tissue cultures from MP has grown; however, there are scarce studies, to our knowledge, in which the biological activities of these SMt obtained by this process are described. The majority of works published only mention the conditions of the biotechnological process and the final concentrations of the different metabolites produced, but do not evaluate the pharmacological activity of these SMt, and the authors solely cite that these have been reported in previous works.
In Table 1 and Figure 1, some examples are described. It is important to mention that on some occasions is difficult to establish the biotechnological process conditions to induce the biosynthesis of bioactive SMt from a MP.
Secondary metabolites obtained for cellular cultures from medicinal plant tissues in vitro and their biological activity.
4. Anti-inflammatory activity of SMt isolated from vegetal material obtained by biotechnological processes
Some SMt with significant anti-inflammatory activity have been obtain from MP through employment some biotechnological processes. From cell suspension cultures Sphaeralcea angustifolia, two compounds with important anti-inflammatory activity (evaluated in murine models) were isolated. The cell suspension was developed in MS medium with total nitrate 2.74 mM, under this condition was obtained scopoletin, sphaeralcic acid (22) and tomentin (23). From the CH2Cl2:CH3OH extract sphaeralcic acid (22) and tomentin (23) were isolated; these compounds showed 58 and 66% anti-inflammatory activity, in the carrageenin model at 45 mg/kg administered by intraperitoneal (i.p.) route. On the other hand, in the topical anti-inflammatory model (TPA, 12-O-TetradecanoylPhorbol-13-Acetate), tomentin (225 mM/ear) exhibited 57% inhibition in the formation of auricular edema, while sphaeralcic acid (174 mM/ear) revealed 86% inhibition with a dose-dependent effect and one half of the Effective Dose (ED50) = 93 mM. Sphaeralcic acid is the most active compound in both models (topical as well as systemic) [124, 131].
In another study, the anti-inflammatory activity of the cell suspension culture from S. angustifolia is described. In this case, aseptic-leaf explants and Naphthalene Acetic Acid (NAA, such as auxin) in several concentrations (0, 0.5, 1.0, and 2.0 mg/L) in combination with a constant concentration of Kinetin (KIN) were used. For the cell suspension culture, they utilized 4% initial inoculum in MS medium with 2.74 mM of the total nitrates, 1 mg/L of NAA and 0.1 mg/L of KIN and supplemented with 30 g/L of sucrose. The main SMt identified in this suspension cultures were the same compounds (scopoletin, tomentin, and sphaeralcic acid). Scopoletin was excrete in the culture medium, although it also accumulated in the biomass. For evaluation of the anti-inflammatory activity, the authors prepared the CH2Cl2:MeOH extract of the cell’s suspension from S. angustifolia and this extract was administered i.p. in male ICR mice (35 g) employing the carrageenin model. This extract showed ED50 = 137.63 mg/kg; sphaeralcic aid and tomentin at 45 mg/kg inhibited 67 and 62%, respectively on carrageenan assay and sphaeralcic acid at 1 mg/ear was more active in TPA assay, showed ED50 = 93 mM and tomentin showed 48% of inhibition at 1 mg/ear [132, 133]. In addition, the same extract from biomass of cells in suspension of S. angustifolia at 100 mg/kg (with 0.10 mg of scopoletin, 0.10 mg of tomentin and 0.19 mg of sphaerelcic acid), as well as tomentin (20 mg/kg) were active as anti-inflammatory agent and reduced the mean body weight lost in Freund adjuvant- and kaolin/carrageenan-induced arthritis, respectively. In this assay, the organic extract and tomentin reduced the levels of pro-inflammatory interleukins such as IL-1β, IL-6 and TNF-α and increased levels of IL-4 and IL-10 (anti-inflammatory cytokines) [133].
In parallel with obtaining cells in vitro of S. angustifolia, the authors performed a preclinical phase study (in rats). The CH2Cl2 extract of the aerial parts of S. angustifolia (wild material) was tested in chronic inflammation model induced with complete Freund’s adjuvant (polyarthritis) The administration of the extract at 100 mg/kg/day during 8 days showed sustained and significant inhibition of edema, being of 62.6% [134]. A double-blind clinical phase study with the extract of S. angustifolia (wild material) standardized at 1% hydroxycoumarin content was conducted; the experiment was performed on 130 patients diagnosed with osteoarthritis. 55 of them were treated with standardized extract of S. angustifolia (gel) and 75 patients were treated with Diclofenac (2%). The therapeutic effectiveness of the gel administered topically for 4 weeks was 89%, while that of the control group (Diclofenac) was 91.3%; it was highlighted in the study that patients who received the treatment (gel of the standardized extract) did not exhibit adverse effects and did show an improvement in their disorder [135].
Another plant utilized in Mexican ethnomedicine is Lopezia racemosa Cav. Callus cultures in MS medium were obtain with variable amounts of NAA, 2,4-Dichlorophenoxiacetic acid (2,4-D) and 6-BenzylAminoPurine (BAP). The authors carried out 10 treatments with the previously mentioned PGR. In this case, they employed three types of explants (hypocotyl, stem nodule, and leaf) and several treatments. The combination of 1.0 mg/L of 2,4-D plus 0.5 mg/L of BAP was the best. From these callus material two novel compounds: 6-O-palmitoyl-3-O-β-D-glucopyranosylcampesterol (174.0 μg/g of biomass) and 6-O-palmitoyl-3-O-β-D-glucopyranosyl-β-sitosterol were isolated. When quantifying these compounds, the authors observed that the wild plant contains less quantity than the callus. The topical anti-inflammatory activity of the biomass obtained from the callus was evaluate in the TPA model on CD-1 male mice at 1 mg/ear. Three extracts (hexanic, CH2Cl2, and methanol), was tested and showed 48.74, 57.14, and 16. 81% of inhibition, respectively. The CH2Cl2 extract was the most active, with a half-maximal Inhibitory Concentration (IC50) = 0.93 mg/ear. On the other hand, the pure compound (6-O-palmitoyl-3-O-β-D-glucopyranosyl-campesterol) was tested in the same model at 1 mg/ear showing a 57.14% inhibition, with IC50 = 0.45 mg/ear [100].
The lipophilic extract containing beta-carotene (LMBC) from plant cell cultures of Cleome spinosa was evaluate in two in vivo models to determine the anti-inflammatory and antinociceptive activities in Swiss Webster (SW) mice of both sexes. The callus culture was obtained of the MS medium supplemented with 1 mg/L of 4- amino-3,5,6-trichloropicolinic acid (picloram) and sub-cultured to culture medium with the same composition at 4-week intervals. The anti-inflammatory activity in carrageenan model at 10 mg/kg by i.p. via was evaluated. LMBC was inactive with respect to extract from whole plant, which showed more than 50% inhibition of edema at the same dose. On the other hand, the LMBC (at 50 mg/kg) showed around 68% decrease in writhes, these data were very similar to that shown in wild plant, and the effect was better than dipyrone (at 100 mg/kg) used as positive control. The authors concluded that the results of LMBC are particularly important; since this active SMt of medicinal interest can be continuously obtain from callus cultures [136].
Buddleja cordata is other medicinal species utilized to treat diseases related with inflammation. This cell suspension was obtained in MS medium supplemented with NAA (9.05 μM) and Kin (2.32 μM). The anti-inflammatory activity of the extracts from wild plant and of the cell suspension cultures were describe. In both extracts, the verbascoside content was quantified by HPLC methods. The extract of the cells suspension has 87.48 mg verbascoside/g Dry Matter (DM), while that the same extract from wild plant only contained 47.34 mg of verbascoside/g DM. In addition, acute toxicity in Balb/C mice of the both extracts were also determined, with half of a Lethal Dose (LD50) of >2 g/kg. On the other hand, the topical anti-inflammatory effect of the wild plant extract and of the cell suspension was assay. The ED50 values was 3.93 and 1.26 mg/ear, respectively, cell suspension extract was the most active due to its greater content of verbascoside. Evaluation of both extracts in the carrageenan model (systemic inflammation), showed ED50 = 251.26 and 204.62 mg/kg for wild plant and cells suspension extracts, respectively; in this case, the latter extract was more active. In the chronic inflammation model (the arthritis model induced with complete Freud’s adjuvant), both extracts showed moderate anti-inflammatory activity (<35%) and favored weight increase in animals with arthritis. The authors concluded that the cell suspension culture of Buddleja cordata obtained through the biotechnological process contained a better anti-inflammatory activity; therefore, it represents a source for obtaining this type of secondary metabolite-of-pharmacological-interest [48].
Cnidoscolus chayamansa is medicinal plant whit anti-inflammatory, antiprotozoal, hepatoprotective, hypoglycemic and antimycobacterial activities [137, 138, 139]. Recently, a biotechnology processes was described to obtain callus using BAP (5 mg/L) and 2,4-D (2.5 or 5 mg/L), this callus was used as a biotechnological alternative for in vitro propagation of this plant [140]. After that, this callus was use to establish a cell suspension culture. From the cell suspension, organic extract was prepared and its antioxidant, antibacterial and anti-inflammatory activities were determined, as well as the main SMt was quantified by HPLC analysis. In cell suspension, lupeol acetate (38.1 mg/g DW) was obtained as a main constituent and scopoletin (3.6 mg/g DW) was also quantified; in wild material, both compounds were isolated in low quantity. The organic extract was active against Staphylococcus aureus, S. coagulase and Listeria monocytogenes, and a moderate antioxidant and anti-inflammatory activities (in TPA and carrageenan models) showed [28, 141].
5. Antineoplasic activity of the plant material obtained by biotechnological cultures
From the callus culture of Eriobotrya japonica, nine triterpenes (ursolic acid; oleanolic acid; maslinic acid; tormentic acid; 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid; 2α-hydroxyursolic acid; hyptadienic acid, and the mixture of 3-O-cis-p-coumaroyl tormentic acid and 3-O-trans-p-coumaroyl tormentic acid) were isolated. The main triterpenes of the callus tissues were tormentic acid (50 mg/g DW) and 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (11.8 mg/g DW), the latter compound (2a,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid) is known as a potent protease inhibitor of the human immunodeficiency virus. All these triterpenes were tested in two cell lines (HSC-2 and HSC); seven of the nine triterpenes were active. Showing mean cytotoxic concentration (CC50) between 10 and 48 μg/ml, while the oleanolic acid and 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid exhibited weak cytotoxic activity. Additionally, the authors evaluated the in vivo antitumor activity of the 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid in female ICR mouse skin (n = 15) during two stages of carcinogenesis; in this assay, carcinogenesis was induced topically with (+)-(E)-4-methyl 2[(E)-hydroxyimino]-5-Nitro-6-methoxy-3-hexenamide (NOR1) at a dose of 90 μg/0.1 mL of acetone. One week after NOR1 administration started, TPA (1 μg/0.1 mL of acetone) was administered twice weekly, yielding as a result a weak inhibition of the carcinogenesis. On the other hand, the authors mention that 2α,19α-dihydroxy-3-oxo-urs-12-en-28-oic acid is an antiproliferative agent and that the number of papillomas diminished by 40% in 20 weeks, indicating that this compound possesses potential for the delay of carcinogen in mouse skin [142].
6. Biological effect of SMt isolated from cell cultures of Galphimia glauca
Galphimia glauca is widely used in Mexican traditional medicine. From this species, some triterpenes such as Galphimine-A, B and E (27) have been isolated. These compounds showed a neuroprotective effect, when these were evaluated in mice convulsions model. To induce the seizure, the authors used strychnine or pentylenetratrazole administered by i.p. or subcutaneous route. In the study’s results, the depressor effects observed on motor activity directed toward an objective or an aim [143]. The pharmacological effect of galphimine B (G-B) was due to selectively inhibiting the discharge of dopaminergic neurons in the central area in in-vivo models [144]. Due to its therapeutic importance of G-B, the authors proceeded to induce the production of this homogeneous raw material through a biotechnological process.
A first step was to obtain callus from hypocotyl explants in MS medium for 30 days with a combination of NAA and KIN; under these conditions, only great cell growth was obtained, and with 2,4-D at 4 mg/L the G-B production was stimulated with a yield of 0.154 mg/g DW. In addition, under this condition, G-E was also obtained but at less concentration (0.057 mg/g DW). Also, friable callus from suspension culture in MS medium with NAA and KIN (2:2 mg/L) was obtain, denominating this line as ggxl. By means of a growth kinetic, galphimines were shown to be produced in the culture’s stationary stage [83, 145]. The next step was to carry out the scaling of galphimine production in the 5-liter airlift bioreactor and in one with mechanical stirring; the growth indices were 11.66 and 1.7, respectively. However, the authors observed that neither the biomass production, nor the time exerted an influence on the yield of G-B. Because the airlift produced a greater biomass but with lower yield of G-B (255 mg/L), while the stirring bioreactor at day 10 shown an intracellular as well as an extracellular content of 1381 mg of G-B/L, 5.4-times higher than the airlift at day 25 [146]. Once the biotechnological conditions for the production of G-B were established, this allowed having raw material to carry out the pharmacological evaluation in different models.
7. Toxicologic effect of Galphimines
Aqueous extract from material obtained by bioreactor was prepared, whose galphamine content was G-A, G-B and G-E = 0.6, 1.034 mg/g, and 1.12 mg/g, respectively. Meanwhile, the content of these galphamine in the ethanolic extract was G-A = 5.35 mg/g, G-B = 18.8 mg/g, and G-E = 17.49 mg/g and the MeOH extract content G-A = 7.29 mg/g, G-B = 17.47 mg/g, and G-E = 11.6 mg/g. Afterward, each extract was administered to Balb/C male and female mice for 28 days (2.5 g/kg). During the study period, there were no deaths, and in the histopathological analysis of the different organs; the latter did not present alterations. Also, analyzed the behavioral parameters, demonstrating a reduction in spontaneous activity. Administration of these extracts for 56 days (2.5 g/kg) in mice did not cause any change in liver-function biochemical parameters. With regard to the cytotoxic evaluation in KB, UISO, and OVCAR-5 cell lines, no cytotoxic effects were found, but all of these extracts specifically inhibited growth of the colon-cancer cell line with ED50 of <2 μg/mL. On the genotoxicity test in vitro, the extracts were evaluated at three concentrations (250, 100, and 50 mg/mL) and none of the three G. glauca extracts showed a genotoxic effect [147].
8. Evaluation of the MeOH extract of Galphimia glauca in Behavioral models of anxiety
The anxiolytic and anti-depressive effects were evaluated for the G. glauca MeOH extract (wild material) standardized with content of G-B (8.3 mg/g), using the elevated light–dark labyrinth and forced swimming in albino (ICR) mice. The extract, administered orally, three times (24, 18, and 1 h prior to the test) at doses of 125, 250, 500, 1,000, and 2,000 mg/kg was capable of significantly increasing (p < 0.05) the number of entries, as well as time spent on the elevated labyrinth’s open arms, which indicates an anti-anxiolytic effect. A similar effect was observed in the light–dark paradigm test: time spent in the light box increased in treated mice. However, this treatment was not able to change any parameter in the forced swimming test [148].
9. Conclusions
The MP form part of the daily life of the worldwide population. It is currently of scientific interest due to its high consumption, as an alternative treatment and/or co-administered with allopathic treatments for the improvement of chronic-degenerative diseases. On the other hand, the population has been responsible for affording a great boost to the use of MP; therefore, its consumption generates a great demand and consequently overexploitation. This overexploitation is a danger in the extinction of species of pharmaceutical interest. Another problem regarding the consumption of MP is that not all the population has access to species that are endemic and that have great biological potential. All the above led to the search for methods to achieve the production and induction of SMt biosynthesis with important biological activity in less time, with constant, controlled and standardized production. Besides helping to preserve plant species without altering the ecosystem.
In some cases, has been reported that cell suspension cultures increase by up to 300% the production of SMt with biological interest respect to wild plant material. In addition, to the increase in SMt production, these are obtained in less complex mixtures, which facilitates the purification process. In the present work, we describe several SMt obtained for biotechnological processing; however, many of these SMt have not been submitted to in vivo studies that prove their potential biological activity. Therefore, it is necessary to develop projects aimed at obtaining metabolites by biotechnological processes and demonstrate their biological activity in in vivo models.
Acknowledgments
Susan Drier for English language corrections.
Funding
This manuscript is a review and we did not have funding.
Competing interest
The author declare no competing interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
SMt
Secondary Metabolites
SMBB
Sociedad Mexicana de Biotecnología y Bioingeniería
TM
Tradicional Medicine
MP
Medicinal Plants
DNA
Deoxyribonucleic acid
PGR
Plany Growth Regulators
BioC
BioCatalyzers
TPA
12-O-Tetradecanoyl Phorbol 13-Acetate
ED50
Half of the Effective Dose
NAA
Naphthalene Acetic Acid
KIN
Kinetina
2,4-D
Dichlophenoxiacetic acid
BAP
6-BenzylAminoPurine
IC50
Hal-maximal Inhibitory concentration
DM
Dry Metter
LD50
Half of a Lethal Dose
DW
Dry Metter
CC50
Mean Cytotoxic Concentration
i.p.
Intraperitoneal
S.C.
Subcutaneous
G-A
Galphimine A
G-B
Galphimine B
G-E
Galphimine E
C.N
Kinetine
\n',keywords:"Elicitors, biotechnology, Mexican medicinal plants, plant tissue culture, secondary metabolites, phenolic compounds",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/78535.pdf",chapterXML:"https://mts.intechopen.com/source/xml/78535.xml",downloadPdfUrl:"/chapter/pdf-download/78535",previewPdfUrl:"/chapter/pdf-preview/78535",totalDownloads:145,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:47,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"February 23rd 2021",dateReviewed:"August 11th 2021",datePrePublished:"September 10th 2021",datePublished:"February 23rd 2022",dateFinished:"September 10th 2021",readingETA:"0",abstract:"Medicinal plants are being utilized as raw material and the use has increased in recent decades due that these biosynthesize compounds with several pharmacological activities. Some plant species with biological potential are of interest to the industry for preparation of drugs, phytodrugs, or food supplements. This causes overexploitation and deforestation, which endangers plant species-of-interest. In recent years, alternatives have been sought to eradicate this problem. A solution that was give and is maintained is plant biotechnology, which favors the production of active Secondary Metabolites (SMt). Plant biotechnology allows us to increase the yield of a compound-of-interest, reduces its production times and costs, and allows constant and controlled production of the raw material, and while aiding in the protection of medicinal plants that are found in danger of extinction. In the scientific literature, procuring the SMt by means of biotechnological processes is described, highlighting the study of four species from Mexican traditional medicine (Lopezia racemosa, Galphimia glauca, Cnidoscolus chayamansa, Sphaeralceae angustifolia and Buddleja cordata), and the main biological activities are as follows: anti-inflammatory, hepatoprotector, neuroprotector, anxiolytic, antitumoral, antibacterial, and antioxidant, among others.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/78535",risUrl:"/chapter/ris/78535",book:{id:"10799",slug:"phenolic-compounds-chemistry-synthesis-diversity-non-conventional-industrial-pharmaceutical-and-therapeutic-applications"},signatures:"María Adelina Jiménez-Arellanes and Mariana Z. Pérez-González",authors:[{id:"172408",title:"Ph.D.",name:"Maria Adelina",middleName:null,surname:"Jiménez-Arellanes",fullName:"Maria Adelina Jiménez-Arellanes",slug:"maria-adelina-jimenez-arellanes",email:"adelinajim08@prodigy.net.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Mexican Social Security Institute",institutionURL:null,country:{name:"Mexico"}}},{id:"349394",title:"Dr.",name:"Mariana Z.",middleName:null,surname:"Pérez-González",fullName:"Mariana Z. Pérez-González",slug:"mariana-z.-perez-gonzalez",email:"marizuley@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Products with pharmaceutical importance",level:"1"},{id:"sec_3",title:"3. Production of SMt by biotechnology tools",level:"1"},{id:"sec_4",title:"4. Anti-inflammatory activity of SMt isolated from vegetal material obtained by biotechnological processes",level:"1"},{id:"sec_5",title:"5. Antineoplasic activity of the plant material obtained by biotechnological cultures",level:"1"},{id:"sec_6",title:"6. Biological effect of SMt isolated from cell cultures of Galphimia glauca",level:"1"},{id:"sec_7",title:"7. Toxicologic effect of Galphimines",level:"1"},{id:"sec_8",title:"8. Evaluation of the MeOH extract of Galphimia glauca in Behavioral models of anxiety",level:"1"},{id:"sec_9",title:"9. Conclusions",level:"1"},{id:"sec_10",title:"Acknowledgments",level:"1"},{id:"sec_10",title:"Funding",level:"1"},{id:"sec_11",title:"Competing interest",level:"1"},{id:"sec_12",title:"Ethical approval",level:"1"},{id:"sec_15",title:"",level:"1"}],chapterReferences:[{id:"B1",body:'Rao SR, Ravishankar GA (2002) Plant cell cultures: chemical factories of secondary metabolites. 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S Afr J Bot 125:30-38. https://doi.org/10.1016/j.sajb.2019.06.030'},{id:"B142",body:'Taniguchi S, Imayoshi Y, Kobayashi E, Takamatsu Y, Ito H, Hatano T, Harukuni S, Tokudac H, Nishinoc H, Sugitad D, Shimurad S, Yoshida T (2002) Production of bioactive triterpenes by Eriobotrya japonica calli. Phytochemistry 59:315-323. https://doi.org/10.1016/S0031-9422(01)00455-1'},{id:"B143",body:'Tortoriello J, Ortega A (1993) Sedative effect of galphimine B, a nor-seco-triterpenoid from Galphimia glauca. Planta Med 59:398-400. doi: 10.1055/s-2006-959717'},{id:"B144",body:'Tortoriello J, Ortega A, Herrera-Ruíz M, Trujillo J, Reyes-Vázquez C (1998) Galphimine-B modifies electrical activity of ventral tegmental area neurons in rats. Planta Med 64:309-313. doi: 10.1055/s-2006-957440'},{id:"B145",body:'Osuna L, Pereda-Miranda R, Tortoriello J, Villarreal ML (1999) Production of the sedative triterpene galphimine B in Galphimia glauca tissue culture. 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Unidad de Investigación Médica en Farmacología, UMAE Hospital de Especialidades, Centro Médico Nacional Siglo XXI (CMN-SXXI), Instituto Mexicano del Seguro Social (IMSS), Ciudad de México (CdMx), Mexico
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1. Introduction
The total body potassium (K+) in an average 70-kg adult is approximately 3000–4000 mEq (50–55 mEq/kg) [1]. About 98% of this is intracellular, approximating to a concentration of 140 mEq/L and 2% in the extracellular compartment, which amounts to 4–5 mEq/L. Potassium’s two primary physiologic functions are cellular metabolism, protein, glycogen, deoxyribonucleic acid (DNA) synthesis, and resting potential membrane maintenance. Multiple physiologic processes have been identified in humans that maintain potassium homeostasis with a goal of appropriate tissue potassium distribution [1]. They can be classified into two groups based on the mechanisms involved: transcellular shifts and potassium excess excretion.
Transcellular mechanisms maintain the ICF (intracellular fluid): ECF (extracellular fluid) potassium ratio by acting immediately within the first few minutes to hours by regulating Na+/K+-ATPase (sodium/potassium adenosine triphosphatase pump), resulting in transcellular shifts. It is an electrogenic pump transporting sodium and potassium in the ratio of three sodium to two potassium. It is an integral membrane protein and serves as an ion channel, maintaining the electrochemical gradient across the cell membrane. The delayed mechanisms are slower to kick in but play a significant role in the excretion of the excess potassium from the body via renal and gastrointestinal mechanisms.
2. Potassium homeostasis mechanisms
2.1 Factors responsible for the transcellular shift of potassium
2.1.1 Insulin
Insulin is released after a meal when the plasma glucose concentration increases. Insulin plays a vital role in shifting dietary potassium into the cells and avoiding hyperkalemia before the kidneys can work on the excretion of the extra potassium [2, 3]. Insulin attaches to specific cell surface receptors and inserts GLUT4 (glucose transporter type-4) into the cell membranes, promoting glucose uptake in insulin-responsive tissues such as skeletal muscles, adipocytes, and cardiomyocytes. More than 80% of glucose is transported into the muscle cells. Also seen is an upregulation of the GLUT4-mediated glucose transport in elevated transport needs, like elevated blood glucose during a carbohydrate-rich meal or during increased metabolic demands by skeletal muscles during exercise [4]. The potassium uptake is also increased during this process by increasing the Na+/K+-ATPase activity. Insulin is also noted to have differential glucose and K uptake regulation, as noted in a metabolic syndrome where insulin-mediated glucose is compromised, but the cellular K+ uptake usually occurs [5, 6].
2.1.2 Catecholamines
Catecholamines play a critical role in potassium homeostasis. They alter internal K+ distribution by acting through alpha and beta receptors. Beta-2 receptors enhance K+ uptake by cells by activating the Na+/K+-ATPase pump [7, 8]. This effect appears to be present at basal catecholamine levels [9, 10]. The beta-adrenergic activity also increases insulin secretion from the pancreas by directly stimulating and enhancing glycolysis, which increases blood glucose levels. A stress response results in epinephrine release that causes an acute drop in plasma K+ by approximately 0.5– 0.6 mEq/L. Alpha-1,2 adrenoreceptors mediate the initial hyperkalemia by activating hepatic calcium-dependent potassium channels [11, 12]. Beta-3 adrenoreceptor stimulation may also affect the plasma potassium [12].
2.1.3 Exercise
Exercise causes an elevation in plasma K+ levels. The rise is proportional to the exercise intensity. There is an increase of 0.3–0.4 mEq/L with slow walking, 0.7–1.2 mEq/L with moderate exercise, and a max of 2.0 mEq/L with strenuous exercise leading to exhaustion [13, 14, 15]. These changes are transient for few minutes and then normalize. This transient increase is due to the release of potassium from the exercising cells. Skeletal muscle cells have ATP-dependent K+ channels. A reduction of ATP (adenosine triphosphate) levels causes the opening of more K+ channels. The release of potassium from the muscles causes a local increase in the plasma K+ concentration, which causes vasodilation, and hence increases blood supply to the muscles during exercise. This mechanism is attenuated in physical conditioning as there is an increase in both cellular K+ concentration and Na+/K+-ATPase activity.
2.1.4 Acid-base balance changes
The changes in acid-base balance cause alterations in K+ levels to maintain electroneutrality. Hence, such changes are seen only in the setting of acidosis caused by inorganic acids. Electroneutrality is maintained by the movement of K+ and Na+into the ECF, as chloride (Clˉ) movement into the cells is limited. The wide range of variation is possibly due to other mechanisms involved in regulating potassium homeostasis [16, 17].
Skeletal muscles also have another mechanism to regulate intracellular pH via Na+-H+ exchanger present on the cell membrane to regulate intracellular pH. The exact mechanism is explained in Figure 1.
Figure 1.
Intracellular pH regulation by skeletal muscles.
2.1.5 Plasma tonicity
The changes in plasma tonicity also affect K+ levels. Effective osmoles such as glucose, mannitol, and sucrose accumulate in the ECF, resulting in an osmotic gradient that causes water movement from ICF to ECF [18, 19, 20]. This effect leads to a decrease in cell volume. During this process, the intracellular K+ concentration increases and causes K+ efflux through K+ permeable channels. This process is shown in Figure 2.
Figure 2.
Plasma tonicity.
2.1.6 Plasma K+ concentration
The plasma K+ concentration itself influences the movement of K+ in and out of cells via passive mechanisms, hence regulating the homeostasis. For example, there is an initial elevation of plasma K+ concentration after a K load, promoting K+ movement inside the cells. Similarly, in K+ losses either via gastrointestinal or renal processes, there is an initial fall in plasma K+ level in the plasma within the required normal range transiently, unless the total body K+ stores are significantly affected [21, 22].
2.1.7 Effect of cell breakdown and production on plasma potassium
Clinical conditions such as severe trauma, tumor lysis syndrome, acute tissue ischemia, and necrosis cause cell breakdown and release of intracellular K+ into the ECF [23]. The hyperkalemia severity is dependent on the ability of other cells to uptake the excess K+ and the capability of the kidney to excrete K+ quickly. Conversely, there is a movement of ECF K+ to ICF due to increased cellular metabolic needs like protein synthesis in situations with increase in rapid cell production. This effect is observed in cases of severe vitamin B 12 or folic acid deficiency. When such individuals are supplemented with vitamin B 12 or folic acid, there is a marked increase in erythropoiesis and red blood cell production, causing hypokalemia; hence, it is recommended to monitor labs and supplement potassium to replete the levels [24].
2.2 Factors responsible for potassium excretion (renal)
The kidney plays a significant role in the excretion of excess K+ and maintaining K+ balance. The colon plays a trivial role as small amounts of K+ are lost through feces each day. Insignificant amounts are lost through sweat.
2.2.1 Potassium handling in proximal convoluted tubule (PCT)
Around 80% of the filtered potassium is reabsorbed in the proximal collecting tubule. The movement of K+ in the PCT is mainly passive, following sodium and water. The Na+ absorption increases across the PCT, by both active and passive processes causing net fluid reabsorption. This process drives K+ reabsorption by solvent drag. There is also a minimal change in the transepithelial voltage from negative to slightly positive as we move down the PCT, favoring K+ and calcium (Ca2+) reabsorption via the paracellular pathway (Figure 3) [2].
Figure 3.
Potassium handling in proximal convoluted tubule (PCT).
2.2.2 Potassium handling in thick ascending limb
K+ reabsorption in this segment occurs by both paracellular and transcellular pathways. Na+/K+/Clˉ co-transporter plays a significant role in the reabsorption of potassium here. This channel is located on the luminal side. The low-intracellular Na+ concentration and high-transcellular Na+ gradient caused by the Na+/K+-ATPase pump activity in the basolateral membrane help activate the Na+/K+/Clˉ co-transporter. This electroneutral process causes an increase in intracellular K+, which then exits via the K+/Clˉ co-transporter located in the basolateral membrane. A ROMK (renal outer medullary potassium channel) is present on the luminal side, allowing K+ out of the cell into the lumen. This activity helps maintain the Na+/K+/Clˉ co-transporter activity by recycling the K+ (Figure 4) [2, 25].
Figure 4.
Potassium handling in the thick ascending limb.
2.2.3 Potassium handling in distal convoluted tubule (DCT) and collecting duct
Less than 10% of the filtered load reaches the distal tubule. The lumen’s K+ concentration increases down the lumen and is secondary to voltage-dependent K+secretion mediated by the ROMK channel. Late DCT has an epithelial Na+ channel (ENaC) responsible for sodium absorption and creating lumen-negative electrochemical gradient and hence effusion of K+, similar to collecting duct [26].
Most potassium secretion is in the connecting segment and the collecting tubules (cortical, outer medullary, and inner medullary). This secretion varies according to the physiologic needs of the body. The connecting tubule has two major types of cells: principal cells and intercalated cells.
In principal cells, K+ movement out of the cell into the tubular lumen is due to the electrochemical gradient generated by the entry of Na+ into the cell via the ENaC channel located on the luminal side. The Na+/K+-ATPase pump at the basolateral membrane moves 3 Na+ out of the cells in exchange for 2 K+ creating a favorable concentration gradient. The gradient leads to the movement of Na+ from the tubular lumen into the cell. This movement creates a negative voltage on the luminal side. This electrochemical gradient favors K+ secretion into the lumen. It also promotes paracellular reabsorption of chloride (Figure 5) [27].
Figure 5.
Potassium handling in principal cells.
Intercalated cells are of two types, type A and type B, involved in acid-base regulation. In type A cells, the H+/K+ATPase pump on the luminal side results in H+ secretion and K+ reabsorption (Figure 6) [28, 29]. The activity of this pump is increased in K+-depleted states and decreased in the setting of elevated K+ levels.
Figure 6.
Potassium handling in intercalated type A cell.
In intercalated type B cells, the reabsorption of K+ is along with the Clˉ reabsorption via Clˉ/HCO3ˉ exchanger, which is a proposed mechanism and not yet substantially proven (Figure 7) [29, 30, 31].
Figure 7.
Potassium handling in intercalated type B cell.
2.3 Role of aldosterone in potassium homeostasis
Aldosterone is a steroid hormone. It enters the cell, binds with a cytosolic receptor and moves to the nucleus, increasing the synthesis of sgk mRNA (serum and glucocorticoid regulated kinase messenger ribonucleic acid), resulting in sgk protein [32]. sgk protein stimulates the ENaC activity sevenfold. An increase in serum K+ levels as little as 0.1–0.2 mEq/L can stimulate significant aldosterone levels [33].
2.4 Tubular flow and potassium secretion
Increasing the distal tubular flow rate potentiates K+ secretion in those segments. This effect is more prominent when a person consumes a high K+ diet as it also causes a simultaneous increase in aldosterone levels. Under normal circumstances, the fluid entering the distal tubule has a K+ concentration of <1 mEq/L as most of the K+ filtered is absorbed in the earlier parts of the nephron. Due to water reabsorption in the presence of ADH (antidiuretic hormone) and K+ secretion in the tube’s distal parts, the tubular K+ concentration increases. However, if the distal flow rate is increased, enhanced flow washes the secreted K+, keeping the K+ concentration in the tubular fluid relatively lower and creating a favorable concentration gradient for K+ secretion [34, 35].
Increased distal flow also increases Na+ delivery to the distal nephron, increasing Na entry into the cells and potentiating the changes to create a favorable electrochemical gradient for K+ secretion.
Two major K+ channels are found in the thick ascending loop, DCT, cortical, and medullary collecting ducts. ROMK, also known as the constitutive K+ secretary channel, is responsible for K+ secretion during normal tubular flow. Cortical ROMK expression is upregulated by aldosterone and increased plasma K+ concentration, whereas medullary ROMK expression is regulated by plasma K+ levels and not aldosterone.
BK channels are also known as big/large conductance channels or “Maxi K” channels opened by the high tubular flow, hence were earlier called a flow-dependent channel. High tubular flow increases Na+ delivery and eventually causes apical membrane depolarization. The depolarization leads to increased intracellular calcium levels and activates the BK channels. Recent studies suggest that K+ secretion by ROMK is also increased in the setting of increased tubular flow. Both these channels work together in maintaining potassium homeostasis and preventing hyperkalemia. Either of them is upregulated in the absence of the other channel [36].
2.5 Role of the colon in potassium homeostasis
The primary absorption site for K+ from the diet is the small intestine. The colon plays a minimal role in the absorption and secretion of potassium. Potassium secretion occurs primarily by passive mechanisms; however, in the rectum and sigmoid colon, K+ is secreted by an active process [37].
Animal studies have shown that active K+ secretion is mediated by apical K+ channels, which coordinate with the basolateral Na+/K+/Clˉ co-transporter. Intermediate conductance K+ (IK) and large-conductance K+ (BK) channels are present on the apical membrane of colonic epithelia. In patients with chronic renal insufficiency, especially when creatinine clearance is less than 10 mL/min, the net colonic K+ secretion increases compared to normal renal function due to increased expression and activity of the BK channel. Colonic K+ losses increase in the setting of diarrhea and by using cation resins (e.g., sodium polystyrene sulfonate) [38].
2.6 Feedforward control of potassium balance
Feedforward control means the response to a specific signal is preset and happens irrespective of the changes in the environment, unlike in the feedback mechanism where the changes in the environment control the pathway.
An increase in dietary intake of K+ causes an increase in renal excretion of potassium, even though the K+ concentration is not sufficient to cause any changes in plasma K+ concentration or stimulate aldosterone. It was also noted that this mechanism acts independently and is not altered by changing the tubular flow rate of urine, urine pH, renal Na+ excretion, or an aldosterone antagonist. `The feedforward mechanism is wholly dissociated from the common pathways involved in the feedback mechanisms of K+ homeostasis [39].
The precise mechanism is still unknown, but it is hypothesized that there is a possible gastrointestinal-renal signaling pathway in humans responsible for this feedforward control of K+ homeostasis [40].
2.7 Circadian rhythm and potassium levels
Potassium excretion is also influenced by the circadian rhythm irrespective of the activity levels or posture. The peak potassium excretion is observed in the middle of the day [41]. The presence of an oscillator system in DCT, connecting tubule and cortical collecting duct renal tubular cells, is responsible for the circadian variation of potassium excretion. The pathway includes cellular receptors for central nervous system signals, intracellular messenger’s, effectors, and renal tubule membrane transporters [42]. The oscillations result in circadian gene and transcriptional factor expression changes modifying the expression of vasopressin V2 receptor and multiple transcellular channels (Aquaporin 2, Aquaporin 4, alpha ENaC, and ROMK-1), maintaining the plasma sodium and potassium concentration [39, 43]. ROMK gene expression is higher during physical activity, whereas the H+/K+ATPase gene expression is higher at rest [44]. Circadian rhythm causes a variation in aldosterone secretion, thus impacting renal potassium excretion [45].
3. Conclusion
To maintain a normal potassium concentration, both the feedback and feedforward mechanisms work in tandem. After a potassium-rich diet, the increased plasma potassium levels gain entry into the cells via transcellular processes. At the same time, the body gears up to activate the renal and the colonic potassium excretion. This is the classical feedback pathway, whereas the feedforward pathway acts independently. Understanding the intricate mechanisms of potassium homeostasis in humans is a must in our clinical approach to potassium disorders for effective treatment strategies.
Acknowledgments
No external funding was received in preparation of this manuscript.
Conflict of interest
We declare no conflict of interest.
Notes/thanks/other declarations
We thank the editor for allowing us to author this manuscript.
Acronyms and abbreviations
K+
potassium
mEq/L
milliequivalent/liter
kg
kilogram
DNA
deoxyribonucleic acid
ICF
intracellular fluid
ECF
extracellular fluid
Na+/K+-ATPase
sodium/potassium-adenosine triphosphatase
Na+
sodium
GLUT4
glucose transporter type 4
ATP
adenosine triphosphate
Clˉ
chloride
pH
a scale used to specify the acidity or basicity of an aqueous solution
H+
hydrogen
MCT
monocarbohydrate transporter
NHE1
sodium hydrogen exchanger 1
PCT
proximal convoluted tubule
Ca2+
calcium
Na+/K+/Clˉco-transporter
sodium/potassium/chloride co-transporter
ROMK
renal outer medullary potassium channel
DCT
distal-convoluted tubule
ENaC
epithelial sodium channel
H+/K+ATPase
hydrogen/potassium adenosine triphosphatase
Clˉ/HCO3ˉexchanger
chloride/bicarbonate exchanger
mRNA
messenger ribonucleic acid
ADH
antidiuretic hormone
BK/Maxi Kchannels
big/large conductance channels
IK
intermediate conductance
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A loss of this gradient results in hyper- or hypopolarization of the cell membrane, especially in cardiac muscles leading to life-threatening arrhythmias. Multiple mechanisms in human maintain homeostasis. Transient initial changes are due to transcellular shifts activating sodium-potassium ATPase pumps on the cell membrane. The kidneys essentially take part in excess potassium excretion, maintaining total body stores constant within normal range. Gastrointestinal secretion of potassium is insignificant in individuals with normal renal function, however plays an essential role in individuals with compromised renal function. So far, a classic feedback mechanism was thought to maintain potassium homeostasis; however, a recently recognized feedforward mechanism acting independently also helps preserve potassium homeostasis. 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Conclusion",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"},{id:"sec_21",title:"Notes/thanks/other declarations",level:"1"},{id:"sec_22",title:"Acronyms and abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Palmer BF, Clegg DJ. Physiology and pathophysiology of potassium homeostasis: Core curriculum 2019. American Journal of Kidney Diseases. 2019;74(5):682-695'},{id:"B2",body:'Palmer BF. Regulation of potassium homeostasis. Clinical Journal of the American Society of Nephrology. 2015;10(6):1050-1060'},{id:"B3",body:'Masharani U, German MS. Pancreatic hormones and diabetes mellitus. In: Gardner DG, Shoback D, editors. Greenspan’s Basic & Clinical Endocrinology. 10th ed. New York, NY: McGraw-Hill Education; 2017'},{id:"B4",body:'Vargas E, Podder V, Carrillo Sepulveda MA. Physiology, Glucose Transporter Type 4. Treasure Island (FL): StatPearls; 2021'},{id:"B5",body:'Nguyen TQ, Maalouf NM, Sakhaee K, Moe OW. 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New England Journal of Medicine. 1983;309(23):1414-1419'},{id:"B11",body:'Struthers AD, Whitesmith R, Reid JL. Prior thiazide diuretic treatment increases adrenaline-induced hypokalaemia. Lancet. 1983;1(8338):1358-1361'},{id:"B12",body:'Moratinos J, Reverte M. Effects of catecholamines on plasma potassium: The role of alpha- and beta-adrenoceptors. Fundamental & Clinical Pharmacology. 1993;7(3-4):143-153'},{id:"B13",body:'Sassard J, Vincent M, Annat G, Bizollon CA. A kinetic study of plasma renin and aldosterone during changes of posture in man. The Journal of Clinical Endocrinology & Metabolism. 1976;42(1):20-27'},{id:"B14",body:'Struthers AD, Quigley C, Brown MJ. Rapid changes in plasma potassium during a game of squash. Clinical Science (London). 1988;74(4):397-401'},{id:"B15",body:'Lindinger MI, Heigenhauser GJ, McKelvie RS, Jones NL. Blood ion regulation during repeated maximal exercise and recovery in humans. American Journal of Physiology. 1992;262(1 Pt 2):R126-R136'},{id:"B16",body:'Adrogue HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. The American Journal of Medicine. 1981;71(3):456-467'},{id:"B17",body:'Magner PO, Robinson L, Halperin RM, Zettle R, Halperin ML. The plasma potassium concentration in metabolic acidosis: A re-evaluation. American Journal of Kidney Diseases. 1988;11(3):220-224'},{id:"B18",body:'Kunin AS, Surawicz B, Sims EA. Decrease in serum potassium concentrations and appearance of cardiac arrhythmias during infusion of potassium with glucose in potassium-depleted patients. New England Journal of Medicine. 1962;266:228-233'},{id:"B19",body:'Nicolis GL, Kahn T, Sanchez A, Gabrilove JL. Glucose-induced hyperkalemia in diabetic subjects. Archives of Internal Medicine. 1981;141(1):49-53'},{id:"B20",body:'Moreno M, Murphy C, Goldsmith C. Increase in serum potassium resulting from the administration of hypertonic mannitol and other solutions. The Journal of Laboratory and Clinical Medicine. 1969;73(2):291-298'},{id:"B21",body:'DeFronzo RA, Lee R, Jones A, Bia M. Effect of insulinopenia and adrenal hormone deficiency on acute potassium tolerance. Kidney International. 1980;17(5):586-594'},{id:"B22",body:'Sterns RH, Cox M, Feig PU, Singer I. Internal potassium balance and the control of the plasma potassium concentration. Medicine (Baltimore). 1981;60(5):339-354'},{id:"B23",body:'Drakos P, Bar-Ziv J, Catane R. Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature. American Journal of Clinical Oncology. 1994;17(6):502-505'},{id:"B24",body:'Lawson DH, Murray RM, Parker JL. Early mortality in the megaloblastic anaemias. QJM. 1972;41(161):1-14'},{id:"B25",body:'Burg MB. Thick ascending limb of Henle’s loop. Kidney International. 1982;22(5):454-464'},{id:"B26",body:'Subramanya AR, Ellison DH. Distal convoluted tubule. Clinical Journal of the American Society of Nephrology. 2014;9(12):2147-2163'},{id:"B27",body:'Wang WH, Schwab A, Giebisch G. Regulation of small-conductance K+ channel in apical membrane of rat cortical collecting tubule. American Journal of Physiology. 1990;259(3 Pt 2):F494-F502'},{id:"B28",body:'Garg LC. Respective roles of H-ATPase and H-K-ATPase in ion transport in the kidney. Journal of the American Society of Nephrology. 1991;2(5):949-960'},{id:"B29",body:'Weiner ID, Wingo CS. Hyperkalemia: A potential silent killer. Journal of the American Society of Nephrology. 1998;9(8):1535-1543'},{id:"B30",body:'Zhou X, Xia SL, Wingo CS. Chloride transport by the rabbit cortical collecting duct: Dependence on H, K-ATPase. Journal of the American Society of Nephrology. 1998;9(12):2194-2202'},{id:"B31",body:'Madsen KM, Verlander JW, Tisher CC. Relationship between structure and function in distal tubule and collecting duct. Journal of Electron Microscopy Technique. 1988;9(2):187-208'},{id:"B32",body:'Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, et al. Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(5):2514-2519'},{id:"B33",body:'Scott JH, Menouar MA, Dunn RJ. Physiology, Aldosterone. Treasure Island (FL): StatPearls; 2021'},{id:"B34",body:'Rodan AR, Huang CL. Distal potassium handling based on flow modulation of maxi-K channel activity. Current Opinion in Nephrology and Hypertension. 2009;18(4):350-355'},{id:"B35",body:'Wald H, Garty H, Palmer LG, Popovtzer MM. Differential regulation of ROMK expression in kidney cortex and medulla by aldosterone and potassium. American Journal of Physiology. 1998;275(2):F239-F245'},{id:"B36",body:'Sansom SC, Welling PA. Two channels for one job. Kidney International. 2007;72(5):529-530'},{id:"B37",body:'Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology. 1994;107(2):548-571'},{id:"B38",body:'Sandle GI, Gaiger E, Tapster S, Goodship TH. Enhanced rectal potassium secretion in chronic renal insufficiency: Evidence for large intestinal potassium adaptation in man. Clinical Science. 1986;71(4):393-401'},{id:"B39",body:'Epstein M, Lifschitz MD. Potassium homeostasis and dyskalemias: The respective roles of renal, extrarenal, and gut sensors in potassium handling. Kidney International Supplements 2016;6(1):7-15.'},{id:"B40",body:'McDonough AA, Youn JH. Potassium homeostasis: The knowns, the unknowns, and the health benefits. Physiology (Bethesda). 2017;32(2):100-111'},{id:"B41",body:'Moore Ede MC, Brennan MF, Ball MR. Circadian variation of intercompartmental potassium fluxes in man. Journal of Applied Physiology. 1975;38(1):163-170'},{id:"B42",body:'Gumz ML, Rabinowitz L. Role of circadian rhythms in potassium homeostasis. Seminars in Nephrology. 2013;33(3):229-236'},{id:"B43",body:'Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, et al. Molecular clock is involved in predictive circadian adjustment of renal function. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(38):16523-16528'},{id:"B44",body:'Salhi A, Centeno G, Firsov D, Crambert G. Circadian expression of H,K-ATPase type 2 contributes to the stability of plasma K(+) levels. The FASEB Journal. 2012;26(7):2859-2867'},{id:"B45",body:'Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, et al. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nature Medicine. 2010;16(1):67-74'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Shakuntala S. 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Our books are available hardcover, printed in full colour and produced to the highest standards on PEFC™ and FSC certified paper, complying with principles of responsible forestry worldwide. The paper size is 180 x 260 mm (7 x 10.2 inches).
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IntechOpen Books are printed specifically for your order
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Ordered, printed, and delivered in 7-15 business days
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IntechOpen works with award winning print-houses and we hold to the fact that all of our printed products are of the highest quality.
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Zoutman"}]},{id:"61594",doi:"10.5772/intechopen.77949",title:"The Utility of M-31000 for Managing Health and Safety Risks: A Pilot Investigation",slug:"the-utility-of-m-31000-for-managing-health-and-safety-risks-a-pilot-investigation",totalDownloads:935,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"The management of occupational health and safety (OHS) risks is an important part of any business. ISO 31000 risk management has been suggested to represent the natural standard for integrating OHS risk management into business operations. However, published research on this standard is very limited, so its ability to influence the management of OHS risks is unknown. The aim of this chapter is to report on the first part of the findings of a pilot study aimed at investigating the utility of the ISO 31000 risk management standard for managing occupational health and safety (OHS) risks. A review of the published literature on ISO 31000 is presented first. This is followed by a modified theoretical framework, M-31000, taking into account OHS risk management practice. The results of 42/149 key informants selected as part of a purposive sampling strategy identified three main advantages of ISO 31000, including acting as a good starting point for risk management, supplementing other risk management strategies, and allowing for easier integration with other similar strategies. The two main shortfalls identified in this pilot included the standard being vague and difficult to implement. The study also revealed that M-31000 was much simpler and more consistent with safety management practice.",book:{id:"6480",slug:"occupational-health-and-safety-a-multi-regional-perspective",title:"Occupational Health and Safety",fullTitle:"Occupational Health and Safety - A Multi-Regional Perspective"},signatures:"Manikam Pillay",authors:[{id:"199145",title:"Dr.",name:"Manikam",middleName:null,surname:"Pillay",slug:"manikam-pillay",fullName:"Manikam Pillay"}]}],mostDownloadedChaptersLast30Days:[{id:"71988",title:"Introductory Chapter: Safety and Health for Workers - Theory and Applications",slug:"introductory-chapter-safety-and-health-for-workers-theory-and-applications",totalDownloads:823,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"7620",slug:"safety-and-health-for-workers-research-and-practical-perspective",title:"Safety and Health for Workers",fullTitle:"Safety and Health for Workers - Research and Practical Perspective"},signatures:"Bankole K. 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Thus, it is incumbent on managers and policy makers to focus their attention on the socio-cultural environment of developing countries if strategies aimed at improving work practices are to be successful.",book:{id:"6480",slug:"occupational-health-and-safety-a-multi-regional-perspective",title:"Occupational Health and Safety",fullTitle:"Occupational Health and Safety - A Multi-Regional Perspective"},signatures:"Kwesi Amponsah-Tawiah",authors:[{id:"224576",title:"Dr.",name:"Kwesi",middleName:null,surname:"Amponsah-Twiah",slug:"kwesi-amponsah-twiah",fullName:"Kwesi Amponsah-Twiah"}]},{id:"71678",title:"Introductory Chapter: Analysis and Prevention of Accidents",slug:"introductory-chapter-analysis-and-prevention-of-accidents",totalDownloads:617,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"8467",slug:"accident-analysis-and-prevention",title:"Accident Analysis and Prevention",fullTitle:"Accident Analysis and Prevention"},signatures:"Murat Darçın and Caner Filiz",authors:[{id:"196869",title:"Dr.",name:"Murat",middleName:null,surname:"Darçın",slug:"murat-darcin",fullName:"Murat Darçın"},{id:"319377",title:"Dr.",name:"Caner",middleName:null,surname:"Filiz",slug:"caner-filiz",fullName:"Caner Filiz"}]},{id:"69474",title:"Working Conditions and Health Inequalities",slug:"working-conditions-and-health-inequalities",totalDownloads:945,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Over the last decades, there has been a considerable progress made to address risks at workplaces and to promote occupational safety and health of workers. Nevertheless, the recent changes of the labor market underline that new risks to the health and well-being of workers should be considered. In this context, a vast amount of studies have analyzed the relationship between work conditions, social inequalities, and health, suggesting a complex net of causation. Only recently, it has been shown that people in lower socioeconomic positions incur higher working risks. The 2008–2013 economic crisis also introduced a reduction of the number of workers in full-time permanent employment with a steady expansion of atypical and precarious workers. The latter have generally been associated with more insecure and unhealthy working conditions. Another important aspect of safety in the workplace is gender differences. Although nowadays there is more information than before about the types of health problems and accidents women incur at the workplace, the gender-related questions are still open issues that require a careful evaluation of work-related risks of men and women. In this chapter, we focused on the current state of the art in the field of occupational health and examined the aspects that are still being debated.",book:{id:"7620",slug:"safety-and-health-for-workers-research-and-practical-perspective",title:"Safety and Health for Workers",fullTitle:"Safety and Health for Workers - Research and Practical Perspective"},signatures:"Anna Maria Giammarioli",authors:[{id:"175022",title:"Dr.",name:"Anna Maria",middleName:null,surname:"Giammarioli",slug:"anna-maria-giammarioli",fullName:"Anna Maria Giammarioli"}]},{id:"72308",title:"Hand Hygiene Practices in Public Restrooms: Effects and Proposed Solutions",slug:"hand-hygiene-practices-in-public-restrooms-effects-and-proposed-solutions",totalDownloads:988,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Human safety is a popular ongoing research area in personal hygiene. Researchers are mostly apprehensive about how to protect humans from different hazards in the environment. Thus, guidelines developed for good hand wash practices in the public restrooms have showed little or no impact on human behavior. This research examined hand wash acts in the public restrooms and proposed possible solutions to improve the practice. There are 427 people who participated in the study. Participant age ranged from 18 years old and upward: statistically, female, 63%; male, 35%; and unidentified, 2%. Descriptive statistics revealed 99.5% respondents approved restroom redesign for appropriate hand hygiene practice, while 49% suggested restroom device automation. Inferential statistics results on redesign with a Welsh t-test were statistically significant (t=1.967, df=300, p<0.0001; t=1.990, df=80, p<0.0001; t=1.9746, df=163, p<0.0001). Findings showed that hand hygiene guidelines and recommendations are insufficient to ensure proper promotion of hand wash practices in restrooms. This study concluded that good hand wash practices in public restrooms could be ergonomically redesigned to include a visual and auditory alert that reminds users to wash their hands after restroom usage and to include hand wash practice in school curriculum. The findings from this study could be applicable in restaurants, schools, and bars, to manage and control transmission of disease through direct hands contacted with infectious diseases in the restrooms.",book:{id:"7620",slug:"safety-and-health-for-workers-research-and-practical-perspective",title:"Safety and Health for Workers",fullTitle:"Safety and Health for Workers - Research and Practical Perspective"},signatures:"Bankole K. Fasanya, Moruf Adegbite, Maged Mikhail and George L. 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",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"June 23rd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:null},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null,editorialBoard:[{id:"114318",title:"Dr.",name:"David",middleName:null,surname:"Rodeiro",slug:"david-rodeiro",fullName:"David Rodeiro",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2a8QAC/Profile_Picture_2022-04-22T08:29:52.jpg",institutionString:null,institution:{name:"University of Santiago de Compostela",institutionURL:null,country:{name:"Spain"}}},{id:"114073",title:"Prof.",name:"Jörg",middleName:null,surname:"Freiling",slug:"jorg-freiling",fullName:"Jörg Freiling",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS2UPQA0/Profile_Picture_1642580983875",institutionString:null,institution:{name:"University of Bremen",institutionURL:null,country:{name:"Germany"}}},{id:"202681",title:"Dr.",name:"Mojca",middleName:null,surname:"Duh",slug:"mojca-duh",fullName:"Mojca Duh",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD2dQAG/Profile_Picture_1644907300283",institutionString:null,institution:{name:"University of Maribor",institutionURL:null,country:{name:"Slovenia"}}},{id:"103802",title:"Ph.D.",name:"Ondrej",middleName:null,surname:"Zizlavsky",slug:"ondrej-zizlavsky",fullName:"Ondrej Zizlavsky",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQJQA0/Profile_Picture_1643100292225",institutionString:null,institution:{name:"Brno University of Technology",institutionURL:null,country:{name:"Czech Republic"}}},{id:"190913",title:"Dr.",name:"Robert M.X.",middleName:null,surname:"Wu",slug:"robert-m.x.-wu",fullName:"Robert M.X. 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Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. He has advised, among others, the United Nations Development Program, Inter-American Development Bank, Organization of American States, Pre-investment Organization of Latin America and the Caribbean, Technical Cooperation of the Suisse Government, and the World Bank. Dr. Ortiz is the author, co-author, or editor of books, book chapters, textbooks, research monographs and technical reports, and refereed journal articles. He is listed in Who’s Who in the World, Who’s Who in America, Who’s Who in Finance and Business, Who’s Who in Business Higher Education, Who’s Who in American Education, and Who’s Who Directory of Economists. Dr. Ortiz has been a Fulbright Scholar and an MSI Leadership Fellow with the W.K. Kellogg Foundation. 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\r\n\tIn order to scientifically address significant issues such as climate change, which puts into question our very survival as a species, the current pandemic with its massive physical, socio-economical, and psychological consequences, and the rise of AI which challenges our established economic structures, we need to ask insightful questions: What is truly human? How can humans develop further? The answers to these questions are necessary not only to find new solutions to the current challenges, but also to shape new visions of what can come next.
\r\n
\r\n\tNeuroscientific research linking brain functions has produced a perspective on human development that includes normal, impaired, and enhanced neurophysiological, emotional and cognitive functioning. Human development has been considered the very aim of education and of educative processes. Indeed, the capabilities built through educational training are included in the UN’s human development index, according to which such capabilities are the ultimate criteria to assess the development of a country, rather than economic growth alone. Yet a full understanding of what Human Development truly constitutes, remains open. For example, tackling the question of what distinguishes human beings from other animals, and what humans’ possible development trajectory might look like, calls for a multidisciplinary approach. Consequently, contributions to such an inquiry might come from very different scientific fields, ranging from cognitive neuroscience to socioeconomics. For instance, in the field of neuroscience, self-awareness—the most specific characteristic of human beings—has been investigated in connection with its neural correlates. Recent research points to self-awareness as the particular ability of our species, directly connecting it to our abstract thinking which in turn enables envisioning new possible futures and self-development
\r\n
\r\n\tTo achieve a broad, multidisciplinary perspective on possible human development, subjects will be considered through varied— yet related—approaches. We will provide a complex yet consistent framework through which we will explore a substantial amount and variety of theories and case studies. Our ultimate goal will be to produce useful indications for policy making in diverse contexts, assist teachers and parents with child development in an optimal way, and enhance theoretical and practical knowledge.
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