The effect of AMF doses level on number of secondary roots at the age of 40 days after inoculation and sowing.
\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.
Arbuscular mycorrhiza (
The role of mycorrhizae becomes important in sub-optimal land, dry land and for sustainable agriculture. Utilization of mycorrhizae, especially for plant growth, soil fertility and mitigation of drought stress by heat and climate change. Mycorrhiza becomes a component of future technology for sustainable agriculture [5, 6].
Mycorrhizae in agricultural land, especially sub-optimal land, functions to reduce soil erosion and leaching of nutrients. This condition is caused by the faster nutrient cycling mechanism. Besides, the absorption of nutrients is more due to the higher root surface area, which causes long-term soil fertility or soil productivity [5, 6, 7]. The presence of mycorrhizae in sub-optimal dry land of plantation crops is useful for renaturation and afforestation, namely stabilizing degraded land and eroding the soil surface [8]. In areas with high rainfall, plants in symbiosis with mycorrhizae also increase ecosystem repair by reducing the leaching of elements in the soil. Mycorrhizae will suppress the loss of nitrogen (N) and P elements by 40% and 50%, respectively in soil [9].
Mycorrhizal inoculation is important in dealing with drought stress and preparing plants for good growth in the field. Treat mycorrhizal inoculation on plantation seedlings to produce plants that have better root morphology and plant growth. These include root surface area in early coconut growth [10], root length, root diameter, root dry weight, and root dry weight ratio, root surface area, and shoot growth of sugarcane seedlings [11]. Likewise, mycorrhizae play a role in accelerating the growth or emergence of secondary roots in sugarcane seedling [12]. Mycorrhizae also appeared to have a significant role in increasing the growth of forest plant seedlings in the nursery, the increase in leaf chlorophyll content, photosynthesis rate, NPK content in root, stem and leaf compared to plants without mycorrhizal inoculation [13].
Thus mycorrhizal inoculation in plantation crops is needed as an effort to mitigate environmental stresses, both drought and high rainfall. In addition, the impact of mycorrhizal inoculum will increase the nutrients cycle in the soil, prevent excessive leaching of nutrients so that it plays a role in afforestation. In mycorrhizal inoculation, the inoculation time and dose are important. The optimal time of mycorrhizal inoculation is plantation seedlings in the nursery which will increase their colonization by 46% compared to field application [14].
The inoculation of mycorrhizae on seedlings of seedlings is expected to increase the morphological performance and plant physiological performance for early growth and morphological properties, increase the adaptive ability of plants to environmental stress. Based on the above, there are several important benefits for using mycorrhizal inoculation in the nursery of industrial plants.
Before the inoculation of AMF on plantation seeds, it is necessary to know the determinants of colonization and the pattern of colonization. According to Sieverding [15], the process of colonization or infection progresses through 6 stages, namely: (1) pre-infection, at this stage, the spores are not yet active and AMF hyphae are in the soil; (2) penetration of the fungus to the roots. (3) arbuscules and vesicle formation. Arbuscule is formed after 2–5 days from penetration in the form of a strong band of hyphae growing around the cell plasmalemma. The vesicle at the tip of the hypha consists of lipids and fungal organs; (4) fungal elongation in roots and rhizosphere; (5) Spread of fungi to the soil. Hyphae grow out of the roots. The hyphae in the rhizosphere form the “external mycelium”; (6) culture of AMF structures into the form of resting spores on the external mycelium.
The elongation of fungi in the roots and rhizosphere consists of 3 stages, namely (a) slow phase, when infection to the target roots begins; (b) an exponential growth phase, maximum at 40 days after infection; (c) slowed growth phase, “plateau phase” balance [15]. Meanwhile, according to the observations of Sulistiono et al. [14] the colonization of sugarcane seedlings will experience a sharp increase at the age of 5–10 days after inoculation, then it will be constant at the age of 10–30 days after inoculation. An interesting point was also conveyed by Sulistiono et al. [14] that the tendency of AMF inoculation of sugarcane seeds in the nursery would result in higher colonization than inoculation carried out in the field when sugarcane at the age of 1–9 weeks after transplanting. However, after 9 weeks of age, the colonization rates of the two differences in inoculation time were similar. This indicates an equilibrium point for colonization or the development of infection at the root (Figure 1).
The pattern of AMF colonization at different inoculation times.
From the results of Figure 1, it shows that AMF inoculation in the nursery has several advantages, including:
Accelerate colonization when transplanting in the field
The AMF inoculated seeds has better growth of roots and shoots of plants
It has better adaptability to environmental stresses in the form of soil moisture and low nutrients, and diseases
Easy to apply
The higher colonization at the early growth of sugarcane was due to the effect of inoculation time which was applied in the nursery. AMF has infected and further developed which arbuscule and vesicle structures have formed [15] In the nursery, the colonization was optimal at 10–30 days after inoculation [12]. This is characterized by the formation of vesicules and arbuscules. The arbuscules and vesicles forms indicate symbiosis has occurred. This is because arbuscule are used for the transportation of nutrients from AMF to the root cells of host plant, especially P and vesicles are the reproductive organs of AMF and as a food reserve. One of the vesicles or arbuscules on the roots of sugarcane in the nursery as in Figure 2.
Colonization on sugarcane bud chips at the age of 10 (A) and 20 days after inoculation (B). Hi: Hyphae; V: Vesicles. Scala bar: 10 μm. Objective 10×.
Therefore, AMF inoculation at seedling time results in an earlier infection growth process. This is indicated by the presence of hyphae structures since the age of 10 days after inoculation and vesicles at the age of 10 days after inoculation [12].
In the next stage, after the AMF structure is formed, it will accelerate the growth of secondary roots in sugarcane seeds, which was significantly different from the control (without inoculation) (Table 1).
Doses of AMF (g/seeds) | Number of secondary roots |
---|---|
0 | 1.60 b |
1 | 2.80 ab |
2 | 4.00 a |
3 | 3.95 a |
The effect of AMF doses level on number of secondary roots at the age of 40 days after inoculation and sowing.
Remarks: Different letters in same column represent significant differences by Duncan’s multiple range test at 5% level.
Secondary roots in sugarcane seedlings are bigger roots and have a role to support the plant’s upright and optimal absorption of nutrients. Thus, AMF inoculation in the nursery has the potential to increase plant growth (sugarcane) after transplanting. This is due to an increase in the number of secondary roots that are larger in diameter and also stronger [12].
Seeds/seedlings that have been inoculated with AMF in the nursery will have better growth properties in terms of leaf area, chlorophyll content, photosynthesis rate, and stem biomass in post-transplanting sugarcane seeds. This is because the application of AMF in the nursery increased the colonization by 41.3% at 7 days after transplanting and had the effect of increasing stem biomass from 11 to 61% (depending on sugarcane variety). This condition shows that there is a positive correlation between the rate of colonization and the weight of stem biomass, namely r = 0.54 [14].
AMF inoculation since seedling in forest plants (
AMF inoculation in perennial/industrial plant nurseries aims to prepare conditions for optimal growth factors, early symbiosis in the rhizosphere. This is because in 7–10 days the AMF structure has been formed, namely hyphae, vesicles, or arbuscule (Figure 2) [12]. With this difference in root symbiosis, plants can grow more optimally, uniformly, and faster. In this condition, it will provide an opportunity for healthy seed selection before transplanting in the field.
In the AMF inoculation treatment in the nursery, the things that need to be considered are the inoculum dose and the variety response. For plantation crops such as sugarcane, the optimal inoculation of AMF as much as 2 g of inoculum/seed or 7.8 spores/seedlings. This treatment resulted in significant root growth characteristics, shoot: root ratio and leaf P concentration compared to control [12]. The application of AMF inoculum is attempted in an optimal amount, in the right dose. The application of a higher dose will cause it to be less economical for a larger scale/volume.
AMF inoculation of industrial plant seedlings in the nursery needs to consider several limiting factors so that the colonization rate is optimal. Environmental factors are prepared since in the nursery. Environmental factors that determine the level of symbiosis with AMF, namely: (1) Light. Konvalinkova and Jansa [18] reported that the decreasing light intensity will decrease mycorrhizal growth (AMF) and decrease P transfer by AMF to host plants. This is because the availability of an energy source in the form of carbon is not sufficient for AMF and plant symbiosis. The light intensity which is only below 65% of a full-beam with 14–84 days shading time decreases the development of AMF in the root transfer of P elements from AMF to the host plant [18]. (2) soil temperature. The optimal soil temperature for AMF symbiosis with host plants is 20° C as indicated by the percentage of arbuscules and vesicles. An increase in temperature of 23–30° C causes a decrease in the arbuscules and vesicles formation [19]. (3) Elemental content of P, The addition of P into the soil showed a decrease in the percentage of mycorrhizal colonization [20]. (4) Host plants. The host plant is in the form of age, species, or variety [20, 21]. Different types of varieties respond to mycorrhizal inoculation as presented in Figure 3.
Mycorrhizal dependence on several varieties of sugarcane.
Figure 3 shows that genetically different varieties (sugarcane) have different mycorrhizal response [22]. These results can be used as the basis for selecting varieties for transplanting in the dry land. It can be concluded that:
Mycorrhizal inoculation to increase root and shoot growth
Preparation of a nursery that supports the symbiosis of AMF with plants
Adjustment of nursery shade for colonization activities
Setting the temperature of the media and nursery room for colonization
Regulation of nutrient content, especially soil P, it should not excess.
Mycorrhizal inoculation in plantation crops aims to promote good early growth and tolerate environmental stresses. A report shown that AMF inoculated seedlings were then transplanted had increased leaf nitrate reductase activity (NRA) and root surface area in early coconut growth [10].
The increase in colonization with the formation of arbuscules and vesicles in early plant growth indicated that the symbiosis was optimal (Figure 4) [14]. This condition causes the host plant to obtain P elements from AMF transfer, more nutrient uptake by hyphae elongation and plant root structure, thus the plant experiences more optimal growth. Planting mycorrhizal inoculated plant seedlings is to increase nutrition in plants, especially P in cropping area [8], reduce nutrient loss due to leaching [6] so as to support sustainable agriculture [3, 8].
The structure of arbuscules and vesicles and hyphae formed at the roots of plants infected with mycorrhizae. Field observations.
More stable nutrients available in mycorrhizae inoculated plant area resulted in increased soil productivity. Many nutrients are bound by the AMF structural system because there is a glomalin system. Glomalin as a glycoprotein forms chelates with inorganic P. Besides, the hyphae structure is more abundant which can directly absorb more nutrients, especially P [6]. Thus the AMF mycorrhizal inoculation treatment is a mitigation measure against climate change so that plants will continue to grow and survive.
AMF inoculation on seedlings is increased the root and shoot growth as well as increased the colonization. The nursery location is adapted for AMF growth and symbiosis. Plants infected with mycorrhizae had better growth (roots and shoots) ability after transplanting the seedlings. Besides that, it can reduce nutrient loss and maintain soil fertility so that it is an effort to mitigate climate change.
This work was supported by a grant from the Institute of research and community service, Lembaga Penelitian dan Pengabdian Kepada Masyarakat (LPPM) Universitas Gadjah Mada Yogyakarta Indonesia (UGM/396/LIT/2014). Authors thank for Prof. Dr. Prapto Yudono, Prof. Dr. Irham. Assesment Institute for Agricultural Technology of North Maluku (DIPA 2018)-Indonesian Agency for Agricultural Research and Development-Ministry of Agriculture. Authors thank for Dr. Andriko Noto Susanto, Dr. Bram Brahmantiyo and Dr. Abdul Wahab for the research facility.
I declare that I have no conflict of interest as an author on the financial and intellectual processes of the entire manuscript.
Heart failure is a major public health issue that is still having a poor prognosis despite all the advancements in scientific research and technologies [1]. The approaches for the drug development of heart disease are majorly relying on the pathophysiology of the cellular mechanisms and inter and intracellular channels in the failing heart. Heart being an organ of extensively high energy demand and mitochondria being the powerhouse of the eukaryotic organisms, they are meant to be closely connected. Any change in mitochondrial function inevitably affects the health of the heart irrespective of the etiology. Recent advances in the field indicate that besides having a compromised powerhouse, mitochondrial malfunctioning accompanies certain pathogenic mechanisms leading to heart failure [2, 3]. Current therapies like ischemic pre- and postconditioning provide symptomatic benefit but do not address the abnormalities at a molecular level. Since the mitochondria play an important role in the pathophysiology of a failing heart, understanding its mechanism can potentially improve the approaches for the therapies for direct improvement of cardiac functions. Among the abnormalities shown by the mitochondria, ruptured electron transport chain, excessive formation of reactive oxygen species (ROS), perturbed ion homeostasis are the basic concerns [4]. An important and potential substrate for therapeutics in heart failure is mitochondrial channels [5]. In this chapter, we intend to discuss the available information about the mitochondrial channel with regards to its pathophysiological effects on heart health and their responses to the ischemic conditioning alongside the available agonist for the mitochondrial channel.
Due to high energy demand, the number of mitochondria in the heart cells is excessively high, with a daily production of approximately 65 kg ATP through oxidative phosphorylation [6]. In the neonatal cardiac myocytes, the mitochondria are highly motile in the cytosol generating energy through glycolysis and glucose metabolism. Whereas, in an adult myocyte the mitochondria have reduced motility, and energy generation occurs from the metabolism of fatty acid [7].
Mitochondria are known to arise billions of years ago through the engulfment of alpha proteobacteria by the precursors of modern eukaryotic cells and it evolved to become an essential multifunctional organelle [8]. Mitochondria are made up of an outer comparatively permeable and inner highly folded relatively impermeable lipid bilayer. The folded inner membrane with a high surface area contains the complexes for the generation and transportation of adenosine triphosphate (ATP) through oxidative phosphorylation. In the myocardial cells, the substrates are oxidized to produce acetyl coenzyme A, which in turn drives the Krebs cycle to produce nicotinamide adenine dinucleotide hydrogen (NADH) and flavin adenine dinucleotide (FADH2) in the mitochondrial matrix. The oxidation of NADH and FADH2 leads to the establishment of proton motive force later fetched by F1F0 ATP synthase to convert adenosine diphosphate (ADP) and inorganic phosphate to ATP [9].
In the process of energy production, approximately 2% of the electrons flowing in the electron transport cycle are reduced to form a superoxide anion which is reduced to H2O2 followed by H2O generation by antioxidant enzymes. Excessive production of these ROS is toxic to the cell, yet these natural byproducts of oxygen metabolism trigger a variety of oxygen sensing machinery including gene expression, however, the overload of ROS impairs the redox potential of the cell leading to various oxidative damages [10].
The dynamics of Ca2+, an important element to trigger various enzymatic processes and a second messenger for contractile functions, is also organized by mitochondria by either transmembrane Ca2+ transport or ROS-mediated signaling pathways [11]. In case of increased workload rapid mitochondrial Ca2+ uptake is facilitated by Ca2+ uptake channel for elevated ATP production. The elimination of Ca2+ from the mitochondrial matrix however is slower and mediated either directly by Na+/Ca2+ exchanger or indirectly by multiple mitochondrial K+ channels with unknown mechanisms [12].
Alongside the role as a life-supporting system, mitochondria can also trigger programmed cell death in the required conditions. The mitochondrial permeability transition pore (MPTP) opens in response to stress and leads to loss of membrane potential, which stops ATP production and release of cytochrome C and other mitochondrial protein causing necrosis and cell apoptosis [13]. In cases of heart failure mitochondria-induced cell death is an important mechanism. Here we intend to discuss important parameters of mitochondrial dysfunction which lead to heart failure, and therapeutic approaches to circumvent the situation.
In cardiac cells the energy consumption should meet the energy production rate on a beat-by-beat basis, failing which the stored energy cannot last more than a few seconds. In a pathological remodeling the oxidative metabolism switch from fatty acid metabolism to glycolysis, which only contributes less than 5% of the total ATP demand of an adult heart [14]. On the other hand, during pathological remodeling the required energy increases due to disturbed cardiac geometry, and impaired ATP homeostasis. Studies have shown that the mitochondrial mechanisms involved in pathological remodeling in efforts to restore the energy homeostasis eventually led to a vicious cycle that drives pathological remodeling towards heart failure. The most puzzling scenario suggests that in the failing heart the ATP content is largely maintained after an initial glitch, thus whether the heart failure occurs due to energy starvation or in efforts to fight that starvation is a question yet to be addressed. Further in-depth analysis of the mitochondrial mechanisms can clarify if the efforts of maintaining the energy hemostasis are either helpful or potentially worsen the failing heart.
The catalysis of degradative oxidation of the nutrients through anaerobic dehydrogenases is facilitated by the reduction of oxidized pyridine and flavin nucleotide like NAD(P+) and FAD. These coenzymes should be again reoxidized since they are non-replenishable and cannot permeate the cell membrane with the degradation rate. During an ischemic episode since the respiratory chain is impaired the oxidation of the above-stated substrates is also hampered, moreover, the NADH(H+) oxidation is carried out by lactate dehydrogenase. Therefore, the anaerobic glycolysis takes over as the only pathway for ATP synthesis provided the phosphocreatinine is depleted with the onset of ischemia. Therefore, in a failing heart the oxidative metabolism switch for alternative carbon sources such as glucose which can be beneficial due to increased ATP production and oxygen uptake but when it takes over the usual fatty acid metabolism the energy production is not sufficient for an adult heart [14]. Increased glycolysis causes anaplerosis, increased lactate production, triggers the heart to go into pathological remodeling, and also inhibits branched-chain amino acid (BCAA) catabolism, and causes the accumulation of BCAA. A hyperacetylation of mitochondrial protein has also been seen as a failing heart the cause of which is not clearly understood [15].
The decrease in ATP concentration causes an immense ionic imbalance across the cell cytoplasm leading to the lowering of the pH of the cell. The inhibition of Na+/K+ ATPase, Na+/H+, Na+/Ca2+ antiporters leads to an overload of Ca2+ inside the cells causing hypercontracture and triggering the irreversible opening of mitochondrial permeability transition pore (MPTP) [16]. The frequently converting ATP into ADP and phosphate seeps out of the cell which further contributes to reduced performance of the heart. Opening of only one pore causes frequent depolarization and triggers the opening of other pores, following which the rapid influx of small molecular weight solutes enters the mitochondrial matrix to compensate for the depolarization and causes the mitochondrial matrix to swell. The expansion of the inner mitochondrial membrane leads to the rupture of the outer membrane which releases proapoptotic proteins leading eventually to cell death. Therefore, it is believed that altering the MPTP pore opening can be helpful in the prevention of cardiac reperfusion and cell death [17].
During an ischemic episode, the release of ROS is formed under the physiological and pathological conditions within the mitochondria. In a regular respiratory chain reaction, 2–4% oxygen undergoes an univalent reaction and produces superoxide [4]. The superoxides that are formed at complex I and complex III level are rapidly transformed by metalloenzymes like superoxide dismutase into hydrogen peroxide. In the first minute, it is small but in a later stage, it increases dramatically, leading to the disruption of mitochondrial membrane potential. Therefore, the consequence of ROS formation has been linked to the opening of the MPTP channel leading to apoptosis. These episodes put together in series lead to a gradual and irreversible decline of the cell integrity.
The opening of MPTP can occur through all the factors mentioned here, such as an increase in Ca2+ ion, depolarization, increase in the ROS, and phosphate concentration [18]. Certain factors like a high concentration of H+, Mg2+, and ADP can counteract the MPTP opening and work as antagonists [19, 20]. On the contrary, in the condition of reperfusion, the change in the pH is recovered by the burst formation of ROS in the presence of Ca2+, which creates the most favorable condition for MPTP opening even though the antagonizing effect of membrane potential recovery occurred. In isolated mitochondria, the MPTP opens at a very high Ca2+ concentration which is practically not possible in vivo therefore the increased Ca2+ alone is not responsible for MPTP opening rather can be triggered by several processes like ROS generating Ca2+ dependent enzyme.
It is believed that to reduce the damage occurring in the heart cells in a prolonged ischemic episode, the heart cells can be trained beforehand through small and regulated episodes of either cardiac ischemia or reperfusion that resulted from ATP deprivation or concentration increase of ROS and Ca2+ (Figure 1). This method has been tested in dogs [21] and higher mammals including humans [22, 23]. This process is known as ischemic preconditioning (IpreC). Similarly, ischemic postcondition (IpostC) can also be done in a brief intermittent cycle after a severe event [24]. These are performed by natural or artificial biomolecules which will be discussed later in this chapter.
The ischemic/reperfused heart mitochondria in comparison to the cardioprotected mitochondria. In cardioprotected mitochondria MPTP and MCU channels are closed and mitoK channel is opened.
The process of IpreC and IpostC usually activates protein kinase C isozymes [25] and other kinases [26] whose roles in cardioprotection are very dicey, because as ε isozyme protects the mitochondrial function by activating ALDH2 aldehyde dehydrogenase which removes the lipid peroxidation products, Baines et al. showed that the translocation of ε isozyme prevents the opening of MPTP pore [27]. Whereas δ isozyme of protein kinase C increases the tissue injury by flawed perfusion of myocytes and inhibits ATP and pyruvate dehydrogenase regeneration [27]. Several mitochondrial pathways are activated in the conditioning process contributing significantly to the process of cardioprotection and therefore they are considered attractive pharmacological targets.
The multifaceted relationship of mitochondria with cell death makes it an ideal target for aiming to preserve cardiomyocytes viability. In the lack of oxygen during ischemia although the ATP synthesis cannot be restored yet can protect through decreasing ATP hydrolysis. Several self-defense mechanisms are triggered by ischemic preconditioning like the depolarization of mitochondrial matrix promotes F1F0 ATPase binding to its natural inhibiter Factor (IF) [29]. A similar effect has been shown by overexpressed the BCL-2 gene in mice hearts, to conclude that ATP hydrolysis is modulated by BCL-2 as well since the oligomycin addition did not possess any additional effect. BCL-2 is upregulated in the preconditioned heart and downregulated by ischemia and reperfusion [30]. However, the cardioprotective effect caused by preconditioning can be abolished by antisense nucleotide in a perfused rat heart [31]. Another way to prevent ATP hydrolysis is by MPTP inhibition, which presents a wide range of protective actions like maintaining Ca2+ homeostasis, NAD+ depletion prevention, and preventing the release of pro-apoptotic protein [20, 32, 33]. The preconditioned heart prevents the opening of MPTP pores conferring stress-tolerant condition of the cardiomyocytes [34, 35].
In addition to protective effects posed by MPTP inhibition, numerous studies have vouched for the supporting effect of the mitochondrial potassium channel, specially mitoKATP and calcium-dependent mitoKCa. The influx of K+ into the inner mitochondrial matrix causes depolarization, with pH increase and matrix swelling [36, 37, 38]. It is suggested that matrix swelling due to K+ uptake compensates for the contraction of the matrix caused by increased potential difference due to lack of oxygen. The K+ uptake and matrix swelling are suggested to increase the recovery of ATP concentration, by preventing the loss of substrate channeling which happened due to increased potential difference at the onset of reperfusion [39].
A sudden increase in the permeability of the solute in the inner mitochondrial membrane (IMM) is known as the permeability transition [16]. The MPTP was first described by Haworth and Hunter in 1979, who showed that the addition of high levels of calcium to bovine myocardial mitochondria induced a nonspecific increase in permeability of the inner mitochondrial membrane [40]. Although the occurrence of permeability transition and its inhibitor as adenine dinucleotide has been known since 1950 [41]. Our understanding of mitochondrial physiology and the acceptance of the pore theory of permeability transition is greatly attributed to the study of a mitochondrial channel.
The opening of the MPTP channel causes depolarization, blocks ATP synthesis, releases Ca2+, depletes pyridine nucleotide, inhibits respiration, causes matrix swelling, which subsequently leads to cytochrome C mobilization and outer mitochondrial membrane rupture which ultimately releases endonuclease G and apoptosis-inducing factor (AIF) and other proapoptotic protein to kill the cell (Figure 1) [42, 43]. It should be noted though, that this detrimental effect of MPTP opening occurs only when the pore opening is long-lasting [44]. Whereas the short-term opening, both in vivo and in vitro [45], is suggested to be involved in the physiological regulation of Ca2+ and the homeostasis of ROS [4], subsequently providing mitochondria a fast mechanism for Ca2+ release. According to a study performed on a mitochondria calcium uniporter (MCU), null mice had an equal I/R injury as the wildtype littermates overruling cyclophilin-D (CyPD) protection (Figure 1). It leads to challenging the established concept and awaits the molecular details of the myocardial reperfusion mechanism and the precise roles of the channels for answers to these contradicting observations. The potential role of MPTP opening in heart failure was recognized way before the discovery of the role of mitochondria in apoptosis.
Although the molecular nature and precise composition of MPTP remain unknown it is believed that some proteins regulate the function of MPTP like CyPD (Figure 1). After the observation that cyclosporin (CsA) is a potent inhibitor of MPTP opening [46, 47], Halestrap et al. demonstrated that it occurred due to an inhibition of a peptidyl-prolyl cis-trans isomerase PPIase in the matrix [48]. They further purified and demonstrated the protein to be CyPD, which is an 18 kDa matrix protein. A range of other CsA analogs and sanglifehrin A (SfA) that showed their potency in preventing MPTP opening also acted as inhibitors of PPIase of CyPD. On the other hand, the MPTP opening is also inhibited by ATP and ADP but their complexes with Mg2+ and other nucleotides like AMP, GTP, or GDP fail to show a similar effect, it is worth noting that none of them are transported by the adenine nucleotide translocase (ANT) [49]. Furthermore, the increased sensitivity of MPTP opening towards Ca2+ is attributed to the inhibition in the binding of the ATP and ADP with ANT either by depleting the matrix of adenine nucleotides or by modifying ANT by thiol [50]. Helstrap group developed a model for MPTP, where CyPD binds to ANT and they undergo conformational changes to induce pore formation under Ca2+ trigger, and they showed that matrix Ca2+ favored ‘C’ conformation for ANT. Several matrices facing glutamate and aspartate residues on ANT are present whose carboxyl groups might play the role of Ca2+ binding as there is no Ca2+ binding motif established on ANT [50]. Another data consistent with the model showed the coprecipitation of CyPD specifically with ANT and the bonding increases with rising oxidative stress and decreases with the introduction of CsA but not with inactive CsH analog [51, 52]. The crystal structure of bovine ANT1 [53] showed a constriction provided by 3 helices, block the channel and if these are rearranged by the change facilitated by CyPD, then an extensive conformational change might account for MPTP formation. Phosphate ion has been known as an MPTP activator and carboxyatractyloside (CAT) prevents ANT from binding the phenyl arsine oxide (PAO) column but still does not prevent MPTP activation, which suggests that PAO can have an additional MPTP activation site apart from the ANT. When CAT treated beef heart mitochondria was passed through the PAO column phosphate carrier protein (PiC) was bound to the column [54]. Pretreatment of the column with MPTP inhibitors like ubiquinone (UQo) prevents the PiC binding to the column which suggests a key role in MPTP formation. Other proteins have also been suggested to have the structural and regulatory role in MPTP formation like peripheral benzodiazepine receptor and voltage-dependent anion channel, hexokinase, creatinine kinase, BCL2 proteins, and Bcl 2 associated X (BAX) proteins may also be associated with MPTP, but which proteins eventually constitute the formation of the pore is still unknown [55, 56].
Recently, another theory of multiple pores in MPTP has been proposed. Studies have been supporting the potential roles of ANT, PiP, F1F0 ATP synthase, and CyPD to be inner membrane component but all of them has shown CsA sensitive permeability despite the genetic deletion of the responsible gene, which raises a question on the hypothesis and further investigation led to propose the multiple pore-forming mechanisms. Deletion of the C subunit of F1F0 ATP synthase showed that CsA induced MPTP synthesis showed much lower conductance as compared to wild-type MPTP [57]. This C-subunit lacking channel could be inhibited by an ANT inhibiter bongkrekic, therefore it was suggested that a classic MPTP was not formed in the knockout mitochondria. It was concluded that the MPTP formation could be enhanced through other proteins e.g. ANT in the lack of c-subunit. Another study proposed that dimer of F1F0 ATP synthase, ANT and PiC can assemble into synthasome complex, and it requires CyPD for disassembly into its components. They further suggest that ATP synthasome assembles and disassembles in high work conditions and MPTP formations respectively. Low ADP, high calcium enhancement leading to increase the membrane potential, and ROS formation trigger the disassembly of ATP synthasome leading to MPTP formation. Additional studies will be required to completely understand all the components of synthasome in generating MPTP [58].
As a result of its central role in myocardial infarction, MPTP poses itself as an obvious target for cardioprotection. A wide variety of cardioprotective protocols have been demonstrated to prevent MPTP opening during reperfusion. Certain drugs directly inhibit MPTP like CsA and SfA and their non-immunosuppressant derivatives like 4-methyl-val-CsA and D-3-MeAla-4-EtVal-CsA etc. and certain protocols that decrease oxidative stress and pH for inhibiting MPTP pore opening such as ischemic preconditioning [35] and ischemic postcondition [59], temperature preconditioning [60], Na+/H+ exchanger inhibiter like cariporide [61], mitochondrial ubiquinone antioxidants [62], the anesthetic propofol [63], urocortin [64], antioxidants including pyruvate [65].
The drugs that directly inhibit MPTP pose great value in protecting the heart during cardiac surgery, it has been shown that CsA improved cardiac performance following angioplasty treatment [66]. However, CsA and Sfa administration pose unwanted side effects because they interact with other cyclophilins like CypA moreover, their MPTP opening inhibition is overruled by the intensity of the pore opening stimulus [67]. This situation requires the development of new MPTP inhibitor drugs which can overcome these constraints. The development of new drugs requires structural insight into the MPTP pores.
The inner mitochondrial anion channel (IMAC) was the first mitochondrial channel to be identified using the patch-clamp method [68]. The pharmacological drug testing on the cardiomyocytes, for analysis of the mitochondrial matrix swelling, led to the discovery of its role in membrane potential perturbation. Its activity is promoted under stressed oxidizing conditions [69]. O’Rourke and co-workers proposed that the arrhythmias and electrophysiological alteration in cardiomyocytes are the results of disturbed membrane potential due to failed cellular mitochondrial network under oxidative stress [70]. The inhibition of IMAC mediated mitochondrial membrane potential oscillation with 4-chlorodiazepam showed a significant reduction and stabilization of the sarcolemmal action potential [71]. High-resolution optical action potential mapping showed that the introduction of 4-chlorodiazepam facilitates the restoration of action potential duration and prevents ventricular fibrillation. The thiol oxidants trigger the oscillation of membrane potential, glutathione, and NADH, which in turn increases the ROS concentration [72]. The inhibition of IMAC activity is triggered by the binding of 4-chlorodiazepam with benzodiazepine receptors. The inhibited IMAC preserves the membrane potential; however, the prohibited efflux of superoxide from IMAC further increases the ROS concentration [73]. The increasing ROS and decreasing glutathione concentration in the mitochondrial matrix trigger the opening of the MPTP pore, and therefore, IMAC can be considered as an instigator of MPTP opening [72].
The macromolecular structural assembly responsible for mitochondrial Ca2+ uptake machinery is known as the mitochondrial calcium uniporter (MCU) complex. It was initially assumed that an active uptake and passive release are required for the transport of Ca2+ across the inner mitochondrial membrane [74], but multiple groups showed that the uptake is energetically favored whereas efflux requires electrogenic ion-exchange [75].
Ca2+ uptake in mitochondria results from a single transport mechanism by a Ca2+ sensitive channel of mitochondria known as MCU (Figure 1). The molecular identification of the MCU protein complex which was closely connected to a comprehensive protein compendium MitoCarta was done in 2008 [76]. Following the establishment of a compendium Ca2+ sensing regulator, mitochondrial Ca2+ uptake 1(MICU1) was discovered in 2010 [77]. MICU1 was predicted to contain no transmembrane domain and was therefore not considered forming a pore. Later 40 kDa two transmembrane domains were identified termed MCU in 2011 [78, 79] followed by the identification of other regulatory subunits.
The concentration Ca2+ increases in the mitochondrial matrix during ischemia and reperfusion and this increase is proposed to activate MPTP opening [16]. Therefore, the inhibition of mitochondrial calcium uniporter is studied to reduce cell damage in I/R. Studies from MCU knockout mice in the germline [80] and MCU mutated gene [81], in both the cases the Ca2+ uptake was hindered leading to no MPTP opening, but neither of the situations reduced the size of cardiac infarct at the onset of I/R. In contrast, where the MCU was deleted after birth in adult hearts showed cardioprotection in an in vivo model [82]. The reason for this kind of difference is not very clear but apparently, the MCU knockout before birth could generate a more robust MPTP pore not regulated by CsA as well. Alongside MCU, the other two core structural components are mitochondrial calcium uniporter b MCUb and an ion transport component termed “essential MCU regulator” or EMRE. MCUb is closely related to MCU with 50% amino acid homology, containing two similar transmembrane domains linked with coiled-coil domain. On the other hand, EMRE is a 10 kDa protein span in the inner mitochondrial membrane that contains an aspartate-rich, highly conserved, C-terminal region, whose topology however is still unclear [83]. It was proposed by Mootha et al. that EMRE is required for Ca2+ channeling activity and also helps in keeping the MICU1/MICU2 intact to the MCU complex [84].
Altering the levels of regulators of MCU complex the calcium uptake can also be regulated in mitochondria, subsequently altering the susceptibility to MPTP-induced cell death. A mitochondria Ca2+ uptake protein1 (MICU1) mutation causing a loss of function in a human patient is associated with ataxia, attributed to mitochondrial Ca2+ overload [85, 86]. In a failing heart, an increase of MICU1 and Na+/Li+/Ca2+ exchanger (NCXL) has been observed to compensate for the Ca2+ overload [87]. MICU2 on the other hand has been observed to increase, with cardiovascular disease in both humans and mice, at the transcriptional level [88]. Mice with deletion of MICU2 showed a certain degree of diastolic dysfunction. The low ratio of MICU/MCU maintains a low threshold of calcium entry in mitochondria and the overexpression of MICU1 causes contractile dysfunction to the heart. Therefore, the rise in MICU1 and MICU2 with age and disease alters the susceptibility of calcium overload and MPTP inhibition.
In a cardiac muscle, constant rhythmic cycles of contraction are dependent on permanent uptake and release of Ca2+ in the cytoplasm and buffering organelles [89]. After a myocardial contraction, the removal of the Ca2+ from the cytoplasm is provided by Na+/Ca2+ exchanger (NCX) in the endoplasmic reticulum, on the other hand in non-muscle cells the cytosolic Ca2+ signals and Ca2+ buffering depends on mitochondrial Ca2+ uptake [90]. Although this mitochondrial Ca2+ uptake in cardiomyocytes possesses a very low MCU current and constitutes less than 1% of total Ca2+ uptake [89, 91], it plays a key role in coordinating between excitation and metabolism coupling [92]. In a healthy heart, two models of mitochondrial Ca2+ dynamics have been suggested by Cao et al., the first model suggests that Ca2+ concentration oscillates in a beat-to-beat manner in cardiomyocytes whereas, the second model emphasizes gradual Ca2+ uptake by cardiac mitochondria. On the contrary, in the damaged heart the Ca2+ mishandling within the mitochondria is well documented [93]. The MICU1 protein content is significantly low following I/R due to inhibition of translocase expression of the outer membrane. Furthermore, treatment attempts using siRNA on myocardial MICU1 aggravated the ischemic episode increasing tissue damage and depressing cardiac function due to apparent Ca2+ overload [87].
As it is quite evident that the uncontrolled influx of Ca2+ is disastrous for cardiomyocytes, and MCU is the major route for Ca2+ entry. Therefore, alteration in the expression of MCU can be a promising target for cardioprotection. For the inhibition of MCU ruthenium red and its derivatives are generally used, however, ruthenium red has nonspecific activity towards other ion channels [94] as well which does not make it a suitable inhibitor and prevents it from usage as a therapeutic agent. Recently, two new highly selective MCU inhibitors were developed one is DS16570511 prevents Ca2+ overload and raises cardiac contractility without affecting heart rate [95]. The second one is Ru265 is negligibly toxic and prevents hypoxia in the cell model [96]. Mitoxanthrone, an anticancer drug that showed its efficiency in inhibiting MCU [97], similarly kaempferol known as an anticancer [98] and cardioprotective drug [99] could prevent Ca2+ created arrhythmias [100]. These can be promising drugs in preventing Ca2+ related risks to cardiomyocytes but they require more animal study, and careful modeling and validation before adapting as therapeutics.
On one side where the opening of mitochondrial mega channels like MPTP and Ca2+ uniporter represents a hallmark of cell death, on the other hand, the transport of K+ through ion channels is known to play a central role in neural and cardioprotection [101, 102, 103]. The membrane potential and permeability of the inner mitochondrial membrane are strictly controlled for efficient ATP production. The presence of an electrophoretic pathway for entry and antiporter mechanism for the exit of K+ has been well established and they critically regulate the mitochondrial volume and function. The transport of K+ ions from the cytosol to the mitochondrial matrix is carefully conducted through ion channels by utilizing electrogenic transport, where the proton ejection by the electron transport system generates enough membrane potential for the influx of K+. There are four kinds of mitochondrial K+ channels (Figure 2) present in the inner membrane the ATP regulated [104], Ca2+ regulated [105], Twin pore TASK channel [106], and voltage-gated Kv1.3 potassium channel [107]. These channels resemble the plasma membrane potassium channels in their basic biophysical properties and are regulated to avoid the membrane potential collapse.
Mitochondrial potassium channels (a) voltage-gated potassium channels (Kv 1.3, Kv 1.1, Kv 1.5), (b) small and large conductance mitoKATP channel (IKCA, BKCa), (c) ATP sensitive K+ channel, (d) twin pore K+ channel. mitoKATP and mitoBKCa having extensively studied for cardioprotection.
Several mitochondrial K+ channels (Figure 2) have been discovered so far but ATP sensitizing uptake of K+ has gazed maximum attention. The cardiac ischemic conditioning was first believed to be working on KATP of the plasma membrane counterpart but based on pharmacological analysis with channel openers and inhibitors shown to affect mitochondrial KATP channel. The mitoKATP channel was first identified in rat liver mitochondria using the patch-clamp method [91] and was later found in the inner mitochondrial membrane [108, 109]. They are situated at the crossroad of metabolism and membrane sensitivity. The molecular identities of a mitoKATP were recently determined by Angela Paggio et al. [110], which is similar to its plasma membrane counterparts that consisting of pore-forming potassium channel CCDC51 (MITOK) and ATP-binding cassette (ABC) transporter ABCB8 (MITOSUR); however, the detailed assembly and function mechanism is still unknown due to the missing of structural information. The plasma membrane KATP is heterooctameric, containing four inward rectifying potassium channel subunits of Kir6.1 and four sulfonylurea receptor subunits, which belong to the ABC transporter family [111]. Whether this newly identified mitoKATP is occupying a similar octameric assembly as the plasma membrane KATP is still unknown and moreover, it may not present the only version of mitoKATP as channels such as Kir6.1 has also been suggested in the formation of mitoKATP [28]. Nevertheless, they are believed to play a central role in cardioprotection, since the bizarre method of cardioprotection called ischemic conditioning was introduced. Ischemic preconditioning was first observed with plasma membrane using KATP channels as effectors, but later mitochondrial potassium channel became an interesting target for the same. The pathway involves activating the protein kinase and generating ROS, but the precise role of mitoKATP is not very well established. Therefore, evidence of molecular structure for the mitoKATP will subside the pharmacology-based arguments of its existence and role in the process of preconditioning. According to a study by Peng Duan et al., mitoKATP channel opening is helpful in the optimal expression of protein kinase B (p-AKT) and forkhead box protein O1 (pFoxo1) in an insulin-resistant cell. The increased p-Foxo1 is phosphorylated by p-AKT, reducing its transcriptional efficiency, and transferred out of the nucleus, and prevents the expression of pro-apoptotic protein, thereby preventing apoptosis [112].
A study done by Garlid et al. in 2006, showed that the K+ ion uptake in the mitochondria leads to increased ROS production as they explain that the opening of the mitoKATP channel will lead to a small amount of K+ uptake but this lowered potential will increase the matrix volume and pH by a persistent steady state. Valinomycin was used to induce the mitoKATP opener and an increased pH caused an increased ROS production, when the acetic acid influx increased for compensation of the alkaline matrix the ROS production also reduced proving that the alkalinity is a cause for ROS production. It was also proved by them that the ROS was generated from the complex I of the electron transport system [113].
These channels were first discovered in the glioma cell line LN-229 and have been extensively studied in the brain and cardiac cells since then [105]. The calcium-activated potassium channel is of two types small and intermediate conductance K+ channel and large or big conductance K+ channel. The small and intermediate channels are only calcium-dependent and not voltage-dependent they possess calmodulin for the Ca2+ binding at the C-terminal region. Their major function is promoting proliferation and migration of dendritic cells and smooth muscle [114].
The first evidence of its presence in the inner mitochondrial membrane was found in the late 90s by Siemen and coworkers although showing that it possesses a conductance of 300 pS [105]. Its role in protecting the heart from ischemic insult was first discovered by Xu et al. and their structural characterization in the plasma membrane indicates that it originates from potassium calcium-activated channel subfamily M alpha 1 (Kcnma1) gene containing extracellular N terminus and intracellular C-terminus [115]. It has been proven in 2013 that the BKCa pore-forming alpha subunits are encoded by the same genes (Kcnma1) as the basis of why they possess the same physiological properties [116].
The big conductance Ca2+ sensitive K+ channel also known as MitoBKCa on the other hand is intuitive to voltage and mechanical stress alongside Ca2+ sensitivity. The knockout experiments have proven for the MitoBKCa channels to have a cardioprotective effect by reversing the ROS production and opening MPTP. It has also been shown that these channels form a multiprotein complex with several proteins involved in apoptotic machinery [117].
mitoBKCa channel [118] represent themselves as a key pathophysiological target due to their sensitivity towards calcium, voltage, and a range of cellular components. Several small molecular openers for BKCa and pharmacological agents have provided very insightful information to decipher the role of BKCa channel. Pharmacological agents like NS1619 and NS11021 have been used to activate BKCa can potentially play a vital role in cardioprotection. However, they fail to reach the clinical applications due to their non-specificity [119, 120, 121, 122]. Although it is posing a great deal of difficulty in developing the BKCa activators, it becomes essential considering that expression of BKCa is vital for cardioprotection [116, 123].
The first representation BKCa playing an essential role in cardioprotection from I/R injury was performed by using NS1619, whose effect was blocked by praxilline [115]. A 3 mM NS1619 preconditioning showed an improved reduction of infarct size, possibly by modulated Ca2+ and ROS concentration [117]. BKCa mediated cardioprotection involves ROS, Ca2+, and MPTP and their interplay. It is anticipated that reduction of deleterious ROS through BKCa activation prevents the excess release of Ca2+ from the endoplasmic reticulum subsequently reducing the influx and overload in mitochondria preventing the cell from injury.
These are the most diverse family of K+ channels. They are grouped into 12 families comprising 40 of the 90 genes present in human cells [124]. These channels mostly consist of six transmembrane helices (S1-S6) where two of them (S5-S6) form the loop and four of them are proceedings to the loop (S1-S4). The fourth positively charged loop senses the change in the membrane potential. These channels have a wide variety and therefore, they represent a fine regulation of K+ flux in the homeostasis and pathological processes. The mitochondrial counterpart mitoKv1.3 is found in lymphocytes [125] and many carcinogenic cells [126, 127], they present similar physiological functions as the plasma membrane counterpart and, they are translated from the same gene. mitoKv1.3 is a target for pro-apoptotic protein Bax [128]. Their complex prevents the opening of mitoKv1.3 channel for K+ influx and therefore causes the disturbance in membrane potential and eventually leads to apoptotic cell death. Therefore, mitoKv1.3 has represented itself as a new tool for targeted cell death for many tumor cells by triggering mitochondria-induced apoptosis. Their presence in cardiac cells has not been reported. Similar to Kv1.3 other potassium channels like Kv1.1 and Kv1.5 have also shown dual origin in both mitochondrial and plasma membrane causing cell apoptosis by targeting macrophages [129, 130].
The mitochondrial TASK-3 was discovered in human keratinocyte HeCaT cells using the patch-clamp method [131]. It shows similarity with its plasma membrane counterpart and its activity is inhibited at acidic pH [132]. Lidocaine and low pH completely block the task channel activity in mitochondria. TASK-3 is essential for the survival of WM35 melanoma cells [133] but its activity in the mitochondrial dysfunction in cardiac reperfusion is not known.
The above discussions have made it clear that since the inner mitochondrial channels regulate the onset of apoptosis and cell death, they present an important target for cardioprotective therapeutics. Not only mitochondrial potassium channel but also MPTP, MCU, connexin-43, and protein uncoupling have shown their potential roles in reducing myocardial infarct size and preventing heart failure.
A sudden opening of MPTP can be triggered through a high concentration of Ca2+, high amount of ROS production, and decrease in mitochondrial membrane potential, which results in the loss of proton gradient appearing as an uncoupling effect, which prevents ATP formation and promotes its hydrolysis [41]. Subsequently, the proton gradient utilizes the Ca2+ uptake and causes the matrix swelling as an approach of the MPTP to prevent the detrimental rise in Ca2+ in the mitochondrial matrix [134]. It is known that opening of MPTP for a short duration can proceed without affecting cell viability and can also contribute to cardioprotection through participating in pre ischemic conditioning and it later prevents the opening of MPTP pore during ischemic reperfusion preventing cell damage and the onset of heart failure [17]. Although the evidence to support its cardioprotective functions is majorly based on the pharmacology and genetic observation that avoided MPTP opening. It has been shown that the administration of cyclosporin A shows a cardioprotective effect by preventing MPTP opening in the mice model; however, the results are mixed for the large mammalian model [135].
As mentioned earlier an increase in the Ca2+ concentration contributes to the opening of the MPTP channel, it is also necessary to mention that the Ca2+ is essential for the key enzyme activation in the oxidation of the substrates that fuel the respiratory chain, followed by ATP formation. It is very unfortunate that despite the advancement in technologies we are still unable to determine the physiological and pathological concentration of Ca2+ in the mitochondrial matrix [136]. Nevertheless, the Ca2+ homeostasis is maintained within the mitochondrial matrix by the uptake of Ca2+ through uniporters and the release is catalyzed by Na+/Ca2+ exchanger. The understanding of the molecular nature of Ca2+ uniporter has advanced our knowledge about Ca2+ homeostasis. The deletion of mitochondrial calcium uniporter gene from the embryonic and adult mice has shown completely contradicting results and the reasons of which have not yet been fully understood. However, the results that appeared in adult mice fully support the role of calcium overload leading to MPTP opening and eventually cell death. This is further supported by the Na+/Ca2+/Li+ exchanger knockout mice which showed the overload of Ca2+ leading to MPTP opening on the onset of ischemic reperfusion leading to cell death. Therefore, the drugs that intend to target Ca2+ uniporter for therapeutics need to validate the contrast effects before large animal and clinical testing [137].
Connexin43(Cx43) is a well-known channel for the intercellular connections by forming the gap junctions, but apart from the plasma membrane occurrence, they are also known to be present in cellular organelle like subsarcolemmal mitochondria [138], nucleus [139], and exosomes [140]. Cx43 plays an important role in ischemic-reperfusion injury and its prevention. According to pharmacological evidence the concentration of Cx43 increases with the introduction of diazoxide DZX or fibroblast growth factor 2 to prevent myocardial injury, but this increase is not observed after the ischemic preconditioning protocol [141]. It also interacts with the mitochondrial potassium channel [141] and regulates nitric oxide formation. The role of Cx43 is certain in cardioprotection but the exact mechanism and function remain to be elucidated.
At last, the presence of several mitochondrial K+ channels and their activity in the failing heart presents them as a crucial target in the therapeutics of myocardial dysfunction. The K+ uptake and release play a central role in the maintenance of mitochondrial matrix volume. The electrophoretic influx of K+ is balanced by the K+/H+ antiporter [142]. Valinomycin triggers the uncontrolled K+ influx disturbing the mitochondrial polarization and causing the swelling of the matrix. The function of potassium channels is basically to maintain the matrix volume. Initially, surface K+ channel was suggested to play an essential role in ischemic pre and postconditioning but later when diazoxide (DXZ), which was involved in cardioprotection of non-contractable heart, did not show any effect on surface K+ channel, whereas drugs that were only targeting surface K+ did not show cardioprotective effect. On the contrary, the isolated mitochondria showed restored activity of ATP inhibited flux and showed inhibition caused by 5-hydroxydecanoate (5HD) [143]. This shifts the attention to the mitochondrial K channel for cardioprotection but ever since the DXZ and 5HD also affect mitochondrial physiology in general it requires the molecular structure information and in vivo attempts for concrete statements. The structural information will provide tools for determining its exact function in myocardial ischemia/reperfusion in a failing heart, Ca2+ transport and MPTP opening, and protein involved in ROS formation, followed by improving therapeutic approaches [144]. Similar to the ATP activated K+ channel, Ca2+ and voltage-activated channels are also pharmacologically proven to play a similar role as mitoKATP, the ischemic conditioning protocol triggers the formation of protein kinase C which is helpful in an increased opening mitoKCa channel.
The strategies used to protect the heart from opening MPTP and mitochondrial calcium uniporter pores and in the case of ischemia conditioning, the opening of mitoKATP and BKCa channel plays a vital role in the cardioprotection. CsA is a well-known desensitizer for MPTP, but it did not prove to be the best option in clinical trials [66]. CsA exerts its activity by binding to CyPD, but in cases of intense stimuli, the pore opening becomes independent of CyPD. Therefore, there is a need of developing more pharmacological agents that can directly inhibit the MPTP openings, but they require further information about the structural insight of the pore. Although CyPD activates pore opening the complete mechanism is still unclear. Similarly, although it is evident that ROS and Ca2+ influence the MPTP opening but without knowing the structural details of MPTP we fail to conclude how they do so.
Mitochondrial calcium regulates a range of myocyte functions alongside energy production like cell division and trophism. With the development of MCU structures over the years, they have emerged as a very important target for cardioprotection, but the development of a reliable drug is still in process. Potassium channels are also widely accepted as an important target and are closely linked to modulating the apoptotic process. This information is present due to the pharmacology of the channel openers and inhibitors. Very limited knowledge is present to show concrete evidence. The molecular structure can be helpful in understanding and curing several mitochondria-associated diseases.
The inhibition of MPTP channel opening and the mitoK channel both elicit the cardioprotection and are likely to be related. Uptake of K+ through mitoK decreased the mitochondrial membrane potential which reduces the mitochondrial Ca2+, which in turn decreases the possibility of MPTP opening. Along with ATP production, and ROS regulation, mitochondrial channels like MPTP, Ca2+ channel, and mitoK channels are established to play a crucial role in cardioprotection. The mechanism, however, for their connection and coordination with each other in the process of cardioprotection is far from conclusive.
Recent attempts to translate cardioprotective strategies that target some of these mitochondrial ion channels have been hugely disappointing, and the translational of these strategies in clinical settings have not been successful. Several drugs have been tested on various animal models that have shown certain cardioprotective mechanisms. However, the lack of knowledge about the underlying mechanism of protective actions needs a lot of following studies to design modulators specific for mitochondrial channels with regards to cardioprotection in human trials. In the light of studies available, we still have a long way to go in the depth of the cardioprotective mechanism.
Conclusively, heart failure is an outcome of cardiac injury that originated due to a variety of etiologies and denotes a complex clinical syndrome. Several mitochondrial channels associated mechanisms have been recognized that drive the depletion of cardiomyocytes before cell death. These observations not only provide a link of overall heart health with mitochondrial channel opening and closing but also inspires therapeutic approaches. The core molecular identity of some mitochondrial channels like MCU and mitoKATP are discovered recently, whereas most mitochondrial potassium channels are in their intermediate state. These channels act as switches to control the development of ischemic injury either towards recovery or the loss of viability. The progress towards understanding the molecular identity and mechanism of channel opening and inhibition will help to translate the experimental approaches into promising therapeutic development to combat a deadly health concern.
We thank Dr. Nileshkumar Dubey for his help with the figures. Figure 1 was created with Biorender.com.
The authors declare no conflict of interest.
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Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"64851",doi:"10.5772/intechopen.80348",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:14464,totalCrossrefCites:32,totalDimensionsCites:56,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ozioma Ezekwesili-Ofili",slug:"josephine-ozioma-ezekwesili-ofili",fullName:"Josephine Ozioma Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"54028",doi:"10.5772/67291",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7509,totalCrossrefCites:13,totalDimensionsCites:48,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]},{id:"58270",doi:"10.5772/intechopen.72437",title:"Toxicity and Safety Implications of Herbal Medicines Used in Africa",slug:"toxicity-and-safety-implications-of-herbal-medicines-used-in-africa",totalDownloads:3440,totalCrossrefCites:17,totalDimensionsCites:41,abstract:"The use of herbal medicines has seen a great upsurge globally. In developing countries, many patronize them largely due to cultural acceptability, availability and cost. In developed countries, they are used because they are natural and therefore assumed to be safer than allopathic medicines. In recent times, however, there has been a growing concern about their safety. This has created a situation of ambivalence in discussions regarding their use. Some medicinal plants are intrinsically toxic by virtue of their constituents and can cause adverse reactions if inappropriately used. Other factors such as herb-drug interactions, lack of adherence to good manufacturing practice (GMP), poor regulatory measures and adulteration may also lead to adverse events in their use. Many in vivo tests on aqueous extracts largely support the safety of herbal medicines, whereas most in vitro tests on isolated single cells mostly with extracts other than aqueous ones show contrary results and thus continue the debate on herbal medicine safety. It is expected that toxicity studies concerning herbal medicine should reflect their traditional use to allow for rational discussions regarding their safety for their beneficial use. While various attempts continue to establish the safety of various herbal medicines in man, their cautious and responsible use is required.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Merlin L.K. Mensah, Gustav Komlaga, Arnold D. Forkuo, Caleb\nFirempong, Alexander K. Anning and Rita A. Dickson",authors:[{id:"190435",title:"Dr.",name:"Caleb",middleName:null,surname:"Firempong",slug:"caleb-firempong",fullName:"Caleb Firempong"},{id:"212111",title:"Dr.",name:"Gustav",middleName:null,surname:"Komlaga",slug:"gustav-komlaga",fullName:"Gustav Komlaga"},{id:"217045",title:"Dr.",name:"Arnold Forkuo",middleName:null,surname:"Donkor",slug:"arnold-forkuo-donkor",fullName:"Arnold Forkuo Donkor"},{id:"217049",title:"Prof.",name:"Merlin Lincoln Kwao",middleName:null,surname:"Mensah",slug:"merlin-lincoln-kwao-mensah",fullName:"Merlin Lincoln Kwao Mensah"},{id:"217488",title:"Dr.",name:"Alexander K.",middleName:null,surname:"Anning",slug:"alexander-k.-anning",fullName:"Alexander K. Anning"},{id:"223959",title:"Prof.",name:"Akosua Rita",middleName:null,surname:"Dickson",slug:"akosua-rita-dickson",fullName:"Akosua Rita Dickson"}]},{id:"26489",doi:"10.5772/28224",title:"Alternative and Traditional Medicines Systems in Pakistan: History, Regulation, Trends, Usefulness, Challenges, Prospects and Limitations",slug:"alternative-and-traditional-medicines-systems-in-pakistan-history-regulation-trends-usefulness-chall",totalDownloads:9220,totalCrossrefCites:9,totalDimensionsCites:21,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Shahzad Hussain, Farnaz Malik, Nadeem Khalid, Muhammad Abdul Qayyum and Humayun Riaz",authors:[{id:"73162",title:"Dr.",name:"Shahzad",middleName:null,surname:"Hussain",slug:"shahzad-hussain",fullName:"Shahzad Hussain"},{id:"82266",title:"Dr.",name:"Farnaz",middleName:null,surname:"Malik",slug:"farnaz-malik",fullName:"Farnaz Malik"},{id:"124185",title:"Dr.",name:"Humayun",middleName:null,surname:"Riaz",slug:"humayun-riaz",fullName:"Humayun Riaz"},{id:"124186",title:"Mr.",name:"Muhammad Abdul",middleName:null,surname:"Qayyum",slug:"muhammad-abdul-qayyum",fullName:"Muhammad Abdul Qayyum"},{id:"125340",title:"Mr.",name:"Nadeem",middleName:null,surname:"Khalid",slug:"nadeem-khalid",fullName:"Nadeem Khalid"}]}],mostDownloadedChaptersLast30Days:[{id:"64851",title:"Herbal Medicines in African Traditional Medicine",slug:"herbal-medicines-in-african-traditional-medicine",totalDownloads:14512,totalCrossrefCites:33,totalDimensionsCites:58,abstract:"African traditional medicine is a form of holistic health care system organized into three levels of specialty, namely divination, spiritualism, and herbalism. The traditional healer provides health care services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Illness is regarded as having both natural and supernatural causes and thus must be treated by both physical and spiritual means, using divination, incantations, animal sacrifice, exorcism, and herbs. Herbal medicine is the cornerstone of traditional medicine but may include minerals and animal parts. The adjustment is ok, but may be replaced with –‘ Herbal medicine was once termed primitive by western medicine but through scientific investigations there is a better understanding of its therapeutic activities such that many pharmaceuticals have been modeled on phytochemicals derived from it. Major obstacles to the use of African medicinal plants are their poor quality control and safety. Traditional medical practices are still shrouded with much secrecy, with few reports or documentations of adverse reactions. However, the future of African traditional medicine is bright if viewed in the context of service provision, increase of health care coverage, economic potential, and poverty reduction. Formal recognition and integration of traditional medicine into conventional medicine will hold much promise for the future.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Ezekwesili-Ofili Josephine Ozioma and Okaka Antoinette Nwamaka\nChinwe",authors:[{id:"191264",title:"Prof.",name:"Josephine",middleName:"Ozioma",surname:"Ozioma Ezekwesili-Ofili",slug:"josephine-ozioma-ezekwesili-ofili",fullName:"Josephine Ozioma Ezekwesili-Ofili"},{id:"211585",title:"Prof.",name:"Antoinette",middleName:null,surname:"Okaka",slug:"antoinette-okaka",fullName:"Antoinette Okaka"}]},{id:"61866",title:"Plants Secondary Metabolites: The Key Drivers of the Pharmacological Actions of Medicinal Plants",slug:"plants-secondary-metabolites-the-key-drivers-of-the-pharmacological-actions-of-medicinal-plants",totalDownloads:9021,totalCrossrefCites:60,totalDimensionsCites:153,abstract:"The vast and versatile pharmacological effects of medicinal plants are basically dependent on their phytochemical constituents. Generally, the phytochemical constituents of plants fall into two categories based on their role in basic metabolic processes, namely primary and secondary metabolites. Primary plant metabolites are involved in basic life functions; therefore, they are more or less similar in all living cells. On the other hand, secondary plant metabolites are products of subsidiary pathways as the shikimic acid pathway. In the course of studying, the medicinal effect of herbals is oriented towards the secondary plant metabolites. Secondary plant metabolites played an important role in alleviating several aliments in the traditional medicine and folk uses. In modern medicine, they provided lead compounds for the production of medications for treating various diseases from migraine up to cancer. Secondary plant metabolites are classified according to their chemical structures into various classes. In this chapter, we will be presenting various classes of secondary plant metabolites, their distribution in different plant families and their important medicinal uses.",book:{id:"6302",slug:"herbal-medicine",title:"Herbal Medicine",fullTitle:"Herbal Medicine"},signatures:"Rehab A. Hussein and Amira A. El-Anssary",authors:[{id:"212117",title:"Dr.",name:"Rehab",middleName:null,surname:"Hussein",slug:"rehab-hussein",fullName:"Rehab Hussein"},{id:"221140",title:"Dr.",name:"Amira",middleName:null,surname:"El-Anssary",slug:"amira-el-anssary",fullName:"Amira El-Anssary"}]},{id:"77433",title:"Extraction of Bioactive Compounds from Medicinal Plants and Herbs",slug:"extraction-of-bioactive-compounds-from-medicinal-plants-and-herbs",totalDownloads:1428,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Human beings have relied on herbs and medicinal plants as sources of food and remedy from time immemorial. Bioactive compounds from plants are currently the subject of much research interest, but their extraction as part of phytochemical and/or biological investigations present specific challenges. Herbalists or scientists have developed many protocols of extraction of bioactive ingredients to ensure the effectiveness and the efficacy of crude drugs that were used to get relief from sickness. With the advent of new leads from plants such as morphine, quinine, taxol, artemisinin, and alkaloids from Voacanga species, a lot of attention is paid to the mode of extraction of active phytochemicals to limit the cost linked to the synthesis and isolation. Thus, the extraction of active compounds from plants needs appropriate extraction methods and techniques that provide bioactive ingredients-rich extracts and fractions. The extraction procedures, therefore, play a critical role in the yield, the nature of phytochemical content, etc. This chapter aims to present, describe, and compare extraction procedures of bioactive compounds from herbs and medicinal plants.",book:{id:"10356",slug:"natural-medicinal-plants",title:"Natural Medicinal Plants",fullTitle:"Natural Medicinal Plants"},signatures:"Fongang Fotsing Yannick Stéphane, Bankeu Kezetas Jean Jules, Gaber El-Saber Batiha, Iftikhar Ali and Lenta Ndjakou Bruno",authors:[{id:"224515",title:"Dr.",name:"Fongang Fotsing",middleName:null,surname:"Yannick Stéphane",slug:"fongang-fotsing-yannick-stephane",fullName:"Fongang Fotsing Yannick Stéphane"},{id:"227816",title:"Dr.",name:"Bankeu Kezetas",middleName:null,surname:"Jean Jules",slug:"bankeu-kezetas-jean-jules",fullName:"Bankeu Kezetas Jean Jules"},{id:"227817",title:"Prof.",name:"Lenta Ndjakou",middleName:null,surname:"Bruno",slug:"lenta-ndjakou-bruno",fullName:"Lenta Ndjakou Bruno"},{id:"349790",title:"Prof.",name:"Gaber",middleName:null,surname:"El-Saber Batiha",slug:"gaber-el-saber-batiha",fullName:"Gaber El-Saber Batiha"},{id:"357350",title:"Dr.",name:"Iftikhar",middleName:null,surname:"Ali",slug:"iftikhar-ali",fullName:"Iftikhar Ali"}]},{id:"26491",title:"Homeopathy: Treatment of Cancer with the Banerji Protocols",slug:"homeopathy-treatment-of-cancer-with-the-banerji-protocols",totalDownloads:54242,totalCrossrefCites:1,totalDimensionsCites:2,abstract:null,book:{id:"542",slug:"a-compendium-of-essays-on-alternative-therapy",title:"A Compendium of Essays on Alternative Therapy",fullTitle:"A Compendium of Essays on Alternative Therapy"},signatures:"Prasanta Banerji and Pratip Banerji",authors:[{id:"79939",title:"Dr",name:"Prasanta",middleName:null,surname:"Banerji",slug:"prasanta-banerji",fullName:"Prasanta Banerji"},{id:"79943",title:"Dr.",name:"Pratip",middleName:null,surname:"Banerji",slug:"pratip-banerji",fullName:"Pratip Banerji"}]},{id:"54028",title:"Chemical Composition and Biological Activities of Mentha Species",slug:"chemical-composition-and-biological-activities-of-mentha-species",totalDownloads:7515,totalCrossrefCites:13,totalDimensionsCites:50,abstract:"The genus Mentha L. (Lamiaceae) is distributed all over the world and can be found in many environments. Mentha species, one of the world’s oldest and most popular herbs, are widely used in cooking, in cosmetics, and as alternative or complementary therapy, mainly for the treatment of gastrointestinal disorders like flatulence, indigestion, nausea, vomiting, anorexia, and ulcerative colitis. Furthermore, it is well documented that the essential oil and extracts of Mentha species possess antimicrobial, fungicidal, antiviral, insecticidal, and antioxidant properties. The economic importance of mints is also evident; mint oil and its constituents and derivatives are used as flavoring agents throughout the world in food, pharmaceutical, herbal, perfumery, and flavoring industry. To provide a scientific basis for their traditional uses, several studies have been conducted to determine the chemical composition of mints and assess their biological activities. This chapter describes the therapeutic effects and uses of Mentha species and their constituents, particularly essential oils and phenolic compounds; some additional biological activities will also be considered.",book:{id:"5612",slug:"aromatic-and-medicinal-plants-back-to-nature",title:"Aromatic and Medicinal Plants",fullTitle:"Aromatic and Medicinal Plants - Back to Nature"},signatures:"Fatiha Brahmi, Madani Khodir, Chibane Mohamed and Duez Pierre",authors:[{id:"193281",title:"Dr.",name:"Fatiha",middleName:null,surname:"Brahmi",slug:"fatiha-brahmi",fullName:"Fatiha Brahmi"},{id:"199693",title:"Prof.",name:"Khodir",middleName:null,surname:"Madani",slug:"khodir-madani",fullName:"Khodir Madani"},{id:"199694",title:"Prof.",name:"Pierre",middleName:null,surname:"Duez",slug:"pierre-duez",fullName:"Pierre Duez"},{id:"203738",title:"Prof.",name:"Mohamed",middleName:null,surname:"Chibane",slug:"mohamed-chibane",fullName:"Mohamed Chibane"}]}],onlineFirstChaptersFilter:{topicId:"172",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517",scope:"Paralleling similar advances in the medical field, astounding advances occurred in Veterinary Medicine and Science in recent decades. These advances have helped foster better support for animal health, more humane animal production, and a better understanding of the physiology of endangered species to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging Human, Animal, and Environmental health, the holistic and integrative “One Health” concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle various animal-related medicine and sciences fields, providing thematic volumes consisting of high-quality significant research directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics, and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.",coverUrl:"https://cdn.intechopen.com/series/covers/13.jpg",latestPublicationDate:"August 7th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:6,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"306970",title:"Mr.",name:"Amin",middleName:null,surname:"Tamadon",slug:"amin-tamadon",fullName:"Amin Tamadon",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002oHR5wQAG/Profile_Picture_1623910304139",institutionString:null,institution:{name:"Bushehr University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón Poggi",slug:"juan-carlos-gardon-poggi",fullName:"Juan Carlos Gardón Poggi",profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",institutionString:null,institution:{name:"Valencia Catholic University Saint Vincent Martyr",institutionURL:null,country:{name:"Spain"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",institutionString:null,institution:{name:"Alexandria University",institutionURL:null,country:{name:"Egypt"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",institutionString:"Kafkas University",institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}}]},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. 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