Some selected medicinal plants used against neglected tropical diseases.
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\r\n\tSince they involve very small amounts of energy, high sound pressure levels are increasingly simpler and cheaper to emit. Noise is everywhere - it can be emitted as an energy waste by traffic or factories, but also by teenagers looking for loneliness in an overpopulated world.
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\r\n\tWhen the noise emission ends, it will not be possible to find its footprint in the environment, hence it is necessary to be in the right place at the right time to measure it. Moreover, having adequate instruments, updated protocols and trained personnel are mandatory to achieve that. Even then, decision makers must clearly understand the reported situation to decide the need and importance of taking further actions.
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\r\n\tThis book will address issues of noise in the city, in the neighborhood or at work, aspects about management and consequences of exposure to high sound pressure levels ranging from the auditory, extra-auditory and psychophysics effects to the addiction to noise and the loss of solidarity.
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\r\n\tThe book aims to provide a various points of view and analysis of cases regarding this omnipresent pollutant.
Cardiomyopathy induced by doxorubicin (DOX) is considered an extremely serious adverse effect of oncologic treatment. It is known that this disease significantly affects the quality of patients’ life who survived cancer, especially children. Since its discovery, several molecular mechanisms have been proposed to understand the pathogenesis of acute and chronic DOX-induced cardiotoxicity (DIC), including oxidative stress, iron metabolism, Ca2+ homeostasis dysregulation, sarcomeric structure alterations, gene expression modulation, and apoptosis. Based on these mechanisms, different strategies have been developed in order to protect the heart during cancer treatment, including the administration of iron-chelating antioxidants and adrenergic receptor agonists. However, the use of these drugs is limited due to their adverse side effects as well as the loss of beneficial cardiac effects years after the end of the treatment. Therefore, the development of new therapies has been a great challenge for the scientific community. In this context, a new emergent strategy is cell therapy. Considering that DOX causes cardiomyocyte death, the transplant of autologous cardiomyocytes obtained through the differentiation of human induced pluripotent stem cells (iPSC) is a viable option for cardiac repair and a promising therapeutic strategy for the treatment of cardiovascular diseases, including DIC.
\nDOX (also known as adriamycin) was isolated in the early 1960s from the pigment-producing bacterium Streptomyces peucetius var. caesius, along with daunorubicin (DAU, also known as daunomycin and rubidomycin), and belongs to the family of anthracyclines [1, 2, 3]. Until to now, DOX remains among the most largely prescribed and effective antineoplastic agents ever developed for the treatment of a variety of adult and pediatric cancers [3, 4, 5]. Whereas DAU has been used against acute lymphoblastic and myeloblastic leukemias, DOX has been used against breast cancer, soft tissue sarcomas, childhood tumors (e.g., Wilms’ tumor), leukemias, Hodgkin’s and non-Hodgkin’s lymphoma, and many other cancers [4, 5].
\nThe minor differences in the chemical structure between DOX and DAU are responsible for the different spectrums of activity of these drugs. The side chain of DOX terminates with primary alcohol, while that of DAU terminates with a methyl group [3, 6]. Unfortunately, in addition to its potent antitumor effect, the use of DOX has been hampered by conventional toxicities (hematopoietic suppression, nausea, vomiting, extravasation, and alopecia), development of resistant tumor cells or toxicity in healthy tissues, especially with serious cardiac toxicity manifested by congestive cardiomyopathy [4, 7]. Over time, more than 2000 analogs were developed in an attempt to reduce the adverse effects of DOX and DAU. However, few analogs have reached the stage of clinical development and approval, such as epirubicin (EPI) and idarubicin (IDA), with DOX- and DAU-like spectrums, respectively [6]. Despite the development of new components, replacing DOX does not eliminate the risk of developing cardiotoxicity [6, 7]. Thus, DOX continues to be considered as a first-line antineoplastic drug [7].
\nSince the late 1970s, DOX-induced cardiotoxicity (DIC) has been recognized as a complication of chemotherapy [5]. The first case report in the literature was that of a 23-year-old patient with osteosarcoma, who was treated for 9 months with DOX. One month after the end of treatment, the patient died due to development of congestive heart failure [8]. A second report describes the case of an 11-year-old patient, also with osteosarcoma, who died 9.5 years after the end of chemotherapy with DOX as a result of progressive heart failure with late severity [9]. In 1991, long-term cardiotoxic effects were identified in patients with acute lymphoid leukemia in childhood [10]. Patients with childhood cancer and those treated with DOX have a high risk of developing symptomatic cardiac events at an early stage, and this risk remains high within 30 years after treatment. In addition, it is estimated that one in eight DOX-treated patients will be afflicted with severe cardiac disease [11].
\nDIC manifests in several forms, ranging from asymptomatic electrocardiography (ECG)-changes to decompensated cardiomyopathy characterized by decreased left ventricular ejection fraction [4, 7]. According to their clinical manifestation, these cardiotoxic events can be classified into three types: (1) acute, occurring during or immediately after treatment; (2) early-onset chronic progressive cardiotoxicity, occurring within 1 year after exposure to chemotherapeutic treatment; and (3) late-onset chronic progressive cardiotoxicity, occurring 1 or more years after the end of treatment [11].
\nAcute cardiotoxicity is characterized by depression of myocardial contractility that may be reversible within 1 week when discontinuing the DOX treatment [12, 13]. In some patients, complications have already been described, such as hypotension; pericarditis; myocarditis; supraventricular, ventricular, or sinus (more common) tachycardia; ST-T wave changes; decrease in QRS complex; prolongation of QT interval; and increase in serum levels of brain natriuretic peptide and cardiac troponin [3, 12, 13, 14]. However, this type of cardiotoxicity is very rare and affects less than 1% of patients [12].
\nEarly-onset chronic progressive cardiotoxicity is characterized by systolic or diastolic ventricular dysfunction within 1 year after the completion of DOX treatment. It can be progressive and occurs in 5–35% of the cases [11, 14, 15]. In the majority of adult patients, early cardiotoxicity is related to the development of a chronic dilated cardiomyopathy, with a decrease in the mass and wall of left ventricle. In the pediatric patient, in addition to chronic dilated cardiomyopathy, restrictive cardiomyopathy characterized by increase in the wall stiffness of the left ventricle cavity may also occur in isolated moments [11, 12, 13]. The typical manifestation of these cardiomyopathies is the progressive reduction of the ejection fraction [13]. Other events, including severe electrical conduction changes, damage to cardiac valves, and/or depression of contractility may also be observed [15].
\nFinally, late-onset chronic progressive cardiotoxicity is characterized by cardiac dysfunction after a latency period of 1 or more years following the completion of DOX treatment [12, 13]. In this type of cardiotoxicity, there is a period during which the patient is asymptomatic (normal cardiac function). After that, chronic dilated and/or restrictive cardiomyopathy can be manifested with subsequent development of congestive heart failure. In this case, mortality rate is more than 50% [3, 12, 13, 15].
\nDespite almost 60 years of research, the mechanisms to explain DIC are not completely understood. It seems to be a multistep process, with different potential pathways involved that leads to cardiomyocyte death [11, 16, 17]. Until now, the main mechanisms that have been proposed by various research groups include oxidative stress, iron metabolism, Ca2+homeostasis dysregulation, sarcomeric structure alterations, gene expression modulation, and apoptosis [4, 13, 16, 17].
\nSince the discovery of DOX, oxidative stress is the most frequently proposed mechanism to explain the complex pathophysiology of DIC [3, 5, 16]. The myocardium injury evidenced by lipid peroxidation occurs as a result of the increase of the reactive oxygen species (ROS) production, including superoxide (O2−˙) and hydroxyl radicals (OH˙) as well as other non-radicals such as hydrogen peroxide (H2O2), singlet oxygen (O2), etc. [3, 4, 11, 17, 18]. Unlike other tissues, the heart is extremely prone to oxidative damage, at least in part, due to lower levels of antioxidant enzymes such as peroxidase, catalase, and superoxide dismutase. In addition, the chemical structure of DOX contains quinone groups that can be reduced to a semiquinone, an unstable metabolite which can react with molecular oxygen (an electron acceptor) and rapidly revert to the parent compound. This redox cycle leads to the formation of superoxide anion radicals within mitochondria, causing cardiotoxicity [11, 16, 17, 18, 19, 20].
\nThe mitochondria have been identified as the main subcellular organelles injured in the heart by DIC [4, 17]. DOX is a cationic drug that binds with high affinity to cardiolipin (a phospholipid) forming nearly irreversible complex in the mitochondrial inner membrane [17, 21]. It is important to know that cardiolipin is required for the proper functioning of the electron-transport chain proteins. In this context, evidence suggests that DOX disrupts the cardiolipin-protein interface, causing more superoxide anion radicals formation [4, 22]. As a result, ROS can induce different forms of cardiomyocyte death (apoptosis or necrosis) [17]. Furthermore, the reduction of mitochondrial function causes energetic metabolism change evidenced by a decrease of the adenosine triphosphate (ATP) production, which may contribute to abnormal contraction and relaxation in the failing heart [4, 11, 23].
\nOther forms of DOX-induced ROS generation in the myocardium include nitric oxide synthases (NOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases pathways. These enzymes interact with DOX and induce oxidative stress [4, 16, 17].
\nNOS are a group of enzymes responsible for the nitric oxide (NO) production from L-arginine and oxygen [24]. The NO generation is altered by the direct binding of DOX to endothelial NOS (eNOS) reductase domain, leading to the reduction of the DOX semiquinone radical, which reacts with oxygen and produces superoxide. There is evidence to suggest that, in low DOX concentrations, eNOS signaling is the main pathway for DOX reduction. In addition, the increase of DOX-eNOS interaction completely modifies normal functioning of the enzyme (NO production) and transforms it into a potent superoxide generator [25]. DOX also affects NOS signaling by increasing eNOS transcription and protein activity in bovine aortic endothelial cells (BAEC). In this study, BAEC were pretreated with eNOS antisense oligonucleotides or antioxidants and the results showed apoptosis decrease [26]. Recently, an in vivo study has shown that the pretreatment with folic acid (FA, a modulator of eNOS) prevented DOX-induced increases in superoxide anion and attenuated DOX-induced decreases in superoxide dismutase, eNOS phosphorylation, and NO production [27]. Another study showed a decrease in ROS generation, preservation of cardiac function, and reduction of mortality rate after acute and chronic DOX administration in the eNOS knock-out (eNOS−/−) mice model, whereas cardiomyocyte-specific eNOS overexpression intensified the pathological response to DOX in the heart [28]. In all, these studies demonstrate the importance of eNOS signaling in DIC.
\nRecent evidence suggests that the other isoform called inducible NOS (iNOS) is also involved with DOX-induced oxidative stress. In some studies, iNOS transcription and expression are increased in mouse and rat hearts and isolated cardiomyocyte after DOX treatment [29, 30, 31]. In iNOS knock-out (iNOS−/−) mice model, cell death and nitrotyrosine (NT) formation induced by DOX were mitigated. The same results were observed when selective iNOS inhibitors such as S,S˙-[1,3-phenylene-bis(1,2-ethanediyl)]bis-isothiourea (1,3-PB-ITU) and L-N6-(1-iminorthyl)-lysine (L-NIL) were administered. In this study, DIC occurs due to the generation of peroxynitrite, a potent oxidant which generates secondary free radicals, including nitrogen dioxide and carbonate radical [30]. It is possible that the reduction of the peroxynitrite production using specific antioxidant(s) is a viable strategy for the decrease of DIC. In support of this view, the significant increase of superoxide radical and peroxynitrite induced by DOX observed in isolated cardiomyocytes was blunted after treatment with vitamin C (Vit C). These results suggest that Vit C provides cardioprotection by reduction of oxidative/nitrosative stress [31]. Altogether, these works thus also highlight the importance of iNOS signaling in DIC.
\nThe activity of the third isoform, neuronal NOS (nNOS), in DOX-induced oxidative stress is poorly understood. It appears that the flavin domain is involved with DOX reduction [32]. Nevertheless, no changes were observed in nNOS transcription and protein activity after the treatment of DOX [30]. Therefore, further studies will be needed to elucidate the role of NOS isoforms as well as the therapeutic potential of their pharmacological targeting in DOX-dependent heart disease.
\nIn relation to NADPH oxidases, also known as NOXs, recent work has identified these enzymes as important sources of myocardial ROS [33]. NADPH oxidase is a multicomponent complex that consists of membrane-bound cytochrome b-558, which is a heterodimer of gp91phox and p22phox, cytosolic regulatory subunits p47phox and p67phox, and the small GTP-binding protein Rac1 [34]. These enzymes mediate the transfer of one electron from NADPH to quinone DOX, leading to DOX semiquinone radical. As result, they can produce superoxide similar to NOSs. The semiquinone radical also reacts with hydrogen peroxide generating hydroxyl radicals [35]. An in vitro study using NADPH oxidase inhibitors (diphenyliodonium and apocynin) on H9c2 cells showed that DOX-induced apoptosis was mitigated, demonstrating NADPH oxidase is also involved in the development of cardiac toxicity induced by DOX [36]. Furthermore, there is accumulating evidence to support an important role for Nox2 NADPH oxidase (one of the seven different NADPH oxidase isoforms) in DIC, identified using Nox2-deficient (Nox2−/−) or gp91phox knock-out (gp91−/−) mice [33, 37, 38, 39]. DOX-induced cardiomyocyte apoptosis and atrophy, interstitial fibrosis, leukocyte infiltration, and cardiac dysfunction in wild-type (WT) mice were attenuated in Nox2−/− mice [33, 39]. DOX-induced superoxide production was also mitigated in this animal model [39].
\nRecently, Rac1 has been reported to be a key regulator of oxidative stress due to its ability to bind and activate the NADPH oxidases [34]. In this context, a study showed that the deletion of Rac1 (a subunit of the NADPH oxidases complex) in cardiomyocytes impairs DOX-induced NADPH oxidases activation, ROS generation, DNA fragmentation and apoptosis, and improves cardiac function [40]. The same results were observed when NSC23766, a RAC inhibitor, was administered. In contrast, the overexpression of Rac1 exacerbated DIC [41]. Therefore, Rac is extremely important for the regulation of DIC by NADPH oxidase/ROS-dependent pathway.
\nPatient’s genetic susceptibility is another factor that has been considered extremely important for the understanding of NADPH oxidases-dependent cardiotoxicity. Single-nucleotide polymorphisms (SNPs) in one of the subunits of the NADPH oxidases complex have been identified in non-Hodgkin lymphoma patients. After the treatment with DOX, these patients developed acute arrhythmias and congestive heart failure. For example, the presence of SNP variants in NADPH oxidase subunit NCF4 and in the p22phox and Rac2 subunits were linked with the development of chronic and acute DIC, respectively [36]. Thus, detection of the genetic polymorphisms in NADPH oxidases complex may help to identify patients who have higher risk to develop DIC.
\nIt is reported that DOX is able to alter iron metabolism due to its strong affinity for this metal, thereby forming iron-DOX complexes which, in turn, react with oxygen and trigger ROS production [42]. Thus, the researchers believed that only oxidative stress was responsible for the cardiotoxicity induced by iron-DOX complexes. However, in physiological conditions, there would not be enough free iron to interact with DOX to the extent necessary to cause cardiomyopathy [6]. On the other hand, another theory suggests that the effect of DOX on iron metabolism occurs due to the interference of this drug in the activity of proteins that transport and bind intracellular iron. For example, one of the mechanisms involves the doxorubicinol (DOXol), a metabolite of DOX, which removes iron from the catalytic Fe-S cluster of the cytoplasmic aconitase (also called iron regulatory protein 1; IRP-1), converting this enzyme to a null protein. Consequently, there is an increase in the stability of transferrin mRNA and preventing translation of iron sequestration proteins. As a result, reduction of IRP-1 causes an increase in free iron, which can lead to free radical production [43, 44]. Furthermore, a recent work reports that DOX can also interact with iron-responsive elements (IREs) of the ferritin heavy and light chains. It is known that ferritin operates as an iron transporter, reducing free iron within the cell. Accordingly, disruption of this protein eventually results in increased free iron, which in turn causes myocardium injury [45]. Another work showed iron-overload, mitochondrial damage, and mortality after DOX treatment in mice depleted of the iron regulatory gene HFE (also known as human hemochromatosis protein). The HFE protein is responsible for the regulation of circulating iron uptake [46]. Therefore, free iron accumulation within the myocardium after DOX treatment seems to be the major determinant of DIC [20].
\nIt is important to recognize that patients undergoing chemotherapy are submitted blood transfusions and iron supplementation due to abnormal losses and nutritional status deficient, respectively. The fact is that these procedures modify body iron stores. In addition, adult and pediatric patients with leukemia can develop a significant level of iron-overload during, and as result of, chemotherapy [46]. Thus, it is possible that the reduction of iron levels is an effective strategy to prevent DOX-induced cardiomyopathy.
\nThe precise control of calcium levels during the contraction-relation cycle in cardiomyocytes is extremely important for normal beat-to-beat contractile activity [47]. Unfortunately, many studies suggest that calcium homeostasis dysregulation has a major role in the pathogenesis of DIC. To date, severe mechanisms have been proposed that are responsible for an increase in calcium intracellular concentrations [4, 16]. One of the mechanisms is related to DOX metabolism, which generates a toxic metabolite, DOXol, through a reduction of its carbonyl group, capable of inhibiting the sodium-calcium exchanger channel [48]. The sodium/potassium pump of the sarcolemma is also affected by DOXol, which disrupts the sodium gradient needed for calcium to flow into the sarcolemma of a cardiomyocyte [49]. Consequently, there is an imbalance in the energetics of the myocardium and diminished systolic function [48]. Furthermore, it is reported that this secondary metabolite is more difficult to eliminate from the cardiomyocyte than the parent drug [50]. Thus, DOXol accumulation contributes significantly to the dysregulation of calcium homeostasis, leading to myocardial damage.
\nMoreover, normal calcium homeostasis is altered by ROS and hydrogen peroxide via disruption of normal sarcoplasmic reticulum function. This is accomplished by inhibiting the Ca2+-ATPase pumps, caused by reducing the expression of SERCA2a mRNA levels and/or the direct activation of the ryanodine calcium-release channels themselves [51, 52]. In addition, a study suggests that DOX induces calcium release from the sarcoplasmic reticulum due to increasing the frequency of opening of these channels [52]. At the same time, DOX induced the inhibition of sodium-calcium channels in the plasma membrane as well as increased L-type calcium channel activation [53, 54]. DOX has also been shown to decrease the calcium storage capacity of mitochondria by specifically activating the selective CsA-sensitive calcium channel, exacerbating the calcium-overload [49]. As result, an increase of calcium cytoplasmic concentrations occurs, leading to mitochondrial dysfunction and apoptosis [55]. Therefore, the preservation of calcium homeostasis is essential to prevent DOX-induced cardiomyopathy.
\nDIC is also accompanied by disarray and loss of myofilaments of the sarcomere. Titin is a giant protein and a key component of the cardiac sarcomeres, extending from the M-line to the Z-disk. This protein has multiple functions, from structural to regulatory [56]. Recent studies have shown that the loss of integrity or function of titin is directly related to the development of dilated cardiomyopathy [57, 58]. It is known that DOX induces rapid degradation of titin through the activation of proteolytic pathways, leading to an imbalance in the energetics of the myocardium. Furthermore, studies have shown that the degradation of titin also occurs by the activation of calpains (calcium-dependent proteases) and reported that the inhibition of this protein is responsible for preserving cardiac function after DOX treatment [59]. Another study showed that the depletion of the cardiac ankyrin repeat protein (CARP), which are important in negative regulation of cardiac genes expression, leads to marked sarcomeric disarray [60]. Taken together, these studies thus also highlight the importance of sarcomeric structure stability to prevent DIC. It is necessary to recognize that other proteins are essential for sarcomeric cytoskeleton such as α-actinin, myomesin, and nebulin, and further studies should be performed to verify the DOX effect on these proteins.
\nSome studies suggest that DOX down-regulates cardiac muscle-specific proteins such as contractile proteins, mitochondrial proteins, sarcoplasmic reticulum proteins, and others. Suppression of the cardiac muscle gene is associated with abnormal contraction and relaxation observed after DOX treatment [3, 11]. Another study showed that DOX induces depletion of GATA-4, leading commitment of the regulation of sarcomeric proteins expression such as myosin heavy chain and troponin I [61, 62]. In addition, suppression of GATA-4 induced by DOX is also related to the induction of apoptosis, suggesting the essential role of GATA-4 in cell survival [63, 64]. Regarding mitochondrial proteins, there is evidence that the suppression of these proteins after DOX treatment results in disruption of myocardial energy production, thereby causing cardiac dysfunction [3].
\nOn the other hand, DOX induces upregulation of endothelin-1 (ET-1) and its receptors’ expression [65, 66]. An in vivo study has shown that DOX-induced cardiotoxicity was reduced when mice were pretreated with the combined endothelin A/B antagonist (bosentan). In addition, the authors suggest that the reduction of TNF-α and BAX expression, lipid peroxidation, and increased expression of GATA-4 are responsible for cardioprotective effects observed in this study [67]. However, it is unclear if combined blocking of endothelin A/B receptors is necessary or whether selective inhibition of one of the ET-1 receptors is sufficient for the observed cardioprotection. In this context, a recent study evaluated the effects of dual (bosentan) and single endothelin receptor antagonism through sitaxentan (receptor A blocker) or BQ788 (receptor B blocker). The results demonstrated more beneficial effects of cardiac function when both receptors were blocked [66]. Taken together, these data support a substantial role of endothelin-1 signaling as a mediator of DIC.
\nDOX can induce apoptosis through different mechanisms, which have been extensively studied in both acute and chronic cardiotoxicity. As mentioned in this chapter, one pathway involves ROS production and oxidative mechanisms and it is accepted that both the extrinsic and intrinsic apoptotic pathways are involved [17]. Increased oxidative stress has been shown to promote apoptosis and antioxidants have been shown to inhibit this process [7]. Oxidative stress also is known to activate apoptosis-signal regulating kinase-1 (ASK1), which activates the c-Jun NH2-terminal kinase (JNK) and p38 MAPK pathways to induce apoptosis [68]. In addition, it is reported that transcription factor NF-κB activated by ROS in DOX-treated neonatal rat cardiomyocytes and myocardium exerts a proapoptotic effect via direct activation of apoptotic genes, including FasL, Fas, c-Myc, and p53 [69, 70, 71]. The activation of p53 by superoxide and hydrogen peroxide activates Bax genes, causing apoptosis [72, 73]. At the same time, evidence indicates that there is also an increase in the production of proapoptotic proteins as a result of p53 stabilization through increased heat shock protein (Hsp)25 production due to the activation of heat shock factor 1 (HSF-1), which is induced by DOX-dependent oxidative stress. In contrast, several studies suggest that Hsp proteins, such as Hsp27, Hsp10, Hsp20, and Hsp60, are involved in the prevention of DOX-induced apoptosis and myocardial dysfunction [74, 75]. Overexpression of Hsp27 plays a beneficial role in the regulation of oxidative stress responses and maintenance of mitochondrial function [74]. Regarding Hsp10 and Hsp60, overexpression of these proteins is associated with an increase in the post-translational modification of Bcl-2 proteins, which are important for the activation of anti-apoptotic pathways [75]. In addition, it is reported that overexpression of Hsp20 inhibits DOX-triggered cardiac injury, and these beneficial effects appear to be dependent on protein kinase B (also known as Akt) activation [76]. Therefore, more studies should be performed to understand the anti- and/or proapoptotic signaling pathways activated by Hsp proteins and their relationship to DOX.
\nRecently, an in vitro study using cardiomyocytes derived from human induced pluripotent stem cells (CM-iPSC) showed that DOX significantly upregulated the expression of death receptors (DRs) (TNFR1, Fas, DR4, and DR5) at both protein and mRNA levels. This study also showed that spontaneous apoptosis is exacerbated by death ligands including TNF-related apoptosis inducing ligand (TRAIL) [77]. Another study reported that Toll-like receptor-2 (TLR-2) functions as a novel “death receptor” that employs the apoptotic apparatus such as FADD and caspase 8 without a conventional cytoplasmic death domain. In this study, the authors observed reduction of apoptosis in myocardium after DOX treatment in TLR-2-knock-out mice (TLR-2−/−) when compared to wild-type mice [78]. These results demonstrate that the induction of death receptors in cardiomyocytes is probably another mechanism by which DOX causes cardiotoxicity.
\nDOX is also appearing to influence caspase activity. Using both rat primary cultured cardiomyocytes and rat hearts from an animal model, the study demonstrated that DOX treatment induces apoptosis through the activation of caspase-3 activity [79]. In addition, another study showed that caspase-3 can be activated after Akt and Bad phosphorylation caused by DOX-induced upregulation of Ser/Thr PP1 phosphatase [76]. In support of this view, in TLR-2-knock-out mice, DOX-induced caspase-3 activity was decreased and this effect is a result of inhibition of NF-κB activation and reduction of proinflammatory cytokine [78, 80]. In all, these data demonstrated the need to understand the molecular signaling pathways that mediate DOX-induced cardiomyocyte apoptosis. This knowledge is extremely important for the advancement and development of new approaches for the treatment and/or prevention of DIC.
\nSeveral studies indicate DIC is associated with modulation of microRNAs due to their role in all cardiac functions, including conductance of electrical signals, heart muscle contraction, and growth [81]. It is reported that a group of microRNAs, such as miR-34a, miR-34c, miR-208b, miR-215, miR-216b, and miR-367 are upregulated in the rat heart when increasing doses of DOX are administered. In this same condition, there is evidence that miR-21, miR-34a, miR-208a, miR-208b, miR-221, miR-222, and miR-320a are upregulated in mice myocardium [81, 82]. On the other hand, other microRNAs including Let-7 g, miR-30a, miR-30c, and miR-30e are downregulated in rat myocardium after DOX treatment, confirming the role of DOX in the modulation of microRNAs [81].
\nRecently, the effects of DOX on the expression of miR-21 were examined in rat H9C9 cardiomyocytes. This study showed that overexpression of miR-21 attenuated DOX-induced apoptosis, whereas knocking down its expression increased DOX-induced apoptosis. In addition, the authors suggest that miR-21 protects cardiomyocytes by modulating the anti-proliferative factor, B cell translocation gene 2 (BTG2) [83]. Furthermore, the effects of DOX on expression of miR-208a were investigated in Balb/C mice hearts. In this study, DOX significantly upregulated miR-208a, downregulated GATA4, and increased myocyte apoptosis. In contrast, therapeutic silencing of miR-208a recovered GATA4 and BCL-2 and decreased apoptosis [84]. DOX also induced overexpression of miR-146a, which are responsible for downregulating ErB2 receptor tyrosine kinase 4 (ErB4), a key component of neuregulin-1-ErbB signaling, resulting in apoptosis in cardiomyocytes [85].
\nIn turn, a recent study demonstrated that the miR-30 family, which is downregulated by DOX, is involved in the modulating of β-adrenergic and mitochondrial apoptotic pathways. In this study, the authors identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. Moreover, they showed that overexpression of miR-30 protects cardiomyocytes from DOX-induced apoptosis [86]. Therefore, these data highlight the importance of modulating microRNA expression as well as providing a novel therapeutic approach to DIC prevention.
\nSince several mechanisms are involved in the development of cardiac toxicity, different strategies are being performed to prevent DOX-induced cardiomyopathy. One of these strategies is the use of dexrazoxane (also known as ICRF-187), an adjunctive agent derivative of ethylenediaminetetraacetic acid (EDTA), which acts as a free radical scavenger. In this case, dexrazoxane is an EDTA-like chelator that interferes with iron-mediated oxygen free radical generation and, consequently, lipid peroxidation [87, 88]. The beneficial effects of dexrazoxane have been demonstrated in murine [89, 90] and canine [91, 92] models. Further, a meta-analysis of six randomized trials that included 1013 adult and pediatric patients demonstrated significantly reduced incidence of heart failure after dexrazoxane treatment, confirming its beneficial effects [93]. In addition, cardioprotective effects have been observed in children with high-risk acute lymphoblastic leukemia (ALL) receiving chronic DOX (10 doses of 30 mg/m2) [94, 95]. The studies concluded that treatment with dexrazoxane is justified individually when the risk of cardiac dysfunction is expectedly high [87]. Unfortunately, according to the current Food Drug Administration (FDA) approval statement and European Medicines Agency (EMA), the use of this drug as a cardioprotective is limited to women with metastatic breast cancer who have received cumulative doses of 300 mg/m2 DOX [95, 96].
\nAnother strategy that has been evaluated is the use of angiotensin-converting enzyme (ACE) inhibitors, including enalapril, zofenopril, and lisinopril. ACE inhibitors are commonly used in patients with heart failure as afterload-reducing agents. In addition to their features as an effective ACE inhibitor, these drugs act as antioxidant and, thus, may contribute to prevent cardiac toxicity [97]. In support of this view, recent preclinical study demonstrated that administration of enalapril attenuated DOX-induced cardiac dysfunction via preservation of mitochondrial respiratory efficiency and reduction in DOX-associated free radical generation [98]. Unluckily, in long-term survivors of childhood cancer treated with DOX, the beneficial effect of enalapril-induced improvement in left ventricle structure and function was lost after 6 or 10 years. It is important to mention that ACE inhibitors have adverse side effects and, therefore, the choice of this drug as a cardioprotective agent during cancer treatment should be carefully evaluated [99].
\nAnother antioxidant that has already been tested against DOX-induced cardiomyopathy is vitamin E. A study has shown that vitamin E only prevents the acute effects of DOX cardiotoxicity in mice [100]. Several other antioxidants also have been tested with limited success, including vitamin C, reduced glutathione, selenorganic compound PZ51, oleanolic and ursolic acids, and ambroxol [101, 102, 103, 104, 105]. On the other hand, probucol, a lipid-lowering agent and potent antioxidant, provided complete protection against DOX-induced cardiomyopathy and heart failure in animal experiments without interfering with the antitumor properties of this antibiotic [106, 107]. In this case, it is extremely important that clinical trials using DOX therapy in combination with probucol are performed to determine a new preventive cardiotoxicity strategy. This approach was recently tested using a β-adrenergic receptor blocker and also an antioxidant agent called carvedilol. As result, this drug protected systolic functions of the left ventricle due to reducing DIC [108]. Therefore, the use of carvedilol may become a promising strategy to improve DIC. However, more studies are needed to assess whether the beneficial effect observed on cardiac function is preserved over the years.
\nIn addition to the antioxidant agents, accumulating evidence indicates that cardiac α1-adrenergic receptors (α1-ARs) protect cardiomyocytes from DIC. In particular, the stimulation of α1-AR-specific agonists phenylephrine (PE) and dabuzalgron have been shown to reduce apoptosis, interstitial fibrosis, and myocardial dysfunction caused by DOX. This protective effect is associated, at least in part, with the expression of anti-apoptotic proteins of the Bcl2 family and preservation of mitochondrial function [64, 109]. Thus, further studies will be needed to elucidate the full mechanisms responsible for the cardioprotective effects observed up to now.
\nAlthough therapeutic strategies to prevent cardiomyopathy have been proposed for more than four decades, it is important to highlight that there is still no specific treatment for total recovery of the myocardial injury caused by DOX. In this case, cardiac transplantation remains a vital option for patients with end-stage heart failure due to DOX-induced cardiomyopathy [3]. However, the major problem is the long time of wait in the queue of transplant due to low donor/acceptor ratio. Statistical data show that 10–20% of the patients in the waiting queue come to death annually [110].
\nIn this scenario, in which therapeutic options for DOX-induced cardiomyopathy are insufficient, a newly emerging strategy is cell therapy. The principle of cell therapy is to restore the function of an organ or tissue by transplanting new cells [111]. In this context, a study has shown that transplanted mouse embryonic stem cell (ESC) in DOX-induced cardiomyopathy mice model attenuated various pathological mechanisms such as: (1) cardiomyocyte apoptosis due to inhibition of phosphoinositol-3-kinase (PI3K)/Akt and ERK pathway; (2) cardiac fibrosis; (3) cytoplasmic vacuolization; and (4) myofibrillar loss [112]. Although beneficial effects have been observed in this study, the teratogenic potential of these cells represents serious limitation to their use [113, 114]. In fact, experimental models of myocardial infarction have demonstrated the formation of teratomas after the transplantation of undifferentiated ESC [115, 116]. Thus, to overcome this limitation, several studies suggest the use of already differentiated ESC in cardiomyocytes [116, 117].
\nConsidering that DOX causes cardiomyocyte death through the activation of different molecular and pathophysiological mechanisms, this therapeutic approach seems to be promissory for future application against DIC. In support of this view, recently, our research group has shown that the transplant of cardiomyocytes derived from mouse ESC (CM-mESC) improved cardiac function and electrical activity of the mice hearts with DIC, as well as reduced the percentage of cardiomyocyte apoptosis [118].
\nFor clinical research, cardiomyocytes derived from human induced pluripotent stem cells (CM-iPSC) are potential cell sources for cardiomyocyte transplantation therapy. The generation of induced pluripotent stem cells (iPSC) from human somatic cells through overexpression of four transcription factors (OCT4, SOX2, c-Myc, and KLF4) represented a scientific milestone opening new perspectives for treatment of heart diseases. In addition to showing the same characteristics of ECS and, thus, the ability to differentiate into cardiomyocytes, these cells are not associated with immune rejection [119, 120].
\nCurrently, the great challenge for the scientific community is the development of pro-maturation strategies to obtain human adult cardiomyocytes in vitro, with ventricular-like phenotype based on action potential, genetic, morphological, and metabolic characteristics [121]. Once maturation is achieved, CM-iPSC are a viable option as an autologous cell source for cardiac repair and a powerful tool for treatment of cardiovascular diseases, including DIC.
\nDIC is an important public health concern given the fact that this disease may not to be detected for many years and remains a life-long threat. Mechanisms contributing to the development of cardiomyopathy involve (1) free radical generation; (2) alteration in iron metabolism through iron-DOX complex formation or interference in the proteins’ activity that transport and bind intracellular iron; (3) increased calcium intracellular concentrations; (4) disarray and loss of myofilaments of the sarcomere; (5) gene expression modulation; (6) activation of apoptosis by different signaling pathways; and (7) modulating microRNA expression. Based on these mechanisms, a variety of strategies to prevent cardiotoxicity have been tried, including the use of iron-chelating antioxidants and adrenergic receptor agonists. However, so far, the ability of these treatments to protect the heart from DOX-induced damage has been limited. Since DOX causes cardiomyocyte death, one recent approach that has shown promise is the transplant of CM-iPSC. In this context, the scientific community has been engaged in the establishment of pro-maturation protocols to obtain adult human cardiomyocytes in vitro. Once this challenge has been overcome, we believe that cell therapy with CM-iPSC may be a promising strategy for the development of effective therapy against DIC.
\nThe authors declare that they have no conflict of interest.
The origin of medicinal plants use had been since time immemorial and traced back to Europe, Egypt, etc. many centuries ago [1]. The first records of knowledge documentation were, however, produced by Shen Nung (a Chinese emperor) 2500 BC ago, describing different recipes of drug preparation from more than 300 medicinal plants for the management of numerous human diseases. Records had it that the use of plants (herbs) as medicine started gaining momentum around 500 BC, though prior to this period, their use was not limited to healing but believed to possess spiritual (ritual) power as well until the advent of scientific era particularly around 1960s when much relevance was played on development of synthetic products based on assumption that they are safer and come with little side effects [2]. Despite the aforementioned, the last two decades witnessed a drastic revival in the use and acceptance of phytomedicine by a majority of the people from developing nations (70–90%) as a major source of primary health care. This was also buttressed by WHO’s submission, encouraging the discovery and development of lead drugs from plant-based formulations and/or medicines which are believed to be effective and safe [2]. In fact, the development of morphine, quinine, reserpine, ephedrine, etc., from Papaver somniferum, Cinchona spp., and Rauwolfia serpentina as first set of drugs from medicinal plants brought much popularity and attested to their acceptance and potential use across different parts of the globe especially from Europe and Egypt, with records of well over 900 drugs compiled in history by chain of scientists such as Discorides and Galen [3]. Moreover, it suffices to submit that China is the only country with complete catalog of phytomedicine [2].
Mankind relies on plants and/or its extract, an integral part of traditional medicine (TM) which as a matter of fact is the origin for medical medicine. The knowledge of TM particularly in issues relating to the health of both humans and animals has continued to emerge in many nations of the world. Despite the unproven quality, safety, and efficacy, they are becoming the major source of health care for 80% of the entire population in both developed and developing countries (such as USA, China, India) in disease control, prevention, and management [4]. Interestingly, TM or phytotherapy (traditional system of health care) in the last two decades is being adopted by every region based on the specific sociocultural context illustrating the way medicinal plants (MP) or the inherent secondary metabolites are used, as well as their disparity in the approach to health and diseases. This TM varies from one community to another and notable among them are Acupuncture (Chinese), Ayurveda (Indian), Kampo (Japanese), Unani (Arabian), Basotho (among Africans), etc., some or majority of which had been in existence many centuries even before the advent of modern medicine.
Similarly, the reliance on plants by humankind is not only limited to medicine but also to other basic needs such as food, clothing, and shelter, all produced or manufactured from plant matrices (leaves, woods, and fibers) and storage parts (fruits and tubers) [5]. Medicinally, plant harbors chemicals referred to as the secondary metabolites, which are derived biosynthetically from plant primary metabolites (e.g., carbohydrates, amino acids, and lipids) though might not be directly involved in the growth, development, or reproduction of plants [6]. These secondary metabolites can be classified into several groups depending on their chemical classes [7].
Secondary metabolites are organic compound produced and found in all plant tissues to drive metabolic activities, as well as providing self-defense against herbivore and any form of environmental toxicity [8]. Plant is a well-known source of medicinal product for both traditional and modern medicines for the treatment and management of human illnesses. The usage of the plant in this regard is attributed to the presence of secondary metabolites [9]. Apart from the fact that they are widely used in medicine, they are also employed industrially in the production and manufacturing of dyes, drugs, polymers, waxes, glues, fibers, antibiotics, herbicides, insecticides, cosmetics, etc. [10]. In general, secondary metabolites found in plants can be categorized into three major groups including terpenes (cardiac glycosides, carotenoids, and sterols), phenolics (flavonoids and nonflavonoids), and nitrogen-based compounds (alkaloids and glucosinolates).
Terpenes are the largest and highly diversified class of secondary metabolites derived as a result of polymerization of isoprenoid unit of five carbon compounds [11]. Based on the five carbon compound used as its building block, it can be subdivided into monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, polyterpenes, and steroids whose precursor is triterpenes. The therapeutic significance of terpenoids from different plants has been reported, e.g., terpenes from eucalyptus oil is known for its antidiabetic property [11], ursolic acid from Rosmarinus officinalis and β-sesquiphellandrene from Piper guineense are known to be psychoprotective [12]. Antibacterial and antifungal potential of terpenoids derived from Pilgerodendron uviferum, Picea abies and other plant sources have also been reported [13, 14, 15]. Furthermore, a steroidal terpenoids called glycyrrhizic acid elicited anti-inflammatory activity [8].
The phenolics are secondary metabolites that are produced in the shikimic acid pathway of plants involving pentose phosphate through phenylpropanoid metabolization of at least one aromatic ring of hydrocarbon attached to one or more hydroxyl groups [10, 16]. Phenolics are generally categorized into two based on their structure, namely, flavonoids and nonflavonoids. Structurally, flavonoids are derived from two aromatic rings linked to a bridge consisting of three carbons (C6▬C3▬C6) and are sub-divided into six main categories, including flavonols, flavones, flavanones, flavan-3-ols, isoflavones, and anthocyanins. However, the nonflavonoids are subdivided into five main categories, including hydroxybenzoates, hydroxycinnamates, lignans, and stilbenes [17]. Compellingly, wide arrays of pharmacological potentials, such as antidiabetic, antioxidant, antiviral, antimicrobial, anticancer, and anti-inflammatory, have been credited to plant-based phenolic compounds. For example, cyanidin 3-sambubioside and 5-caffeoyl quinic acid derived from the fruit of Viburnum dilatatum Thumb. had been found to elicit significant antioxidant and radical scavenging activities while also inhibiting the syndrome-linked complications of postprandial hyperglycemia [16]. Furthermore, plant-based phenolic acids such as garcinone E, kaempferol, resveratrol, syringaresinol, and quercetin are known to be potent anticancer agents [18]. The anti-inflammatory, antiviral, and antibacterial potential of phenolics in the management of skin disorder have also been reported [17, 19, 20, 21].
Alkaloids are structurally diversified secondary metabolites derived from nitrogen-based amino acid with nitrogen atom in the heterocyclic ring. Based on the nature of their heterocyclic and building block, alkaloids are classified into different subgroups such as indole, tropane, piperidine, purine, imidazole, pyrrolizidine, pyrrolidine, quinolizidine, and isoquinoline alkaloids [22]. Noteworthy, therapeutic effects have been credited to a wide range of alkaloids from plants. Typical examples from alkaloids are Callistemon citrinus and Vernonia adoensis reported to elicit antibacterial effects on Staphylococcus aureus and Pseudomonas aeruginosa [23]. Additionally, alkaloids originating from Aerva lanata roots were able to mitigate postprandial hyperglycemia in diabetic rats [24]. The in vitro antioxidant activity of Phoebe declinata leaves extract has also been attributed to its alkaloid. It was found to inhibit 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical while consequently reducing ferric chloride to ferrous [25]. Furthermore, plant-based alkaloidal compounds such as reserpiline, α-yohimbine, methylaplysinopsin, isoquinoline, physostigmine, and pilocarpine are good psychoprotective agents [12].
Healing with medicinal plants is as old as mankind itself. The link between man and his quest for medicines in nature dates back to ancient times, when there were convincing proofs from written documents, monuments, and even original plant medicines [26]. Specifically, the oldest written evidence of usage of medicinal plants for preparation of drugs was found on a Sumerian clay slab from Nagpur, approximately 5000 years old. It comprised 12 recipes for drug preparation referring to over 250 plants [27]. Awareness of medicinal plants usage is a result of the many years of struggles against illnesses, which has prompted man to seek medicines in leaves, roots, barks, and other parts of plants [28]. The knowledge of the development of ideas related to the usage of medicinal plants, as well as the evolution of awareness, has increased the ability of health providers to respond to the challenges that have emerged with the spreading of professional services in the enhancement of man’s life. Until the advent of iatrochemistry in sixteenth century, plants had been the source of treatment and prophylaxis for many diseases [27]. This is well exemplified globally where medicinal plants have always being an integral part of the health care system since time immemorial.
During the last decades, it has become evident that there exists a plethora of plants with medicinal potential, and it is increasingly being accepted that medicinal plants are offering potential lead compounds in the drug discovery process. In fact, the developed world has also witnessed an ascending trend in the utilization of complementary or alternative medicine (CAM) particularly herbal remedies [29]. While over 80% of the population in Sub-Saharan African countries like Nigeria and South Africa use herbal remedies for their primary health care, reports from developed countries such as Canada, Germany, and the US revealed that more than 70% of their populations have tried CAM at least once [29]. The most common traditional medicine in common practice across the globe is the use of medicinal plants. In most of the countries, medicinal plants are the most easily accessible health resource available to the community. In addition, they are most often the preferred option for the patients. For most of these people, traditional healers offer information, counseling, and treatment to patients and their families in a personal manner, as well as having an understanding of their patient’s environment [30].
Indeed, modern allopathic medicine has its roots in traditional medicine, and it is likely that many important new remedies will be developed and commercialized in the future from plant biodiversity, as it has been till now, by following the leads provided by traditional knowledge and experiences. The extensive use of traditional medicine, composed mainly of medicinal plants, has been argued to be linked to cultural and economic reasons. This is why the WHO encourages member states to promote and integrate traditional medical practices in their health system [31]. While a good number of plants (with only selected representatives listed here) have elicited significant therapeutic and pharmacological effects against well-known debilitating and degenerating diseases such as diabetes (Artemisia afra, Chilianthus olearaceus, Vernonia amygdalina [32], Dicoma anomala [33], Psidium guajava [34], and Solanum incanum [35]), cancer (Taxus brevifolia, Podophyllum peltatum [36], and Catharanthus roseus [37]), malaria (Plumbago indica, Garcinia mangostana, Dioscorea membranacea, Artemisia annua, Piper chaba, Myristica fragrans, and Kaempferia galangal) [38], HIV/AIDS (Geranium phaeum, Sambucus racemosa [39], Tuberaria lignosa, and Sanguisorba minor magnolia [40]), schizophrenia (Abrus precatorius, Acacia ataxacantha, Adansonia digitata, Datura innoxia, Ficus sycomorus, Parkia biglobosa, and Ximenia Americana) [41], tuberculosis (Adhatoda vasica, Alpinia galangal, and Ocimum sanctum) [42], microvascular and macrovascular disorders (Anisodus tanguticus, Salvia miltiorrhiza [43], Camellia sinensis, Castanospermum australe, Curcuma longa, Ocimum santum [44], Stigma maydis [45], Spondias mombin [46], and Gazania krebsiana [47]), etc., studies are also in the forefront on the evaluation of plants against the neglected tropical diseases (NTD). Table 1 presents some of the medicinal plants with reported significant efficacy against the NTDs.
Disease/infection | Selected plants for treatment | Reference(s) |
---|---|---|
Buruli ulcer | Acacia nilotica, Ageratum conyzoides, Albizia zygia, Allium sativum, Capsicum annuum, Cassia alata, Chalcas exotica, Carica papaya, Dysphania ambrosioides, Moringa oleifera, Nauclea latifolia, Pergularia daemia, Psidium guajava, Spondias mombin, Zingiber officinale | [66, 67] |
Chagas disease | Argemone ochroleuca, Capparis spinosa, Commicarpus grandiflorus, Cucumis prophetarum, Euphorbia ammak, Hypoestes forskaolii, Kleinia odora, Marrubium vulgare, Peganum harmala, Psiadia punctulata, Ricinus communis, Solanum villosum, Tribulus macropterus, Withania somnifera | [68] |
Dengue and chikungunya | Aloysia gratissima, Andrographis paniculata, Artemisia douglasiana, Citrus limon, Cymbopogon citratus, Cleome aculeata, Eupatorium catarium, Heterotheca latifolia, Hyptis mutabilis, Lantana grisebachii, Momordica charantia, Ocimum sanctum, Pelargonium citrosum, Senna angustifolia, Tridax procumbers, Vernonia cinerea | [69, 70, 71] |
Dracunculiasis | Moringa oleifera | [72] |
Echinococcosis | Azadirachta indica | [73] |
Foodborne trematodiasis | Artemisia annua | [74] |
Helminthiasis | Aloe ferox, Cassinopsis ilicifolia, Coddia rudis, Combretum molle, Elephantorrhiza elephantina, Gazania krebsiana, Hypoxis colchicifolia, Leonotis leonurus, Markhamia obtusifolia, Tulbaghia violacea | [75, 76, 77, 78, 79, 80, 81] |
Leishmaniasis | Aloe vera, Chenopodium ambrosioides, Hyptis pectinata, Pfaffia glomerata, Ruta graveolens | [82] |
Leprosy | Achyranthes aspera, Amaranthus spinosus, Aristolochia indica, Azadirachta indica, Calotropis gigantea, Eclipta alba, Ficus benghalensis, Jasminum grandiflorum, Michelia champaca, Piper betle, Thespesia populnea, Trichodesma indicum | [83] |
Lymphatic filariasis | Acacia auriculiformis, Aegle marmelos, Centratherum anthelminticum, Ficus racemosa, Hibiscus mutabilis, Mallotus philippensis, Moringa oleifera, Sphaeranthus indicus, Zingiber officinale, Vitex negundo | [84, 85, 86, 87, 88, 89, 90] |
Mycetoma | Acacia nilotica, Acacia nubica, Boswellia papyrifera, Citrullus colocynthis, Cuminum cyminum, Moringa oleifera, Nigella sativa | [91, 92] |
Onchocerciasis | Annona senegalensis, Anogeissus leiocarpus, Polyalthia suaveolens, Discoglypremna caloneura, Homalium africanum, Khaya senegalensis, Margaritaria discoidea, Parquetina nigrescens | [93, 94, 95, 96] |
Rabies | Amarantheus spinosus, Croton macrostachyus, Phytolacca dodecandra | [97, 98] |
Scabies | Abelmoschus esculentus, Aegle marmelos, Boerhavia diffusa, Clerodendrum infortunatum, Heliotropium indicum, Pongamia pinnata, Phyllanthus emblica, Schleichera oleosa | [99, 100] |
Schistosomiasis | Abrus precatorius, Allium sativum, Citrus reticulata, Pterocarpus angolensis, Ozoroa insignis, Vernonia amygdalina | [101, 102, 103, 104] |
Snakebite envenoming | Allium cepa, Areca catechu, Aristolochia shimadai, Byrsonima crassa, Casearia sylvestris, Davilla elliptica, Delonix elata, Eclipta prostrata, Emblica officinalis, Hemidesmus indicus, Schumanniophyton magnificum, Vitis negundo | [105, 106, 107] |
Taeniasis | Capillipedium foetidum, Cymbopogon nardus, Cyperus rotundus, Gardenia lucida, Hedychium coronarium, Hedychium spicatum, Inula racemosa, Litsea chinensis, Pistacia integerrima, Randia dumetorum | [108, 109, 110, 111] |
Trachoma | Abrus precatorius, Aloe marlothii, Calpurnia aurea, Dodonaea viscosa, Erythrina abyssinica, Eucomis pallidiflora, Gethyllis namaquensis, Hypoxis obtusa, Kleinia longiflora, Primula auriculata, Protea caffra, Terfezia claveryi, Tinospora smilacina, Tribulus terrestris, Ziziphus mucronata | [112, 113, 114, 115, 116, 117, 118] |
Trypanosomiasis | Acacia nilotica, Allium sativum, Albizia gummifera, Bombax buonopozense, Heterotis rotundifolia, Morinda lucida, Pterocarpus erinaceus, Securinega virosa, Terminalia avicennioides, Vernonia subuligera, Ximenia americana, Zanthoxylum zanthoxyloides | [119, 120, 121, 122, 123, 124, 125] |
Yaws | Alafia multiflora, Boerhavia diffusa, Commicarpus plubaginieus, Dioscorea hispida, Hibiscus diversifolius, Indigofera hirsuta, Spondias mombin, Strychnos ignatii | [126] |
Some selected medicinal plants used against neglected tropical diseases.
The development of new drug is a complex, time-consuming, and expensive process (Figure 1). The time taken from discovery of a new drug to its reaching the clinic is approximately 12 years, involving more than 1 billion US dollars of investments in today’s context [48]. Essentially, the new drug discovery involves the identification of new chemical entities (NCEs), having the required characteristic of drug ability and medicinal chemistry. These NCEs can be sourced either through chemical synthesis or through isolation from natural products. Initial success stories in new drug discovery came from medicinal chemistry inventions, which led to the need of development of higher number of chemical libraries through combinatorial chemistry. This approach, however, was proven to be less effective in terms of overall success rate. The second source of NCEs for potential use as drug molecules has been the natural products. Before the advent of high throughput screening and the post genomic era, more than 80% of drug substances were purely natural products or were inspired by the molecules derived from natural sources (including semisynthetic analogs) [49]. There are various examples of development of new drugs from the plant sources. Morphine was isolated from opium produced from cut seed pods of the poppy plant (Papaver somniferum) approximately 200 years ago [50]. Pharmaceutical research expanded after the Second World War to include massive screening of microorganisms for new antibiotics, inspired by the discovery of penicillin [50]. Few drugs developed from natural sources have undoubtedly revolutionized medicine like antibiotics (e.g., penicillin, tetracycline, erythromycin), antiparasitics (e.g., avermectin), antimalarials (e.g., quinine, artemisinin), lipid control agents (e.g., lovastatin and analogs), immune-suppressants for organ transplants (e.g., cyclosporine, rapamycins), and anticancer drugs (e.g., paclitaxel, irinotecan) [51].
Modern drug discovery and development processes from the medicinal plant [127].
The WHO has estimated that the majority of the populations in Africa, Asia, and Latin America still use TM for their primary health care needs [52]. In industrialized countries, plant-based TM or phytotherapeuticals are often termed complementary or alternative medicine (CAM), and their use has increased steadily over the last 10 years [53]. In the USA alone, the total estimated “herbal” sale for 2005 was $4.4 billion, a significant increase from $2.5 billion in 1995 [54] while also accounting for an estimated 1 billion Malaysia ringgit annually [55]. However, such “botanical dietary supplements” are regulated as foods rather than drugs by the United States Food and Drug Administration (US FDA) [54].
With the recent interest in molecular modeling, combinatorial chemistry, and other synthetic chemistry techniques by pharmaceutical companies and funding organizations, natural products, and particularly medicinal plants, remains an important source of new drugs, new drug leads, and NCEs [56]. In both 2001 and 2002, approximately one quarter of the bestselling drugs worldwide were natural products or derived from natural products. Some of the plant-derived drugs and their significance are listed in the Table 2. Many plant-derived compounds have been used as drugs, either in their original or semisynthetic form. Recent developments in drug discovery from plants, including information on approved drugs and plant extracts or compounds now in clinical trials, are available [57]. It is anticipated that in the future, plant-derived compounds will still be an essential aspect of the therapeutic array of medicines available to the physician [57].
S/N | Compound | Plant name | Classification | Biological function |
---|---|---|---|---|
1 | Aescin | Aesculus hippocastanum | saponins | Anti-inflammatory, vasoconstrictor and vasoprotective effects |
2 | Ajmalicine | Rauwolfia spp., Catharanthus roseus, and Mitragyna speciosa | alkaloid | Antihypertensive drug used in the treatment of high blood pressure |
3 | Berberine | Berberis vulgaris | alkaloid | Treatment for bacillary dysentery |
4 | Colchicine | Colchicum autumnale | alkaloid | Antitumor agent |
5 | Curcumin | Zingiberaceae | phenols | dietary supplement |
6 | Emetine | Cephaelis ipecacuanha | alkaloid | Amoebicide, emetic |
7 | Hesperidin | Citrus species | Flavonoid | Treatment for capillary fragility |
8 | Lapachol | Handroanthus impetiginosus | phenols | Anticancer, antitumor |
9 | Nordihydroguaiaretic acid | Larrea tridentata | phenols | Antioxidant activity |
10 | Quinine | Cinchona officinalis | alkaloid | Antimalarial drug |
Selected compounds derived from medicinal plants.
Phyto (plants in the form of leaves, flowers and roots) therapy (treatment) has continued to reflect a great deal of significance in health care around the world in curing diseases while also ensuring a good state of health and/or conditions is maintained. In fact, a significant proportion of the entire global populace had found solace in phytomedicine, embracing it as a major source for their health care system as maintained by WHO in one of their submissions; hence, presenting the impact or relevance of herbal therapy in this chapter cannot be out of context with regard to medicine or medicinal products emanating from these MPs such as Papaver somniferum, Cinchona, Hibiscus sabdariffa, Rosmarinus officinalis, Nigella sativa, Artemisia afra, Vatica rassak, etc., some (about 5000 out over 250,000) had either being developed (as drugs or vaccines) and commercialized (morphine, quinine, ephedrine, etc.) and many others in the final process of drug development [2] for confirmation of safety and efficacy (clinical trials) against avalanches of illnesses including but not limited to hypertension, asthma, malaria, pain, hemorrhage, psychosis, cancer, migraine, etc. [58, 59]. This makes herbal medicine to become a basic health service to people of diverse culture irrespective of their status (poor or rich) and location (remote or urban), and this acceptance (in use either singly or combination with orthodox medicine) has continued to escalate in recent times [60], thereby complementing or reducing the use of modern medicine (despite its availability) probably due to inadequacies in providing holistic healing where behavioral, emotional, and/or spiritual factors are the underlying causes of the diseases [61]. In view of the foregoing, continents such as Asia, Africa, and Latin America with countries such as China, India, etc., had embraced the adoption of the two systems (phytotherapy and modern medicine) for their national health care needs. Although issues of safety, efficacy, and quality of herbal medicines have undermined their integration into national health care policy in some countries, this had not prevented, in any big amount, the popular use by the citizenry. Interestingly too, because MPs are core sources for pharmaceutical manufacturing, they in addition to herbal medicines play an important role in pharmaceutical market (PM). In fact, in a reported submission, in 1995, they occupied 33.1% of the total PMs [55].
Globally, the high demand of use for herbal medicine for the treatment of illnesses is undisputable, and one begs to ask or wonder whether these products are actually of good quality, safe, and effective. There are assumptions and/or claims that despite general usage, few of them have been attributed to illnesses and fatalities as some of them have reported to cause liver and kidney damage [62, 63, 64]. In fact, this was also attributed to why they have not been globally accepted as par with conventional medicine within the national health care policy of many countries. The reason for this was not far-fetched. A lot of people believed that many herbal formulations lacked safety evaluations such as clinical trials as to why they cannot be placed in the same pedigree with modern medicine, but this was somehow disagreed by some researchers and/or policy makers who opined that clinical trials may be conducted only when large batches are intended. Additionally, in clinical practice, the failure to integrate phytotherapy as one of the courses or modules in medical school was seen in some quarters as the reason why it became somehow extremely difficult for medical practitioners to prescribe it, hence, the advantage convention medicine enjoys nowadays. Other problems include but not limited to storage conditions, inexplicit dosage, wrong labeling information, individualization of prescription with numerous active ingredients and other components, lack of information on the industrial use of MPs, little or no fact on the market benefit and business potentials, etc. [65]. It is worthy of mention that despite these limitations, phytotherapy had the potentials in salvaging numerous human diseases.
The use of phytotherapy in preventing or curing ill-effects faced by mankind was established by the great roles played by natural products obtained from MP. With continued efforts in research and utilization of HM on daily basis, it is envisioned that it would attain its rightful place and be embraced as efficient system worthy of acceptance within the global health care practice.
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\\n\\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
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\\n\\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
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LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t\n\t\t\t 1 July 2005 (2005-07-01) \n\t\t\t | \n\t\t\t\n\t\t\t 3 October 2011 (2011-10-03) \n\t\t\t | \n\t\t
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The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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\n\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\n\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
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\n\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\n\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
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\n\nContent reuse:
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\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
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\n\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
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\n\nPolicy last updated: 2016-06-08
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