Phytochemicals as Prototypes for Pharmaceutical ...

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Current Pharmaceutical Design, 2016, 22, 3058-3070

Phytochemicals as Prototypes for Pharmaceutical Leads Towards Drug Development Against Diabetic Cardiomyopathy Shreesh Ojha1, Amani Kurdi2, Bassem Sadek1, M. Kaleem1, Lu Cai3, M.A. Kamal4,5 and Mohanraj Rajesh1* 1

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, UAE; 2Department of Pharmacology & Therapeutics, Biuret Arab University, Lebanon; 3Kosair Children's Hospital Research Institute and Departments of Pediatrics, Radiation Oncology and Pharmacology and Toxicology, University of Louisville, USA; 4King Fahd Medical Research Center, King Abdulaziz University, P.O.Box 80216, Jeddah, Kingdom of Saudi Arabia & 5Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia Abstract: Globally diabetes mellitus (DM) is swiftly reaching epidemic proportions and impose major health care and socio-economic challenges that are associated with its complications. DM is considered as the major risk factor for the development of debilitating micro & macro vascular complications. Clinical studies have revealed that deMohanraj Rajesh velopment of diabetic cardiomyopathy (DCM) in subjects with diabetes can occur both- dependent and independent of pre-existing increased risk factors such as poor glycemic control, hyperlipidemia, and or hypertension. Therefore, DCM represents as a major challenge for the clinical community for the prompt diagnosis and devising the treatment paradigm to combat the diabetes induced cardiac dysfunction. In Chinese traditional medical practice, heart ailments have been coped with herbal extracts. Phytochemicals bioavailability and pharmacokinetic properties are to yet be established completely in human subjects. However, tremendous progress has been made to isolate, purify the phytochemicals and characterize their effects on mitigating the development of DCM in pre-clinical models. Currently there are no approved drugs available for the treatment of DCM. In this review, we have discussed the progress made in understanding the mechanisms for the phytochemicals cardio-protective actions in the diabetic milieu and their caveats and provide future perspectives for proposing these agents to serve as prototypes in the development of drugs for the management of DCM.

Keywords: Phytochemicals, diabetes mellitus, diabetic cardiomyopathy, cardiovascular complications, cardiac function, oxidative stress, inflammation, apoptosis, fibrosis. 1. INTRODUCTION As per the projection of the international diabetes federation and world health organization, the incidence of diabetes is estimated to reach above 325 million in the age group of 20-75 years by 2025 [1, 2]. Cardiovascular diseases account for the major cause of morbidity associated with diabetes. A major factor attributed to the development of heart failure in the diabetic subjects is the observation of cardiac dysfunction and it is referred as diabetic cardiomyopathy (DCM). DCM can affect both type 1 and 2 diabetic subjects and is characterized by early-onset of diastolic dysfunction and later progressive deterioration of systolic function, resulting in heart failure [3]. DCM was first described as cardiovascular anomaly nearly four decades ago by Rubler et al. and since then it has gained significant attention among primary care, endocrinologists and cardiovascular physicians [4]. DCM is defined as diabetes-induced myocardial structure and functional alterations and it is imperative to consider that in subjects with diabetes and particularly in subjects with type 2 diabetes mellitus, these changes are profoundly accelerated by the existence of pre-existing cardiovascular risk factors such as hyperlipidemia and hypertension, which eventually result in the development of left ventricular hypertrophy, myocardial remodeling (fibrosis) and finally progressing to heart failure [5]. Strict control of cardiovascular risk factors (hyperglycemia, hypertension and hyperlipidemia) has been shown to decrease the risk of development of DCM in diabetic patients. However recent clinical studies have pointed that in fact DCM tends to develop good control over cardiovascular risk factors [6]. Therefore it is imperative to identify the biomarkers and *Address correspondence to this author at the Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain – 17666, UAE; Tel: +97137137513; Fax: +97137672033; E-mail: [email protected] 1381-6128/16 $58.00+.00

specific therapeutic targets and/ or agents that can thwart the development of DCM in the early stage. In this review we discuss the progresses made with harnessing the potentials of phytochemicals in mitigating the development of DCM in pre-clinical studies and provide future perspectives for the drug development based on phytochemicals. The key patho-mechanisms purported for the development of DCM include oxidative stress, inflammation and apoptosis and these topics are elegantly reviewed elsewhere [7-10]. 2. OVERVIEW OF PATHOMECHAMIMS INVOLVED IN THE DEVELOPMENT OF DCM DCM can develop in both type 1 and type 2 diabetic subjects and is characterized by early onset of diastolic dysfunction and later progressive deterioration of systolic function, resulting in heart failure. The etiopathogenesis of DCM is complex, multifactorial and yet to be fully defined. Insulin is the key hormone that governs the intermediary metabolism and links carbohydrate, protein and lipid metabolism. Deregulated insulin action in diabetic milieu affects the intermediary metabolism, which results in deranged energy production and utilization in the peripheral tissues and this effect could be deleterious in metabolically active organ such as heart [3]. Hyperglycemia (glucose toxicity) caused by the lack of insulin or insulin resistance and hyperlipidemia characterized by increased myocardial triacylglycerol (TAG) and free fatty acids (FFA) accumulation are the major players identified in the pathogenesis of DCM [11]. Chronic hyperglycemia results in glucotoxicity, imparts cardiac injury via plethora of pathways affecting cardiomyocytes, cardiac fibroblasts and endothelial cells. Uncontrolled hyperglycemia stimulates the excessive generation of reactive oxygen species (ROS) via the un-coupled electron transport chain, activates poly (ADP-ribose) polymerase [PARP] and xanthine oxidase [10], which then depletes the ATP, thus resulting in the demise of cardiomyo© 2016 Bentham Science Publishers

Cardioprotective Effects of Phytochemicals in Diabetes

cytes [7, 9, 12, 13]. Hyperglycemia also accelerates and increases the formation of advanced glycation end products (AGE), activates polyol pathway and protein kinase C (PKC), which inflicts cardiomyocytes injury [14]. Further hyperglycemia also induces alterations in the cardiac structure and function via post-translational modification of extracellular proteins (ECM), which alters the expression and activities of key components of Ca2+ handling system such as ryanodine receptor (RyR) and sarcoendoplasmic reticulum ATPase (SERCA), resulting in the aberrant cardiomyocytes mechanical function, leading to perturbed systolic and diastolic functions [15-18]. In uncontrolled diabetes, increased lipid de novo synthesis occurs in the liver and lipolysis in the adipocytes, thereby resulting in the increased pool of circulating free fatty acids and TAG. Increased entry of FFAs occurs during the state of insulin resistance, which overpowers the oxidative capacity of the myocardium and thus results in cardiac steatosis, which then alters the functional capacity of the myocardium. Numerous mechanisms have been postulated for the cardiac lipotoxicity pathway in the pathogenesis of DCM [19]. These include ceramide generation, ROS production via various sources such as NADPH oxidase, Xanthine Oxidase, uncoupled endothelial nitric oxide synthase etc. which perpetuates myocardial insulin resistance and impaired contractility [20]. In particular, elevated FFAs oxidation results in the de novo synthesis of ceramide via activation of serine palmitotyl-CoA transferase [20, 21]. Ceramide produced in turn activates the apoptotic paradigm via inhibition of mitochondrial respiration and perturbation of mitochondrial potential, whereby generating increased mitochondrial ROS, which imparts cardiomyocytes injury [22]. Next, ceramide has also been shown to increase the serine phosphorylation of the insulin receptor substrate (IRS), which results in feed-back inhibition of insulin signal transduction pathway in the diabetic myocardium [23]. These phenotypic changes feed in to a vicious cycle that propagates and produces cardiomyocyte injury in the diabetic milieu [23]. In addition, ceramide both directly and indirectly induces ROS generation, which results in NFB activation and production of pro-inflammatory cytokines, such as TNF-, IL-1, MCP-1, etc. and adhesion molecules such as ICAM-1 and VCAM-1 in the diabetic myocardium, producing inflammatory injury [24]. Next ceramide also up-regulates the expression of pro-fibrotic mediators such as TGF-, fibronectin and connective tissue growth factor (CTGF), which results in the enhanced extracellular matrix (ECM) deposition [24-26]. Increased ECM remodeling directly impairs the myocardial compliance/contractility and hence reduces the functional capacity of the myocardium, resulting in the heart failure. Recently overactivation of cannabinoid receptor type 1 (CB1R) and altered autophagy has been implicated in the development of DCM, involving oxidative/nitrative stress, inflammatory and apoptotic pathways [27]. The molecular cascades of events purported in the pathogenesis of DCM are summarized in Fig. (3). 3. EFFECTS OF PHYTOCHEMICALS IN DIABETIC MYOCARDIUM Phytochemicals are the natural chemical constitutes of plants. They are responsible for imparting color (for example - purple color of blueberries), smell (pungent smell of garlic) etc. Importantly, phytochemicals have been used in the traditional medicine for thousands of years; however, without the presence of specific knowledge about their pharmacological properties. There are considerable evidences from in vitro and pre-clinical studies that phytochemicals extracted from various plant sources may impede the tumor growth, elicit antioxidant and anti-inflammatory effects [28]. Most importantly the anticancer agent Taxol (Paclitaxel) is a phytochemical originally identified, extracted and purified from the bark of pecific yew tree (Taxus brevifolia) [29]. In the present day, most of the drug development did not come from the plant but rather they are synthetically prepared. Lately there is a revived interest to harness the potential of medicinal plants in the drug discovery. This enthu-

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siasm has led to significant strides and several potential phytochemicals have been identified and are being pursued for their translational potential. In this direction, here we have discussed the developments made with the use of phytochemicals to attenuate the development of DCM in various animal models of diabetes and ex vivo studies conducted on isolated ventricular cardiomyocytes. The various phytochemicals and their plant sources are depicted in (Fig. 1), and their respective chemical structures are illustrated in (Fig. 2). Next, the summary of effects observed with phytochemicals in the pre-clinical and or ex vivo studies is provided in (Table 1). In the following section, we have systematically discussed the effects of various specific phytochemicals that have been targeted and investigated for its attenuating effect on the diabetes induced myocardial tissue injury and the development of DCM. 3.1. Aralosides of Aralia elata (Miq) Seem (TASAES) Total aralosides of Aralia elata (Miq) Seem (TASAES) are compounds extracted from Aralia elata [30]. When the streptozotocin rendered diabetic rats were treated with varying doses of TASAES, for eight weeks, it did not significantly reduce the blood sugar levels. However, TASAES attenuated the diabetes induced impairments in the systolic arterial pressure (SAP) and diastolic arterial pressure (DAP). Although treatment of diabetic rats with low doses of TASAES did not significantly prevent diabetes induced impairments –decrease in the left ventricular systolic pressure (LVSP), but significantly reversed diabetes induced alterations in the left ventricular end diastolic pressure (LVEDP), absolute values of dp/dtmax decline and heart rate (HR). At higher dose, TASAES completely prevented diabetes-induced abnormalities of cardiac functions. Further, TASAES also significantly prevented diabetes induced pro-fibrotic mediator CTGF expression in the myocardium and improved the ultrastructure changes. In addition, in the isolated ventricular myocytes, TASAES also mitigated diabetes induced impairments in the myocytes contractility indices and Ca2+ handling capacity. These results collectively suggests that TASAES, could potentially ameliorate the diabetes induced compromised cardiac function [31]. 3.2. Astragalus Polysaccharides Astragalus polysaccharides (APS) are the main active extracts from the traditional Chinese medicinal herb Astragalus membranaceus [32]. Chen W et al., in their series of studies, reported that diabetic hamsters treated with APS, inhibited diabetes-induced chymase, angiotensin-II (Ang-II) expressions and activity in the myocardial tissues [33, 34]. Chymase is a proteolytic enzyme expressed primarily in mast cells and in other tissues such as skeletal muscles and derma. Hyperglycemia upregulates chymase expression and activity, which in turn converts Ang-I to Ang-II, resulting in the ROS generation, cardiac hypertrophy and fibrosis [35, 36]. These phenotypic changes were mitigated with APS treatment. However, the precise role of chymase in cardiac pathologies is yet to be fully established [37]. Further, Chen W et al., also demonstrated that in obese diabetic mice [db/db]-[a model of type 2 diabetes mellitus], treatment with APS, significantly inhibited diabetes induced myocardial lipotoxicity, improved energy expenditure and cardiac function. Similar results were observed in transgenic mice overexpressing peroxisome proliferator-activated receptor - (PPAR-) in the myocardium, upon treatment with APS. These PPAR- overexpressed transgenic mice exhibited a similar cardiac phenotype observed in patients with DCM, i.e. increased cardiac steatosis and left ventricular hypertrophy. In addition, when these transgenic mice fed with high-fat diet for 16 weeks, exhibited lipotoxicity and diminished cardiac function with myocardial structural abnormalities. All these changes were mitigated when they were treated with APS [34, 38]. PPAR- myocardium transgenic mice were also reported to develop atherosclerosis when fed with a highfat diet [21]. However, this was not investigated in the above studies and the precise molecular mechanisms purported for diminution

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Ojha et al.

Fig. (1). Plant/herbs wherein phytochemicals were extracted and employed in testing for its inhibiting effect on the diabetic myocardial tissue injury.

of myocardial lipotoxicity by APS and its action in the liver has also not been explored. Regardless of these caveats, authors conclude that APS could significantly ameliorate the development of DCM by targeting myocardial lipotoxicity. 3.3. Berberine Berberine, an isoquinoline alkaloid and it is the principal constituent of wild berries - Berberis vulgaris [39]. Berberine has been widely used as anti-parasitic/fungal agent in Chinese traditional medicine and it has also been used as an adjuvant in treating diabetes mellitus [40]. However, their effects on diabetic cardiovascular complications are unknown. To this end, Hong-Li Shan et al., investigated the effect of berberine treatment in diabetic rats and reported that it significantly improved the cardiac arrhythmias and improved the cardiomyocyte contractile dynamics, via augmentation of calcium transient currents in ventricular myocytes [41]. However, the precise mechanism purported for the beneficial effect of berberine in mitigating DCM has not been investigated in depth. 3.4. Breviscapine Breviscapine is a flavonoid isolated from Erigeron breviscapus and has been used in Chinese traditional medicine as vasodilation agent [42]. Recently it was demonstrated that, when diabetic rats

were treated with breviscapine, it significantly inhibited diabetesinduced cardiac dysfunction by suppressing PKC expression and augmenting the expression of proteins involved in Ca2+ handling such as SERCA-2 and phospholamban (PLB) via modulation of protein phosphatase inhibitor-1 expression (PPI-1) [43]. PLB protein is an inhibitor of cardiac muscle SERCA activity when they are in de-phosphorylated state; however this is reversed upon their phosphorylation. The overall effect of PLB decreases the contractility and the rate of cardiac muscle relaxation, thereby decreasing stroke volume and heart rate respectively [44]. In this study authors report that diabetes induced PKC mediated inactivation of PPI-1, which had resulted in the over activation of PLB in the diabetic myocardium, and this in turn significantly impaired the indices of diastolic function. These changes were mitigated upon treatment with breviscapine, however the precise mechanism by which it had elicited these positive effects in the diabetic myocardium is still not clear. Further, breviscapine treatment of diabetic rats mitigated diabetes-induced cardiac hypertrophy by blunting the activation of crucial players involved in the hypertrophy induction such as PKC and NFB and c-fos activation [45]. Recently breviscapine has also been reported to protect the diabetic myocardial tissue injury by attenuating diacylglycerol-protein kinase C (DAG-PKC) signal transduction pathway and fibrosis [46]. Interestingly, breviscapine also inhibited the vascular smooth muscle proliferation via sup-



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Fig. (2). Chemical structures of phytochemicals investigated in the context of ameliorating diabetic cardiomyopathy in the pre-clinical animal models of DCM.

pressing mitogen activated protein kinase pathway. Collectively, these observations suggest that breviscapine can be of significant potential in baring the development of diabetic vascular complications. Accordingly, efforts are in progress to improve the delivery and bioavailability so that it can be perused for further states of drug development [47].

kines levels and alterations in the insulin like growth factor (IGF) in the myocardial tissues [49-51]. However, these studies failed to establish the precise mechanism of cardio-protection by CAPE. Also, its direct effect on cardiac hemodynamic function has not yet been investigated. Moreover, the precise role of IGF in the pathogenesis of DCM is still unclear.

3.5. Caffeic Acid Caffeic acid phenethyl ester (CAPE) is a flavonoid-like compound with reported anti-inflammatory, anti-carcinogenic, antiviral and immune-modulatory activities [48]. In addition, CAPE has also been reported to elicit protection against ischemic renal injury. Treatment of diabetic rodents with CAPE revealed that it significantly attenuated the oxidative tissue injury and inflammatory cyto-

3.6. Cannabidiol Cannabidiol is the most abundant non-psychoactive phenolic compound and constituent of Cannabis sativa (marijuana) plant [52]. Earlier studies have reported that cannabidiol elicited potent protection against ischemic-reperfusion injury in the neuronal, hepatic, renal and cardiac tissues [53]. Recently it has been reported that when diabetic animals were treated with cannabidiol, it signifi-


Ojha et al.

Fig. (3). Activators, interceders, and aftermath of events purported in the pathogenesis of diabetic cardiomyopathy. denotes culmination of pathways

denotes inhibition of these pathways by phytochemicals. Phytochemicals target the key mediators’ such as oxidative stress, inflammation, apoptosis, and metabolic alterations in ameliorating diabetic myocardial tissue injury. A red arrow indicates the molecular markers that are up regulated and contribute in the pathogeneses of DCM. A green arrow indicates the pathways mitigated by the phytochemicals.

cantly ameliorated diabetes-induced decline in the cardiac hemodynamic functions, mitigated oxidative stress, inflammation, stress kinases activation, apoptosis, and fibrosis in the myocardial tissues and in isolated neonatal ventricular myocytes. Interestingly cannabidiol also exhibited therapeutic potential while reversing the development of DCM, when the diabetic animals were treated at a later time-point characterized with significant deterioration of cardiac function [54]. It is also pertinent to note that cannabidiol also abrogated the ischemic injury in the myocardium [55] and mitigated diabetes induced retinal injury and development of diabetic retinopathy [56]. In addition, cannabidiol has also been demonstrated to improve the vasorelaxation in the chronic diabetic rats [57]. Recently, cannabidiol has also been approved by Canada and European Union for the management of chronic neuropathic pain in patients with multiple sclerosis and it is waiting for the approval by United States Food and Drug Administration (USFDA) for its use in USA [58]. 3.7. Chelerythrine Chelerythrine is an isoquinoline alkaloid extracted from Chelidonium majus [59]. It has been reported that chelerythrine chloride, possesses anti-inflammatory, oncostatic and neuro-sedative properties [60]. However, the breakthrough happened with the discovery of its specific inhibitory action on the protein kinase C activity (PKC), and since then it has been widely used as pharmacological inhibitor of pan-PKC isoforms in various pre-clinical and in vitro studies [61]. As mentioned previously, PKC has been implicated as a key player in the pathogenesis of insulin resistance. Davidoff et

al. investigated its effect on the diabetic myocardium. They observed that ventricular myocytes obtained from diabetic animals which have been treated with chelerythrine chloride, exhibited remarkable improvements in the cardiac contractility indices [shortening/relaxation]. However, in their study in vivo cardiac-hemodynamic measurements were not performed and further the resolution of myocardial fibrosis and apoptosis is also indiscernible [62]. Nonetheless several studies have nailed hard on the role of PKC in the pathogenesis of DCM and reported beneficial effects of PKC inhibition in arresting the development of diabetic vascular complications. In addition isoform specific - PKC- inhibitor [Ruboxistaurin – was recently approved as a new investigational drug by USFDA] is currently undergoing the phase-3 clinical trial for the treatment of diabetic retinopathy, also ameliorated the development of DCM in pre-clinical studies, by attenuating oxidative stress, inflammation, apoptosis and fibrosis [63, 64]. 3.8. Curcumin Curcumin is an unsaturated diketone and it is the principal component of turmeric plant Curcuma longa [65]. Curcumin has been used as flavoring and spicing agent in the food preparations and several studies have established its beneficial effects which were linked to its antioxidant, anti-tumorigenic and antiinflammatory properties [65]. Curcumin treatment to diabetic rodents mitigated the development of DCM by blunting the diabetes induced - oxidative stress mediated by NADPH oxidases, PKC activation, NF-B, receptor for advanced glycation end products (RAGE), inflammatory cytokines, adhesion molecules, and



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Table 1. Phytochemicals evaluated in the animal models of diabetes and ex vivo studies in isolated ventricular myocytes and their purported molecular mechanisms. Phytochemical

Model Employed

Dose Studied and Duration of Treatment

Method Used in the Assessment of Cardiac/cardiomyocyte function

Summary of effects observed in myocardium/cardiomyocytes

Refs.

Aralosides

STZ induced diabetes in Wister rats

4.9-19.6 mg/kg/day by gavage for 8 weeks

LV functions by PV catheter.

Improved LV function, fibrosis, improved Ca2+ handling in cardiomyocytes.

[31]

Astragalus polysaccharides

STZ induced diabetes in Hamsters

1g/kg/day by gavage 10 for16 weeks

Hemodynamic measurements with pressure senor catheter.

Chymase expression, ACE and Ang-II expression and fibrosis and improved cardiac function.

[3336,38]

db/db mice and MHC-PPAR on high fat diet

2g/kg/day by gavage for 16 weeks

Berberine

Alloxan induced diabetes in SD rats

200 mg/kg/day by gavage for 3 weeks

Not performed [NP]

Cardiac arrhythmias and improved contraction of ventricular myocytes.

[41]

Breviscapine

STZ induced diabetes in SD rats

10-25 mg/kg alternate days for 6 weeks via intragastric administration.

Echocardiography

Ameliorates cardiac dysfunction, PKC expression and improves Ca2+ apparatus.

[45,46]

Caffeic acid

STZ induced diabetes in SD rats or Balb/C mice

10 μmol/kg/day via I.P injection for 2-8 weeks ; 2g/100g diet fortified chow for 12 weeks

NP

Lipid peroxidation, augments antioxidant enzymes, inhibits alterations in IGF expression, Inflammation and procoagulatory state.

[49-51]

Cannabidiol

STZ induced diabetes in C57BL6/J mice

20 mg/kg/day by I.P injection for 11 weeks & prophylactic treatment for 4 weeks after established diabetes for 8 weeks.

LV functions by PVcatheter.

Improved cardiac function, MAPKs, inflammation, oxidative stress, apoptosis & fibrosis. Further prophylactic treatment mitigates above phenotypic changes in the diabetic myocardium.

[54]

Chelerythrine


Ex vivo studies in isolated adult ventricular myocytes

NP

Improved fractional shortening/relengthening of myocytes and augments insulin mediated glucose uptake.

[62]

Curcumin


100-200mg/day per oral for 8 weeks.

Echocardiography

NADPH oxidase, PKC, NFB activation, AGE accumulation and RAGE expression and fibrosis and apoptosis.

[66-69]

Daidzein

Ex vivo studies in isolated adult ventricular myocytes [AVM]

50μM in high glucose culture medium.

Ex vivo cardiomyocyte mechanics

Improved myocytes contractile indices

[74]

Geneistein

Ex vivo studies in isolated AVM

20μM in high glucose culture medium.


Improved myocytes contractile indices.

[75]

EGCG

Ex vivo studies in neonatal rat ventricular myocytes

5-80 μM in high glucose culture medium

NP

MAPKs, PKC, restored cardiac gap function proteins expression.

[78,79]

Ferulic acid


110 mg/kg/day by gavage for 12 weeks

NP

Oxidative stress and fibrosis.

[81]

Echocardiography Improved LV function, Ca2+ handling, FA oxidation, improved glucose oxidation, and mitochondrial capacitation.


Ojha et al. (Table 1) Contd….

Phytochemical

Model Employed

Dose Studied and Duration of Treatment

Method Used in the Assessment of Cardiac/cardiomyocyte function

Summary of effects observed in myocardium/cardiomyocytes

Refs.

Gallic acid


25-100mg/day by per oral for 8 weeks.

Heart rate and blood pressure by tail –cuff monitor

Controlled the heart rate and blood pressure and oxidative stress and fibrosis.

[84]

Ginkgolide B

Ex vivo studies in isolated AVM

0.5-2μg/mL in high glucose culture medium


Improved myocyte contractile/relaxation indices and SERCA2a expression.

[86]

Gypenosides


100 mg/kg/day by oral administration for 6 weeks

LV functions by Pressure sensor catheter

Improved cardiac function, without altering the cytoskeletal components of the myocytes.

[89]

Luteolin


200 mg/kg/day by oral administration for 8 weeks


Improved cardiac function, oxidative stress, apoptosis [augments AKT activation], and fibrosis.

[91]

Pycnogenol


10-50mg/day in drinking water for 8 weeks


Improved cardiac function, lipid peroxidation, and fibrosis.

[93]

Resveratrol

STZ induced diabetes in CD1/SIRT1 +/mice

Diet fortified chow @0.067% food composition for 8 weeks

Echocardiography & LV functions by Pressure sensor catheter

Improved cardiac function, fibrosis, restored Ca2+ handling in isolated myocytes, cardiac hypertrophy, inflammation and oxidative stress.

[99103]


2.5mg/kg/day by I.P injection for 8 weeks

Sulforaphane

STZ induced diabetes in FVB mice

0.5 mg/day by I.P injections for 12 weeks

Echocardiography

Improved cardiac function, fibrosis, inflammation and oxidative stress and induces Nrf2

[107108]

Tanshinone IIA


5mg/kg/day via I.P injections for 1 week after 11 week of established diabetes [prophylactic treatment]

Echocardiography

Improved LV function, inflammation, augments Akt phosphorylation, apoptosis via kinin B2 receptor pathway.

[110,11 2]

Decreased; STZ – streptozotocin; I.P - intra-peritonial injections; LV – left ventricle, PV – pressure volume catheter; NP- not performed. Other nonstandard abbreviations/acronyms are explained in the text wherever appropriate.

myocardial fibrosis and apoptosis [66, 67]. Further, curcumin also significantly improved cardiac function in the diabetic animals which were treated with curcumin, and assessed with echocardiography. It is also important to note that, recently a novel synthetic analogue of curcumin (C66), also attenuated the diabetes-induced myocardial tissue damage and the development of DCM, via aforementioned mechanisms [68, 69]. Although curcumin has been shown to perform exceptionally well in the pre-clinical studies, the bio-availability and pharmacological activity is seldom established in human subjects [70]. 3.9. Daidzein & Geneistein Daidzein and geneistein are phytoestrogens [isoflavones class] which can be found in several cereal grains [for instance soybean], vegetables and medicinal plants [71]. Phytoestrogens are comprised of several chemical entities such as isoflavones, coumestans, lignans and lactones [71]. Recently, phytoestrogens have attracted much attention because of epidemiological reports which revealed

that individuals with low-intake of dietary phytoestrogens especially soybean isoflavones (e.g., genistein, daidzein), are at greater propensity of developing cardiovascular complications, chronic inflammatory diseases and cancers [72, 73]. Furthermore, it has been reported that both geneistein and daidzein treatment of isolated ventricular myocytes, markedly improved myocytes contractile abnormalities under high glucose conditions. In addition, both isoflavones, also, ameliorated the accumulation of cardiac collagen in the diabetic myocardium [74]. It is also interesting to note that daidzein ameliorated ischemic injury in the diabetic animals [75]. However, in all these studies the precise effects of geneistein, daidzein on the in vivo cardiac functions were not completely investigated. In spite of geneistein being recognized as pan tyrosine kinase inhibitor [76], the precise mechanisms purported for these beneficial effects of geneistein and, daidzein on the development of DCM of are yet to be defined completely.


3.10. Epigallocatechin Gallate Epigallocatechin-3 gallate (EGCG), is a polyphenol compound and it is the major component of green tea leaves (Camelis sinesis) and has been reported to exert numerous health benefits derived from its anti-inflammatory, anti-aging, anti-tumorigenic and metabolic toner properties [77]. It has also been reported that EGCG attenuated, attenuated high glucose mediated changes in the cardiac gap junction proteins, which are crucial in maintaining the functional capacity of myocytes. Furthermore, it also mitigated hypertrophy of ventricular myocytes maintained in the high glucose environment, via suppressing the mitogen activated protein kinases [MAPKs] and PKC respectively [78]. However these effects were not re-capitulated in animal models of DCM and it is yet to be explored. Recently treatment of EGCG to spontaneously type 2 diabetic rats (Goto-Kakizaki strain) for 12 weeks significantly blunted mitochondrial ROS generation, augmented autophagy and oxidative stress in the diabetic hearts. However, the effect of EGCG on cardiac dysfunction and myocardial remodeling has not been reported in this study [79]. 3.11. Ferulic acid Sodium ferulate (SF) is sodium salt of ferulic acid and it can be found in various grains and aromatic spices. Particularly, it is the principal component of giant fennel seeds [Ferula asfoetida] [80]. Ferulic acid has been documented to elicit anti-inflammatory activity in variety of cell culture and animal model studies. To this end, it has recently been reported that the treatment of diabetic rats with ferulic acid, significantly attenuated the myocardial tissue injury via attenuating oxidative stress and fibrosis [81]. However, its effect on the cardiac function was not determined, but other studies have demonstrated that in a diabetic rat model of type 2 diabetes mellitus, ferulic acid, significantly ameliorated the renal tissue injury and nephropathy via counteracting oxidative and inflammatory stress and improved the renal function in the diabetic rats [82]. 3.12. Gallic Acid Gallic is a phyto-phenol compound and can be found in various plant sources such as gallnuts, witch hazel flower (Corylopsis pauciflora), oak bark, etc. It has been reported to be a less-potent inhibitor of carbonic anhydrase and in pre-clinical studies demonstrated to have the ability to disrupt the aggregation of amyloidfibrils in Alzheimer’s disease model [83]. Recently, one study had reported gallic acid’s beneficial effect in mitigating the development of DCM in diabetic animals by attenuating myocardial oxidative stress and fibrosis. Interestingly, in this study, gallic acid significantly reduced the glycosylated hemoglobin (HbA1c) levels and circulating insulin levels after eight weeks of treatment [84]. However, considering the fact that HbA1c levels truly reflect the glycemic status/control over the period of three months, it is important to note that in this study upon eight weeks of treatment with gallic acid, there was marked reduction in the HbA1c levels, which is paradoxical and authors have failed to address this discrepancy. Accordingly, unless the mechanism behind pancreatic islets revival presented in the future, these findings should be interpreted with discretion. 3.13. Ginkgolide B Ginkgolide B is a polyphenolic terpenic lactone and it is the principal component of Chinese medicinal herb Ginkgo biloba [85]. Ginkgo biloba has been used in ancient Chinese medicinal practice for treating heart ailments, menstrual issues, sea and high altitude sickness etc. [85]. Kim J et al. have demonstrated that incubation of freshly isolated adult ventricular myocytes with Ginkgolide B, in the high glucose conditions, was able to significantly inhibit the cardiomyocytes contractile/relaxation parameters, without any effect on the proteins involved in the Ca2+ handling. However, till


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date there are no studies that have reported its direct effect on improvements of cardiac function in the diabetic hearts [86]. 3.14. Gypenosides Gynostemma pentaphyllum has traditionally been used in the Chinese medicinal practice for the treatment of cardiovascular diseases and cancer [87]. Further it has also been reported to have antiinflammatory, anti-aging and anti-oxidant properties [87]. Gypenosides belong to the class of glycoside and it has been shown to elicit protection against ischemic myocardial injury [88]. Ge M et al. have demonstrated that treatment of diabetic rats with gypenosides, significantly improved the diabetes induced alterations in the cardiac hemodynamic parameters, without any effect on the proteins that were responsible in Ca2+ handling and myofilaments [89]. However, the precise molecular mechanism for these purported effects of gypenosides is still not clear. 3.15. Luteolin Leuteolin is the flavonoid present in several green leafy vegetables and in tomatoes [90]. Leuteolin has been shown to possess several pharmacological properties including anti-inflammatory and antioxidant activities [90]. In a recent study, Guoguang Wang et al. have reported that treatment of diabetic rats with leuteolin significantly improved the cardiac hemodynamic functions and decreased oxidative stress, apoptosis via augmentation of Akt and hemeoxygenase-1 (HO-1) expressions respectively in the myocardial tissues. Further it also significantly reduced the pro-fibrotic marker CTGF in the diabetic myocardium; however the direct histopathological evidence of decreased collagen accumulation in the diabetic myocardium was not presented [91]. Interestingly in their study leuteolin treatment significantly increased the HDL levels, which can partly explain the beneficial effects of leuteolin in the diabetic myocardium via amelioration of lipotoxicity. 3.16. Pycnogenol Pycnogenol belongs to the class of phyto-tannin and also possesses phenolic groups. It has been shown to be the major constituent of pacific pine tree bark (Pinis pinaster), and its effect on the diabetic myocardium is hitherto unknown [92]. To this end, Jan Klimas et al. explored its effect on the diabetic myocardium and reported that it significantly improved the cardiac function, and decreased lipid-peroxidation in the myocardium. However it did not significantly affected the molecular maladaptations in the ROSgeneration enzyme – NADPH-oxidase and cytoskeletal proteins [93]. Therefore, it was inferred that pycnogenol protective effect in ameliorating diabetes-induced myocardial injury can be directly ascribed to its free-radical quenching activity. Paradoxically, same groups of authors recently reported contradictory observations that pycnogenol was ineffective in reducing the QT prolongation in the diabetic myocardium [94, 95]. Therefore further studies are warranted to establish the clear-cut effect of pycnogenol in the diabetic myocardium. 3.17. Resveratrol Resveratrol is a natural trans-stilbene compound with phenolic functional groups and is found in the skin of red grapes (Vitis vinefera) and it has been reported to exert a variety of biological effects [96]. Through its anti-oxidative properties, it has been shown to prevent or dampen the progression of a wide variety of illnesses, including cardiovascular diseases, neurodegenerative diseases and cancer [96]. Resveratrol has been reported to modulate the activation of key transcription factor – nuclear factor (erythroidderived 2)-like 2 (Nrf2), which plays a pivotal in regulation of antioxidant defense against various stress conditions [97]. In addition, resveratrol also activates sirtuin (silent mating type information regulation 2 homolog) 1(SIRT1), a transcription factor which regulates the energy metabolism and mitochondrial function [98]. Sulaiman M et al. reported that treatment of the diabetic animals sig-


nificantly augmented the SIRT1 activation, induction of SERCA expression and activity and improved the cardiac function [99]. In addition resveratrol also reduced the oxidative-stress, inflammatory cytokine expression, fibrosis and apoptosis in the diabetic myocardium [99-101]. Next, resveratrol also significantly inhibited diabetes induced decreased mitochondrial capacitance, via arresting the de novo ceramide synthesis and by restoration of autophagy capacity, thus preventing the demise of cardiomyocytes by apoptosis [102, 103]. Although several pre-clinical studies have demonstrated significant beneficial effects of resveratrol on mitigating vascular inflammation and the pathogenesis of diabetic vascular complications, however, the pharmacological activity (bioavailability and activity) of resveratrol in human subjects cannot be established. 3.18. Sulforaphane Sulforaphane is an organosulfur compound and can be found in significant amount in cruciferous vegetables, especially in broccoli (Brassica oleracea) [104]. Numerous studies have reported that sulforaphane protects against oxidative stress mediated tissue injury and inflammation in several pre-clinical disease models [104]. Most of these effects were related to its potent ability to activate the pivotal transcription factor – NEF-2related factor (Nrf2), a crucial rheostat, which regulates redox status and metabolic activity in the cells and it has also been shown to interact with peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1), which regulates the energy metabolism and insulin action in liver, adipocytes and skeletal muscles [105, 106]. Recently, we demonstrated that treatment of diabetic animals with sulforaphane counteracted diabetes-induced oxidative stress mediated myocardial tissue injury via activation of Nrf2, which resulted in the induction of heme-oxygenase -1 (HO-1) an acute-phase respondent, that augmented endogenous anti-oxidant defenses and blunted inflammation, apoptosis and fibrosis in the diabetic hearts. Similar findings were recapitulated in vitro studies which were conducted in cardiomyoblasts (H9c2), wherein sulforaphane mitigated high glucose induced pro-fibrotic and inflammatory changes via activation of Nrf2, and these phenotypic changes were abrogated when Nrf2 was genetically ablated, indicating that sulforaphane specifically recruits Nrf2 in conferring protection against diabetic myocardial tissue injury [107]. In a separate study, we also demonstrated that in a murine model of type-2 diabetes, sulforaphane treatment rescued diabetes-mediated suppression of 5’ - AMP activated protein kinase activity [(AMPK) - an enzyme that plays a pivotal role in the energy metabolism activity], via up-regulation PGC-1. This finally resulted in attenuation of diabetes-induced myocardial lipotoxicity, oxidative stress, inflammation, apoptosis and fibrosis. In addition sulforaphane treatment exhibited marked improvements in cardiac function in the diabetic animals [108]. 3.19. Tanshinone IIA Tanshinone IIA is a diterpenoid napthaquinoline compound and it has been extracted from Chinese herb Salvia miltiorrhiza. Salvia miltiorrhiza has been traditionally used in the treatment of cardiovascular diseases, hepatitis B infection and stroke [109]. Sun D et al. reported that tanshinone IIA treatment to diabetic animals significantly inhibited myocardial oxidative stress, inflammation and apoptosis. They postulated that tanshinone IIA induced myocardial protection in the diabetic milieu, was via augmentation of Akt activation and glycogen synthase kinase 3- (GSK)-3 phosphorylation [110]. GSK-3 plays a crucial role in governing cell cycle and proliferation, under physiological conditions, GSK-3 is inactive in its phosphorylated state, upon stress stimulus, it gets dephosphorylated and participates in programmed cell death pathway. Previous studies have suggested that GSK-3 undergoes de-phosphory-lation in the diabetic myocardium, which concurred with enhanced apoptosis [111]. Further tanshinone IIA has been found to restore cardiac function in the diabetic animals as assessed by echocardiography. Same group of authors have also demonstrated that tanshinone IIA

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attenuated ischemic-reperfusion injury in diabetic myocardium via aforementioned mechanism, and reduced the infract size and improved cardiac function [112]. CONCLUSION From the compilation of pre-clinical studies presented here with respect to the effect of phytochemicals in the diabetic myocardium, it is apparent that these plants derived chemicals, significantly attenuated the myocardial tissue damage in the diabetic heart via counteracting lipotoxicity, oxidative stress, inflammation, and apoptosis, being the key mediators involved in the development of DCM (Fig. 3). While several epidemiological studies have associated the consumption of fruits and vegetables with a decreased risk of developing several chronic cardiovascular complications, interventional studies have generally not confirmed these beneficial effects. The reasons for this discrepancy are not fully understood but may include potential differences in dosing, interaction with the food matrix, and differences in phytochemical bioavailability and genetic polymorphisms of the drug metabolism and disposition enzymes [113]. In addition to endogenous factors such as micro biota and digestive enzymes, phytochemicals-drug interactions can also considerably affect its bio-accessibility, uptake, and further metabolism, which could compromise its bioactivity [114]. Several reports in the literature have demonstrated dietary curcumin and resveratrol reduces inflammation and delays or prevents obesity-induced insulin resistance and associated complications, cardiovascular diseases such as hypertension and atherosclerosis in variety of pre-clinical and cell culture studies. On the other hand, ironically, it is pertinent to consider that dietary curcumin/resveratrol is poorly absorbed by the digestive system and undergoes glucuronidation and excretion rather than being released into the serum and systemically distributed, which is essential for its bioactivity [115, 116]. Nonetheless improvised and effective techniques of curcumin delivery methods need to be developed. For instance coating with nanoparticles and lipid/liposome formulations, which could increase the absorption and bioavailability of curcumin, are to be perused [70]. The above arguments could also hold good for the other phytochemicals discussed herein, since their pharmacological activity in human beings is yet to be established. In addition, majority of the phytochemicals that have been investigated in the pre-clinical models of DCM, were based on preventive strategy, i.e., wherein phytochemicals were administered right after the animals had developed hyperglycemia. However, only limited number of studies have examined and reported the therapeutic interventional potential of phytochemicals on the mitigation of myocardial tissue injury in diabetic heart, which enacts the true clinical significance. To tap the therapeutic potential of these natural compounds for treatment of DCM, it requires extensive studies to elucidate its precise/bonafide effects on the known molecular targets that are apparently altered in the myocardial cellular components such as cardiomyocytes, fibroblasts, and endothelial cells. This approach could be accomplished by focusing our attention on synthesizing phytochemical analogues/derivatives by applying our medicinal chemistry knowledge of phytochemicals, and use them as template/prototypes, to selectively target a key molecular target/pathway and or use them as adjuvant agents to treat the DCM. As a major thrust to this approach, PKC- inhibitor (Ruboxistaurin) has been developed based on the chemical structure of chelerythrine and it is currently undergoing phase 3 clinical trials for the treatment of diabetic retinopathy. Similarly, cannabidiol (CBD) being a non-psychoactive phytocannabinoid with proven safety, tolerability and pharmacokinetics has been approved by United States food and drug administration (USFDA) for the treatment of chronic pain associated with multiple sclerosis [117]. Recently, clinical trials on diabetic neuropathy revealed that CBD provided promising results in alleviating pain, however, this needs to be confirmed in large scale clinical trials.


Next, CBD also exhibited potential beneficial effects in improving the quality of life in patients with Parkinson’s disease [118]. Moreover, CBD has also been approved for further clinical testing for the treatment of childhood epilepsy [119]. Hence, CBD has profound potential to be translated for clinical use in the management of DCM. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Mohanraj Rajesh, Bassem Sadek, and Shreesh Ojha were supported by intramural research grants sponsored by office of graduate studies and research from United Arab Emirates University. Lu Cai was supported by grants from American Heart Association (# 1-11-BS-17 & 1-15-BS-18) respectively. LIST OF ABBREVIATIONS Akt = Protein kinase B AMPK = 5’AMP activated protein kinase CTGF = Connective tissue growth factor DAG-PKC = Diacylglycerol protein kinase C FFAs = Free fatty acids GSK-3 = Glycogen synthase kinase 3 HO-1 = Heme-oxygenase-1 ICAM-1 = Intercellular adhesion molecule 1 IL-1 = Interleukin 1 beta MAPK = Mitogen activated protein kinase MCP-1 = Monocyte chemotactic protein = Nuclear factor kappa B NFB Nrf2 = Nuclear factor (erythroid-derived2) - like factor 2 PARP = Poly (ADP-ribose) polymerase PKC = Protein kinase C PPAR- = Peroxisome proliferator-activated receptoralpha PPI-1 = Protein phosphatase inhibitor-1 = Ryanodine receptor RrR SERCA = Sarcoendoplasmic reticulum ATPase SIRT1 = Silent mating type information regulation homolog 1 TNF = Tumor necrosis factor alpha VCAM-1 = Vascular cell adhesion molecule REFERENCES [1] [2] [3] [4] [5]

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Received: January 28, 2016

Accepted: March 21, 2016

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