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«DOCTOR OF PHILOSOPHY By NEHA ATALE (10401004) Department of Biotechnology JAYPEE INSTITUTE OF INFORMATION TECHNOLOGY (Declared Deemed to be ...»

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Synopsis of the Thesis submitted in fulfillment of the requirements for

the Degree of





Department of Biotechnology


(Declared Deemed to be University U/S 3 of UGC Act) A-10, SECTOR-62, NOIDA-201307, INDIA February 2016 (A) Introduction I. Importance of the present study The prevalence of diabetes is rapidly increasing day by day and has reached epidemic proportions worldwide. It is found to be associated with various micro and macrovascular complications such as coronary artery diseases and other cardiovascular disorders [1, 2]. The stress generated in hyperglycemia lead to two to four fold increase in cardiovascular diseases as compared to the non-diabetic groups [3, 4]. In developing countries, this ratio will occur more than double till the end of 2030 [5] and will become a leading cause of substantial morbidity and mortality among people. This pathological condition generates an imbalance between reactive oxygen species (ROS) production and the antioxidant defense system, thereby increasing ROS mediated oxidative stress on cardiac cell [6, 7].

The state of glucose induced oxidative stress not only disrupts the activity of cellular metabolism but also regulate extracellular matrix in cells and degrades structural collagens (mainly type IV collagen) leading to cardiac remodelling that involves molecular, cellular, and interstitial changes which ultimately modulate the size, shape and function of the heart.

Cardiac failure is an outcome of the cascade of such events and contributes to modulation of the extracellular matrix (ECM) [8, 9]. Gelatinases, primarily MMP-2 (Gelatinase A- 72 kDa) and MMP-9 (Gelatinase B- 92 kDa) are most characterized matrix metalloproteinases in cardiac system [10]. The central role of MMPs in ECM remodeling makes them an attractive drug target during diabetic cardiomyopathies [11, 12]. A number of MMP inhibitors have been developed over the past few years, however, their design, synthesis, development and testing has been a big challenge due to their toxic side effects and no satisfactory results are obtained till date as they fail in clinical trials [13]. To identify new MMP inhibitors having less toxicity and more specificity is therefore of utmost importance [14]. In addition, drugs like metformin and pioglitazone prescribed by clinical practitioners against diabetes create more problems in the longer run in different organs eg. cardiovascular system, eyes, kidneys and nerves [15]. Therefore, there is a great need for the development of an effective, safe and cost effective therapy against diabetes associated cardiac complications.

Plants are natural source of phytochemicals, which have the potential to act against various diseases through their multifold properties [16, 17]. Recently, there is a great deal of interest Synopsis-2 observed among scientists in identifying the safe and cheaper source of antioxidants that hold health promoting therapeutic potential.

At the same time, these plant based polyphenols are found to be less toxic and their marked effects in the prevention of oxidative stress have been well documented [18]. Plant based therapies are in trend from the a ncient time. Various plants and plant products as shown in Table 1 were known to have protective activities in various pathological conditions [19-22].

However the exact mechanism of their action is poorly defined.

Syzygium cumini (L.) skeels, (Myrtaceae) is found to be important in Ayurveda and Unani medicine to fight against diabetes. The plant is evergreen in nature with fruits rich in iron, calcium, phosphorus, minerals, vitamin-C, sodium, potassium and carotene and are known to useful in suppressing oxidative stress [23, 24]. S. cumini leaves have been used extensively for treatment of diabetes, stomach ache, leucorrhoea, fever, constipation gastropathy, dermopathy and possess antibacterial, anthelmintic, hypoglycemic and anti-diarrhoeal activities attributed to the presence of phytochemicals [25-27]. We selected Syzygium cumini for our study due to its antidiabetic nature and with an intention to explore its cardioprotective properties under glucose stress. The present study was designed to carry out analysis of bioactive components and anti glycoxidative properties in pulp and seeds of S. cumini and enriched extract was selected to investigate the cardioprotective potential under in vitro hyperglycemic conditions.

Many herbal products despite of their significant potential in in vitro systems failed to replicate similar efficiency in in vivo models due to their poor lipid solubility and size, resulting in poor absorption leading to poor bioavailability. To counter this issue we also synthesized silver nanoparticles (SNPs) by green methods using S. cumini methanol seed extract as reducing agent. SNPs have recently been studied for their antidiabetic potential where a significant reduction in blood glucose level was observed in diabetic rats and also found to be beneficial in delayed diabetic wound healing [28-30]. Our hypothesis is that, silver nanoparticles containing S. cumini phytoneutrients may pass blood brain barrier and be less toxic to human cardiac cells (dose & time dependent manner).

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Table 1 shows list of some Indian medicinal plants exhibiting biological activities as observed from literature and studies conducted in our laboratory. Some of the plants such as T. arjuna were reported to be cardioprotective under glucose stress but was found to be failed in clinical trial and also their mechanism is not well characterized. Based on such comparative analysis, we selected S. cumini, suitable for our study as being a well known antidiabetic, it cardioprotective, antiapoptotic and anti- MMP activity under glucose induced cardiac stress were not explored earlier. S. cumini is non toxic and taken as a dietary supplement. Most interestingly, we conducted our study on nonconsumed fruit part, the seeds of S. cumini that may provide a cost effective, safe and natural therapy in future against glucose induced cardiac stress.

(B) Origin of the proposed work Diabetes is found to be commonly associated with cardiovascular diseases causing significant morbidity and mortality. Many antidiabetic drugs have cardiovascular side effects too.

Cardiac toxicity believed to be a multi-factorial process and leads to cardiomyocytes death as


terminal downstream events. In diabetes, the levels of free radicals increase drastically, thereby disturbing the equilibrium between free radical productions and antioxidant capability which ultimately lead to cardiac failure. Based on the growing demands of natural products and considering the disadvantages associated with synthetic drugs, the study stimulate s the usage of natural products. Reports have demonstrated that anti-oxidant natural substances including herbal medicines could inhibit the diabetic cardiomyopathies by inhibition of ROS generation. Hence S. cumini as an antidiabetic plant, may represent a promising source for protecting cardiac cells against the diabetic cardiomyopathy. Use of crude extracts rather than isolated compounds could be an approach to increase the efficacy of the therapy. To take into account the increasing diabetic population and associated cardiac malfestations, there is an upsurge to develop a safe and less toxic therapy for long-term relief. The proposed study is therefore designed to investigate the effect of S. cumini against glucose induced cardiac stress.

(C) The relevance and expected outcome of the proposed study Proposed work aims to study the screening of cardioprotectants from traditionally used Indian medicinal plant, Syzygium cumini which would contribute to study the molecular mechanism of bioactive molecules and to develop therapeutic antioxidative and cardioprotective strategies against diabetic cardiomyopathies, a major cause of mortality worldwide.

(D) Key Questions The key questions of the proposed studies wereWhat are the various bioactive components in Syzygium cumini?

2. Which is the most enriched extract of Syzygium cumini?

3. What is the optimised glucose dose and time for generating stress on cardiac myocytes?

4. What is the safe Syzygium cumini dose for treatment of stressed cardiomyocytes?

5. Is the well known antidiabetic agent S. cumini, a persuasive cardioprotectant too?

6. Is there any effect of Syzygium cumini on extracellular matrix components?

7. Does S. cumini act as a therapeutic target for MMP inhibition under glucose induced cardiac stress?

8. What is the effect of S. cumini on inflammatory cytokines and apoptotic proteins?


9. Can we increase the bioavailability of most enriched Syzygium cumini extract?

10. Do silver nanoparticles synthesised using S. cumini methanol seed extract efficiently suppress glucose induced stress on cardiac myocytes?

(E) Objectives of the study In order to answer these questions, the present study was designed to characterize S. cumini for the presence of phyochemicals and to analyze its cardioprotective potential under glucose induced stress. The main objectives of the study wereObjective 1: Screening of Syzygium cumini pulp and seed extracts for their anti- glycoxidative potential and detailed characterization of selected S. cumini extracts Objective 2: To investigate the effect of S. cumini methanol seed extract (MSE) on glucose induced cardiac stress Objective 3: To evaluate the effect of S. cumini methanol seed extract (MSE) on extra cellular matrix components Objective 4: Characterization of S. cumini silver nanoparticles (ScSNPs) and analyzing their cardioprotective potential on glucose induced stress

Based on the above objectives, the thesis is structured as follows:

Chapter 1- Introduction Chapter 2- Review of literature Chapter 3- Discusses about screening of Syzygium cumini pulp and seed extracts for their anti-glycoxidative potential and detailed characterization of selected S. cumini extracts Contains study conducted to investigate the effect of S. cumini methanol seed Chapter 4 extract (MSE) on glucose induced cardiac stress Demonstrates the experiments and results performed to evaluate the effect of S.

Chapter 5 cumini methanol seed extract (MSE) on extra cellular matrix components Includes study to characterize the S. cumini silver nanoparticles (ScSNPs) and Chapter 6 analyzing their effect on glucose induced cardiac stress

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Chapter 1 Represents the introduction and the current perspectives of the proposed work.

Chapter 2 Describes the review of literature on national and international status of diabetes associated cardiac malfunction and the limitations of the existing therapies.

Chapter 3: Screening of Syzygium cumini pulp and seed extracts for their anti glycoxidative potential and detailed characterization of selected S. cumini extracts This section deals with the introduction, material and methods, results, discussion and conclusions of the objective 1. The comparative analysis of various S. cumini extracts were performed to find out the most enriched extract. Initially, S. cumini fruits were collected and authenticated by a botanist. The seeds and fruits were separately examined for the presence of phytocontents. Aqueous and organic solvents pulp and seed extracts prepared in ethanol, methanol, diethyl ether, n-hexane, benzene and chloroform were screened for the presence of tannins, flavonoids, terpenoids, glycosides, phenol, alkaloids, steroids, saponins, reducing monosaccharide, anthraquinones and proanthocyanidins. Aqueous (ASE), ethanol (ESE) and methanol seed extracts (MSE) as well as aqueous (APE), ethanol (EPE) and methanol pulp extracts (MPE) showed the presence of most of the phytochemicals in higher amount as compared to diethyl ether (DSE; DPE), n-hexane (HSE; HPE), benzene (BSE; BPE) and chloroform (CSE; CPE) extracts. Therefore we limited our study towards the aqueous, ethanol and methanol pulp and seed extracts and performed a comparative analysis to explore most enriched extract of S. cumini.

For that, firstly, anti-glycoxidative potential of S. cumini seeds and fruit pulp was evaluated by antiglycation [31] as well as 2,2-diphenyl-1-picrylhydrazyl (DPPH) [32], 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) ABTS [33], Nitric Oxide (NO) [34], hydrogen peroxide (H2O 2) [35] and superoxide anion (O 2 ) [36] assays. At 1 mg/ml concentration, methanol seed extract showed highest antiglycation (79 ± 1.00%) and scavenging potential for DPPH (60.87 ± 0.06%), ABTS (84.86 ± 2.18%), NO (72.87 ± 1.18%), H2 O2 (75.65 ± 1.45%) and O2 (71.53 ± 2.04%) as compared to methanol pulp extract which showed antiglycation potential (59 ± 1.32%) and inhibition potential for DPPH (59.76 ± 0.50%), ABTS (81.61 ± 1.37%), NO (68.33 ± 1.33%), H2O 2 (70.19 ± 2.38%) and O2 (64.19 ± 1.43%) respectively.

Hence, our study illustrated that among aqueous, ethanol and methanol seed and pulp extracts,


methanol extracts showed highest scavenging for such free radicals. On further comparison between methanol pulp and seed extracts, highest antioxidative potential was observed for MSE.

Increasing evidences in both experimental and clinical studies suggest that free radicals formed disproportionately during diseases lead to increased lipid peroxidation. We therefore investigated the effect of S. cumini pulp and seed extracts on non enzymatic peroxidation of lipids by measuring the levels of malondialdehyde (MDA), which is produced based on the acid-catalyzed decomposition of lipid peroxides. The Ferric thiocyanate method indicates the amount of peroxide in the initial stages of lipid peroxidation whereas the thiobarbituric acid method shows the amount of peroxide in the secondary stage of lipid peroxidation [37, 38].

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