A.J.A. Petrus - PhcogFirst maderaspatana (Linn.).pdftimes indicates that the regular consumption of non-nutri - ... Gujarati Chanak-chibhdi Tindori Hindi ... dishes in the South Indian

Phcog J | Dec 2012 | Vol 4 | Issue 34 1

R E V I E W A R T I C L EP H C O G J

ABSTRACT

Mukia maderaspatana (Linn.) M. Roemer, (Family: Cucurbitaceae) [syn.: Melothria maderaspatana (L.) Cogn.], is distributed throughout the tropics and subtropics of the Old World. Different organs of the drug-plant are utilised in Ayurveda, Siddha, Naturopathy and Folkloric traditional medicines of India as well as the indigenous medical systems of the Sub-Saharan African, Asian and Australian communities for health-care needs. The leafy vegetable is reported to exhibit potent antioxidant capacity in vitro and in vivo and to possess antihypertensive, vasodialatory, antihyperglycemic, antihyperlipidemic, hepatoprotective, immunomodulatory, antiinflammatory, antirheumatic, antiulcer, anxiolytic, antimicrobial, and antiplatelet aggregation activities. The present review is an attempt to highlight, for the first time, the current clinical and experimental evidences available in literature on the extent of its potentials to protect against vascular events and diabetes.

Keywords: Mukia maderaspatana, Melothria maderaspatana, Cucurbitaceae, Antihypertensive, Antihyperglycemic, Antihyperlipidemic.

Mukia maderaspatana (Linn.) M. Roemer: A potentially antidiabetic and vasoprotective functional

leafy-vegetableA.J.A. Petrus

Department of Chemistry, Kanchi Mamunivar Centre for Post-Graduate Studies (Autonomous), Puducherry-605008, India

Submission Date: 3-10-2012; Review Completed: 10-11-2012; Accepted Date: 30-11-2012

INTRODUCTION

The focus of nutrition research, today, is heading towards the concept of ‘Preventive Medicine’, and experts have predicted that nutrition will become the primary treatment modality in the 21st century.[1] Meta analysis of epidemi-ologic (case-control and cohort) studies of the present times indicates that the regular consumption of non-nutri-tive bioactive phytoconstituents, derived from plant-based diet, can reduce the risk of a number of diseases, including cardiovascular.[2,3] Edible plants possessing health promot-ing capacities are, therefore, being re-scrutinised to exploit their potentials as nutraceuticals, which are bioactive com-pounds that confer protection from chronic diseases via

mechanisms that are well beyond simply providing nutri-tion. Research has clearly demonstrated that similar to pharmaceutical agents, functional foods and nutraceuticals possess physiological and molecular targets that modulate clinical end-points associated with chronic diseases. Con-sequently, functional foods/ingredients also tend to offer new economic opportunities. The present review is an attempt to offer for the first time an overview of the antidia-betic and vasoprotective potentials of the functional leafy- vegetable, Mukia maderaspatana (Linn.) M. Roemer, ( Family: Cucurbitaceae) [syn.: Melothria maderaspatana (L.) Cogn.], which is a coveted taxon in Ayurveda, Siddha, Naturopathy and Folkloric traditional medicines of India as well as the indigenous medical systems of the Sub- Saharan African, Asian and Australian communi-ties. Literature reports the widespread occurrence of M. maderaspatana throughout the tropics and subtropics of the Old World[4] and the common names of the food plant are briefed in Table 1. The drug is an ingredient of the Ayurvedic preparations, like Pipalyasava, Rasayanar-ishta, Srikandasava and Manasamitra vatakam, according to the descriptions in Sarngadhra Samhita, Bhaishajya Ratnavali, Kadhanikragam, Yogaratnagaram and Sahasrayaham. In Siddha,

*Corresponding author. A.J.A. Petrus 212, Lal Bahadur Sastry Street Puducherry 605001Tel.: +91(413)2221419

E-mail: [email protected]

DOI: 10.5530/pj.2012.34.1

A.J.A. Petrus: Antidiabetic and vasoprotective potential of Mukia maderaspatana

2 Phcog J | Dec 2012 | Vol 4 | Issue 34

Language Common/Local NamesEnglish Madras pea pumpkin

Bristly bryonyRough bryonyWild cucurbit (Punjab-Pakistan)

Burmese SathakhivaThabwotkha

Chinese Hong guaMao er gua Mao hua ma jiao er (Taiwan)

Filipino Melon-gubat Hausa Gautan zomo

MalamiMalami na mata

Japanese Sango ju suzume uriMundari Huringkaubutuki

JapaputusJhajinariKauasanggaKaubutukiMerommed

Nepalese Matyangre kankriSunkeshre laharoLadbhadi (Bantar) Nagilangiai (Tamang)

Sindhi BellariChirati

Sinhala Gon-kekiriHeen-kekiri syn. HinkekiriKekiriLene-kekiri syn. Lenkekiri

Tagalog Melon-gubatThai Taeng nok (Kanchanaburi)

Taeng nu (Northern, Northeastern)Taeng phi pluk (Chai Nat) Taeng nu khon (Prachuap Khiri Khan) Taneng nuu

Urdu MusmusaChibbher (Punjab-Pakistan) Chibhari Wal (Pakistan) Chirati (Pakistan)

Vietnamese Cãu qua ãnCầu qua nhám

Bengali AgmukiBilariPatilalau (Bangladesh)

Gujarati Chanak-chibhdiTindori

Hindi Aganaki AgumakiAnkh-PhodAnkh phutani belAunkharoBilariGulya kakriLaghumukhiMusmusaParipushkaraPindilaSetu

Kannada ChitratiKaadu paavate balliMani toned syn.Mani tondeMani thonde syn.ManidondeSanna hindele kaayi

Language Common/Local NamesKonkani ChiratiKumaoni Agumarki

BilariGwalakakri

Malayalam AattangaChitratiMukkapeeram syn.MukkapiramMukkalpeeramMukkaalpiramMukkappeeramMucca-pinMukkappiriMushumushka

Manipuri Lam-thabiMarathi Bilavi

ChiraatiGhugri KharwadMeka Ringana vaela

Punjabi Gwala kakriRajasthani Ankh-Phutani ki belSanskrit Ahilaykhan

GhantaaliKritarandraKrtarandhrahMusimusikkayiParipushkaraPindilaSetuTrikoshaki

Tamil MusumusukkaiMochumochukkai (Sri Lanka)Muchumuchukkai (Mosumosukkai)AayilaiyamBommusutaiCempucattumuliCunaikkotiElavalukamKattumucukkaiKattuvellariMaamooliNagilangiaiParipuskarai

Telugu Budama dosaChedupullaKutaru budamaKuturu budamLingadondaMusumusukayaNugudosa syn.NoogudosaPotti budamuPutribudinga

Tulu Baana koraluMukkattere

Trade or popular name Gwala KakriBariba (Benin, West Africa) KobionPulaar and Fulfulde (Senegal, West Africa)

Pomey

Banda (Oubangui)Manja (Oubangui, Central African Republic)

AkayaNya chindo

Swahili (Bushi area, Kivu province, Democratic republic of Congo)

Murhalagala

Table 1. Common/Local names of M. maderaspatana.4



the root and leaf are used to treat fever, dyspnoea, abdomi-nal disorders, hepatic disorders, cough and vomiting and the leaf decoction to treat HT and nasobronchial diseases. The drug is also marketed in India under the trade names: Asthacure, Asthmex, Bronkease, Respease and Musumusuk-kai chooranam, for treating bronchial asthma, allergic bron-chitis, chronic bronchitis, bronchiectasis, productive cough and cold, upper and lower respiratory tract infections and difficulty in breathing. In the Philippine folkloric medicine, the tender shoots and bitter leaves of melon-gubat (Filipino) are used as gentle aperient and also for treating vertigo and biliousness. The Paniya, Kuruma and Kattunaikka com-munities[5] and the Palliyars[6] of the Western Ghats and reportedly certain tribes of the West Himalaya,[7] gather M. maderaspatana as wild edible greens for food. Leaves, stem, fruits and roots are reported to be used as a functional veg-etable among various communities.[8–10] Deliciously cooked savouries using the leaves and tender shoots are common dishes in the South Indian cuisine and a few recipes are also available in the internet. The drug-plant has been reported to possess antihypertensive, vasodialatory, antihyperglyce-mic, antihyperlipidemic, hepatoprotective, immunomodula-tory, antiinflammatory, antirheumatic, antiulcer, anxiolytic, antimicrobial, and antiplatelet aggregation activities as well as potent antioxidant capacity in vitro and in vivo.[11–13]

VASOPROTECTIVE POTENTIAL

A significant amount of research has demonstrated the health benefits of plant-based diets, which have consis-tently been associated with reduced risk of a number of ailments prevalent today, and increase longevity.[14] CVD continues to be the leading clinical and public health issue in developed countries and increasingly so throughout the world. HT and hypercholesterolemia are well-defined risk factors for CVD and the most important cause of stroke and coronary heart disease. According to WHO estimates, CVD will be the leading cause of death and dis-ability worldwide by the year 2020.[15,16] Diet is considered the cornerstone for CVD treatment, as it can lower not only atherogenic lipoprotein levels and degree of oxida-tion, but also BP, thrombogenesis and concentrations of certain relevant factors.[16]

Protection in hypertension and dyslipidemia

Clinical evaluations

Hypertension is a CVD with the greatest epidemiological impact in the world and also represents a major risk fac-tor for developing other diseases such as endothelial dys-function, metabolic syndrome, diabetes, renal dysfunction,

congestive heart failure, coronary artery disease and stroke. Insulin resistance has also been recently suggested as a key contributor to the metabolic syndrome (a cluster of medi-cal conditions characterized by overweight/ obesity, disli-pemia, hyperglycemia, and HT) that play a significant role and contributes considerably to CVD risk.[16]

Published literature claims that the Siddha practitioners of Tamil Nadu, India, have been treating HT using decoctions of the leaves of M. maderaspatana over centuries.[17] Attempts have, therefore, been made to elucidate the impacts of its aqueous leaf extract on mild-to-moderate hypertensive human volunteers. The treatment, according to Raja et al.,[18] has significantly attenuated both, SBP and DBP, strength-ened blood antioxidant potential, and lowered glycoprotein components among hypertensive subjects. The study has subsequently been extended to include a total of 50 subjects: 25 mild-to-moderate hypertensives (SBP≥140 and DBP≥ 90 mm Hg) and 25 normotensives. Treatment prescribing the consumption of the traditionally decocted aqueous leaf-tea (2.0 ± 0.5 g twice a day, for 45 days) has again been observed to result in significant reductions in both SBP (from 159.4 to 135.6 mmHg) and DBP (101.0 to 85.5 mm Hg), pulse rate (81 to 72 / min), BW (66 to 61 Kg) and BMI (25.0 to 22.6 Kg/m2). A significant decrease has also been noticed in TC (from 202 to 186 mg/dL), LDL (131.5 to 118.7 mg/dL), VLDL (34.5 to 28.8 mg/dL), TG (172.4 to 143.9 mg/dL), FFA (30.9 to 26.7 mg/dL) and PL (170.8 to 161.1 mg/dL), concomitantly with an increase in the HDL (36.0 to 38.2 mg/dL) during the post-treatment evaluation.[19] A significant decrease in plasma fibrinogen (from 315.9 to 298.4 mg/dL) and increase in serum bilirubin (0.78 to 0.88 mg/dL) levels have additionally been observed with no difference in albumin levels. The authors have commented that these effects might have contributions from phytoster-ols, since low-dose phytosterol-supplementation has been reported earlier to produce significantly lowered plasma TC. Vasanthi[20] has characterized a number of pharmaco-logically significant terpenoids (13–24), including phytoster-ols (Fig. 1) from the lipophilic fraction of the leaf-extract. Phytosterols are cholesterol homologues and their lipid-lowering effect is mediated by competitive inhibition of cholesterol absorption and by transcriptional induction of genes implicated in cholesterol metabolism in both entero-cytes and hepatocytes.[21] The reduced absorption stimu-lates LDL-receptor formation, which, in turn, increases the hepatic uptake of LDL and thus decreases LDL levels.

A total of 234 subjects, consisting of 89 men and 82 women hypertensive patients (mean age = 58 ± 7.0 y) and 39 men and 24 women normotensive volunteers (mean age = 48 ± 6.0 y), who had no history of HT, DM, alcoholism,



cigarette smoking or any other chronic illness have been recruited as control subjects for further investigations.[22] Treatment on similar lines has been reported to significantly reduce SBP, DBP and pulse pressure as well as BW and BMI. Saturated fatty acid content of erythrocytes had been reduced significantly from 59.5 to 47.1 mg/dL, while mono unsatu-rated fatty acids, poly unsaturated fatty acids and membrane fluidity of erythrocytes have been recorded to have improved (p<0.01) among the hypertensive subjects. Membrane fluid-ity, in this study has been assessed using spin labelling tech-niques and electron paramagnetic resonance spectroscopy.

Preclinical animal experiments

Long-term administration of DOCA to rats induces sodium retention and consumption of high salt results in volume-dependent HT. Veeramani et al.,[23] have investigated the antihypertensive effect of CELE of M. maderaspatana on

sham-operated and uninephrectomized DOCA-salt-induced-hypertensive Wistar rats. Subcutaneous injection of DOCA-salt solution (25 mg/Kg BW, twice-weekly) in dimethyl formamide, and feeding the animals with a solution of 1% sodium chloride in lieu of drinking water ad libitum had induced HT in the animals. The SBP, DBP and mean arterial BP have been reported to have significantly elevated after six-week injection of DOCA-salt, compared to the sham-oper-ated control. Treatment with CELE (200 mg/Kg BW) had manifested significant decrease in the elevated BP to a magni-tude, closer to those of the calcium channel blocker nifedipine (20 mg/Kg BW), at the end of the six-week study period.[24]

Effect on the antioxidant status in DOCA-salt hypertensive rats

The effect of the CELE on the antioxidant status of the animals has also been investigated by Veeramani et al.[24] LP

Figure 1. Biologically significant classes of metabolites characterized from M. maderaspatana.



initiated by RS, results in a number of secondary oxida-tion marker products, including MA. MA is the commonly monitored marker biomolecule to evaluate the antioxidant capacity of substances in LP systems and MA-TBA assay has evolved as a model to evaluate the antioxidant capaci-ties of various natural products. However, TBA reacts with many different carbonyl compounds formed from

LP and hence, a more relevant parameter, viz., the total carbonyl compounds reacting with TBA, called TBARS has come into existence. Administration of CELE (200 mg/Kg BW, 6 weeks) to the DOCA-salt-hypertensive rodents has been reported to cause significant reductions in the salt-induced elevations of the TBARS in plasma as well as in liver, kidney and heart tissues (Table 2).

Table 2. Effect of M. maderaspatana crude ethanolic leaf extract on the blood pressure, TBARS, lipid hydroperoxide, and enzymatic and non-enzymatic antioxidant status in DOCA–salt hypertensive rats.24

Activities & Specimen analysed

Sham-operated control DOCA-salt + 1% saline control

DOCA-salt + 1% saline + 200 mg/Kg leaf-extract

DOCA-salt + 1% saline + 20mg/Kg nifedipine

Blood pressure Systolic (mm Hg) 127 212 135 132 Diastolic (mm Hg) 91 175 96 93 TBARS Plasma (mmol/dL) 0.153 0.445 0.165 0.180 Liver (mmol/100 g) 0.854 2.600 0.905 1.030 Kidney (mmol/100 g) 1.450 4.000 1.525 1.775 Heart (mmol/100 g ) 0.525 3.175 0.600 0.825 Lipid hydroperoxide Plasma (mmol/dL) 9.16 20.47 10.65 13.50 Liver (mmol/100 g) 78.57 99.07 82.52 86.97 Kidney (mmol/100 g) 65.48 170.24 70.83 75.95 Heart (mmol/100 g) 69.64 139.88 72.02 77.05 Superoxide dismutasea

Erythrocyte 7.47 3.09 6.93 6.49 Liver 7.94 4.21 6.96 5.66 Kidney 14.48 8.55 12.91 12.35 Heart 5.10 2.81 4.83 4.24 Catalaseb Erythrocyte 168.90 97.26 160.26 153.59 Liver 76.99 52.81 72.47 68.08 Kidney 31.99 18.07 28.04 24.29 Heart 48.57 28.19 44.86 39.30 Glutathione peroxidasec Erythrocyte 15.47 6.64 13.95 10.65 Liver 7.25 4.48 7.02 5.56 Kidney 8.11 3.52 7.15 5.93 Heart 6.93 3.73 5.98 4.94 vitamin E Plasma (mg/dL) 1.88 0.96 1.79 1.51 Liver (μg/mg) 6.01 3.45 5.84 4.92 Kidney (μg/mg) 4.06 1.52 3.86 2.96 Heart (μg/mg) 4.13 1.67 3.98 2.87 vitamin C Plasma (mg/dL) 2.07 0.91 2.03 1.82 Liver (μg/mg) 0.77 0.56 0.74 0.69 Kidney (μg/mg) 0.65 0.39 0.62 0.57 Heart (μg/mg) 0.54 0.27 0.50 0.45 reduced glutathione (GSH) Plasma (mg/dL) 34.73 21.86 32.64 31.36 Liver (μg/mg) 11.77 7.73 10.07 9.12 Kidney (μg/mg) 9.94 4.65 9.01 8.53 Heart (μg/mg) 7.97 3.78 7.20 7.17 DOCA = deoxycorticosterone acetate; TBARS = Thiobarbituric acid-reacting substances;aenzyme concentration required to inhibit the chromogen produced by 50% in one min under standard condition/mg Hb (erythrocyte)/protein (tissue).bμmol of H2O2 consumed/min/mg Hb (erythrocyte)/protein (tissue).cμmole of GSH utilized/min/mg Hb (erythrocyte)/protein (tissue).



It is claimed that the effect has been more pronounced and better realised at 200 mg/Kg BW than the standard nifedipine at 20 mg/Kg BW. Lipid hydroperoxide levels have also been similarly affected in the plasma and tis-sues. Further, the activities of the enzymatic antioxidants such as SOD, CAT and GPx in the erythrocyte and tis-sues, which had been significantly decreased among the DOCA-salt-hypertensive rats, are reported to have sub-stantially elevated towards the magnitudes of the sham-operated controls (Table 2). A similar effect has been reported in the levels of the non-enzymatic antioxidants, vitamins C and E and GSH, in the plasma and tissues (Table 2). The authors have expressed that the phenolic phytochemicals that possess high antioxidant, antihyper-tensive and antidiabetic activities and coumarins having multiple pharmacological activities including anticlotting, hypotensive and antiinflammatory activities might con-tribute significantly to the activities observed. The leaf-extract has been determined earlier to contain 292.4 mg GAE of phenolics/100 g FL.[9] Flavonoids are the ubiq-uitous phenolics of our diet and proven to possess an effect on antioxidant activity and thereby prevent cardio-vascular and other free radical-mediated diseases. A total of 247.1 mg quercetin equivalents of flavonoids/100 g FL, composed mainly of 7-O-β-D-glucopyranosyl-6-C-β-D-glucopyranosyl-luteolin (1) and -apigenin (2), together with 6-C-β-D-glucopyranosyl-apigenin (3) and -luteolin (4) and their isomers, 8-C-β-D-glucopyranosyl-apigenin (5) and -luteolin (6) have been characterised from the leaves (Fig. 1). These compounds have been evaluated to possess RS, including superoxide and nitric oxide scav-enging and metal chelating antioxidant capacities.[12] The flavone 2 (Fig. 1) has been determined by HPLC to be the predominant polyphenol of the leaf, existing to the extent of 220.80 mg/100 g FL.[9] Coumarin (7), in addi-tion to vanillic (8), gallic (9), p-coumaric (10), caffeic (11) and ferulic (12) acids, are the other phenolics that have been identified.[25] The total leaf-antioxidant capacities have also been reported to be contributed by vitamins C and E, and carotenoids to the extent of 17.05, 0.19 and 0.81 mg/100 g FL, respectively.[9] Vasanthi has characterized γ-tocopherol from the lipophilic HFM.[20] γ-Tocopherol is the major tocopherol in circulation and has been found to be an unique antioxidant that protects cells from damages associated with nitrogen-based oxi-dants.[26] γ-Tocopherol, but not α-tocopherol, also acts as an antiinflammatory agent and may, therefore, reduce long-term damages to cells. Limited epidemiologic evi-dence from a prospective study has found a five-fold increase in prostate cancer for those with the lowest γ-tocopherol levels compared with those with the highest levels and α-tocopherol has been associated with reduced

prostate cancer incidence only when γ-tocopherol levels have been high.[26]

Lipid metabolism stabilizing potential in DOCA-salt hypertensive rats

Hypertension is often associated with metabolic abnor-malities, including lipid metabolism. Hyperlipidemia is the primary risk factor of coronary and atherosclerotic heart diseases and is characterized by elevations in TG, TC, LDL, VLDL and depression in HDL. Veeramani et al. have succeeded in demonstrating the antihyperlipidemic potential of CELE on DOCA-salt-hypertensive rats.[27] TG, FFA, PL, TC, LDL and VLDL levels in plasma and tissues had significantly increased while HDL had depressed among the salt-induced-hypertensive animals. Administration of CELE (200 mg/Kg BW, p.o., q.d., 6 weeks) has been reported to normalise the parame-ters, establishing its potent antihyperlipidemic potential (Table 3). Histopathology of the liver, kidney and heart of the animals had revealed favourable reductions in the DOCA-salt-induced damages. Increased LP is thought to be a consequence of OS and the potent antioxidant capacity of M. maderaspatana, which has been demonstrated in a number of studies,[4] might have contributed significantly to the observed eleva-tions in plasma antioxidant levels. This antioxidant strength could have caused a decrease in LP, as dis-cussed in their paper. Consequently, membrane dam-age is prevented, resulting in the decreased plasma and tissue PL and FFA levels.

Effects on the metabolic alterations in magnesium, copper and zinc in DOCA-salt hypertensive rats

The CELE has subsequently been fractionated into CFM, EAFM and MFM. Treatment administering each of these fractions (60 mg/Kg BW, p.o., by intubation, q.d.) in 0.5% DMSO, had resulted in significant lowering of the SBP and DBP (Table 4) only among the EAFM-treated rodents after six weeks.[25] A significant inverse association between dietary phenolics and mortality from coronary heart disease is well established epide-miologically and hence the authors have claimed that the phenolics, especially the antihypertensive ferulic acid (Fig. 1), could have contributed to the elicited antihy-pertensive property. A study has concurrently reported 10.71 mg GAE of phenolics to be present in EAFM.[28] It can also be read from the paper that the EAFM-treatment had re-established the salt-induced metabolic alterations in the levels of magnesium, copper and zinc in plasma, liver, kidney and heart tissues of the test- animals (Table 4).



Table 3. Effect of M. maderaspatana crude ethanolic leaf extract on the lipid profile in DOCA–salt hypertensive rats after 6-week treatment.27


Sham-operated control

Sham-operated control + 200 mg/Kg

leaf-extract

DOCA-salt + 1% saline control

DOCA-salt + 1% saline + 200 mg/Kg

leaf-extract

DOCA-salt + 1% saline + 20mg/Kg

nifedipinePlasmaa

Triglycerides 57.52 55.27 160.39 61.29 118.36 Free fatty acids 55.84 53.46 123.58 59.57 88.45 Phospholipids 80.53 78.08 148.91 84.27 106.68 Total cholesterol 82.16 79.35 166.73 84.47 132.64 High density lipoprotein 46.88 47.64 27.57 43.64 36.07 Very low density lipoprotein 11.50 11.05 32.08 12.26 23.67 Low density lipoprotein 23.78 20.66 107.08 29.37 73.70Liverb Total cholesterol 4.37 3.97 6.46 4.59 5.86 Triglycerides 3.63 3.61 7.37 3.87 5.47 Free fatty acids 8.48 7.89 15.39 8.74 10.48 Phospholipids 24.57 23.77 45.85 25.38 36.26Kidneyb Total cholesterol 4.80 4.45 7.83 4.97 6.19 Triglycerides 3.52 3.43 6.87 3.87 5.13 Free fatty acids 4.63 4.18 9.86 4.86 7.43 Phospholipids 16.57 15.82 30.46 17.57 23.58Heartb

Total cholesterol 2.57 2.44 4.73 2.74 3.75 Triglycerides 4.64 4.04 6.15 4.82 5.37 Free fatty acids 5.47 5.03 10.42 5.83 8.54 Phospholipids 12.07 11.58 22.17 13.03 18.66DOCA = deoxycorticosterone acetate; amg/dL; bmg/g wet tissue.

Protective effect on electrolytes, catecholamines, endothelial nitric oxide synthase and endothelin-1 peptide in DOCA-salt hypertensive rats

Sodium, potassium and chloride play important roles in cellular metabolism and energy transformation and in the regulation of cellular membrane potentials, espe-cially those of muscle and nerve cells. Misregulation of these electrolytes induces a wide range of clinical dis-orders, including HT. Nitric oxide is synthesized and released from the endothelial cell by the activation of eNOS and it plays an important role in the regulation of medullary blood flow. Changes in the medullary flow too can reset the pressure-natriuresis relationship, promote sodium retention and contribute to the development of HT. Also, impaired nitric oxide synthesis, resulting in abnormal regulation of renal blood flow and sodium handling, may aggravate salt-sensitive-HT. In the HT-induced rats, the levels of serum sodium and chloride together with plasma epinephrine and norepinephrine is reported to have increased while potassium, total plasma nitrite-nitrate and L-arginine amounts had decreased.[29] Treatment with EAFM, as before, is recorded to have brought these parameters back to normality (Table 4). It is speculated that stimulation of ET-1 production in vascular tissues is one of the factors that contribute to

the development and/or maintenance of DOCA-salt-induced-HT. eNOS protein expression has been found to have significantly down-regulated (ca. 65%) in the heart and kidney while the ET-1 got up-regulated to similar magnitude in the kidney, but to a lesser extent in the heart of the HT-rats. Treatment with EAFM had prevented the down-regulation of eNOS, and signifi-cantly down-regulated ET-1 protein expressions.

Hypolipidemic potential

Abnormalities in lipids and lipoprotein metabolism, discussed in the preceding paragraphs, play a central role in the pathogenesis of HT. Administration of the aqueous extract of M. maderaspatana (2 g/Kg BW, p.o.) concomitantly with high fat diet to normal albino rats for seven weeks had displayed significant improvements in the lipid profile, according to a literature.[30] Decrease has been realised significantly in the BW (29%), plasma TC (197 mg/dL), TG (118 mg/dL), LDL (100 mg/dL), VLDL (23.5 mg/dL) and hepatic-LPO (772 nmol/g), in addition to improvements in HDL (74 mg/dL) in the blood. However, the authors have claimed to have observed no significant changes in the serum athero-genic index. Histological evaluation of the hepatic tissue of the treated-rat liver has revealed only micro vesicular



fatty changes as against the marked degenerative and fatty changes in the high fat diet-fed animals. The results are claimed to be comparable with the ayurvedic drug, Navaka guggulu churna (400 mg/Kg, p.o.).

In vitro antiplatelet aggregation potential

CVD is characterized not only by the factors reviewed earlier but also include calcification of arteries and increased blood platelet aggregation. HT is a major risk factor for stroke/myocardial infarction as expression of the atherogenic processes and platelets play a fun-damental role in the processes. There exists an equilib-rium between the pro-aggregating and anti-aggregating factors under normal physiological conditions. But in pathological situations, this equilibrium gets disturbed and pro-aggregating factors tend to dominate. Patients with HT have a state of hyper-aggregation and dysequi-librium in the production of icosanoids. A number of phytoconstituents tend to inhibit platelet aggregation and re-establish the broken equilibrium in icosanoid pro-duction. The in vitro antiplatelet aggregation property of the HFM, CFM, EAFM and MFM (100–500 μg/mL in

DMSO) of the powdered aerial parts of M. maderaspa-tana has been studied using platelet-rich plasma.[31] The EAFM extract has been registered to exhibit a dose-dependent activity. Maximum activity for the HFM and MFM have been realized only at the 400 μg/mL dose and the CFM fraction had failed to offer protection against platelet aggregation, according to the study. However, the activity observed has been reported to be only 50% of the activity of the standard tested drug, aspirin (100 μg/mL). The authors have claimed that coumarins and flavonoids (Fig. 1) accumulated in the plant part might have contributed to the prevention of adhesion and aggregation of platelets. Flavonoids appear to inhibit platelet aggregation by mediating increase in cyclic ade-nosine monophosphate levels of the platelets by either stimulation of adenylate cyclase or inhibition of cyclic adenosine monophosphate phosphodiesterase activity.

PROTECTIVE POTENTIAL IN DIABETES

Diabetes mellitus is a group of chronic metabolic disor-ders, which is characterized by hyperglycemia and altered

Table 4. Effect of the ethyl acetate fraction (EAFM) of M. maderaspatana leaf extract on the blood pressure and electrolytes, catecholamines, endothelial nitric oxide synthase and endothelin-1 peptide levels in DOCA–salt

hypertensive rats after 6-week treatment.25,29


Sham-operated control

DOCA-salt + 1% saline control

DOCA-salt + 1% saline + 60 mg/Kg EAFM

DOCA-salt + 1% saline + 20 mg/Kg nifedipine

Blood pressure Systolic (mm Hg) 125 216 130 132 Diastolic (mm Hg) 88 173 93 95Magnesium Plasma (mg/dL) 1.53 1.83 1.56 1.57 Liver (μg/g) 34.36 26.51 33.18 32.81 Kidney (μg/g) 42.19 30.90 41.44 40.04 Heart (μg/g) 38.28 29.34 36.74 36.46Copper Plasma (mg/dL) 0.95 2.63 0.97 0.99 Liver (μg/g) 45.58 28.57 42.93 41.44 Kidney (μg/g) 50.41 34.02 48.55 47.15 Heart (μg/g) 48.21 35.66 46.43 44.14Zinc Plasma (mg/dL) 0.72 1.46 0.74 0.76 Liver (μg/g) 35.09 48.49 37.78 39.18 Kidney (μg/g) 46.68 59.38 48.37 49.01 Heart (μg/g) 40.77 54.97 43.77 43.86Serum (mEq/L) Sodium 142.49 178.70 145.54 147.03 Potassium 6.83 3.02 6.43 6.14 Chloride 104.71 129.91 106.50 107.32Plasma Epinephrine (ng/mL) 0.61 0.87 0.61 0.63 Norepinephrine (ng/mL) 0.68 0.95 0.68 0.70 Nitrite-nitrate (μM) 12.63 4.32 12.86 11.56 L-Arginine (μM) 18.53 9.84 17.84 16.57DOCA = deoxycorticosterone acetate; EAFM = ethyl acetate soluble fraction of the crude leaf-extract



metabolism of lipids, carbohydrates and proteins, affecting the physical, psychological and social health of humans. Next to cardio- and cerebro-vascular diseases and cancer, DM is the most prevalent disease. The occurrence and consequences associated with DM are expected to remain high in countries such as India (79.4%), China (42.3%) and USA (30.3%) even by 2030.[32] Type 2 DM remains a leading cause of CVD, blindness, end-stage renal failure, amputations, increased risk of cancer, serious psychiatric illness, cognitive decline, chronic liver disease, accelerated arthritis, and other disabling or deadly conditions and demands preventive interventions. In most Asian coun-tries, the medical challenge posed by the burden of diabe-tes is huge. However, the Chinese Da-Qing study and the Indian Diabetes Prevention Program have revealed the benefits of life style modification focused on improved physical activity and healthy diet habits.[33]

A 15-day-study has been chosen by Balaraman et al.[34] to evaluate the antidiabetic and hypolipidemic effects of the EtOH-extract of the aerial parts of M. mader-aspatana in STZ-induced diabetic Sprague-Dawley rat model. Extract-treated (100 and 200 mg/Kg BW/day, p.o., 14 days) animals have been investigated on the day-15. Fasting BG level has been found to get reduced by half among the 200 mg/Kg treated animals and a significant dose-dependent increase in the BW has been claimed.

In a related investigation, subjecting STZ-induced- diabetic rats,[35] administration of the aqueous decoction of the whole plant (500 and 1000 mg/Kg BW, q.d., p.o.) has not altered the BG levels significantly, at the end of the 7-day-treatment-schedule. A dose of only 2000 mg/Kg could decrease the BG level in the diabetic rats to significant extent. The histopathalogical assessment of the pancreas of the treated-rats has demonstrated protec-tive features against the STZ-induced cell damage.

The effect of the EtOH-extract of M. maderaspatana (100 and 200 mg/Kg, p.o.) on alloxan-induced diabetic-rat model has also been reported.[36] 20.0 and 24.4% reduc-tions in BG levels have respectively been observed for the dosages in diabetic-rats after 5 h of treatment, compared to 31.8% decrease at 0.2 g/Kg glibenclamide standard, with no apparent hypoglycaemic effect in normal rats. Alloxan-induced diabetic Sprague rats that have been treated with EtOH and aqueous stem extracts have also been observed to exhibit significant hypoglycaemic activ-ity by the increased glucose uptake in L-6 skeletal muscle cells in vitro.[37] At a concentration of 200 mg/Kg BW, the extract-treated rats in vivo have demonstrated significantly

lowered serum glucose levels compared to 7 mg/Kg glibenclamide-treated animals. 500 mg/Kg methanolic root-extract treatment (p.o., q.d., 21 days) was capable of correcting the metabolic deviations in the serum glucose levels of alloxan-induced-diabetic-rats.[38] The treated-rats have manifested reduction in the serum glucose concen-trations (237.4 from 349. 1 mg/dL) and improvements in total protein (6.94 from 4.84 g/dL).

The change in plasma glucose levels in response to an oral glucose load has long been used as a clinical procedure for the diagnosis of DM and in preclinical trials to evaluate the efficacy of hypoglycemic agents. Oral glucose toler-ance test has been performed on overnight-fasted male C57BL/6 mice to determine the effect of the drug on insulin and β-cell functions of pancreas at glucose load in normal condition.[39] Consumption of 200 mg/Kg, p.o., EtOH-extract of the aerial parts of M. maderaspatana is reported to have markedly altered the glucose tolerance in the test animals, equivalent to 300 mg/Kg, p.o. of the standard metformin.

Effect on glucose absorption from the intestine and insulin secretion in vitro

Balaraman et al.[39] have designed another protocol to check the ability of the EtOH-extract of the aerial parts of the plant to inhibit glucose absorption through intes-tine. The estimations of the glucose contents of the everted jejunal sacs have revealed dose-response varia-tions in glucose absorption. The maximum inhibition of ca. 30% had occurred at doses 2.5 and 5.0 mg/dL. The insulinotropic effect has also been assessed using iso-lated pancreatic islets and insulinoma cell line, INS-1E. Notable effect on glucose-induced-insulin secretion has been reported at the concentrations of 1–100 μg/mL from the isolated mice splenic pancreatic islets. Similar effect has also been significantly exerted on the insulin secretion from INS-1E insulinoma cell clusters. Insulin secretion has been apparently dose-dependent, with the highest inhibition on glucose absorption recorded at 1000 μg/mL. The authors are also of the opinion that the observed antidiabetic activity of M. maderas-patana could have been the result of its high flavonoid antioxidant content,[12] as these compounds have been proved to protect cells from OS-mediated cell injuries and exert a remarkably broad array of beneficial biologi-cal implications on humans.[40]

α-Glucosidase and α-amylase inhibitory activities

Starch is the principal source of glucose in the diet. Pan-creatic α-amylase is a key enzyme in the digestive system



and acting at random locations along the starch chain, cat-alyzes the hydrolysis of 1,4-glycosidic linkages of starch, glycogen and various oligosaccharides. α-Glucosidase, another key enzyme for carbohydrate digestion, further breaks down oligosaccharides and polysaccharides into the readily available simpler sugars for intestinal absorption. α-Glucosidase has been recognized as a therapeutic target for modulation of postprandial hyperglycemia, which is the earliest metabolic abnormality to occur in type 2 DM. Inhibition of α-amylase and α-glucosidase activities in the digestive tract of humans is considered to be effective to control diabetes, as the absorption of glucose, which is decomposed from starch by these enzymes, get minimized. The EtOH-extract of the whole plant has been reported to exhibit α-amylase and α-glucosidase inhibitory activities, with IC50 = 35.5 and 45.9 respectively.[41] CFM has been reported to manifest respectively an IC50 of 39.1 and 51.2 and the 1-butanol fraction of the extract correspondingly showed an IC50 of 40.9 and 47.3. Phenolics, flavonoids and saponins are known to bind and inhibit digestive enzymes[42] and hence the authors also have attributed the observed activities to the flavonoids and other phenolics and terpenoids (Fig. 1) elaborated in the drug species.

Hypolipidemic and hepatoprotective potentials in diabetes

Diabetes in adults is associated with a high risk of vascu-lar disease, with CVD being the primary cause of death among people with type 1 or type 2 diabetes. Aggressive management of all CV risk factors, including dyslipidemia, is therefore generally necessary. The most common lipid pattern in type 2 diabetes consists of hypertriglyceridemia, low HDL and normal plasma concentrations of LDL. However, in the presence of even mild hypertriglyceride-mia, LDL particles are typically small and dense and may be more susceptible to oxidation. Chronic hyperglycemia promotes the glycation of LDL and both these processes are believed to increase the atherogenicity of LDL. In those with type 1 diabetes, plasma lipid and lipoprotein concentrations may be normal, but there may be oxidation and glycation of the lipoproteins, which may impair their function and/or enhance their atherogenicity.[43]

In the study of Balaraman et al.,[34] there has been an interestingly low content of hepatic glycogen during diabetes (15.2 mg/g liver tissue), when compared to the corresponding control group (47.8 mg/g) and the drug treatment (200 mg/Kg BW/day, p.o., 14 days) has signifi-cantly improved the status (33.8 mg/g). The biochemi-cal parameters have also been found to have improved. TC had improved to 165.5 from 266.7 mg/dL, and similarly TG (to 149.5 from 230.3 mg/dL), LDL (to

144.0 from 232.8 mg/dL) and HDL (to 42.7 from 31.2 mg/dL) also. The derangements of the metabolic processes are often associated with alteration in serum enzymatic activities and thereby necessitating the assay of serum enzymes also during diabetes. Serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase activities have all suffered more than two-fold drop in magnitude and thereby have been brought back to near normal ones by the treatment.

The serum TC (201 mg/dL) and LPO (44 mg/dL) and hepatic-LPO (480 nmoles/g wet tissue) levels have reportedly got altered following STZ-induction and administration of the aqueous decoction (2000 mg/Kg, p.o.) had significantly normalised these serum TC (84.6 mg/dL) and LPO (24.6 mg/dL) and hepatic-LPO (378.0 nmoles/g wet tissue) parameters.[35] Adminis-tration of aqueous decoction to normal rats for five days had significantly lowered the fasting BG lev-els compared to untreated normal animals. However, pre-treatment with the decoction is reported to offer no protective action against STZ-induced hypergly-cemia, according to the authors. The authors have also observed no mortality to the rats upto a dose of 20 g/Kg BW, p.o. LPO-mediated tissue damage is learnt to play an important role in the development of both type 1 and type 2 diabetes and hence, the results of the study have been claimed by the authors to be sugges-tive of the ability of the decoction to prevent LPO and in turn protect the tissue from RS. A number of other studies too have well established the RS scavenging anti-oxidant capacity of M. maderaspatana.[4] Wani et al.,[38] have also reported decreased levels of the diabetic-related elevations in TC (271 from 341 mg/dL), PL (10.9 from 12.3 mg/dL) and LDL (87.5 from 145.3 mg/dL) param-eters. An increase in the lowered HDL-level (114.7 from 87.7 mg/dL) has also been concomitantly noticed.

CONCLUSIONS

It is fairly clear today that OS is at the core of the physi-ological processes and pathological mechanisms that maintain a healthy body and longevity. Investigations on this potentially antioxidative functional leafy- vegetable, to date, have substantiated its efficacy on a number of OS-mediated metabolic disorders. Among them, the hitherto reviewed attempts to explore the protective potentials in CVD and DM have yielded fairly encouraging results. Diabetic neuropathy is another commonly prevailing complication for which this plant-food is likely to offer protection, since dietary flavonoids have been demon-strated to exert cardioprotective, chemopreventive, and



neuroprotective effects. As flavonoids can traverse the blood-brain barrier, they are believed to be the promis-ing candidates for intervention in neurodegeneration and as possible candidates for the development of general food-based neuroprotectives and as brain food constitu-ents.[44] M. maderaspatana that elaborates both lipophilic and hydrophilic antioxidants, especially the carotenoids, vitamins C and E and flavonoids to a considerable extent, offers ample scope for exploring its chemopreventive and neuroprotective potentials as well.

ABBREVIATIONS

BP = blood pressure; BG = blood glucose; BMI = body- mass index; BW = body weight; CELE = crude ethanolic leaf-extract; CFM, HFM, EAFM and MFM = chloroform, hexane, ethyl acetate and methanol soluble fractions of the crude leaf-extract; CVD = car-diovascular diseases; CAT = catalase; SOD = superoxide dismutase; GPx = glutathione peroxidise; GSH = reduced glutathione; DM = diabetes mellitus; DOCA = deoxy-corticosterone acetate; DBP = diastolic blood pressure; SBP = systolic blood pressure; DMSO=dimethyl sul-phoxide; eNOS = endothelial nitric oxide synthase; ET-1 = endothelin-1; EtOH = ethanol; FL = fresh leaves; FFA = free fatty acids; GAE = gallic acid equivalent; HT = hypertension; HDL = high-density lipoprotein-cholesterol; LDL = low-density lipoprotein-cholesterol; VLDL = very low-density lipoprotein-cholesterol; LP = lipid peroxidation; LPO = lipid peroxide; MA = malonaldehyde; PL = phospholipids; OS = oxi-dative stress; p.o. = oral administration; q.d. = one time daily; RS = reactive species; STZ = streptozotocin; TBA = thiobarbituric acid; TBARS = thiobarbitu-ric acid-reacting substances; TC = total cholesterol; TG = triglycerides.

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