hyperlipidemia role of berry honey and its comparison with ... · considerable number of people,...

Issues in Biological Sciences and Pharmaceutical Research Vol.7(5),pp.91-105, December 2019 Available online at https://www.journalissues.org/IBSPR/ https://doi.org/10.15739/ibspr.19.012 Copyright © 2019 Author(s) retain the copyright of this article ISSN 2350-1588

Original Research Article

Hyperlipidemia – Role of berry honey and its comparison with simvastatin in a rat model

Received 18 September, 2019 Revised 14 November, 2019 Accepted 18 November, 2019 Published 10 December, 2019

Usman Saeed1, Salman Iftikhar*2,

Zonera Awais3, Yasir Arfat4,

Rao Salman Aziz2, and

Maheen Rana5

1Department of Pharmacology, FMH College of Medicine and Dentistry, Lahore, Pakistan

2Department of Pharmacology, Rashid Latif Medical and Dental

College, Lahore, Pakistan 3Department of Dermatology, Allama Iqbal Medical College/

Jinnah Hospital, Lahore Pakistan 4College of Chemistry and

Chemical Engineering, Shaanxi University of Science and Technology, Xian, China

5Department of Pathology, Rashid Latif Medical and Dental

College, Lahore, Pakistan

*Corresponding Author Email: [email protected]

The fear of Coronary Heart Disease looms over the medical science. In a considerable number of people, hyperlipidemia remains undiagnosed and it lurks silently over years until its consequences appear. Therefore, to manage hyperlipidemia is a medical challenge to reduce the burden of CHD. Statins, HMG CoA reductase inhibitors, have superseded other pharmacological therapies to manage hyperlipidemia. The use of statins is not only costly but also associated with side effects and about one-third of symptomatic patients quit taking statin therapy due to discomfort. Therefore, the quest for a better treatment of hyperlipidemia urges scientists to look for alternatives of statins. Therefore, a randomized controlled experimental study was conducted to gauge the lipid lowering effect of berry honey and to compare it with simvastatin. Honey is suggested to have lipid-lowering effect. It is suggested that darker the color of honey the greater the antioxidant effect. Presence of berry trees (Ziziphus) makes Pakistani honey special due to its darker color. Rats of age 4-5 months were randomly divided into four groups with ten rats in each group (Normal Control Group A, Experimental Control Group B, Honey Group C and Simvastatin Group D). Rats in Groups B, C & D were induced hyperlipidemia by giving 4% cholesterol diet + 1% cholic acid for the initial six weeks. For the next six weeks, Group C was given Honey solution, in a single oral dose of 0.5G/Kg daily and Group D was given Simvastatin solution, in a single oral dose of 10mg/Kg daily. Blood samples were taken at zero, six and twelve weeks through cardiac puncture for serum TC, TGs, LDL and HDL level. Honey decreased TC, TGs and LDL by about 20%, 31% and 21% respectively. Simvastatin decreased TC, TGs and LDL by about 30%, 37% and 38% respectively. Honey raised HDL level by about 15% and Simvastatin by about 43%. Berry honey has a beneficial effect on lipid profile. Honey did not improve lipid profile to the extent as did by Simvastatin but it can be valuable if it is included as part of normal diet in the long run to decrease the incidence of hyperlipidemia and its consequences later in life. Keywords Hyperlipidemia, berry honey, simvastatin, hypercholesterolemia

INTRODUCTION Coronary Heart Disease has outnumbered any other disease in causing deaths. 1 out 5 deaths in the USA is due to CHD (Whelton et al., 2018). Wide-ranging epidemiological research has conspicuously suggested the

role of hyperlipidemia, diabetes, hypertension and smoking in the pathogenesis of CHD as independent risk factors (Hajar, 2017). Hyperlipidemia is of medical concern because of its strong association with CVD (Cardiovascular

Issues Biol. Sci. Pharma. Res. 92 Disease) as a risk factor. It is a modifiable risk factor of CHD and an important cause of death for both males and female of all races and ethnicities. Therefore it has become an important arena for physicians to diagnose and manage hyperlipidemia to forestall CHD (Navar-Boggan et al., 2015; Singh et al., 2018). Hyperlipidemia is a metabolic disorder characterized by population specific elevations of fasting total cholesterol concentrations with or without elevated TGs concentration. Lipids are transported by lipoproteins in the blood; therefore, hyperlipidemias are described on the basis of abnormalities of lipoproteins such as increased plasma concentrations of LDL-C, lipoproteins (Lpa), apolipoproteins (ApoB), or decreases levels of HDL-C and its protein component ApoA1 (Ference et al., 2017). Factors that may affect the prevalence of dyslipidemia in any population are dietary intake and composition, physical activity, insulin resistance and genetic traits (Brandhorst and Longo, 2019; Paras et al., 2010). In the late half of the twentieth century many epidemiological and experimental studies identified high levels of LDL cholesterol as being atherogenic and advocated a linear relationship between levels of total cholesterol (or LDL cholesterol) and rate of onset of CHD (Mahmood et al., 2014). High concentrations of nonfasting triglycerides are expected to be associated with heart failure (Varbo et al., 2018). High density lipoprotein cholesterol (HDL-cholesterol) has emerged as a negative risk factor for coronary heart disease. People with low levels of HDL-cholesterol are at greater risk of developing CHD whereas those with high levels are less prone (Rosenson et al., 2018).Familial combined hyperlipidemia (FCHL) is most commonly occurring genetic dyslipidemia disorder accompanied by increased levels of triglycerides and cholesterol (Taghizadeh et al., 2019). The characteristics of familial heterozygous hypercholesterolemia include increased plasma LDL (Low Density Lipoprotein) concentrations, decreased cellular uptake of LDL, and early cardiovascular disease. Even with intensive treatment with statins many patients fail to achieve recommended targets levels of cholesterol (Raal et al., 2015). Lipid abnormality that commonly occurs in persons with premature CHD is atherogenic dyslipidemia that is a lipid triad of elevated plasma TGs, small dense LDL particles and low HDL-C, thus having the components of metabolic syndrome (MetS), a pertinent cause of CHD (Valensi et al., 2016).

Statins, 3-hydroxymethyl-3-methylglutaryl coenzyme A reductase inhibitors, are in medical limelight to treat hyperlipidemia for the primary and secondary prevention of CHD since they were introduced in 1987 (Zambrano et al., 2018). Statins inhibit HMG Co-A reductase and result in decreased hepatic synthesis of cholesterol. This up regulates the hepatic expression of LDL-receptors through SERBP (Sterol regulatory element-binding protein) pathway leading to increased plasma clearance of LDL-C (Sultan et al., 2019). The Scandinavian Simvastatin Survival Study (4S) provided the first unequivocal evidence that a statin could lower heart attacks (Pedersen and Tobert, 1996). Since then their rampant use has superseded other

medicines to treat hyperlipidemia on the basis of better efficacy and minimum adverse effects. However, their use is not free from adverse effects (Huddy et al., 2013). Most of the statins are metabolized by hepatic cytochrome P450 system except pravastatin (Catapano, 2012). Statins also interfere with metabolic pathways that are not involved in cholesterol regulation. These non-lipid effects of statins may be clinically helpful or harmful. Non-lipid effects that have resulted in improved outcome of patients are called “pleiotropic” effects of statins (Abate and Chandalia, 2006). Since intervention with statins to reduce CHD-risk is a time-long course, so the non-lipids effects that are clinically harmful are increasing becoming an issue. Muscle and skeletal related symptoms are the most common side effects of statins that may warrant their discontinuation. The spectrum of their side effects may vary from asymptomatic increase in creatine kinase to myalgia and myositis, and from tendinopathy to even rhabdomyolysis (Coste et al., 2019). These side effects are more common in reality than described in clinical trials and a number of patients give up their statin therapy out of discomfort (Abate and Chandalia, 2006). Drug-interaction is another issue with the use of statin. The risk of rhabdomyolysis increases due to concomitant use of statins that are metabolized by CYP3A4 and inhibitors of CYP3A4 and the same risk increases by ten times when a statin is combined with gemfibrozil (Dalugama et al., 2018).

WHO indicates that 65% of the world’s population uses plant-derived medicines for the their primary health (Salaverry, 2013). Honey is a natural concentrated solution of about 200 substances made by bees (Apis mellifera) using the nectar from different plants. The chemical composition of honey depends mainly on the botanical source and to some extent on environmental factors and processing. Depending upon the geographical variation in plants, different types and grades of honey are available (Eteraf-Oskouei and Najafi, 2013). Adherence to healthy lifestyle and modification of risk factors are cornerstone in the prevention and treatment of CHD (Chomistek et al., 2015). Multitude uses of honey have been reported, the benefits of using honey for the prevention of CHD can be many folds. This protective function is the work done through anti-oxidant, antithrombotic, anti-inflammatory and vasodilating properties of honey in addition to the beneficial metabolic effects of honey on lipid profile and plasma glucose level (Eteraf-Oskouei and Najafi, 2013). Phenolic compounds, Vitamin C and flavonoids in honey are anti-oxidants and prevent the oxidation of LDLs (Alvarez-Suarez et al., 2013). Flavonoids can increase the perfusion of heart by dilating coronary arteries through increasing the endothelial cGMP content (Chirumbolo, 2015). Honey can modulate cardiovascular risk factors such as hyperlipidemia, obesity, HTN, DM, homocysteine and C-reactive protein. Scientific data increasingly favors the use of honey in these patients (Al-Waili et al., 2013). Therefore the effect of berry honey on the lipid profile of diet induced hyperlipidemic rats has been observed in this study and is compared with simvastatin.

MATERIALS AND METHODS Study design and settings It is as randomized controlled experimental study conducted at department of Pharmacology and Therapeutics, University of Health Sciences Lahore, Pakistan.

Forty male albino rats of Wistar strain, 4-5 months of age and weighing 180-220 gms, were obtained from National Institute Of Health, Islamabad and were kept in the Animal House in the University Of Health Sciences, Lahore at room temperature of 22 ± 1 °C with 50 ± 10 % humidity throughout the experiment. For the purpose of acclimatization, all rats were fed on standard rat diet for one week. Groups of Experimental Animals Forty rats were randomly divided into four groups comprising ten rats in each group. The groups were labeled as A, B, C and D. Three (B, C and D) out of four groups were made hyperlipidemic by giving high cholesterol diet (4% cholesterol + 1 % cholic acid-CC diet mixed with rat chow). Group A (Normal Control) Rats in Group A served as normal control and were fed with standard rat diet and water ad libitum throughout the study. Group B (Experimental Control) Rats in Group B served as experimental control and they were fed with a high-cholesterol diet (4% cholesterol + 1 % cholic acid-CC diet mixed with rat chow) for initial six weeks to induce hypercholesterolemia. After the collection of blood samples through cardiac puncture at the end of 6th week for lipid profile, the group was fed with standard rat diet throughout the study (Thiruchenduran et al., 2011). Group C (Honey Group) This group was also made hyperlipidemic by giving high-cholesterol diet for the first six weeks. Blood samples were collected at the end of the 6th week and the rats were exposed to standard rat diet and were treated with berry honey at a dose of 0.5 G/Kg orally once daily in the morning for the next six weeks (Sibel et al., 2014). Pakistan Council of Scientific and Industrial Research (PCSIR) ascertained Berry honey after testing that it contained more than 45% pollens of Berry plant. Group D (Simvastatin Group) Hyperlipidemia was also induced in this group of rats by giving high-cholesterol diet in the same way for the first six weeks. Blood samples were collected at the end of 6th week

Saeed et al. 93 for the estimation of lipid profile and subsequently the rats were put on standard rat diet and were treated with simvastatin at a dose of 10 mg/kg orally once daily in the morning for the next six weeks with water ad libitum (Song et al., 2013). Collection of blood Sample For the estimation of lipid profile, blood samples were collected at three intervals through cardiac puncture. At Zero Week (Baseline Value) At the start of the experiment two rats from each group (A, B, C and D) were randomly picked up and were operated upon for cardiac puncture. Collected blood samples were tested for lipid profile for baseline readings. At Sixth Week For the first six weeks high-cholesterol diet was given to three (B, C and D) out of four groups of rats to induce hyperlipidemia. At the end of the 6th week, three rats from each group were randomly selected for cardiac puncture and blood samples were tested for lipid profile to confirm hyperlipidemia in the three groups i.e. B, C and D. Group A served as normal control. At Twelfth Week Blood samples were collected from all the remaining animals at the end of the 12th week to observe the effects of drugs on lipid profile given for six weeks. Collection of serum Vacutainers containing the blood were held upright and then run in a centrifuge machine at 3000 rev/min for 10 min. The clear plasma separated at the top was transferred to Eppendorf tubes to be stored at -20 C° till the analysis of lipid profile (Bansode et al., 2012). Serum Analysis The Serum was analyzed for the following tests of lipid profile: • Serum total cholesterol. • Serum triglycerides. • Serum LDL. • Serum HDL. Semiautomatic biochemistry analyzer Humalyzer 3000 (Human, Germany) was used for the analysis of lipid profile (Lagos et al., 2014). Randox laboratory kits (UK) were used for the quantitative analysis of total cholesterol, TGs, LDL and HDL in the semiautomatic biochemistry analyzer Humalyzer 300. Certified technicians carried out the tests in the laboratory of Allied Health Sciences at UHS, Lahore.

Issues Biol. Sci. Pharma. Res. 94

Table 1. Mean TC level in Groups A, B, C and D at 0 Week

Serum Cholesterol mg/dl

Mean ± S.E.M

Group A Group B Group C Group D

79 ± 9.0 80 ± 2.0 93 ± 4.0 86 ± 6.0

Table 2. Mean TC level in Groups A, B, C and D at 6th week

Serum Cholesterol mg/dl Mean ± S.E.M

Group A Group B Group C Group D Value of P 82.3 ± 5.4 178.3 ± 1.5 174.3 ± 2.3 144.0 ± 22.3 0.001

Value of p< 0.05 is considered significant.

Statistical analysis SPSS (Statistical package for social sciences) software version 21 compatible with Macintosh was used for the analysis of data.

• Normally distributed quantitative variables were expressed as Means ± S.E.M.

• One-way ANOVA (analysis of variance) was applied to analyze the differences among group means for various variables (Total cholesterol, TGs, HDL and LDL) at six and twelve weeks. A p-value of less than <0.05 was deemed significant.

• Post hoc Tukey test was applied to find means that were significantly different from each other. A p-value of <0.05 was considered statistically significant.

• Independent Samples T-test was performed to find out any difference in the means of groups at Zero Week. A p-value of less than <0.05 was deemed significant. RESULTS Total Cholesterol level at Zero Week TC range of Group A at Zero Week was 79 ± 9.0 mg/dl. Group B had a cholesterol range of 80 ± 2.0. TC range of Group C was 93 ± 4.0. Group D had a cholesterol range 86 ± 6.0 mg/dl. No significant difference was observed in the means of TC levels at Zero Week among Groups A, B, C and D. Value of p> 0.05 as seen in Table 1. Total Cholesterol at Sixth Week TC range of Group A at six weeks was 82.3 ± 5.4 mg/dl. Group B had a cholesterol range of 178.3 ± 1.5 mg/dl. TC range of Group C was 174.3 ± 2.3 mg/dl. Group D had a cholesterol range of 144 ± 22.3mg/dl.

One-way ANOVA showed a significant difference in the means of TC levels at 6 weeks among Groups A, B, C and D. Value of p < 0.001 (Table 2)

Post hoc Tukey test showed a significant difference in the means of TC levels between Groups A and B (82.3 ± 5.4 vs. 178.3 ± 1.5), p<.002, indicating that TC level in Group B was higher than in Group A (Table 3).

Significant difference was seen in the means of TC levels

between Groups A and C (82.3 ± 5.4 vs. 174.3 ± 2.3), p< .002, indicating that TC level in Group C was higher than in Group A (Table 3).

Significant difference was also observed in the means of TC levels between Groups A and D (82.3 ± 5.4 vs. 144.0 ± 22.3), p< .022, indicating that TC level in Group D was higher than in Group A.

However, no significant difference was observed in the means of TC levels between Groups B and C (178.3 ± 1.5 vs. 178.3 ± 1.5), p> 0.99; Groups B and D (178.3 ± 1.5 vs. 144.0 ± 22.3), p>0.23; and Groups C and D (174.3 ± 2.3 vs. 144.0 ± 22.3), p> 0.32 at six weeks (Table 3). Total Cholesterol at Twelfth Week TC range of Group A at twelve weeks was 80.0 ± 3.6 mg/dl. Group B had a cholesterol range of 146 ± 14.6 mg/dl. TC range of Group C was 118.6 ± 6.7mg/dl. Group D had a cholesterol range of 103 ± 4mg/dl (Table 4, Figure 1).

One-way ANOVA showed a significant difference in the means of TC levels at 12th weeks among Groups A, B, C and D. Value of p < 0.0001 (Table 4).

Post hoc Tukey test showed a significant difference in the means of TC levels between Groups A and B (80.0 ± 3.6 vs. 146 ± 14.6), p< .01, indicating that TC level in Group B was higher than in Group A (Table 5).

Significant difference was seen in the means of TC levels between Groups A and C (80.0 ± 3.6 vs. 118.6 ± 6.7), p< .025, indicating that TC level in Group C was higher than in Group A (Table 5).

Significant difference was also observed in the means of TC levels between Groups B and D (146 ± 14.6 vs. 103 ± 4.0), p< .012, indicating that TC level in Group B was higher than in Group C.

However, no significant difference was observed in the means of TC levels between Groups A and D (80.0 ± 3.6 vs. 103 ± 4.0), p> 0.26; Groups B and C (146 ± 14.6 vs. 118.6 ± 6.7), p>0.14; and Groups C and D (118.6 ± 6.7 vs. 103.4), p> 0.57 at 12th week (Table 5). Serum Triglyceride Level at Zero Week TGs range of Group A at Zero Week was 63.5 ± 5.5 mg/dl. Group B had a TGs range of 65.5 ± 2.5 mg/dl. TGs range of Group C was 74.0 ± 4.0 mg/dl. Group D had a TGs range of

Saeed et al. 95

Table 3. Multiple Comparisons among Groups A, B, C and for TC at 6th week

Dependent Variable: Serum Cholesterol Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -96.00000* 16.31462 0.002

C -92.00000* 16.31462 0.002 D -61.66667* 16.31462 0.022

B A 96.00000* 16.31462 0.002

C 4 16.31462 0.994 D 34.33333 16.31462 0.23

C A 92.00000* 16.31462 0.002

B -4 16.31462 0.994 D 30.33333 16.31462 0.316

D A 61.66667* 16.31462 0.022

B -34.33333 16.31462 0.23 C -30.33333 16.31462 0.316

*The mean difference is significant at the 0.05 level.

Table 4. Mean TC level in Groups A, B, C and D at 12th Week

Serum Cholesterol mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 80.0 ± 3.6 146 ± 14.6 118.6 ± 6.7 103 ± 4 0.000


Zero Week

Six Week

Twelve Week

Figure 1: Cholesterol level among Groups A, B, C and D at 0, 6th and 12th week respectively.

78.0 ± 2.0 mg/dl. No significant difference was observed in the means of TGs levels at Zero Week among Groups A, B, C and D (Table 6). Serum Triglyceride Level at Sixth Week TGs range of Group A at six Weeks was 73.7 ± 4.1mg/dl.

Group B had a TGs range of 142.7 ± 3.9 mg/dl. TGs range of Group C was 161 ± 26.2 mg/dl. Group D had a TGs range of 148 ± 6.0 mg/dl.

One-way ANOVA showed a significant difference in the means of TGs levels at 6 weeks among Groups A, B, C and D. Value of p < 0.008 (Table 7)

Post hoc Tukey test showed a significant difference in the


Table 5. Multiple Comparisons among Groups A, B, C and for TC at 12th week

Dependent Variable: Serum Cholesterol. Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -66.00000* 12.01582 0

C -38.60000* 12.01582 0.025 D -23 12.01582 0.261

B A 66.00000* 12.01582 0

C 27.4 12.01582 0.144 D 43.00000* 12.01582 0.012

C A 38.60000* 12.01582 0.025

B -27.4 12.01582 0.144 D 15.6 12.01582 0.577

D A 23 12.01582 0.261

B -43.00000* 12.01582 0.012 C -15.6 12.01582 0.577

*The mean difference is significant at the 0.05 level

Table 6. Mean TGs level in Groups A, B, C and D at 0 Week

Serum TG mg/dl

Mean ± S.E.M

Group A Group B Group C Group D 63.5 ± 5.5 65.5 ± 2.5 74.0 ± 4.0 78.0 ± 2.0

Table 7. Mean TGs level in Groups A, B, C and D at 6th week.

Serum TG mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 73.7 ± 4.1 142.7 ± 3.9 161 ± 26.2 148 ± 6.0 0.008

Value of p< 0.05 is considered significant

Table 8. Multiple Comparisons among Groups A, B, C and for TGs at 6th week

Dependent Variable: Serum Triglycerides. Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -69.00000* 19.39931 0.03

C -87.33333* 19.39931 0.009 D -74.66667* 19.39931 0.02

B A 69.00000* 19.39931 0.03

C -18.33333 19.39931 0.783 D -5.66667 19.39931 0.991

C A 87.33333* 19.39931 0.009

B 18.33333 19.39931 0.783 D 12.66667 19.39931 0.912

D A 74.66667* 19.39931 0.02

B 5.66667 19.39931 0.991 C -12.66667 19.39931 0.912


means of TGs levels between Groups A and B (73.7 ± 4.1 vs. 142.7 ± 3.9), p< .03, indicating that TGs level in Group B was higher than in Group A (Table 8).

Significant difference was seen in the means of TGs levels

between Groups A and C (73.7 ± 4.1 vs. 161 ± 26.2), p< .009, indicating that TGs level in Group C was higher than in Group A (Table 8).

Significant difference was also observed in the means of

Saeed et al. 97

Table 9. Mean TGs level in Groups A, B, C and D at 12th Week

Serum TG mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 79 ± 9.8 164.6 ± 11.9 115 ± 5.5 104 ± 6.2 0.000


Zero Week

Six Week

Twelve Week

Figure 2: Triglyceride level among Groups A, B, C and D at 0, 6 and 12 weeks respectively

TGs levels between Groups A and D (73.7 ± 4.1 vs. 148 ± 6.0), p< .020, indicating that TGs level in Group D was higher than in Group A (Table 8).

However, no significant difference was observed in the means of TGs levels between Groups B and C (142.7 ± 3.9 vs. 161 ± 26.2), p> 0.78; Groups B and D (142.7 ± 3.9 vs. 148 ± 6.0), p>0.99; and Groups C and D (161 ± 26.2 vs. 148 ± 6.0), p> 0.91 at sixth week (Table 8). Serum Triglyceride Level at Twelfth Week TGs range of Group A at 12th week was 79 ± 9.8 mg/dl. Group B had a TGs range of 164.6 ± 11.9 mg/dl. TGs range of Group C was 115 ± 5.5mg/dl. Group D had a TGs range of 104 ± 6.2mg/dl.

One-way ANOVA showed a significant difference in the means of TGs levels at 12th weeks among Groups A, B, C and D. Value of p < 0.001 (Table 9, Figure 2).

Post hoc Tukey test showed a significant difference in the means of TGs levels between Groups A and B (79 ± 9.8 vs. 164.6 ± 11.9), p< .001, indicating that TGs level in Group B was higher than in Group A (Table 10).

Significant difference was also observed in the means of TGs levels between Groups A and C (79 ± 9.8 vs. 115 ± 5.5), p< .045, indicating that TGs level in Group C was higher than in Group A (Table 10).

Significant difference was noted in the means of TGs levels between Groups B and C (164.6 ± 11.9 vs. 115 ± 5.5), p< .005, indicating that TGs level in Group B was higher than in Group C (Table 10).

Significant difference was seen in the means of TGs levels between Groups B and D (164.6 ± 11.9 vs. 104 ± 6.2), p< .001, indicating that TGs level in Group B was higher than in Group D (Table 10). However, no significant difference was observed in the means of TGs levels between Groups A and D(79 ± 9.8 vs. 104 ± 6.2), p> 0.221; and Groups C and D (115 ± 5.5 vs. 104 ± 6.2), p> 0.81 (Table 10). Serum LDL Level at 0 Week Serum LDL range of Group A at zero week was 43 ± 3 mg/dl. Group B had a LDL range of 43.5 ± 5.5 mg/dl. LDL range of Group C was 50.5 ± 9.5 mg/dl. Group D had a LDL range of 61.5 ± 7.5 mg/dl (Table 11).


Table 10. Multiple Comparisons among Groups A, B, C and for TGs at 12th week

Dependent Variable: Serum Triglycerides Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -85.60000* 12.3584 0

C -36.00000* 12.3584 0.045 D -25 12.3584 0.221

B A 85.60000* 12.3584 0

C 49.60000* 12.3584 0.005 D 60.60000* 12.3584 0.001

C A 36.00000* 12.3584 0.045

B -49.60000* 12.3584 0.005 D 11 12.3584 0.81

D A 25 12.3584 0.221

B -60.60000* 12.3584 0.001 C -11 12.3584 0.81


Table 11. Mean Serum LDL at 0 week

Serum LDL mg/dl

Mean ± S.E.M

Group A Group B Group C Group D 43 ± 3 43.5 ± 5.5 50.5 ± 9.5 61.5 ± 7.5

Table 12. LDL level in Groups A, B, C and D at 6th week

Serum LDL mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 50.7 ± 1.8 106 ± 3.5 103 ± 4.7 107.3 ± 9.7 0.000

Value of p< 0.05 is considered significant

No significant difference was observed in the means of LDL levels at Zero Week among Groups A, B, C and D. Value of p> 0.05 Serum LDL Level at Sixth Week Serum LDL range of Group A at six week was 48-54 with a mean of 50.7 ± 1.8 mg/dl. Group B had a TLDL range of 106 ± 3.5 mg/dl. LDL range of Group C was 103 ± 4.7mg/dl. Group D had a LDL range of 107.3 ± 9.7 mg/dl (Table 12, Figure 3).

One-way ANOVA showed a significant difference in the means of LDL levels at 6 weeks among Groups A, B, C and D. Value of p < 0.001 (Table 12).

Post hoc Tukey test showed a significant difference in the means of LDL levels between Groups A and B (50.7 ± 1.8vs. 106 ± 3.5), p< .001, indicating that LDL level in Group B was higher than in Group A (Table 13).

Significant difference was seen in the means of LDL levels between Groups A and C (50.7 ± 1.8 vs. 103 ± 4.7), p< .001, indicating that LDL level in Group C was higher than in Group A (Table 13).

Significant difference was also observed in the means of LDL levels between Groups A and D (50.7 ± 1.8 vs. 107.3 ±

9.7), p< .001, indicating that LDL level in Group D was higher than in Group A (Table 13).

However, no significant difference was observed in the means of LDL levels between Groups B and C (106 ± 3.5 vs. 103 ± 4.7), p> 0.98; Groups B and D (106 ± 3.5 vs. 107.3 ± 9.7), p>0.99; and Groups C and D (103 ± 4.7 vs. 107.3 ± 9.7), p> 0.95 at sixth week (Table 13). LDL level at Twelfth Week LDL range of Group A at 12th week was 59.6 ± 4.8 mg/dl. Group B had a LDL range of 112.8 ± 6.6mg/dl. LDL range of Group C was 89.2 ± 3.0 mg/dl. Group D had a LDL range of 70.4 ± 3.5mg/dl (Table 14).

One-way ANOVA showed a significant difference in the means of LDL levels at 12th weeks among Groups A, B, C and D. Value of p < 0.001 (Table 14)

Post hoc Tukey test showed a significant difference in the means of LDL levels between Groups A and B (59.6 ± 4.8 vs. 112.8 ± 6.6), p< .001, indicating that LDL level in Group B was higher than in Group A (Table 15).

Significant difference was also observed in the means of LDL levels between Groups A and C (59.6 ± 4.8 vs. 89.2 ± 3.0), p< .002, indicating that LDL level in Group C was

Saeed et al. 99

Zero Week

Six Week

Twelve Week

Figure 3: LDL levels among Groups A, B, C and D at 0, 6 and 12 weeks respectively.

Table 13. Multiple Comparisons among Groups A, B, C and for LDL at 6th week

Dependent Variable: Serum LDL Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -55.33333* 8.10007 0.001

C -52.33333* 8.10007 0.001 D -56.66667* 8.10007 0.001

B A 55.33333* 8.10007 0.001

C 3 8.10007 0.981 D -1.33333 8.10007 0.998

C A 52.33333* 8.10007 0.001

B -3 8.10007 0.981 D -4.33333 8.10007 0.948

D A 56.66667* 8.10007 0.001

B 1.33333 8.10007 0.998 C 4.33333 8.10007 0.948


Table 14. Mean LDL level in Groups A, B, C and D at 12th Week

Serum LDL mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 59.6 ± 4.8 112.8 ± 6.6 89.2 ± 3.0 70.4 ± 3.5 0.001


higher than in Group A (Table 15).

Significant difference was seen in the means of LDL levels between Groups B and C (112.8 ± 6.6 vs. 89.2 ± 3.0), p<.001, indicating that LDL level in Group B was higher than in

Group C (Table 15). Significant difference was noted in the means of LDL

levels between Groups B and D (112.8 ± 6.6 vs. 70.4 ± 3.5), p< .012, indicating that LDL level in Group B was higher


Table 15. Multiple Comparisons among Groups A, B, C and for LDL at 12th week

Dependent Variable: Serum LDL. Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B -53.20000* 6.6106 0 C -29.60000* 6.6106 0.002 D -10.8 6.6106 0.389 B A 53.20000* 6.6106 0 C 23.60000* 6.6106 0.012 D 42.40000* 6.6106 0 C A 29.60000* 6.6106 0.002 B -23.60000* 6.6106 0.012 D 18.8 6.6106 0.052 D A 10.8 6.6106 0.389 B -42.40000* 6.6106 0 C -18.8 6.6106 0.052


Table 16. Mean HDL level among Groups A, B, C and D at 0 Week

Serum HDL mg/dl

Mean ± S.E.M

Group A Group B Group C Group D 24.5 ± 3.5 23.0 ± 3.0 27.0 ± 3.0 22.5 ± 3.5


than in Group D (Table 15).

However, no significant difference was observed in the means of LDL levels between Groups A and D (59.6 ± 4.8 vs. 70.4 ± 3.5), p> 0.39; and Groups C and D (89.2 ± 3.0 vs. 70.4 ± 3.5), p> 0.53 (Table 15). HDL at Zero Week Serum HDL range of Group A at zero week was 24.5 ± 3.5 mg/dl. Group B had an HDL range of 23.0 ± 3.0 mg/dl. HDL range of Group C was 27.0 ± 3.0 mg/dl. Group D had an HDL range of 22.5 ± 3.5 mg/dl.

No significant difference was observed in the means of LDL levels at Zero Week among Groups A, B, C and D. Value of p> 0.05 (Table 16). Serum HDL Level at Sixth Week Serum HDL range of Group A at six week was 24 ± 1.2 mg/dl. Group B HDL range was 17.7 ± 0.33 mg/dl. HDL range of Group C was16.7 ± 1.2 mg/dl. Group D had an HDL range of 17 ± 0.6 mg/dl.

One-way ANOVA showed a significant difference in the means of HDL levels at 6 weeks among Groups A, B, C and D. Value of p < 0.001 (Table 17).

Post hoc Tukey test showed a significant difference in the means of HDL levels between Groups A and B (24 ± 1.2 vs. 17.7 ± 0.33), p< .005, indicating that HDL level in Group A was higher than in Group B (Table 18).

Significant difference was seen in the means of HDL levels between Groups A and C (24 ± 1.2 vs. 16.7 ± 1.2), p< .002, indicating that HDL level in Group A was higher than in Group C (Table 18).

Significant difference was also observed in the means of HDL levels between Groups A and D (24 ± 1.2 vs. 17 ± 0.6), p< .003, indicating that HDL level in Group A was higher than in Group D (Table 18).

However, no significant difference was observed in the means of HDL levels between Groups B and C (17.7 ± 0.33 vs. 16.7 ± 1.2), p> 0.86; Groups B and D (17.7 ± 0.33 vs. 17 ± 0.6), p>0.95; and Groups C and D (16.7 ± 1.2 vs. 17 ± 0.6), p> 0.99 at sixth week (Table 18). Serum HDL level at Twelfth Week HDL range of Group A at 12th week was 24 ± 1.4 mg/dl. Group B had an HDL range of 16.4 ± 1.2 mg/dl. HDL range of Group C 18.8 ± 1.0 mg/dl. Group D had an HDL range of 23.4 ± 0.6 mg/dl.

One-way ANOVA showed a significant difference in the means of HDL levels at 12th weeks among Groups A, B, C and D. Value of p < 0.001 (Table 19, Figure 4).

Post hoc Tukey test showed a significant difference in the means of HDL levels between Groups A and B (24 ± 1.4 vs. 16.4 ± 1.2), p< .001, indicating that HDL level in Group A was higher than in Group B (Table 20).

Significant difference was also observed in the means of HDL levels between Groups A and C (24 ± 1.4 vs. 18.8 ±

Saeed et al. 101

Table 17. Mean HDL level in Groups A, B, C and D at 6th Week

Serum HDL mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 24 ± 1.2 17.7 ± 0.33 16.7 ± 1.2 17 ± 0.6 0.001


Table 18. Multiple Comparisons among Groups A, B, C and HDL at 6th week

Dependent Variable: Serum HDL Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B 6.33333* 1.2693 0.005

C 7.33333* 1.2693 0.002 D 7.00000* 1.2693 0.003

B A -6.33333* 1.2693 0.005

C 1 1.2693 0.858 D 0.66667 1.2693 0.951

C A -7.33333* 1.2693 0.002

B -1 1.2693 0.858 D -0.33333 1.2693 0.993

D A -7.00000* 1.2693 0.003

B -0.66667 1.2693 0.951 C 0.33333 1.2693 0.993


Table 19. Mean HDL level in Groups A, B, C and D at 12th Week.

Serum HDL level mg/dl

Mean ± S.E.M

Group A Group B Group C Group D Value of P 24 ± 1.4 16.4 ± 1.2 18.8 ± 1.0 23.4 ± 0.6 0.000


Zero Week

Six Week

Twelve Week

Figure 4: Comparison of mean HDL level among Groups A, B, C & D at 0, 6 and 12 weeks.


Table 20. Multiple Comparisons among Groups A, B, C and for HDL at 12th week

Dependent Variable: Serum HDL Tukey HSD (I) Groups of rats (J) Groups of rats Mean Difference (I-J) Std. Error Sig.

A B 7.60000* 1.54272 0.001 C 5.20000* 1.54272 0.018 D 0.6 1.54272 0.979 B A -7.60000* 1.54272 0.001 C -2.4 1.54272 0.43 D -7.00000* 1.54272 0.002 C A -5.20000* 1.54272 0.018 B 2.4 1.54272 0.43 D -4.60000* 1.54272 0.04 D A -0.6 1.54272 0.979 B 7.00000* 1.54272 0.002 C 4.60000* 1.54272 0.04


1.0), p< .018, indicating that HDL level in Group A was higher than in Group C (Table 20).

Significant difference was seen in the means of HDL levels between Groups B and D (16.4 ± 1.2vs. 23.4 ± 0.6), p< .002, indicating that HDL level in Group D was higher than in Group B (Table 20).

Significant difference was noted in the means of HDL levels between Groups C and D (18.8.2 ± 1.0 vs. 23.4 ± 0.6), p< .004, indicating that HDL level in Group D was higher than in Group C (Table 20).

However, no significant difference was observed in the means of HDL levels between Groups A and D (24 ± 1.4 vs. 23.4 ± 0.6), p> 0.90; and Groups B and C (16.4 ± 1.2 vs. 18.8.2 ± 1.0), p> 0.43 (Table 20). DISCUSSION Hyperlipidemia is a common and important risk factor for atherosclerosis and CHD. Development of hyperlipidemia even at an early age increases the future risk of CHD in a dose-dependent fashion. Therefore, healthy life-style and dietary modification are important lipid management strategies to reduce the global burden of CHD clinically as well as economically (Navar-Boggan et al., 2015). The use of animal models to provide new approaches for improving the treatment of dyslipidemia is a common practice in cardiovascular medicine (Korolenko et al., 2016). Honey has established antibiotic, anti-inflammatory and antioxidant properties. The revived interest in honey is due the fact that it has tremendous health benefits and now many studies are scientifically exploring its effects on lipid profile, blood sugar and body weight (Al-Waili et al., 2013). The biochemical properties of honey depends both on its botanical and geographical origin (Muñoz and Palmero, 2006). Honeys from different parts of the world including

Malaysia, the U.S.A, U.A.E, India, Algerian and Iran haven been studied for chemical composition and biochemical properties (Aljadi and Kamaruddin, 2004; Ouchemoukh et al., 2007; Saxena et al., 2010). Presence of berry trees (Ziziphus) makes Pakistan honey special. Present study was conducted to evaluate the lipid-lowering effect of berry honey and its comparison with simvastatin.

Serum TC was found to be lower in the hyperlipidemic rats treated with berry honey in a dose of 0.5G/Kg body Wt. (Group C) and in the hyperlipidemic rats treated with Simvastatin in a dose of 10mg/Kg body Wt. (Group D) when compared with experimental Control Group B. Honey decreased 20% TC while Simvastatin 30% in experimental rats (Group C and D respectively) in comparison with experimental control Group (B) (Figure 1). Observation made by Yaghoobi et al. (2008) showed that natural honey decreased TC by 3.3%;another study conducted by Alagwu et al. (2014) is also in-keeping with our results as they also reported that honey improved lipid profile.

Similarly, TGs levels were found to be lower in hyperlipidemic rats treated with berry honey and Simvastatin (Groups C and D) as compared to experimental control rats (Group B). Berry honey decreased TGs by about 31% while simvastatin by about 37% when compared with experimental control rats (Figure 2). This agrees with Nemoseck et al. (2011) as they concluded that honey-fed rats showed a 30% decline in TGs level as compared to sucrose-fed rats.

Both berry honey and simvastatin decreased serum LDL level by about 21% and 38% respectively in in hyperlipidemic rats when compared with experimental control rats (Group B) (Figure 3). Al-Waili et al. (2004), concluded that natural honey decreased LDL-C by about 11% in hyperlipidemic individuals.

Berry honey raised HDL level by about 15% and Simvastatin by about 43% in hyperlipidemic rats (Group C

&D respectively) when compared with experimental control rats (Group B) (Figure 4). Chepulis and Starkey (2008), also reported 15% and 20% increases in HDL level in honey-fed rats when compared with sucrose-fed rats and rats that were fed on sugar-free diet respectively. The effect of honey on lipid profile is due to a number of factors and each contributes in a different way (Ahmad et al., 2008). Honey contains amino acids, proteins, vitamins, minerals and enzymes. It has been shown that Vit.B complex in high dose can decrease blood cholesterol and triglycerides levels. Niacin is present in Vit.B complex and it raises HDL level (Saggini et al., 2010). In addition, honey is a rich source of antioxidants and Trapani et al., (2011) suggested that antioxidants have the potential to become an additional approach to treat hyperlipidemia since they modulate the activity of HMG CoA reductase enzyme: the rate limiting enzyme in the synthesis of cholesterol. A recent breakthrough research, that can help understand more precisely the lipid-lowering mechanism of honey, indicates that honey modulates the activity of adrenoceptors in producing anti-inflammatory and analgesic effects. Honey has well established analgesic and anti-inflammatory properties (Alzubier and Okechukwu, 2011).Owoyele et al., (2014), observed that concurrent use of propranolol (beta adrenoceptor blocker) with honey blocked the anti-inflammatory effect of honey.

Depending upon these observations and related literature available, it can be postulated that honey has a beneficial effect on lipid profile due to agonism of β-adrenoceptors in addition to antioxidant, anti-inflammatory and NO producing properties. Besides modulating plasma lipids, a risk factor for CHD, the overall benefits of honey on reducing CHD risk may be many folds and continue to be unfolded in the future. Conclusion Berry honey improved lipid profile in the hyperlipidemic rats but it did not reduce the values to the baseline as achieved by Simvastatin. So it can be best exploited when it is consumed regularly by adding it to the part of normal diet for the primary prevention of CHD. Moreover, it can possibly decrease the dose of Simvastatin required to treat hyperlipidemia both for primary and secondary prevention of CHD. Further studies would be required to identify and isolate the active ingredient in honey that is responsible for its lipid-lowering effect. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of the paper. REFRENCES Abate N, Chandalia M (2006). Other than potency, are all

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