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ORIGINAL ARTICLE
Year : 2018  |  Volume : 8  |  Issue : 1  |  Page : 3-9

Attenuation of Arsenic-Induced Dyslipidemia by Fruit Extract of Emblica Officinalis in Mice


1 Department of Biochemistry, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
2 Department of Pharmacology, King George’s Medical University, Lucknow, Uttar Pradesh, India
3 Department of Pharmacology, All Institute of Medical Sciences, Jodhpur, Rajasthan, India
4 Department of Criminology and Forensic Science, School of Applied Sciences, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar, Madhya Pradesh, India

Date of Web Publication15-Jan-2018

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnpnd.ijnpnd_69_17

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   Abstract 

Introduction: In our earlier studies, we reported that arsenic-induced enhanced oxidative stress, apoptosis, immunotoxicity and inflammation in the spleen and thymus of mice and hepatotoxicity have been protected through treatment with Emblica officinalis (amla). The present study is focused on to the efficacy of amla in mitigation of arsenic-induced dyslipidemia and alterations in inflammatory biomarkers in the blood of mice. Materials and Methods: Mice were randomly divided into four groups and treated with sodium arsenite (3 mg/kg b.w., per os), amla (500 mg/kg b.w., per os) and simultaneously with arsenic and amla daily for 30 days. Results: Arsenic treatment altered the hematological and lipid profile by increasing total cholesterol (TC), triglyceride (TG), phospholipid (PL) and low-density lipoprotein (LDL) levels and decreasing high-density lipoprotein (HDL) levels as compared to controls. Treatment with arsenic also disturbed the levels of inflammatory biomarkers. Concurrent treatment with arsenic and amla significantly restored serum TC level (0.83-fold), TG level (0.92-fold), LDL level (0.72-fold), PL level (1.29-fold), and increased HDL level (1.4-fold). Inflammatory cytokine levels were also corrected significantly as serum interleukin-8 level (0.6-fold) and C-reactive protein level decreased (0.7-fold) respectively, while interleukin-10 level was increased (1.5-fold) as compared to those treated with arsenic alone. The alterations in hematological parameters were also found to be normalized by treatment of amla. Conclusion: The results of the present study strengthen the fact that nutritional supplement of amla in arsenic affected areas might improve the adverse effects of arsenic on lipid profile.

Keywords: Arsenic, Emblica officinalis, hematology, inflammation, lipid profile


How to cite this article:
Singh MK, Singh PK, Yadav SS, Singh US, Dwivedi P, Yadav RS. Attenuation of Arsenic-Induced Dyslipidemia by Fruit Extract of Emblica Officinalis in Mice. Int J Nutr Pharmacol Neurol Dis 2018;8:3-9

How to cite this URL:
Singh MK, Singh PK, Yadav SS, Singh US, Dwivedi P, Yadav RS. Attenuation of Arsenic-Induced Dyslipidemia by Fruit Extract of Emblica Officinalis in Mice. Int J Nutr Pharmacol Neurol Dis [serial online] 2018 [cited 2018 Dec 14];8:3-9. Available from: http://www.ijnpnd.com/text.asp?2018/8/1/3/223264


   Introduction Top


The consumption of arsenic-contaminated groundwater for a longer period of time has been found to be associated with the chronic arsenic poisoning in several countries of the world including India, Bangladesh, China, and Taiwan.[1] The contamination of arsenic in groundwater in the Ganga–Brahmaputra fluvial plains in India and Padma–Meghna fluvial plains in Bangladesh and the resulting adverse health effects of human being have been reported as one of the world’s biggest natural groundwater tragedies to the mankind.[2] According to the World Health Organization (WHO), the recommended value of arsenic is 10 μg/l.[3],[4] More than 50% of the aquifers in the Ganga–Meghna–Brahamaputra plain of India and Bangladesh have high levels of arsenic level which is above the WHO recommended limit.[5]

Chronic exposure of arsenic leads to the pathogenesis of myocardial tissue, leading to various cardiovascular problems.[6] Fragmentation of deoxyribonucleic acid (DNA), enhanced oxidative stress linked with generation of reactive oxygen species, change in mitochondrial membrane potential and induction of apoptosis in the primary immune organ and myocardial tissue are the possible mechanisms of arsenic-induced immunotoxicity and cardiotoxicity in mice.[7],[8] A high prevalence of cardiovascular events including hypertension, atherosclerosis, peripheral vascular disease, cardiomyopathy, Blackfoot disease, etc. is seen in arsenic exposed populations.[9],[10] Epidemiological studies have also identified that alterations in the levels of lipid and lipoprotein could be some independent risk factors in the pathogenesis and progression of hypertension, atherosclerosis and cardiovascular diseases (CVDs).[11] Afolabi et al., identified two common factors in arsenic-induced dyslipidemia namely, inhibition of reverse cholesterol transport and increase in plasma free fatty acid as a mediate of CVD.[12] Exposure of arsenic up-regulates the expression of various inflammatory molecules and inhibits key regulators of lipid homeostasis, these two are the key components in the initiation of atherosclerosis.[13],[14] These events may ultimately lead to endothelial dysfunction and increase the risk of CVDs.[15] This is due to the induction of oxidative stress, which may in turn mediate abnormal gene expression, inflammatory responses, or impaired nitric oxide homeostasis.[16],[17] There are also some increasing evidences suggesting that environmental factors (metals and pesticide toxicity) may also contribute to dyslipidemia.[18]

The problem of arsenicosis becomes very serious due to its exposure in a larger population and the absence of effective treatments. Thus, the use of pharmacological agents and nutritional supplementation approaches to this problem form an attentive possibility.[19],[20] The other factors, including low socioeconomic status and malnourishment also play an important role in the increasing risk of disease conditions because the affected population do not have any alternative for arsenic-contaminated drinking water.[21],[22] Studies have suggested that nutritious diet could be useful in reducing the risk of arsenic toxicity through their antioxidant activity and also by increasing the methylation of arsenic.[23]

Abundant medicinal plants are present in the Indian traditional systems of medicine, and the most commonly used one among them is Indian gooseberry, also known as Emblica officinalis (amla), belongs to the family Euphorbiaceae,[24] which is an important medicinal herb used as a tonic to restore the lost body’s energy and vigor. The fruit extract of amla and its active constituents have shown to have anti-oxidative, anti-inflammatory, anti-cancer and immunomodulatory properties.[17],[25] The therapeutic activity of amla can be attributed to its antioxidant potential.[26] Previous studies have suggested that arsenic-induced enhanced oxidative stress linked to apoptosis in thymocytes of mice could be protected through simultaneous treatment with amla.[7],[27] Arsenic-induced hepatic toxicity associated with impaired antioxidant status has also been protected following simultaneous treatment with arsenic and amla.[28] Studies have also reported that arsenic-induced immunotoxicity linked with inflammation has been significantly protected through simultaneous treatment with arsenic and amla that was due to anti-inflammatory, antioxidant and metal binding property of amla which could reduce the load of arsenic in spleen and thymus and help to decrease the generation of reactive oxygen and nitrogen species and imparts its protective effects.[17] In view of the previously published reports, the present study was designed to assess the effect of supplementation of amla extract on arsenic-induced alterations in inflammatory biomarkers and lipid profile in the blood of mice.


   Materials and Methods Top


Animals and treatment

The present study was approved by the institutional animal ethics committee of King George’s Medical University, Lucknow (No. 121 IAH/Pharma-11), India, and all experiments were conducted in accordance with the guidelines set by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forests (Government of India), New Delhi, India. Male Balb/c mice (23 ± 2 g) were obtained from the animal-breeding colony of CSIR-Indian Institute of Toxicology Research (Lucknow, UP). Mice were housed in an air-conditioned room at 25 ± 2°C with a 12 h light/dark cycle under standard hygiene conditions. Mice had free access to a pellet diet and filtered water ad libitum. The dose of fruit extract of amla and arsenic is based on our previous studies[7],[17],[27] and for the study, the mice were randomly divided into four groups with eight animals/group, and the dose of arsenic and amla was given orally with the help of cannula after dissolving it in a suitable solvent:
  • Group I: Mice treated with vehicle (2% gum acacia) for the duration of the treatment and served as controls.
  • Group II: Mice treated with sodium arsenite (dissolved in distilled water at 3 mg/kg body weight, per os daily for 30 days).
  • Group III: Mice treated with fruit extract of amla (500 mg/kg body weight, suspended in 2% gum acacia, per os daily for 30 days).
  • Group IV: Mice co-treated with arsenic and fruit extract of amla daily for 30 days as in Groups II and III.


Blood collection

At the end of the experimental period (30 days), animals were sacrificed by cervical dislocation. Immediately after that, a heart puncture was made and 2 ml of blood was quickly collected − 1 ml in 10% ethylenediaminetetraacetic acid (EDTA) tubes for the separation of plasma and 1 ml in plain vacutainer, used for the assessment of different inflammatory markers. The blood collected from another set of mice was separated into serum and plasma and these had been used for the assessment of lipid profile level and hematological examinations, respectively.

Hematological analysis

The blood plasma was collected after centrifugation of samples at 3000 rpm for 5 min. The white blood cells (WBCs) in thousands per cubic milliliter and red blood cells (RBCs) in millions per cubic millimeter were measured using cell counter (Sysmex, model KX21N). The packed cell volume (PCV), mean cell volume (MCV), mean cell hemoglobin (MCH), and platelet count were also determined.

Assay of serum lipid markers examination

Serum collected from the blood samples was subjected to biochemical estimations. Serum lipid markers such as total cholesterol (TC), triglycerides (TGs), and high-density lipoprotein (HDL) were evaluated using standard kits. The low-density lipoprotein (LDL) cholesterol was determined by using Freidewald’s formula, LDL cholesterol = [total cholesterol − (triglycerides/5) − HDL cholesterol].

Lipid parameters in serum were measured through a fully automated biochemical analyzer (Chemwell1520, USA). All serum samples were analyzed in duplicate, and mean values were represented in the result.

Serum interleukin level

The levels of interleukin-8 (IL-8) and interleukin-10 (IL-10) in all groups were quantified through enzyme-linked immunosorbent assay (ELISA) by using respective kits (R&D Systems, USA).

Serum C-reactive protein

The level of C-reactive protein (CRP) in serum sample exposed to arsenic and simultaneous treatment of arsenic and amla was estimated using the solid phase ELISA by using the respective kit (R&D Systems, USA). The assay employs the quantitative sandwich enzyme immunoassay technique. The 96-well pre-coated plate with polyclonal antibody specific for mouse CRP was used. The intensity of the color was measured in proportion to the amount of mice serum CRP bound to the sample, and the levels of CRP were calculated by using a standard curve.

Statistical analysis

Data were analyzed using one-way analysis of variance followed by a Newman–Keuls test for multiple pairwise comparisons among the groups. All values were expressed as standard error mean (±SEM). P value <0.05 was considered significant.


   Results Top


Effect on the serum hematological parameters in mice

The effect on the serum hematological level in mice following exposure to arsenic is presented in [Table 1]. The results showed that arsenic treatment significantly decreased RBCs count (0.42-fold, P < 0.05), MCV (0.68-fold, P < 0.05), MCH level (0.62-fold, P < 0.05), hemoglobin (Hb) (0.57-fold, P < 0.05), phospholipid (PL) (0.55-fold, P < 0.05) and significantly increased WBCs count (1.10-fold, P < 0.05), platelets (0.63-fold, P < 0.05) as compared to the control group. Co-treatment with arsenic and amla significantly increased RBC count (1.8-fold, P < 0.05), MCV (1.14-fold, P < 0.05), MCH level (1.18-fold, P < 0.05), Hb (1.4-fold, P < 0.01), PL (1.2-fold, P < 0.01) and significantly decreased platelets (1.35-fold, P < 0.01) and no significant change was found in WBC count (1.4-fold, P > 0.05), as compared to those of mice treated with arsenic alone. No significant effect was observed in mice treated with amla alone as compared to controls [Table 1].
Table 1: Effect on hematological parameters in mice exposed to arsenic, amla and their simultaneous treatment for 30 days

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Effect on the serum lipid biomarker in mice

Effect of arsenic and co-treatment of arsenic and amla on mice is presented in [Table 2]. Exposure to arsenic in mice caused a significant increase in TC (1.69-fold, P < 0.01), TG (1.62-fold, P < 0.01), PL (0.55-fold, P < 0.05), and LDL (2.57-fold, P < 0.001), while it significantly decreased HDL (0.58-fold, P < 0.01) level as compared to that of controls suggested dyslipidemic effect of the arsenic. Co-treatment with arsenic and amla corrected lipid profile near significant level by decreasing the TC (0.83-fold, P < 0.05) TG (0.92-fold, P < 0.05), PL (1.29-fold, P > 0.01), and LDL (0.72-fold, P < 0.01) level while increasing HDL (1.41-fold, P < 0.01) level as compared to that of arsenic-treated group. No significant effect on lipid profile was observed in mice treated with amla alone as compared to that of controls [Table 2].
Table 2: Effect on lipid profile in mice exposed to arsenic, amla and their simultaneous treatment for 30 days

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Effect on interleukin-8 in serum of mice

Effect of arsenic and co-treatment of arsenic and amla on the serum level of IL-8 in mice is presented in [Figure 1]. Mice exposed to arsenic exhibited a significant increase in IL-8 level (1.8-fold, P < 0.01) as compared to controls. Co-treatment with arsenic and amla decreased the serum level of IL-8 as compared to arsenic-treated group (0.6-fold, P < 0.05). No significant effect on serum IL-8 level was observed in mice treated with amla alone as compared to controls [Figure 1].
Figure 1: Effect of serum IL-8 in mice exposed to arsenic, amla and their co-treatment on cell viability in thymus of mice. Values are mean ± SEM of five animals in each group. (a) Compared to control group. (b) Compared to arsenic-treated group. *Significantly differs (P < 0.05)

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Effect on C-reactive protein in serum of mice

Effect of arsenic and co-treatment of arsenic and amla on CRP level in the serum is presented in [Figure 2]. Mice exposed to arsenic exhibited a significant increase in CRP level (0.5-fold, P < 0.01) as compared to that of controls. Co-treatment with arsenic and amla significantly decreased the CRP (0.7-fold, P < 0.05) level in serum as compared to those treated with arsenic alone. No significant effect on serum CRP level was observed in mice treated with amla alone as compared to that of controls [Figure 2].
Figure 2: Effect of serum CRP in mice exposed to arsenic, amla and their co treatment on cell viability in thymus of mice. Values are mean ± SEM of five animals in each group. (a) Compared to control group. (b) Compared to arsenic-treated group. *Significantly differs (P < 0.05)

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Effect on interleukin-10 in serum of mice

[Figure 3] indicates the effect of arsenic and co-treatment of arsenic and amla on serum level of IL-10 in mice. Exposure to arsenic in mice caused a significant decrease in the levels of serum IL-10 (0.4-fold, P < 0.001) in mice as compared to that of controls. Co-treatment with arsenic and amla increased the levels of IL-10 (1.5-fold, P < 0.05) in the serum of mice as compared to those treated with arsenic alone. No significant effect on the levels of IL-10 was observed in the mice treated with amla alone as compared to that of controls [Figure 3].
Figure 3: Effect of serum IL-10 in mice exposed to arsenic, amla and their co-treatment on cell viability in thymus of mice. Values are mean ± SEM of five animals in each group. (a) Compared to control group. (b) Compared to arsenic-treated group. *Significantly differs (P < 0.05)

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   Discussion Top


Prolonged consumption of arsenic-contaminated drinking water caused obstructive and restrictive disorders, oxidative stress and inflammation to pulmonary organ and immune system.[29],[30] Chronic inflammation caused by the consumption of arsenic-contaminated water and food materials contributes to the development of many disease processes such as respiratory, cardiovascular, and other metabolic diseases. The pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) are also secreted due to the arsenic toxicity and generate inflammatory responses.[31],[32],[33] These pro-inflammatory mediators are involved in the various biological and cellular comebacks, including tumor progression, growth factor, transcription factor, and activation of proapoptotic proteins.[34] The toxico-pathogenesis of respiratory system due to arsenic exposure resulted in lung and pulmonary dysfunction. Studies have reported that the deposition of arsenic may increase inflammation and cause fibrosis that may further lead to cause pulmonary cellular dysfunction.[35] Studies have shown that incidences of autoimmune-mediated diseases, increased expression of TNF-α and IL-8 could be linked to increased arsenic exposure.[6]

Studies have also been reported that chronic arsenic exposure causes immunosup­pression and affects the secretion of a variety of cytokines in the exposed population.[36],[37],[38] Further, the generation of free radicals is also found to be associated with these cytokines, including TNF-α, IL-1β, and IL-6.[39],[40] Exposure to arsenic through contaminated drinking water and airway also raised pro-inflammatory mediators and lowered anti-inflammatory IL-10 in circulation and may contribute to metabolic syndrome and CVD.[41],[42] After absorption into the body, the first tissue encounters with arsenic is blood. The accumulation of arsenic in erythrocytes has been found to cause anemia linked with leucopenia, neutrophil depletion and thrombocytopenia.[43],[44] Arsenic-induced depletion in the counts of erythrocyte, leukocyte, and platelet along with total Hb content has been reported by a number of investigators.[45],[46] Further, the reduction in PCV, Hb, and RBC counts as a result of inhibition of porphyrin or heme synthesis has also been reported in arsenic-induced toxicity.[47] Reduced deformability and premature destruction of RBCs in anemia are very common in inflammation due to arsenic exposure.[48] Studies have been shown that arsenic exposed rat was significantly increased serum TC, LDL, VLDL, and TGs followed by a significant decrease in the HDL cholesterol.[49],[50] The increased oxidative stress due to arsenic exposure may influence inflammatory responses in the vascular cells.

Inflammation has been found to be one of the most important factors that contribute to CVD. Elevated levels of monocyte chemo attractant protein (MCP-1), IL-6, and TNF-α, produced by the immune system play an important role in increasing the risk of CVDs. Both IL-6 and TNF-α play an important role in the regulation of the synthesis of other acute phase proteins which are established risk factors for atherosclerosis.[51] CVD and accounts for more than half of all the deaths in the developed world. Epidemiological and experimental studies in adult mice showed strong correlation between arsenic exposure and atherosclerosis.[52],[53],[54] A significantly increased level of plasma concentrations of MCP-1, IL-6 and MDA were also reported in arsenic-exposed mice.[13]

In the present study arsenic treatment has been found to decrease the hematological cells and altered lipid profile by increasing TC, TG, PL, and LDL levels and decreasing HDL levels as compared to controls. Treatment with arsenic also disturbed the levels of inflammatory biomarkers from their normal physiological levels. The results are consistent with the previous studies.[13],[50],[54]

Plant based pharmacological preparations were reported to be used against arsenic-induced oxidative damage.[55],[56] Phyto constituents including flavanoids present in the plant extracts, and herbal agents are found to have radical scavenging properties and inhibit the levels of lipid peroxidation and inflammation.[57],[58],[59] Amla contains a wide variety of phenolic compounds which are associated with its strong antioxidant potential. Reddy et al.[60] reported that alcohol-induced oxidative stress in plasma of rats could be ameliorated through the treatment with. In another study; Kumar et al.[61] found that amla significantly protects lead induced toxicity by decreasing the oxidative stress in one day old male broiler chicks.[61]

Numerous studies have suggested that flavonoids from amla effectively reduced lipid levels in serum and tissues and also inhibit the activity of hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A (HMGCo-A) reductase in rats.[62] It also increases cardiac glycogen levels and decreases serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and LDL in rats having myocardial necrosis.[63] Other studies clearly demonstrate the utility of amla fruit as a possible food supplement in significantly reducing the fluoride induced hyperlipidemia and lipid peroxidation.[64],[65] Abnormal lipid profiles associated with a higher risk of CVDs. Shaik et al. reported that elevation of creatine kinase, lactate dehydrogenase (LDH) and transaminase enzyme activities in arsenic exposed mice is a clear indication of cardiac muscle damage. These enzymes are leaking out of blood during low oxygen or glucose supply to myocardium causing myocardial infarction.[66]

In the present study, simultaneous treatment with arsenic and amla significantly balance the serum lipid profile and levels of pro-inflammatory (IL-8, CRP) and anti-inflammatory (IL-10) marker in serum. Further, arsenic-induced alterations in hematological cells and damage Hb has been found to be protected following simultaneous treatment with arsenic and amla as compared to those treated with arsenic alone. In our earlier study, we have also demonstrated that simultaneous treatment with arsenic and amla significantly decreased the levels of TNF-α, IL-1β, IL-6 in serum as compared to those treated with arsenic alone.[17]


   Conclusion Top


We can conclude that significant protection against cardiovascular risk factors through simultaneous treatment with arsenic and amla is due to its anti-inflammatory and hypolipidimic activity. The metal binding property of amla could reduce the load of arsenic in serum and help to pacify the lipid biomarker associated with the inflammation and it further imparts its protective effects. As the protective mechanism of amla is not clearly understood, further studies are required to investigate the detailed therapeutic mechanism of amla in arsenic-induced CVDs.

Acknowledgements

The authors are thankful to the Department of Pharmacology and Biochemistry, King George’s Medical University, Lucknow, India and Department of Biochemistry, Moti Lal Nehru Medical College Allahabad, India for their interest and support in the study. The technical support by Mr. Veerendra Kumar Saini and Mr Durgesh Yadav is also acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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