|Year : 2016 | Volume
| Issue : 3 | Page : 125-132
Zingerone ameliorates hepatic and renal damage in alcohol-induced toxicity in experimental rats
Vijay Mani, Aktarul Islam Siddique, Sivaranjani Arivalagan, Nisha Susan Thomas, Nalini Namasivayam
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Chidambaram, Tamil Nadu, India
|Date of Submission||30-Apr-2016|
|Date of Acceptance||27-May-2016|
|Date of Web Publication||23-Jun-2016|
Dr. Nalini Namasivayam
Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar - 608 002, Chidambaram, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Alcoholic liver disease (ALD) comprises a wide variety of damage, starting from steatosis to liver cancer. ALD results from a multifactorial interaction between behavioral, ecological, and hereditary factors. The aim of this study was to identify whether zingerone ameliorates liver and renal damage in alcohol-induced toxicity in experimental rats. Materials and Methods: Group 1 rats received isocaloric glucose and dimethyl sulfoxide (DMSO) every day, Group 2 rats received zingerone (40 mg/kg body weight [b.w.] in DMSO postorally [p.o]) everyday during the past 30 days of the experimental period, Groups 3-6 received 30% ethanol (6 g/kg b.w. p.o) everyday for 60 days. In addition, Groups 4-6 received different doses of zingerone (10, 20 or 40 mg/kg b.w. in DMSO) every day for the past 30 days of the experimental period. Results: Our results revealed significant elevation in the activities/levels of liver marker enzymes, hepatic alcohol dehydrogenase, serum total bilirubin, renal markers and decreased levels/activities of serum total proteins, albumin, globulin, hepatic aldehyde dehydrogenase and significant changes in the liver and kidney histology of ethanol treated rats as compared to the control rats. Supplementation with zingerone to ethanol-fed rats reversed the ethanol-induced alterations in the liver marker enzymes, serum total bilirubin, serum total proteins, albumin, globulin, hepatic alcohol metabolizing enzymes, renal markers and also restored the histological changes in the liver and kidney. Conclusion: Thus, zingerone can be suggested to offer distinct protection against ethanol-induced organ damage.
Keywords: Alcohol metabolizing enzymes, ethanol, hepatic markers, hepatotoxicity, renal markers, zingerone
|How to cite this article:|
Mani V, Siddique AI, Arivalagan S, Thomas NS, Namasivayam N. Zingerone ameliorates hepatic and renal damage in alcohol-induced toxicity in experimental rats. Int J Nutr Pharmacol Neurol Dis 2016;6:125-32
|How to cite this URL:|
Mani V, Siddique AI, Arivalagan S, Thomas NS, Namasivayam N. Zingerone ameliorates hepatic and renal damage in alcohol-induced toxicity in experimental rats. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2019 Oct 13];6:125-32. Available from: http://www.ijnpnd.com/text.asp?2016/6/3/125/184585
| Introduction|| |
Worldwide, alcoholic liver disease (ALD) is a major cause of illness and mortality.  ALD, a common effect of prolonged and heavy alcohol intake, is one of the leading health problems after cancer and cardiovascular diseases. In the modern way of life, intake of alcoholic beverages is a common characteristic and nowadays alcoholism ranks as a major health problem.  Experimental and epidemiologic studies confirmed that the duration and the degree of alcohol consumption promote the progression and genesis of liver damage. Ethanol affects all organs of the body because of its ability to permeate all tissues due to its water and fat soluble properties. Among the many organ systems in the human body that are affected by alcohol are the liver and kidney.
The liver is the major site of ethanol metabolism. Liver executes several important mechanisms which play crucial roles in digestion, storage, assimilation, and detoxification.  Kidney also serves to maintain and functions to remove the waste products of metabolism. Chronic exposure to alcohol may result in pathophysiologic changes in cellular function caused by alcohol itself or the effects of its metabolites. The toxicity of alcohol is associated with its metabolism through alcohol dehydrogenase (ADH) which converts ethanol to the toxic acetaldehyde which is finally oxidized to acetate through aldehyde dehydrogenase (ALDH). Acetaldehyde is the most important metabolite of ethanol that leads to liver damage.  In addition, growing evidence suggests that oxidative stress plays a vital role in the pathogenesis of ALD and other toxic consequences.  Previous reports illustrate that ethanol causes the accumulation of reactive oxygen species (ROS) such as hydroxyl radical, superoxide radical, and hydrogen peroxide in the hepatocytes that leads to the oxidation of DNA, protein, and cellular membranes, resulting in the depletion of reduced glutathione and liver damage. 
Ethanol oxidation by the kidney is favored in ethanol treated rats thereby suggesting a pathogenic role for acetaldehyde in the hepatoprotective effect of alcohol ingestion. Regular alcohol consumption rises the blood pressure which by itself is a risk factor for renal damage. Renal damage may occur as a result of acute intoxication or chronic alcoholism.  Protein deficiency and enzyme activity impairment with decreased serum albumin concentration and changes in enzyme activities have also been associated with ALD. 
Despite great progress made in the field, the development of suitable drugs for the treatment of alcoholism remains a challenging goal for alcohol research. In general, plants contain some biologically active compounds, which are responsible for the prevention and detoxification of free radicals thereby protecting themselves from oxidative stress and the subsequent consequences.  Hence, identification of an effective hepatoprotective agent will be a useful tool for the treatment of liver diseases. Zingerone [Figure 1], a dietary phenolic compound has been reported to exhibit a number of beneficial pharmacological properties such as antioxidant,  anticancer,  antiinflammatory,  antimicrobial,  and radioprotective  effects. Therefore, this study was carried out to characterize the mechanisms by which zingerone protects against alcohol toxicity by assaying liver and renal markers, alcohol metabolizing enzymes, total proteins, bilirubin, albumin, globulin, and tissue histology in experimental rats.
|Figure 1: Chemical structure of zingerone [4-(4-hydroxy-3-methoxyphenyl) butan-2-one]|
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| Materials and Methods|| |
Chemicals and reagents
The chemicals and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA). Ethanol was obtained from E.I.D Parry India Ltd., (Nellikuppam, Cuddalore District, India). All other chemicals and reagents used were of analytical grade obtained from Himedia Laboratory Ltd., Mumbai, India.
Preparation of zingerone
Zingerone was dissolved in 2% dimethyl sulfoxide (DMSO) just before treatment and was administered orally by intragastric intubation every day at the dose of 10, 20, or 40 mg/kg body weight (b.w.).
Male albino Wistar rats weighing about 150-180 g were obtained from the Central Animal House, Rajah Muthiah Medical College and Hospital, Annamalai University. Rats were maintained as per the principles and guidelines of the ethical committee for animal care and use of Annamalai University in accordance with the Indian National Law on Animal Care (Reg. No. 160/1999/CPCSEA/1095). The experiments were conducted in accordance with the "Guide for the care and Use of Laboratory Rats." The animals were housed in plastic cages with paddy husk for bedding at a temperature of 27 ± 2°C with 12 h: 12 h light:dark cycles.
Animals were divided into six groups of 6 animals each. Experiments were performed for 60 days.
- Group 1: Rats received standard pellet diet, isocaloric glucose (40% glucose in drinking water) and 2% DMSO postorally (p.o) for the entire experimental period of 60 days
- Group 2: Rats received standard pellet diet along with isocaloric glucose everyday throughout the experimental period and zingerone (40 mg/kg b.w. p.o) was administered from the 31 st day till the end of the experiment
- Group 3: Rats received 30% ethanol (equivalent to 6 g/kg b.w. p.o) everyday throughout the experimental period of 60 days
- Group 4-6: Rats received 30% ethanol everyday throughout the experiment and zingerone (10, 20 or 40 mg/kg b.w. p.o respectively) were administered from the 31 st day till the end of the experiment.
At the end of experimental period, the animals were sacrificed by cervical dislocation. Blood was collected in a heparinized tube, and the plasma was separated. The liver was removed and immediately cleaned with ice-cold saline (0.9% sodium chloride). Tissue samples were homogenized and the supernatant used for the biochemical estimations and histological studies.
The activities of serum aspartate aminotransferase (AST; E.C.220.127.116.11) and alanine aminotransferase (ALT; E.C.18.104.22.168) were assayed by the method of Reitman and Frankel.  Serum alkaline phosphatase (ALP; E.C.22.214.171.124) was assayed using the diagnostic kit based on the method of Kind and King.  Serum γ-glutamyl transpeptidase (GGT; E.C.126.96.36.199) was assayed by the method of Rosalki and Rau,  serum total bilirubin was estimated by the method of Malloy and Evelyn,  the activity of lactate dehydrogenase (LDH; E.C.188.8.131.52) by the method of King,  total proteins by method of Lowry et al.  and serum albumin by the method of Doumas et al., 1971.  Serum globulin concentration was calculated using the formula: globulins = total proteins − albumin.
ADH (E.C.184.108.40.206) and ALDH (E.C.220.127.116.11) were assayed in the liver homogenate by the method of Agarwal and Goedde. 
Serum urea was determined by the method of Fawcett and Scott,  serum uric acid by the method of Caraway  and serum creatinine by Jaffe's method. 
For histopathologic studies, liver and kidney were excised immediately from the rats, cleared of blood and fixed in a neutral buffered solution of 10% formalin for 24 h. The tissues were subsequently embedded in paraffin, thinly sectioned with a microtome, stained with hematoxylin and eosin and examined using a light microscope.
Results were expressed as means ± standard deviation of six rats per group. Data were analyzed by one-way analysis of variance and any significant differences among treatment groups were evaluated using Duncan's multiple range test. Results were considered statistically significant when P < 0.05. All statistical analyses were performed using SPSS version 15.0 software package (SPSS, Tokyo, Japan).
| Results|| |
[Table 1] depicts the initial and final body weight, body weight gain of control and experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the bodyweight as compared to that of the control rats. Ethanol treated rats (Group 3) showed a decrease in the weight gain as compared to the control rats. On supplementation with zingerone (Group 4-6) to ethanol treated rats, the weight gain improved significantly while the liver to body weight ratio decreased significantly as compared to the ethanol alone fed rats.
|Table 1: Effect of zingerone on body weight and liver to body weight ratio |
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[Table 2] shows the activities of the liver markers enzymes such as AST, ALT, ALP, and GGT of the control and ethanol treated experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the activities of liver marker enzymes as compared to that of the control rats. Ethanol treated rats (Group 3) showed significantly elevated activities of AST, ALT, ALP, and GGT as compared to the control, whereas on supplementation with zingerone (Groups 4-6) to ethanol-fed rats, the activities of these enzymes were significantly decreased (P < 0.05) as compared to the ethanol alone fed rats.
|Table 2: Effect of zingerone and ethanol on the hepatic marker enzymes of the control and experimental rats |
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[Table 3] shows the effect of zingerone on the levels of serum proteins of the control and experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the levels of serum proteins as compared to that of the control rats. However, significantly reduced levels of serum total proteins, albumin, and globulin were observed in ethanol-fed rats (Group 3) as compared to the control rats. On supplementation with zingerone (Groups 4-6), the levels of serum proteins were elevated significantly as compared to the ethanol alone administered rats. A/G ratio was below 1.0 in ethanol-fed rats whereas on supplementation with zingerone A/G ratio was above 1.0 which was significantly higher (P < 0.05) as compared to the A/G ratio of ethanol-fed rats.
|Table 3: Effect of zingerone and ethanol on the serum proteins of control and experimental rats |
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[Table 4] depicts the levels/activities of serum total bilirubin and LDH of control and experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the levels of serum total bilirubin and LDH as compared to control rats. However, total bilirubin levels and LDH activity in ethanol alone fed rats (Group 3) were significantly increased as compared to the control rats. Supplementation with zingerone (Groups 4-6) to ethanol-fed rats significantly decreased (P < 0.05) the levels/activities of bilirubin and LDH as compared to the ethanol alone treated rats.
|Table 4: Effect of zingerone and ethanol on bilirubin and LDH of control and experimental rats |
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[Figure 2] shows that the activities of ADH and ALDH in the liver of the control and experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the activities of alcohol metabolizing enzymes as compared to that of the control rats. Ethanol-fed rats (Group 3) showed significantly (P < 0.05) increase in the activity of ADH and a significant decrease in the ALDH activity (Group 3) as compared to those of the control rats. Supplementation with zingerone (Groups 4-6) to ethanol-fed rats, showed significant (P < 0.05) decrease in ADH and an increase in the ALDH activities as compared to the ethanol alone fed rats.
|Figure 2: Effect of zingerone and ethanol on hepatic alcohol metabolizing enzymes of control and experimental rats. Values are given as means ± standard deviation for six rats in each group. Groups not sharing a common superscript letter differ significantly at P < 0.05. DMRT = Duncan's multiple range test; ADH = Alcohol dehydrogenase; ALDH = Aldehyde dehydrogenase|
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[Table 5] shows the effect of zingerone on renal function markers of the control and experimental rats. Rats treated with zingerone alone (Group 2) did not show any statistically significant (P < 0.05) difference in the levels of serum urea, uric acid, and creatinine as compared to that of the control rats. However, the serum levels of urea, uric acid, and creatinine were significantly increased (P < 0.05) in the ethanol alone treated rats (Group 3) as compared to the control and zingerone alone treated rats. Supplementation with zingerone (Groups 4-6) showed significantly decreased levels of serum urea, uric acid, and creatinine as compared to the ethanol alone fed rats.
|Table 5: Effect of zingerone and ethanol on serum urea, uric acid and creatinine of control and experimental rats |
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[Figure 3] and [Figure 4] show the histological changes in the liver and kidney of control and experimental rats. Liver of the control rat shows normal architecture with normal appearance of the hepatocytes and central vein (Group 1). The levels of zingerone supplemented control rat depict hepatocytes with normal lobular architecture (Group 2). Ethanol fed rat liver (Group 3) shows alterations in the hepatocytes such as infiltration with inflammatory cells, micro- and macro-vesicular fatty changes and eroding of the portal triad. Supplementation with zingerone (10, 20, or 40 mg/kg b.w) to ethanol-fed rats effectively reduced the pathological abnormalities.
|Figure 3: Liver histology of control and experimental rats (H and E, ×40). (a and b) Normal liver histology. (c) Ethanol fed rat liver shows infiltration with inflammatory cells, micro and macro vesicular fatty changes and eroded portal triad. (d) Ethanol + zingerone (10 mg/kg body weight) treated rat liver shows fatty cysts. (e) Ethanol + zingerone (20 mg/kg body weight) administered rat shows reduced ethanol induced abnormalities such as vesicular fatty changes and inflammation. (f) Ethanol + zingerone (40 mg/kg body weight) supplemented rat liver shows the normal appearance of hepatocytes|
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|Figure 4: Kidney histology of control and experimental rats (H and E, ×40). (a and b) Normal kidney histology. (c) Ethanol fed rat shows severe degenerative alterations in the tubules, congestion of blood vessels and diffused inflammatory cell infiltration. (d) Ethanol + zingerone (10 mg/kg body weight) treated rat kidney shows few tubules containing fat vacuoles. (e) Ethanol + zingerone (20 mg/kg body weight) treated rat kidney shows slight congestion of peritubular capillaries and normal glomeruli. (f) Ethanol + zingerone (40 mg/kg body weight) treated rat kidney shows normal histology|
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Kidney of the control rat and zingerone alone treated rat shows the normal appearance of renal parenchymal cells, normal tubules, and glomeruli, whereas, the ethanol-fed rat kidney shows congestion of blood vessels, swelling of tubules, scattered inflammatory cell infiltration, and damaged glomeruli. However, on supplementation with zingerone, the changes induced by ethanol were reversed as evident by the normal appearing glomeruli and regeneration of renal cells. The more pronounced effect of zingerone treatment was observed in the groups of rats treated with 20 mg/kg b.w. (Group 5).
| Discussion|| |
ALD often results from a complex interaction between environmental, genetic and behavioral factors. Epidemiologic and experimental studies demonstrate that the degree and duration of alcohol consumption promote the genesis and progression of liver damage. The mechanisms of alcohol-induced hepatotoxicity are complex and multifactorial. ROS produced during the extensive metabolism of ethanol causes oxidative stress and is suggested to be one of the major mechanisms underlying the toxicity.  Growing evidence support the hypothesis that ethanol-induced tissue damage may not only be a consequence of oxidative stress but also due to nutritional deficiencies. Since body weight is considered as a putative indicator of health, the increased weight gain by rats supplemented with zingerone suggests the beneficial effects of zingerone against alcohol-induced liver damage.
Serum aminotransferases and GGT are the most sensitive markers employed in the diagnosis of liver damage, as they are located in the cytoplasm and released into the circulation, once the cells are damaged.  Bilirubin levels in the circulation can also increase due to liver cell damage not only due to the decreased capacity of the liver to conjugate but also the reduced capacity to excrete it through the bile. Bilirubin levels are also known to be raised significantly in alcohol-induced hepatotoxicity.  Thus, enhanced activities of these liver marker enzymes in the circulation reflect active destruction of the hepatocytes. In the present study, ethanol-induced hepatotoxicity is indicated by a significant increase in the activities/levels of AST, ALT, ALP, GGT, LDH, and bilirubin in the circulation indicating increased permeability, necrosis, and hepatocyte damage. Our current results correlate with those of the previous reports by Yang et al., 2012,  who suggested that ethanol enhances the activities of AST, ALT, and ALP in the circulation. Supplementation with zingerone decreased the activities of aminotransferases, GGT and total bilirubin to near those of the control values which could be attributed to the ability of zingerone to prevent ethanol-induced hepatic damage and dysfunction. Similar hepatoprotective findings were observed when a crude extract of ginger (one of its active principles is zingerone) was fed to ethanol treated rats. 
A major common feature of ALD is progressive hypoalbuminemia.  In line with this observation, our study also revealed decreased levels of total proteins, albumin, and globulin in ethanol-fed rats, which were reversed on supplementation with zingerone. This property of zingerone is possibly either due to the inhibition of protein degradation or the enhancement of protein synthesis or both. Moreover, due to its inherent antioxidant properties  zingerone could prevent ethanol-induced ROS and subsequently hepatic damage. On the whole, effective control of liver marker enzymes, bilirubin, total protein, albumin, and globulin levels by zingerone points toward an early improvement in the function/secretory mechanisms of the liver cells.
Polymorphisms of ADH and ALDH genes correlate with the occurrence of ALD.  Relatively high ADH activity in the liver can cause an increase in the levels of acetaldehyde after alcohol ingestion resulting in ethanol-dependent injury to the liver. Quintanilla et al., 2007  have also reported that after ethanol administration hepatic ADH activity is significantly elevated in rats resulting in a marked surge of blood acetaldehyde. Similarly in our study, the activity of ADH was disproportionately high, and that of ALDH significantly low in ethanol treated rats. This suggests that the damaged hepatic cells have a greater capability for ethanol oxidation and considerably less ability to remove acetaldehyde than healthy tissues. Acetaldehyde, considered to be toxic, can bind to proteins such as enzymes, microsomal proteins, and microtubules. Formation of acetaldehyde-protein adducts in hepatocytes impairs protein secretion, which has been proposed to play a role in hepatomegaly. 
Moreover, during ethanol oxidation, NAD is converted to its reduced form NADH, resulting in the decreased NAD/NADH ratio. This effect of ethanol on the NAD + /NADH ratio occurs during the time that ethanol remains detectable in the blood.  An alteration in the cellular redox state is known to affect the expression of certain genes. In addition, an alteration in the NAD/NADH ratio resulting from ethanol metabolism has been suggested to cause fatty liver due to inhibition of fatty acid oxidation and tricarboxylic acid (TCA) cycle and the stimulation of lipogenesis.  Supplementation with zingerone to ethanol treated rats significantly reduced the ADH activity and elevated the ALDH activity in the liver resulting in improved NAD/NADH ratio. Further, the elevated ALDH activity enhances the conversion of acetaldehyde to acetic acid leading to the rapid clearance of acetaldehyde from the blood, thereby decreasing its toxicity. These data underline the hepatoprotective ability of zingerone against ethanol-induced liver damage.
Renal function markers such as serum urea, uric acid, and creatinine were evaluated to assess the functional capacity of the nephrons. These parameters are considered to be significant markers of renal dysfunction.  In addition to the liver, the function of the kidneys were also remarkably affected on ethanol administration as evidenced by the significantly elevated levels of serum urea, uric acid, and creatinine in ethanol treated rats as compared to the control. This increase is also mainly caused by the increased production of acetaldehyde which mediates tissue damage and finally leads to decline in the glomerular filtration rate, altered kidney function, and renal failure. However, all the kidney function markers such as serum urea, uric acid, and creatinine were significantly normalized on zingerone supplementation, which suggests that zingerone preserves the functional capacity of the kidneys against ethanol toxicity. These results correlate with the studies by Shanmugam et al., 2010,  who reported that ginger extracts supplemented to alcohol treated male rats prevented massive congestion of renal tubules and degenerative changes in the renal tissues.
Histopathological alterations in the liver due to ethanol administration causes liver damage as evidenced by the structural changes, i.e., disruption of the normal architecture, necrosis, cellular infiltration, and leading to pathological damage. In this context, Reddy et al., 2010,  have also reported that ethanol causes liver damage including changes in the normal histology, increased permeability and necrosis of hepatocytes. Histological changes in the kidney of ethanol-fed rats showed rupture of blood vessels, fatty infiltration and damage to glomeruli and tubules which correlate with the studies by Shanmugam et al., 2010,  who reported that ethanol causes renal damage which includes damage to glomeruli and tubules. On the other hand, supplementation with zingerone markedly reduced the pathogenicity, more importantly restoring the healthy state of the liver and kidney cells. This could be due to the antioxidant efficacy of zingerone, which helps in wiping out the generation of free radicals, thereby preventing the destruction of hepatic/renal cells which correlated with the previous report demonstrated that glycine has a significant protective role against free radical-induced oxidative stress in the erythrocyte membrane, plasma and hepatocytes of rats with alcohol-induced liver injury.  On the other hand, Shubham et al., 2015  clearly portrays the beneficial effects of glycine in alcohol-induced hepatotoxicity. Moreover, all the above beneficial effects of zingerone on the liver and kidney observed in our microscopic studies (histopathology) correlate with our biochemical findings.
| Conclusion|| |
To conclude, these observations confirm that ethanol-induced liver and kidney damage can be alleviated by the potential beneficial effects of zingerone as evidenced by the improvement in the liver function, hastening of alcohol metabolism, improvement of renal function and thereby the restoration of the liver and kidney architecture (histological findings). The effect of zingerone was more pronounced in the rats supplemented with 20 mg/kg b.w. zingerone to ethanol-fed rats. However, further detailed studies on zingerone such as specific organ toxicity are warranted to unravel its mechanism of action and to ascertain the efficacy of zingerone.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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| ||Fatih Mehmet Kandemir,Serkan Yildirim,Sefa Kucukler,Cuneyt Caglayan,Amdia Mahamadu,Muhammet Bahaeddin Dortbudak |
| ||Biomedicine & Pharmacotherapy. 2018; 105: 981 |
|[Pubmed] | [DOI]|