|Year : 2019 | Volume
| Issue : 4 | Page : 368-376
Pomegranate peels ameliorate renal nitric oxide synthase, interleukin-1β, and kidney injury molecule-1 in nephrotoxicity induced by acrylamide in rats
Mohamed A.M Kandeil1, Kamel M.A Hassanin2, Mahmoud M Arafa3, Hebatullah A Abdulgawad3, Ghada M Safwat1
1 Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
2 Department of Biochemistry, Faculty of Veterinary Medicine, Minia University, Minia, Egypt
3 Biochemistry Department, Animal Health Research Institute, ARC, Giza, Egypt
|Date of Submission||16-May-2019|
|Date of Acceptance||24-Jun-2019|
|Date of Web Publication||28-Jan-2020|
PhD Hebatullah A Abdulgawad
Department of Biochemistry, Animal Health Research Institute, Dokki, Giza 12618
Source of Support: None, Conflict of Interest: None
Background and objectives Acrylamide (AA) is considered a toxic intermediate product of the Millard reaction and liberated in high-carbohydrate foods exposed to high temperatures. AA formed during baking, frying, roasting, or grilling of such food. Various studies have recorded the toxic effects of AA on many biological functions. The aim of our study is to determine such toxic effect on the kidney and the prophylactic role of pomegranate peels (PP) as a waste portion of the fruit.
Materials and methods In this study, 60 male albino rats were administered 40 mg/kg body weight AA orally for 17 consecutive days. To evaluate the nephrotoxic effects of AA, some biochemical parameters were measured. Also, 200 mg/kg body weight PP were administered orally as a prophylaxis for 31 consecutive days.
Results and conclusion In the AA group, alterations in renal function were observed, which was evident from significantly high levels of urea, creatinine, and uric acid. Estimation of serum and urine electrolytes (Na+, K+, and Cl−) showed electrolyte imbalance as well. AA-induced renal oxidative stress was expressed as low levels of renal antioxidants (glutathione, glutathione peroxidase, and superoxide dismutase) and high levels of renal oxidants (malondialdehyde and nitric oxide). To clarify the Pathogenesis of AA nephrotoxicity, estimation of renal nitric oxide synthase and interleukin-1β is carried out showing high significant level. Direct damage in renal tissue is resembled in high level of renal kidney injury molecule-1. As stated before, the administration of AA resulted in acute nephrotoxicity, whereas PP played a vital role in reducing this toxicity. Lower levels of urea, creatinine, and uric acid were observed in the AA+PP group and electrolyte balance was achieved, indicating the prophylactic effect of PP. PP showed antioxidant activity as higher levels of glutathione, glutathione peroxidase, and superoxide dismutase recorded and also lower levels of nitric oxide and malondialdehyde controlling oxidative stress of AA. The levels of kidney injury molecule-1, interleukin-1β, and nitric oxide synthase improved significantly. Finally, we can state that PP could ameliorate the nephrotoxic effect of AA.
Keywords: acrylamide, heated food, interleukin-1β, nitric oxide synthase, kidney injury molecule-1, nephrotoxicity, pomegranate peels
|How to cite this article:|
Kandeil MA, Hassanin KM, Arafa MM, Abdulgawad HA, Safwat GM. Pomegranate peels ameliorate renal nitric oxide synthase, interleukin-1β, and kidney injury molecule-1 in nephrotoxicity induced by acrylamide in rats. Egypt Pharmaceut J 2019;18:368-76
|How to cite this URL:|
Kandeil MA, Hassanin KM, Arafa MM, Abdulgawad HA, Safwat GM. Pomegranate peels ameliorate renal nitric oxide synthase, interleukin-1β, and kidney injury molecule-1 in nephrotoxicity induced by acrylamide in rats. Egypt Pharmaceut J [serial online] 2019 [cited 2020 Aug 3];18:368-76. Available from: http://www.epj.eg.net/text.asp?2019/18/4/368/276724
| Introduction|| |
Thermal food processing is a common practice both in homes and in food manufacture for food microbiological safety and preservation, and for enhancing food texture, color, and taste. One of the food reactions, called the Millard reaction or nonenzymatic browning , occurs when rich carbohydrate food is exposed to high temperatures (>120°C) . Millard reaction products (MRPs) produces many intermediate and end products called MRPs; some of these have benefits and others do not . One of the MRPs has received more attention because of its adverse impact on humans: acrylamide (AA) . Human exposure to AA is widespread in the world. Previous studies proved that AA is a neurotoxic compound and also exerts carcinogenic effects on many organs, but in humans, it is considered a probable carcinogen that human studies could not approve it .
In 2002, Swedish scientists first reported that AA formed in heated foods (during frying, baking, and roasting of some foods) . The levels of AA in heated food are variable according to eating habits and different cooking methods . Potatoes provides about 50% of human AA intake, 20% is counted for baking products and bread and the rest is mainly for roasted coffee .
AA may be released into drinking water through water flocculant agents and soil stabilizers; thus, drinking water is considered a probable source of AA human exposure, but food is the main source of AA . WHO and FAO have reported that the average AA intake in humans is in the range of 0.3–0.8 µg/kg body weight/day , whereas the European Food Safety Authority (EFSA)  has reported that the mean AA exposure is 0.4−1.9 µg/kg body weight/day.
Heating food at high temperature (>120°C) leads to the formation of AA through the reaction between asparagine (amino group) and reducing sugar glucose and fructose (carbonyl group), both of which are found naturally in food. On the basis of the amount of asparagine (the precursor) found in food, the level of AA can be determined ,.
Cytochrome P450 2E1 can metabolize AA, resulting in the production of an epoxide derivative called glycidamide, which is oversensitive to attach DNA and proteins (especially hemoglobin) than AA forming adducts . AA and glycidamide (its metabolite) can also be metabolized by attacking glutathione (GSH) with the aid of hepatic GSH-S-transferases  and are then excreted as byproducts of mercapturic acid in human urine . In the Zamani et al.  study, the kinetics of AA at various doses (0.5–100 mg/kg) were assessed after intravenous and oral administration in rats. They found that AA is extensively and rapidly absorbed in the gastrointestinal tract and is broadly distributed to tissues throughout the blood stream. The AA distribution is the highest in the muscle tissue, about 50% of the absorbed dose, followed by the liver, ∼20%, and then the gastrointestinal tract, kidney, pancreas, testis, brain, and gallbladder, as well as epithelia of the oral cavity, esophagus, and bronchi ,. Obviously, some of the systemic effects exerted by AA exposure lead to known neurotoxicity, genotoxicity, and carcinogenicity , but there is a lack of data on the direct effect of AA on kidneys; however, some studies have reported an association between renal cell carcinoma and dietary AA intake .
Recently, the global attention is drawn to natural, active biological, and nontoxic treatments especially those of plants. One of the plants that has received more attention in the last few decades is pomegranate because of the proved potent antioxidant, anti-inflammatory , and antimutagenic effects of the fruit besides the nonedible part: peels . Pomegranate peels (PP) weigh about 40–50% of the total fruit weight. It produced by a huge amount through food industries causing a difficulty to get rid of . Pomegranate is used as a natural medicine in several cultures, especially in the Middle East. In Egypt, various common unhealthy conditions such as inflammation, gastrointestinal tract disorders, cough, and infertility are treated by PP . Some studies have confirmed this prophylactic role of PP against nephrotoxicity such as in gentamicin-induced nephrotoxicity , hexachlorobutadiene-induced nephrotoxicity , mercuric chloride-induced nephrotoxicity , and carbon tetrachloride-induced nephrotoxicity . The main benefits of PP have been attributed to its unique bioactive compounds including hydrolyzable tannins, containing gallic acid and ellagic acid esters, punicalin, punicalagin, hexahydroxydiphenic acid (HHDP) and its derivatives, and also caffeic acid, vanillic acid, p-coumaric acid, and quercetin .
However, many clinical studies have examined the nephroprotective effects of PP as mentioned before; no studies have focused on the eventual benefits of consumption of PP on AA-induced nephrotoxicity. Therefore, the aim of our study is to investigate the nephrotoxicity of AA and the ameliorating effects of PP as it can be added to food naturally, especially heat-treated high-carbohydrate food.
| Materials and methods|| |
Acrylamide and pomegranate peels
AA (99% purity) was purchased from Merck-Schuchardt Chemical Company (Hohenbrunn, Germany). PP were purchased from ordinary Egyptian market. PP were ground and soaked in drinking water from the tap the day before administration and were administered without filtration.
Animals and group designing
The present study was carried out on 60 male Albino rats of 150±30 g body weight purchased from the Animal Health Research Institute, Dokki, Giza, Egypt. The rats were kept under observation for 2 weeks before the experiment for acclimatization. They were housed in nine plastic cages at a room temperature of 22±1°C under a 12-h light–dark cycle. Our study was carried out in accordance with the regulations for the use and care of experimental animals.
During the experiment, rats were Kept on tap drinking water and standard normal chewable diet in a free manner.
After 2 weeks of acclimatization, the rats were divided into three groups (20 rats/group) for 31 days:
Control (Cr) group: 20 rats were maintained on tap drinking water in a free manner for 31 days.
AA group: 20 rats were administered AA dissolved in tap drinking water daily through an oral gavage at a dose of (40 mg/kg body weight according to Ghorbel et al.  study) during the last 17 days of the experiment.
AA+PP group: 20 rats were administered PP (200 mg/kg body weight according to El-Habibi  study) dissolved in tap drinking water daily through an oral gavage separately during the first 14 days of the experiment and with AA (40 mg/kg body weight) during the rest of the experiment. PP was administered half an hour before the administration of AA.
Blood samples were taken through the puncture of the medial acanthus of the eye in a nonheparinized capillary tube. Tubes containing samples were handled gently, then chilled and slanted until centrifugation with a Heraeus centrifuge at 3500 rpm for 15 min for serum separation. Serum samples were distributed into Eppendorf tubes and were kept at −8°C for the subsequent analysis of different biochemical measurements.
All rats were killed after about 13 h of fasting. Abdominal incisions were performed immediately after the blood samples were obtained for separation of kidneys. The kidneys were immediately excised, washed with cold physiological saline (0.9%), and then dried from excess saline using a filter paper. After the kidneys were cut into several parts, some parts of the kidney tissue were placed in glass Packard tubes and kept at −8°C for homogenization.
Urine samples of the Cr group were collected in a metabolic cage, whereas those of the AA group and the AA+PP group were collected after the rats were killed by a sterile syringe directly from the urinary bladder where urine retention was observed ([Figure 1]).
|Figure 1 Nervous urine retention in the AA group and collection of urine with a sterile syringe. AA, acrylamide. Motor dysfunction in the AA group (dragging of hind limbs). AA, acrylamide.|
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Serum biochemical analysis
Renal function tests (urea, creatinine, and uric acid) were estimated according to the methods of Patton and Crouch ; Jaffe ; and Trinder , respectively, to illustrate the nephrotoxic effects of AA and the prophylactic role of PP.
Electrolytes (sodium, potassium, chloride, magnesium, phosphorus, and calcium) were estimated according to the methods of Tietz ; Feldikamp and Zklin ; Bohuon ; Daly and Ertingshausen ; and Young et al. , respectively, to evaluate the renal function and electrolyte balance. All serum measurements were carried out by a spectrophotometer using kits purchased from Egychem Biomed diagnostics Company (Cairo, Egypt).
Urine electrolytes analysis
Urine electrolytes (sodium, potassium, and chloride) were measured directly using a Sensa core electrolyte analyzer ST-200 plus device (Andhra Pradesh, India) with an ion-selective electrode technique to evaluate the role of kidney in electrolyte balance.
Renal homogenate oxidants and antioxidants analysis
Estimation of renal oxidants, malondialdehyde (MDA) and nitric oxide (NO), were determined according to the methods of Satoh ; Montgomery and Dymock , respectively, and renal antioxidant superoxide dismutase (SOD), GSH, and glutathione peroxidase (GPx) were determined according to the methods of Nishikimi et al. ; Beutler et al. ; Paglia and Valentine , respectively, were carried out to evaluate the renal oxidative stress induced by AA and antioxidant effect of PP on renal tissue.
All measurements were carried out spectrophotometrically using kits purchased from Biodiagnostics Company (Cairo, Egypt).
Enzyme-linked immunosorbent assay for the quantitative detection of renal kidney injury molecule-1, nitric oxide synthase, and interleukin-1β
Kidney injury molecule-1 (KIM-1), nitric oxide synthase (iNOS), and interleukin-1β (IL-1β) were measured in kidney homogenate using rat enzyme-linked immunosorbent assay kits according to the manufacturer’s protocol (MyBioSource Company, San Diego, California, USA) to evaluate tissue damage, oxidative stress, and inflammation, respectively.
Statistical analysis was carried out using GraphPad Instat software (version 3, ISS-Rome, Italy). Unless specified otherwise, groups of data were compared using an unpaired t test and one-way analysis of variance (ANOVA), followed by the Tukey–Kramer multiple-comparisons posttest. Values of P less than 0.05 were considered to be significant. The data, as indicated clearly, are reported in the tables and figures as mean±SE.
| Results and discussion|| |
AA has been classified as a neurotoxic compound as well as a probable carcinogen to humans according to IARC . In our study, AA will be discussed as a nephrotoxic compound. After the administration of AA in rats, motor dysfunction (hind limbs dragging [Figure 1]) and coordination impairment were observed. In PM examination, a distended urinary bladder was observed which is called ‘nervous retention,’ explained by Erkekoglu and Baydar  as an extent of neurotoxic effect of AA.
Measurements of urea, creatinine, and uric acid are initial and important markers of kidney function. A highly significant increase in serum urea (48.4±1.503 at P<0.001), creatinine (1.56±0.06 at P<0.001), and uric acid (7.2±0.35 at P<0.001) concentrations was observed in the AA group compared with the Cr group in ([Table 1]). These results are in agreement with those of Ghorbel et al.  and Uthra et al.  as Wistar rats administered 40 mg/kg body weight AA orally for 20 and 10 days, respectively, showed increased levels of urea (P<0.001), uric acid (P<0.001), and creatinine (P<0.001). Raju et al. , in their AA intoxication study, attributed the increase in serum urea, creatinine, and uric acid to a decrease in glomerular filtration.
|Table 1 Serum urea, creatinine, and uric acid (mg/dl) concentrations of the control group, the acrylamide group, and the acrylamide+pomegranate peels group at the end of the experiment (31st day)|
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For more confirmation, estimation of serum and urine electrolytes was carried out, showing electrolyte imbalance as mentioned before in ([Table 2], [Table 3]), which is marked by hyponatremia (130.8±1.16 at P<0.001) and hyperkalemia (5.54±0.25 at P<0.01), indicating renal insufficiency. In contrast to the AA group, we observed an improvement in kidney function and electrolyte imbalance in the AA+PP group, indicating the nephroprotective effect of PP.
|Table 2 Serum electrolyte [phosphorus (mg/dl), magnesium (mg/dl), calcium (mg/dl), sodium (mEq/l), potassium (mEq/l), and chloride (mEq/l)] concentrations of the control group, the acrylamide group, and the acrylamide+pomegranate peels group at the end of the experiment (31st day)|
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|Table 3 Urine electrolyte [sodium (mmol/l), potassium (mmol/l), and chloride (mmol/l)] concentrations of the control group, the acrylamide group, and the acrylamide+pomegranate peels group at the end of the experiment (31st day)|
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In our study, we support two hypotheses. The first hypothesis is affecting cellular redox state, oxidant/antioxidant imbalance as AA either forms conjugates with GSH, yielding N-acetyl-S- (3-amino-3-oxopropyl) cysteine, or reacts with cytochrome P450 to produce the major metabolite glycidamide . Glycidamide further forms conjugates with GSH . During higher intake of AA, more GSH consumed in AA conjugation leading to GSH depletion, which was observed in our study (20.4±0.93 at P<0.001). However, we observed an increase in cellular oxidants through high levels of MDA (136.4±9.02 at P<0.001) and NO (213.5±6.1 at P<0.001) as shown in [Table 4], indicating renal lipid peroxidation and oxidative stress.
|Table 4 Kidney homogenate oxidants and antioxidant: malondialdehyde (μmol/g tissue), nitric oxide (μmol/g tissue), glutathione (mg/g tissue), glutathione peroxidase (μmol/g tissue), and superoxide dismutase (μmol/g tissue) concentrations of the control group, the acrylamide group, and the acrylamide+pomegranate peels group at the end of the experiment (31st day)|
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The Bao et al.  study explained these effects by stating that AA affects the redox state of the renal tissue, causing oxidant/antioxidant disproportion in favor to oxidants, resulting in the subsequent excessive production of reactive oxygen species (ROS), which causes lipid peroxidation and high levels of its end product, MDA. Lipid peroxidation affects cell membrane integrity and permeability, resulting in impairment of cellular vitality ended with apoptosis . Also, NO, the second estimated oxidant, causes cellular apoptosis as NO has an unpaired electron; thus, it reacts with superoxide (one of ROS), producing peroxynitrite anion that oxidizes sulfhydryl groups and thioesters, causing DNA damage . The superoxide is dismutated by SOD into H2O2 (one of ROS), which in turn can be eliminated through reduction reaction by aid of GPx enzyme and GSH as a substrate producing H2O . As shown in [Table 4], SOD (1.44±0.16 at P<0.001) and GPx (13.62±0.39 at P<0.001) decreased significantly; besides the previous noticed GSH depletion causing cellular antioxidant decline and more production of ROS.
In conclusion, oxidative stress resembled in GSH depletion and excessive ROS production is the key factor of AA nephrotoxicity. These results are in agreement with those of Abdel-Daim et al. ; El-Beltagi and Mahgoub  as 20 mg/kg body weight of AA administered in rats orally for 14 and 30 days, respectively, led to decreased levels of GSH (P<0.05), GPx (P<0.05), and SOD (P<0.05). An elevated renal MDA level (P<0.001) was recorded by Alturfan et al.  after the administration of 40 mg/kg body weight AA in rats for 10 days.
Our results showed a highly significant increase in the renal IL-1β level (125.62±5.1 at P<0.001), iNOS activity (6.14±1.2 at P<0.001), and NO level (213.5±6.1 at P<0.001), indicating the inflammatory effects of AA. In agreement with our results, Abdel-Daim et al.  reported high levels of serum IL-1β (P<0.05) and renal NO (P<0.05) after the administration of 20 mg/kg body weight AA orally in rats for 14 consecutive days. Also, an elevated renal NO (P<0.05) level was observed by Aydemir et al.  after the oral administration of AA in rats by 40 mg/kg body weight for 10 days; however, no study detected renal iNOS activity with AA toxicity.
The Pan et al.  study attributed the inflammatory effects of AA to GSH depletion and the subsequent increase in intracellular ROS, resulting in the activation of IL-1β production, which is a vital stimulator of the nuclear factor-κB (NF-κB) signaling pathway, inducing an inflammatory response. Also, Zamani et al.  reported that the increase in NF-κB expression that was induced downstream to the inflammatory effect of AA activated iNOS production and subsequently activated NO generation. On the basis of these evidences, we attempted to clarify the role of the NF-κB signaling pathway in AA nephrotoxicity through determination of IL-1β (one of NF-κB direct stimulators) and iNOS (one of the downstream expressions of the NF-κB pathway). NF-κB is an inducible transcriptional factor activated in stressed cells undergoing cellular apoptosis and also regulates immune and inflammatory responses of the cells . Under normal cellular conditions, NF-κB proteins bound to IκB proteins, forming an inhibitory complex localized in the cytoplasm, blocking nuclear localization. Under stressed or inflamed cellular conditions, nuclear translocation of NF-κB proteins occurred . IL-1β plays a crucial role in this translocation, directly stimulating the NF-κB signaling pathway. IL-1β aids in the phosphorylation of IkB kinases (IKK), converting them into the active form. IKK are responsible for the phosphorylation and ubiquitination of IκB proteins, followed by subsequent degradation separating from NF-κB proteins resulting in nuclear translocation . However, IL-1β activates the NF-κB pathway and also induces the expression of the IL-1β gene, resulting in excessive IL-1β production and so on . With continuous stimulation of the NF-κB pathway, stimulation of iNOS gene expression occurred, leading to excessive production of the iNOS enzyme . Expression of iNOS accompanied by inflammatory conditions resulted in liberating large amounts of NO . Finally, our results support the two hypotheses that AA-induced nephrotoxicity is related to GSH depletion and NF-κB expression as discussed before.
KIM-1 is a newly recognized protein that is released only in damaged renal tissue; thus, it is considered a specific and sensitive marker for proximal tubule injury . KIM-1 is a type-1 transmembrane protein that consists of two portions: a short cytoplasmic tail called endodomain and ectodomain, which has an Ig-like domain and a glycosylated mucin domain . It plays a vital role in apoptotic condition that KIM-1 acts as a receptor for dead cells as well as oxidized lipoprotein, converting normal tubular renal cells into semiprofessional macrophages, in which aid tissue repair . Therefore, it is logically liberated only in damaged tissue according to its function. In our study, we evaluated the possible role of KIM-1 in association with AA-induced renal apoptosis, which has not been reported before. On the basis of the results shown in [Table 5], we observed a significant increase in the level of KIM-1 (192.24±7.7 at P<0.001) in the AA group compared with the Cr group (37.7±1.8), indicating renal tubular injury in the AA group.
|Table 5 Kidney homogenate nitric oxide synthase (ng/ml homogenate), interleukin-1β (pg/ml homogenate), and kidney injury molecule-1 (pg/ml homogenate) concentrations of the control group, the acrylamide group, and the acrylamide+pomegranate peels group at the end of the experiment (31st day)|
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In our study, AA causes nephrotoxicity but administration of PP could ameliorate such toxicity. As shown in [Table 4], an increase in the renal antioxidant levels, GSH (61.4±2.06 at P<0.001), SOD (4.8±0.28 at P<0.001), and GPx (25.86±0.92 at P<0.001), a reduction in the oxidant NO level (131±8.86 at P<0.01), and a reduction in lipid peroxidation (lowered MDA level (74.8±4.08 at P<0.001) indicate the antioxidant effects of PP. The same results were obtained by Ahmed and Ali , and Abdel Moneim et al.  after the administration of 200 mg/kg body weight PP orally for 7 consecutive days in rats to improve renal oxidative damage with a significant level (P<0.05). Also, Karwasra et al.  obtained the same results with a significant level (P<0.001) after the administration of the same dose of PP, but for a longer duration in cisplatin-treated rats in addition to low levels of serum creatinine (P<0.001) and urea (P<0.001), in agreement with our results.
The antioxidant activity of Egyptian PP is counted for 96.24% which determined by Ashoush et al.  through scavenging 1, 1-diphenyl-2-picrylhydrazyl free radical (DPPH). However, Ibrahium  determined the Egyptian PP biological phytochemicals using high-performance liquid chromatography recording the following measurements: total phenolic compounds (867 mg/g) with the most highly component punicalagin (296 mg/g) followed by gallic acid and contained flavonols (quercetin and kaempferol). Punicalagin can be hydrolyzed to punicallin, another ellagitannin, and both can be hydrolyzed to egallic acid under certain conditions such as intestinal microbial fermentation.
All are reported to have a range of biological activities, involving antioxidant and anti-inflammatory activities . The free radical scavenging activity of PP phenolics depends on electron donation to free radicals, converting them into more relative stable compounds . Also, PP could ameliorate renal inflammation induced by AA. This is evidenced by lower levels of renal IL-1β (66.7±8.01 at P<0.001), iNOS (1.872±0.25 at P<0.01), and NO (131±8.86 at P<0.01) after the administration of PP as shown in ([Table 5]). The ameliorative effect of PP was explained by Dell’Agli et al. ; Iris and Sissi  as punicalagin and its hydrolyzed compounds inhibit the NF-κB pathway through blocking NF-κB-driven transcription, which in turn decreases iNOS production and subsequent NO. In Lee et al. study  punicalagin and punicalin caused potent inhibition of iNOS activity was recorded. Also, El-Beltagi and Mahgoub  study refered to the antioxidant activity of quercetin, one of PP flavonols, in AA toxicity reducing level of NO through scavenging NO radical (electron donation) and inhibition of NF-κB pathway. Viladomiu et al.  attributed NF-κB downregulation induced by pomegranate to inhibition of IKK and subsequent IκB degradation, preventing NF-κB nuclear translocation.
NF-κB regulates the transcription of multiple pro-inflammatory molecules; thus, its inhibition will inhibit the inflammatory cascade, clarifying the anti-inflammatory role of PP . KIM-1 also shows a significant decrease (88.76±7.9 at P<0.001) in the AA+PP group, indicating the nephroprotective effect of PP. The antioxidant and anti-inflammatory activities of PP elucidate the improved results of AA toxicity in our study. Therefore we support the saying of ‘Plants afford a cheap source of medicine for majority of human beings’ .
| Conclusion|| |
AA 40 mg/kg body weight induced elevated renal KIM-1, iNOS, and IL-1β, possibly by GSH depletion, oxidative stress, and NF-κB activation. PP 200 mg/kg body weight showed antioxidant and anti-inflammatory effects, ameliorating AA nephrotoxicity through its potent phenolic compounds, possibly by scavenging activity of free radicals, maintenance of antioxidants, and inhibition of the NF-κB pathway. Therefore, supplementation with PP can be useful in individuals who are exposed to AA toxicity.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Gökmen VA. Perspective on the evaluation of safety risks in thermal processing of foods with an example for acrylamide formation in biscuits. Qual Assur Saf Crops Foods 2014; 63:319–325.
Parker JK. The kinetics of thermal generation of flavor. J Sci Food Agric 2013; 93:197–208.
Fogliano V, Morales FJ. Estimation of dietary intake of melanoidins from coffee and bread. Food Funct 2011; 2:117–123.
DeAnn JL, Chad MC, Ding DW, John S. Maillard reaction products and potatoes: have the benefits been clearly assessed? Food Sci Nutr 2016; 4:234–249.
Nikolai LC, Remi G, Timothy M, Byron K, Cheryl AH, Leslie R, Carole LY. Transcriptional proling of male F344 rats suggests the involvement of calcium signaling in the mode of action of acrylamide-induced thyroid cancer. Food Chem Toxicol 2017; 107:186–200.
Tareke E, Rydberg P, Karlsson P, Eriksson S, Tornqvist M. Analysis of acrylamide, a carcinogen formed in heated foodstuffs. J Agric Food Chem 2002; 50:4998–5006.
Rydberg P, Eriksson S, Tareke E, Karlsson P, Ehrenberg L, Tornqvist M. Investigations of factors that influence the acrylamide content of heated foodstuffs. J Agric Food Chem 2003; 51:7012–7018.
Eriksson S. Acrylamide in food products: Identification, formation and analytical methodology [thesis]. Sweden: Department of Chemistry, Stockholm University, 2005.
World Health Organization (WHO). Acrylamide in drinking-water. Geneva, Switzerland: WHO; 2011.
European Food Safety Authority (EFSA). Panel on contaminants in the food chain, scientific opinion on acrylamide in food. EFSA: Parma, Italy; 2015.
Granvogl M, Schieberle P. Thermally generated 3-aminopropionamide as a transient intermediate in the formation of acrylamide. J Agric Food Chem 2006; 54:5933–5938.
Jayadev R, Jennifer R, Marnie T, Dominique P, Emily C, Don C et al.
Toxicological effects of short-term dietary acrylamide exposure in male F344 rats. Env Toxicol Pharmacol 2015; 39:85–92.
Pedreschi F, Maria SM, Kit G. Current issues in dietary acrylamide:formation, mitigation and risk assessment. J Sci Food Agric 2014; 15:9–12.
Ma Y, Shi J, Zheng M, Liu J, Tian S, He X et al.
Toxicological effects of acrylamide on the reproductive system of weaning malerats. Toxicol Ind Health 2011; 27:617–627.
Riboldi BP, Vinhas AM, Moreira JD. Risks of dietary acrylamide exposure: a systematic review. Food Chem 2014; 157:310–322.
Zamani E, Shokrzadeh M, Fallah M, Shaki F. A review of acrylamide toxicity and its mechanism. Pharm Biomed Res 2017; 3:1–8.
Ikeda G, Miller E, Sapienza P. Comparative tissue distribution and excretion of acrylamide in beagle dogs and miniature pigs. Food Chem Toxic 1987; 25:871–875.
Sumner SCJ, Bahman A, Williams CC, Moore TA, Fennell TR. Acrylamide, metabolism, distribution, and hemoglobin adducts in male F344 rats and B6C3F1 mice following inhalation exposure and distribution. Research Triangle Park, NC: CIIT; 2001.
Hogervorst JG, Baars BJ, Schouten LJ, Konings EJ, Goldbohm RA, van den Brandt PA. The carcinogenicity of dietary acrylamide intake: a comparative discussion of epidemiological and experimental animal research. Crit Rev Toxicol 2010; 40:485–512.
Rajeh N, Hamdy A, El Assoli S. Protective effect of 5-aminosalicylic acid on acrylamide toxicity in the testis and blood leukocytes of the rat. Kuwait Med J 2014; 46:32–43.
Howell AB, D’Souza DH. The pomegranate: effects on bacteria and viruses that influence human health. Evid Based Complement Altern Med 2013; 2013:606212.
Cam M, Hisil Y. Pressurised water extraction of polyphenols from pomegranate peels. Food Chem 2010; 123:878–885.
Gullon B, Pintado ME, Viuda-Martos M. Assessment of polyphenolic profile and antibacterial activity of pomegranate peel (Punicagranatum) flour obtained from coproduct of juice extraction. Food Control 2016; 59:94–98.
Lansky EP, Newman RA. Punicagranatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol 2007; 109:177–206.
Cekmen M, Otunctemur A, Ozbek E, Cakir S, Dursun M, Polat EC et al.
Pomegranate extract attenuates gentamicin-induced nephrotoxicity in rats by reducing oxidative stress. Ren Fail 2013; 35:268–274.
Bouroshaki MT, Sadeghnia HR, Banihasan M, Yavari S. Protective effect of pomegranate seed oil on hexachlorbutadiene- induced nephrotoxicity in rat kidneys. Ren Fail 2010; 32:612–617.
Boroushaki MT, Mollazadeh H, Rajabian A, Dolati K, Hoseini A, Paseban M, Farzadnia M. Protectiveeffect of pomegranate seed oil against mercuric chloride induced nephrotoxicity in rat. Ren Fail 2014; 36:1581–1586.
Abdel Moneim AE, El-Khadragy MF. The potential effects of pomegranate (Punicagranatum) juice on carbon tetrachloride-induced nephrotoxicity in rats. J Physiol Biochem 2013; 69:359–370.
Kharchoufia S, Licciardellob F, Siracusac L, Muratoreb G, Hamdia M, Restuccia C. Antimicrobial and antioxidant features of ‘Gabsiʼ pomegranate peel extracts. Ind Crops Prod 2018; 111:345–352.
Ghorbel I, Elweja A, Fendrib N, Mnifc L, Jamoussib K, Boudawarac T et al.
Olive oil abrogates acrylamide induced nephrotoxicity by modulating biochemical and histological changes in rats. Ren Fail 2017; 39:236–245.
El-Habibi EM. Reno-protective effects of punica granatum (pomegranate) against adenine-induced chronic renal failure in male rats. Life Sci J 2013; 10:2059–2069.
Patton CJ, Crouch SR. Determination of serum urea. Anal Chem 1977; 49:464–469.
Jaffe M. About the precipitation caused by pikrinic acid in normal urine and about a new reaction of creatinine Z. Physiol Chem 1986; 10:391.
Trinder P. Enzymatic colorimetric method for estimation of glucose test (GOD-PAP method), uric acid and phosohlipids. Ann Clin Biochem 1969; 6:24.
Tietz NW. Fundamentals of clinical chemistry. Philadelphia: W.B. Saunders Co.; 1976. 983.
Feldikamp CD, Zklin S. Colometric determination of chloride ion. Biochemicals 1974; 12:146.
Bohuon C. Spectrophotometric determination of magnesium with 1-azo-2-hydroxy-3-(2.4-dimethylcarboxanilido)-naphtha-lene-1-(2-hydroxybenzene). Clin Chem Acta 1975; 16:155.
Daly JA, Ertingshausen G. Direct method for determining inorganic phosphorus in serum. Clin Chem 1972; 18:263–265.
Young DS, Pastaner LC, Gibberman V. Effects of drugs on clinical laboratory tests. Clin Chem 1975; 21:272.
Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chem Acta 1978; 90:37.
Montgomery HAC, Dymock JF. The determination of nitrite in water. Analyst 1961; 86:414.
Nishikimi M, Roa NA, Yogi K. The occurrence of supeoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Bioph Res Common 1972; 46:849–854.
Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61:882.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70:158–169.
International Agency for Research in Cancer (IARC). Monographs on the evaluation of carcinogen risk to humans: some industrial chemicals. IARC Monogr Eval Carcinogen Humans 1994; 60:389–433.
Erkekoglu P, Baydar T. Acrylamide neurotoxicity. Nutr Neurosci 2014; 17:49–57.
Uthra C, Shrivastava S, Jaswal A, Sinha N, Reshi MS, Shukla S. Therapeutic potential of quercetin against acrylamide induced toxicity in rats. Biomed Pharmacother 2017; 86:705–714.
Raju J, Robert J, Taylor M, Patry D, Chomyshyn E, Caldwell D et al.
Toxicological effects of short-term dietary acrylamide exposure in male F344 rats. Environ Toxicol Pharmacol 2015; 39:85–92.
Beland FA, Mellick WT, Olson GR, Mendoza MCB, Marques MM, Doerge DR. Carcinogenicity of acrylamide in B6C3F1 mice and F344/N rats from a 2-year drinking water exposure. Food Chem Toxicol 2013; 51:149–159.
Klaunig JE. Acrylamide carcinogenicity. J Agric Food Chem 2008; 56:5984–5988.
Bao W, Ca C, Li S, Bo L, Zhang M, Zhao X et al.
Metabonomic analysis of quercetin against the toxicity of acrylamide in rat urine. Food Funct 2017; 8:1204–1214.
Adil M, Kandhare AD, Visnagri A, Bodhankar SL. Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1,Caspase-3, TGF-β, and TNF-α. Ren Fail 2015; 37:1–12.
Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene 2003; 22:5734–5754.
Weydert CJ, Cullen JJ. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc 2010; 5:51–66.
Abdel-Daim MM, Abd Eldaim MA, Hassan AG. Trigonellafoenum-graecum ameliorates acrylamide-induced toxicity in rats: roles of oxidative stress, proinflammatory cytokines, and DNA damage. Biochem Cell Biol 2015; 93:192–198.
El-Beltagi HS, Mahgoub MA. Assesment the protective role of quercetin on acrylamide-induced oxidative stress in rats. J Food Biochem 2016; 40:715–723.
Alturfan AA, Beceren AT, Sehirli AO, Demiralp E, Sener G, Omurtag GZ. Resveratrol ameliorates oxidative DNA damage and protects against acrylamide-induced oxidative stress in rats. Mol Biol Rep 2012; 39:4589–4596.
Aydemir S, Sahin H, Ozkan N, Yuksel M, Erdogan N, Omurtag GZ. Antioxidant effects of UMCA® on acrylamide-induced toxicity in rats. Toxicol Lett 2015; 238:256–383.
Pan X, Wu X, Yan D, Peng C, Rao C, Yan H. Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs. Toxicol Lett 2018; 15:55–64.
Yamamoto Y, Gaynor RB. Role of NF-κB pathway in the pathogenesis of human disease states. Curr Mol Med 2001; 1:287–296.
Bowie A, O’Neill LA. Oxidative stress and nuclear factor-kB activation: a reassessment of the evidence in the light of the recent discoveries. Biochem Pharmacol 2000; 59:13–23.
Zha L, Chen J, Sun S, Mao L, Chu X, Mao L et al.
Soyasaponins can blunt inflammation by inhibiting the reactive oxygen species-mediated activation of PI3K/Akt/NF-kB pathway. PLoS One 2014; 9:e107655.
Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci 2004; 75:639–653.
Linda M, Hayesa A, Caprndab M, Petrovic D, Rodrigod L, Kruzliake P, Zulli A. Inducible nitric oxide synthase: good or bad? Biomed Pharmacother 2017; 93:370–375.
Bonventre JV. Kidney injury molecule‐1 (KIM‐1): a specific and sensitive biomarker of kidney injury. Scand J Clin Lab Invest 2008; 68:78–83.
Ahmed SA, Hamed MA. Kidney injury molecule-1 as a predicting factor for inflamed kidney, diabetic and diabetic nephropathy Egyptian patients. J Diab Metab Disord 2015; 14:1–6.
Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 2008; 118:1657–1668.
Ahmed MM, Ali SE. Protective effect of pomegranate peel ethanol extract against ferric nitrile triacetate induced renal oxidative damage in rats. J Cell Mol Biol 2010; 7:35–43.
Abdel Moneim AE, Othman MS, Mohmoud SM, El-Deib KM. Pomegranate peel attenuates aluminum-induced hepatorenal toxicity. Toxicol Mech Methods 2013; 23:624–633.
Karwasra R, Kalra P, Gupta YK, Saini D, Kumarb A, Singh S. Antioxidant and anti-inflammatory potential of pomegranate rind extract to ameliorate cisplatin induced acute kidney injury. Food Funct 2016; 7:3091–3101.
Ashoush IS, El-Batawy OI, El-Shourbagy GA. Antioxidant activity and hepatoprotective effect of pomegranate peel and whey powders in rats. Ann Agr Sci 2013; 58:27–32.
Ibrahium MI. Efficiency of pomegranate peel extract as antimicrobial, antioxidant and protective Agents. World J Agr Sci 2010; 6:338–344.
Landete JM. Ellagitannins, ellagic acid and their derived metabolites: A review about source, metabolism, functions and health. Food Res Int J 2011; 44:1150–1160.
Ismail T, Sestili P, Akhtar S. Pomegranate peel and fruit extracts: a review of potential anti-inflammatory and anti-infective effects. J Ethnopharmacol 2012; 143:397–405.
Dell’Agli M, Galli GV, Bulgari M, Basilico N, Romeo S, Bhattacharya D et al.
Ellagitannins of the fruit rind of pomegranate (Punicagranatum) antagonize in vitro the host inflammatory response mechanisms involved in the onset of malaria. Malaria J 2010; 9:208–217.
Iris FF, Sissi WG. Pomegranate ellagitannins, Herbal medicine: Biomolecular and clinical aspects. 2 ed. London, UK: Taylor and Francis; 2011. 202.
Lee CJ, Chen LG, Liang WL, Wanga CC. Anti-inflammatory effects of Punica granatum Linne in vitro and in vivo. Food Chem 2010; 118:315–322.
Viladomiu M, Hontecillas R, Lu P, Bassaganya-Riera J. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. Evid Based Complement Altern Med 2013; 2013:789764.
Sanz AB, Sanchez-Nino MD, Ramos AM, Moreno JA, Santamaria B, Ruiz-Ortega M et al.
NF-κB in renal inflammation. J Am Soc Nephrol 2010; 21:1254–1262.
Bashir S, Gilani AH. Antiurolithic effect of Bergenialigulata rhizome: an explanation of the underlying mechanisms. J Ethnopharmacol 2009; 122:106–116.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]