The Open Pharmacology Journal




(Discontinued)

ISSN: 1874-1436 ― Volume 10, 2020
RESEARCH ARTICLE

Single Time Heated Different Vegetable Oils Use-Impact on the Magnitude of Total Parenteral Nutrition (TPN) Associated Adverse Effects



Gul Ambreen1, 2 , *, Afshan Siddiq1, Kashif Hussain2, Sadia G. Baig1
1 Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, Pakistan
2 Aga Khan University Hospitals, Karachi, Pakistan

Abstract

Background:

In clinical practice, Total Parenteral Nutrition (TPN) is standard of care for patients of gastrointestinal tract disorders. TPN therapy is associated with a number of adverse effects like hepatobiliary dysfunction, dyslipidemia, and oxidative stress. Different vegetable oils are used by every individual daily in routine life.

Objective:

This study assessed the magnitude of TPN-associated adverse effects in animals fed on different vegetable oils.

Methods:

Healthy adult rabbits of local strain were divided into 5 groups (n= 8). The study was divided into 2 phases. Phase I: oil feeding; the first set of rabbits served as control and fed on a normal rabbit diet. Four sets of rabbits were treated for 16 weeks with 1 ml/kg/day of single time heated olive (STH-OO), canola (STH-CO), sunflower oils (STH-SO) or a mixture of these oils (STH-MVO). In phase II: TPN was given to each group, including the control group, for 2 weeks. Before and after TPN therapy, body and liver weights were measured. Plasma lipid profile [triglycerides, total cholesterol, high-density lipoproteins, low-density lipoproteins, very-low-density lipoproteins], liver function marker [total-protein, albumin, total and direct bilirubin, serum glutamic pyruvic transaminase, serum glutamic-oxaloacetic transaminase, gamma-glutamyl transferase, and alkaline phosphatase], oxidative stress and tissue damage parameters [malondialdehyde, C-reactive protein, lactate dehydrogenase, and creatine phosphokinase] of all the groups weremeasured at the end of TPN therapy.

Results:

Significantly (p <0.05) elevated hepatic enzymes, oxidative stress and tissue damage markers along with dyslipidemia were observed in STH-MVO and STH-SO fed groups, in comparison to control. In STH-OO and STH-CO groups, all these parameters were insignificantly different than control after 2 weeks of TPN therapy. The higher plasma levels of, High-Density Lipoproteins (HDL), total protein and albumin and reduced Malondialdehyde (MDA) levels, were observed in STH-OO and STH-CO groups than the control.

Conclusion:

This study recommends that high monounsaturated fatty acids containing oils like olive and canola oils, are found to have strong resistance against the hepatic injury and lipid peroxidation. The study also recommends taking the history of oil use by an individual before the initiation of therapeutic agents with known side effects of hepatic toxicity and dyslipidemia.

Keywords: Total Parenteral Nutrition (TPN), Hepatobiliary disorders, Poly Unsaturated Fatty Acids (PUFA), Monounsaturated Fatty Acids (MUFA), High-Density Lipoproteins (HDL), Malondialdehyde (MDA) levels.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 10
First Page: 1
Last Page: 7
Publisher Id: TOPHARMJ-10-1
DOI: 10.2174/1874143602010010001

Article History:

Received Date: 16/02/2020
Revision Received Date: 13/04/2020
Acceptance Date: 04/05/2020
Electronic publication date: 15/06/2020
Collection year: 2020

© 2020 Ambreen et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, Pakistan; Tel: +92 3002402035; E-mail: gul.ambreen@aku.edu





1. BACKGROUND

Total Parenteral Nutrition (TPN) is a lifesaving modality by preventing and curing the nutritional deficiencies in individuals with gastrointestinal tract disorders [1Dudrick SJ. Early developments and clinical applications of total parenteral nutrition. JPEN J Parenter Enteral Nutr 2003; 27(4): 291-9.
[http://dx.doi.org/10.1177/0148607103027004291] [PMID: 12903895]
]. Hepatobiliary dysfunction, cirrhosis, and hepatic failure are well-known TPN associated complications. A study has reported TPN-induced classical picture of cholestasis, fibrosis, and portal inflammation [2Moss RL, Das JB, Raffensperger JG. Total parenteral nutrition-associated cholestasis: Clinical and histopathologic correlation. J Pediatr Surg 1993; 28(10): 1270-4.
[http://dx.doi.org/10.1016/S0022-3468(05)80311-2] [PMID: 8263685]
]. These hepatobiliary changes are mostly multifactorial and mainly due to the exclusion of enteral nutrition, infections, excessive biliary secretions, TPN composition, and toxic TPN bag materials like plasticizers of Polyvinyl Chloride (PVC) [3Kaufman SS. Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant 2002; 6(1): 37-42.
[http://dx.doi.org/10.1034/j.1399-3046.2002.1o061.x] [PMID: 11906641]
, 4Loff S, Kabs F, Witt K, et al. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000; 35(12): 1775-81.
[http://dx.doi.org/10.1053/jpsu.2000.19249] [PMID: 11101735]
]. In addition, the nature of lipid emulsion, as the dense energy source in TPN, may also contribute to these complications [5Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J Parenter Enteral Nutr 2000; 24(6): 345-50.
[http://dx.doi.org/10.1177/0148607100024006345] [PMID: 11071594]
]. In Pakistan, commercially available Intravenous Lipid Emulsion (IVLE), is manufactured from soybean-based oils, which contains a higher percentage (about 62%) of Polyunsaturated Fatty Acids (PUFA) and gamma-tocopherol. High PUFA content increases oxidative stress through the free radical formation and increased production of the proinflammatory cytokines [interleukin-α and interleukin-β, interleukin-6, interleukin-8, Tumor Necrosis Factor (TNF)-α], and further inflammatory mediator like platelets activating factor, mostly through the metabolism of arachidonic acid [6Mayer K, Meyer S, Reinholz-Muhly M, et al. Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. J Immunol 2003; 171(9): 4837-43.
[http://dx.doi.org/10.4049/jimmunol.171.9.4837] [PMID: 14568963]
]. These proinflammatory cytokines, especially TNF directly involves in the pathogenesis of TPN-associated cholestasis [7Jones A, Selby PJ, Viner C, Hobbs S, Gore ME, McElwain TJ. Tumour necrosis factor, cholestatic jaundice, and chronic liver disease. Gut 1990; 31(8): 938-9.
[http://dx.doi.org/10.1136/gut.31.8.938] [PMID: 2387521]
].

The internal chemical balance of our body is controlled by the liver [8Thirumalai T, David E, Viviyan Therasa S, et al. Restorative effect of Eclipta alba in CCl4 induced hepatotoxicity in male albino rats Asian Pac J Trop Dis 2011; 1(4): 304-7.
[http://dx.doi.org/10.1016/S2222-1808(11)60072-8]
], it detoxifies and eliminates all the chemicals including drugs and other xenobiotics [9Mohamed Saleem T. Chetty Madusudhana C, Ramkanth S, Rajan VST, kumar Mahesh k, Gauthaman k: Hepatoprotective herbs-A Review. Int J Res Pharmaceut Sci 2010; 1(1)], through conjugating, reducing or oxidizing them [10Wang H, Sit WH, Tipoe GL, Wan JM. Differential protective effects of extra virgin olive oil and corn oil in liver injury: A proteomic study. Food Chem Toxicol 2014; 74: 131-8.
[http://dx.doi.org/10.1016/j.fct.2014.09.002] [PMID: 25303780]
]. Free radical generation may lead to liver damage and cause hepatitis, cirrhosis, and liver cancer [11Ilavenil S, Karthik D, Valan Arasu M, et al. Hepatoprotective mechanism of lycorine against carbon tetrachloride induced toxicity in Swiss albino mice : A proteomic approach. Asian Pac J Reprod 2015; 4(2): 123-8.
[http://dx.doi.org/10.1016/S2305-0500(15)30008-7]
], which are amongst the leading causes of morbidity and mortality worldwide and have diverted the researchers to find the solution from nature [12Obogwu MB, Akindele AJ, Adeyemi OO. Hepatoprotective and in vivo antioxidant activities of the hydroethanolic leaf extract of Mucuna pruriens (Fabaceae) in antitubercular drugs and alcohol models Chin J Nat Med 2014; 12(4): 273-83.
[http://dx.doi.org/10.1016/S1875-5364(14)60054-6] [PMID: 24863352]
]. Exposure of different environmental toxins and xenobiotics, such as acetaminophen, thioacetamide, Carbon Tetrachloride (CCl4), and alcohol harm the liver by generating Reactive Oxygen Species (ROS) [12Obogwu MB, Akindele AJ, Adeyemi OO. Hepatoprotective and in vivo antioxidant activities of the hydroethanolic leaf extract of Mucuna pruriens (Fabaceae) in antitubercular drugs and alcohol models Chin J Nat Med 2014; 12(4): 273-83.
[http://dx.doi.org/10.1016/S1875-5364(14)60054-6] [PMID: 24863352]
]. Liver damage is also produced by deadly chemicals, drugs, and viral infections [13Shen B, Chen H, Shen C, et al. Hepatoprotective effects of lignans extract from Herpetospermum caudigerum against CCl4-induced acute liver injury in mice J Ethnopharmacol 2015; 164: 46-52.
[http://dx.doi.org/10.1016/j.jep.2015.01.044] [PMID: 25666426]
].

Several plants are used as therapeutic agents, especially in the south Asian region [14Bnouham M, et al. Medicinal plants with potential antidiabetic activity-A review of ten years of herbal medicine research (1990-2000). Int J Diabetes Metab 2006; 14(1): 1.
[http://dx.doi.org/10.1159/000497588]
]. Studies have reported the health benefits of different edible oils like, Moringa oleifera Lam seed oil is reported to have hepatoprotective properties by producing antioxidants, which have scavenging potential for free radical [15Al-Said MS, Mothana RA, Al-Yahya MA, et al. Edible oils for liver protection: hepatoprotective potentiality of Moringa oleifera seed oil against chemical-induced hepatitis in rats. J Food Sci 2012; 77(7): T124-30.
[http://dx.doi.org/10.1111/j.1750-3841.2012.02698.x] [PMID: 22757719]
]. A recently conducted animal studies reported hypocholesterolemic and hepatoprotective effects of virgin avocado oil [16Tan CX, Chong GH, Hamzah H, Ghazali HM. Effect of virgin avocado oil on diet-induced hypercholesterolemia in rats via1 H NMR-based metabolomics approach Phytother Res 2018; 32(11): 2264-74.
[http://dx.doi.org/10.1002/ptr.6164] [PMID: 30051518]
], and hepatoprotective effects of coconut oil [17Zakaria Z, et al. Hepatoprotective activity of dried-and fermented-processed virgin coconut oil. Evidence-Based Complementary and Alternative Medicine 2011.
[http://dx.doi.org/10.1155/2011/142739]
], antioxidant properties with better lipid metabolism of olive oil [18Gorinstein S, Leontowicz H, Lojek A, et al. Olive oils improve lipid metabolism and increase antioxidant potential in rats fed diets containing cholesterol. J Agric Food Chem 2002; 50(21): 6102-8.
[http://dx.doi.org/10.1021/jf020306k] [PMID: 12358487]
], along with antineoplastic properties against various cancers, like breast, stomach, ovary, colon, and endometrium [19Rodriguez-Rodriguez R, Perona JS, Herrera MD, Ruiz-Gutierrez V. Triterpenic compounds from “orujo” olive oil elicit vasorelaxation in aorta from spontaneously hypertensive rats. J Agric Food Chem 2006; 54(6): 2096-102.
[http://dx.doi.org/10.1021/jf0528512] [PMID: 16536581]
]. Another olive oil study (used with camel milk), reported its protective effects on hepatocytes in animals with acetaminophen-induced hepatic damage [20Ibrahim MAB, Wani FA, Rahiman S. Hepatoprotective effect of olive oil and camel milk on acetaminophen-induced liver toxicity in mice. Int J Med Sci Public Health 2017; 6(1): 186-95.
[http://dx.doi.org/10.5455/ijmsph.2017.07092016614]
].

We hypothesized that the type of oil used by an individual in daily life may affect the magnitude of the outcome and the adverse effects of any therapeutic agent. The present study designed to evaluate the impact of single time heated commonly used vegetable oils (either individual or in the blends) on TPN associated lipid peroxidation, oxidative stress, and hepatobiliary complications. To our information, no such effort has been reported from Karachi, Pakistan. In Pakistan, oils are mostly used with processed food, so all oils were processed through single time heating for the same duration as routine cooking time, to mimic the real-time scenario.

2. MATERIALS AND METHODS

2.1. Phase I: Oil Feeding Model

2.1.1. Oil Samples Preparation

Standard food-grade canola, sunflower, and olive oils (7 liters of each oil) were purchased from Karachi local market. Sufficient quantity of oil (4 liters from each sample) was separated and thermally treated above its smoke point [olive oil 180 °C; canola oil 200 °C; and sunflower oil 225 °C] for 45 minutes with potatoes frying and then cooled to room temperature, labeled as Single Time Heated Canola Oil (STH-CO), Single Time Heated Sunflower Oil (STH-SO) and single time heated olive oil (STH-OO) [21Aydar AY, Rodriguez-Martinez V, Farkas BE. Determination and modeling of contact angle of Canola oil and olive oil on a PTFE surface at elevated temperatures using air or steam as surrounding media. Lebensm Wiss Technol 2016; 65: 304-10.
[http://dx.doi.org/10.1016/j.lwt.2015.08.022]
, 22Fauziah A, Razali I, Nor-Aini S. Frying performance of palm olein and high oleic sunflower oil during batch frying of potato crisps. Palm Oil Developments 2000; 3: 1-7.]. Then one liter from each a single time heated oil was taken and mixed and labeled as Single Time Heated Mix Vegetable Oils (STH-MVO). To prevent photodegradation, all samples were stored in amber color bottles.

2.1.2. Experimental Animals

Healthy male rabbits weighing 1450 ±10g were purchased from the department of pharmacology, University of Karachi, Pakistan. Rabbits were kept individually in wire-topped steel cages with wooden bottoms, in control conditions (temperature 23 ± 2 °C and 50-60% relative humidity) for 16 weeks with an estimated 12/12 hours light/dark photo-cycle. Animals were acclimatized for seven days before starting the experiment. The animals were handled throughout according to the institutional animal ethical committee guidelines.

2.1.3. Animals Grouping and Oil Feeding

The study was performed by randomly allocating rabbits into five groups (n = 8). Unexposed control rabbits were fed on fresh hay and water only (normal diet). In 4 treatment groups, animals were treated with 1 ml/kg/day of either of single time heated oils (STH-OO, STH-CO, STH-SO or STH-MVO) once daily at 10.00 am for 16 weeks (equivalent to 12 years of human life). For the rest of the day, animals of all the groups were fed ad libitum on a regular normal diet. Daily oil dose was calculated based on previous animal studies [23Perumalla Venkata R, Subramanyam R. Evaluation of the deleterious health effects of consumption of repeatedly heated vegetable oil. Toxicol Rep 2016; 3: 636-43.
[http://dx.doi.org/10.1016/j.toxrep.2016.08.003] [PMID: 28959587]
].

2.2. Phase II: Establishing a TPN Model

At the end of the oil therapy, animals’ bodyweight ranged from 1630g–1680g. The rabbits were kept in an individual clean stainless-steel cage (used 70% isopropyl alcohol for the cleaning). Animals were given anesthesia by administering ketamine (dose = 60 mg/kg) intramuscularly [24DURRANI U.F., M. Ashraf, and M.A. Khan. A comparison of the clinical effects associated with xylazine, ketamine, and a xylazine-ketamine cocktail in pigeons (Columba livia). Turk J Vet Anim Sci 2009; 33(5): 413-7.]. Ear vein catheterization was performed [25Kuwahara T, et al. Cyclic infusion is effective in reducing phlebitis caused by peripheral parenteral nutrition solutions: An experimental study in rabbits. e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 2009; 4(6): e344-7.
[http://dx.doi.org/10.1016/j.eclnm.2009.10.003]
] for the administration of cyclic TPN to all groups of animals, including the unexposed control group.

2.2.1. TPN Solution Composition and Preparation

Certified nutrition support pharmacists performed all TPN calculations according to adult requirements. The average weight of rabbits [1650 g (range, 1630-1680 g)] was taken for TPN formula calculation. Each rabbit received 30 Kcal/kg/day, 65% from dextrose, and 35% from lipid source as non-protein calories. This provided non-protein calorie to grams of nitrogen ratio of 160:1 [26Shaw JH, Wildbore M, Wolfe RR. Whole body protein kinetics in severely septic patients. The response to glucose infusion and total parenteral nutrition. Ann Surg 1987; 205(3): 288-94.
[http://dx.doi.org/10.1097/00000658-198703000-00012] [PMID: 3103555]
, 27Mirtallo JM. Parenteral nutrition ordering processes. JPEN J Parenter Enteral Nutr 2012; 36(2)(Suppl.): 29S-31S.
[http://dx.doi.org/10.1177/0148607111434775] [PMID: 22282872]
]. Doses of all the component were calculated as per standard guidelines and animal weight; amino acids were given with 0.8 g/kg/day, IVLE with 1 g/kg/day and dextrose was given as the source of glucose with Glucose Infusion Rate (GIR) of 5.5 mg/kg/minute. Total fluid volume was calculated with 50 ml/kg/day [28Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: Intensive care. Clin Nutr 2009; 28(4): 387-400.
[http://dx.doi.org/10.1016/j.clnu.2009.04.024] [PMID: 19505748]
, 29Biesalski H, et al. Water, electrolytes, vitamins and trace elements–Guidelines on Parenteral Nutrition 2009; 7.
].

TPN formulas were prepared in the piggy bags. It was a 3 in 1formula, providing all the macro and micronutrients in one bag (Table 1) with the stability of 24 hours at room temperature. All the components were mixed under aseptic conditions daily to supply 24 hours requirement only. Each bag was labeled after preparation and wrapped with aluminum foil to protect from light [30Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr 2004; 28(6): S39-70.
[http://dx.doi.org/10.1177/0148607104028006S39] [PMID: 15568296]
, 31A., Safe practices for parenteral nutrition formulations. JPEN J Parenter Enteral Nutr 1998; 22(2): 49-66.
[http://dx.doi.org/10.1177/014860719802200249] [PMID: 9527961]
].

Table 1
Composition of TPN bag.



2.2.2. TPN Administration

After 16 hours of the anesthesia recovery period, TPN infusion was started by injecting micropump, to maintain the uniform infusion rate over 12 hours from 8 am till 8 pm daily. 1ml of Normal Saline (NS) was used to flush the line before and after completion of the TPN infusion daily. IV set was replaced every 24 hours. All the syringes and tubing used for TPN administration were polyvinyl chloride-free and were protected from light. On the first day of TPN, each rabbit was given half of the volume, with an infusion rate of 4 ml/Kg/ hour, with no other change in TPN composition and calculations, followed by 6 ml/kg/hour on the second day. The target rate of 8 ml/kg/hour was given from third till the fourteenth day of TPN therapy. TPN was the only provided caloric nutritional source for the study animals [30, 31].

2.3. Gross Monitoring

Morbidity and mortality were monitored through the study period. Body weight was recorded at baseline and followed by weekly monitoring at weeks 4, 8, 12, 16, and 18. At the end of phase I and II three rabbits were sacrificed with the administration of intravenous sodium pentobarbital 100mg/kg followed by decapitation as per American Veterinary Medical Association (AVMA) guidelines for the euthanasia of animals [32Leary SL, et al. AVMA guidelines for the euthanasia of animals 2013 edition. 2013.]. Furthermore, animals were necropsied to retrieve the liver for organ weight evaluation.

2.3.1. Blood Sample Collection for Lipid Profile and Liver Function Markers Analysis

Blood was collected from ear veins in a fasting state at the end of the 18th week. To evaluate the hematological parameters, 2 ml blood was taken in EDTA.K3 tubes and 5 ml blood in a gel tube, then centrifugation was performed at 3000 rpm for 15min, to isolate the serum. With the use of clean, dry disposable plastic syringes, the supernatant was parted and stored at -18°C and then used to analyze the lipid profile [(Triglycerides (TG), Total Cholesterol (TC), High-Density Lipoproteins (HDL), Low-Density Lipoproteins (LDL), Very-Low-Density Lipoproteins (VLDL)] and liver function marker [total-protein, Albumin (ALB), Total Bilirubin (TB), Direct Bilirubin (DB), Serum Glutamic-Pyruvic Transaminase (SGPT), Serum Glutamic-Oxaloacetic Transaminase (SGOT), Gamma-Glutamyl Transferase (GGT), and Alkaline Phosphatase (ALP)] by using analytical kits of RANDOX Laboratories Ltd. following the manufacturer’s instructions.

2.3.2. Oxidative Stress and Tissue Damage Parameters

Lipid peroxidation was measured by determining plasma Malondialdehyde (MDA), following Kikugawa et al. method [33Kikugawa K, Kojima T, Yamaki S, Kosugi H. Interpretation of the thiobarbituric acid reactivity of rat liver and brain homogenates in the presence of ferric ion and ethylenediaminetetraacetic acid. Anal Biochem 1992; 202(2): 249-55.
[http://dx.doi.org/10.1016/0003-2697(92)90102-D] [PMID: 1519749]
]. The plasma C-Reactive Protein (CRP) was measured by using the ELISA kit (Abnova, Taipei, Taiwan), as per the manufacturer’s instruction for use. A commercially available kit was used to analyze Lactate Dehydrogenase (LDH) levels (BioVision, USA). The samples, as well as standards, were prepared as per the manufacturer’s instructions, following Hamsi et al. method [34Hamsi MA, et al. Effect of consumption of fresh and heated virgin coconut oil on the blood pressure and inflammatory biomarkers: An experimental study in Sprague Dawley rats. Alexandria Journal of Medicine 2015; 51(1): 53-63.
[http://dx.doi.org/10.1016/j.ajme.2014.02.002]
]. To measure the fasting plasma homocysteine concentrations, we adopted the method described by Sheu et al. [35Sheu WH-H, Lee W-J, Chen Y-T. Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects. Am J Hypertens 2000; 13(1 Pt 1): 14-20.
[http://dx.doi.org/10.1016/S0895-7061(99)00138-7] [PMID: 10678266]
]. Creatine Phosphokinase (CPK) was measured by a commercially available kit (Beckman Coulter, Brea, USA), followed by manufacturer instructions.

2.4. Statistical Analysis

In our study, the final data is presented in the form of mean ± Standard Deviation (SD). We applied Analysis of Variance (ANOVA) followed by post hoc Tukey’s Honest Significant Difference (HSD) test to find out the statistical significance. A paired t-test was applied for pre and post-analysis. The value p <0.05 was considered as significant and p<0.005 as highly significant. The data analysis of this study was performed using SPSS (Statistical Product and Service Solutions) software.

3. RESULTS

3.1. Gross Observation of Animals

No death and unexpected signs and symptoms were noticed in experimental animals throughout the study period. Increment in the body and liver weights were observed in all the groups after 2 weeks of TPN administration, but statistically significant (p <0.05) difference was observed in STH-SO fed animals in comparison with control and other treatment groups. On the other hand, an insignificant difference was observed in STH-OO, STH-CO, and STH-MVO groups. Comparison of body and liver weights between before and after TPN administration shows, statistically significant (p <0.05) weight gain in STH-SO and STH-MVO groups animals, however, in STH-OO and STH-CO groups the weight gain is statistically not significant across the TPN therapy (Table 2).

3.2. Biochemical Markers of Hepatic-Function

The serum levels of GGT, SGOT, SGPT, ALP, TB, and DB were elevated in all oil-fed groups after TPN administration in comparison with control. Statistically highly significant results were found in STH-SO (p<0.005) and STH-MVO (p<0.05) treated group when compared to control, STH-CO and STH-OO fed groups (Table 3).

3.3. Plasma Lipid Profile

Significantly (p <0.005) increased levels of TGs, TC, LDL-Cholesterol and VLDL-cholesterol, whereas lower HDL-cholesterol, serum protein, and Albumin (ALB) levels were observed in STH-SO and STH-MVO treated group in comparison with control and other oil-fed groups. Least variations in plasma lipid profiles were observed in STH-OO, and STH-CO fed groups (Table 3).

3.4. Oxidative Stress and Tissue Damage Parameters

After 14 days of TPN administration, the plasma of levels of MDA (lipid peroxidation marker), CPK, LDH and homocysteine (tissue damage markers) and CRP (inflammatory marker) were significantly elevated in STH-MVO (p<0.05) and STH-SO (p<0.005) fed groups. In these variables, no significant change was observed in STH-OO and STH-CO fed animals, as compared to control. Among all groups, tissue damage markers were found with the least variation in STH-OO fed animals in pre and post TPN administration phases (Table 3).

Table 2
Body and liver Weights before and after 2 weeks of TPN administration (n=8).


Table 3
Comparison of liver function markers, lipid profile, and tissue damage parameters among all the group after 2 weeks of TPN administration (n=8).


At (p <0.05) values with a statistically significant difference and (p <0.005) values with a statistically highly significant difference

4. DISCUSSION

In this study, we compared and explained the possible health effects of 2 weeks TPN therapy in rabbits, fed on single time heated different oils in a moderate daily dose of 1ml/kg. The outcome and magnitude of TPN-associated adverse effects were different in different oil-fed groups, which supported our hypothesis. Oil consumption for 16 weeks in rabbits justified the long term use of edible oils in humans (equivalent to 12 years of human life), which exerts its effect even after discontinuation of intake [36Vicario IM, Malkova D, Lund EK, Johnson IT. Olive oil supplementation in healthy adults: Effects in cell membrane fatty acid composition and platelet function. Ann Nutr Metab 1998; 42(3): 160-9.
[http://dx.doi.org/10.1159/000012729] [PMID: 9657460]
].

Weight gain was observed in all the groups after 2 weeks of TPN administration to oil fed animals. The highest body and organ weight gain was reported in STH-SO, and STH-MVO fed groups, which is suggestive of induced oxidative stress, damage at the cellular level and poor glycemic and lipid level control. Other groups showed fewer weight variations throughout the study, with the least variations in olive and canola oils. The presence of high Monounsaturated Fatty Acids (MUFA) content in olive and canola oils may explain the resistance of significant weight gain with potent control on blood glucose and lipid profile [37Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial. JAMA 2004; 292(12): 1440-6.
[http://dx.doi.org/10.1001/jama.292.12.1440] [PMID: 15383514]
].

The hepatobiliary adverse effects associated with TPN therapy were insignificant in olive and canola oils fed animals. Olive oil with a high content of MUFA and antioxidant polyphenolic compounds exerted hepatoprotective effect again, the TPN induced plasma lipid peroxidation and oxidative stress [38Covas M-I, Nyyssönen K, Poulsen HE, et al. The effect of polyphenols in olive oil on heart disease risk factors: A randomized trial. Ann Intern Med 2006; 145(5): 333-41.
[http://dx.doi.org/10.7326/0003-4819-145-5-200609050-00006] [PMID: 16954359]
]. With low erucic acid and suitable Linolenic Acid /Alpha-Linolenic Acid (LA/ALNA) ratio in canola oil, it effectively kept the serum total cholesterol and LDL levels lower [39Gillingham LG, Gustafson JA, Han SY, Jassal DS, Jones PJ. High-oleic rapeseed (canola) and flaxseed oils modulate serum lipids and inflammatory biomarkers in hypercholesterolaemic subjects. Br J Nutr 2011; 105(3): 417-27.
[http://dx.doi.org/10.1017/S0007114510003697] [PMID: 20875216]
]. The minimal magnitude of TPN induced hepatic toxicity in the olive oil fed group explains the effect of olive oil on maintaining the functional integrity of transaminases and hepatocytes [40Al-Seeni MN, El Rabey HA, Zamzami MA, Alnefayee AM. The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats BMC Complement Altern Med 2016; 16(1): 438.
[http://dx.doi.org/10.1186/s12906-016-1422-4] [PMID: 27814700]
]. Furthermore, the results of our study suggest that consumption of single time heated olive and canola oil in the normal recommended daily dose for longer duration may prevent the hepatic damage induced by any hepatotoxic therapeutic agent, like TPN.

On the other hand, in STH-SO and STH-MVO treated groups significantly elevated SGPT, ALP, GGT, and direct bilirubin indicate the induction of TPN associated hepatobiliary disorders, like cholestasis [41Schefer KD, Hagen R, Ringer SK, Schwarzwald CC. Laboratory, electrocardiographic, and echocardiographic detection of myocardial damage and dysfunction in an Arabian mare with nutritional masseter myodegeneration. J Vet Intern Med 2011; 25(5): 1171-80.
[http://dx.doi.org/10.1111/j.1939-1676.2011.00787.x] [PMID: 21985146]
]. Theses elevated liver enzymes also indicate cellular damage and tissue breakdown that allow the escape of intracellular enzymes from the cytosol into the blood. The decreased serum level of albumin and total protein also supports the TPN associated hepatic toxicity in both the groups [42Jaswal A, Shukla S. Therapeutic efficacy of Nigella sativa Linn Seed extract against CCl 4 induced hepatic injury in wistar rats 2015.]. The magnitude of hepatobiliary dysfunction was higher in STH-SO than STH-MVO, which is justified with the high content of PUFA and LA/ALNA ratio in sunflower oil [43Ghafoorunissa G. Dietary lipids and heart disease-the Indian context. Natl Med J India 1994; 7(6): 270-6.
[PMID: 7841878]
]. Moreover, the results of our study show that serum levels of albumin and total protein were consistently higher even after TPN administration in olive and canola oils fed animals, showing the integrality of liver functions in these groups. Our results are consistent with previous studies [40Al-Seeni MN, El Rabey HA, Zamzami MA, Alnefayee AM. The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats BMC Complement Altern Med 2016; 16(1): 438.
[http://dx.doi.org/10.1186/s12906-016-1422-4] [PMID: 27814700]
, 44Lin L, Allemekinders H, Dansby A, et al. Evidence of health benefits of canola oil. Nutr Rev 2013; 71(6): 370-85.
[http://dx.doi.org/10.1111/nure.12033] [PMID: 23731447]
].

TPN therapy is associated with induced hyperlipidemia [45Crook MA. Lipid clearance and total parenteral nutrition: The importance of monitoring plasma lipids. Nutrition 2000; 16(9): 774-5.
[http://dx.doi.org/10.1016/S0899-9007(00)00381-6] [PMID: 10978859]
] and oxidative stress [46Tazuke Y, Drongowski RA, Btaiche I, Coran AG, Teitelbaum DH. Effects of lipid administration on liver apoptotic signals in a mouse model of Total Parenteral Nutrition (TPN). Pediatr Surg Int 2004; 20(4): 224-8.
[http://dx.doi.org/10.1007/s00383-003-1115-1] [PMID: 15034728]
]. Insignificant changes in lipid profile of STH-OO and STH-CO fed animals, suggest that daily use of olive and canola oils for longer duration may exert resistance to hyperlipidemic effects of therapeutic agents, like TPN. In fact, in olive and canola oils groups, HDL levels were even higher than the control animals. These results are consistent with previous olive and canola oils studies [40Al-Seeni MN, El Rabey HA, Zamzami MA, Alnefayee AM. The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats BMC Complement Altern Med 2016; 16(1): 438.
[http://dx.doi.org/10.1186/s12906-016-1422-4] [PMID: 27814700]
, 44Lin L, Allemekinders H, Dansby A, et al. Evidence of health benefits of canola oil. Nutr Rev 2013; 71(6): 370-85.
[http://dx.doi.org/10.1111/nure.12033] [PMID: 23731447]
].

The significantly increased levels of oxidative stress marker (MDA), tissue damage markers (CPK, LDH, and homocysteine) and inflammatory marker (CRP) in STH-MVO and even higher levels in STH-SO fed animals suggest the effect of sunflower oil. These results recommend that consumption of sunflower oil, alone or in the blended form, may induce degenerative tissue disorders and oxidative stress. A multicenter epidemiologic study supports our results [47Rastogi T, Reddy KS, Vaz M, et al. Diet and risk of ischemic heart disease in India. Am J Clin Nutr 2004; 79(4): 582-92.
[http://dx.doi.org/10.1093/ajcn/79.4.582] [PMID: 15051601]
]. On the other hand, our results show that the highest resistance against TPN- induced oxidative stress and tissue damage was present in single time heated olive and canola oils fed animals. Results show that MDA levels in STH-OO and STH-CO were even lower than control. This resistance against pathological changes in the olive oil group might be linked with the presence of high content of flavonoids and phenolic antioxidant compounds in olive oil [19Rodriguez-Rodriguez R, Perona JS, Herrera MD, Ruiz-Gutierrez V. Triterpenic compounds from “orujo” olive oil elicit vasorelaxation in aorta from spontaneously hypertensive rats. J Agric Food Chem 2006; 54(6): 2096-102.
[http://dx.doi.org/10.1021/jf0528512] [PMID: 16536581]
]. In canola oil-fed animals, this could be explained with the potential of canola oil to reduce plasma E-selectin by targeting the inflammation and atherogenic pathways, which further resisted the pathological changes induced by TPN administration [39Gillingham LG, Gustafson JA, Han SY, Jassal DS, Jones PJ. High-oleic rapeseed (canola) and flaxseed oils modulate serum lipids and inflammatory biomarkers in hypercholesterolaemic subjects. Br J Nutr 2011; 105(3): 417-27.
[http://dx.doi.org/10.1017/S0007114510003697] [PMID: 20875216]
].

CONCLUSION

Our study concludes that the type of daily consumed cooking oils exerts a strong effect on the magnitude of outcome and adverse effects of any therapeutic agents and further suggests the importance of the oil consumption history of any patient before therapy initiation. Especially for therapeutic agents with known adverse effects of hepatotoxicity and dyslipidemia. We also conclude that high PUFA containing oils degrade easily and exert more hepatotoxic effects, especially when used for long-duration, so fail to protect from further injury. On the other hand, high MUFA containing oils like olive and canola oils, are found to have strong resistance against the hepatic injury and lipid peroxidation. Therefore, the oil or the blend of oils used in daily life must contain the most appropriate ratio of different vegetable oils that finally have the potential to resist the adverse effects associated with other therapeutic agents.

AUTHORS' CONTRIBUTIONS

1. G. A. contributed to the conception or design of the work, conducted the study and wrote the paper. She performed analysis or interpretation of data and edited the paper as per reviewers’ comments

2. A. S. revised the work critically for important intellectual content, supervised the research, and approved the final version for publishing

3. K. H. co-wrote the paper and did final review of the manuscript

4. S. G. B. co-wrote the manuscript in the revision phase with PI , edited the paper as per reviewers’ comments

All the authors read and approved the final manuscript before submission.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Research study protocol along with the procedures to be followed during our research study, euthanasia, and ethical authorization of the study all got approved from the Board of Advanced Studies & Research (BASR) of the University of Karachi (BASR number:03296/Pharm).

HUMAN AND ANIMAL RIGHTS

No humans were used for studies that are the basis of this research. All animal experiments were conducted in accordance with the Guidelines for euthanasia and ethical authorization of the study, all got approved from the Board of Advanced Studies & Research (BASR) of the University of Karachi (BASR number:03296/Pharm).

CONSENT FOR PUBLICATION

Not Applicable

AVAILABILITY OF DATA AND MATERIALS

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

We acknowledge Abdul Moiz Hussain for providing the technical and editing support in the process of final submission. Authors are highly thankful to Dr. Muhammad Mohtasheemul Hasan of the Department of Pharmacognosy, the University of Karachi, for providing specimen authentication for oils used in the study.

REFERENCES

[1] Dudrick SJ. Early developments and clinical applications of total parenteral nutrition. JPEN J Parenter Enteral Nutr 2003; 27(4): 291-9.
[http://dx.doi.org/10.1177/0148607103027004291] [PMID: 12903895]
[2] Moss RL, Das JB, Raffensperger JG. Total parenteral nutrition-associated cholestasis: Clinical and histopathologic correlation. J Pediatr Surg 1993; 28(10): 1270-4.
[http://dx.doi.org/10.1016/S0022-3468(05)80311-2] [PMID: 8263685]
[3] Kaufman SS. Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant 2002; 6(1): 37-42.
[http://dx.doi.org/10.1034/j.1399-3046.2002.1o061.x] [PMID: 11906641]
[4] Loff S, Kabs F, Witt K, et al. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000; 35(12): 1775-81.
[http://dx.doi.org/10.1053/jpsu.2000.19249] [PMID: 11101735]
[5] Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J Parenter Enteral Nutr 2000; 24(6): 345-50.
[http://dx.doi.org/10.1177/0148607100024006345] [PMID: 11071594]
[6] Mayer K, Meyer S, Reinholz-Muhly M, et al. Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. J Immunol 2003; 171(9): 4837-43.
[http://dx.doi.org/10.4049/jimmunol.171.9.4837] [PMID: 14568963]
[7] Jones A, Selby PJ, Viner C, Hobbs S, Gore ME, McElwain TJ. Tumour necrosis factor, cholestatic jaundice, and chronic liver disease. Gut 1990; 31(8): 938-9.
[http://dx.doi.org/10.1136/gut.31.8.938] [PMID: 2387521]
[8] Thirumalai T, David E, Viviyan Therasa S, et al. Restorative effect of Eclipta alba in CCl4 induced hepatotoxicity in male albino rats Asian Pac J Trop Dis 2011; 1(4): 304-7.
[http://dx.doi.org/10.1016/S2222-1808(11)60072-8]
[9] Mohamed Saleem T. Chetty Madusudhana C, Ramkanth S, Rajan VST, kumar Mahesh k, Gauthaman k: Hepatoprotective herbs-A Review. Int J Res Pharmaceut Sci 2010; 1(1)
[10] Wang H, Sit WH, Tipoe GL, Wan JM. Differential protective effects of extra virgin olive oil and corn oil in liver injury: A proteomic study. Food Chem Toxicol 2014; 74: 131-8.
[http://dx.doi.org/10.1016/j.fct.2014.09.002] [PMID: 25303780]
[11] Ilavenil S, Karthik D, Valan Arasu M, et al. Hepatoprotective mechanism of lycorine against carbon tetrachloride induced toxicity in Swiss albino mice : A proteomic approach. Asian Pac J Reprod 2015; 4(2): 123-8.
[http://dx.doi.org/10.1016/S2305-0500(15)30008-7]
[12] Obogwu MB, Akindele AJ, Adeyemi OO. Hepatoprotective and in vivo antioxidant activities of the hydroethanolic leaf extract of Mucuna pruriens (Fabaceae) in antitubercular drugs and alcohol models Chin J Nat Med 2014; 12(4): 273-83.
[http://dx.doi.org/10.1016/S1875-5364(14)60054-6] [PMID: 24863352]
[13] Shen B, Chen H, Shen C, et al. Hepatoprotective effects of lignans extract from Herpetospermum caudigerum against CCl4-induced acute liver injury in mice J Ethnopharmacol 2015; 164: 46-52.
[http://dx.doi.org/10.1016/j.jep.2015.01.044] [PMID: 25666426]
[14] Bnouham M, et al. Medicinal plants with potential antidiabetic activity-A review of ten years of herbal medicine research (1990-2000). Int J Diabetes Metab 2006; 14(1): 1.
[http://dx.doi.org/10.1159/000497588]
[15] Al-Said MS, Mothana RA, Al-Yahya MA, et al. Edible oils for liver protection: hepatoprotective potentiality of Moringa oleifera seed oil against chemical-induced hepatitis in rats. J Food Sci 2012; 77(7): T124-30.
[http://dx.doi.org/10.1111/j.1750-3841.2012.02698.x] [PMID: 22757719]
[16] Tan CX, Chong GH, Hamzah H, Ghazali HM. Effect of virgin avocado oil on diet-induced hypercholesterolemia in rats via1 H NMR-based metabolomics approach Phytother Res 2018; 32(11): 2264-74.
[http://dx.doi.org/10.1002/ptr.6164] [PMID: 30051518]
[17] Zakaria Z, et al. Hepatoprotective activity of dried-and fermented-processed virgin coconut oil. Evidence-Based Complementary and Alternative Medicine 2011.
[http://dx.doi.org/10.1155/2011/142739]
[18] Gorinstein S, Leontowicz H, Lojek A, et al. Olive oils improve lipid metabolism and increase antioxidant potential in rats fed diets containing cholesterol. J Agric Food Chem 2002; 50(21): 6102-8.
[http://dx.doi.org/10.1021/jf020306k] [PMID: 12358487]
[19] Rodriguez-Rodriguez R, Perona JS, Herrera MD, Ruiz-Gutierrez V. Triterpenic compounds from “orujo” olive oil elicit vasorelaxation in aorta from spontaneously hypertensive rats. J Agric Food Chem 2006; 54(6): 2096-102.
[http://dx.doi.org/10.1021/jf0528512] [PMID: 16536581]
[20] Ibrahim MAB, Wani FA, Rahiman S. Hepatoprotective effect of olive oil and camel milk on acetaminophen-induced liver toxicity in mice. Int J Med Sci Public Health 2017; 6(1): 186-95.
[http://dx.doi.org/10.5455/ijmsph.2017.07092016614]
[21] Aydar AY, Rodriguez-Martinez V, Farkas BE. Determination and modeling of contact angle of Canola oil and olive oil on a PTFE surface at elevated temperatures using air or steam as surrounding media. Lebensm Wiss Technol 2016; 65: 304-10.
[http://dx.doi.org/10.1016/j.lwt.2015.08.022]
[22] Fauziah A, Razali I, Nor-Aini S. Frying performance of palm olein and high oleic sunflower oil during batch frying of potato crisps. Palm Oil Developments 2000; 3: 1-7.
[23] Perumalla Venkata R, Subramanyam R. Evaluation of the deleterious health effects of consumption of repeatedly heated vegetable oil. Toxicol Rep 2016; 3: 636-43.
[http://dx.doi.org/10.1016/j.toxrep.2016.08.003] [PMID: 28959587]
[24] DURRANI U.F., M. Ashraf, and M.A. Khan. A comparison of the clinical effects associated with xylazine, ketamine, and a xylazine-ketamine cocktail in pigeons (Columba livia). Turk J Vet Anim Sci 2009; 33(5): 413-7.
[25] Kuwahara T, et al. Cyclic infusion is effective in reducing phlebitis caused by peripheral parenteral nutrition solutions: An experimental study in rabbits. e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 2009; 4(6): e344-7.
[http://dx.doi.org/10.1016/j.eclnm.2009.10.003]
[26] Shaw JH, Wildbore M, Wolfe RR. Whole body protein kinetics in severely septic patients. The response to glucose infusion and total parenteral nutrition. Ann Surg 1987; 205(3): 288-94.
[http://dx.doi.org/10.1097/00000658-198703000-00012] [PMID: 3103555]
[27] Mirtallo JM. Parenteral nutrition ordering processes. JPEN J Parenter Enteral Nutr 2012; 36(2)(Suppl.): 29S-31S.
[http://dx.doi.org/10.1177/0148607111434775] [PMID: 22282872]
[28] Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: Intensive care. Clin Nutr 2009; 28(4): 387-400.
[http://dx.doi.org/10.1016/j.clnu.2009.04.024] [PMID: 19505748]
[29] Biesalski H, et al. Water, electrolytes, vitamins and trace elements–Guidelines on Parenteral Nutrition 2009; 7.
[30] Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr 2004; 28(6): S39-70.
[http://dx.doi.org/10.1177/0148607104028006S39] [PMID: 15568296]
[31] A., Safe practices for parenteral nutrition formulations. JPEN J Parenter Enteral Nutr 1998; 22(2): 49-66.
[http://dx.doi.org/10.1177/014860719802200249] [PMID: 9527961]
[32] Leary SL, et al. AVMA guidelines for the euthanasia of animals 2013 edition. 2013.
[33] Kikugawa K, Kojima T, Yamaki S, Kosugi H. Interpretation of the thiobarbituric acid reactivity of rat liver and brain homogenates in the presence of ferric ion and ethylenediaminetetraacetic acid. Anal Biochem 1992; 202(2): 249-55.
[http://dx.doi.org/10.1016/0003-2697(92)90102-D] [PMID: 1519749]
[34] Hamsi MA, et al. Effect of consumption of fresh and heated virgin coconut oil on the blood pressure and inflammatory biomarkers: An experimental study in Sprague Dawley rats. Alexandria Journal of Medicine 2015; 51(1): 53-63.
[http://dx.doi.org/10.1016/j.ajme.2014.02.002]
[35] Sheu WH-H, Lee W-J, Chen Y-T. Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects. Am J Hypertens 2000; 13(1 Pt 1): 14-20.
[http://dx.doi.org/10.1016/S0895-7061(99)00138-7] [PMID: 10678266]
[36] Vicario IM, Malkova D, Lund EK, Johnson IT. Olive oil supplementation in healthy adults: Effects in cell membrane fatty acid composition and platelet function. Ann Nutr Metab 1998; 42(3): 160-9.
[http://dx.doi.org/10.1159/000012729] [PMID: 9657460]
[37] Esposito K, Marfella R, Ciotola M, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial. JAMA 2004; 292(12): 1440-6.
[http://dx.doi.org/10.1001/jama.292.12.1440] [PMID: 15383514]
[38] Covas M-I, Nyyssönen K, Poulsen HE, et al. The effect of polyphenols in olive oil on heart disease risk factors: A randomized trial. Ann Intern Med 2006; 145(5): 333-41.
[http://dx.doi.org/10.7326/0003-4819-145-5-200609050-00006] [PMID: 16954359]
[39] Gillingham LG, Gustafson JA, Han SY, Jassal DS, Jones PJ. High-oleic rapeseed (canola) and flaxseed oils modulate serum lipids and inflammatory biomarkers in hypercholesterolaemic subjects. Br J Nutr 2011; 105(3): 417-27.
[http://dx.doi.org/10.1017/S0007114510003697] [PMID: 20875216]
[40] Al-Seeni MN, El Rabey HA, Zamzami MA, Alnefayee AM. The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats BMC Complement Altern Med 2016; 16(1): 438.
[http://dx.doi.org/10.1186/s12906-016-1422-4] [PMID: 27814700]
[41] Schefer KD, Hagen R, Ringer SK, Schwarzwald CC. Laboratory, electrocardiographic, and echocardiographic detection of myocardial damage and dysfunction in an Arabian mare with nutritional masseter myodegeneration. J Vet Intern Med 2011; 25(5): 1171-80.
[http://dx.doi.org/10.1111/j.1939-1676.2011.00787.x] [PMID: 21985146]
[42] Jaswal A, Shukla S. Therapeutic efficacy of Nigella sativa Linn Seed extract against CCl 4 induced hepatic injury in wistar rats 2015.
[43] Ghafoorunissa G. Dietary lipids and heart disease-the Indian context. Natl Med J India 1994; 7(6): 270-6.
[PMID: 7841878]
[44] Lin L, Allemekinders H, Dansby A, et al. Evidence of health benefits of canola oil. Nutr Rev 2013; 71(6): 370-85.
[http://dx.doi.org/10.1111/nure.12033] [PMID: 23731447]
[45] Crook MA. Lipid clearance and total parenteral nutrition: The importance of monitoring plasma lipids. Nutrition 2000; 16(9): 774-5.
[http://dx.doi.org/10.1016/S0899-9007(00)00381-6] [PMID: 10978859]
[46] Tazuke Y, Drongowski RA, Btaiche I, Coran AG, Teitelbaum DH. Effects of lipid administration on liver apoptotic signals in a mouse model of Total Parenteral Nutrition (TPN). Pediatr Surg Int 2004; 20(4): 224-8.
[http://dx.doi.org/10.1007/s00383-003-1115-1] [PMID: 15034728]
[47] Rastogi T, Reddy KS, Vaz M, et al. Diet and risk of ischemic heart disease in India. Am J Clin Nutr 2004; 79(4): 582-92.
[http://dx.doi.org/10.1093/ajcn/79.4.582] [PMID: 15051601]
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2022 Bentham Open