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Your critique should be at least 1000 words, not including title and reference pages. The article critique should include a minimum of 3 sources, including the article you review as well as the textbook. Use APA format for your critique, including all references and in-text citations.Review the article and briefly summarize the purpose for the study. The discussion should include the following:Include a summary of the purpose of the research and the research findings.Discuss how the findings of at least two other articles support or contradict the findings of the main article.Discuss how this information might be useful in the field of safety. unitv_study_guide.pdf oxidative_stress_and_nephrotoxicity.pdf mos_5425_u5.docx nephrotoxicity_article.pdf Unformatted Attachment Preview UNIT V STUDY GUIDE Toxicology of the Kidneys, Skin, and Eyes Course Learning Outcomes for Unit V Upon completion of this unit, students should be able to: 6. Assess the effects of various toxicants on body systems. 6.1 Analyze research findings related to nephrotoxicity. 6.2 Relate scientific research findings to the field of safety. Course/Unit Learning Outcomes 6 6.1 6.2 Learning Activity Unit Lesson Unit Lesson Chapter 7 Article Critique Chapters 7 and 9 Article Critique Reading Assignment Chapter 7: Nephrotoxicity: Toxic Responses of the Kidney, pp. 139-155 Chapter 9: Dermatotoxicity: Toxic Effects on the Skin, pp. 169-176 Unit Lesson This unit covers toxicology of the kidneys and skin. Although not discussed in the textbook, this lesson also includes a noteworthy discussion of the eye. Your reading begins with examining toxicology of the kidneys. If you have ever taken an anatomy course, you may recall that we have two kidneys that are each about the size of your fist, located near the base of the rib cage. The main function of the kidneys is to remove waste products from the body. This is a very important job because waste that is not removed and remains in the body can be potentially toxic. The kidneys are also involved in other important functions such as maintenance of the balance of certain electrolytes in the body, blood pressure regulation, vitamin D activation, and red blood cell production (National Kidney Foundation, n.d.). The kidneys are commonly known for their function of removing wastes from the body, but the kidneys also perform other important functions. Another function of the kidneys is to maintain homeostasis of various electrolytes such as potassium and sodium and to maintain proper levels of water within the body. The kidneys also possess specialized endocrine functions such as production of vitamin D and the protein erythropoietin (Roberts, James, & Williams, 2015). In additional, the kidneys are able to metabolize certain drugs. How do the kidneys remove waste from the body? This is done by the excretion of waste products in the urine. There are many terms that you will want to understand and identify when studying the kidneys. When discussing the production of urine and removal of waste from the body, you will need to focus your attention to the nephrons. Imagine the nephron as a long, continuous tube with varying diameters. This tube is bigger in some sections and smaller in other sections. In addition to the varying diameter, this tube has many bends and turns. Keeping this in mind, pay attention to the different names and specific functions of each area along this tube. Your textbook provides a diagram of the nephrons with each section labeled with the appropriate name. Take some time to look for other diagrams of nephrons on the Internet; doing so may provide a clearer overall understanding. MOS 5425, Advanced Toxicology 1 The kidneys function to remove wastes, drugs, and toxicants from the body through excretion of urine. UNIT xthe STUDY GUIDE Different toxicants affect specific parts of the kidneys and ultimately can affectTitle the proper functioning of the kidneys as organs. Many antibiotics are secreted by the proximal tubules and can induce alterations in the tubular functions and affect the overall function of the kidneys. In your textbook reading, note the different toxicants and the specific areas of the kidneys that they affect. Chemicals may cause acute as well as chronic injury to the kidneys. Various chemicals in the environment and industry as well as therapeutic drugs can induce nephrotoxicity. Halogenated solvents (e.g., dichloroethylene and perchloroethylene), heavy metals (e.g., mercury and cadmium), analgesics (e.g., acetaminophen, antibiotics), and antineoplastics (e.g., cisplatin) are all examples of chemicals that can induce nephrotoxicity (Roberts et al., 2015). The degree of damage that is induced depends not only on the type of chemical but the dose and duration of exposure to the chemical. The next section in your reading is about toxicology of the skin. The skin may be referred to as one of the largest organs of the body. The skin has several protective functions. It protects against water loss, slows chemical absorption, acts as a barrier for physical trauma, prevents ultraviolet (UV) light penetration and damage, inhibits microorganism growth and penetration, and helps to maintain homeostasis through regulation of body temperature and water loss (Roberts et al., 2015). It is the first line of defense in protecting our bodies from the invasion of harmful substances and toxicants. The skin serves as a barrier between external factors and the internal environment of our bodies. As a result, this barrier comes in contact with and encounters damage from a variety of substances as it serves to protect the body. Despite the skin being fairly thin compared to other organs of the body, it consists of three different layers: (1) the epidermis, (2) the dermis, and (3) the hypodermis. Your textbook discusses the first two layers. The epidermis is the outermost layer, and it is much thinner than the dermis. While reading the textbook, you should pay attention to the different cells that make up each of these layers and the role that each type of cell plays in the skin. Not only can toxicants damage the layers of skin, but they can also alter the hair, sebaceous glands, and sweat glands that span the epidermis and are embedded in the dermis (Roberts et al., 2015). The skin is a good barrier but not a perfect barrier against numerous substances. There are some substances that the skin is not able to shield from entering the body. Many factors influence the entrance or diffusion rate of chemicals across the skin (Roberts et al., 2015). The stratum corneum is the primary layer determining the rate of diffusion of chemicals through the skin. Due to the composition of the stratum corneum, small hydrophobic agents can more readily cross the skin barrier than molecules that are larger in size or molecules that are hydrophilic (Roberts et al., 2015). Certain conditions may compromise the skin’s ability to act as an effective barrier. One example is skin that has been exposed to water for an extended periods of time becomes more susceptible to hydrophilic substances passing through the skin’s surface. Toxicants can have different effects on the skin. Irritant dermatitis can occur on initial exposure; repeated exposure is not required becaise it is in contact dermatitis. Irritant dermatitis is limited to the local area of exposure and can include symptoms such as skin redness, blistering, eczema, and rashes (Roberts et al., 2015). Other types of dermal toxicity include allergic contact dermatitis, which is a hypersensitive reaction by the immune system following a repeat exposure to a chemical, and systemic contact dermatitis when a contact allergen enters an individual’s systemic circulation. Some of the symptoms of systemic contact dermatitis include headaches and malaise. Photosensitivity can be a result of dermal toxicity. It can be described simply as an extreme sensitivity to sunlight. Acneiform dermatoses, commonly referred to as acne, can be a response to dermal toxicity as a result of workplace exposures to petroleum, coal, and tar (Roberts et al., 2015). One of the last effects of dermal toxicity that the textbook mentions is the most common cancer in humans, skin cancer. UV exposure is the main cause of skin cancer, but chemical exposure to the skin may also induce skin cancer. The textbook does not include a discussion of the eye nor toxicity that may occur. However, the eyes are a vital part of the average person’s ability to function, so it is a noteworthy topic to address. The main function of the eye is for sight. The sense of sight serves an important role in protecting the body from harm. The eye has a complex anatomy with many intricate parts. You are encouraged to utilize your resources on the Internet to look at several detailed colored pictures and diagrams of the eye to get a good basic understanding of this structure. One question that may arise is how do we see objects? Light that is reflected off of objects travels MOS 5425, Advanced Toxicology 2 through many parts of the eye, including the cornea and aqueous humor all the wayxtoSTUDY the lens and retina. UNIT GUIDE Signals that travel to the optic nerve are sent to the brain for interpretation to create Title the forms that we see. Damage to any part of the structure of the eye can inhibit light from successfully traveling to the optic nerve and sending signals to the brain to interpret sight. Various chemicals may have different effects on various parts of the eyes. A brief search on corneal toxicity may reveal numerous chemicals that cause toxicity to the eye. Take note of how various chemicals affect different structures of the eye. There are several tests that can be performed to assess damage caused by exposure to various toxicants. Rabbits are the most common animal used in testing effects of chemicals on the eye. It is not uncommon for products that are sold in stores and are common household products used daily to be tested for the toxicological effects on the eye. One product that comes to mind is makeup. There is a high probability that in applying and wearing make-up people will at some point get make-up in their eyes. Consumers would like to believe Cross-section of the eye showing major that these products will not have adverse effects and, thus, components are tested prior to being placed on the retail shelves to be (Clker-Free-Vector-Images, 2012) sold. The tests performed to determine toxicity to the eye may include, but are not limited to, procedures for gross anatomy testing, instrumental examinations using ophthalmoscopy, visual perimetry, and histological and biochemical examinations (Roberts et al., 2015). References Clker-Free-Vector-Images. (2012). Eye diagram [Image]. Retrieved from https://pixabay.com/en/eye-diagrameyeball-body-pupil-39998/ National Kidney Foundation. (n.d.). How your kidneys work. Retrieved from http://www.kidney.org/kidneydisease/howkidneyswrk.cfm#where Roberts, S. M., James, R. C., & Williams, P. L. (Eds.). (2015). Principles of toxicology: Environmental and industrial applications (3rd ed.). Hoboken, NJ: Wiley. MOS 5425, Advanced Toxicology 3 Original Research Article Therapeutic potential of Origanum vulgare leaf hydroethanolic extract against renal oxidative stress and nephrotoxicity induced by paraquat in rats Ali Sharifi-Rigi1, Esfandiar Heidarian1,* 1 Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran Article history: Received: Aug 13, 2018 Received in revised form: Mar 22, 2019 Accepted: Apr 22, 2019 Vol. 9, No. 6, Nov-Dec 2019, 563-573. * Corresponding Author: Tel: +98 383 3346720 +98 913 314 5229 Fax: +98 383 3346721 heidarian46@yahoo.com heidarian_e@skums.ac.ir Keywords: Antioxidant Kidney Nephrotoxicity Paraquat Oxidative stress TNF-α Abstract Objective: Paraquat is a herbicide with potent toxicity in humans and animals. This study aimed to evaluate the protective effects of Origanum vulgare (O. vulgare) leaf extract on the acute nephrotoxicity and renal oxidative stress caused by paraquat. Materials and Methods: We randomly assigned forty male rats into five groups (G1-G5). The G1 was used as control; G2 only received paraquat (25 mg/kg body weight (bw)/day, po); and G3, G4 and G5 received 25 mg/kg b.w/day oral doses of paraquat and O. vulgare hydroethanolic leaf extract (200, 400, 800 mg/kg bw/day, po, respectively). After 2 weeks, superoxide dismutase (SOD), renal catalase (CAT), vitamin C levels, histopathological changes, and tumor necrosis factor-α (TNF-α) gene expression as well as serum levels of urea, creatinine (Cr), and protein carbonyl (PC) were determined. Results: In G2, oral administration of paraquat significantly increased (p<0.05) serum Cr, urea, PC, and renal TNF-α gene expression relative to those of the control group. Renal catalase, superoxide dismutase, and vitamin C levels were decreased significantly (p<0.05) in G2 as compared to G1. Administration of O. vulgare leaf extract not only increased the renal vitamin C, CAT, and SOD but also decreased the renal TNF-α gene expression, malondialdehyde (MDA), serum urea and creatinine in paraquatinduced nephrotoxicity in rats. Conclusion: Our results show that O. vulgare leaf extract has protective effects against nephrotoxicity induced by paraquat in rats. It seems that the nephroprotective effects of O. vulgare extract may be related to its antioxidant and anti-inflammatory effects. Please cite this paper as: Sharifi-Rigi A, Heidarian E. Therapeutic potential of Origanum vulgare leaf hydroethanolic extract against renal oxidative stress and nephrotoxicity induced by paraquat in rats. Avicenna J Phytomed, 2019; 9(6): 563-573. Introduction Paraquat is a commonly used nonselective herbicide (Li et al., 2015). This herbicide’s chemical composition is 1, 1dimethyl-4, 4-bipyridinium dichloride. It is a very toxic herbicide to both humans and animals. There are many reports of death due to accidental exposure to paraquat in humans, which can occur due to unavailability of an effective treatment (Atashpour et al., 2017; Han et al., 2014; Hu et al., 2017). Paraquat can damage some AJP, Vol. 9, No. 6, Nov-Dec 2019 563 Effect of Origanum vulgare on paraquat-induced nephrotoxicity human organs including the lung, kidney, and heart (Liu et al., 2017). This herbicide spreads out rapidly in different body tissues. Paraquat can accumulate within the kidneys at high concentrations. Also, paraquat-induced nephrotoxicity is one of the leading causes of the paraquat-induced death (Wei et al., 2014). Renal tubules lose their regular shapes when exposed to paraquat and paraquat can induce congestion of kidney blood vessels and degeneration of glomeruli (Gu et al., 2016). Paraquat exerts its herbicide action by preventing reduction of NADP+ to NADPH during photosynthesis (Atashpour et al., 2017). In mammals, this herbicide is converted to paraquat radical by NADPHoxidases. Then, it passes its extra electrons to molecular oxygen and forms reactive oxygen species (ROS) such as superoxide anion (O2-), hydroxyl radical (HO-), and hydrogen peroxide (H2O2). ROS induce oxidative stress and damage to DNA, proteins, lipids, and disruption of the cell structure and function (Awadalla, 2012; Charão et al., 2015; Han et al., 2014; Malekinejad et al., 2010). Also, superoxide anion causes lipid peroxidation and cell death by attacking membrane’s unsaturated lipids (Atashpour et al., 2017). Antioxidants are compounds which can prevent oxidative stress (Mittler, 2002). Origanum vulgare (O. vulgare) is a globally well-known aromatic herb widely used in the western diets as a spice (Savković et al., 2016; Zhang et al., 2014). O. vulgare is a Mediterranean herb from Lamiaceae family with anti-carcinogenic, anti-mutagenic, and antimicrobial properties (Kubatka et al., 2016). The important phenolic compounds of O. vulgare with antioxidant properties are ursolic acid, rosmarinic acid, caffeic acid, and carnosic acid (Kaurinovic et al., 2011; Pahlavan et al., 2013). The protective effects of O. vulgare on gentamicininduced nephrotoxicity were confirmed in a previous study in a rat model (Mirzaei et al., 2016). Therefore, based on the abovementioned properties of O. vulgare, this study sought to investigate the effects of O. vulgare leaf extract on renal superoxide dismutase (SOD), catalase (CAT), vitamin C, malondialdehyde (MDA) levels, tumor necrosis factor-α (TNF-α) gene expression as well as serum levels of creatinine (Cr), protein carbonyl (PC), and urea in paraquatinduced renal toxicity in rats. Materials and Methods Chemicals Paraquat (paraquat dicholoride, 20\% purity) was obtained from Shandong Luba Chemical Co. Ltd., Jinan, China. Blood urea and creatinine (Cr) kits were prepared from Pars Azmoon Company (Tehran, Iran). SYBR® Green polymerase chain reaction (PCR) Master Mix was purchased from Qiagen (Düsseldorf, Germany). Sodium acetate and thiobarbituric acid were provided by Merck Co. (Darmstadt, Germany). Nitro blue tetrazolium, riboflavin, 2, 4, 6-tripyidyl-s-triazine, and vitamin C were obtained from SigmaAldrich company (St. Louis, Mo USA). All other chemicals were of analytical grade. Herbs and extraction procedure Medical Plants Research Center of Isfahan University of Medical Sciences, Isfahan, Iran kindly provided us with necessary amount of O. vulgare. Also, a voucher specimen was deposited (herbarium No. 502). O. vulgare leaves were air-dried at ambient temperature and ground to fine powder. Then, O. vulgare’s hydroalcoholic extract was prepared through mixing the powder in a solution of ethanol and water (70:30, v/v), at ambient temperature for 2 days. The resulting solution was carefully filtered and dried using a rotary evaporator at 50C. The resulting extract was stored at 5°C for future use. Measuring antioxidant, flavonoid, and phenolic contents The methods described by Chang et al. and McDonald et al. were used for determining the antioxidant capacity and AJP, Vol. 9, No. 6, Nov-Dec 2019 564 Sharifi-Rigi et al. the total phenolic content of O. vulgare leaf extract (Chang et al., 2002; McDonald et al., 2001). Animal treatment and experimental design We used forty 10-12 week old male Wistar rats weighting about 180-220 g. Rats were kept under standard laboratory conditions (22±2°C, 60±5\% humidity, and 12:12 light/dark cycle) during the study period with free access to standard rat pellet diet and water. These animals were divided randomly into five groups of eight each. Group 1 (control group) only received oral distilled water for 2 weeks. Group 2 were treated by oral paraquat (25 mg/kg body weight (bw)/day) through gastric gavage for 2 weeks (Akinloye et al., 2013). Groups 3, 4, and 5 received oral paraquat (25 mg/kg bw/day) and treated with oral O. vulgare hydroethanolic leaf extract (200, 400, and 800 mg/kg bw/day, respectively) at an interval of 1 h for 2 weeks. Thereafter, rats were anesthetized using chloroform, cardiac puncture procedure was used for collecting blood specimens, and serum and plasma were separated. Also, we collected kidney sample for determination of TNF-α gene expression, CAT and SOD levels, and histopathological examinations. All procedures were conducted following approval of the Ethics Committee of Shahrekord University of Medical Sciences, Shahrekord, Iran (Ethic number IR. SKUMS. REC. 1395. 151). Biochemical analysis Enzymatic assessment using auto analyzer system (BT 3000, Rome, Italy) was done for measurement of urea and Cr. Serum TNF-α was measured by enzymelinked immune-sorbent assay (ELISA) kit (Bioassay technology laboratory Shanghai, China). Determination of serum and renal malondialdehyde (MDA) levels Serum and renal MDA levels were determined as discussed previously (Heidarian and Soofiniya, 2011). Measurement of ferric reducing ability of plasma (FRAP) Plasma antioxidant capacity of the experimental groups were assessed using Heidarian and Soofiniya (2011) protocol. Determination of renal catalase (CAT) and superoxide dismutase (SOD) activities Renal catalase activity was measured as described previously (Heidarian et al., 2014). The renal SOD activity was explored using renal tissue samples by Beauchamp and Fridovich (1971) method. Bradford method was used for measuring total protein content (Bradford, 1976). Determination of renal vitamin C levels We measured renal vitamin C level in the experimental groups through application of Omaye et al. method (Omaye et al., 1979). A standard curve for vitamin C was prepared using a concentration range of 0-20 μg/μl. Determination of TNF-α gene expression Real-Ti ... 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