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Hepatoprotective Effects of Aqueous Extract of Celosia Argentea on Animals with Acetaminophen-induced Liver Damage

do not necessarily reflect the views of UKDiss.com.

Treatment of liver disease or hepatic damage with conventional forms of treatment using drugs is often associated with toxicity since doses are not standardized, similarly, synthetic drugs are also associated with many side effects that may cause damage to other organs. As a result of this shortcoming in human medicine, research is directed towards discovery and development of active chemicals from medicinal plants which are commonly consumed foods that produce protective and therapeutic effects that are comparable to that of standard drugs and showing low side effects (Salama et al., 2013). Studies are also required to screen commonly consumed natural foods and vegetables for their antioxidative and protective properties to recommend them for use as natural remedies for many ailing individuals.

 

1.1 OBJECTIVES OF THE STUDY

The objectives of this study is to

  • Investigate the hepatoprotective effects of aqueous extract of Celosia argentea on animals with acetaminophen-induced liver damage.
  • Compare the activity of Celosia argentea with standard drug, silymarin in the treated rats.

 

 

 

 

 

CHAPTER TWO

LITERATURE REVIEW

 

2.1 SILYMARIN

Silymarin is the polyphenolic fraction of milk thistle (Silybum marianum) largely found in Spain and Greece. The active extract of milk thistle is a mixture of flavonoligans, made up of approximately 70-80% of silymarin and 20-30% of a chemically undefined fraction, made up of polymeric and oxidized polyphenolic fraction. The main component of silymarin is silibinin which has antioxidative properties. Other flavonoligans in silymarin include isosilibinin, dehydrososilibin, silychristin, silydianin and taxifolin, (Figure 2.1) found in the seeds of Silybum marianum (Kren et al., 2005).

2.1.1 Benefits of Silymarin

Seeds of milk thistle have been used to treat a range of liver diseases such as hepatitis, cirrhosis. It also protect the liver against chemical and environmental toxins and also against alcohol abuse. Silymarin has reactive oxygen species scavenging properties which was proved by atomic force microscope examination, indicating a potential to reduce toxic effects of other drugs. Silymarin is also used in veterinary medicine, precisely plant preparations from milk thistle. They are used as feed supplements to improve animal health and their productivity and also for therapeutic purposes for example, some dairy cows are exposed to simple steatosis at calving which could impair their liver function, and usage of hepatoprotective agents such as silymarin can protect the liver of these dairy cows (Gazak et al., 2007). Seeds of milk thistle added to the feeds of dairy cows also increases the milk yield of the cows. Addition

https://2e9be637a5b4415c18c5-5ddb36df15af65ab8482e83373c53fe5.ssl.cf1.rackcdn.com/images/178.png

Figure 2.1 Components of Silymarin (Source: www.google.com)

of silymarin to the feeds of broiler chicks also reduces the aflatoxin B1 toxicity as demonstrated by serum alanine aminotransferase (ALT) activity, liver histology, feed intake and body weight gain (Tedesco et al., 2004). Silymarin is also used in veterinary medicine to treat various hepatic disorders in pigs, dogs, sheep etc.

 

2.1.2 Pharmacological action of silymarin

Silymarin has membrane-stabilizing and antioxidant activity. It promotes hepatocyte regeneration by stimulating protein synthesis in the liver, reduces inflammatory reaction and inhibits fibrinogenesis i.e. synthesis of fibrin for blood clot (Feher and Lengyel, 2012). Silymarin also reduces the production of nitric oxide which modulates inflammatory response. It increases glutathione in the liver, thereby increasing the availability of glutathione to detoxify hormones, chemicals, drugs in the body (Radko et al., 2007).

Silymarin is insoluble in water and administered with a standard extract containing 70-80% silymarin. The acute, sub-acute and chronic toxicity of the compound is low. The acute toxicity of silymarin studied in different laboratory animals such as mice, rats, rabbits has been studied with reported LD50 of 2g/kg b.w. when administered by slow infusion (Radko et al., 2007). Silymarin or its active agent, silibibin has low oral bioavailability, hence, silibinin is combined with phosphatidyl choline (Barzaghi et al., 1990), liposomes containing cholesterol and phospholipids (Maheshwari et al., 2003)  and lipid microspheres formed by surfactans e.g., soybean, lecithin to increase its oral bioavailability and facilitate effective transport to the target organ, liver, the pharmacological activity compared to thereby exhibiting greater bioavailability compared to the crude compound ( Abrol et al., 2004)

2.1.3 Silymarin in Liver Damage

Milk thistle is the dietary supplement taken frequently by patients with chronic liver diseases. Hepatoprotective activity of silymarin has been demonstrated by various researchers in experimental animals using acetaminophen, ethanol, carbon tetrachloride etc. induced liver damage. In the experiments, the liver damage marker enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), caused by toxic effects of the inducers were reduced. It also protects the liver cell from injury caused by ischemia, radiation and viral hepatitis (Pradan and Girish, 2006).

In liver damage caused by poisonous mushroom, amatoxin is the toxic agent that causes hepatocyte damage, silymarin inhibit the uptake of the amatoxin into the hepatocytes by competing with its basolateral transport system. This prevents inhibition of RNA polymerase II and inhibits blockage of protein synthesis (Sonnenbichler et al., 1986). It can also prevent absorption of toxins into the hepatocytes by occupying the binding sites of the toxin and also inhibit many transport proteins at the membrane. It also exerts strong anticancer activity against hepatocellular carcinoma cells by modulating cell cycle and associated proteins. Inhibiting the growth of the cancer cells and also causes apoptosis of the cancerous cells.

 

 

 

 

 

2.2 ACETAMINOPHEN

Acetaminophen (Paracetamol) is a commonly used analgesic and antipyretic of the para-aminophenol group of the no-steroidal anti-inflammatory drugs (Figure 2.2). It is considered to be the safest of all the commonly used analgesics, however it has minimal anti-inflammatory when compared to aspirin (Graham et al., 2001). It was discovered in 1889 and is an active metabolite of phenacetin. The analgesic effect of paracetamol depends on the rate and amount of the active drug reaching the central nervous system, where it takes place.

 

2.2.1 Pharmacological action of Acetaminophen

Acetaminophen is one of the most common and widely used analgesic and is currently recommended as the first-line pharmacological therapy by different international guidelines for various acute or chronic painful conditions (Jordan et al., 2003). The lack of anti-inflammatory action of acetaminophen is due to lack of prostaglandin inhibition peripheral in the body. It is available in oral, rectal and injectable form.

 

2.2.2 Metabolism of Acetaminophen

Paracetamol, as a result of its acceptance as one of the most common analgesic is also one of the most abused drugs. The toxicity of paracetamol is not from the drug itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQ1) which is yielded through a minor pathway through cytochrome P450. The biotransformation of paracetamol (Figure 2.3) is a phase II reaction which involves conjugation with glucuronide and sulphate and the metabolite, NAPQ1 is stabilized

http://0.tqn.com/d/chemistry/1/S/t/M/1/paracetamol.jpg

Figure 2.2 Structure of Acetaminophen (Source: Helmenstine, Anne)

 

Figure 2.3 Metabolism of Acetaminophen (Source: www.google.com)

through conjugation with glutathione and eliminated through the kidney. Under normal conditions, NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturic acid conjugates, however,in overdose, large amount of paracetamol are metabolized by oxidation because of saturation of the sulphate conjugation pathway (Pajoumand et al., 2003) and the protective intracellular glutathione stores are then depleted because the production of NAPQ1 exceeds the ability to detoxify it leading to hepatic and renal damage. The excess NAPQ1 has also been associated to oxidative stress (Ojo et al., 2006). The renal damage effects of paracetamol overdose is less common than the hepatic damage.

The general recommended daily dose for paracetamol is 3g for a healthy adult and a single dose of above 10g or 200mg/kg body weight is likely to cause toxicity in adults (Daly et al., 2008).  Many individuals with paracetamol toxicity may have no symptoms at all in the first 24 hours following overdose. Others may initially have nonspecific complaints such as vague abdominal pain and nausea. With progressive disease, signs of liver failure may develop; these include low blood sugarlow blood pHeasy bleeding, and hepatic encephalopathy. Some will spontaneously resolve, although untreated cases may result in death. Risk factors for toxicity include excessive chronic alcohol intake, fasting or anorexia nervosa, and the use of certain drugs such as isoniazid.

2.2.3 Acetaminophen and liver damage

As a result of its high availability and usage as an over-the-counter analgesic, it is one of the most common cause of hepatic damage as it is easily and commonly overused. Hepatotoxicity caused by acetaminophen overdose has been linked to formation of a highly reactive metabolite, N-acetyl-p-benzoquinone imine, by the action of hepatic cytochrome P450 (Savides and Oehne, 1983). Necrosis of the liver cells is one of the most common effects of paracetamol toxicity (Bessems and Vermeulen, 2001). The excess NAPQ1 that is unable to be detoxified due to depletion of glutathione covalently binds to cysteine residues on proteins to form adducts. These adducts only occur in hepatic centrilobular cells that develop into necrosis (Roberts et al., 1991). According to Hinson and his colleaguesin 1998, acetaminophen induced toxicity in mice is accompanied by increased nitric oxide (NO) synthesis in the liver and by the formation of nitrotyrosine adducts. Nitrotyrosine adducts are said to be formed by nitration of tyrosine by peroxynitritre which is a reactive specie generated from superoxide and NO but is normally detoxified by glutathione but since glutathione has been depleted by excess NAPQ1, peroxynitrite is able to form the nitrotyrosine adduct (Reid et al., 2005). According to another study by Yousef and colleagues in 2010, paracetamol -induced hepatocellular necrosis in rats led to an increase in serum aspartate aminotransferase, alkaline phosphatase and alanine aminotransferase which indicates cellular leakage and loss of functional integrity of the liver cell membrane and also a reduction in plasma total protein, albumin and globulin and an increase in total bilirubin. Their results also showed a significant renal impairment in the paracetamol treated animals with evidence of increase in plasma urea and creatinine.

2.3 LIVER DISEASES

2.3.1 Alcoholic Liver Disease

Alcoholic drinks are largely consumed and one of the most addictive substance all over the world and its excessive consumption has been regarded to lead to health, economic and social problems. It is also regarded as one of the common causes of preventable deaths in the world. Alcoholic liver disease is characterized by excessive consumption of alcohol and since the liver is the organ in charge of ethanol metabolism, toxic by-products of the metabolism end up in the liver, leading to various liver diseases. A liver that is exposed to excessive alcohol undergoes changes as a result of oxidative stress and inflammation.  Alcoholic liver disease represents a spectrum of diseases ranging from alcoholic steatosis to alcoholic hepatitis and in severe cases, fibrosis and cirrhosis (Tome et al., 2004). As a matter of fact, more than 90% heavy drinkers develops fatty liver, and about 30% of heavy drinkers further develops advance forms of ALD. Possible factors that affect the development of liver injury in ALD patients are; dose, duration and type of alcohol consumed, drinking patterns, sex, ethnicity, associated risk factors, infection with viral hepatitis and genetic factors (O’Shea et al., 2010). Excessive alcohol consumption also damage other organs such as brain, heart, muscles, bones, lungs etc.

Ethanol has the capacity to increase levels of ROS, RNS and lipid peroxidation. The primary pathway for the ethanol metabolism is dehydrogenase system. It is initiated by alcohol dehydrogenase (ADH), a NAD+ requiring enzyme expressed at high levels in hepatocytes, which oxidizes ethanol to acetaldehyde. Then, acetaldehyde enters the mitochondria where it is oxidized to acetate by aldehyde dehydrogenases (ALDH). The products formed is destructive to the liver cells as it is a reactive metabolite that reacts with DNA that creates adducts that result in tissue injury. In the cytosol, ethanol metabolism enables the formation of both acetaldehyde and ROS and the acetaldehyde produced also increases mitochondria damage, causing a reduction of oxygen to superoxide. The production of nicotinamide adenine dinucleotide (NADPH) and reduced form of hydrogen also interferes with electron movement in the mitochondria, facilitating more production of ROS. One of the main determinants of oxidative stress during alcohol consumption is the induction of CYP2E1, which is an isoform of cytochrome P450 into the hepatocytes and Kupffer cells. According to Ronis and colleaguesin 2005, CYP2E1 has high NADPH oxidase activity and lipid peroxidation in hepatic microsomes of alcoholic subjects and rodents fed with ethanol. CYP2E1 also increases vulnerability of alcoholics to toxicity of different drugs, industrial solvents and anesthetics (Leiber, 2000).

During excessive alcohol consumption, different pathways of ethanol metabolism leads to overproduction of ROS, leading to oxidative stress as a result of depletion of the body’s natural antioxidant, glutathione to scavenge these free radicals. Polyunsaturated lipids which is necessary for lipid peroxidation to take place can be replaced with saturated lipids in the diet to reduce lipid peroxidation and hepatic damage, Administration of other antioxidants such as vitamin E, vitamin C, superoxide dismutase or other agents that replace glutathione such as N-acetylcysteine, silymarin etc. can prevent toxic effects of alcohol and improve the quality of life of ALD patients.

2.3.2 Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a disease of the liver that is not associated with excessive alcohol intake but is as a result of metabolic syndromes such as obesity, insulin resistance etc. NAFLD has become a public health issue because of its high prevalence, potential progression to severe liver disease and association with metabolic syndromes. It is a disease that affects all ages as it has been seen in children as young as 2 years of age. Management of these metabolic disorders which are also categorized as risk factors of NAFLD is important to control progression of the disease. NAFLD is categorized into non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver (NAFL) or simple steatosis. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury with or without fibrosis while NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury (Chalasani et al., 2012). NAFLD is accompanied by several predisposing, factors such as obesity, diabetes, dyslipidemia, jejunoileal bypass, drugs and parenteral nutrition. Hepatic stellate cells undergo activation, and progression to advanced fibrosis and cirrhosis is also possible.

The most widely accepted model to explain the development of NAFLD and the progression from simple steatosis to NASH is the two-hit hypothesis. The first hit is the accumulation of triglycerides in the hepatocytes and the second hit leads to hepatocyte injury, inflammation and fibrosis. Oxidative stress, lipid peroxidation, pro-inflammatory cytokines, adipokines and mitochondrial dysfunction are the factors initiating the second hit process (James and Day, 1998).  Oxidative stress is especially harmful to mitochondria, causing damage that results in impaired gene expression, alterations in proteins synthesis, decreased mitochondrial content and impaired mitochondrial beta-oxidation.

The pathogenesis of NAFLD is based on the disrupted uptake, synthesis, oxidation and export of fatty acids. This imbalance leads to excessive fat accumulation in the liver which induces high levels of β-oxidation, with the production of ROS at the mitochondrial chain level leading to the induction of necrosis (Aronis et al., 2005). This indicates that there is high rate of ROS production leading to oxidative stress in a patient suffering from NAFLD. It has also been seen that there is an increase in lipid peroxidation, hydroperoxide content and protein oxidation with a concomitant reduction in the internal antioxidant activity in a NAFLD patient (Pettinelli et al., 2011).

It has been found that AST levels, but not of ALT levels were reduced significantly in patients with NAFLD by antioxidant intervention (Sha-Li et al., 2015). Hence, supplementing the diet with enough antioxidants and also lifestyle modification can reduce the prevalence of NAFLD.

2.3.3 Liver Cirrhosis

Cirrhosis is a type of liver damage where healthy liver tissue are replaced by scar tissues leading to an increased resistance to blood flow and higher pressure in the portal vein that transport blood from the organs of the digestive tracts to the liver resulting in portal hypertension which results in ascites, splenomegaly, esophageal varices etc.  It is caused as a result of excessive alcohol, hepatitis B and C and metabolic syndromes associated with NAFLD.  Liver cirrhosis can also be as a result of inherited conditions such as; Wilson’s disease, haemochromatosis, galactosemia, cystic fibrosis etc. This leads to a reduction in the liver’s ability to perform its functions maximally as a result of the blockage of blood flow through the liver by the scar tissue. Cirrhosis of the liver is slow and gradual in its development and its symptoms include; loss of appetite, weight loss, nausea, jaundice, hair loss, fluid retention in the abdomen and legs etc. Liver cirrhosis can be diagnosed using liver function tests, blood and urine tests, liver biopsy, imaging study which includes ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI).

Natarajan and colleagues described implication of oxidative stress in liver cirrhosis, an increase in oxidative stress parameters were seen in mitochondria, peroxisomes and microsomes from the liver after chronic administration with carbon tetrachloride and thioacetamide to induce liver cirrhosis. Another study by Clot and his colleagues in 1994also revealed decreased level of glutathione activities and stimulation of lipid peroxidation in cirrhotic patients associated with alcohol abuse. Patients with liver cirrhosis display alterations in their erythrocyte membranes caused by the redox state. This phenomenon is reflected by elevated levels of nitric oxide in these patients (Geeta et al., 2007).

Liver cirrhosis is incurable but in some cases, treatment that can reduce the progression of the disease include: making dietary and lifestyle changes, avoiding alcohol, treatment of the underlining cause such as; Hepatitis B and C virus infection, having regular endoscopic procedures and in severe cases, liver transplant. Antioxidative therapy, using natural or synthetic antioxidants are also used as therapeutic approach for prevention and treatment of the disease as a result of implication of oxidative stress in initiation of the disease.

2.3.4 Hepatitis C

Hepatitis C is an infection caused by hepatitis C virus (HCV) which is a human pathogen that attacks the liver and leads to inflammation. It accounts for chronic liver disease in about 2-3% of the world population. HCV can cause both acute and chronic infection, most patients with acute infection are asymptomatic and it doesn’t pose a major life-threatening disease but patients with chronic HCV infection progress to liver cirrhosis and development of hepatocellular carcinoma. In addition chronic HCV carriers are exposed to metabolic disorders such as iron overload, insulin resistance and steatosis (Arrese et al., 2010). HCV is a spherical, enveloped, single stranded RNA virus belonging to the Flaviviridae family with its natural targets being the hepatocytes and in some cases B lymphocytes. RNA-dependent RNA polymerase is an enzyme critical in HCV replication that generates a large number of mutant viruses which makes it difficult for the immune system to fight the virus and for vaccine development. In most infected persons, the virus persists in the bloodstream and is accompanied by hepatic inflammation and fibrosis leading to cirrhosis and hepatocellular carcinoma.

HCV infection can be transmitted through transfusion of infected to an healthy individual, intravenous drug abuse with non-sterile needles, tattooing, sharing sharp objects and in some cases, maternal-fetal infusion occurs. Antiviral medicines can cure approximately 90% of persons with HCV infection, thereby reducing the risk of liver cirrhosis and hepatocellular carcinoma, but access to diagnosis and treatment is low. Symptoms of the disease include; fever, fatigue, jaundice, abdominal pain, dark urine etc. The disease can be diagnosed by screening for anti-HCV antibodies to identify people who have been infected with the virus and a nucleic acid test for HCV RNA is needed to confirm chronic HCV infection, liver biopsy can also be done to detect the extent of liver damage.

Occurrence of oxidative stress during chronic hepatitis C was detected ae early as the 1990s. The extent of mitochondrial injury and severity of oxidative injury exerted on the liver tissues determines the severity of the infection (Barbaro et al., 1999). Implication of ROS and oxidative stress in HCV has been tested by various approaches which includes measurement of ROS, measurement of antioxidants, expression levels and activities of antioxidant defense enzymes and measurement of products of interaction of ROS with biological molecules (Ivanov et al., 2013). According to a research done by Swietek and Juszczyk in 1997, chronic HCV patients display decreased level of glutathione and other antioxidants as well as reduced total antioxidant activity in blood and liver biopsies. Lipid peroxidation and advanced protein oxidation products were also found at a significantly high level in HCV patients (Bhargava et al., 2011).

HCV has also been shown to activate several pathways that lead to ROS productions, both in the hepatocytes and blood cells in the liver and it has been shown to be activated through calcium redistribution between the endoplasmic reticulum (ER), cytoplasm and mitochondria (Ivanov et al., 2013). ROS production in HCV infected cells also occur through ER- residing CYP2E1 which is involved in ethanol breakdown which explains why heavy alcohol consumption during chronic HCV leads to more severe oxidation stress. HCV-induced oxidative stress not only contribute to virus-associated disorders but also affect HCV propagation in the host, ROS can induce viral genome heterogeneity which facilitates viral escape during treatment (Seronello et al., 2011). HCV core proteins has also been found to increase oxidative stress in the liver.

It has been established that oxidative stress plays an important role in pathogenesis of HCV, therefore antioxidant and antiviral therapies can be employed to protect against liver cell damage and also reverse the damaging effects of HCV by repairing functions of DNA repair enzymes (Pal et al., 2010).

2.3.5 Hepatocellular Carcinoma (HCC)

HCC is a malignancy of the liver that occurs in patients with chronic liver disease such as chronic hepatitis C virus infection and liver cirrhosis. It differs from metastatic liver cancer which starts in another organ and spreads to the liver, HCC starts in the liver. The tumor progresses with local expansion, intrahepatic spread and metastases. HCC has been regarded as the 3rd leading cause of cancer death in the world (Moreira and Rodrigues, 2014), its incidence is higher in places with endemic high prevalence of hepatitis C and hepatitis B virus infection by repeatedly causing the immune system to attack the liver cells. Alcohol abuse, aflatoxin B1, inflammation, necrosis, fibrosis and cirrhosis also contribute to HCC development. Obese individuals with NAFLD can progress to NASH which leads to fibrosis, cirrhosis and HCC. The progression of the disease, which result in malignant transformation include pathways that are modified by external and environmental factors that eventually lead to genetic changes that delay apoptosis and increases cell proliferation.

Symptoms of HCC include abdominal pain, easy bruising, jaundice, enlarged abdomen, unexplained weight loss etc. Liver biopsy, liver function tests, abdominal CT scan, liver MRI can be done to diagnose the disease. HCC rarely occurs in children and adolescents, however if they suffer from congenital liver disorders, there is a chance of developing HCC.

2.4 OXIDATIVE STRESS AND LIVER DYSFUNCTION

The term oxidative stress began to be used frequently in the 1970s, but its conceptual origins can be traced back to the 1950s to researchers pondering the toxic effects of ionizing radiation, free radicals, and the similar toxic effects of molecular oxygenFree radicals are molecules that have an unpaired electron in their valence orbital. In biology system, oxygen based radicals and nitrogen based radicals are two types of free radicals. Oxygen free radicals, such as superoxide, hydroxyl radicals, and peroxyl radicals, with the addition of non-radicals, such as hydrogen peroxide, hypochlorous acid and ozone, are known as reactive oxygen species (ROS). They are generated during the metabolism process of oxygen with the most reactive, and therefore damaging, products assumed to be the oxygen-based hydroxyl radical. Reactive nitrogen species (RNS), including nitrogen based radicals and non-radicals, such as nitrogen dioxide, nitric oxide radicals and peroxynitrite, are derived from nitric oxide and superoxide via inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, respectively and the nitrogen-based peroxynitrite anion being the most dangerous.

However, since the body is able to remove ROS/RNS to a certain degree, these reactive species are not necessarily a threat to the body under physiological conditions (Mittler, 2002). The RNS have a longer half-life than ROS, making them more damaging. As a matter of fact, ROS are required at certain level in the body to perform its physiological functions. The generation of molecular oxygen in the form of reactive oxygen species (ROS) is a natural part of aerobic life that is responsible for the manifestation of cellular functions ranging from signal transduction pathways, defense against invading microorganisms and gene expression. However, interference with electron transport can increase superoxide production to such an extent that their role becomes harmful, inducing cell death through necrosis or apoptotic mechanisms, leading to cellular or tissue injury.

There is a growing awareness that oxidative stress plays a role in various clinical conditions which includes cancer, diabetics, rheumatoid arthritis, atherosclerosis, liver diseases. Oxidative stress has also been shown to induce malignant transformation of cells in culture. Diseases associated with oxidative stress such as cancer, diabetics etc. show pro-oxidative shift in the redox state and impaired glucose clearance suggesting that muscle mitochondria is the major site of elevated ROS production. The inflammatory oxidative conditions are typically associated with an excessive stimulation of NADPH oxidase by cytokines and other factors.

2.4.1 Oxidative stress and Liver Disease

Mitochondria are the main source of cellular ROS within non-phagocytic human cells and these oxygen metabolites are produced during the course of oxidative phosphorylation. Liver is a major organ attacked by ROS (Sanchez-Valle et al., 2012). In addition to the mitochondria, the endoplasmic reticulum can also produce ROS in the liver via the cytochrome P450 enzymes, and this reaction can occur in macrophages and neutrophils. Chronic liver diseases are characterized by increased oxidative stress, regardless of the cause of the liver disorders.  Because of its metabolic activity, the liver constitutes an organ that is particularly susceptible to oxidative stress. The liver is therefore equipped with a special defense mechanism to scavenge ROS, in which nuclear factor E2-related factor 2 (Nrf2) plays an important role.  ROS undoubtedly play a crucial role in the development of numerous chronic liver diseases and stimulate their progression.

Parenchyma cells are also subjected to liver injury induced by oxidative stress. The Kupffer cells, hepatic stellate cells and endothelial cells are potentially more sensitive to oxidative stress-related molecules and contributes to ischemia/regeneration, necrosis and apoptosis. The oxidative stress not only triggers hepatic damage by inducing alteration of lipids, proteins and DNA but also modulate pathways that control normal biological functions (Sha-Li et al., 2015). Since these pathways regulate genes transcription, protein expression, cell apoptosis, and hepatic stellate cell activation, oxidative stress is regarded as one of the pathological mechanisms that results in initiation and progression of various liver diseases, such as chronic viral hepatitis, alcoholic liver diseases and non-alcoholic steatohepatitis (Feng et al., 2011).Moreover, systemic oxidative stress arising during liver disease can also cause damage to extra-hepatic organs, such as brain impairment and kidney failure.

Oxidative stress is considered one of the mechanisms by which HCV promotes liver cell proliferation leading to HCC. ROS that was detected using an electron paramagnetic resonance spin probe, were implicated in histological disease activity in chronic hepatitis C that leads to HCC. It has also been shown that oxidative stress is a key mediator in HCC. Chemical mutagenesis of DNA leading to mutation of critical cellular genes is a key mechanism by which oxidative stress contribute to HCC. A study by Moreira and Rodrigues on oxidative stress and cell damage in advanced hepatocellular carcinoma rats in which HCC was induced in rats through chronic exposure to carcinogenic agents showed changes in superoxide dismutase and NrF2 which are markers of oxidative stress and cell damage in early onset of HCC. Oxidative stress indicated by increased serum levels of derivatives of reactive oxygen metabolites (d-ROM) has also been implicated in recurrence of HCC after curative treatment in patients (Suzuki et al., 2013).  Another study was performed in which the levels of antioxidants was altered to examine their effects in mice deficient in zinc superoxide dismutase which converts superoxide to hydrogen peroxide showed a reduced life span in the mice and an increased incidence of nodular hyperplasia and HCC which indicates a redox mechanism of HCC development (Elchuri et al., 2005). Iron depletion therapy reduced oxidative damage, improved ALT levels reduced inflammation and progression of fibrosis and decreased the risk of HCC among chronic HCV infected individuals (Kato et al., 2007). Other therapeutic approaches are liver transplantation, surgical ablation etc.

2.5 Celosia argentea

C. argentea is a group of edible, ornamental plant of the Amaranthaceae family. It is found in India, Africa, especially West Africa, Indonesia, Sri Lanka etc. It is an herbaceous, erect and branching plant C. argentea is commonly named as Lagos spinach, silver cock’s comb, cock’s comb, quail grass in English.  The plant has been said to grow like a weed without demanding much care. It is one of the most commonly consumed leafy vegetable in Nigeria and it is referred to as soko yokoto. C. argentea has been used traditionally in the treatment of sores, ulcers and skin eruptions and possesses laxative, antioxidant, and anti-inflammatory activities (Okpako and Ajibesin, 2015).

Figure 2.4: Celosia argentea (Source: Wikipedia)

 

 

 

2.5.1 Classification of Celosia argentea

Kingdom: Plantae

Division: Magnoliophyta

Class: Magnoliospida

Order: Caryophyllales

Family: Amaranthaceae

Genus: Celosia

Species: Celosia argentea

Binomial name: Celosia argentea L.

2.5.2 Origin and Distribution

The plant is common in West Africa, from Sierra Leone to Nigeria. It is also known in Ethiopia, Somalia, Kenya, and other parts of East Africa, Mexico and Central Africa (Nidavani et al., 2013). It also grows as weed in rainy season in India, Sri Lanka, Indonesia, America etc.

2.5.3 Botanical Description

The plant is a tender, annual dicotyledonous herb, branched, coarse, and erect with 0.5-2 ft. high and of tropical origin that grows best in full sunlight. The roots are white in color with a cylindrical shape and the leaves are alternate entire or rarely lobed, light green. They are typically 2 X 6cm, although those on flowering shoots are slightly longer. The brightly colored flowers have dense heads and largely occur in spikes, and stand like spears in the garden bedand also yield large numbers of seeds that are about 1 mm in diameter and are normally black in color.

2.5.4 Economic and Medicinal Uses

The whole plant is known traditionally for its use in the treatment of wounds, ulcers, skin diseases, diarrhea, piles, bleeding nose, disinfectant, inflammation, haematological and gynaecologic disorders (Nidavani et al., 2014). Anti-inflammatory, immunostimulating, anticancer, hepatoprotective, antioxidant, wound healing, antidiabetic and antibacterial activities have been reported in the extracts and its constituents. A study by Okpako and Ajibesin in 2015 established the antimicrobial activities of the stem, root and leaf extracts with the roots exhibiting the most potent activity. The antimicrobial activity was attributed to the presence of phytochemical constituents such as saponins, tanins, alkaloids etc. The anti-diabetic activity of the ethanolic extract plant was also studied by Xue and colleagues in 2011 and it showed significant hypoglycemic action against streptozotocin induced diabetes in rats. Seed extract of the plant has been shown to scavenge free radicals due to its abundant polyphenol (Rukhsana et al., 2013).  A study of hepatoprotective activity of the ethanolic extract of the seed against CClinduced hepatotoxicity has also been done by Jain in 2005 to confirm its hepatoprotective activity

2.6 Nicotiana tabacum (Tobacco)

Tobacco is a plant of the Solanaeceae family that contains over four thousand chemicals along with nicotine, being the most important and responsible for the stimulant and addictive property of tobacco. Nicotine (Figure 2.5) is also found in many plants but tobacco has a higher concentration than other plants. Tobacco use dates back to the 14th century when it was used by Native American tribes and the Mexicans for both traditional, social and ceremonial use. In the 17th century, tobacco smoking, chewing and sniffing became popular in Europe and its colonies (Burns, 2006). In the 19th century, tobacco became popular and its adverse health effects came into limelight in the 20th century. Apart from its deleterious effects in human, it is also used to ward off herbivores in plantations as they contain germacrene, anabasine and piperidine. It has also been used traditionally as disinfectant, anesthetic, toothpaste to whiten the teeth,  Tobacco is consumed in different forms such as; cigar smoking, pipe smoking, tobacco water, cigarettes, chewing etc. The rate of smoking tobacco continue to rise in developing countries though it has reduced in developed countries where the effects are well emphasized (WHO, 2013). Tobacco contains phytochemicals such as nicotine, anatabine, anabasine, glucosides etc. It is also the first plant to be genetically modified to make it resistant to herbicides, insecticides, viruses, fungi and to reduce the nicotine content, thereby, exposing users of tobacco and its products to other harmful substances.

2.6.1 Classification of Tobacco

Kingdom: Plantae

Division: Magnoliophyta

Class: Magnoliospida

Order: Solanales

Family: Solanaceae

Genus: Nicotiana

Species: Nicotiana tabacum

2.6.2 Origin and Distribution

The plant originates from native America and is also found in Mexico, Cuba, Haiti, and Europe. It is now commercially cultivated all over the world and also cultivated as ornamental plant or may grow as weed.

2.6.3 Botanical Description of Tobacco

Tobacco is an annual herb that grows up to 8m high and has large green leaves with flowers. The parts of the leaves are sticky and are covered with short hairs and also secretes a yellow substance

C:UsersFeyisayoDownloads	obacco 2_files220px-Nicotine-2D-skeletal.png

Figure 2.5: Nicotine, which is the addictive substance in tobacco (Source: Wikipedia)

C:UsersFeyisayoDownloads	obacco3_filesTobacco_Leaves.jpg

Figure 2.6: Tobacco plant (Source: Wikipedia)

that contains nicotine. The seeds are very numerous, small, kidney shaped and brown in colour and it is the only part of the plant that lacks nicotine. The leaves contain 2-8% nicotine, although the nicotine content depends on the age of the plant.

2.6.4 Deleterious Effects of Tobacco

The active ingredient and the most abundant substance found in tobacco is an alkaloid, nicotine which was first isolated by Posselt and Reimann in 1828 (Anne Charlton, 2004). Nicotine increases the heart rate and the blood pressure, and may contribute directly to the excess of thrombosis and atheroma in smokers. It was also implicated in cancer, respiratory disorders, liver diseases and circulatory diseases and is regarded as the most common cause of preventable disease and death in the world. Carcinogenic polycyclic aromatic hydrocarbons and N-nitroso compounds, irritant substances such as acrolein, benzene, formaldehyde, ammonia, acetone, acetic acid, and carbon monoxide are also found in tobacco smoke which are responsible for its harmful effects. Smoking of tobacco products pose a more harmful effect than any other form in which tobacco and its products can be taken because during smoking, the lungs take in all the substances that the digestive tracts would have recognized and filtered out, enabling the plant to exert more of its toxic effects. The use of tobacco as a therapeutic agent has also been uncontrolled which could lead to excess usage resulting in toxic effects (Anne Charlton, 2004).

2.6.5 Economic and Medicinal Uses

Although tobacco use has been implicated in various diseases, studies have also shown that it has a large number of medicinal uses such as constipation, haemorhoidal bleeding, fever, snake bites, ulcers, tetanus, wounds etc. Fresh tobacco leaves and flowers have also been found to contain anti-cancer agent, cembranoids, although this compound is lost during tobacco processing (Wahlberg and Enzell, 1984). This compound, cembranoids, has been shown potential for controlling and preventing metastatic breast and prostate cancer (Baraka et al., 2010). Nicotine, the active ingredient in tobacco is an anti-inflammatory agent that has been found to be effective in treatment of Alzheimer’s disease or delay the onset of Parkinson’s disease. It also contains some alkaloids that act as monoamine oxidase inhibitors, preventing the breakdown of neurotransmitters serotonin and dopamine which are monoamine neurotransmitters responsible for maintaining a sense of wellbeing, attention, learning etc. According to a research by Beate Ritz and colleagues in 2007, risk of Parkinson’s disease is low among intense smokers.



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