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Herbal medicine, sometimes referred to as botanical medicine or herbalism, involves the use of plants, or parts of plants, to treat injuries or illnesses. This field also covers the use of herbs or botanicals to improve overall health and wellness. Herbalist, herbal medicine practitioners, traditional medicine practitioners, and Ayurvedic, homeopathic, and naturopathic healers all use herbal remedies in their practices. (A.N.Kalia, 2009)
Seeds, leaves, stems, bark, roots, flowers, and extracts of all of these have been used in herbal medicine over the millennia of their use. These supplemental treatments have been delivered raw, in teas and tinctures, as topical applications, in liquid forms, and in pills and capsules. In the beginning the plants were consumed raw or combined with hot water as a soup or tea. Later, the plants were dried and crushed for other uses. The plants were found in the wild and uses were often based on superstitious or visual cues. Plants were often used to treat body systems because they were shaped like that body part or because they grew in a particular area. As science began to take a closer look at herbal remedies, their use became more refined. Herbs, and other plants, are actually the precursors to many of today's medicinal drugs. Some of the pharmaceutical medications on the market are extracts of some of these traditional herbs.
Today, many modern, and Western, medicine practitioners are beginning to look at herbal remedies for some common and not-so common, disorders. The lower cost, and often safer use, has attracted many medical professionals. Some physicians use herbs to off-set the side effects of pharmaceuticals.
Importance of herbal therapies
Herbal medicines are prepared from a variety of plant material such as leaves, stems, roots, bark, etc. They usually contain many biologically active ingredients and are used primarily for treating mild or chronic ailments.
Herbal remedies can also be purchased in the form of pills, capsules or powders, or in more concentrated liquid forms called extracts and tinctures. They can apply topically in creams or ointments, soaked into cloths and used as compresses, or applied directly to the skin as poultices. (www.herbalplace.com).
Plants are considered to be medicinal if they possess pharmacological activities of possible therapeutic use. These activities are often known as a result of millennia of trial and error, but they have to carefully investigate if we wish to develop new drugs that meet the criteria of modern treatment.
The identification of the active principles of medicinal plants, and investigation of the extracts in order to ensure that they are safe, effective, and of constant activity. The isolation these active principles and determination of their structure, in order that they may be synthesized, structurally modified, or simply extracted more efficiently.
Prospects of Herbal Research
There is a worldwide 'green revolution, (Mukherjee, P.K., 2002) which is reflected in the belief that herbal remedies are safer and less damaging to the human body than synthetic drugs. Furthermore, underlying this upsurge of interest in plants is the fact that many important drugs in use today were derived from plants or from starting molecules of plant origin.
Indian medicinal herbs in diabetic disorder:
In developing countries like India where poverty and malnutrition is rampant, knowledge of plant derived antioxidants could reduce the cost of health care. India has rich history of using various herbs and herbal components for the treating various disease. Many Indian plants have been investigated for their beneficial use as antioxidants or source of antioxidants using presently available experimental techniques. (K.R Kiritkar & B.D. Basu et al, 2004)
In modern medicine, the beneficial effects on hypoglycemic levels are well documented; the preventing activity of these drugs against progressive nature of diabetes and its micro- and macro vascular complications was modest and always effective. The insulin therapy affords effective glycemic control, yet its short comings such as ineffectiveness on oral administration, short self life, requirement of constant refrigeration, and in the event of excess dosages-fatal hypoglycemia limits its usage. Treatment with sulfonylurea's and biguanids is also associated with side effects. For the various reasons in recent years, the popularity of complementary medicine has increased. Dietary measures and traditional plant therapies as prescribed by Ayurvedic and other indigenous system of medicine were used commonly in India. (Upadhaya, V.P et al., 1984) Surveys conducted in Australia and US indicate that almost 48.5 and 34% respondents had used at least one form of unconventional therapy including herbal medicine. (Oliver and Zahnd, 1979). WHO (1980) has also recommended the evaluation of plants effective and in conditions where we lack safe modern drugs. Since time immemorial, patients with diabetes mellitus have been treated orally by folklore with a variety of plant extracts. In the indigenous system of medicine (Ayurveda), a mention was made on good number of plants for the cure of diabetes mellitus or 'Madhumeha' and some of them have been experimentally evaluated and the active principles were isolated. However, search for newer Antidiabetic drug continues.
INTRODUCTION TO DIABETES MELLITUS
Diabetes mellitus was known to ancient Indian physicians as 'Madhumeha'. Many herbal products including several metals and minerals have been described for the care of diabetes mellitus in ancient literature. (The wealth of India, 2005) Ayurveda has been first to give an elaborate description of this disease, its clinical features and patterns and its management by herbal or herb mineral drugs. Plant drugs are frequently considered to be less toxic and free from side effects than synthetic ones.
Although many drugs are available to manage diabetes, in most instances these are expensive for a developing country like India and they may also have adverse effects, e.g. Hypoglycemia, Obesity. On the other hand, India is country with a vast reserve of natural resources and rich history of traditional medicine. More than 400 plants with glucose-lowering effect are known.
Many herbal medicines as single agents or in different oral formulations have been recommended for diabetes mellitus due to the fact that they are less toxic than oral hypoglycemic agents such as sulfonylurea, metformin etc.
Anatomy of pancreas
The Pancreas is pale grey gland weighing about 60 gm. It is about 12 to 15 cm long and is situated in the epigastric and left hypochondriac regions of the abdominal cavity. (Anne Waugh and Allison Grant,2006).
It consists of broad head, a body and narrow tail. The head lies in the curve of the duodenum, the body behind the stomach and tail lies in front of left kidney and just reaches the spleen.
Histology of Pancreas:
The Pancreas is mixture of exocrine and endocrine tissue. The predominant exocrine part consists of grape like clusters of secretory cells that form sacs known as acini, which connect to ducts that eventually empty in to duodenum. The smaller endocrine part consists of isolated island of endocrine tissue, the islet of Langerhans, which are dispersed throughout the pancreas. The most important hormones secreted by the islet cells are insulin and glucagon.
Composition and function of pancreatic juice:
Each day the pancreas produces 1200-1500ml (about 1.2-1.5qt) of pancreatic juice, which is clear, colorless liquid consisting mostly of water, some salts, sodium bicarbonate and several enzymes. The sodium bicarbonate gives alkaline pH (7.1-8.2) that buffers acidic gastric juicing chime, stops the action of digestive enzyme in small intestine. The enzyme in pancreatic juice include a carbohydrate digesting enzyme called pancreatic amylase; several proteins digestive enzyme called trypsin, chymotrypsin, carboxypeptidase and elastase; the principle triglyceride-digesting lipase; and nucleic acid-digesting enzyme called ribonuclease and deoxyribonuclease.
ÂInsulin and regulation of insulin secretion:
Insulin was the first hormone identified (late1920's) by a doctor and medical student who discovered and won the Nobel Prize (Banting and Best). Insulin is the main hormone controlling intermediary metabolism. Its obvious acute effect is to lower blood glucose. Reduced (or absent) secretion of insulin, often coupled with reduced sensitivity to its action (insulin resistance) causes diabetes mellitus. Insulin was the first protein for which an amino acid sequence was determined. (Bertram G Katzung 6th edn, 1995).It consists of two peptide chains (A and B, of 21 and 30 amino acid residues, respectively). The islets of Langerhans contain mainly four cell types: B (or Î²) cells secrete insulin, A-cell secretes glucagon, D-cell secretes somatostatin and PP-cell secretes pancreatic polypeptide. Insulin is synthesized as precursor (proinsulin) in rough endoplasmic reticulum is transported to the Golgi apparatus where it undergoes proteolytic cleavage first to proinsulin and then to insulin and c-peptide are stored in granules in Î²-cells.
Regulation of Insulin secretion:
Insulin, synthesized from proinsulin in Î²-cells of islets of Langerhans is stored in secretary granules, which are released in to circulation by exocytosis. This insulin release is promoted by a vagal stimulation, glucose, amino acid, fatty acid and ketone bodies. Orally administered glucose induce more stimulation of insulin release than intravenously administered glucose, because orally administered glucose stimulate the production of gut digestive hormone like secretin, gastrin and pancreozymin, which stimulate insulin secretion. Islet Î²-receptor also modulates insulin secretion. Thus, Î²-adrenergic agonists, like adrenaline, increase insulin secretion by increasing intra cellular cAMP. Adrenergic Î±-receptors attenuate insulin release.
Insulin circulates in blood and lymph in the free state and is degraded by hepatic and renal proteolytic enzyme. About 40% of the daily out put of insulin is destroyed and only a fraction is excreted uncharged in urine.
Figure: 1. Mechanism of insulin release in normal pancreatic Î²-cells.
Diabetes mellitus often referred to simply as diabetes (Ancient Greek: "to pass through [urine]"), is a syndrome of disordered metabolism (Joseph T.DiPiro et al, 6th Edn) usually due to a combination of hereditary and environmental causes, resulting in abnormally high blood sugar levels (hyperglycemia).
Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or alternatively, when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels.
The World Health Organization (WHO) estimates that more than 180 million
people worldwide have diabetes. This number is likely to more than double by 2030.
In 2005, an estimated 1.1 million people died from diabetes.
Almost 80% of diabetes deaths occur in low and middle-income countries.
Almost half of diabetes deaths occur in people under the age of 70 years; 55% of diabetes deaths are in women.
WHO projects that diabetes death will increase by more than 50% in the next 10 years without urgent action. Most notably, diabetes deaths are projected to increase by over 80% in upper-middle income countries between 2006 and 2015.
Diabetes is a disease that affects how the body uses glucose, the main type of sugar in the blood. Glucose comes from the foods we eat and is the major source of energy needed to fuel the body's functions.
Insulin works like a key that opens the doors to cells and allows the glucose in. Without insulin, glucose can't get into the cells (the doors are "locked" and there is no key) and so it stays in the bloodstream. As a result, the level of sugar in the blood remains higher than normal. High blood sugar levels are a problem because they can cause a number of health problems.
Diabetes and its treatments can cause many complications. Acute complications (hypoglycemia, ketoacidosis, or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications (i.e., chronic side effects) include cardiovascular disease (doubled risk), chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and micro vascular damage, which may cause impotence and poor wound healing. Poor healing of wounds, particularly of the feet, can lead to gangrene, and possibly to amputation. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as not smoking and maintaining a healthy body weight), may improve the risk profile of most of the chronic complications. In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly and the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis in the United States.
The principal two idiopathic forms of diabetes mellitus are known as type 1 and 2. The term "typeÂ 1 diabetes" has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus (IDDM).( Tripathi KD, 2002). Likewise, the term "typeÂ 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined "type 3 diabetes" as, among others, gestational diabetes, insulin-resistant typeÂ 1 diabetes (or "double diabetes"), typeÂ 2 diabetes which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "typeÂ 1.5" diabetes).
Type 1 diabetes:
Type 1 diabetes results when the pancreas loses its ability to produce the hormone insulin. In type 1 diabetes, the person's own immune system attacks and destroys the cells in the pancreas that produce insulin. Once those cells are destroyed, they won't ever produce insulin again. Although no one knows for certain why this happens, scientists think it has something to do with genes. But just getting the genes for diabetes isn't usually enough. A person probably would have to be exposed to something else - like mumps virus - to get type 1 diabetes. Once a person has type 1 diabetes, it does not go away The main cause of this beta cell loss is a T-cell mediated autoimmune attack (Bertram G Katzung 6th edn, 1995). There is no known preventive measure which can be taken against typeÂ 1 diabetes. The average glucose level for the typeÂ 1 patient should be as close to normal (80-120Â mg/dl, 4-6Â mmol/l) as is safely possible. Some physicians suggest up to 140-150Â mg/dl (7-7.5Â mmol/l) for those having trouble with lower values, such as frequent hypoglycemic events. Values above 400Â mg/dl (20Â mmol/l) are sometimes accompanied by discomfort and frequent urination leading to dehydration. Values above 600Â mg/dl (30Â mmol/l) usually require medical treatment and may lead to ketoacidosis, although they are not immediately life-threatening.
Type 2 diabetes:
Type 2 diabetes is different from type 1 diabetes. Type 2 diabetes results from the body's inability to respond to insulin normally. Unlike people with type 1 diabetes, most people with type 2 diabetes can still produce insulin, but not enough to meet their body's needs. Glucose is less able to enter the cells and do its job of supplying energy. This causes the blood sugar level to rise, making the pancreas produce even more insulin.In the early stage the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver. As the disease progresses the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary. There are numerous theories as to the exact cause and mechanism in typeÂ 2 diabetes. Central obesity (fat concentrated around the waist in relation to abdominal organs, but not subcutaneous fat) is known to predispose individuals for insulin resistance. Abdominal fat is especially active hormonally, secreting a group of hormones called adipokines that may possibly impair glucose tolerance. Obesity is found in approximately 55% of patients diagnosed with typeÂ 2 diabetes. Other factors include aging (about 20% of elderly patients in North America have diabetes) and family history (typeÂ 2 is much more common in those with close relatives who have had it).
Gestational diabetes mellitus (GDM) resembles typeÂ 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2%-5% of all pregnancies and may improve or disappear after delivery (Joseph T.DiPiro et al, 6th Edn). Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%-50% of affected women develop typeÂ 2 diabetes later in life.Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respirator distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, prenatal death may occur, most commonly as a result of poor placental profusion due to vascular impairment. Induction may be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystopia.
A 2008 study completed in the U.S. found that more American women are entering pregnancy with preexisting diabetes. In fact the rate of diabetes in expectant mothers has more than doubled in the past 6 years.
There are several rare causes of diabetes mellitus that do not fit into typeÂ 1, typeÂ 2, or gestational diabetes; attempts to classify them remain controversial. Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from typeÂ 2 diabetes); this form is very uncommon. Genetic mutations (Autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). (Bertram G Katzung 6th edn, 1995). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999.
COMMON CONSEQUUENCES OF DIABETES:
Over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves.
Diabetic retinopathy is an important cause of blindness, and occurs as a result of long-term accumulated damage to the small blood vessels in the retina. After 15 years of diabetes, approximately 2% of people become blind, and about 10% develop severe visual impairment.
Diabetic neuropathy is damage to the nerves as a result of diabetes, and affects up to 50% of people with diabetes. Although many different problems can occur as a result of diabetic neuropathy, common symptoms are tingling, pain, numbness, or weakness in the feet and hands.
Combined with reduced blood flow, neuropathy in the feet increases the chance of foot ulcers and eventual limb amputation
Diabetes is among the leading causes of kidney failure. 10-20% of people with diabetes die of kidney failure.
Diabetes increases the risk of heart disease and stroke. 50% of people with diabetes die of cardiovascular disease (primarily heart disease and stroke).
The overall risk of dying among people with diabetes is at least double the risk of their peers without diabetes.
TREATMENT AND MANAGEMENT:
The principal treatment of typeÂ 1 diabetes, even from its earliest stages, is replacement of insulin combined with careful monitoring of blood glucose levels using blood testing monitors. Without insulin, diabetic ketoacidosis often develops which may result in coma or death. Treatment emphasis is now also placed on lifestyle adjustments (diet and exercise) though these cannot reverse the progress of the disease. Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels, and the ability to program doses (a bolus) of insulin as needed at meal times. An inhaled form of insulin, Exubera, was approved by the FDA in January 2006, although Pfizer discontinued the product for business reasons in October 2007. TypeÂ 2 diabetes is usually first treated by increasing physical activity, decreasing carbohydrate intake, and losing weight. These can restore insulin sensitivity even when the weight loss is modest, for example around 5Â kg (10 to 15Â lb), most especially when it is in abdominal fat deposits. It is sometimes possible to achieve long-term, satisfactory glucose control with these measures alone. However, the underlying tendency to insulin resistance is not lost, and so attention to diet, exercise, and weight loss must continue. The usual next step, if necessary, is treatment with oral antidiabetic drugs. Insulin production is initially only moderately impaired in typeÂ 2 diabetes, so oral medication (often used in various combinations) can be used to improve insulin production (e.g., sulphonylurea's), to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g., metformin), and to substantially attenuate insulin resistance (e.g., Thizolidinediones). According to one study, overweight patients treated with metformin compared with diet alone, had relative risk reductions of 32% for any diabetes endpoint, 42% for diabetes related death and 36% for all cause mortality and stroke.
DIABETES AND OXIDATIVE STRESS:
It is accepted that oxidative stress result from an imbalance between the generations of oxygen derived radicals and the organism's antioxidant potential. Various studies have shown that diabetes mellitus is associated with increased formation of free radicals and decrease in antioxidant potential. Due to these events, the balance normally present in cells between radical formation and protection against them is disturbed. This leads to oxidative damage of cell components such as proteins, lipids, and nucleic acid. In both insulin dependent (type1) and non-insulin-dependent diabetes (type2) there is increased oxidative stress.Increased oxidative stress as measured by indices of lipid peroxidation and protein oxidation has been shown to be increased in both IDDM and NIDDM, even in patient without complications. Increased oxidized low density lipoprotein (LDL) or susceptibility to oxidation has also been shown in diabetes.The mechanisms behind the apparent increased oxidative stress in diabetes are not entirely clear. Accumulating evidence point to a number of interrelated mechanisms, increasing production of free radicals such as superoxide or decreasing antioxidant status. These mechanisms include glycoxidation and formation of advanced glycation products, activation of polyol pathway and altered cell26 and Glutathione redox state and ascorbate metabolism antioxidant enzyme inactivation and perturbation in nitric oxide and prostaglandin metabolism. (Bertram G Katzung, 1995)
Figure: 2. Mechanisms for increased oxidative stress in diabetes mellitus. ROS; reactive oxygen species, GSH; reduced glutathione, GSSG; oxidized glutathione, GRD; glutathione reductase, GPX; glutathione peroxidase, AR; aldose reductase.
Oxygen free radicals:
Free radicals are highly reactive atoms or molecules with an unpaired electron in their outer orbits. The production of free radicals occurs either by the addition or by the removal of an electron in a reduction/Oxidation reaction. Since oxygen has two electrons with parallel spin in its outermost shell, it is characterized as a biradical which requires four electrons to be completely reduced to water. Oxygen is also the terminal acceptor of electrons for oxidative phosphorylation and this tetravalent reduction is associated with the production of high energy phosphates (Fig.). However, sequential univalent reduction results in the formation of reactive oxygen intermediates. In the univalent reduction pathway, the addition of a single electron to molecular oxygen results in the production of superoxide anion radical (O2) the addition of another electron to the O2 results in the formation of peroxide anion which protonates to form hydrogen peroxide (H2O2). The latter is not a radical, but is capable of causing cell damage by interacting with transition metals such as iron. A single electron reduction of H2O2 results in the formation of the hydroxyl radical (OH-) which is highly reactive, has an extremely short half-life, and therefore has a very limited diffusion capacity. The addition of a fourth electron finally results in the formation of water. The first excited state of O2 is a singlet oxygen (O2) which can also initiate oxygen radical chain reactions. This univalent electron reduction reaction is illustrated in figure 1. Reactive oxygen intermediates such as O2, H2O2, OH- and O2 are called activated oxygen species and are collectively known as partially reduced forms of oxygen (PRFO). Superoxide radical reacts with nitric oxide during reperfusion to form peroxynitrite which also has a harmful effect by opposing the vasodilator effect of nitric oxide. These reactive species can interact with macromolecules and initiate free radical chain reactions resulting in membrane and cell damage.
Figure: 3. A diagrammatic representation of the production of oxygen free radicals by univalent reduction pathway. Different antioxidants (enzymatic and non-enzymatic) in the biological system may offer protection against free radical-induced injury.
FREE RADICAL MEDIATED CELL INJURY:
The targets of free radical attack are the cell membranes and sub cellular organelles. The lipid peroxidation chain reaction is initiated by the removal of a hydrogen atom from the unsaturated site in a fatty acid resulting in the production of a lipid radical.
This radical can further react with other neighboring polyunsaturated fatty acids (PUFA) to propagate the reaction. The addition of an oxygen molecule to these lipid radicals results in the formation of lipid peroxides. Free radical-induced lipid peroxidation has been suggested to alter membrane structure and function. Considerable evidence also suggests that PRFO can modify protein structure and function ultimately affecting cell metabolism. In this regard, proteins rich in sulphydryl groups are highly susceptible to free radical attack. In the myocardium, oxygen radicals have been shown to affect Na1/Ca11 exchange, Na1-K1 ATPase and Ca11 ATPase activities. Free radicals can also attack the nucleic acids by producing base damage, single strand breaks, adducts and chromosomal aberrations. Such modifications have been shown to cause cellular abnormalities such as mutations and cell death.
Evidence is available to suggest the role of increased oxidative stress and depressed antioxidant enzyme activities in the pathogenesis of diabetic cardiomyopathy. A decrease in myocardial SOD and catalase activity and an increase in oxidative stress have been demonstrated in STZ-induced diabetic rat. Furthermore, probucol treatment in these rats resulted in improved cardiac function. Similarly, some other studies reported reduced oxidative stress upon vitamin E supplementation in animals and patients.
Hyperglycemic, as a common end point for all type of diabetes mellitus, is followed by micro- and macro vascular complications leading to cardiovascular disease (CVD), neuropathy, retinopathy and nephropathy. Vascular complications are the most common reason of morbidity and mortality in diabetic patient.
Hyperglycemia has been found to increase production of ROS such as superoxide anion (O2.-) and hydrogen peroxide (H2O2) which reduce NO bioavailability in cultured endothelial cells and in vascular tissue. Impaired release and/or bioavailability may result in endothelial dysfunction, a well-documented phenomenon in diabetes which is attributed to decreased vasorelaxant and increased contractile response to physiological and pharmacological stimuli. Use of antioxidant may provide therapeutic benefits in diabetes related endothelial dysfunction as well as in oxidative damage to pancreatic cells.
CHEMICALS USED TO INDUCE DIABETES:
Alloxan (2, 4, 5, 6-tetraoxypyrimidine; 5, 6-dioxyuracil) diabetes has been commonly utilized as an animal model of insulin dependent diabetes mellitus (IDDM). Alloxan exerts its diabetogenic action when it is administered parenterally, intravenously, intraperitonially or subcutaneously. The dose of alloxan required for inducing diabetes depends on the animal species, route of administration and nutritional status. Human islets considerably more resistant to alloxan than those of the rat and mouse. The most frequently used intravenous dose of this drug to induce diabetes in rats is 65 mg/kg body weight. When alloxan is given intraperitonially or subcutaneously its effective dose must be 2-3 times higher. The intraperitoneal dose below 150 mg/kg body weight may be insufficient for inducing diabetes in the rat. Fasted animals are more susceptible to alloxan, where as increased blood glucose provides partial protection. Alloxan-induced insulin release is however, short duration and is followed by complete suppression of the islet response to glucose, even when high concentrations (16.6 mM) of this sugar were used.
Alloxan is a hydrophilic and unstable substance and its half-life at neutral pH and 37 Â°C is about 1.5 min and is longer at lower temperatures. On the other hand, when diabetogenic dose is used, the time of alloxan decomposition is sufficient to allow it to reach the pancreas in amounts that are deleterious.
The action of alloxan in the pancreas is preceded by its rapid uptake by Î²- cells. Another aspect concerns the formation of reactive oxygen species. However, the liver and other tissues are more resistant to reactive oxygen species in comparison to pancreatic Î²- cells and this resistance protects against alloxan toxicity.
Figure: 4. Mechanism of action of alloxan on Î² cells of rat pancreas
The formation of ROS is preceded by alloxan reduction. In Î² -cells of the pancreas its reduction occurs in the presence of different reducing agents. Since alloxan exhibits a high affinity to the SH- containing cellular compounds, reduced glutathione (GSH), cysteine and protein-bound sulfahydryl groups (including SH-containing enzymes) are very susceptible to its action. Dialuric acid is formed as a result of alloxan reduction. It is then re-oxidized back to alloxan establishing a redox cycle for the generation of superoxide radicals. Superoxide radicals are able to liberate ferric ions from ferritin and reduce them to ferrous ions. Moreover, superoxide radicals undergo dismutation to hydrogen peroxide (Zhang et al., 1992).
O2Ë™- + O2Ë™- + 2H+ H2O2 + O2
This reaction may occur spontaneously or may be catalyzed by superoxide dismutase. In the presence of Fe2+ and hydrogen peroxide,
Highly reactive hydroxyl radicals are then formed according to the Fenton reaction.
Fe2+ + H2O2 Fe3+ + OH- + OH.-
One of the targets of the reactive oxygen species is DNA of pancreatic islets. Its fragmentation takes place in Î² cells exposed to Alloxan. (Takasu, 1991)
â€¢ Streptozotocin (STZ):
Streptozotocin (STZ, 2-deoxy-2-(3-(methyl-3-nitrosoureido)-glucopyranose) is synthesized from Streptomycetes achromogenes and is used to induce both insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM and NIDDM). The dose of STZ is not narrow as in the case of alloxan. The frequently used single intravenous dose in adult rats to induce IDDM is between 40 and 60 mg/kg body weight, but higher doses are also used. STZ is also efficacious after intraperitoneal administration of a similar or higher dose, but single dose below 40 mg/kg body weight may be ineffective. NIDDM can easily be induced in rats by intravenous or intraperitoneal treatment with 100 mg/kg b.w. STZ on the day of birth.
Streptozotocin action in Î²-cells is accompanied by characteristic alterations in the blood insulin and glucose concentrations. Two hours after injection, the hyperglycemia is observed with concomitant drop in blood insulin. About 6 h later, hypoglycemia occurs with high levels of insulin. Finally, hyperglycemia develops and blood insulin levels decrease. The changes in blood glucose and insulin concentrations reflect abnormalities in Î²-cell function. STZ impairs glucose oxidation and decreases insulin biosynthesis and secretion. It was observed that STZ at first abolished the Î²-cell response to glucose which is followed by its permanent loss and cells are damaged. STZ is taken up by pancreatic Î²- cells via glucose transporter GLUT2. A reduced expression of GLUT2 has been found to prevent the diabetogenic action of STZ. Intracellular action of STZ results in changes of DNA pancreatic Î²-cells fragmentation. The main reason for the STZ-induced Î²- cell death is due to alkylation of DNA.
STZ is a nitric oxide (NO) donor and NO was found to bring about the destruction of pancreatic islet cells; it was proposed that this molecule contributes to STZ-induced DNA damage. STZ was found to generate ROS, which also contribute to DNA fragmentation and evoke other deleterious changes in the cells. The formation of superoxide anions results from both STZ action on mitochondria and increased activity of xanthenes oxidase.
STZ inhibits the Krebs cycle and substantially decrease oxygen consumption by mitochondria. These effects strongly limit mitochondrial ATP production and cause depletion of this nucleotide in Î²- cells. STZ-induced DNA damage activates poly ADP - ribosylation.
This process leads to depletion of cellular NAD+, further reduction of the ATP content and subsequent inhibition of insulin synthesis.
INTRODUCTION TO WOUND HEALING
Wound may be defined as disruption of anatomic/functional continuity of living tissue; the causative factors for wound may be physical, chemical thermal and electrical (Schilling, JA, 1968). As a consequence, the affected tissue triggers responses that culminate in restoration of damaged living tissue. The restoration process of disruptive tissues leads to wound healing (Howes EL et al.,1939).
Wounds are inescapable events in life. The four phases of normal wound healing include Haemostasis, Inflammation, Proliferation and Remodeling. Wound healing processes are well organized biochemi-cal and cellular events leading to the growth and regeneration of wounded tissue in a special manner. Healing of wounds involves the activity of an intricate net work of blood cells, cytokines and growth factors which ultimately leads to the restoration to normal condition of the injured skin or tissue (Clark, 1991). Despite the considerable progress in the treatment of wound by external synthetic or herbal formulations, search for new drug continues due to associated disadvantages of synthetic drugs.
Destroyed or injured tissues must be repaired by regeneration of the cells or the formation of scar tissue. The goal of both types of repair is to fill in the areas of damage in order to return structural integrity to the tissue.Tissue regeneration and scar formation begin with inflammatory reactions . Platelets control bleeding and white blood cells digest and remove dead tissue in the area. Growth factors and immune peptides (cytokines) are released that draw healing cells to the area. Other factors are produced to stimulate mitosis or scar tissue formation.
Types of Wound Repair
Tissues that heal cleanly and quickly are said to heal by primary intention. Large wounds that heal slowly and with a great deal of scar tissue heal by secondary intention.
Delayed Healing and Repair
Tissue repair can be delayed if the host is compromised in any way by malnutrition, systemic disease, or a poorly functioning immune system. Healing can also be poor or delayed if there is reduced blood flow to the injured tissue or if an infection develops.
CONDITIONS OF INJURY
Hypoxia is the decreased concentration of oxygen in the tissues. The concentration of oxygen in the tissues reflects the concentration of oxygen in the blood, which depends on the amount of oxygen brought in by the lungs and the amount carried in the blood, either dissolved or bound to hemoglobin. Decreased oxygen in the blood is called hypoxemia.
Too hot or too cold temperatures may injure or kill cells. Exposure to very high temperatures can cause burn injuries, which directly kill cells or indirectly injure or kill cells by causing coagulation of blood vessels or the breakdown of cell membranes. Exposure to very cold temperatures injures cells in two ways. First, cold exposure causes constriction of the blood vessels that deliver nutrients and oxygen to the extremities. This constriction occurs as the body attempts to preserve its core (central) temperature, initially at the expense of the fingers, toes, ears, and nose. Decreased blood flow causes cellular and tissue ischemia. Sluggish blood flow also increases the risk of clot formation, which further blocks tissue oxygenation. The second effect of exposure to very cold temperature is the formation of ice crystals in the cells. These crystals directly damage the cells and can lead to cell lysis (bursting). Prolonged exposure to the cold can lead to hypothermia.
Radiation is the transmission of energy through the emission of rays or waves. Radiation energy may be in the visible range of light, or it may be higher or lower energy than visible light. High-energy radiation (including ultraviolet radiation) is called ionizing radiation because it has the capability of knocking electrons off atoms or molecules, thereby ionizing them. Low-energy radiation is called non-ionizing radiation because it cannot displace electrons off atoms or molecules.
Injury caused by microorganisms
Microorganisms infectious to humans include bacteria, viruses, mycoplasmas, rickettsiae, chlamydiae, fungi, and protozoa. Some of these organisms infect humans through direct access, such as inhalation, whereas others infect through transmission by an intermediate vector, such as from an insect bite. Cells of the body may be destroyed directly by the microorganism or by a toxin released from the microorganism, or may be indirectly injured as a result of the immune and inflammatory reactions stimulated in response to the microorganism . In addition, as described earlier, infection of a cell by a microorganism may so destabilize the cell that it undergoes apoptosis.
INTRODUCTION TO INFLAMMATION
The inflammatory process is the response to an injurious stimulus. It can be evoked by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries). The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. No matter what the initiating stimulus, the classic inflammatory response includes calor (warmth), dolor (pain), rubor (redness), and tumor (swelling).
Inflammatory responses occur in three distinct temporal phases, each apparently mediated by different mechanisms: (1) an acute phase, characterized by transient local vasodilation and increased capillary permeability; (2) a delayed, subacute phase characterized by infiltration of leukocytes and phagocytic cells; and (3) a chronic proliferative phase, in which tissue degeneration and fibrosis occur.
Most currently available traditional NSAIDs (tNSAIDs) act by inhibiting the prostaglandin G/H synthase enzymes, colloquially known as the cyclooxygenases. The inhibition of cyclooxygenase-2 (COX-2) is thought to mediate, in large part, the antipyretic, analgesic, and antiinflammatory actions of tNSAIDs, while the simultaneous inhibition of cyclooxygenase-1 (COX-1) largely but not exclusively accounts for unwanted adverse effects in the gastrointestinal tract. Selective inhibitors of COX-2 are a subclass of NSAIDs that are also discussed. Aspirin, which irreversibly acetylates cyclooxygenase, is discussed, along with several structural subclasses of tNSAIDs, including propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin), and enolic acids (piroxicam), all of which compete in a reversible manner with the arachidonic acid (AA) substrate at the active site of COX-1 and COX-2. Acetaminophen is a very weak antiinflammatory drug; it is effective as an antipyretic and analgesic agent at typical doses that partly inhibit COXs, but appears to have fewer gastrointestinal side effects than the tNSAIDs.
INTRODUCTION TO HELMINTHIASIS
Helminthes infections are commonly found in community and being recog-nized as cause of much acute as well as chronic illness among the various human beings as well as cattle's. More than half of the population of the world suffers from various types of infection and majority of cattle's suffers from worm infections (Chaturvedi et al., 2009). Intestinal infections with worms can more easily treated than those the infections occurs in other loca-tions in the body, because the worms need to be killed by the drug and the drug need not be absorbed when given by oral route. Because of increasing anthel-mintic resistance and impact of conventional anthel-mintic on the environment, it is important to look for alternative strategies against gastrointestinal nema-todes. Use of herbs could be one of the major options to control these pathologies.
Antihelminthics are those agents that expel parasitic worms (helminthes) from the body, by either stunning or killing them.
The current anthelmintic therapies act by incapacitating the parasite by paralysis (e.g. by preventing muscular contraction), damaging the worm such that the immune system can eliminate it, or by altering its metabolic processes (e.g. by affecting microtubule function). Because the metabolic requirements of these parasites vary greatly from one species to another, drugs that are highly effective against one type of worm may be ineffective against others. Clearly, to be an effective anthelmintic, a drug must be able to penetrate the tough exterior cuticle of the worm or gain access to its alimentary tract in sufficient concentrations to be effective. This in itself may present difficulties, because some worms are exclusively haemophagous (blood eating), while others are best described as 'tissue grazers'. A further complication is that many helminths contain active drug efflux pumps that reduce the concentration of the drug in the parasite. The route and dose of anthelmintic are therefore important and must be chosen carefully, because parasitic worms cannot be relied on to consume sufficient amounts of the drug to be effective. Benzimidazoles, Praziquantel, Piperazine and Niclosamide are found to be effective anthelmintic drugs.