Mayuresh S. Garud

Hyperglycemia to Nephropathy via Transforming Growth Factor Beta

Nephropathy is one of the major complications of diabetes which further directs to end stage renal disease. Extensive work has been done to find out the mechanisms involved in pathogenesis of the DN. Now, many researchers have been convinced that almost all of the molecular mediators and intracellular signaling pathways involved in progression of diabetic nephropathy have involvement in transforming growth factor beta (TGF- β) at some stage. In DN, hyperglycemia causes increase in the expression of TGF- β genes, TGF- β proteins and their receptors. Increased glucose level mediates these effects through activation of polyol pathway, protein kinase C pathway, hexosamine pathway, increases advanced glycation end products (AGE) and increases oxidative stress. Hyperglycemia also activates the TGF- β via activation of glucose transporters (GLUT), angiotensine II and platelet derived growth factor (PDGF). Activated TGF-β further leads to glomerular basement membrane (GBM) thickening and glomerulosclerosis through activation of connective tissue growth factor (CDGF) and vascular endothelial growth factor (VEGF). We have discussed the progression of hyperglycemia to DN via TGF- β, whose schematic presentation may serve as an effective way to understand the mechanisms and to find out an effective way for the management of diabetic nephropathy.

Gallic acid attenuates type I diabetic nephropathy in rats

Literature suggests that TGF-β1 has a central role in the progression of diabetic nephropathy and its down regulation can improve the disease condition. Oxidative stress, generation of advanced glycation end products and activation of renin angiotensin system are the connecting links between hyperglycemia and TGF-β1 over expression. Gallic acid is a phytochemical having wide range of biological activities. Gallic acid is reported to have antioxidant and advanced glycation inhibitory activity. It has also shown inhibitory effects on angiotensin converting enzyme. Gallic acid qualifies as a drug candidate to be tested in the diabetic nephropathy, one of the important complication of diabetes. Streptozotocin (55 mg/kg body weight, i.p.) induced diabetic nephropathy was used as an experimental model. Gallic acid was evaluated for its possible effect at the dose of 20 and 40 mg/kg body weight. Gallic acid treatment significantly lowered plasma levels of the creatinine and blood urea nitrogen and elevated the levels of the protein and albumin. Gallic acid also improved creatinine clearance. Determination of oxidative stress parameters showed that the oxidative stress in kidney tissues was reduced significantly in gallic acid treated animals. Results of the plasma, urine and oxidative stress parameters were also reflected in the histopathological evaluation showing improvement in kidney pathophysiology. ELISA assay for circulating TGF-β1 evaluation and immunohistochemical study for determination of kidney expression of TGF-β1 revealed that gallic acid significantly lowered both the circulating and tissue levels of TGF-β1. Results support the hypothesis that gallic acid can be effectively used in the treatment of diabetic nephropathy.

Bauhinia variegata (Caesalpiniaceae) leaf extract: An effective treatment option in type I and type II diabetes.

Among various metabolic disorders, diabetes mellitus is one of the most common disorder. Present study was designed to evaluate the effectiveness of aqueous extract of Bauhinia variegata leaves (AE) in animal models of type I and type II diabetes. Type I diabetes was induced by streptozotocin at the dose of 55mg/kg (i.p.) in male Sprague Dawley rats while type II diabetes was induced by high fat diet and streptozotocin at the dose of 35mg/kg (i.p.). Diabetic animals were treated with AE at the dose of 250, 500 and 1000mg/kg. Glipizide (5mg/kg) was used as standard treatment drug. Treatment was given for 28days. Parameters evaluated were body weight, plasma glucose, cholesterol, triglyceride, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, total proteins, albumin, creatinine and bun urea nitrogen. In type II diabetes, high density lipoprotein levels in plasma and plasma insulin level were also evaluated. Histopathological study of pancreases were carried out in type I study. AE showed significant decrease in plasma glucose significantly. AE was also found to decrease cholesterol, triglyceride, creatinine and blood urea nitrogen level in both types of diabetes. AE did not show any significant effect on plasma levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase. AE was found to increase the albumin and total protein levels. Histopathological study showed that AE decreases the necrotic changes in the pancreatic tissue. Aqueous extract of B. variegata leaves was found effective in treatment of both type I and type II diabetes.

Diabetes, diabetic complications, and flavonoids

Abstract Diabetes mellitus is among the most prevalent diseases with which a large population of world is suffering from. Incidence of diabetes is on rise all over the world. Hence management of diabetes and related complications is of prime importance. Finding of new drugs and betterment of current therapeutic regimen is necessary to achieve the target of decreasing the mortalities and morbidities related with the diabetes and its complications. Plants have served as a great source of medicines for variety of diseases and aliments including diabetes and its complications. Various groups of phytochemicals derived from plant are identified and reported to have antidiabetic activity along with having potential to treat complications of it. In this chapter we have discussed flavonoid and its different subclasses in context with their antidiabetic activity along with their potential in management and treatment of diabetic complications.

Effect of Jyotishmati (Celastrus paniculatus) seeds in animal models of pain and inflammation

Background: Jyotishmati, scientifically known as Celastrus paniculatus Wild (Celastraceae) is one of the most important medicinal plants in Ayurveda. The plant has shown significant pharmacological activities like anti-arthritic, wound healing, hypolipidemic, and antioxidant. Objective: To study possible effects of alcoholic extract of Celastrus paniculatus seeds (AlcE) in experimentally induced pain and inflammation in mice. Materials and Methods: The antinociceptive activity was evaluated in Swiss albino mice by tail immersion, hot plate, and acetic-acid-induced writhing tests at doses of 250, 500, and 1,000 mg/kg. Anti-inflammatory activity was evaluated in model of carrageenan-induced acute plantar inflammation in Wistar rats. Results: In tail immersion test, AlcE showed significant (P < 0.05) increase in tail withdrawal response at dose of 250 mg/kg with maximum possible effect of 15.71%. The maximum possible effect of 23.32% and 30.16% (P < 0.001) was seen at dose of 500 and 1000 mg/kg at 3 hours after administration of extract, respectively. In hot plate test, increase in paw licking time was reported at dose of 500 and 1000 mg/kg. AlcE (1,000 mg/kg) showed maximum response (6.23 ± 0.46) when compared with control (3.20 ± 0.18) at 90 min. In acetic acid induced writhings, AlcE at dose of 250, 500, and 1,000 mg/kg body weight showed 32.35%, 49.01%, and 58.82% inhibition in writhings, respectively. AlcE treated animals (500 and 1,000 mg/kg) showed significant decrease in paw edema at 3 hours and 4 hours, when compared with control animals. Conclusion: Jyotishmati seed extract possesses significant antinociceptive and anti-inflammatory activity.

Attenuation of Renal Damage in Type I diabetic Rats by Umbelliferone- a Coumarin Derivative

BACKGROUND It is well known that diabetes is one of the non-communicable disease affecting a large population worldwide. When diabetes remains untreated or uncontrolled, it leads to further serious complications, affecting vital organs like eyes, kidney, heart, etc. The present study was designed to evaluate effects of umbelliferone, a phytochemical, in treatment of diabetic nephropathy. METHODS Experimental model used was streptozotocin (55mg/kg, ip) induced diabetic nephropathy in male Sprague Dawley rats. After 28days of streptozotocin administration, diabetic animals were treated with umbelliferone at two dose levels, 20 and 40mg/kg for next 28days. RESULTS The results of the study showed that umbelliferone treatment significantly decreased the elevated plasma creatinine and blood urea nitrogen level while significantly increased the total protein and albumin level in diabetic animals. Creatinine clearance was improved in umbelliferone treated animals. Renal oxidative stress was decreased in umbelliferone treated animals significantly. Histopathological study of the kidney was carried out by specific stains like Hematoxylin-Eosin, Periodic Acid Schiff and Masson Trichrome stain. The sections of the kidney showed that umbelliferone treatment decreased the glomerular damage, mesangial matrix expansion as well as the renal fibrosis. Determination of renal transforming growth factor beta one (TGF-β1) expression by immunohistochemical analysis, western blotting and circulating TGF-β1 by ELISA assay showed that umbelliferone decreased the renal tissue and circulating TGF-β1 level. CONCLUSION Umbelliferone treatment can significantly reduce the diabetes induced renal damage and can improve the pathological conditions related to the diabetic nephropathy by down regulation of TGF-β.

Natural Remedies for Treatment of Cancer Pain

Abstract Pain is one of the most critical indications related with cancer. Intensity of cancer pain increases with advancement in stage of cancer. More than one third patients of cancer suffer from moderate to severe pain. World Health Organization (WHO) has developed a three step analgesic ladder for treatment of cancer pain. Natural drugs are being used for treatment of cancer but very less natural drugs are used in cancer pain. Morphine, a naturally occurring opioid is considered as a gold standard for treatment of cancer pain. Another natural opioid codeine is also being successfully used for the management of cancer pain. Cannabis, also known as marijuana, is used for treatment of moderate to severe cancer pain. Tetrodotoxin, a sodium channel blocker, of marine origin is in clinical trial for its use in cancer pain management. Vitamin supplementation is proving effective in decreasing the intensity of pain, as well as the dose of opioid analgesics. Many other natural drugs are being used as supportive treatments in cancer pain management.

Biomarkers of Multiple Sclerosis and Their Modulation by Natural Products

Abstract Multiple sclerosis (MS) is one of the leading causes of neurological disabilities and can be explained as a chronic, inflammatory, and autoimmune disease related to the central nervous system. Biomarkers play an important role in defining and understanding the various mechanisms involved in the progression of disease. The success of therapeutic treatment of MS can be measured by evaluating biomarkers, which can serve as a “surrogate end point” of clinical outcomes. Biomarkers of MS can be categorized as immune system biomarkers, blood–brain barrier disruption biomarkers, demyelination biomarkers, oxidative stress and excitotoxicity biomarkers, axonal/neuronal damage biomarkers, and remyelination and repair biomarkers. Studies have shown that natural products can modulate biomarkers of MS and can be used for its treatment. Polyunsaturated fatty acids, vitamins (specifically vitamin D), minerals, and trace elements all have promising effects on biomarkers of MS. Phytochemicals like adenanthin, cannabinoids, curcumin, epigallocatechin gallate, glucoraphanin, sulforaphane, hyperforin, matrine, plumbagin, and quercetin have also shown promise as potential treatments for MS. There is a wide scope for research in the domain of multiple sclerosis biomarkers and their modulation by natural products.

Fibromyalgia Syndrome: Role of Obesity and Nutrients

Abstract Fibromyalgia syndrome (FMS) is a devastating musculoskeletal disorder with characteristic symptoms of fatigue, chronic pain, headache, anxiety, morning stiffness, and memory loss that ultimately affects the quality of life. Although the clear pathogenesis of FMS is unknown, multiple lines of evidence propose a link between obesity, diet, nutritional status, and FMS. Several studies have reported that overweight and obese people have higher incidence of FMS, and weight reduction in these patients seems to be effective in improving symptoms. Vegetarian and vegan diets were reported to have beneficial effects on FMS due to the high amounts of antioxidants consumed. Nutritional deficiencies of magnesium, iron, iodine, selenium, thiamine, and manganese have been described, but there are no detailed studies available that show a direct relationship between FMS and deficiencies of these micronutrients. Extremely limited data is available about the nutritional supplements in FMS which indicates that more studies are needed to determine the types of nutritional supplements that could help reduce the symptoms of FMS. In conclusion, physical exercise, weight control, and dietary supplements, including antioxidants and micronutrients, are important in improving FMS patients’ quality of life.

Recent developments in using plant-derived natural products as tubulin inhibitors for the management of cancer

Abstract Defeating cancer has become a global battle calling for development of new treatment options. Better understanding of the biological processes involved in development of cancer has made it possible to screen various drugs against a wide range of targets. Targeting of microtubule dynamics has remained one of the favorite targets for researchers. Tubulin inhibitors are drugs of choice in many of the treatment strategies employed by the oncologists. Tubulin inhibitors are classified under two types as microtubule stabilizers or destabilizers. Three different sites are identified where these inhibitors binds. Natural sources have played an important role in development of modern medicines for treating various diseases including cancer. Vinca alkaloids, colchicine, and taxane are the first drugs in these categories which are named after different binding sites. Drugs binding to vinca domain and colchicine domain fall under microtubule destabilizers; and those binding to taxane domain fall under microtubule stabilizers. These drugs have served as prototypes for the development of their semisynthetic derivatives which are having wide range of anticancer activities. In present review, various aspects of the natural tubulin inhibitors and their role in development of chemotherapeutic agents for cancer treatment are discussed.