K. Kemparaju

Emerging roles of anacardic acid and its derivatives: a pharmacological overview.

Anacardic acid (AA) is a bioactive phytochemical found in nutshell of Anacardium occidentale. Chemically, it is a mixture of several closely related organic compounds, each consisting of salicylic acid substituted with an alkyl chain. The traditional Ayurveda depicts nutshell oil as a medicinal remedy for alexeritic, amebicidal, gingivitis, malaria and syphilitic ulcers. However, the enduring research and emerging evidence suggests that AA could be a potent target molecule with bactericide, fungicide, insecticide, anti-termite and molluscicide properties and as a therapeutic agent in the treatment of the most serious pathophysiological disorders like cancer, oxidative damage, inflammation and obesity. Furthermore, AA was found to be a common inhibitor of several clinically targeted enzymes such as NFκB kinase, histone acetyltransferase (HATs), lipoxygenase (LOX-1), xanthine oxidase, tyrosinase and ureases. In view of this, we have made an effort to summarize the ongoing research on the therapeutical role of AA and its derivatives. The current MiniReview sheds light on the pharmacological applications, toxicity and allergic responses associated with AA and its derivatives. Although the available records are promising, much more detailed investigations into the therapeutical properties, particularly the anti-cancer and anti-inflammatory activities, are urgently needed. We hope the present MiniReview will attract and encourage further research on elucidating and appreciating the possible curative properties of AA and its derivatives in the management of multifactorial diseases.

Variations in biochemical and pharmacological properties of Indian cobra (Naja naja naja) venom due to geographical distribution

Indian cobra (Naja naja naja) venom obtained from three different geographical regions was studied in terms of electrophoretic pattern, biochemical and pharmacological activities. SDS-PAGE banding pattern revealed significant variation in the protein constituents of the three regional venoms. The eastern venom showed highest indirect hemolysis and hyaluronidase activity. In contrast, western and southern venoms were rich in proteolytic activity. All the three regional venoms were devoid of p-tosyl-L-arginine methyl ester hydrolysing activity. The eastern venom was found to be most lethal among the three regional venoms. The lethal potency varied as eastern > western > southern regional venoms. In addition, all the three regional venoms showed marked variations in their ability to induce symptoms/signs of neurotoxicity, myotoxicity, edema and effect on plasma coagulation process. Polyclonal antiserum prepared against the venom of eastern region cross-reacted with both southern and western regional venoms, but varied in the extent of cross-reactivity by ouchterlony immunodiffusion and ELISA.

Snake venom hyaluronidase: an evidence for isoforms and extracellular matrix degradation.

The present study attempts to establish the isoforms of hyaluronidase enzyme and their possible role in the spreading of toxins during envenomation. Screening of venoms of 15 snakes belonging to three different families revealed varied hyaluronidase activity in ELISA-like assay, but with relatively similar pH and temperature optima. The zymograms of individual venoms showed varied activity banding patterns and indicated the presence of at least two molecular forms of the enzyme. During envenomation, activity of hyaluronidase is considered crucial for the spreading of toxins and is presumed to distort the integrity of extracellular matrix through the degradation of hyaluronic acid in it. This property has been addressed through localization of hyaluronic acid in human skin and muscle tissue sections using the probe, biotinylated hyaluronic acid binding protein. Faint and discontinuous staining pattern of hyaluronidase treated tissue sections over intense staining of untreated tissue sections confirm the selective degradation of hyaluronic acid in extracellular matrix and thus provide an evidence for the spreading property of the enzyme.

Inhibition of Naja naja Venom Hyaluronidase by Plant-Derived Bioactive Components and Polysaccharides

The inhibitory effect of several bioactive compounds on the activity of hyaluronidase enzyme purified from Naja naja venom was investigated in vitro. Compounds were found to inhibit the hyaluronidase activity dose dependently. Among glycosaminoglycans, heparin, heparan sulfate, and dermatan sulfate showed maximum inhibition compared to chondroitin sulfates. Different molecular forms of chitosan inhibit the enzyme, and inhibition appears to depend on the chain length. In addition, plant-derived bioactive compounds also inhibited the activity of hyaluronidase dose dependently. Among those tested, aristolochic acid, indomethacin, quercetin, curcumin, tannic acid, and flavone exhibited inhibition, with aristolochic acid and quercetin completely inhibiting the enzyme activity. It is concluded that the inhibitors of hyaluronidase could be used as potent first aid agents in snakebite therapy. Furthermore, these inhibitors not only reduce the local tissue damage but also retard the easy diffusion of systemic toxins and hence increase survival time.

An overview on genus garcinia: phytochemical and therapeutical aspects

The genus Garcinia belongs to the family Clusiaceae and has been involved in ayurvedic preparations to medicate various pathophysiological disorders. The bioactive molecules like hydroxycitric acid (HCA), flavonoids, terpenes, polysaccharides, procyanidines and polyisoprenylated benzophenone derivatives like garcinol, xanthochymol and guttiferone isoforms have been isolated from the genus Garcinia. The genus has received the attention of pharmaceutical industries due to their immense remedial qualities. The HCA has been known for its hypolipidemic property. The polyisoprenylated benzophenone and xanthone derivatives are known for their antioxidant, apoptotic, anti-cancer, anti-inflammatory, anti-bacterial, anti-viral, anti-fungal, anti-ulcer, anti-protozoal, and HAT inhibiting properties. Future studies on the synthesis of therapeutically important products and their analogs and evaluation of their safety and efficacy would be of great interest. Though the genus includes more than 300 species, we have made an effort to conceive the curative qualities of bioactive compounds of selected plants to the best of our knowledge.

N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine

Abstract In the present human health scenario, implication of oxidative stress in numerous pathologies including neurodegenerative, cardiovascular, liver, renal, pulmonary disorders, and cancer has gained attention. N-Acetylcysteine (NAC), a popular thiol antioxidant, has been clinically used to treat various pathophysiological disorders. However, NAC therapy is routine only in paracetamol intoxication and as a mucolytic agent. Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability. In order to overcome the limitations of NAC, an amide derivative N-Acetylcysteine amide (NACA) has been synthesized to improve the lipophilicity, membrane permeability, and antioxidant property. Recent studies have demonstrated the blood–brain barrier permeability and therapeutic potentials of NACA in neurological disorders including Parkinsons disease, Alzheimers disease, Multiple sclerosis, Tardive dyskinesia, and HIV-associated neurological disorders. In addition, NACA displays protective effect against pulmonary inflammation and antibiotic-induced apoptosis. Forthcoming research on the possible therapeutic properties of NACA and its generics in the management of pathologies associated with extracellular matrix degradation and oxidative stress-related inflammation is highly exiting. Superior bioavailability of NACA is likely to fulfill the promises of NAC as well as a molecule to improve the endurance and resident time of bioscaffolds and biomaterials. Till date, more than 800 reviews on NAC have been published. However, no comprehensive review is available on the therapeutic applications of NACA. Therefore, the current review would be the first to emphasize the therapeutic potentials of NACA and its derivatives.

Overlooked Issues of Snakebite Management: Time for Strategic Approach

Snakebite is a medical emergency in many parts of the world, particularly in the temperate regions. According to 2007 World Health Organization (WHO) report, there are about 5 million snakebite incidences resulting in 2.5 million envenoming, and 125,000 deaths occur annually. Most affected are the healthy individuals like children and farming populations with resource poor settings and away from health care centers in low-income countries of Africa, Asia and Latin America. In view of this, the WHO has declared snakebite as an ignored health crisis and a tropical disease. Although the death rate has reduced markedly due to anti-venom regiment, several limitations of it offer scope for better understanding of various ignored issues. Currently, snakebite therapeutics facing plethora of scientific, technological and public health challenges, including secondary/long term complications that have not been given importance so far. Because of dearth of knowledge, venom researchers and medical practitioners from affected countries worldwide should join together to accomplish this scenario. In view of this, the present review provides a broader perspective on the possible production and application of highly effective therapeutic master anti-venom, designing master diagnostic kit and also to deal with the inefficacy of anti-venom therapy against local manifestations and secondary complications of snakebite. The review demands thorough understanding of venom pharmacology, inculcating new strategies to handle and to enhance the efficacy of snakebite management and urge the governing systems of affected countries to take steps to curtail accidental debilitation and death rate of healthy individuals due to snakebite.

A non-toxic anticoagulant metalloprotease: purification and characterization from Indian cobra (Naja naja naja) venom

A non-toxic potent anticoagulant metalloprotease NN-PF(3) has been purified to homogeneity from the Indian cobra (Naja naja naja) venom through a combination of column chromatography and electrophoresis. NN-PF(3) is a single chain protein with a molecular weight of 68 kDa by SDS-PAGE. It hydrolysed casein, gelatin, haemoglobin and bovine fibrinogen, but did not hydrolyse bovine serum albumin or synthetic substrates such as TAME, BAEE and BAPNA. EDTA, EGTA and cyanide inhibited the enzymatic activity while 1,10-phenanthroline, PMSF, leupetin and pepstatin did not show any effect. NN-PF(3) is a metalloprotease containing Ca(2+) and Zn(2+) at a molar ratio of 1:1.2 and 1:0.4, respectively, as revealed by atomic absorption spectroscopy. NN-PF(3) was non-lethal up to an i.p. dose of 15 mg/kg body weight of mice and is devoid of myotoxicity, cytotoxicity and haemorrhagic activity. It is weakly oedematic, but strongly anticoagulant in property and the effect observed was both dose and time dependent.

A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status

Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-κB pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-α, IL-1β, NF-κB, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.

Crocin, a dietary colorant, mitigates cyclophosphamide-induced organ toxicity by modulating antioxidant status and inflammatory cytokines.

This study investigated the protective efficacy of crocin against hepatotoxicity induced by cyclophosphamide (CP) in Wistar rats.