Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies.

Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, ß-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from - 11.5 to - 8.5 kcal mol-1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

Perturbations in the catecholamine metabolism and protective effect of "3-(3, 4-dimethoxy phenyl)-1-4(methoxy phenyl) prop-2-en-1-one" during ketamine-induced schizophrenia: an in vivo and in silico studies.

Different kinds of secondary metabolites present in the medicinal plants play an important role to alleviate different human ailments including neurodegenerative disorders such as Parkinson's, Alzheimer's, epilepsy and schizophrenia etc. Recently we have isolated and characterized a novel bioactive compound viz. 3-(3,4-dimethoxy phenyl)-1-4(methoxy phenyl)prop-2-en-1-one from the methanolic extract of Celastrus paniculatus (CP) which has been widely used for the treatment of neurodegenerative diseases. The present investigation is mainly aimed to evaluate the neuroprotective potential of the above bioactive compound against ketamine-induced schizophrenia with particular reference to catecholaminergic metabolism using in vivo and in silico methods. Ketamine-induced schizophrenia caused significant elevation in biogenic amines (epinephrine, nor epinephrine, dopamine and 5-HT) and monoamine oxidase activity levels which were restored to normal during the treatment with the bioactive compound akin to the reference compound, clozapine. In addition, the compound has shown highest binding score against all the biogenic amine receptors viz. D1, D2, D3, D4 and serotonin receptor, 5-HT2A with lowest inhibition constant values than the reference compound, clozapine. The present findings suggest that modulation of CNS monoamine neurotransmitter system might partly contribute to the impairments associated with schizophrenia and the plant compound alleviates the monoaminergic abnormalities associated with the neurological dysfunction.Communicated by Ramaswamy H. Sarma.

In silico and in vitro antioxidant and anticancer activity profiles of urea and thiourea derivatives of 2,3-dihydro-1H-inden-1-amine.

Synthesis of a series of new urea and thiourea compounds have been accomplished by the reaction of 2,3-dihydro-1H-inden-1-amine with various phenyl isocyanates and isothiocyanates. These compounds were evaluated for their antioxidant activity by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and nitric oxide (NO) radical scavenging assay methods including IC50 values. Some of the compounds exhibited potential activity in the two tested methods. Among the series of compounds, urea derivative linked with 4-bromo phenyl ring (4b), and thiourea derivatives bonded with phenyl ring (4e), 4-fluoro phenyl ring (4f) and 4-nitro pheyl ring (4h) were found to exhibit promising anti oxidant activity with low IC50 values. Where four of the title comounds exhibited higher bindig energies than the reference compound (Imatinib) in in silico molecular docking studies with Aromatase. All the synthesized compounds were characterized by IR, 1H, 13C NMR and mass spectral data.

Sophora interrupta Bedd. root-derived flavonoids as prominent antiviral agents against Newcastle disease virus.

The discovery and development of novel antiviral drugs from natural sources is continuously increasing due to limitations of currently available drugs such as toxic side effects, drug residue risk factors, high costs, and poor therapeutic strategies. Also, there are very few known antiviral drugs that are effective against only specific viruses. Hence, the present study is intended to isolate and characterize potent antiviral compounds from the methanolic root extract of Sophora interrupta Bedd. against avian paramyxovirus, Newcastle disease virus (NDV) and to distinguish the molecular basis of antiviral compounds. The two isolated flavonoids, maackiain (SR-1) and echinoisoflavanone (SR-2) exhibited the best antiviral activities against NDV infection in chicken embryo fibroblast cell lines compared to the standard antiviral drug, Ribavirin. Further, the in vitro studies and quantitative PCR analysis suggests that these flavonoids inhibit the viral entry, replication, and transcription, which may be beneficial as a promising strategy for the treatment of viral infections. Besides, the molecular docking studies of SR-1 and SR-2 exhibited high binding affinities of -7.6 and -8.0 kcal mol-1, respectively, and marked interactions with the NDV surface glycoprotein, hemagglutinin neuraminidase (HN). Also, the in silico toxicity properties as well pharmacokinetic studies of isolates revealed them as pharmacologically potent antiviral compounds.

In silico and in vitro antioxidant activity profiles of urea and thiourea derivatives of 5-hydroxytryptophan.

A series of new urea and thiourea derivatives of 5-hydroxy tryptophan 3a-l was designed and synthesized from 5-hydroxy tryptophan (1) by treating various isocyanates 2a-g and isothiocyanates 2h-l in the presence of triethylamine (TEA) as a base. The antioxidant activities of the newly synthesized compounds were evaluated by using different in vitro assays such as 1, 1-diphenyl-2-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2) and superoxide. The results obtained from the in vitro studies revealed that the compounds 3a, 3g, 3h, and 3l exhibited the significant high content of antioxidant activity. Besides, molecular docking studies indicated that, all the compounds 3a-l have formed higher binding energies with 3MNG protein than the reference compound 1. Among all the synthesized compounds, 3a, 3l, 3g, 3b, 3c and 3h have exhibited the highest dock scores than the rest of the compounds including the reference compound. Hence, it is concluded that the title compounds will open new vistas for the discovery of strong antioxidants and will stand as remarkable antioxidant moieties in future.

Meglumine as a green, efficient and reusable catalyst for synthesis and molecular docking studies of bis(indolyl)methanes as antioxidant agents.

An efficient and convenient Meglumine catalyzed procedure for the synthesis of bis(indolyl) methanes at ambient temperature under aqueous conditions in high yields. The catalytic reaction proceeds very smoothly. Clean reaction, ease of product isolation/purification, easily available reactants, metal free and environmentally friendly reaction conditions are the notable advantages of the present methodology. All the entitled compounds were characterized by IR, 1H, 13C NMR, mass spectra and evaluated for their antioxidant (DPPH, H2O2 and NO scavenging methods). They exhibited potent in vitro antioxidant activity dose-dependently. The binding interactions and molecular docking studies for entitled compounds were studied against 3MNG protein. 4d exhibited marked binding affinity with excellent docking score of -7.6 K.cal/mol and emerged as a lead compound.

Synthesis, spectral characterization, docking studies and biological activity of urea, thiourea, sulfonamide and carbamate derivatives of imatinib intermediate.

A series of new urea/thiourea derivatives 3a-j were synthesized by simple addition reaction of functionalized phenyl isocyanates/isothiocyanates 2a-j with N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (imatinib intermediate) (1) in the presence of 1,4-dimethyl piperazine (DMPZ) as a base, and another series of new sulfonamide/carbamate derivatives 5a-k were synthesized by reacting 1 with various substituted aromatic sulfonyl chlorides 4a-f and aromatic/aliphatic chloroformates 4g-k in the presence of DMPZ as a base. The title compounds 3a-j and 5a-k were characterized by IR, 1H, 13C NMR and mass spectral data. Antimicrobial, antioxidant and in silico molecular docking studies were made against aromatase.

Design, synthesis, neuroprotective, antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids.

A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88 µg/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16 µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells.

Hepatoprotective role of Ricinus communis leaf extract against d-galactosamine induced acute hepatitis in albino rats.

Ricinus communis (RC) is a traditional medicinal plant which has been used by Chenchu and Yerukula tribes for treating their liver ailments. The present work is aimed to explore the hepatoprotective efficacy of Ricinus communis against d-galactosamine (D-GalN) induced hepatitis rat model and its therapeutic potential compared with standard drug, silymarin (100mg/kg.bw). In vitro antioxidant activity of Methanolic extract of Ricinus communis leaves (MERCL) was assayed through DPPH and H2O2 free radical scavenging activity. Qualitative and quantitative analysis of MERCL using HPLC, demonstrated that Rutin was found to be predominant bioactive compound in the extract. Hepatitis was induced by treating the rats with D-GalN at a single intraperitoneal dose of 800mg/kg.bw. Serum markers viz, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) and Malondialdehyde (MDA) levels were significantly increased and the activity levels of antioxidant enzymes such as Superoxide dismutase (SOD),Catalase (CAT), Glutathione reductase (GR), Glutathione peroxidase (GPx), non-enzymatic antioxidant Glutathione (GSH) levels were decreased in the liver of hepatitis induced rats when compared to controls. Pre and post treatment with MERCL significantly altered the enzyme activities, GSH and MDA to normal levels. Histopathological observations also showed protective and curative effects of MERCL against D-GalN intoxication. These results demonstrated that MERCL significantly protected the liver from d-galactosamine induced hepatitis, improved the curative effect in the liver and hence, MERCL can be used as a potent hepatoprotective drug in future.

Development of novel HER2 inhibitors against gastric cancer derived from flavonoid source of Syzygium alternifolium through molecular dynamics and pharmacophore-based screening.

Continuous usage of synthetic chemotherapeutic drugs causes adverse effects, which prompted for the development of alternative therapeutics for gastric cancer from natural source. This study was carried out with a specific aim to screen gastroprotective compounds from the fruits of Syzygium alternifolium (Myrtaceae). Three flavonoids, namely, 1) 5-hydroxy-7,4'-dimethoxy-6,8-di-C-methylflavone, 2) kaempferol-3-O-ß-d-glucopyranoside, and 3) kaempferol-3-O-α-l-rhamnopyranoside were isolated from the above medicinal plant by employing silica gel column chromatography and are characterized by NMR techniques. Antigastric cancer activity of these flavonoids was examined on AGS cell lines followed by cell cycle progression assay. In addition, pharmacophore-based screening and molecular dynamics of protein-ligand complex were carried out to identify potent scaffolds. The results showed that compounds 2 and 3 exhibited significant cytotoxic effect, whereas compound 1 showed moderate effect on AGS cells by inhibiting G2/M phase of cell cycle. Molecular docking analysis revealed that compound 2 has higher binding energies on human growth factor receptor-2 (HER2). The constructed pharmacophore models reveal that the compounds have more number of H-bond Acc/Don features which contribute to the inhibition of HER2 activity. By selecting these features, 34 hits were retrieved using the query compound 2. Molecular dynamic simulations (MDS) of protein-ligand complexes demonstrated conspicuous inhibition of HER2 as evidenced by dynamic trajectory analysis. Based on these results, the compound ZINC67903192 was identified as promising HER2 inhibitor against gastric cancer. The present work provides a basis for the discovery a new class of scaffolds from natural products for gastric carcinoma.

Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus.

Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds.

Newcastle disease virus (NDV) induces protein oxidation and nitration in brain and liver of chicken: Ameliorative effect of vitamin E.

The present study was aimed at investigating the therapeutic efficacy of vitamin E on oxidative injury in brain and liver of Newcastle disease virus (NDV) challenged chickens. We have analyzed the xanthine oxidase (XOD) activity; uric acid (UA) levels and superoxide radical generation by using electron spin resonance spectroscopy. Further, protein oxidation, nitration and apoptosis were evaluated in the brain and liver of the control, NDV-infected and NDV+Vit. E treated groups. A significant elevation was observed in XOD activity and UA levels in brain (p<0.001) and liver (p<0.05) of NDV infected birds when compared to controls. Further, significant increase in the production of superoxides, enhanced intracellular protein carbonyls and nitrates were observed in the brain and liver of NDV-infected birds over healthy subjects. Apoptosis studies also suggested that a larger number of TUNEL positive cells were observed in brain and a moderately in liver of NDV-infected chickens. However, all these perturbations were significantly ameliorated in NDV+Vit. E treated chickens as compared to NDV-infected birds. Taken together, our results suggested that NDV-induced neuronal and hepatic damage at least in part mediates oxidative stress and on the other hand, supplementation of vitamin E mitigates NDV-induced oxidative damage thereby protects brain and liver of chickens. These findings could provide new insights into the understanding of NDV pathogenesis and therapeutic effects of dietary antioxidants.

Evaluation of soluble CD44 protein marker to distinguish the premalignant and malignant carcinoma cases in cervical cancer patients.

The main objective of the present study was to estimate the levels of soluble CD44 in cervical cancer patients by determining whether it consistently discriminates the carcinoma of the cervix from early or premalignant stage of the cervical cancer. Serum concentrations of sCD44s in cervical cancer patients were determined by an enzyme-linked immunosorbent assay from serum of 50 cases of cervical cancer patients and 50 cases of suspected patients with premalignant disease of cervical intraepithelial neoplasia. The sensitivity and specificity of the test for differentiating carcinoma of the cervix from premalignant stage were evaluated by plotting receiver operating characteristic (ROC) curve. Significant increase in the levels of soluble CD44 was observed in cervical cancer patients (664.80 ± 26.58 ng/ml), when compared to healthy (P < 0.001) and suspected (P < 0.05) or premalignant cases (275.19 ± 24.39 and 514.33 ± 54.57 ng/ml, respectively). High-grade squamous intraepithelial lesions, adenocarcinoma in situ and premalignance with dysplasia show significant (P < 0.001) increase in the concentration of soluble CD44 levels when compared to other types. A ROC curve was plotted and estimated the threshold value as 633.11 ng/ml. In conclusion, the data indicated an up-regulation of soluble CD44 protein which detect and differentiates the cervical carcinoma from premalignant cases with 62.6 % sensitivity.

Evaluation of microbial enzymes in normal and abnormal cervicovaginal fluids of cervical dysplasia: a case control study.

The aim of the present study was to evaluate the role of microbial enzymes in normal and abnormal cervicovaginal fluids of cervical dysplasia. The cervicovaginal infections were evaluated through the estimation of microbial enzymes in patients with and without abnormal cervical cytology like bacterial and fungal infections. The patients were categorized based on infection caused by organism and stages of dysplasia. The pH, Whiff test, and Pap smear tests were conducted for normal and abnormal cervical swabs based on standard protocols. Microbial enzymes include mucinase, sialidases, and proteases of the cervical swabs and are estimated according to standard methods. The results of abnormal cervical cytological smears showed increased pH and the presence of amines with different levels of Pap smear test. Increased levels of microbial enzymes were observed in patients with abnormal cytology than normal cytology. Three microbial enzymes mucinase, sialidase, and protease were significantly (P < 0.01) more elevated in patients with bacterial infections (8.97 ± 0.64, 10.39 ± 0.28, 8.12 ± 0.64) than without dysplasia (2.02 ± 0.8, 1.98 ± 0.3, 1.96 ± 0.8). The results reinforce that the microbial infection seems to be more prone to cervical dysplasia and may act as risk-factor for the development of cervical cancer along with HPV infection.

Effect of concurrent radiochemotherapy and chemotherapy on serum proteins for prospective predictors of patients with HPV induced cervical cancer.

OBJECTIVES: To evaluate the effectiveness of radiochemotherapy and chemotherapy on human papilloma virus induced cervical cancer patients by the estimation of serum proteins and magnetic resonance imaging. METHODS: HPV 16/18 viral DNA was detected in the plasma of cervical cancer patients (n=50) by PCR using HPV consensus primers. Of the 50 cervical cancer patients, 25 cases undergoing radiation with chemotherapy and another 25 cases undergoing chemotherapy. Levels of pre- and post-treated serum squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 were measured and evaluated the tumour size at pre- and post-radiation based on magnetic resonance images. The effectiveness of treatment was evaluated in terms of protein levels and represented as whisker line graphs. RESULTS: Of the amplified 50 samples, HPV 16 and 18 strains were identified as 48 and 44%, respectively. Serum protein levels were significantly increased in both pre-treated groups when compared to healthy group. Post-treated (radiotherapy) cervical cancer patients' shows decreased tumour size when compared to pre-treated groups. Taking consideration of proteins, squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 levels are more decreased in patients treated with radiochemotherapy than chemotherapy alone. The decreased levels of proteins were significantly higher in early stage of the cervical cancer than the advanced stage of cancer patients. CONCLUSION: Serum levels of protein markers are more improved in patients treated with radiochemotherapy than chemotherapy hence, radiochemotherapy may be the best choice of treatment with reference to proteins at early stage of cervical cancer when compared to chemotherapy alone.

Design, synthesis, antioxidant, and anti-breast cancer activities of novel diethyl(alkyl/aryl/heteroarylamino)(4-(pyridin-2-yl)phenyl)methylphosphonates.

A series of new diethyl(alkyl/aryl/heteroarylamino)(4-(pyridine-2-yl)phenyl)methylphosphonates (4a-t) were synthesized via three-component Kabachnik-Field's reaction of 4-(pyridin-2-yl)benzaldehyde, diethylphosphite and various primary amines, catalyzed by cupric acetate monohydrate [Cu(OAc)(2) ∙ H(2)O] under solvent-free and microwave irradiation conditions. Their computational docking analysis supported them as good therapeutic agents to the breast cancer aromatase enzyme and ascertained 4a, 4h, 4m, 4n, and 4t as potential molecules with good binding affinities varying from -9.0 to -9.6 kcal/mol and containing the 4-(pyridine-2-yl)phenyl moiety as a pharmacophore. Their in vitro screening performed for the anti-cell proliferation activity against MBC-MCF7 cells by MTT and Trypan blue assays confirmed 4m, 4n, and 4q as promising compounds to sustain a low percentage of cell viability at 20 µg/mL concentration. These compounds were also evaluated for their antioxidant activity by the DPPH method and the results established that compounds 4m, 4n, and 4q show around 10% higher activity than the standard antioxidant ascorbic acid.

Perturbations in the antioxidant metabolism during Newcastle disease virus (NDV) infection in chicken : protective role of vitamin E.

The aim of the present study was to investigate the effect of vitamin E on pro/anti-oxidant status in the liver, brain and heart of Newcastle disease virus (NDV) infected chickens. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and the levels of reduced glutathione and malonaldehyde were estimated in selected tissues of uninfected, NDV-infected and NDV + vit. E-treated chickens. A significant increase in MDA levels in brain and liver (p < 0.05) was observed in NDV-infected chickens when compared to controls. The activities of SOD, CAT, GPx, GR, GST and levels of GSH were significantly (p < 0.05) decreased in brain and liver of NDV-infected chickens over controls. On the other hand, a significant decreased MDA levels and enhanced antioxidant enzyme activity levels were observed in NDV + vit. E-treated animals compared to NDV-infected chickens. Histopathological studies revealed that liver of NDV infected chicken shows focal coagulation and infiltration of hepatocytes, whereas neuronal necrosis and degeneration of Purkinje cells were observed in brain and moderate infiltration of inflammatory cells was observed in heart. However such histological alterations were not observed in NDV + vit. E-treated animals. The results of the present study, thus demonstrated that antioxidant defense mechanism is impaired after the induction of NDV, suggesting its critical role in cellular injury in brain and liver. Further, the results also suggest that vitamin E treatment will ameliorate the antioxidant status in the infected animals. The findings could be beneficial to understand the role of oxidative stress in the pathogenesis of NDV and therapeutic interventions of antioxidants.

Evaluation of the anticonvulsant effect of Centella asiatica (gotu kola) in pentylenetetrazol-induced seizures with respect to cholinergic neurotransmission.

The study described here was carried out to investigate the anticonvulsant effect of different extracts of Centella asiatica with respect to cholinergic activity on pentylenetetrazol (PTZ)-induced seizures. Rats were randomly divided into eight groups of six rats each: nonepileptic rats treated with saline; PTZ (60 mg/kg, IP)-induced seizure rats treated with saline; PTZ-induced seizure rats pretreated with n-hexane, chloroform, ethyl acetate, n-butanol, and water extracts of C. asiatica; and PTZ-induced seizure rats pretreated with diazepam (2mg/kg body wt). The seized rats pretreated with different extracts were administered a dose of 200mg/kg body wt orally for 1 week before induction of epilepsy. Increased acetylcholine content and decreased acetylcholinesterase activity were recorded in different brain regions during PTZ-induced seizures. Pretreatment with C. asiatica extracts caused recovery of the levels of acetylcholine and acetylcholinesterase. These findings suggest that C. asiatica causes perceptible changes in the cholinergic system as one of the facets of its anticonvulsant activity.

Functional expression of lepidopteran-selective neurotoxin in baculovirus: potential for effective pest management.

Recombinant baculovirus expressing insect-selective neurotoxins derived from venomous animals are considered as an attractive alternative to chemical insecticides for efficient insect control agents. Recently we identified and characterized a novel lepidopteran-selective toxin, Buthus tamulus insect-selective toxin (ButaIT), having 37 amino acids and eight half cysteine residues from the venom of the South Indian red scorpion, Mesobuthus tamulus. The synthetic toxin gene containing the ButaIT sequence in frame to the bombyxin signal sequence was engineered into a polyhedrin positive Autographa californica nuclear polyhedrosis virus (AcMNPV) genome under the control of the p10 promoter. Toxin expression in the haemolymph of infected larvae of Heliothis virescens and also in an insect cell culture system was confirmed by western blot analysis using antibody raised against the GST-ButaIT fusion protein. The recombinant NPV (ButaIT-NPV) showed enhanced insecticidal activity on the larvae of Heliothis virescens as evidenced by a significant reduction in median survival time (ST50) and also a greater reduction in feeding damage as compared to the wild-type AcMNPV.

Toxins in anti-nociception and anti-inflammation.

The use of toxins as novel molecular probes to study the structure-function relationship of ion-channels and receptors as well as potential therapeutics in the treatment of wide variety of diseases is well documented. The high specificity and selectivity of these toxins have attracted a great deal of interest as candidates for drug development. This review highlights the involvement of the proteins and peptide toxins as well as non-proteinaceous compounds derived from both venomous and non-venomous animals, in anti-nociception and anti-inflammation. The possible mechanisms of these potential therapeutic agents and possible clinical applications in the treatment of pain and inflammation are also summarized.