Targeting metabolic syndrome with phytochemicals: Focus on the role of molecular chaperones and hormesis in drug discovery.

Adaptive cellular stress response confers stress tolerance against inflammatory and metabolic disorders. In response to metabolic stress, the key mediator of cellular adaptation and tolerance is a class of molecules called the molecular chaperones (MCs). MCs are highly conserved molecules that play critical role in maintaining protein stability and functionality. Hormesis in this context is a unique adaptation mechanism where a low dose of a stressor (which is toxic at high dose) confers a stress-resistant adaptive cellular phenotype. Hormesis can be observed at different level of biological organization at various measurable endpoints. The MCs are believed to play a key role in adaptation during hormesis. Several phytochemicals are known for their hormetic response and are called phytochemical hormetins. The role of phytochemical-mediated hormesis on the adaptive cellular processes is proposed as a potential therapeutic approach to target inflammation associated with metabolic syndrome. However, the screening of phytochemical hormetins would require a paradigm shift in the methods currently used in drug discovery.

Sida cordifolia accelerates wound healing process delayed by dexamethasone in rats: Effect on ROS and probable mechanism of action.

ETHNO PHARMACOLOGICAL RELEVANCE: Sida cordifolia is used commonly in traditional systems of medicine (TSM) and as folk remedies for treating the wounds (both external and internal), infected area, rheumatic disorders, muscular weakness, tuberculosis, heart problems, bronchitis, neurological problems etc. Therefore, in order to authenticate the claims, a mechanism-oriented investigation of the wound healing properties of this plant is essential. AIM OF THE STUDY: The overall aim of the present research is to understand the precise unknown cellular and molecular mechanism by which S. cordifolia accelerates wound healing delay caused by the steroidal drug dexamethasone. Here, we have also tried to quantify intracellular superoxide with the help of a unique fluoroprobe MitoSOX based on fluorescence measurements in yeast MATERIALS AND METHODS: Wound healing property of successive extracts (ethyl acetate, methanol and aqueous) of S. cordifolia against dexamethasone-induced retardation of wound healing in rats was studied. The various extracts of S. cordifolia were characterised by determining the various phytochemicals and quantifying the total phenolic content and flavonoidal content by High throughput assays. In order to know the probable mechanism of action of the successive fractionates, assessed the antioxidant activity both by in-vitro (DPPH-assay) and in-vivo methods in wild-type Saccharomyces cerevisiae BY 4743 (WT) and knock-out strain (Δtrx2) against H2O2-induced stress mediated damages. The cell survival was evaluated after exposure to the oxidizing reagent (4 mM H2O2) by two methods which included the ability of cells to proliferate on solid or liquid medium. The cell membrane integrity/amount of mitochondrial ROS was determined by treating the strains with extract/standard in presence of H2O2 and propidium iodide (PI)/MitoSOX Red RESULTS: During the preliminary in-vivo wound healing study, the period for complete re-epithelialization of the wound tissue was reduced significantly (pin the treatment groups as compared to the negative control group. The formulation HF3 containing aqueous extract of S. cordifolia (SCA) showed highest wound healing potential against dexamethasone-retarded wounds in rats which justifies its traditional use. In the growth curve assay, the H2O2-induced growth arrest was restored by aqueous extract of S. cordifolia (SCA) in a concentration-dependent(pmanner both in the WT and Δtrx2 strains similar to the standard (ascorbic acid), H2O2 after 24 hours incubation which was also confirmed by the findings of CFU method. We got almost similar results of cell viability when stained with PI. The lower level of mitochondrial superoxide was indicated by a significant (preduction in the amount of MitoSOX stained cells, in the extract-treated group in contrast to the H2O2-stressed group. CONCLUSION: It was concluded that HF3 can be applied topically in hydrogel form in the case of delayed wound healing caused by the steroidal drug-dexamethasone, aptly justifying its traditional use. Regarding its mechanism of action, our findings report that the potent adaptive response of SCA-treated WT and Δtrx2 strains towards intracellular ROS specifically mitochondrial-ROS confirms its antioxidant potential. Moreover, as SCA was able to rescue the Δtrx2 strains from stress, it can be inferred that it might be able to induce the enzyme thioredoxin-II to restore redox homeostasis. The findings with the conditional mutant ∆trx2 are the first proof linking SCA action related to particular cellular pathways which may be because of the phenols and flavonoids and their synergistic effect.

Nephroprotective effect of Murraya koenigii on cyclophosphamide induced nephrotoxicity in rats.

OBJECTIVE: To evaluate the nephroprotective effect of defatted methanolic extract and aqueous extract of Murraya koenigii (M. koenigii) against cyclophosphamide drug. METHODS: Nephrotoxicity was induced by cyclophosphamide in 7 days at 150 mg/kg body weight through intraperitoneal route in rat model. Nephroprotective activity of M. koenigii extract (100 mg/kg and 200 mg/kg in intraperitoneal route) was measured, including nephrological source, oxidative stress parameters like superoxide dismutase, glutathione, the lipid peroxide and in vivo assay like blood urea nitrogen, creatinine were determined and analyzed by One way analysis of variance followed by Tukey's test. RESULTS: The study result showed that important phytochemicals such as carbohydrates, flavonoids, tannin, alkaloids, glycosides, protein and steroids were found to be present in the extract of M. koenigii. The renal function markers like blood urea nitrogen and creatinine level were found to be decreased significantly by M. koenigii extract treatment. A significant difference was found to be at P < 0.01. CONCLUSIONS: The present study reveals the protective role of M. koenigii extract against cyclophosphamide induced nephrotoxicity.

Effects of flavonoids from Martynia annua and Tephrosia purpurea on cutaneous wound healing.

OBJECTIVE: Martynia annua L. (M. annua), (Martyniaccae) has been traditionally used in the treatment of epilepsy, sore throat and inflammatory disorders. The leaf paste is used topically on Tuberculosis of the lymphatic glands and wounds of domestic animals. Tephrosia purpurea (T. purpurea), (Fabaceae) has been used traditionally as a remedy for asthma, gonorrhea, rheumatism and ulcers. This study aimed to evaluate the potential wound healing effects of different fractions ofethanol extract of M. annua leaves and aerial parts of T. purpurea. MATERIALS AND METHODS: Methanol fraction of M. annua (MAF-C) and ethyl acetate fraction of T. purpurea (TPF-A) were evaluated for healing potential in dead-space and burn wound models. An ointment (5% w/w) of MAF-C and TPF-A, pongamol (0.2 and 0.5% w/w) and luteolin (0.2 and 0.5% w/w) was applied topically twice a day. The effects were compared with Povidone Iodine ointment with respect to protein, collagen content, enzymatic assay and histopathological finding of granuloma tissues. RESULTS: Ethanol extracts of M. annua and T. purpureawere exhibited total flavonoid contents of 126.2 ± 4.69 and 171.6 ± 6.38 mg (quercetin equivalent), respectively. HPLC fingerprinting confirmed the presence of luteolin in M. annua and quercetin in T. purpurea. TPF-A and MAF-C ointments (5% w/w) significantly increases the hydroxyproline and protein contents. Luteolin and pongamol ointments were also found to be effective in both wound models. CONCLUSION: Our findings suggested that 5% w/w ointment of TPF-A and MAF-C fractions were more effective than isolated flavonoids in wound healing which may be due to synergistic interactions between the flavonoids and other constituents.

Exploring the role of curcumin containing ethanolic extract obtained from Curcuma longa (rhizomes) against retardation of wound healing process by aspirin.

AIM: The aim of the study was to assess the curcumin containing ethanolic extract (EtOH) obtained from Curcuma longa (Cl) against retardation of wound healing by aspirin. MATERIALS AND METHODS: Wound healing process was retarded by administering the dose of 150 mg/kg body weight of aspirin orally for 9 days to observe the effect of EtOH obtained from Cl using excision and incision wound model in rats. The various parameters such as % wound contraction, epithelialization period, hydroxyproline, tensile strength were observed at variant time intervals and histopathological study was also performed. RESULTS: Curcumin containing 5% and 10% ethanolic extract ointment have shown significant (P < 0.01) wound healing activity against an aspirin (administered 150 mg/kg body weight orally for 9 days) retarded wound healing process. Topical application of ointment showed significant (P < 0.01) difference as compared to the control group. Histopathological studies also showed healing of the epidermis, increased collagen, fibroblasts and blood vessels. CONCLUSION: Ethanolic extract of Cl ointment (EtOHCl) containing 10% curcumin displayed remarkable healing process against wound retardation by aspirin.

Synthesis and anticonvulsant evaluation of some novel 2,5-disubstituted 1,3,4-thiadiazoles: pharmacophore model studies.

A novel series of N'-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-(4-substituted benzaldehyde)-semicarbazones, N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl)ethanone]-semicarbazones and N1-{5-[(1H-indol-3-ylmethyl)-1,3,4-thiadiazol-2-yl}-N4-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazones were synthesized and evaluated for their anticonvulsant potential using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPFZ) models. The minimal motor impairment (neurotoxicity) was determined by rotorod test. The results of the present study confirmed the requirements of various structural features of four binding site pharmacophore model for anticonvulsant activity.

Design, synthesis and biological evaluation of some novel benzimidazole derivatives for their potential anticonvulsant activity.

Selective GABA(A) receptor ligands are widely used clinically to reduce the occurrence of convulsions. Hence there is an intense interest in developing new benzimidazole derivatives demonstrating high selectivity and high affinity for GABA(A) receptors. With the purpose of designing new chemical entities with an enhanced binding affinity for GABA(A)/BZd receptor complex, we carried out a QSAR study on benzotriazine derivatives. We studied 28 potent GABA(A) receptor ligands; derivatives of benzotriazines, using a combination of various tested physicochemical, steric, electronic and thermodynamic descriptors to determine the quantitative correlation between binding affinity and structural features. The developed and validated final model showed a good correlative and predictive ability expressed by a squared correlation co-efficient (r(2)) of 0.954. The equation indicated that the binding affinity is strongly dependent upon the thermodynamic properties (CDE, DDE and PC). Correlation between these properties and anticonvulsant activity was used to synthesize compounds possessing potent anticonvulsant activity. Most of the compounds showed an ability to inhibit the maximum electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Compound 1A, i.e. 2-(4-Chloro-phenyl)-5-nitro-1H-benzimidazole exhibited maximum activity in both the convulsion models.

Erythropoietic activity of Asteracantha longifolia (Nees.) in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Asteracantha longifolia Nees. (Family-Acanthaceae) is a wild herb commonly used in traditional ayurvedic medicine as Kokilaaksha and the Unani drug as Talimakhana in India and Srilanka for various medicinal uses as aphrodisiac, tonic, sedative and blood diseases etc. AIM OF THE STUDY: The aim of the current study was to validate and explore the folk use of Asteracantha longifolia Nees. (AL) (Leaf part) on pharmacological grounds using haloperidol induced iron deficiency anemia for the assessment of erythropoietic activity. MATERIALS AND METHODS: Determination of iron in plant extracts was carried out using spectrophotometric method. Plant extract was obtained from crude drugs using extraction with ethanol. In vivo study, haloperidol induced iron deficiency anemia model was used in experimental studies. RESULTS: An administration of ethanolic extract of AL at the doses of 100 mg/kg and 200 mg/kg body weight, i.p., demonstrated a significant (P<0.05) increase in erythrocyte count, haemoglobin count, serum iron and serum protein etc. This effect may be due to the presence of iron (622 microg/50 mg) in extract estimated by spectrophotometric method. CONCLUSION: An ethanolic extract of AL effectively restored the hematological parameters, serum iron and serum protein and normalized the microcytic (smaller in size), anisocytosis (disturbed shape) and hypochromic RBCs. These observations could justify the inclusion of this plant in the management of iron deficiency anemia due the presence of iron and other constituents as flavonoids, terpenoids, steroids, lupeol and betulin.

Wound healing potential of Tephrosia purpurea (Linn.) Pers. in rats.

Tephrosia purpurea is a well-known herb for its hepatoprotective, anticancer, antiulcer, antibacterial and in healing bleeding piles, etc. The present study was aimed for wound healing potential of ethanolic extract of Tephrosia purpurea (aerial part) in the form of simple ointment using three types of wound models in rats as incision wound, excision wound and dead space wound. The results were comparable to standard drug Fluticasone propionate ointment, in terms of wound contraction, tensile strength, histopathological and biochemical parameters such as hydroxyproline content, protein level, etc. Histopathological study showed significant (P<0.05) increase in fibroblast cells, collagen fibres and blood vessels formation. All parameters were observed significant (P<0.05) in comparison to control group.