[Show abstract][Hide abstract] ABSTRACT: The present study was carried out to evaluate the role of apoptotic proteins in REC-2006-mediated radiation protection in hepatoma cell lines. REC-2006 treatment 2 h before irradiation strongly inhibited the cleavage of ATM and PARP-1 in HepG2 cells. The expression of nuclear apoptosis inducing factor (AIF) was found to be more inhibited (~17%) in HepG2 cells in REC-2006 + radiation-treated group. More inhibition (~33%) of cytochrome c was observed in HepG2 cells upon REC-2006 treatment 2 h prior irradiation. Similarly, significantly more (P<.05) inhibition of Apaf-1, caspase-9 and caspase-3 was observed in REC-2006 + radition-treated group in HepG2 cells. REC-2006 treatment restored the expression of ICAD in HepG2 cells; however, no restoration was observed in Hep3B cells. Lower nuclear to cytoplasmic CAD ratio was observed in HepG2 cells (~0.6) as compared with Hep3B cells (~1.2) in REC-2006 + radiation-treated group. In conclusion, REC-2006 rendered higher protection in HepG2 cells by inhibiting the expression and translocation of AIF, inhibiting the cleavage of ATM and PARP-1, restoring the expression of ICAD, inhibiting the release of cytochrome c and thus modulating the expression of Apaf-1 caspase-9 and activity of caspase-3.
Evidence-based Complementary and Alternative Medicine 03/2011; 2011:758326. DOI:10.1093/ecam/neq059 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The emergence of novel H1N1 has posed a situation that warrants urgent global attention. Though antiviral drugs are available in mainstream medicine for treating symptoms of swine flu, currently there is no preventive medicine available. Even when available, they would be in short supply and ineffective in a pandemic situation, for treating the masses worldwide. Besides the development of drug resistance, emergence of mutant strains of the virus, emergence of a more virulent strain, prohibitive costs of available drugs, time lag between vaccine developments, and mass casualties would pose difficult problems. In view of this, complementary and alternative medicine (CAM) offers a plethora of interesting preventive possibilities in patients. Herbs exhibit a diverse array of biological activities and can be effectively harnessed for managing pandemic flu. Potentially active herbs can serve as effective anti influenza agents. The role of CAM for managing novel H1N1 flu and the mode of action of these botanicals is presented here in an evidence-based approach that can be followed to establish their potential use in the management of influenza pandemics. The complementary and alternative medicine approach deliberated in the paper should also be useful in treating the patients with serious influenza in non pandemic situations.
Evidence-based Complementary and Alternative Medicine 01/2011; 2011(1741-427X):586506. DOI:10.1155/2011/586506 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Radiolabeling and dose fixation study of alpha-ketoglutarate (A-KG).
A-KG is a potential oral antidote for cyanide poisoning. Its protective efficacy in animals was best exhibited at a dose of 2.0 g/kg body weight, which when extrapolated to human is very high. The objective of this study was to reduce the dose of A-KG in humans with concomitant increase in its bioavailability, employing pharmacoscintigraphic techniques to assess kinetics in man.
A-KG was radiolabeled with technetium-99m pertechnetate (Tc-99m) and its purity, labeling efficiency, and stability in vitro were determined by instant thin layer chromatography. Time-dependent bio-absorption of the drug in rats and rabbits was assessed by gamma scintigraphy after oral administration of a tracer dose of (99m)Tc-A-KG mixed with nonradioactive A-KG at a concentration of 0.1-2.0 g/kg in the presence or absence of aqueous dilution. Furthermore, scintigraphy and radiometry studies were performed in healthy human volunteers using 5-20 g of A-KG, given in single or split doses followed by different quantity of water. Drug bioavailability was estimated periodically.
High radiolabeling (>97%) of A-KG with a stability of 24 h in vitro was obtained. Less than 1% absorption of the drug occurred within 20 min after A-KG was administered in animals at a concentration of 2.0 g/kg body weight. One-tenth reduction in dose increased the bioavailability to 15%. Significant improvement in gastric emptying of the drug was achieved when the drug was administered along with 1-5 mL of water. In humans, two doses of 10 g A-KG given at an interval of 10 min, followed by 300 mL of water, increased the drug bioavailability to 40% as compared to a single dose of 20 g.
Significant reduction in A-KG dose was achieved in humans as compared to the recommended dose in animals.
Aqueous dilution improves the bioavailability of A-KG in humans.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE The overexploitation of wild medicinal flora for use in modern medicinal systems has led to a significant threat to the endemic medicinal flora. It is, therefore, imperative to develop biotechnological interventions to ensure regular availability of these bioactive compounds.
METHOD: In the present study, with a view to developing a biotechnological alternative, an endophyte- Entrophosphora infrequens was isolated from the inner bark of the medicinal plant Nothapodytes foetida. The endophyte was authenticated using CLUSTAL W-based phylogenetic analysis; subsequently its independent culture and unequivocal demonstration of production of camptothecin (CPT), an anti-cancer secondary metabolite was proved.
RESULTS: A comparison was made between CPT- (CPT devoid) and CPT+ (CPT enriched) fractions, followed by evaluation of their pro-antioxidant (biphasic) activity in lipid phase. Mechanistic analysis revealed a significant (p< 0.05) prooxidant activity in the CPT+ fraction (50μg/ml) and could be attributed to the resence
of CPT, as compared to CPT- fraction that exhibited antioxidant behavior at higher concentrations tested (100–1000μg/ml). Presence of CPT also resulted in significant (p<0.05) enhancement in net electron donation potential (R2 = 0.912) and free radical scavenging potential (R2 = 0.963). Both the fractions exhibited comparable nitric oxide modulatory activity (~> 65%), while Ferric Reducing Ability in Plasma (FRAP) equivalence value of CPT+ fraction was found to be 1.02 ± 0.04 times higher as compared to CPT- fraction (time points x, 8x and 16x; x= 300s), explaining its prooxidant
behavior at lower concentrations. CONCLUSIONS: In conclusion, the prooxidant activity positively correlated with the presence of CPT, acting in synergism/antagonism with other active constituents. The contrasting potential of both fractions indicates its usage as an anti-cancer drug and as antioxidants and/or radiomodulator.
[Show abstract][Hide abstract] ABSTRACT: Microorganisms that thrive in extreme adverse environmental conditions are extremophiles. Examples of these conditions are
temperature (>45°C; <10°C), pressure (>500 atmosphere), pH (>8.0; <5.0), oxygen tension, nutrient depletion, salinity (>1.0M
NaCl), high concentrations of calcitrant, heavy metals, high levels of radiation exposure etc. The discovery of extremophiles
has enabled the biotechnology industry to innovate corresponding bioproducts, extremolytes, for people’s benefit. The production
of Taq DNA polymerase has revolutionized biotechnology research in many ways. Many thermostable enzymes including cellulase,
lipase, amylase, and proteases have contributed significantly as industrial bioproducts. Extremophilic radioresistant bacteria
and fungi can be used strategically for the development of radioprotective drugs to protect against radiation exposure. Further
these extremophiles can be used to develop cryoprotectants. Categorically, the piezophilic microorganisms in the deep sea
are a prominent source of specific bio-molecules that has ability to stabilize cell membrane blebbing by maintaining the membrane
fluidity. Extremophiles are a sustainable resource for biotechnology industry, which needs to be explored. This chapter provides
a comprehensive view of the extremophiles and their products with the possible implications in human interest.
[Show abstract][Hide abstract] ABSTRACT: Mentha spicata Linn. (mint), a herb well known for its gastroprotective properties in the traditional system of medicine has been shown to protect against radiation-induced lethality, and recently its constituents have been found to possess calcium channel antagonizing properties. The present study examined the behavioral radioprotective efficacy of mint oil (obtained from Mentha spicata), particularly in mitigating radiation-induced conditioned taste aversion (CTA), which has been proposed as a behavioral endpoint that is mediated by the toxic effects of gamma radiation on peripheral systems, primarily the gastrointestinal system in the Sprague-Dawley rat model. Intraperitoneal administration of Mentha spicata oil 10% (v/v), 1 h before 2 Gy gamma radiation, was found to render significant radioprotection against CTA (p < 0.05), by blocking the saccharin avoidance response within 5 post-treatment observational days, with the highest saccharin intake being observed on day 5. This finding clearly demonstrates that gastroprotective and calcium channel antagonizing properties of Mentha spicata can be effectively utilized in preventing radiation-induced behavioral changes.
Phytotherapy Research 02/2009; 23(2):293-6. DOI:10.1002/ptr.2604 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A partially characterized extract of Podophyllum hexandrum rhizomes was studied for its radioprotective potential in mice. A major portion of the podophyllotoxin was obtained from the extract by further fractionation. Acute toxicity and maximum tolerated dose (MTD) of a single intraperitoneal dose of the extract were studied in mice to evaluate the toxicity of the extract, if any. Radioprotective efficacy was determined in terms of survival against 10 Gy whole-body irradiation (WBI), protection against 1 Gy-induced chromosomal aberration (CA), and estimation of dose reduction factor (DRF) in irradiated and extract pretreated mice. The MTD was observed to be 60 mg/kg of body weight, whereas a dose of 90 mg/kg of body weight yielded 50% death in mice within 72 hours of intraperitoneal administration of the extract. A dose range of 15-20 mg/kg of body weight administered 2 hours before 10 Gy WBI of mice yielded 66% survival, while administration of 10-15 mg/kg of body weight of the extract 1 hour before WBI yielded more than 90% survival. A DRF of 1.625 was estimated for 10 and 15 mg/kg of body weight of the extract administered 1 hour before WBI. Further studies on modulation of 1 Gy-induced CA revealed significant radioprotective efficacy of the extract in mouse bone marrow cells. Partial removal of podophyllotoxin was useful in reducing toxicity of the extract without altering its radioprotective efficacy.
[Show abstract][Hide abstract] ABSTRACT: The RAS protein controls signaling pathway are major player in cell growth, its regulation and malignant transformation. Any activation in RAS brings alteration in upstream or downstream signaling component. Activating mutation in RAS is found in approximately 30% of human cancer. RAS plays essential role in tumor maintenance and is therefore an appropriate target for anticancer therapy. Among the anti-RAS strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (prenylation and post prenylation inhibitors). (2) Downstream signaling (kinase inhibitor), (3) upstream pathway (kinase inhibitor and monoclonal antibody), (4) Expression of RAS or other component of pathway (siRNA and antisense oligonucleotide). Several of these new therapeutic agents are showing promising result in the clinic and many more are on the way. Here, we review the current status and new hopes for targeting RAS as an anticancer drug.
Cancer Investigation 10/2008; 26(9):948-55. DOI:10.1080/07357900802087275 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Immense interest has been generated in recent years for the development of drugs of herbal origin for the mitigation of deleterious effects of environmental pollutants like ionizing radiation, mainly to protect against radiation leakages resulting from mishaps in nuclear reactors, deliberate use of dirty bombs, etc. Method: The radio modifying effects of a fractionated extract of the high-altitude Himalayan plant species Rhodiola imbricata, along with its electron-donation potential, super-oxide ion scavenging (IC50 ≤ 0.025 mg/ml), nitric oxide (NO) scavenging potential (IC(50) = 0.5 mg/ml), and antihemolytic activity were evaluated in the present study. Reducing power, superoxide ion (O(2)(•-)), and nitric oxide scavenging ability of the fractionated extract increased in a dose-dependent manner. Rhodiola imbricata also exhibited antihemolytic potential preventing radiation-induced membrane degeneration of human erythrocytes. Conclusion: Thus, it can be stated that Rhodiola imbricata provides protection against gamma radiation via multifarious mechanisms that act in a synergistic manner. Rhodiola imbricata is widely used as a nutraceutical supplement in the trans-Himalayan region nations, and the current study shows that Rhodiola has immense potential for alleviation of biological damage in a radiation environment.
Journal of Dietary Supplements 01/2008; 5(2):147-63. DOI:10.1080/19390210802332695
[Show abstract][Hide abstract] ABSTRACT: The current study has concentrated on assessment of the radioprotective potential of REC-2001, a semi-purified fraction of rhizomes of Podophyllum hexandrum, in Swiss albino Strain 'A' mice exposed to 10 Gy whole-body gamma radiation. Animals were treated with 10 and 15 mg/kg b wt (i.p.) of REC-2001 1h prior to exposure to a lethal dose of gamma-radiation (10 Gy) and observed upto 30 days. For analysis of maximum tolerable dose (MTD), LD(50) and acute toxic dose, different concentrations of the extract were administered to animals and their mortality and morbidity status was observed upto 72 h and one week, respectively. Dose reduction factor (DRF) was determined by exposing REC-2001 pre-treated mice to supra-lethal doses of gamma-radiation. Endogenous spleen colony forming units (CFU), DNA strand breaks in thymocytes (alkaline halo assay) and lipid degradation was studied to understand the mechanism of radioprotection. A single dose of REC-2001 (10 and 15 mg/kg b wt i.p.) exhibited >90% survival in the pre-treated irradiated group versus no survival in radiation control group. Single doses of upto 75 mg/kg b wt (i.p.) did not cause any mortality (MTD) in mice. REC-2001, a dose of 90 mg/kg b wt, resulted in 50% mortality (LD(50)), while the LD(100) was 115 mg/kg b wt REC-2001 exhibited a DRF of 1.62. CFU counts in the REC-2001 treated group were found significantly high (5.33/spleen) as compared to controls. Exposure of thymocytes to 10 Gy radiation resulted in increased halo diameter (45+/-3 microm) in comparison to untreated controls (8+/-1 microm). REC-2001 administration (500 microg/ml) decreased the halo diameter to 15+/-2 microm. Radiation-induced lipid degradation was also inhibited by REC-2001. The present study has revealed that REC-2001 is a promising radioprotective fraction that can be effectively used against lethal doses of gamma-radiation after further investigations in higher animal models.
Phytomedicine: international journal of phytotherapy and phytopharmacology 07/2007; 16(1):47-55. DOI:10.1016/j.phymed.2007.04.010 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The radioprotective effect of a hydroalcoholic extracted material (REC-2000) from the rhizome of Podophyllum hexandrum was studied in mice exposed to lethal gamma radiation (10 Gy). The extract (REC-2000) was found to restore the hemoglobin content (14.73 +/- 0.33) and total leukocyte count (TLC) (4166.66 +/- 0.02) in lethally (10 Gy) gamma-irradiated mice on the 15th day in comparison to the radiation control mice. The hemoglobin content of the drug + radiation group was observed to be significantly (21.25%) higher than the radiation control group on the 10th day. Similarly, the TLC was significantly increased (83.33 times) in the drug + radiation group as compared to a radiation (10 Gy) only group on the 10th day. Enhanced expression of heme-oxygenase-1 and Bcl-2 protein observed by Western blotting further supports the observation of hemopoietic recovery in irradiated mice. These findings indicate that the bioactive constituents present in REC-2000 exert the radioprotective effect by modulating the hemopoietic system.
Integrative Cancer Therapies 04/2007; 6(1):54-65. DOI:10.1177/1534735406298303 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A fraction of high altitude Podophyllum hexandrum rhizome, REC-2006, was evaluated for its radioprotective efficacy against lethal gamma-irradiation (10 Gy, whole body) in Swiss albino mice. The maximum tolerated dose (MTD) and LD50 of this fraction were found to be 45 mg/kg b.w. and 74 mg/kg b.w. respectively. Pre-irradiation (- 2 h, ) administration (i.p.) of 6 or 8 mg/kg b.w. of REC-2006 rendered > 90% survival in lethally irradiated mice. The dose reduction factor was calculated to be 1.62 considering survival as the end point. REC-2006 treatment marked in significant increase in endogenous spleen colony forming units. In REC-2006 treated group, super oxide dismutase activity was increased significantly compared to the radiation control group (Liver, p = 0.00, Jejunum p = 0.00). The extract also inhibited radiation induced lipid peroxidation in liver (p = 0.00) at 24 h. REC-2006 administration (100-200 microg/ml) significantly reduced the halo diameter in mice thymocytes. Nearly 10 fold difference between the effective dose (6 mg/kg b.w.) and LD50 and the high degree of whole body survival (> 90% against 10 Gy irradiation) indicates REC-2006 to be safe and highly promising to achieve significant radioprotection against lethal radiation. Further purification and identification of active molecules and their efficacy studies in higher animals therefore demand attention.
[Show abstract][Hide abstract] ABSTRACT: We have evaluated the effect of variation in aryl-tetralin lignans on the radioprotective properties of Podophyllum hexandrum. Two fractionated fractions of P. hexandrum [methanolic (S1) and chloroform fractions (S2)], with varying aryl-tetralin lignan content were utilized for the present study. The peroxyl ion scavenging potentials of S1 and S2 were found to be comparable [i.e. 45.88% (S1) and 41% (S2)] after a 48 h interval in a time-dependent study, whereas in a 2 h study, S2 exhibited significant (P < 0.05) antioxidant activity in different metal ion + flux states. In the aqueous phase, S2 exhibited non-site-specific reactive oxygen species scavenging activity, i.e. 73.12% inhibition at 500 mug ml(-1). S1 exhibited 58.40 +/- 0.8% inhibition (at 0.025 mug ml(-1)) of the formation of reactive nitrite radicals, comparable to S2 (52.45 +/- 0.825%), and also showed 45.01% site-specific activity (1000 mug ml(-1)), along with significant (P < 0.05) electron donation potential (50-2000 mug ml(-1)) compared to S2. Such activities of S1 could be attributed to the significantly (P < 0.05) higher levels of podophyllotoxin beta-d-glucopyranoside (16.5 times) and demethyl podophyllotoxin glucoside (2.9 times) compared with S2. Together, these findings clearly prove that aryl-tetralin lignan content influences the radiation protective potential of the Podophyllum fractions to a great extent.
Evidence-based Complementary and Alternative Medicine 01/2007; 3(4):503-11. DOI:10.1093/ecam/nel037 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: At the organismic level, exposure to radiation can produce taste aversion (CTA) learning and emesis, which have been proposed as behavioral endpoints that are mediated by harmful effects of radiations on peripheral systems, primarily the gastrointestinal system. Thus, the aim of the present investigation was to study the gastroprotective action of hydroalcoholic extract of zingiber rhizome (Zingiber officinale Rosc.) against radiation-induced conditioned taste aversion (CTA) in both male and female species of animals, for testing its potential as a behavioral radioprotector. Administration of zingiber extract 1 h before 2-Gy gamma-radiation was significantly effective in blocking the saccharin avoidance response, with 200 and 250 mg/kg b.wt. i.p., being the most effective doses for male and female rats, respectively. A comparison of the efficacy of zingiber extract with two antiemetic drugs, ondansteron and dexamethasone, revealed that the extract rendered comparable protection against radiation-induced CTA. Our experiments also confirmed the existence of sex dichotomy (i.e., the sex of animal greatly influenced response towards radiation exposure) in relation to behavioral responses (CTA) or differential metabolism. The observed gender variations were hypothesized to be a result of hormonal fluctuations and differences in pharmacological parameters in male and female rats. To correlate the mechanism of action, the free-radical-scavenging potential of zingiber extract to scavenge hydroxyl ion and nitric oxide was also tested, in cell-free system and a concentration of 1000 microg/ml, was found to be the most potent, which has been proposed as one the many activities assisting in its overall ability to modulate radiation-induced taste aversion. The results demonstrate that Z. officinale possesses antioxidant, radioprotective and neuromodulatory properties that can be effectively utilized for behavioral radioprotection and for efficiently mitigating radiation-induced CTA in both males and females species.