Chemical biology of mutagenesis and DNA repair: cellular responses to DNA alkylation

The reaction of DNA-damaging agents with the genome results in a plethora of lesions, commonly referred to as adducts. Adducts may cause DNA to mutate, they may represent the chemical precursors of lethal events and they can disrupt expression of genes. Determination of which adduct is responsible for each of these biological endpoints is difficult, but this task has been accomplished for some carcinogenic DNA-damaging agents. Here, we describe the respective contributions of specific DNA lesions to the biological effects of low molecular weight alkylating agents.National Institutes of Health (U.S.) (grant CA080024)National Institutes of Health (U.S.) (grant CA26731)National Institutes of Health (U.S.) (grant ES02109

Influence of tobacco on median and ulnar nerve in the population of South Rajasthan

Background: Chemicals present in tobacco have been implicated in causing subclinical changes in myelin sheaths of peripheral nerves. This may contribute to nerve dysfunction particularly in the form of decreases in nerve conduction velocity. So, present study aims to measure nerve conduction velocity in the median nerve and ulnar nerve among tobacco users.Methods: This was a cross-sectional case-control study involving 50 normal healthy subjects and 150 tobacco users. The nerve conduction study was performed using fully computerized electromyography (EMG) and nerve conduction velocity (NCV) machine. By this machine Sensory nerve conduction velocity (SNCV) and Motor nerve conduction velocity (MNCV) tests of both the nerves (median and ulnar) was performed on subjects. Data was analyzed by using appropriate statistical methods.Results: In our study statistically significant changes (P < 0.001) were found in the Sensory nerve conduction velocity of both the nerves whereas no such changes were found in Motor nerve conduction velocity of both the nerves in tobacco users as compared to nontobacco users.Conclusions: We conclude that use of tobacco results in reduction of conduction velocities in sensory fibers of the median nerve and ulnar nerve but not in motor fibers

Hyperuricaemia and essential hypertension: a case control study in Southern Rajasthan

Background: Hypertension is one of the current emerging community health problems, which is very common affecting one in four individuals. Hyperuricemia is predictive for the development of both hypertension and coronary artery disease. Since there are various etiological factors associated with hypertension so it is very difficult to predict which one is the most common cause of hypertension. Little or no information is present in the population of Rajasthan, on the association between serum uric acid and essential hypertension. Hence this study is carried out to investigate the existence of an association between serum uric acid and essential hypertension.Methods: In this hospital based case control study, a total of 75 newly diagnosed essential hypertensive cases, 75 prehypertensive cases and 50 normotensive healthy controls, aged 20-50 years of both sexes were enrolled after excluding gout, diabetes mellitus, cardiovascular diseases, renal diseases, metabolic syndrome, secondary hypertension or history of having relevant drugs by taking detailed history and physical examination. Serum uric acid was measured in all study cases as well as control subjects.Results: The results of our study revealed that the mean serum uric acid level and the frequency of subjects with increased serum uric acid level were significantly higher in newly diagnosed cases of essential hypertension as compared to prehypertensive and normotensive controls (p0.05). These results indicate a definite association between hyperuricaemia and essential hypertension.Conclusions: In the present study, Elevated level of SUA is significantly linked with PreHT and EHT after controlling various confounding factors. The present study showed that the number of hyperuricaemic individuals and mean SUA level were significantly higher in newly diagnosed cases of hypertension as compared to prehypertensive and normotensive control.

COMPARATIVE EVALUATION OF FIRST ORDER, ABSORBANCE RATIO AND BIVARIATE SPECTROPHOTOMETRIC METHODS FOR DETERMINATION OF ATOVAQUONE AND PROGUANIL IN PHARMACEUTICAL FORMULATION MALARONE®

Objective: Three simple, rapid, accurate and precise spectrophotometric methods have been developed for the simultaneous estimation of atovaquone and proguanil hydrochloride in pharmaceutical preparations.Methods: The determination of drugs was carried out using the first order derivative, absorbance-ratio and bivariate spectrophotometric methods. The methods were validated for their linearity, accuracy and precision, recovery and ruggedness according to the ICH guidelines.Results: The linearity was established in the concentration range of 1.0-10 µg/ml for atovaquone and 0.5-8.0 µg/ml for proguanil hydrochloride by all three methods. The limit of detection (LOD) and the limit of quantitation (LOQ) of the methods varied from 0.252 to 0.270 µg/ml and 0.764 to 0.825 µg/ml for atovaquone and 0.119 to 0.156 µg/ml and 0.361 to 472 µg/ml for proguanil hydrochloride respectively. The intra-and inter-batch accuracy (% recovery) and precision (% RSD) ranged from 99.16 to 101.05 % and 0.603 to 1.048 for atovaquone and 99.74 to 101.12 % and 0.593 to 1.001 for proguanil respectively.Conclusion: The proposed methods were applied to a pharmaceutical formulation with acceptable accuracy and precision without any interference from commonly used excipients and additives. The results show that all three methods are comparable, cost effective and rapid and thus can be readily used in quality control labs for routine analysis of these drugs.Â

Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy.

Anti-angiogenic therapies for cancer such as VEGF neutralizing antibody bevacizumab have limited durability. While mechanisms of resistance remain undefined, it is likely that acquired resistance to anti-angiogenic therapy will involve alterations of the tumor microenvironment. We confirmed increased tumor-associated macrophages in bevacizumab-resistant glioblastoma patient specimens and two novel glioblastoma xenograft models of bevacizumab resistance. Microarray analysis suggested downregulated macrophage migration inhibitory factor (MIF) to be the most pertinent mediator of increased macrophages. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naive tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Media from macrophages exposed to bevacizumab-resistant tumor cell conditioned media increased glioma cell proliferation compared with media from macrophages exposed to bevacizumab-responsive tumor cell media, suggesting that macrophage polarization in bevacizumab-resistant xenografts is the source of their aggressive biology and results from a secreted factor. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naive patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth

Beneficial Effect of Oryzanol on Transient Middle Artery Occlusion Induced Ischemic Stroke in Atherosclerotic Rats. Improvement in Behavioural and Biochemical Parameters

The present study was designed to determine the beneficial effect of oryzanol treatment in the ischemic stroke in atherosclerotic rats. Atherosclerosis was induced in rats using high fat diet (containing 20% ground nut oil, 0.5% cholesterol, 1% cholic acid) for 32 days. Ischemic stroke was induced in the atherosclerotic rat (AT rats) on 33rd day using tMCAO model. In the oryzanol treatment group, oryzanol (100 mg/kg, po) was administered on the very first day (day rats were fed with high fat diet), ischemic stroke was induced on 33rd day and oryzanol treatment was continued after the induction of ischemia from 34th day to 40th day. The neurological score was determined for 7days with gap of 24 hrs between the testing procedure. Rats were sacrificed followed by the blood collection and excision of whole brain for the determination of various parameters including brain damage (infarct volume, brain hemisphere weight difference, and Na+-K+-ATPase activity) and oxidative stress parameter (SOD activity, reduced GSH level, MDA level, nitrite level and LDH level). It was observed that ischemia-reperfusion (IR rats) in atherosclerotic rats increased the neurological score, increase in infarct volume, brain hemisphere weight difference and reduced activity of Na+-K+-ATPase. Further IR rats showed the decreased activity of SOD activity and GSH, whereas the level of MDA, nitrite and LDH activity was found to be increased in the atherosclerotic-IR rats. Further it was observed that the oryzanol treatment in the atherosclerotic counteracted the high fat induced rise in the TG, LDL, and VLDL level and increased the level of HDL in the treated animals. Further the administration of oryzanol improved the neurological score, reduce the infarct volume, brain hemisphere weight difference and improve the activity of Na+-K+-ATPase. Oryzanol treatment further improved the SOD activity, increased the level of GSH, reduced the level of MDA, nitrite and LDH activity in atherosclerotic-IR rat

Mass-Transport Models with Multiple-Chipping Processes

We study mass-transport models with multiple-chipping processes. The rates of these processes are dependent on the chip size and mass of the fragmenting site. In this context, we consider k-chip moves (where k = 1, 2, 3, ....); and combinations of 1-chip, 2-chip and 3-chip moves. The corresponding mean-field (MF) equations are solved to obtain the steady-state probability distributions, P (m) vs. m. We also undertake Monte Carlo (MC) simulations of these models. The MC results are in excellent agreement with the corresponding MF results, demonstrating that MF theory is exact for these models.Comment: 18 pages, 4 figures, To appear in European Physical Journal

PROTECTIVE EFFICACY OF TRIDAX PROCUMBENS AND FICUS RELIGIOSA AGAINST ISONIAZID AND RIFAMPICIN INDUCED HEPATOCELLULAR DAMAGE IN RATS: A PRELIMINARY COMPARATIVE EVALUATION ON BIOCHEMICAL PARAMETERS

ABSTRACTObjective: There are limited therapies available for prevention and treatment of hepatitis following antitubercular therapy. Very few reports areavailable regarding the hepatoprotective activity of Tridax procumbens (Tridax daisy) and Ficus religiosa (Aswatha) against the hepatitis induced byantitubercular drugs. Hence, we studied the hepatoprotective activity of Tridax and Ficus in isoniazid- and rifampicin-induced hepatitis in rats.Methods: The rats were divided into five groups. Group 1 - Control, Group 2 - Toxic control received isoniazid + rifampicin (100 mg/kg intraperitonealeach), Group 3 - Received Tridax extract (200 mg/kg p.o.) along with isoniazid and rifampicin, Group 4 - Received Ficus extract (200 mg/kg p.o.)with isoniazid and rifampicin, Group 5 - Standard group receiving Liv-52 (10 mg/kg p.o.) along with isoniazid and rifampicin. After 21 days, alkalinephosphatase (ALP), alanine transaminase, aspartate transaminase, and bilirubin levels were estimated from the serum. One-way ANOVA was appliedto test for significance of biochemical data of the different groups. The significance is set at p≤0.05. As evident from our study, rats receiving Tridaxshows significant improvement in all liver function test (LFT) parameters.Results: There is a significant difference in all the LFT parameters between Tridax group and Liv-52 group (p=0.004 for total bilirubin, 0.001 for ALP).Between Liv-52 group and Ficus group only significant in total bilirubin (p=0.04).Conclusion: From this study, it can be concluded that methanolic extract of both Tridax and Ficus has got significant hepatoprotective effect.Keywords: Isoniazid, Rifampicin, Liver function tests, Hepatoprotective

Antitumor Effect of Some 3d-Metal Complexes of N-Isonicotinoyl-N'-o-Hydroxythiobenzhydrazide

A new ligand, N-isonicotinoyl-N'-o-hydroxythiobenzhydrazide (H2Iotbh), forms complexes [Co(Iotbh)(H2O)2], [M(Iotbh)] [M Ni(II) Cu(II) and Zn(ll)] and [M(Iotbh-H)(H2O)2] [M Mn(III), Fe(III)], which were characterized by various physico-chemical techniques. DMSO solution of metal complexes was observed to inhibit the growth of tumor in vitro, whereas the ligand did not. In vivo administration of these complexes resulted in prolongation of survival of tumor-bearing mice. Tumor-bearing mice administered with the solution of metal complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implications of the H2lotbh and its metal complexes in tumor regression and tumor growth associated immunosuppression

Simultaneous analysis of aliskiren and hydrochlorothiazide in pharmaceutical preparations and spiked human plasma by HPTLC

AbstractA simple, selective and precise method based on HPTLC has been developed for the simultaneous determination of aliskiren and hydrochlorothiazide in a fixed-dose tablet formulation and human plasma. The chromatography was performed on silica gel 60 GF254 plates, with a mobile phase consisting of methanol–chloroform (6:4, v/v). Densitometric analysis of the analytes was carried out at 225nm. Under optimized conditions, the Rf values were 0.26±0.02 and 0.71±0.02, and the resulting regression plots were linear (r2≥0.9997) in the concentration ranges of 1.00–10.0 and 0.10–1.00μgband−1 for aliskiren and hydrochlorothiazide. The limit of detection and limit of quantitation of the validated method were 0.206 and 0.624μgband−1 for aliskiren and 0.015 and 0.046μgband−1 for hydrochlorothiazide, respectively. The % expected content of aliskiren and hydrochlorothiazide in the commercial tablet formulation was 99.2% and 101.3%, respectively. For spiked plasma sample preparation, the analytes and nebivolol internal standard were extracted from 500μL of plasma sample by solid-phase extraction on LiChrosep® DVB-HL cartridges. The mean extraction recovery of aliskiren and hydrochlorothiazide from human plasma was 87.2% and 76.5%, respectively. In addition, the stability of the analytes in plasma was established under different storage conditions