Search

Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals 1-3 . During extrusion, a cell detaches from a layer of surrounding cells while maintaining the continuity of that layer 4 . Vertebrate epithelial tissues primarily eliminate cells by extrusion, and the dysregulation of cell extrusion has been linked to epithelial diseases, including cancer 1,5 . The mechanisms that drive cell extrusion remain incompletely understood. Here, to analyse cell extrusion by Caenorhabditis elegans embryos 3 , we conducted a genome-wide RNA interference screen, identified multiple cell-cycle genes with S-phase-specific function, and performed live-imaging experiments to establish how those genes control extrusion. Extruding cells experience replication stress during S phase and activate a replication-stress response via homologues of ATR and CHK1. Preventing S-phase entry, inhibiting the replication-stress response, or allowing completion of the cell cycle blocked cell extrusion. Hydroxyurea-induced replication stress 6,7 triggered ATR-CHK1- and p53-dependent cell extrusion from a mammalian epithelial monolayer. We conclude that cell extrusion induced by replication stress is conserved among animals and propose that this extrusion process is a primordial mechanism of cell elimination with a tumour-suppressive function in mammals.

Insulin and insulin-like signaling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. For example, the inhibition of insulin-like signaling in C. elegans mediates its response to both osmotic stress and starvation. We report that in response to osmotic stress the cytosolic sulfotransferase SSU-1 antagonizes insulin-like signaling and promotes developmental arrest. Both SSU-1 and the DAF-16 FOXO transcription factor, which is activated when insulin signaling is low, are needed to drive specific responses to reduced insulin-like signaling. We demonstrate that SSU-1 functions in a single pair of sensory neurons to control intercellular signaling via the nuclear hormone receptor NHR-1 and promote both the specific transcriptional response to osmotic stress and altered lysophosphatidylcholine metabolism. Our results show the requirement of a sulfotransferase-nuclear hormone receptor neurohormonal signaling pathway for some but not all consequences of reduced insulin-like signaling.

Neuropathic pain arises because of neuronal injury. Unlike inflammatory pain which can be managed by classical nonsteroid anti-inflammatory drugs (NSAIDs), neuropathic pain is difficult to treat. The classical NSAIDs work through inhibition of cyclooxygenase 2 (COX2) enzyme. However, COX2 inhibitors are insufficient to treat neuropathic pain. Hence, it becomes important to explore for novel molecules acting through cell surface molecules like ion channels, for the treatment of neuropathic pain. We investigated multiple bromobenzothiophene carboxamides for their efficacy against neuropathic pain. Interestingly, AS6 was found to be very effective in treating neuropathic pain through inhibition of Kv4.3 ion channel. AS6 also reduced the COX2 overexpression associated with neuropathic pain. These results as well as results from our previous study indicate that AS6 can be a potent antinociceptive agent against both inflammatory and neuropathic pain.

We investigated the protective role of ceftriaxone plus sulbactam with VRP1034 (Elores) on hematological, lipid peroxidation, antioxidant enzymatic activities and Cd levels in the blood and tissues of cadmium exposed rats. Twenty-four male rats were divided into three groups of eight rats each. The control group received distilled water whereas group II received CdCl2 (1.5 mg/4 ml/body weight) through gastric gavage for 21 days. Group III received CdCl2 and was treated with ceftriaxone plus sulbactam with VRP1034 for 21 days. The hematological, biochemical, lipid peroxidation levels and enzymatic parameters were measured in plasma and tissues (brain, liver and kidney) of all groups. The Cd, Zn and Fe levels were measured in blood and tissues of all groups. Our findings showed significantly decreased cadmium (p<0.001), malonaldialdehyde (p<0.001) and myloperoxidase (MPO) levels along with significantly increased hemoglobin (p<0.01), RBC (p<0.05), hematocrit (p<0.05) levels and all antioxidant enzymatic activities (SOD, CAT, GR, GPx) in plasma and tissues of ceftriaxone plus sulbactam with VRP1034 treated group as compared to cadmium exposed group. Delta aminolevulinate dehydratase (δ-ALAD) activity was significantly (p<0.001) increased in the blood of ceftriaxone plus sulbactam with VRP1034 treated group as compared with cadmium exposed group. The levels of hepatic and renal parameters were significantly (p<0.001) decreased in ceftriaxone plus sulbactam with VRP1034 treated group as compared to cadmium exposed group. These findings indicate that ceftriaxone plus sulbactam with VRP1034 acts as a potent free radical scavenger and exhibits metal chelating properties that reduce free radical mediated tissue injury and prevent dysfunction of hepatic and renal organs during metal intoxication.

Etimicin sulfate, an ethylization derivative of gentamicin, is a new soluble wide-spectrum synthetic aminoglycoside drug. It has wide antibacterial spectrum with high effect and less cross resistance as compared to other aminoglycosides. In order to further explore its safety and tolerance, we have conducted a subactute toxicity study on swiss albino mice. Results from the present study have elucidated that treatment of etimicin sulfate exerts no significant signs of toxicity at any dose level used in the study. Physiological as well as hematological parameters were unaltered throughout the study. Biochemical examination and histopathology of all organs confirmed no significant alteration at any dose levels. The result of this study has suggested there was no obvious toxicity observed with the treatment of etimicin sulphate. It was found to be a safe alternative for various severe infections.

We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms.

The aim of this study was to compare the efficacy of ceftriaxone plus vancomycin (Vancoplus) versus ceftriaxone alone against cephalosporin resistant methicillin-resistant Staphylococcus aureus (MRSA) strain by using meningitis mice model. The MRSA strain ATCC 43300 was used to induce meningitis in mice. The mice were fed standard pelleted diet and water ad libitum. The test room was air conditioned with temperature 23 +/- 2 degrees C, humidity 65+/- 5% and with artificial fluorescent light 10-14 hrs. of light and dark, respectively. Twenty four mice were divided into four group containing six rats in each group. The ceftriaxone group received 28.57 mg/Kg body weight/day and the vancoplus group received 42.8 mg/Kg body weight/day and control as well as infected group received normal saline. The bacterial susceptibility test in CSF was performed for cephalosporin resistance MRSA strain by determining the lytic zone for the vancoplus and ceftriaxone antibiotic. The lytic zone was more in vancoplus as compared to ceftriaxone. It was also found that activities of antioxidant enzymes such as catalase were significantly increased (p<0.001) along with decreased (p<0.001) in lipid peroxidation (malonaldialdehyde) level in CSF of vancoplus treated group as compared to infected as well as ceftriaxone resistance group and come back to normal level. It was concluded that vancoplus beneficial for the patients who suffered from cephalosporin resistant MRSA bacterial strain.

Pneumonia is a severe infection that causes high morbidity and mortality rate worldwide. It is caused by Klebsiella pneumoniae, which generally causes upper respiratory tract infection. In case of such type of infection, levels of oxidant and antioxidant become imbalanced, which may contribute to lung injury. The present study was planned to evaluate the status of oxidant and antioxidant enzyme activities in plasma and lung tissue of pneumonia-infected rats model. Animals were randomly distributed into 3 groups of 8 rats each: groups I (control, normal saline treated), II (infected group), and III (infected + treated group). The findings showed that there was significant increase (P < .001) in body temperature along with decreased body weight in the infected group as compared to the control group. Similarly, all the activities of antioxidant enzymes (superoxide dismutase [SOD], catalase) were significantly decreased along with increased malonaldialdehyde (MDA) levels in plasma and lung tissue of the infected group as compared to the control group. These enzyme activities along with MDA levels were improved and came back near to normal level after administration of cefepime plus amikacin (potentox) for 7 days in group III. These studies concluded that fixed-dose combination of potentox improved oxidant and antioxidant levels in pneumonia infection.

Drug toxicity is a common cause of liver injury and kidney failure. This study was designed to elucidate whether administration of high doses of Ceftriaxone or Vancomycin induce oxidative stress in liver as well as kidney, and to investigate the protective effects of VRP 1020 with fixed dose combination of ceftriaxone-vancomycin (Immunox-V). Twenty four Mus musculus mice (weighing 30 +/- 5 g) were divided into four groups containing six mice in each group. The activities of antioxidant enzymes such as superoxide dismutase, catalase and the level of malonaldialdehyde, as an marker of lipid per oxidation, were measured to evaluate oxidative stress in homogenates of the liver and renal tissue. Ceftriaxone or vancomycin administration significantly increased malonaldialdehyde levels (p < 0.001) but significant decreased in superoxide dismutase (p<0.01) and catalase (p<0.001) activities. Co-administration of VRP 1020 with FDC of Immunox-V injections caused significantly decreased malonaldialdehyde levels (p< 0.001) and increased superoxide dismutase (p<0.01) and catalase (p<0.001) activities in liver and renal tissue when compared with other treated groups. Similarly, the levels of extracellular antioxidant (Creatinine and Uric acid) were found to be significant lowered in Immunox-V treated group when compared to ceftriaxone or vancomycin alone treated group. These results indicate that chemical mediated technology of VRP 1020 with fixed dose combination of Immunox-V can prevent drug induced nephrotoxicity and oxidative stress which protects liver injury as well as renal tissue damage by reducing reactive oxygen species which improve the activities of free radical scavenging enzymes.

Oxidative stress and free radical are causative factors for aminoglycoside induced tissue injury. The objective of present study was to evaluate effect of fixed dose combination of cefepime + amikacin on antioxidant enzymes such as superoxide dismutase (SOD), catalase along with malonaldialdehyde (MDA) levels in liver of Mus musculus mice. Our findings showed that the activities of the antioxidant enzymes such as superoxide dismutase (p<0.001, 62.2%), catalase (p<0.05, 47.5%) were significantly lowered along with increase in the MDA levels (66.0%) after the single treatment of amikacin as compared to control group. A significant improvement in the activities of superoxide dismutase and catalase along with decrease in MDA levels were observed in fixed dose combination of cefepime plus amikacin treated groups as compared to amikacin alone treated group. These findings suggest that the fixed dose combination therapy of cefepime + amikacin (Potentox) show significant free radical scavenging property which may contribute to decrease in aminoglycoside induced liver injury.

Pro-oxidant and anti-oxidant systems and their levels have significant roles in occlusive vascular diseases. In the present communication, we have measured the levels of some representative anti-oxidant enzymes in the blood of the patients of myocardial infarction after reperfusion and compared them to age and sex matched healthy persons. Our findings show that the activities of anti-oxidant enzymes (viz. SOD, catalase and glutathione reductase) are significantly decreased whereas there is significant increase in the levels of malonaldialdehyde (a marker of free radical-mediated damage) in the patients. The findings point out that ischemic myocardial disorders are associated with excessive free radical generation and free radical-mediated damage of lipids.

Effect of administration of 600 mg. vitamin E each day, for six days, was observed on activity of some of the anti-oxidant enzymes and levels of malondialdehyde (as an index of free radical mediated damage) in the platelets of patients reperfused after myocardial infarction. It has been found that vitamin E administration significantly lowers the level of malondialdehyde in the patients. Vitamin E administration increases the activities of anti oxidant enzymes (viz. superoxide dismutase, glutathione reductase and catalase) tested both in the patients and healthy controls. Vitamin E administration causes general stimulation of anti-oxidant enzyme activities both in healthy persons and the patients, however, lowering of lipid per-oxidation upon administration of vitamin E is specific for patients. These findings exhibit beneficial role of vitamin E administration in the management of the patients reperfused after myocardial infarction.

Objective: To synthesize some new alpha-mercapto-beta-substituted aryl acrylic acids, characterize them and investigate their in vitro cadmium chelating ability., Methods: Six alpha-mercapto-beta-substituted aryl acrylic acids were prepared by the alkaline hydrolysis of 5- (aryl methylene) rhodanines, obtained from the condensation of substituted aldehydes and rhodanine following the reported procedure. The new compounds were characterized by elemental analysis, infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The liver and kidney from cadmium chloride pre-administered rats were homogenized and their nuclear mitochondrial fraction (NMF) and supernatant cytosol fraction (SCF) were separated. A measured volume of each fraction was dialyzed separately using "dialysis sack" against buffered-KCl medium containing a compound in the final concentration of 1 x 10(-3) mol/L for 3 h at 37 degrees C. The whole content of "sack" was subjected to cadmium estimation following digestion with conc. Nitric acid was detected using flame atomic absorption spectrometer., Results: The in vitro screening showed that alpha-mercapto-beta-(p-methoxyphenyl) acrylic acid (compound 2) and alpha-mercapto-beta-(m-methoxy, p-hydroxyphenyl) acrylic acid (compound 4) were more effective than alpha-mercapto-beta-thienyl acrylic acid (compound 1) and alpha-mercapto-beta-(p-dimethylaminophenyl) acrylic acid (compound 3) in mobilizing cadmium as their dialyzable chelates. The presence of a methoxy group on the phenyl moiety (compounds 2 and 4) increases the metal chelating ability of mercapto acrylic acids., Conclusions: Compounds 2 and 4 seem to have accessibility to the cellular system and capability of chelating-out the intracellularly bound cadmium.

The influence of an antioxidant agent such as N-acetyl cysteine (NAC) or mannitol on the cadmium chelating ability of monoisoamyl 2,3-dimercaptosuccinate (MiADMS) was investigated in cadmium pre-exposed rats. This ester of 2,3-dimercaptosuccinic acid (DMSA), an accepted drug for lead poisoning, being lipophilic in nature was expected to be an efficient cadmium chelator. The treatment of cadmium intoxicated animals with MiADMS reversed cadmium induced increase in blood catalase, superoxide dismutase (SOD) and malondialdehyde (MDA), liver MDA and brain SOD and MDA levels but not the decrease in blood, liver brain reduced glutathione (GSH) and increase in oxidized glutathione (GSSG) levels, consistent with the lowering of tissue cadmium burden. The administration of NAC or mannitol reversed the cadmium induced alterations in blood and liver GSH, GSSG, blood catalase, SOD, MDA, liver SOD, MDA and brain MDA levels without lowering blood and tissue cadmium contents. However, treatments with the combination of MiADMS and NAC or MiADMS and mannitol reversed these alterations as well as reduced blood and tissue cadmium concentrations. The combined treatment with MiADMS and mannitol was better than that with MiADMS and NAC, and was significantly more effective in normalizing blood, liver GSH, GSSG, brain GSSG, and their GSH/GSSG ratios than that by either of them alone. The combined treatments also improved liver and brain endogenous zinc levels, which were decreased due to cadmium toxicity. The results suggest that the administration of an antioxidant during chelation of cadmium may provide beneficial effects by reducing oxidative stress without its cadmium removing ability.