Current Issue : April - June Volume : 2011 Issue Number : 2 Articles : 9 Articles
Due to intensified research over the past decade, the Hedgehog (HH) pathway has been identified as a pivotal defect implicated in roughly 25% of all cancers. As one of the most frequent cancer worldwide, the development of Basal cell carcinoma (BCC) due to activation of the HH pathway has been convincingly demonstrated. Thus the discovery of this central tumor-promoting signalling pathway has not only revolutionized the understanding of BCC carcinogenesis but has also enabled the development of a completely novel therapeutic approach. Targeting just a few of several potential mutations, HH inhibitors such as GDC-0449 achieved already the first promising results in metastatic or locally advanced BCC. This paper summarizes the current understanding of BCC carcinogenesis and describes the current ââ?¬Å?mechanism-basedââ?¬Â therapeutic strategies....
Background\r\nFragile X syndrome is caused by loss of function of the fragile X mental retardation 1 (FMR1) gene and shares multiple phenotypes with autism. We have previously found reduced expression of the protein product of FMR1 (FMRP) in vermis of adults with autism.\r\nMethods\r\nIn the current study, we have investigated levels of FMRP in the superior frontal cortex of people with autism and matched controls using Western blot analysis. Because FMRP regulates the translation of multiple genes, we also measured protein levels for downstream molecules metabotropic glutamate receptor 5 (mGluR5) and ?-aminobutyric acid (GABA) A receptor �Ÿ3 (GABR�Ÿ3), as well as glial fibrillary acidic protein (GFAP).\r\nResults\r\nWe observed significantly reduced levels of protein for FMRP in adults with autism, significantly increased levels of protein for mGluR5 in children with autism and significantly increased levels of GFAP in adults and children with autism. We found no change in expression of GABR�Ÿ3. Our results for FMRP, mGluR5 and GFAP confirm our previous work in the cerebellar vermis of people with autism.\r\nConclusion\r\nThese changes may be responsible for cognitive deficits and seizure disorder in people with autism....
Background\r\nGlycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor a/? (PPARa/?) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.\r\nMethods\r\nA 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period.\r\nResults\r\nCompared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043).\r\nConclusions\r\nAleglitazar, a dual PPARa/? agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM....
In quiescent aortic spiral preparation of rat, hydrogen peroxide (H2O2) in concentration range of 10-6 to 10-3 caused the contraction of aortic spiral preparation dose dependently, while broad range of concentration caused triphasic response: a transient contraction (10-6-10-3 M) , relaxation (10-3-10-2.5 M) and persistence contraction (10-2 M). Endothelium removal potentiated the contractile response but did not affect the relaxant response suggesting relaxant response to H2O2 is independent of endothelium. Catalase (1000 U/ml), H2O2 scavenger, inhibit almost contractile as well as relaxant response, where as tempol (100 μM), superoxide anion scavenger and DMSO (dimethyl sulphoxide) (5 mM), hydroxyl radical scavenger, unable to inhibit contractile as well as relaxant response produced by H2O2, conforming the response is only due to H2O2 and not due to hydroxyl radical or superoxide anion. Genistein (100 μM), tyrosine kinase inhibitor, and verapamil (1 μM), voltage dependent Ca2+ channel blocker, inhibited contractile response whereas they could not inhibit the relaxant response. KCl (30 mM), potassium channel blocker, inhibits the relaxant response when added at the starting point of the relaxation, suggesting the role of the K+ channels in relaxant response to H2O2. TEA (tetra ethyl ammonium bromide- KCa blocker) (5 mM), 4-AP (5 mM), 4- amino pyridine, KV blocker and a KATP blocker Glybenclamide (10 μM), caused inhibition of relaxant phase but unable to potentiate or diminish contractile phase. Where as BaCl2 (0.1 mM), inward rectifier K+ channel blocker, could not inhibit relaxant as well as contractile phase to H2O2. So it is reasonably to conclude that relaxation, found in triphasic responses of H2O2, is not dependent on endothelium and it is due to the activation of the potassium channels like KCa, KATP, KV....
The chimeric Bcr-Abl oncoprotein with constitutive tyrosine kinase activity plays a pivotal role in the pathogenesis of chronic myeloid leukemia (CML), therefore being an ideal target for the drug development. Although tyrosine kinase inhibitors achieved great success in the treatment of CML, their effect could be abrogated by mutation in the kinase domain where they bind to. Therefore inducing Bcr-Abl degradation could be an alternative strategy to treat Bcr-Abl-driven leukemia. Celastrol is a quinone methide triterpene with various biological activities including anticancer activity. In the current study, we reported that celastrol induced time-dependent Bcr-Abl degradation and apoptosis in K-562 CML cells. We also found that short-time exposure to celastrol was sufficient to induce committed apoptotic signal; removal of celastrol could cause re-expression of Bcr-Abl, which however cannot rescue the cell from undergoing apoptosis. In addition, we found that celastrol-induced Bcr-Abl degradation and cell apoptosis were not suppressed by commonly used protease inhibitors or their mixture under the selected experimental conditions. Our study clearly demonstrated that celastrol inhibits Bcr-Abl expression/function by inducing its degradation, which at least contributes to our understanding of this natural product�s ability to induce tumor cell apoptosis. Our finding strongly supports the idea that celastrol could be developed into a novel anti-CML drug....
The learning and memory deficits have been recognized as severe and consistent neurological disorders associated with numerous neurodegenerative states. Cognition enhancers can be used to facilitate attention abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with age and age-related pathologies. Research in this area has gained momentum only in the recent past after the biochemical and physiological basis of these processes have been understood. A considerable alteration in the neurotransmission is a consistent finding in cognitive disorders. Therefore, many therapeutic strategies to augment the concentration of neurotransmitters in brain such as cholinergic agents, biogenic amines and neuropeptides etc. have been evaluated in cognitive deficits. CNS modulators are the type of antiamnesics that act via modulation of the neurological processes underlying memory storage. These include psychostimulants, excitatory amino acids and most important of all “nootropics”. In this review, some conventional as well as newer strategies have been discussed....
Background\r\nStromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling.\r\nMethods\r\nThese experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice.\r\nResults\r\nIn the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells. \r\nConclusions\r\nThese observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI....
Copper-zinc superoxide dismutase (SOD1) is a detoxifying enzyme localized in the cytosol, nucleus, peroxisomes, and mitochondria. The discovery that mutations in SOD1 gene cause a subset of familial amyotrophic lateral sclerosis (FALS) has attracted great attention, and studies to date have been mainly focused on discovering mutations in the coding region and investigation at protein level. Considering that changes in SOD1 mRNA levels have been associated with sporadic ALS (SALS), a molecular understanding of the processes involved in the regulation of SOD1 gene expression could not only unravel novel regulatory pathways that may govern cellular phenotypes and changes in diseases but also might reveal therapeutic targets and treatments. This review seeks to provide an overview of SOD1 gene structure and of the processes through which SOD1 transcription is controlled. Furthermore, we emphasize the importance to focus future researches on investigating posttranscriptional mechanisms and their relevance to ALS....
This study was performed to evaluate adverse toxicological effects mediated by transactivation and transrepression mechanism on oral administration of Prednisolone in female ICR Mice. Twenty four female ICR mice of 5-7 weeks old were randomly divided in two groups (Group I and Group II); 12 animals in each group. Animals of Group I served as vehicle control and Group II as Prednisolone treated group at 40 mg/kg body weight per day for 14 consecutive days. Test item was formulated in distilled water and administered orally with gavage needle fitted on the graduated syringe. Animals of control group were administered with vehicle alone (Elix water) and handled in same manner as treated group. Animal were observed for clinical signs of toxicological significance and mortality, body weight, body weight changes, feed consumption, hematology and clinical chemistry investigations, organ weight and relative organ weight parameters. Significant decrease in body weight was observed on day 7 onwards till the end of treatment period in treated group as compared to concurrent control group; however significant reduction in body weight gain was observed in treated group on day 4 and day 7 of the treatment period. Feed consumption was comparatively more in treated group of animals compared to concurrent control group but this change was statistically not significant. Significant decrease in WBC, MCV, lymphocyte and basophils; increase in RBC, Hb, MCHC and neutrophils were observed in treated group compared to concurrent control group of animals. Changes noticed in hematological profile are considered to be adverse effect of drug on bone marrow leading to altered leucopoiesis and erythropoiesis. Significant increase in serum glucose, triglyceride, total cholesterol, HDL cholesterol, total protein, albumin and calcium were observed in treated group compared to concurrent control group of animals. Significant decrease in urea level was observed in treated animals as compared to concurrent control group. Changes noticed in serum biochemical profile are indicative of catabolic effects of glucocorticoid on body system. Significant reduction in spleen, thymus and lungs absolute organ weight was observed in treated mice compared to concurrent control group. Changes in absolute organ weight are indicative of immunosuppressive effect of prednisolone on treated animals. Significant reduction in spleen and thymus relative organ weight was observed in treated mice compared to concurrent control group of animals. Changes observed in relative organ weight are indicative of immunosuppressive effect of prednisolone on treated animals....
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