Current Issue : July - September Volume : 2018 Issue Number : 3 Articles : 6 Articles
The objective of this research is to generate leads for developing our ultimate\npoly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active\nmolecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling\n(via cholinesterase inhibition) are still being sought for combating Alzheimerââ?¬â?¢s disease (AD).\nWe differentiate ââ?¬Å?poly-activeââ?¬Â agents from ââ?¬Å?multi-targetââ?¬Â ones by defining them as single\nmolecular entities designed to target only specific contributory synergistic pharmacologies in\na disease. For instance, in AD, free radicals either initiate or act in synergy with other\npharmacologies, leading to disease worsening. For this preliminary report, a total of 14\n(i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives\nwere synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and\ninhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives\n(4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance\ncapacity (ORAC) assay. The antioxidant values were either comparable or more potent than the\ncomparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c)\nyielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base\nsearch confirmed that most of the compounds reported herein are new, except 9a and 9c which are\nalso commercially available....
Recent evidence demonstrates that a double dose of Jasminoidin (2�JA) ismore effective than Jasminoidin (JA) in cerebral ischemia\ntherapy, but its dosage-effect mechanisms are unclear. In this study, the software GeneGo MetaCore was used to perform pathway\nanalysis of the differentially expressed genes obtained in microarrays of mice belonging to four groups (Sham, Vehicle, JA, and\n2�JA), aiming to elucidate differences in JA and 2�JA�s dose-dependent pharmacological mechanism from a system�s perspective.\nThe top 10 enriched pathways in the 2�JA condition were mainly involved in neuroprotection (70% of the pathways), apoptosis and\nsurvival (40%), and anti-inflammation (20%), while JA induced pathways were mainly involved in apoptosis and survival (60%),\nanti-inflammation (20%), and lipid metabolism (20%). Regarding shared pathways and processes, 3, 1, and 3 pathways overlapped\nbetween the Vehicle and JA, Vehicle and 2�JA, and JA and 2�JA conditions, respectively; for the top ten overlapped processes these\nnumbers were 3, 0, and 4, respectively.The common pathways and processes in the 2�JA condition included differentially expressed\ngenes significantly different from those in JA. Seven representative pathways were only activated by 2�JA, such as Gamma-Secretase\nregulation of neuronal cell development. Process network comparison indicated that significant nodes, such as alpha-MSH, ACTH,\nPKR1, and WNT, were involved in the pharmacological mechanism of 2�JA. Function distribution was different between JA and\n2�JA groups, indicating a dosage additive mechanism in cerebral ischemia treatment. Such systemic approach based on wholegenome\nmultiple pathways and networks may provide an effective and alternative approach to identify alterations underlining\ndosage-dependent therapeutic benefits of pharmacological compounds on complex disease processes....
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Compared with other therapies for diabetic\npatients, islet transplantation can effectively prevent and reverse diabetes-induced microvascular disease, such as diabetic\nretinopathy and nephropathy. PTX3 is the only long pentraxin that can be detected in renal tissue. In this study, we investigated\nthe expression of PTX3 when early DN was reversed after islet transplantation. Methods. Diabetes was induced in rats by\ninjecting streptozotocin (STZ). Twelve weeks later, the diabetic rats were divided into 2 groups: the islet transplantation group\n(IT) and the diabetic nephropathy group (DN). Renal injury, renal function, and the expression of PTX3 in the plasma and the\nkidneys were assessed with urinalysis, immunohistochemical staining, and Western blot, respectively. Results. The expression of\nPTX3 in the kidney was significantly decreased in the DN group but increased in the IT group because of the reversal of DN.\nConclusions. Our data showed that the level of PTX3 in renal tissue is closely related to renal injury in DN. This may be used to\nquantify the extent of renal injury in DN, provide a potential early indicator of renal tubular injury in early DN patients, and\nassess DN clinical progression....
The objective of our work is to make a pharmacological study of molecules derived from 4-phenyl-1,5-benzodiazepin-2-one\ncarrying long chains so that they have a structure similar to surfactants, with the benzodiazepine as a hydrophilic head and\na carbon chain as a hydrophobic tail. First, we studied the acute toxicity of the above mentioned 4-phenyl-1,5-benzodiazepin-2-one\nderivatives. This study was conducted according to OECD 423 guidelines in female mice and revealed that these compounds are\nnontoxic. We then assessed the psychotropic effects of our products on the central nervous system (CNS). The results obtained\nshow that 4-phenyl-1,5-benzodiazepin-2-one has no sedative effect at therapeutic doses of 100 and 200 mg/kg. On the other hand,\nits long-chain derivatives possess them. Moreover, all these products have no cataleptic and hypnotic effects at the doses studied.\nBut at 100 mg/kg, these compounds all have the ability to significantly prolong the hypnotic effect of thiopental sodium....
NF-�ºB signaling pathways play an important role in the regulation of cellular immune\nand stress responses. Aberrant NF-�ºB activity has been implicated in almost all the steps of cancer\ndevelopment and many of the direct and indirect contributions of this transcription factor system\nfor oncogenesis were revealed in the recent years. The indirect contributions affect almost all\nhallmarks and enabling characteristics of cancer, but NF-�ºB can either promote or antagonize these\ntumor-supportive functions, thus prohibiting global NF-�ºB inhibition. The direct effects are due to\nmutations of members of the NF-�ºB system itself. These mutations typically occur in upstream\ncomponents that lead to the activation of NF-�ºB together with further oncogenesis-promoting\nsignaling pathways. In contrast, mutations of the downstream components, such as the DNA-binding\nsubunits, contribute to oncogenic transformation by affecting NF-�ºB-driven transcriptional output\nprograms. Here, we discuss the features of recently identified oncogenic RelA fusion proteins and the\ncharacterization of pathways that are regulating the transcriptional activity of NF-�ºB by regulatory\nphosphorylations. As NF-�ºBâ��s central role in human physiology prohibits its global inhibition,\nthese auxiliary or cell type-specific NF-�ºB regulating pathways are potential therapeutic targets....
Background. Renal vasoconstriction, oxidative stress, endothelial dysfunction, and apoptosis are the major causes of contrastinduced\nnephropathy (CIN). The aim of this study was to evaluate the protective effects of enalapril maleate and folic acid tablets\nonCIN in diabetic rats. Methods. Thirty-two Sprague-Dawley rats were divided into four groups: CIN (C), CIN + enalapril maleate\n(CE), CIN + folic acid (CF), and CIN + enalapril maleate and folic acid tablets (CEF). CE, CF, and CEF rats were treated orally\nwith enalapril maleate, folic acid, or enalapril maleate and folic acid tablets, respectively, for 5 days. CIN was induced in all groups\nfollowed by analyzed biochemical parameters, oxidative stress markers, endothelial dysfunction parameters, renal histopathology,\nand TUNEL staining. Results. Serum creatinine, blood urea nitrogen, and malondialdehyde levels were lower in the CEF group\nthan in the C group. Homocysteine, superoxide dismutase, glutathione peroxidase, and nitric oxide levels were higher in the CEF\ngroup than in the C group. Histopathology scores and percentage of apoptotic kidney cells in the CEF group were significantly\ndecreased compared with those in the C group. Conclusions.These results suggest that enalapril maleate and folic acid tablets have\na protective effect against CIN in diabetic rats....
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