Alterations in hippocampal serotonergic and INSR function in streptozotocin induced diabetic rats exposed to stress: neuroprotective role of pyridoxine and <Emphasis Type="Italic">Aegle marmelose</Emphasis>

Diabetes and stress stimulate hippocampal 5-HT synthesis, metabolism and release. The present study was carried out to find the effects of insulin, Aegle marmelose alone and in combination with pyridoxine on the hippocampal 5-HT, 5-HT_2A receptor subtype, gene expression studies on 5-HT_2A, 5-HTT, INSR, immunohistochemical studies and elevated plus maze in streptozotocin induced diabetic rats. 5-HT content showed a significant decrease (p < 0.001) and a significant increase (p < 0.001) in 5-HIAA in hippocampus of diabetic rats compared to control. 5-HT receptor binding parameters B_max and K_d showed a significant decrease (p < 0.001) whereas 5-HT_2A receptor binding parameters B_max showed a significant decrease (p < 0.001) with a significant increase (p < 0.05) in K_d in hippocampus of diabetic rats compared to control. Gene expression studies of 5-HT_2A, 5-HTT and INSR in hippocampus showed a significant down regulation (p < 0.001) in diabetic rats compared to control. Pyridoxine treated in combination with insulin and A. marmelose to diabetic rats reversed the 5-HT content, B_max , K_d of 5-HT, 5-HT_2A and gene expression of 5-HT_2A, 5-HTT and INSR in hippocampus to near control. The gene expression of 5-HT_2A and 5-HTT were confirmed by immunohistochemical studies. Behavioural studies using elevated plus maze showed that serotonin through its transporter significantly increased (p < 0.001) anxiety-related traits in diabetic rats which were corrected by combination therapy. Our results suggest that pyridoxine treated in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalising diabetic related stress and anxiety through hippocampal serotonergic function. This has clinical significance in the management of diabetes.     

Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC₅₀ ? 50 nM versus CK1δ. The two lead compounds have ?100 nM EC₅₀ values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.     

Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c

The gene encoding human IAP-like protein (hILP) is one of several mammalian genes with sequence homology to the baculovirus inhibitor-of-apoptosis protein (iap) genes. Here we show that hILP can block apoptosis induced by a variety of extracellular stimuli, including UV light, chemotoxic drugs, and activation of the tumor necrosis factor and Fas receptors. hILP also protected against cell death induced by members of the caspase family, cysteine proteases which are thought to be the principal effectors of apoptosis. hILP and Bcl-x_L were compared for their ability to affect several steps in the apoptotic pathway. Redistribution of cytochrome c from mitochondria, an early event in apoptosis, was not blocked by overexpression of hILP but was inhibited by Bcl-x_L. In contrast, hILP, but not Bcl-x_L, inhibited apoptosis induced by microinjection of cytochrome c. These data suggest that while Bcl-x_L may control mitochondrial integrity, hILP can function downstream of mitochondrial events to inhibit apoptosis.     

Clinical, anatomical and biophysical data on a case of encephalopathy with aluminum deposits]

A man presented at 27 years of age, the first signs of a progressive neurological and mental deterioration which eventually lead to his death at 37, from an intercurrent pulmonary infection. He was a severe alcoholic. The pathological examination of the brain revealed patchy demyelination and deposits of crystalline material, resembling so called calcifications. The biophysical examination showed the presence in the brain and other organs, of aluminum and phosphorus in all deposits, sometimes associated with iron, sulfur and calcium. Nothing in his past history suggests any contact with aluminum. Presumably this is a case of "generalized aluminosis", with the main clinical and pathological features manifesting in the central nervous system.     

Trisomy/partial monosomy 13 mosaicism associated with relatively mild clinical malformation.

A female fetus with a rare de novo chromosome abnormality involving mosaicism with two cell lines with trisomy 13 and presumptive partial monosomy 13 due to a Robertsonian translocation and ring chromosome, respectively, was prenatally diagnosed. On termination this case, together with apparently the only other three reported cytogenetically similar cases, was found to have much less severe clinical abnormalities than might have been predicted. The possibility in these cases that the effects of the trisomy and monosomy for the common segment of chromosome 13 may have counterbalanced each other at the tissue level in embryogenesis thereby resulting in less disturbance of morphogenesis than would be expected for each type of imbalance acting in isolation is considered.     

Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors

The design and synthesis of a novel series of c-jun N-terminal kinase (JNK3) inhibitors is described. The development and optimization of the 2-phenoxypyridine series was carried out from an earlier pyrimidine series of JNK1 inhibitors. Through the optimization of the scaffold 2, several potent compounds with good in vivo profiles were discovered.     

Pegged and smooth rhizoids in complex thalloid liverworts (Marchantiopsida): structure,function and evolution

Rhizoids played essential roles in the early evolution of land plants. All liverworts, the closest living relatives of the first land plants, produce unicellular rhizoids, except for Haplomitrium. The complex thalloids are uniquely characterized by dimorphic rhizoids: smooth rhizoids like those also produced by the simple thalloid and leafy clades and pegged rhizoids. Although this dimorphism has been long and widely recognized, considerations of its functional basis are few and contradictory. Here we present conclusive cytological and experimental evidence that the function of smooth and pegged rhizoids is markedly different, as reflected by major differences in their structure, physiology and vital status. Mature smooth rhizoids are alive (indeed their main functions in nutrition, anchorage and as conduits for mycobiont entry all depend on living cytoplasm) and dehydration causes irreversible collapse of their cell walls, but pegged rhizoids, which are dead at maturity, function as a highly effective internalized external water‐conducting system, especially within carpocephala. Their cavitation‐resistant, elastic walls ensure retention of functional integrity during periods of desiccation. Our structural and functional data now raise novel hypotheses on patterns of rhizoid evolution in Marchantiopsida and open the way for dissecting the molecular basis of rhizoid morphogenesis in liverworts. © 2013 The Linnean Society of London, Botanical Journal of the Linnean Society, 2014, 174 , 68–92.