Okadaic acid: a tool to study regulatory mechanisms for neurodegeneration and regeneration in Alzheimer’s disease

<正>Okadaic acid:Okadaic acid(OKA),a polyether(C38 fatty acid)toxin,is a potent and selective inhibitor of protein phosphatase,PP1 and protein phosphatase 2A(PP2A).It is mainly extracted from a black sponge Hallichondria okadaii and has been suggested to play a potent probe for studying the various molecular,cellular,biochemical and mechanism     

Determination of LCt50 of aerosolized paraquat and its pulmonary toxic implications in non-anesthetized rats

Paraquat (PQ), a highly popular agricultural herbicide, is a serious occupational hazard with lethality reported at doses as low as 35?mg/kg body weight with intoxication occurring via inhalation or dermal route. The main objective of this study was to determine the median lethal concentration (LCt₅₀) of paraquat through whole body exposure in adult male Wistar rats. Aerosolized PQ dissolved in water was delivered in a dose-dependent manner, to fully conscious rats confined in whole body plethysmograph (WBP), in a nebulized form with concentrations ranging from 40–200?mg/kg of air over a 4?h exposure period. Animals were observed up to 24–48?h post-exposure to observe any lethality. LCt₅₀ estimates (±95% confidence interval) were obtained from the sequential stage-wise experiments using probit analysis. Rat lungs were examined radiologically and histopathologically. Gas chromatography–mass spectrometry (GC-MS) analysis determined the correlation of PQ accumulation in the lungs with the actual exposed dose of PQ. The actual LCt₅₀ was found to be 218?g·min/m³ whereas 57.9?±?2.90?µg/g of PQ accumulated in the lungs of each lifeless animal. All animals exhibited severe respiratory changes and pulmonary abnormalities. This study demonstrated that when compared with the actually exposed dose, the amount of PQ that accumulated in the lungs was very low, but enough to cause death in 50% of animal population and cause pulmonary abnormalities in each of the experimental animal. The PQ exposure carried out in WBP also facilitated the dermal absorption of aerosolized PQ, which replicated the real-life situation in workers operating with PQ.     

Analysis of risk factors contributing to road traffic accidents in a tertiary care hospital. A hospital based cross-sectional study

Purpose: Road traffic accidents (RTAs) are a public health issue and cost a lot to individuals, families, communities and nations. Trauma care systems in India are at a nascent stage of development. There is gross disparity between trauma services available in various parts of the country. Rural area in India has inefficient services for trauma care, due to the varied topography, financial constraints, and lack of appropriate health infrastructure. The present study is to study the trends of occurrence of RTA cases by month, week and time of accident occurrence as well as to research the types of vehicle involved in accidents and other various risk factors related to them. Methods: During 1st January 2017 to 31st December 2017, a hospital-based and cross-sectional study of RTA victims was conducted. The patients were admitted in emergency department of Uttar Pradesh University of Medical Sciences, Saifai, Etawah, when stabilized, they were shifted to the orthopaedics and surgery ward. Results: In the study, 654 road accident victims were included, of which the majority were males (77.5%) and the most of them belonged to rural (67%). RTA victims according to the month of occurrence majority were found in January (12.5%) and evening was time of a day with maximum accidents (32.1%). Mortality cases of RTA victims based on type of road user and it shows decreasing trend of mortality of motorcyclists (54.2%) followed by pedestrian (25.1%). Conclusion: There should be control over people driving vehicles under the influence of alcohol and drivers over-speeding and rash driving on urban roads as well as rural village roads.     

Preserved exocrine function in patients with acute cholera and acute non-cholera diarrhoea

Summary Exocrine pancreatic function was assessed by means of the Lundh test in 14 patients with acute cholera and 18 patients with acute infectious non-cholera diarrhoea within the first 24 h of their admission. Mean tryptic activity amounted to 39.8 ±4.8 μEq/min/ml in the cholera group and to 64.4±11.0 μEq/min/ml in the non-cholera group. None of these patients shared a value below the lower limit of normal. In fact, the mean tryptic activity per 2 h was significantly higher than that reported previously in a control group from the Bengal area. It is therefore concluded that the exocrine pancreatic function is preserved and responds to food stimulation in various types of acute infectious diarrhoea, including cholera. These findings provide the pathophysiological background for the recent observation that oral rehydration solutions containing high-molecular-weight nutrients such as rice powder are at least as efficient or even more potent than the WHO-recommended glucose-electrolyte formula in acute diarrhoea.     

From the Cover: Specialized insulin is used for chemical warfare by fish-hunting cone snails

More than 100 species of venomous cone snails (genus Conus) are highly effective predators of fish. The vast majority of venom components identified and functionally characterized to date are neurotoxins specifically targeted to receptors, ion channels, and transporters in the nervous system of prey, predators, or competitors. Here we describe a venom component targeting energy metabolism, a radically different mechanism. Two fish-hunting cone snails, Conus geographus and Conus tulipa, have evolved specialized insulins that are expressed as major components of their venoms. These insulins are distinctive in having much greater similarity to fish insulins than to the molluscan hormone and are unique in that posttranslational modifications characteristic of conotoxins (hydroxyproline, γ-carboxyglutamate) are present. When injected into fish, the venom insulin elicits hypoglycemic shock, a condition characterized by dangerously low blood glucose. Our evidence suggests that insulin is specifically used as a weapon for prey capture by a subset of fish-hunting cone snails that use a net strategy to capture prey. Insulin appears to be a component of the nirvana cabal, a toxin combination in these venoms that is released into the water to disorient schools of small fish, making them easier to engulf with the snail’s distended false mouth, which functions as a net. If an entire school of fish simultaneously experiences hypoglycemic shock, this should directly facilitate capture by the predatory snail.The venoms of predatory marine cone snails are remarkably potent and diverse (1). Most bioactive venom components are small disulfide-rich peptides, termed conotoxins (1), that target specific receptors and ion channel subtypes located in the prey’s nervous system (2, 3). Here, we provide evidence for a specialized insulin in the venom of Conus geographus that is part of the chemical arsenal used by the snail for capturing prey. This finding significantly extends known molecular mechanisms of envenomation beyond conventional neurotoxins.Unlike other fish-hunting cone snails that inject venom as they tether the prey, C. geographus engulfs its fish prey with its highly distended false mouth before venom injection (1). It has been suggested that C. geographus releases specialized toxins, called the “nirvana cabal,” into the water to suppress the sensory circuitry of schools of small fish prey (4). Our data strongly suggest that the specialized C. geographus insulin we characterized, Con-Ins G1, forms part of this venom cabal.Vertebrate insulin, synthesized in pancreatic β cells, is the key hormone regulator of carbohydrate and fat metabolism (5); in the brain, it functions as a neuromodulator of energy homeostasis and cognition (6). Insulin is initially synthesized as a precursor comprising three regions (A, B, and C) (7), from which proteolytic cleavage of the C peptide in the Golgi releases the mature insulin heterodimer with an A and B chain connected by two disulfide bonds. The A chain contains an additional intramolecular disulfide. The primary sequence and arrangement of cysteines that form disulfides are highly conserved in all vertebrates (5). In contrast, invertebrate insulin family members are more variable and serve in neuronal signaling, memory, reproduction, growth, and metabolism (8, 9). In molluscs, insulins are primarily expressed in neuroendocrine cells, including neurons and cerebral ganglia (9, 10). Molluscan and most other invertebrate insulins differ from the vertebrate hormone in containing two additional cysteines (one in each chain) that are assumed to form an additional disulfide between the A and B chain (9). Moreover, the mature molluscan insulin chains are generally larger than vertebrate insulins. Thus, sea hare (Aplysia californica) insulin (AI) has a molecular mass of 9,146 Da (10) (compared with 5,808 Da for human insulin).The venom gland of cone snails is highly specialized for conotoxin biosynthesis and secretion (11). Our discovery that an insulin is expressed in the venom gland of C. geographus at levels comparable to conotoxins was unexpected. When injected into fish this insulin significantly lowers blood glucose levels, and direct application into the water column significantly reduces locomotor activity. We show that this peptide has unusual features, including posttranslational modifications unprecedented in insulin but often found in conotoxins.