Response of hepatic carbohydrate and cyclic AMP metabolism to cadmium treatment in rats.

Daily intraperitoneal injection of cadmium chloride (0.25 or 1 mg/kg) for 21 or 45 days into rats significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase, and glucose-6-phosphatase, increased the concentrations of glucose and urea in the blood, and decreased the levels of glycogen in the liver. Whereas chronic cadmium treatment failed to alter adenosine-3',5'-monophosphate phosphodiesterase (phosphodiesterase) activity, the endogenous levels of cyclic AMP (cAMP) and the activity of basal- and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased in cadmium-injected animals. Treatment with the higher dose (1.0 mg/kg) of cadmium chloride for 45 days produced greater metabolic alterations in hepatic tissue than those seen with the lower dose (0.25 mg/kg) given for a shorter period of time (21 days). Discontinuation of cadmium administration for 14 days in rats previously injected with cadmium chloride (1 mg/kg per day) for 21 days, failed to reverse the observed changes in hepatic cAMP or carbohydrate metabolism. A similar persistence of metabolic alterations was noted in rats treated with cadmium (1 mg/kg per day) for 45 days and subsequently maintained without additional treatment for 28 days. Administration of an acute dose of cadmium chloride (60 mg/kg) decreased hepatic phosphodiesterase activity and glycogen content 1 h after the injection. In addition, acute cadmium exposure increased blood glucose, serum urea, and hepatic cAMP levels, and produced an augmentation of basal- and fluoride-activated AC. However, the activities of various hepatic gluconeogenic enzymes remained unaffected in animals given an acute dose of cadmium chloride (60 mg/kg). Data provide evidence that suggests that the gluconeogenic potential of liver is markedly enhanced following chronic exposure to cadmium and that the cadmium-induced changes in carbohydrate metabolism may be associated with an enhanced synthesis of cAMP. In addition, the present study shows that the cadmium-induced metabolic alterations persist even after the cessation of cadmium treatment for a period of 28 days.     

Evidence for Compromised Insulin Signaling and Neuronal Vulnerability in Experimental Model of Sporadic Alzheimer’s Disease

Evidence from animal studies categorizes sporadic Alzheimer’s disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as “silent partners” to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co-culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and β-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures. Increased amyloidogenesis was accompanied by decreased expression of mediators in insulin signaling pathway that included insulin receptor (IR), insulin receptor substrate 2 (IRS2), insulin-like growth factor 2 (IGF2), insulin-like growth factor 1 receptor (IGF1R), total-glycogen synthase kinase 3β (t-GSK3β), and phosphorylated-GSK3β^ser9 (p-GSK3β^ser9), suggesting that neuronal cells are more prone to metabolic variability when cultured in the presence of glial cells. Findings from the sAD model induced by intracerebroventricular (ICV) injection of STZ revealed that increased amyloid beta (Aβ) load in the hippocampus was potentially responsible for the hyperphosphorylation of tau at ser³⁹⁶. Furthermore, impaired cognitive functions and decreased dendritic spine density and axonal thinning in CA1 region of hippocampus were associated with decreased IR and p-GSK3β^ser9/t-GSK3β expression. Taken together, the present study provides evidence that glia mediated response and insulin signaling defects drive pathological changes in sAD and represent potential targets for delaying sAD progression.     

Rotenoids from roots of Millettia pachycarpa

Roots of Millettia pachycarpa furnished retenone, cis-12a-hydroxyrotenone, rot-2′-enonic acid and cis-12a-hydroxyrot-2′-enonic acid.     

Effects of anoxia, hyperoxia, and salinity on neurons in the leech Nephelopsis obscura (Erpobdellidae): RNA redistribution by fluorescence histochemistry

The histochemical distribution of cytoplasmic RNA in ganglion cells of the freshwater leech Nephelopsis obscura has been studied using the fluorochrome acridine orange as a marker of nucleic acids. Two series of experiments, employing 50 adult animals, involved changes in oxygen tension in the water and changes in salinity. Normal leech neurons exhibit finely granular orange fluorescence uniformly distributed throughout the cytoplasm, with a perinuclear ring of especially strong fluorescence. After exposure to anoxic (0% O2), hypoxic (20% O2), or hyperoxic (200% O2) conditions at 20 degrees C for 1-15 days, the orange cytoplasmic fluorescence is no longer uniformly distributed; the redistribution is generally toward the periphery, leaving the perinuclear zone without RNA fluorescence, but irregular zones of cytoplasm devoid of RNA also occur not as a gradient. Leeches exposed to salinity of, or greater than, 2.5 ppt for 15 days exhibit similar changes. These alterations are confirmed by electron microscopy. Seasonal fluctuations in oxygen tension and salinity of lake water affect the distribution and abundance of organisms. The acridine orange method provides one measure of stress to the nervous system in freshwater invertebrates that might be applicable to ecological studies as well as to metabolic studies of individual animals.