Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury

Although augmented prostaglandin E(2) (PGE(2)) synthesis and accumulation have been demonstrated in the lesion sites of rodent transient focal ischemia models, the role of PGE(2) in neuronal survival has been controversial, showing both protective and toxic effects. Here we demonstrate the induction of microsomal PGE synthase 1 (mPGES-1), an inducible terminal enzyme for PGE(2) synthesis, in neurons, microglia, and endothelial cells in the cerebral cortex after transient focal ischemia. In mPGES-1 knockout (KO) mice, in which the postischemic PGE(2) production in the cortex was completely absent, the infarction, edema, apoptotic cell death, and caspase-3 activation in the cortex after ischemia were all reduced compared with those in wild-type (WT) mice. Furthermore, the behavioral neurological dysfunctions observed after ischemia in WT mice were significantly ameliorated in KO mice. The ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as WT mice by intracerebroventricular injection of PGE(2) into KO mice. Our observations suggest that mPGES-1 may be a critical determinant of postischemic neurological dysfunctions and a valuable therapeutic target for treatment of human stroke.     

Galantamine increases hippocampal insulin-like growth factor 2 expression via α7 nicotinic acetylcholine receptors in mice

Rationale and objective

Galantamine, a drug for the treatment of Alzheimer’s disease, has neuroprotection in several experimental models and stimulates adult neurogenesis in the rodent brain, but the exact mechanism remains unclear. This study examined whether galantamine affects the expression of neurotrophic/growth factors in the mouse hippocampus and prefrontal cortex.

Methods

Nine-week-old male ddY mice were used. The mRNA levels of neurotrophic/growth factors were analyzed by a real-time quantitative PCR. The protein levels of insulin-like growth factor 2 (IGF2) were analyzed by Western blotting.

Results

Acute administration of galantamine (0.3–3 mg/kg, i.p.) increased IGF2 mRNA levels in the hippocampus, but not in the prefrontal cortex, in time- and dose-dependent manner. Galantamine (3 mg/kg, i.p.) caused a transient increase in fibroblast growth factor 2 mRNA levels and a decrease in brain-derived neurotrophic factor mRNA levels in the hippocampus, while it did not affect the mRNA levels of other neurotrophic/growth factors. The galantamine-induced increase in the hippocampal IGF2 mRNA levels was blocked by mecamylamine, a nonselective nicotinic acetylcholine (ACh) receptor (nAChR) antagonist, and methyllycaconitine, a selective α7 nAChR antagonist, but not by telenzepine, a preferential M₁ muscarinic ACh receptor antagonist. Moreover, the selective α7 nAChR agonist PHA-543613 increased the IGF2 mRNA levels, while donepezil, an acetylcholinesterase inhibitor, did not. Galantamine also increased hippocampal IGF2 protein, which was blocked by methyllycaconitine.

Conclusions

These findings suggest that galantamine increases hippocampal IGF2 levels via α7 nAChR activation in mice and imply that the effect may contribute to its neuroprotection or neurogenesis.     

Studies regarding the goals of indirect request

Why do people make requests indirectly? We examined the goals of indirect requests in order to answer this question. In study 1, 162 university students completed a questionnaire regarding the goals of indirect requests. Exploratory factor analysis indicated that the goals of indirect requests could be classified into five types: concern for the listener, making an effective request, avoidance of explicit refusal, self-impression management, or conveyance of indebtedness. In study 2, we examined whether these goals actually affect the use of indirect requests by conducting a questionnaire study with 25 university students. The results indicated that some goals (making an effective request, avoidance of explicit refusal, self-impression management, and conveyance of indebtedness) have positive effects on indirect requests, whereas the goal of concern for the listener has no effect. Therefore, we concluded that these four goals which have positive effects are reasonable goals for indirect requests.     

Coding visual images of objects in the inferotemporal cortex of the macaque monkey

1. The inferotemporal cortex (IT) has been thought to play an essential and specific role in visual object discrimination and recognition, because a lesion of IT in the monkey results in a specific deficit in learning tasks that require these visual functions. To understand the cellular basis of the object discrimination and recognition processes in IT, we determined the optimal stimulus of individual IT cells in anesthetized, immobilized monkeys. 2. In the posterior one-third or one-fourth of IT, most cells could be activated maximally by bars or disks just by adjusting the size, orientation, or color of the stimulus. 3. In the remaining anterior two-thirds or three-quarters of IT, most cells required more complex features for their maximal activation. 4. The critical feature for the activation of individual anterior IT cells varied from cell to cell: a complex shape in some cells and a combination of texture or color with contour-shape in other cells. 5. Cells that showed different types of complexity for the critical feature were intermingled throughout anterior IT, whereas cells recorded in single penetrations showed critical features that were related in some respects. 6. Generally speaking, the critical features of anterior IT cells were moderately complex and can be thought of as partial features common to images of several different natural objects. The selectivity to the optimal stimulus was rather sharp, although not absolute. We thus propose that, in anterior IT, images of objects are coded by combinations of active cells, each of which represents the presence of a particular partial feature in the image.     

Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice

Chemerin is an adipokine that regulates adipogenesis and metabolic functions of mature adipocytes mainly through the activation of chemokine‐like receptor 1 (CMKLR1). Elevated levels of chemerin have been found in individuals with obesity, type 2 diabetes, and osteoporosis. This adipokine was identified as an inflammatory and metabolic syndrome marker. Considering that the association between metabolic syndrome and bone health remains unclear, the present study aimed to clarify the role of chemerin in the pathophysiology of bone loss induced by dyslipidemia, particularly modulating osteoclastogenesis. In vitro analyses showed a downregulation of CMKLR1 at the early stage of differentiation and a gradual increase at late stages. Strikingly, chemerin did not modify osteoclast differentiation markers or osteoclast formation; however, it increased the actin‐ring formation and bone resorption activity in mature osteoclasts. The increased bone resorption activity induced by chemerin was effectively inhibited by CMKLR1 antagonist (CCX832). Chemerin boosting mature osteoclast activity involves ERK5 phosphorylation. Moreover, two models of dyslipidemia (high‐fat diet [HFD]‐treated C57/BL6 and db/db mice) exhibited significantly increased level of chemerin in the serum and gingival tissue. Morphometric analysis showed that HFD‐treated and db/db mice exhibited increased alveolar bone loss compared to respective control mice, which was associated with an up‐regulation of chemerin, CMKLR1 and cathepsin K mRNA expression in the gingival tissue. The treatment of db/db mice with CCX832 effectively inhibited bone loss. Antagonism of chemerin receptor also inhibited the expression of cathepsin K in the gingival tissue. Our results show that chemerin not only increases osteoclasts activity in vitro, but also that increased level of chemerin in dyslipidemic mice plays a critical role in bone homeostasis. © 2016 American Society for Bone and Mineral Research.     

Gender-specific vascular effects elicited by chronic ethanol consumption in rats: a role for inducible nitric oxide synthase

BACKGROUND AND PURPOSE: Epidemiological data suggest that the risk of ethanol-associated cardiovascular disease is greater in men than in women. This study investigates the mechanisms underlying gender-specific vascular effects elicited by chronic ethanol consumption in rats. EXPERIMENTAL APPROACH: Vascular reactivity experiments using standard muscle bath procedures were performed on isolated thoracic aortae from rats. mRNA and protein for inducible NO synthase (iNOS) and for endothelial NOS (eNOS) was assessed by RT-PCR or western blotting, respectively. KEY RESULTS: In male rats, chronic ethanol consumption enhanced phenylephrine-induced contraction in both endothelium-intact and denuded aortic rings. However, in female rats, chronic ethanol consumption enhanced phenylephrine-induced contraction only in endothelium denuded aortic rings. After pre-incubation of endothelium-intact rings with L-NAME, both male and female ethanol-treated rats showed larger phenylephrine-induced contractions in aortic rings, compared to the control group. Acetylcholine-induced relaxation was not affected by ethanol consumption. The effects of ethanol on responses to phenylephrine were similar in ovariectomized (OVX) and intact (non-OVX) female rats. In the presence of aminoguanidine, but not 7-nitroindazole, the contractions to phenylephrine in rings from ethanol-treated female rats were greater than that found in control tissues in the presence of the inhibitors. mRNA levels for eNOS and iNOS were not altered by ethanol consumption. Ethanol intake reduced eNOS protein levels and increased iNOS protein levels in aorta from female rats. CONCLUSIONS AND IMPLICATIONS: Gender differences in the vascular effects elicited by chronic ethanol consumption were not related to ovarian hormones but seemed to involve the upregulation of iNOS.     

Fructose 1,6-bisphosphate inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB/NFATc-1

Inflammation Research - Although some glycolytic intermediates have been shown to modulate several cell type formation and activation, the functional role of fructose 1,6-bisphosphate (FBP) on...     

Amniotic fluid alpha-fetoprotein testing in native Japanese women.

Owing to differences in maternal serum alpha-fetoprotein, human chorionic gonadotrophin and oestriol levels between native Japanese and Caucasian women screened in this laboratory, a study was conducted to measure amniotic fluid alpha-fetoprotein (AFAFP) levels in native Japanese pregnancies. When the native Japanese AFAFP levels were compared with a United States (non-Black) population, the Japanese medians did not decrease as rapidly over the 14 to 22 weeks of gestation period investigated. At 14 weeks, the difference was negligible, graduating to a difference of 20 per cent by 22 weeks' gestation. Native Japanese pregnancy AFAFP levels should be interpreted based upon population data from that group alone. From these findings, prenatal screening laboratories should be encouraged to collect preliminary data for comparison before screening is initiated for a defined ethnic group.     

Characterization of N-acylation of Go alpha purified from bovine retinas.

Heterogeneous N-terminal acylation has been identified in several retinal proteins localized predominantly in the outer segments of the photoreceptor cells, but it is still unclear whether such a unique heteroacylation is determined by a photoreceptor cell-specific factor or not. Here, we characterized the N-terminal modification of bovine retinal Go alpha, which seems to be involved in the neural activities and is not detected in the photoreceptor outer segments. In the proteolytic fragments of immunoaffinity-purified retinal Go alpha, we found a single N-terminal peptide modified with myristate, and concluded that retinal Go alpha is purely myristoylated, just like brain Go alpha. This result indicates that the heteroacylation has a more restricted origin in the retina, and supports the idea that it is a photoreceptor cell-specific modification.     

Emerging Aspects of the Body Composition,Bone Marrow Adipose Tissue and Skeletal Phenotypes in Type 1 Diabetes Mellitus

Anthropomorphic measures among type 1 diabetic patients are changing as the obesity epidemic continues. Excess fat mass may impact bone density and ultimately fracture risk. We studied the interaction between bone and adipose tissue in type 1 diabetes subjects submitted to two different clinical managements: (I) conventional insulin therapy or (II) autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST). The study comprised 3 groups matched by age, gender, height and weight: control (C = 24), type 1 diabetes (T1D = 23) and type 1 diabetes treated with AHST (T1D-AHST = 9). Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by dual X-ray absorptiometry (DXA). ¹H Magnetic resonance spectroscopy was used to assess bone marrow adipose tissue (BMAT) in the L3 vertebra, and abdominal magnetic resonance imaging was used to assess intrahepatic lipids (IHL), visceral (VAT) and subcutaneous adipose tissue (SAT). Individuals conventionally treated for T1D were more likely to be overweight (C = 23.8 ± 3.7; T1D = 25.3 ± 3.4; T1D-AHST = 22.5 ± 2.2 Kg/m²; p > 0.05), but there was no excessive lipid accumulation in VAT or liver. Areal BMD of the three groups were similar at all sites; lumbar spine TBS (L3) was lower in type 1 diabetes (p < 0.05). Neither SAT nor VAT had any association with bone parameters. Bone marrow adipose tissue (BMAT) lipid profiles were similar among groups. BMAT saturated lipids were associated with cholesterol, whereas unsaturated lipids had an association with IGF1. Overweight and normal weight subjects with type 1 diabetes have normal areal bone density, but lower trabecular bone scores. Adipose distribution is normal and BMAT volume is similar to controls, irrespective of clinical treatment.