Calcium Signaling Regulated by Cellular Membrane Systems and Calcium Homeostasis Perturbed in Alzheimer's Disease.

Although anything that changes spatiotemporally could be a signal, cells, particularly neurons, precisely manipulate calcium ion (Ca2+) to transmit information. Ca2+ homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca2+ concentration ([Ca2+]CYT) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca2+ buffers. Furthermore, efficient and effective Ca2+ flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca2+ is released from the ER followed by mitochondrial Ca2+ uptake in sequence. Hence, the ER intraluminal Ca2+ concentration ([Ca2+]ER), the mitochondrial matrix Ca2+ concentration ([Ca2+]MT), and the [Ca2+]CYT are related to each other. Ca2+ signaling dysregulation and Ca2+ dyshomeostasis are associated with Alzheimer's disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca2+ signaling regulation and Ca2+ homeostasis maintenance at ER and mitochondria levels, focusing on AD. Integrating the amyloid hypothesis and the calcium hypothesis of AD may further our understanding of pathogenesis in neurodegeneration, provide therapeutic targets for chronic neurodegenerative disease in the central nervous system.

Molecular characterization, expression and function analysis of Epinephelus coioides MKK4 response to SGIV and Vibrio alginolyticus infection.

Mitogen-activated protein kinase 4 (MKK4), a member of the MAP kinase family, play important roles in response to many environmental and cellular stresses in mammals. In this study, three MKK4 subtypes, EcMKK4-1, EcMKK4-2 and EcMKK4-3, were obtained from grouper Epinephelus coioides. The open reading frame (ORF) of EcMKK4s are obtained and the EcMKK4s proteins contain highly conserved domains: a S_TKc domain, a canonical diphosphorylation group and two conserved MKKK ATP binding motifs, Asp-Phe-Gly (DFG) and Ala-Pro-Glu (APE). EcMKK4s could be found both in the cytoplasmic and nuclear. The EcMKK4s mRNA were detected in all E. coioides tissues examined with the different expression levels, and the expression were up-regulated during SGIV (Singapore grouper iridescent virus) or Vibrio alginolyticus infection. EcMKK4 could significantly reduce the activation of AP-1 reporter gene. The results suggested that EcMKK4s might play important roles in pathogen-caused inflammation.

Severe pneumonia in mycophenolate mofetil combined with low-dose corticosteroids-treated patients with immunoglobulin A nephropathy.

The tolerance of mycophenolate mofetil (MMF; Shanghai Roche, China) in Lee Classes III, IV, and V immunoglobulin A nephropathy (IgAN) remains unclear. This article reports nine cases of severe pneumonia (SP), including pneumocystis pneumonia (PCP) and cytomegalovirus (CMV) pneumonia, and its risk factors in MMF plus low-dose corticosteroid-treated patients with Lee Classes III, IV, and V IgAN. Fifty-three patients with IgAN were included in this single-center study. The treatment regimen was MMF (1-1.5 g/d) plus low-dose corticosteroids (0.5 mg/kg/d). SP was defined as diffuse bilateral lung infiltrate with respiratory failure. PCP was diagnosed by detecting the organisms in the sputum and bronchoalveolar lavage. CMV infection was diagnosed through serum screening for CMV-IgG and IgM antibodies and CMV-DNA testing by a real-time polymerase chain reaction assay. The risk factors of SP were analyzed. Nine cases (16.9%) of SP occurred in this study. All SP developed at approximately the 10(th)-14(th) week after the initiation of the regimen: PCP was diagnosed in four cases and CMV infection in two cases. Renal function impairing was more serious in patients with SP than in those without SP, as evidenced by estimated glomerular filtration rate (p = 0.019) and serum creatinine level (p = 0.016). Six of the nine SPs occurred in MMP plus low-dose methylprednisolone group, which was statistically higher than that in the MMF plus low-dose prednisone group (p = 0.000). The incidence of SP in this study was 16.9%. Chronically impaired renal function and the use of methylprednisolone may be the risk factors for SP.

[Synthesis of novel beta-aminoalcohols containing nabumetone moiety with potential antidiabetic activity].

Twenty five new beta-aminoalcohols containing nabumetone moiety were prepared via the reduction of potassium borohydride with a convenient and efficient procedure, starting from beta-aminoketones that have been synthesized by our group. Their chemical structures were determined by IR, MS, 1H NMR, 13C NMR, HR-MS and antidiabetic activities were screened in vitro. Preliminary results revealed that the antidiabetic activity of most beta-aminoalcohols were better than that of the corresponding beta-aminoketones. Although most compounds showed weak antidiabetic activity, the alpha-glucosidase inhibitory activity of compounds 5hd(1) and 5id(2) reached 74.37% and 90.15%, respectively, which were superior to the positive control. The relative peroxisome proliferator-activated receptor response element (PPRE) activity of five compounds were more than 60%, among them compound 5ca possessed the highest activity (112.59%). As lead molecules of antidiabetic agents, compounds 5hd(1), 5id(2) and 5ca deserve further study.