Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1G93A mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1G93A mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

A site-specific C to U editing reaction modifies nuclear apolipoprotein B100 (apoB100) mRNA, producing apolipoprotein B48 in the mammalian small intestine. This reaction is mediated by a multicomponent enzyme complex, which contains a catalytic subunit, Apobec-1. We have used gene targeting to disrupt mouse apobec-1 in order to establish its requisite importance in apoB mRNA editing and also, in view of its widespread tissue distribution in rodents, as a preliminary indication of other potential roles. Both heterozygous (apobec-1+/-) and homozygous (apobec-1-/-) gene-targeted mice appear healthy and fertile with no alterations in serum cholesterol or triglyceride concentrations. The apobec-1+/- mice demonstrated reduced levels of hepatic apoB mRNA editing. By contrast, levels of small intestinal apoB mRNA editing were indistinguishable in wild-type and apobec-1+/- animals, suggesting that Apobec-1 is expressed in limited quantities in the liver but not in the small intestine. The apobec-1-/- mice lacked detectable levels of Apobec-1 mRNA, expressed only unedited apoB mRNA in all tissues, and contained no apoB48 in their serum, demonstrating that there is no functional duplication of this gene.

Lipid rafts on the cell surface are believed to be very important as platforms for various cellular functions. The aim of this study was to know whether defective lipid efflux may influence lipid rafts on the cell surface and their related cellular functions. We investigated macrophages with defective lipid efflux from ATP binding cassette transporter A1-deficient (Abca1-KO) mice. Lipid rafts were evaluated by the following two novel probes: a biotinylated and protease (subtilisin Carlsberg)-nicked derivative of u-toxin and a fluorescein ester of polyethylene glycol-derived cholesterol. Lipid rafts in Abca1-KO macrophages were increased, as demonstrated by both probes. Moreover, activities of nuclear factor kB, mRNA and intracellular distribution, and secretion of tumor necrosis factor-a (TNF-a) were examined after stimulation by lipopolysaccharides (LPSs). LPS-induced responses of the activation of nuclear factor kB and TNF-a were more prompt and accelerated in the Abca1-KO macrophages compared with wild-type macrophages. Modification of lipid rafts by cyclodextrin and nystatin corrected the abnormal response, suggesting an association between the increased lipid rafts and abnormal TNF-a secretion.We report here that Abca1-KO macrophages with defective lipid efflux exhibited increased lipid rafts on the cell surface and accelerated TNF-a secretion. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role as a shuttle carrying cholesterol derived from peripheral tissues to the liver (1). Cholesterol efflux from the cells is the initial step of RCT, in which free apolipoprotein A-I (apoA-I) or small HDLs take up cholesterol from the peripheral cells. We have been trying to elucidate the molecular mechanism for RCT and cholesterol efflux by analyzing the pathophysiology of patients with abnormal HDL metabolism. We have identified molecules involved in cellular cholesterol efflux and apoA-I and HDL binding proteins on macrophages (2-5).Tangier disease (TD) is a model for the impairment of cholesterol efflux from the cells (6, 7). Patients with TD suffer from genetic HDL deficiency, hepatosplenomegaly, orange tonsils, and premature atherosclerosis (8, 9). Many laboratories including ours have reported that mutations in the Abca1 gene lead to defective cholesterol efflux from the cells (10-12). As a result of the mutation(s) in the Abca1 gene, cells from TD patients exhibited a deficiency of apoA-I-mediated cholesterol efflux and a subsequent accumulation of intracellular lipids as lipid droplets, which is closely related to the development of atherosclerosis in this disorder.On the other hand, in the plasma membrane, cholesterol is distributed abundantly in some domain structures Abbreviations: Abca1-KO, ATP binding cassette transporter A1-deficient; apoA-I, apolipoprotein A-I; BCu, biotinylated and protease (subtilisin Carlsberg)-nicked derivative of u-toxin; fPEG-chol, fluorescent polyethylene glycol cholesteryl ether; L...

Purpose To clarify the relative frequency of various histopathological primary spinal cord tumors and their features in Japanese people and to compare this data with other reports. Methods Primary spinal cord tumor surgical cases from 2000 to 2009, which were registered in our affiliated hospital database were collected. We examined age at surgery, sex, anatomical location, vertebral level of the tumor, and pathological diagnosis in each case.Results Of the 678 patients in our study, 377 patients (55.6 %) were males and 301 patients (44.4 %) were females (male/female ratio 1.25). The mean age at surgery was 52.4 years. Of these tumors, 123 cases (18.1 %) were intramedullary, 371 cases (54.7 %) were intradural extramedullary, 28 cases (4.1 %) were epidural, and 155 cases (22.9 %) were dumbbell tumors. The pathological diagnoses included 388 schwannomas (57.2 %), 79 meningiomas (11.6 %), 54 ependymomas (8.0 %), 27 hemangiomas (4.0 %), 23 hemangioblastomas (3.4 %), 23 neurofibromas (3.4 %), and 9 astrocytomas (1.3 %). The male/female ratios for schwannomas, meningiomas, ependymomas,Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan e-mail: imagama@med.nagoya-u.ac.jp K. Sato Department of Orthopaedic Surgery, Nagoya Daini Red Cross Hospital, 2-9, Myoken-cho, Showa-ku, Nagoya 466-8650, Japan (2012( ) 21:2019( -2026( DOI 10.1007( /s00586-012-2345 hemangiomas, hemangioblastomas, neurofibromas, malignant lymphomas, and lipomas are 1.4, 0.34, 1.3, 1.5, 2.3, 1.3, 2.7 and 2.3, respectively. Conclusion This is the first published research in English on the epidemiology of primary spinal cord tumors in Japanese people. Similar to other reports from Asian countries, our data indicates a higher male/female ratio overall for spinal cord tumors, a higher proportion of nerve sheath cell tumors, and a lower proportion of meningiomas and neuroepithelial tumors compared to reports from non-Asian countries. Data in the current study represent the characteristics of primary spinal cord tumors in Asian countries.

It is well known that obesity is frequently associated with low levels of serum high-density lipoprotein (HDL) cholesterol. However, the mechanism for this reduction has not been fully clarified. Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins and plays an important role in regulating the concentration and composition of HDL. To elucidate the mechanism for the reduction of serum HDL cholesterol in obesity, we analyzed serum lipoproteins, CETP, and postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities in 30 obese subjects (17 women and 13 men, age 44±14 years, mean±SD). We also investigated the relationship between these variables, total adiposity, and indices of body fat distribution. The average body mass index of the obese subjects was 33.1±4.8 kg/m 2 (range, 26.4 to 43.8 kg/m 2 ). The obese subjects showed significantly lower serum HDL cholesterol levels than control subjects (1.04±0.28 versus 1.50±0.34 mmol/L, P<.01). In the obese subjects, both activities and protein mass of CETP and postheparin HTGL activities were significantly increased, whereas postheparin I t is well known that obese patients are often associated with low serum high-density lipoprotein (HDL) cholesterol levels. 1 Although some studies suggest that low HDL cholesterol in obesity might be a risk factor for coronary heart disease (CHD), 2 -3 few data show that low HDL cholesterol in obesity directly caused or was closely associated with the occurrence and development of CHD. Recent studies have shown that the degree of body fat distribution was more important for the occurrence of complications, particularly CHD, than body fat accumulation.4 -8 Therefore, it appears necessary to clarify the mechanism and pathophysiological significance of low serum HDL cholesterol levels in obesity.Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that transfers cholesteryl ester (CE) from HDL to apolipoprotein (apo) B-containing lipopro- 9 and is one of the major determinants of plasma HDL cholesterol levels. 10 In Japan, some laboratories, including ours, reported that some types of familial hyperalphalipoproteinemia are associated with a genetic deficiency of plasma CETP. 1014 Our studies have shown that lipoprotein abnormalities in CETP-deficient patients are characterized by the presence of polydisperse low-density lipoprotein (LDL) 1112 and a marked elevation of HDL cholesterol.13 ' 14 These results indicate that CETP plays an important role in modulating both the quality and quantity of plasma lipoproteins. Plasma CETP is synthesized by the liver, small intestine, spleen, adrenal gland, and adipose tissues. In particular, Jiang et al 15 reported that adipose tissue is one of the major sites of CETP synthesis in mammals.Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) are known to regulate HDL cholesterol levels. 1617 We reported that postheparin plasma LPL activity was positively correlated with s...