Retraction: 'Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia'.

The above article from Human Psychopharmacology, first published on 25 January 2012 in Wiley OnlineLibrary (onlinelibrary.wiley.com), and in Volume 90, pp. 90-100, has been retracted by agreement between the authors, the journal Editor in Chief, David Baldwin, and John Wiley & Sons Ltd. The retraction has been agreed following an investigation by the St Marianna University Ethics Committee which determined that the paper was not as originally designed and approved. REFERENCES: Tenjin, T., Miyamoto, S., Miyake, N., Ogino, S., Kitajima, R., Ojima, K., … Yamaguchi, N. (2012). Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia. Hum. Psychopharmacol Clin Exp, 27, 90-100. https://doi.org/10.1002/hup.1276.

Serum peptides as candidate biomarkers for dementia with Lewy bodies.

OBJECTIVE: For diagnosis of dementia with Lewy bodies (DLB), we tried to find blood biomarkers for the disease. METHODS: Serum peptides were comprehensively detected by mass spectrometry. Peptides of interest were identified by tandem mass spectrometry. RESULTS: One hundred forty-six peptides were detected in a training set consisting of 30 DLB patients, 30 patients with Alzheimer's disease (AD), and 28 healthy control (HC) subjects. Multivariate analysis for discriminating the DLB group from the non-DLB (AD and HC) group using ion intensity of four peptides (2898, 4052, 4090, and 5002 m/z) showed sensitivity of 93.3% and specificity of 87.9% (DLB/nonDLB-4P model). In a testing set consisting of 20 DLB patients, 30 AD patients, and 14 HC subjects, this model showed sensitivity of 90.0% and specificity of 88.6%. DLB/nonDLB-4P model detected 86.7% and 90.0% of the AD patients as non-DLB in the training and testing sets, respectively, and discriminated all the 15 patients with amnestic mild cognitive impairment as non-DLB. Notably, a combination of two peptides (1737 and 5002 m/z) showed sensitivity of 95.0% and specificity of 93.3% for discriminating the DLB group from the AD group (DLB/nonDLB-2P model) in the testing set. The peptides used in these models included fragments from complement 4b, Wnt-2b, and lipopolysaccharide-binding protein, which were reported to be involved in the pathology of DLB or Parkinson's disease and hippocampal neurogenesis. CONCLUSIONS: Serum peptide profiles would provide useful DLB biomarker candidates, which may be implicated in the pathophysiology of the disease.

Roles of serum fibrinogen α chain-derived peptides in Alzheimer's disease.

OBJECTIVE: To find a blood biomarker and disease-related peptides in Alzheimer's disease (AD), we comprehensively detected serum peptides. METHODS: Ion intensity of serum peptides from 62 AD patients and 82 control subjects was measured by mass spectrometry. RESULTS: A total of 157 peptides were detected from 30 AD patients and 30 healthy control (HC) subjects. Sixty out of the 157 peptide profiles discriminated between the AD and HC groups. Sixteen out of the 60 peptides were identified, 10 out of which were fragments of a fibrinogen α chain (FIBA). Among the 10 peptides, four and six peptides were derived from fibrinopeptide A (FPA, Aα1-16) and the C-terminal region of the αC-domain (αCDC, Aα557-610), respectively. The profile of 10 FIBA-derived peptides combined with age discriminated between the two groups with an area under the receiver operating characteristic curve (AUROC) of 0.940. Validation of this model using a testing set of 32 AD patients and 19 HC subjects showed an AUROC of 0.717, sensitivity of 65.6%, and specificity of 73.7% by a cutoff value of 0.56420. Another value, 0.04029, showed sensitivity of 96.9%, suggesting that subjects with values less than 0.04029 rarely possess AD. FPA and αCDC showed increased ion intensity in the AD group compared with the HC group (p < 0.05). CONCLUSIONS: The profile of 10 FIBA-derived peptides combined with age would be a candidate biomarker for AD, which facilitates screening of the disease. The significant release of FPA and αCDC may be involved in the aberrant coagulation that leads to vascular damage in AD.

Benefits and limits of anticholinergic use in schizophrenia: focusing on its effect on cognitive function.

All currently available antipsychotic drugs are the dopamine D2 receptor antagonists and are capable of producing extrapyramidal side-effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side-effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long-term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long-term use of anticholinergics. However, the high use of long-term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long-acting injectable antipsychotics.

Long-term efficacy and safety of blonanserin in patients with first-episode schizophrenia: a 1-year open-label trial.

AIMS: The purpose of this study was to evaluate the long-term effectiveness and safety of blonanserin, a second-generation antipsychotic drug developed in Japan, in patients with first-episode schizophrenia. METHODS: Twenty-three antipsychotic-naïve patients with first-episode schizophrenia were treated within an open-label, 1-year, prospective trial of blonanserin (2-24 mg/day). Clinical evaluations were conducted at baseline and 2, 6, and 12 months after the start of treatment. The main outcome measures were changes in subjective well-being and subjective quality of life, as assessed by the Subjective Well-being under Neuroleptic treatment scale Short form-Japanese version and the Schizophrenia Quality of Life Scale-Japanese version, respectively. Secondary outcome measures included the Positive and Negative Syndrome Scale, the Brief Assessment of Cognition in Schizophrenia-Japanese version, laboratory tests, bodyweight, and extrapyramidal symptoms. RESULTS: Fourteen patients (60.9%) remained on the study at 1 year. In the intention-to-treat analysis, significant improvements were observed in several subscales on the Subjective Well-being under Neuroleptic treatment scale Short form-Japanese version, the Schizophrenia Quality of Life Scale-Japanese version, and the Brief Assessment of Cognition in Schizophrenia-Japanese version, and in all factor scores on the Positive and Negative Syndrome Scale. Improvement in depressive symptoms with blonanserin treatment was positively correlated with improvements in subjective well-being and subjective quality of life, as well as verbal memory. No significant changes were noted for any safety measure during the 1-year study period. CONCLUSIONS: Blonanserin was well tolerated and effective for the treatment of first-episode schizophrenia in terms of subjective wellness, cognition, and a wide range of pathological symptoms. Further large-scale studies are warranted to confirm our findings.

Selective coexpression of multiple chemical markers defines discrete populations of neocortical GABAergic neurons.

Whether neocortical γ-aminobutyric acid (GABA) cells are composed of a limited number of distinct classes of neuron, or whether they are continuously differentiated with much higher diversity, remains a contentious issue for the field. Most GABA cells of rat frontal cortex have at least 1 of 6 chemical markers (parvalbumin, calretinin, alpha-actinin-2, somatostatin, vasoactive intestinal polypeptide, and cholecystokinin), with each chemical class comprising several distinct neuronal subtypes having specific physiological and morphological characteristics. To better clarify GABAergic neuron diversity, we assessed the colocalization of these 6 chemical markers with corticotropin-releasing factor (CRF), neuropeptide Y (NPY), the substance P receptor (SPR), and nitric oxide synthase (NOS); these 4 additional chemical markers suggested to be expressed diversely or specifically among cortical GABA cells. We further correlated morphological and physiological characteristics of identified some chemical subclasses of inhibitory neurons. Our results reveal expression specificity of CRF, NPY, SPR, and NOS in morphologically and physiologically distinct interneuron classes. These observations support the existence of a limited number of functionally distinct subtypes of GABA cells in the neocortex.

Effect of blonanserin on cognitive function in antipsychotic-naïve first-episode schizophrenia.

OBJECTIVE: The purpose of this study was to evaluate the effects of blonanserin, a novel antipsychotic, on cognitive function in first-episode schizophrenia. METHODS: Twenty-four antipsychotic-naïve patients with first-episode schizophrenia participated in the study. Blonanserin was given in an open-label design for 8 weeks. The Brief Assessment of Cognition in Schizophrenia-Japanese language version (BACS-J) was administered as the primary outcome measure at baseline and 8 weeks. Clinical evaluation included the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale-Japanese language version (SQLS-J), and the Clinical Global Impression-Severity of Illness Scale (CGI-S). To exclude the possibility of retest effects on the BACS-J, 10 age-matched patients with chronic schizophrenia treated with blonanserin were tested at baseline and after an 8-week interval. RESULTS: Twenty first-episode patients completed the study. Repeated measures analysis of covariance revealed a significant group-by-time interaction effect on the letter fluency task due to better performance in the first-episode group, but not in the control group. Main effect of time or group-by-time interaction effect on the Tower of London task was not significant; however, the first-episode group, but not the control group, showed substantial improvement with a moderate effect size. All items on the PANSS, SQLS-J, and CGI-S significantly improved after 8 weeks of treatment. CONCLUSIONS: These results suggest that blonanserin improves some types of cognitive function associated with prefrontal cortical function.

Replacement of Arg-386 with Gly in dynamin 1 middle domain reduced GTPase activity and oligomer stability in the absence of lipids.

Dynamin plays an important role in membrane fission during endocytosis, and its middle domain is involved in the formation of functional oligomers. In this study, we found that replacement of Arg-386 with Gly in the middle domain region of dynamin 1 did not affect the intermolecular interactions of dynamin 1 in the presence of phosphatidylserine-liposomes. But, unexpectedly, this variant showed lower guanosine 5'-triphosphatase activity in the absence of phosphatidylserine-liposomes and enhanced monomer formation from oligomers. Our results indicate that GTPase activity in the absence of lipids is important in the dissociation of oligomer complexes, i.e., reduced basal dynamin 1 GTPase activity is associated with instability of dynamin oligomers.

Involvement of the JAK-STAT pathway and SOCS3 in the regulation of adiponectin-generated reactive oxygen species in murine macrophage RAW 264 cells.

Adiponectin is a protein hormone produced by differentiating adipocytes and has been proposed to have anti-diabetic and immunosuppressive properties. We previously reported that the globular form of adiponectin (gAd) induces the generation of reactive oxygen species (ROS) and nitric oxide (NO), followed by caspase-dependent apoptotic cell death in RAW 264 cells. Here, we demonstrate that gAd-induced ROS generation and apoptosis were diminished by suppressor of cytokine signaling 3 (SOCS3). The phosphorylation level of signal transducer and activator of transcription (STAT) 3 detected by Western blotting was highest at 20 min in gAd-treated RAW 264 cells. This phosphorylation was inhibited by AG490, a specific inhibitor of janus-activator kinase (JAK). The gAd-induced ROS and NO were reduced by administration of AG490 and Jak-2-specific siRNA in RAW 264 cells. The gAd stimulation transiently induced SOCS3 mRNA expression and protein production. We examined SOCS3-overexpressing RAW 264 cells to investigate the role of the JAK-STAT pathway in gAd-induced ROS and NO generation. SOCS3 overexpression significantly reduced both ROS and NO generation. Additionally, gAd-induced caspase activation and apoptotic cell death were reduced in SOCS3 transfectants compared with vector control transfectants. These results suggest that the JAK-STAT pathway, which can be suppressed by SOCS3 expression, is involved in gAd-induced ROS and NO generation followed by apoptotic cell death.

Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis.

Dynamin (Dyn) 1 plays a role in recycling of synaptic vesicles, and thus in nervous system function. We previously showed that sertraline, a selective serotonin reuptake inhibitor (SSRI), is a mixed-type inhibitor of Dyn 1 with respect to both GTP and L-alpha-phosphatidyl-L-serine (PS) in vitro, and we suggested that it may regulate the neurotransmitter transport by modulating synaptic vesicle endocytosis via inhibition of Dyn 1 GTPase. Here, we investigated the effect of sertraline on endocytosis of marker proteins in human neuroblastoma SH-Sy5Y cells and HeLa cells. Sertraline inhibited endocytosis in both cell lines. Western blotting showed that SH-Sy5Y expresses Dyn 1 and Dyn 2, while HeLa expresses only Dyn 2. GTPase assay showed that sertraline inhibited Dyn 2 as well as Dyn 1. Therefore, the effect of sertraline on endocytosis was mediated by Dyn 2, at least in HeLa cells, as well as by Dyn 1 in cell lines that express it. Moreover, the inhibition mechanism of transferrin (Tf) uptake by sertraline differed from that in cells expressing Dyn 1 K44A, a GTP binding-defective variant, and sertraline did not interfere with the interaction between Dyn 1 and PS-liposomes.

Predictors of response to electroconvulsive therapy obtained using the three-factor structure of the Montgomery and Asberg Depression Rating Scale for treatment-resistant depressed patients.

OBJECTIVE: Electroconvulsive therapy (ECT) is one of the most effective treatments for refractory major depressive disorder (MDD). Although studies have examined different predictors of a positive response to ECT, predictors based on symptoms listed on a depression rating scale have not been studied. METHODS: This study included 24 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for MDD or bipolar disorder with current major depressive episode. All subjects had a score of 21 or higher on the Montgomery and Asberg Depression Rating Scale (MADRS). The 3-factor model of MADRS was used for analysis: factor 1 (dysphoria) was defined by 3 items, factor 2 (retardation) was defined by 4 items, and factor 3 (vegetative symptoms) was defined by 3 items. Electroconvulsive therapy was performed 2 times a week for a total of 6 sessions using the Thymatron System IV device (Somatics, Inc., Lake Bluff, Ill) with the brief-pulse technique. A clinical response was defined as a 50% or greater decrease on the pretreatment total MADRS score. RESULTS: The mean factor 1 score of responders (n = 17) at pretreatment was significantly higher than that of the nonresponders (n = 7). Furthermore, a significant difference in mean factor 3 scores between responders and nonresponders was observed 1 week after the 6 ECT sessions were complete, indicating a lag in response time. No significant differences were observed in age, number of previous episodes, and duration of current episodes between the responders and nonresponders. CONCLUSIONS: This study suggests that a high factor 1 MADRS score at pretreatment was a good predictor of response to ECT in patients with treatment-resistant MDD.

Involvement of Ca(2+) in globular adiponectin-induced reactive oxygen species.

Globular adiponectin (gAd) induces the generation of reactive oxygen species (ROS) and nitric oxide (NO) in the murine macrophage cell line RAW 264. We investigated the role of Ca(2+) in gAd-induced ROS and NO generation. Pretreatment with BAPTA-AM, a selective chelator of intracellular Ca(2+) ([Ca(2+)](i)), partially reduced gAd-induced generation of ROS and NO in gAd-treated RAW 264 cells. The lowest [Ca(2+)](i) occurred 30min after gAd treatment, after which [Ca(2+)](i) increased continually and exceeded the initial level. The mitochondrial Ca(2+) ([Ca(2+)](m)) detected by Rhod-2 fluorescence started to increase at 6h after gAd treatment. Pretreatment with a NAD(P)H oxidase inhibitor, diphenyleneiodonium, prevented the reduction of [Ca(2+)](i) in the early phase after gAd treatment. Calcium depletion by BAPTA-AM had no effect on the gAd-induced [Ca(2+)](m) oscillation. The administration of a specific calmodulin inhibitor, calmidazolium, significantly suppressed gAd-induced ROS and NO generation and NOS activity.

Regulation of globular adiponectin-induced apoptosis by reactive oxygen/nitrogen species in RAW264 macrophages.

Adiponectin, produced predominantly by differentiating adipocytes, is a protein hormone with antidiabetic and immunosuppressive properties. Here, we report evidence that treatment with globular adiponectin (gAd) induces apoptosis in murine macrophage-like RAW264 cells through the generation of reactive oxygen and/or nitrogen species (ROS/RNS). Treatment with gAd induced apoptosis and enhanced the activities of caspase-3 and -9, but not caspase-8. The gAd stimulation increased ROS generation and significantly reduced the ratio of NADPH to total NADP. Pretreatment with diphenyleneiodonium or apocynin reduced ROS and apoptosis in gAd-treated cells. In addition, transfection with p47(phox)- or gp91(phox)-specific small interfering RNA (siRNA) partially reduced ROS and apoptosis in response to gAd treatment. These results suggest that the administration of gAd induces apoptosis after ROS generation involving activation of NADPH oxidases. The gAd stimulation increased the release of NO into the culture medium, the activity of nitric oxide synthase (NOS), and the expression of inducible NOS (iNOS) mRNA in RAW264 cells. l-NAME reduced gAd-induced apoptotic cell death. In addition, transfection with an iNOS-specific siRNA markedly reduced the generation of NO and the population of apoptotic cells. Taken together, these results demonstrate that the gAd-induced apoptotic process in RAW264 cells involves ROS and RNS, which are generated by NADPH oxidases and iNOS, respectively.

Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling.

We investigated here whether adiponectin can exhibit an inhibitory effect on tumor necrosis factor-alpha (TNF-alpha)- and receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis by using RAW264 cell D clone with a high efficiency to form osteoclasts. Globular adiponectin (gAd) strongly inhibited TNF-alpha/RANKL-induced differentiation of osteoclasts by interfering with TNF receptor-associated factor 6 production and calcium signaling; consequently, the induction of nuclear factor of activated T cells c1 (NFATc1) was strongly inhibited. Moreover, we observed that inhibition of AMP-activated protein kinase abrogated gAd inhibition for TNF-alpha/RANKL-induced NFATc1 expression. Our data suggest that adiponectin acts as a potent regulator of bone resorption observed in diseases associated with cytokine activation.

Induction of granulocyte colony-stimulating factor by globular adiponectin via the MEK-ERK pathway.

Adiponectin, an adipocyte-derived cytokine, affects a number of physiological processes, including immune function and inflammation. We investigated whether globular adiponectin (gAd) affects the expression of inflammation-related genes in murine macrophages (RAW264 cells). DNA microarray analysis indicated that granulocyte colony-stimulating factor (G-CSF) showed the largest increase in expression in gAd-stimulated RAW264 cells. The gAd-induced secretion of G-CSF increased in a time- and dose-dependent manner. U0126 (MEK1/2 inhibitor) and PD98059 (MEK1 inhibitor) reduced the gAd-induced G-CSF mRNA expression and G-CSF protein production. gAd induced the phosphorylation of MEK1/2 and ERK1/2 in RAW264 cells. In addition, the gAd-induced phosphorylation of MEK1/2 and ERK1/2 was dramatically reduced by PD98059 and U0126, respectively. Collectively, these results suggest that MEK1/2-ERK1/2 signaling is involved in the adiponectin-induced secretion of G-CSF.

Predictors of antidepressant response to fluvoxamine obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale for major depressive disorders in Japanese patients.

AIMS: Fluvoxamine, a selective serotonin reuptake inhibitor, is widely used to treat major depression. However, the symptomatological predictors of the response to fluvoxamine have not been studied. METHODS: This study included 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was 21 or higher. Eighty-one patients were included. Patients with a pretreatment MADRS score of >or=31 were defined as 'severe' (n = 32) and the rest were defined as 'non-severe' (n = 49). The three-factor model of MADRS was used for analysis: the first factor was defined by three items, the second factor was defined by four items, and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Fluvoxamine (100-200 mg/day) was administered twice daily for 6 weeks. RESULTS: In the non-severe patients, the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders. However, a significant difference was observed in the mean factor 3 scores from 1 week onwards between the non-severe responders and non-responders. Furthermore, the fluvoxamine response rate in the severe patients was 75% and higher than that of the non-severe patients (65.3%). CONCLUSIONS: This study suggested that a low factor 3 score at pretreatment was a good predictor of the response to fluvoxamine in non-severe patients. The marked efficacy of fluvoxamine in the treatment of severe patients was also confirmed.

No predictors of antidepressant patient response to milnacipran were obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale in Japanese patients with major depressive disorders.

AIMS: Milnacipran, a new specific serotonin and norepinephrine re-uptake inhibitor, is as effective as tricyclic antidepressants. Symptomatological predictors of antidepressant response to milnacipran have not been studied until now. METHODS: This study included 101 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was > or =21. Eighty-three patients were finally included. Patients with a pretreatment MADRS score > or =31 points were defined as severe (n = 28), and the rest as non-severe (n = 55). The three-factor model of MADRS was used for analysis; the first factor was defined by three items, the second factor was defined by four items and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Milnacipran was administered twice daily for 6 weeks. The initial dose was 50 mg/day; after a week it was increased to 100 mg/day. RESULTS: No significant difference was observed in the mean score of first factor, second factor and third factor at pretreatment time between responders and non-responders in both severe and non-severe patients. CONCLUSIONS: No predictor of antidepressant response to milnacipran was obtained using the three-factor structures of the MADRS in Japanese patients with major depressive disorders.

How valid is the self-administered visual analogue scale for assessing the health status of elderly people?

The population of Japan is aging rapidly, and maintaining the quality of life of elderly people has become an important issue in contemporary Japan. This study was conducted to verify the validity of the self-administered visual analogue scale (VAS) for assessing the health status of elderly people. A survey was conducted in two villages in western Japan in 2003. A total of 2040 participants, aged between 60 and 75 years, completed questionnaires comprising the VAS and six Likert-type items for health status, physical strength, life enjoyment, appetite, sleep, and life satisfaction. Data of the valid participants who properly completed both the VAS and the Likert-type item on health status were analyzed (n=1579, 77.4%). Among the Likert-type items, the VAS score was the most associated with health status (r = 0.532), followed by physical strength (r = 0.509). The VAS score showed a weak negative correlation with age (r = -0.130), but no association with socioeconomic factors such as the number of family members or annual income. The correlations between the VAS and the Likert-type item on health status varied between categories in some attributes. Since the VAS score was moderately correlated with similar questions about health status in the Likert-type health questionnaire, it was considered that the VAS is a valid self-administered instrument for collecting data on the health status of elderly people. However, further investigations need to be conducted to improve the VAS and to establish better explanations for aged respondents.

Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans.

Previous epidemiologic studies have suggested that periodontal disease is closely related to obesity and glucose tolerance. As the level of adiponectin, an adipocyte-derived cytokine, in plasma had been reported to decrease in obese and type 2 diabetes patients, we explored the role of adiponectin in the etiology of periodontitis using the D clone of RAW264, a clone that exhibits highly efficient osteoclast formation, to determine whether adiponectin acts as a regulatory molecule in osteoclast formation stimulated by lipopolysaccharide of periodontopathic bacteria. We observed that adiponectin acted as a potent inhibitor of osteoclast formation stimulated by Toll-like receptor 4 (TLR4) ligand and receptor activator of NF-kappaB ligand (RANKL). Because NF-kappaB is an important transcription factor in osteoclast formation, we examined the effect of adiponectin on its transcriptional activity. A luciferase assay showed that adiponectin was able to inhibit the TLR4-mediated NF-kappaB activity in RAW264 cells. In addition, we observed that the cytokine was actually able to inhibit TLR4-mediated expression of the gene for inducible nitric oxide synthase and production of nitric oxide in the cells. These observations strongly suggest that adiponectin may function as a negative regulator of lipopolysaccharide/RANKL-mediated osteoclast formation in periodontal disease.