Concise Total Synthesis of (+)-Pleiocarpamine and Convergent Total Syntheses of (+)-Voacalgine A and (+)-Bipleiophylline via an Aerobic Oxidative Coupling.

The stereocontrolled total synthesis of (+)-pleiocarpamine and the total syntheses of (+)-voacalgine A and (+)-bipleiophylline have been achieved. The scalable and concise 10-step synthesis of (+)-pleiocarpamine features construction of stereochemistry at the C16 position by radical cyclization and that of the highly strained cage-like structure via Pd-catalyzed intramolecular aromatic C-H functionalization. By modifying the biomimetic aerobic oxidative coupling of tryptophane derivatives catalyzed by FePc(CO2H)8, the oxidative coupling of the synthesized (+)-pleiocarpamine with pyrocatechuic acid was established to produce (+)-voacalgine A. The total synthesis of (+)-bipleiophylline was completed by the second coupling of (+)-voacalgine A with (+)-pleiocarpamine or one-pot couplings of 2 equiv of (+)-pleiocarpamine with pyrocatechuic acid.

Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-a]indole skeleton via Tf2O-mediated Bischler-Napieralski reaction and stereoselective radical cyclization.

The total synthesis of (±)-vinoxine was achieved featuring the assembly of a multi-substituted tetrahydropyrido[1,2-a]indole skeleton through the Tf2O-mediated Bischler-Napieralski reaction. The characteristic diazabicyclo[3.3.1]nonane skeleton was stereoselectively constructed via radical cyclization based on the one stereochemistry of the C3 position. The established methodology provides new options for the synthesis of natural products and pharmaceuticals containing the multi-substituted pyrido[1,2-a]indole skeleton.

Clinical and anthropometric characteristics of non-obese non-alcoholic fatty liver disease subjects in Japan.

AIM: The underlying mechanism of non-obese non-alcoholic fatty liver disease (NAFLD) has not been fully elucidated. We classified patients with NAFLD by sex and body mass index and compared their clinical features to clarify the background pathophysiology of non-obese NAFLD. METHODS: A total of 404 patients with NAFLD were divided according to their body mass index (<25 [non-obese], 25 to <30 [obese], and ≥30 [severe obese]), and were further compared with 253 patients without obesity and NAFLD (non-NAFLD). RESULTS: The proportion of the individuals with non-obese NAFLD was 25.7% in men and 27.6% in women. The male and female non-obese NAFLD groups had lower skeletal muscle mass and muscle strength than the obese NAFLD groups. The visceral fat area, although low, was ≥100 cm2 in 59.3% of men and 43.8% of women. An increase in liver fat accumulation, hepatic fibrosis, homeostasis model assessment of insulin resistance, and leptin levels was modest in the non-obese NAFLD group compared with a marked increase in the obese NAFLD groups. The muscle mass of the non-obese NAFLD group was similar to that of the non-NAFLD group, but muscle steatosis was particularly common among women. Multivariate analysis revealed that the factors contributing to increased liver fat accumulation in the non-obese NAFLD group were visceral fat area, HbA1c, myostatin, and leptin. CONCLUSIONS: In patients with non-obese NAFLD, a sex difference was observed in the clinical features. In addition to increased visceral fat, decreased muscle mass and muscle strength, muscle atrophy (presarcopenia), and impaired glucose tolerance were considered to be important pathophysiological factors.

A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

[The relationship between death from renal insufficiency and diuretic therapy among older adults at two nursing homes catering atomic bomb survivors].

AIM: In Geriatrics Gerontology International we previously reported the efficacy of reducing diuretics to prevent falls and fractures in older adults. We have since noticed another important problem, regarding the diuretic therapy for older adults with decreased muscle and water volumes. We performed a study on renal insufficiency and diuretic therapy in an attempt to confirm the need for case control study between standard diuretic therapy administered, according to guidelines and "NY-mode" diuretic therapy, which involves the administration of the mineral-corticoid receptor inhibitor spironolactone at 12.5 mg orally every other day. METHODS: We reviewed the causes of death among 1,855 residents living at 2 atomic bomb survivors nursing homes, with a focus on the death certification and diuretic therapy status of 48 older adults who died due to renal insufficiency. We also evaluated the relationship between the estimated glomerular filtration rate of 407 residents using serum creatinine data and the level of independence in daily life of disabled older adults. RESULTS: We found that deaths due to chronic renal insufficiency were concentrated within certain period in two nursing homes examined and in patients receiving standard diuretic therapy (continuous daily loop diuretics or combination of loop diuretics with mineral-corticoid receptor inhibitor). Older adults with a relatively low level of independence in daily life showed a relatively higher estimated glomerular filtration rate, depending on their muscle volume. CONCLUSION: These results suggest the need for a case control study of standard diuretic therapy and "NY-mode" therapy among older adults with decreased muscle and water volumes to not only prevent falls and fall-related fractures but also protect the kidney from damage.

IL-15 and RANKL Play a Synergistically Important Role in Osteoclastogenesis.

Interleukin-15 (IL-15), a cytokine secreted by several cell types, has important physiological roles in the activity, proliferation, and viability of immune cells. It has both chemoattractant and proinflammatory properties, and may promote bone destruction. A previous study has shown that IL-15 alone exerts no effect on osteoclastogenesis. Therefore, the current study addressed the synergistic effect of IL-15 on osteoclast formation using RAW264.7 (RAW) cells by co-stimulation with receptor activator of nuclear factor (NF)-κB ligand (RANKL) that has a major role in osteoclastogenesis involving the pathogenesis of rheumatoid arthritis and periodontal disease. Co-stimulation of RAW cells by IL-15 and RANKL significantly increased the gene expression of osteoclast differentiation and osteoclastogenesis markers compared with stimulation by RANKL or IL-15 independently as evaluated by tartrate-resistant acid phosphate-positive cell numbers, the fusion index, a pit formation assay with Alizarin red staining (calcification estimation), and quantitative polymerase chain reaction. Phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase, p38 mitogen-activated protein kinase, and NF-κB was significantly increased by RANKL and IL-15 (P < 0.05) compared with RANKL alone. In addition, these differentiation activities induced by RANKL and IL-15 were comparatively suppressed by inhibition of ERK, suggesting that this synergistic effect on osteoclastogenesis is mainly mediated by ERK. Taken together, our results demonstrate that IL-15 and RANKL induce osteoclastogenesis synergistically, and IL-15 might play a novel and major role in destructive inflammatory bone diseases. J. Cell. Biochem. 118: 739-747, 2017. © 2016 Wiley Periodicals, Inc.

New Irradiation Method with Indocyanine Green-Loaded Nanospheres for Inactivating Periodontal Pathogens.

Antimicrobial photodynamic therapy (aPDT) has been proposed as an adjunctive strategy for periodontitis treatments. However, use of aPDT for periodontal treatment is complicated by the difficulty in accessing morphologically complex lesions such as furcation involvement, which the irradiation beam (which is targeted parallel to the tooth axis into the periodontal pocket) cannot access directly. The aim of this study was to validate a modified aPDT method that photosensitizes indocyanine green-loaded nanospheres through the gingivae from outside the pocket using a diode laser. To establish this trans-gingival irradiation method, we built an in vitro aPDT model using a substitution for gingivae. Irradiation conditions and the cooling method were optimized before the bactericidal effects on Porphyromonas gingivalis were investigated. The permeable energy through the gingival model at irradiation conditions of 2 W output power in a 50% duty cycle was comparable with the transmitted energy of conventional irradiation. Intermittent irradiation with air cooling limited the temperature increase in the gingival model to 2.75 °C. The aPDT group showed significant bactericidal effects, with reductions in colony-forming units of 99.99% after 5 min of irradiation. This effect of aPDT against a periodontal pathogen demonstrates the validity of trans-gingival irradiation for periodontal treatment.

Serum Amyloid A Promotes E-Selectin Expression via Toll-Like Receptor 2 in Human Aortic Endothelial Cells.

Periodontitis is a chronic inflammatory disease that affects the periodontium. Recent studies suggest an association between periodontal and cardiovascular diseases. However, the detailed molecular mechanism is unknown. A previous study has demonstrated that experimental periodontitis induces serum amyloid A (SAA) in the liver and peripheral blood of ApoE-deficient mice as an atherosclerosis model. SAA is an acute-phase protein that affects systemic inflammation. The aim of this study is to investigate the atherosclerosis-onset mechanism using human aortic endothelial cells (HAECs) stimulated by SAA in vitro. Atherosclerosis PCR array and qPCR analyses showed upregulation of adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in HAECs upon SAA stimulation. In addition, the results demonstrated that Toll-like receptor, TLR2, could serve as an important receptor of SAA in HAECs. Furthermore, small interfering RNA (siRNA) against TLR2 inhibited the upregulation of adhesion molecules in HAECs stimulated by SAA. Our results suggest that SAA stimulates the expression of adhesion molecules via TLR2. SAA could be an important molecule for atherosclerosis induced by periodontal disease.

The experience of dissolving polypharmacy by reducing the prescription of anti-ulcer drugs in residents of a special geriatric nursing home.

AIM: As part of a broader study on polypharmacy among elderly nursing home residents, we examined the impact of reducing or discontinuing the prescription of proton pump inhibitors and other anti-ulcer drugs. METHODS: We employed a strategy of reducing and discontinuing the prescription of drugs to 160 elderly residents of the Hiroshima Atomic Bomb survivors nursing home, Kandayama Yasuragien. The residents had entered the home between April 2012 and November 2015. As part of this study into anti-ulcer drugs, we also measured the concentrations of Helicobacter pylori antigen in stool specimens, and the serum concentrations of H pylori antibodies and pepsinogen I and II. RESULTS: The proportions of residents who were taking more than six drugs on April 2012, August 2014 and November 2015 were 55.2%, 49.0% and 43.0%, respectively. At the same times, the proportions of residents who were taking anti-ulcer drugs were 50.0%, 49.0% and 6.0%, respectively. The presence of H pylori antigen and antibodies, and serum pepsinogen concentrations, did not influence the decisions to continue or discontinue anti-ulcer drugs. CONCLUSIONS: We have already reported that reduction of diuretics reduces the incidence of falls and fall-related fractures in our residents, and have demonstrated the benefits of discontinuing folic acid and drugs that are given to control hyperkalemia. In the present study, we found that many anti-ulcer drugs were also of low necessity to elderly care home residents. It is essential to examine the clinical benefits of addressing polypharmacy in elderly individuals. In the future, we intend to focus on reducing hypnotics, laxatives and other drugs.

Adjunctive Application of Antimicrobial Photodynamic Therapy in Nonsurgical Periodontal Treatment: A Review of Literature.

Periodontal disease is caused by dental plaque biofilms, and the removal of these biofilms from the root surface of teeth plays a central part in its treatment. The conventional treatment for periodontal disease fails to remove periodontal infection in a subset of cases, such as those with complicated root morphology. Adjunctive antimicrobial photodynamic therapy (aPDT) has been proposed as an additional treatment for this infectious disease. Many periodontal pathogenic bacteria are susceptible to low-power lasers in the presence of dyes, such as methylene blue, toluidine blue O, malachite green, and indocyanine green. aPDT uses these light-activated photosensitizer that is incorporated selectively by bacteria and absorbs a low-power laser/light with an appropriate wavelength to induce singlet oxygen and free radicals, which are toxic to bacteria. While this technique has been evaluated by many clinical studies, some systematic reviews and meta-analyses have reported controversial results about the benefits of aPDT for periodontal treatment. In the light of these previous reports, the aim of this review is to provide comprehensive information about aPDT and help extend knowledge of advanced laser therapy.

Deficiency of p62/Sequestosome 1 causes hyperphagia due to leptin resistance in the brain.

The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.

Cross-sectional studies of tuberculosis prevalence in Cambodia between 2002 and 2011.

OBJECTIVE: To measure trends in the pulmonary tuberculosis burden between 2002 and 2011 and to assess the impact of the DOTS (directly observed treatment, short-course) strategy in Cambodia. METHODS: Cambodia's first population-based nationwide tuberculosis survey, based on multistage cluster sampling, was conducted in 2002. The second tuberculosis survey, encompassing 62 clusters, followed in 2011. Participants aged 15 years or older were screened for active pulmonary tuberculosis with chest radiography and/or for tuberculosis symptoms. For diagnostic confirmation, sputum smear and culture were conducted on those whose screening results were positive. FINDINGS: Of the 40,423 eligible subjects, 37,417 (92.6%) participated in the survey; 103 smear-positive cases and 211 smear-negative, culture-positive cases were identified. The weighted prevalences of smear-positive tuberculosis and bacteriologically-positive tuberculosis were 271 (95% confidence interval, CI: 212-348) and 831 (95% CI: 707-977) per 100,000 population, respectively. Tuberculosis prevalence was higher in men than women and increased with age. A 38% decline in smear-positive tuberculosis (P = 0.0085) was observed with respect to the 2002 survey, after participants were matched by demographic and geographical characteristics. The prevalence of symptomatic, smear-positive tuberculosis decreased by 56% (P = 0.001), whereas the prevalence of asymptomatic, smear-positive tuberculosis decreased by only 7% (P = 0.7249). CONCLUSION: The tuberculosis burden in Cambodia has declined significantly, most probably because of the decentralization of DOTS to health centres. To further reduce the tuberculosis burden in Cambodia, tuberculosis control should be strengthened and should focus on identifying cases without symptoms and in the middle-aged and elderly population.

A novel predictive formula for highly accurate discrimination between truly Helicobacter pylori-uninfected and currently infected/spontaneously eradicated individuals for gastric cancer screening.

The ABC classification, which categorizes gastric cancer risk based on serum Helicobacter pylori (H pylori) antibody and pepsinogen levels, has a limitation of potentially misclassifying high-risk individuals as low risk. To overcome the problem, we previously developed a 4-parameter predictive formula (age, serum H pylori antibody, PGI, and PGII) using logistic regression analysis to accurately identify low-risk truly H pylori-uninfected status. Our predictive formula demonstrated superior sensitivity and specificity in distinguishing between low-risk truly uninfected individuals and high-risk currently/spontaneously eradicated status individuals, compared to the modified ABC classification based on latex immunoassay kits (traditional 3-parameter model). This study aimed to revalidate the diagnostic accuracy of the predictive formula in a new and different study population. We applied the predictive formula to the target population and compared the sensitivity and specificity with those of the traditional 3-parameter model. A total of 788 enrollees were analyzed: 703 were classified as truly uninfected, 45 as currently infected, and 40 as spontaneously eradicated according to the results of stool antigen testing and endoscopic findings. The sensitivities and specificities of the predictive formula and the traditional 3-parameter model were 89.5% and 87.1% versus 89.8% and 80.0%, respectively. The specificity of the predictive formula was superior in the 70 to 89 age range and H pylori antibody < 3 U/mL groups. The predictive formula had higher specificity than the traditional 3-parameter model. The results should contribute to efficient gastric cancer screening by predicting H pylori infection status.

Applicability of artificial intelligence-based computer-aided detection (AI-CAD) for pulmonary tuberculosis to community-based active case finding.

BACKGROUND: Artificial intelligence-based computer-aided detection (AI-CAD) for tuberculosis (TB) has become commercially available and several studies have been conducted to evaluate the performance of AI-CAD for pulmonary tuberculosis (TB) in clinical settings. However, little is known about its applicability to community-based active case-finding (ACF) for TB. METHODS: We analysed an anonymized data set obtained from a community-based ACF in Cambodia, targeting persons aged 55 years or over, persons with any TB symptoms, such as chronic cough, and persons at risk of TB, including household contacts. All of the participants in the ACF were screened by chest radiography (CXR) by Cambodian doctors, followed by Xpert test when they were eligible for sputum examination. Interpretation by an experienced chest physician and abnormality scoring by a newly developed AI-CAD were retrospectively conducted for the CXR images. With a reference of Xpert-positive TB or human interpretations, receiver operating characteristic (ROC) curves were drawn to evaluate the AI-CAD performance by area under the ROC curve (AUROC). In addition, its applicability to community-based ACFs in Cambodia was examined. RESULTS: TB scores of the AI-CAD were significantly associated with the CXR classifications as indicated by the severity of TB disease, and its AUROC as the bacteriological reference was 0.86 (95% confidence interval 0.83-0.89). Using a threshold for triage purposes, the human reading and bacteriological examination needed fell to 21% and 15%, respectively, detecting 95% of Xpert-positive TB in ACF. For screening purposes, we could detect 98% of Xpert-positive TB cases. CONCLUSIONS: AI-CAD is applicable to community-based ACF in high TB burden settings, where experienced human readers for CXR images are scarce. The use of AI-CAD in developing countries has the potential to expand CXR screening in community-based ACFs, with a substantial decrease in the workload on human readers and laboratory labour. Further studies are needed to generalize the results to other countries by increasing the sample size and comparing the AI-CAD performance with that of more human readers.

A two-stage spectral model for sound texture perception: Synthesis and psychophysics.

The natural environment is filled with a variety of auditory events such as wind blowing, water flowing, and fire crackling. It has been suggested that the perception of such textural sounds is based on the statistics of the natural auditory events. Inspired by a recent spectral model for visual texture perception, we propose a model that can describe the perceived sound texture only with the linear spectrum and the energy spectrum. We tested the validity of the model by using synthetic noise sounds that preserve the two-stage amplitude spectra of the original sound. Psychophysical experiment showed that our synthetic noises were perceived as like the original sounds for 120 real-world auditory events. The performance was comparable with the synthetic sounds produced by McDermott-Simoncelli's model which considers various classes of auditory statistics. The results support the notion that the perception of natural sound textures is predictable by the two-stage spectral signals.

Common eating habit patterns are associated with a high maximum occlusal force and pre-eating cardiac vagal tone.

Background: Masticatory function is associated with nervous function, including autonomic nervous function, and both functions are influenced by human habits. In a previous preliminary study of 53 young women, we found that eating habit patterns were associated with occlusal force as an indicator of masticatory function. Therefore, we hypothesized that relationships exist between occlusal force, the autonomic nervous system, and eating habit patterns. Methods: To test our hypothesis, we analyzed the relationship between heart rate variability measured before and after lunch in 53 young women, and measured and surveyed maximum occlusal force and eating habit patterns, respectively, in these participants. Results: High occlusal force was associated with an increased high-frequency (HF) component (vagal tone index) of the heart rate variability index immediately before lunch (standardized regression coefficient (ß) = 0.417, P = 0.002). Each of the eating habit items surveyed in a questionnaire showed a similar tendency for the HF component immediately before lunch and maximum occlusal force; in particular, "Habit of eating breakfast" and "Number of meals per day" were significantly associated with both variables. Additionally, total eating habit scores related to higher maximum occlusal force were associated with an increase in the HF component immediately before lunch (ß = 0.514, P < 0.001). The maximum occlusal force and the pre-eating HF component values were stratified by total eating habit scores (into low, medium, high categories), and the high scores were significantly higher than the medium or low scores. Conclusions: Occlusal force and the pre-eating cardiac vagal response of individuals were characterized by their common eating habit patterns, indicating that eating habits may be simultaneously associated with the development of masticatory function, nervous system development, and cardiovascular rhythm. Although further research is needed to investigate these relationships in detail, our findings provide insights that will inform the study of physical functions, neurodevelopment, habitual behaviors, and health in humans.

Renal tubular function and morphology revealed in kidney without labeling using three-dimensional dynamic optical coherence tomography.

Renal tubule has distinct metabolic features and functional activity that may be altered during kidney disease. In this paper, we present label-free functional activity imaging of renal tubule in normal and obstructed mouse kidney models using three-dimensional (3D) dynamic optical coherence tomography (OCT) ex vivo. To create an obstructed kidney model, we ligated the ureter of the left kidney for either 7 or 14 days. Two different dynamic OCT (DOCT) methods were implemented to access the slow and fast activity of the renal tubules: a logarithmic intensity variance (LIV) method and a complex-correlation-based method. Three-dimensional DOCT data were acquired with a 1.3 [Formula: see text]m swept-source OCT system and repeating raster scan protocols. In the normal kidney, the renal tubule appeared as a convoluted pipe-like structure in the DOCT projection image. Such pipe-like structures were not observed in the kidneys subjected to obstruction of the ureter for several days. Instead of any anatomical structures, a superficial high dynamics appearance was observed in the perirenal cortex region of the obstructed kidneys. These findings suggest that volumetric LIV can be used as a tool to investigate kidney function during kidney diseases.

Immunohistochemical expression of NRF2 is correlated with the magnitude of inflammation and fibrosis in chronic liver disease.

BACKGROUND: The nuclear factor E2-related factor 2-Kelch-like Ech-associated protein (NRF2-KEAP1) pathway is a major cellular defense mechanism against oxidative stress. However, the role of NRF2-KEAP1 signaling in the development of chronic liver disease remains unclear. METHODS: Clinical liver specimens from 50 hepatocellular carcinoma (HCC) developed from non-alcoholic steatohepatitis (NASH), 49 HCCs developed from chronic viral hepatitis C (CHc), and 48 liver metastases of colorectal cancer (CRC) from both tumorous and non-tumorous areas were collected during hepatic resection surgery. They were evaluated by immunohistochemical analyses of hematoxylin-eosin, Masson's trichrome, NRF2, and KEAP1, and compared with clinicopathological information. RESULTS: Hepatic inflammation and fibrosis were more severe in the low-intensity NRF2 group than in the high-intensity NRF2 group both between CRC and NASH (Low vs. High: inflammation; p = 0.003, fibrosis; p = 0.014), and between CRC and CHc (Low vs. High: inflammation; p = 0.031, fibrosis; p = 0.011), which could indicate that NRF2 expression in cytosol of hepatocytes was inversely correlated with liver inflammation and fibrosis in non-tumorous areas. The dense staining of NRF2 in the nuclei of non-tumor hepatocytes positively correlated with liver inflammation (CRC and NASH; R = 0.451, p < 0.001, CRC and CHc; R = 0.502, p < 0.001) and fibrosis (CRC and NASH; R = 0.566, p < 0.001, CRC and CHc; R = 0.548, p < 0.001) in both NASH and CHc, and was inversely correlated with hepatic spare ability features such as platelet count (R = -0.253, p = 0.002) and prothrombin time (R = -0.206, p = 0.012). However, KEAP1 expression was not correlated with NRF2 expression levels and nuclear staining intensity. CONCLUSIONS: Nuclear translocation of NRF2 was correlated with the magnitude of liver inflammation and fibrosis in chronic liver disease. These results suggest that NRF2 plays a protective role in the development of chronic liver diseases such as NASH and CHc.

Macrophage specific restoration of the Nrf2 gene in whole-body knockout mice ameliorates steatohepatitis induced by lipopolysaccharide from Porphyromonas gingivalis through enhanced hepatic clearance.

Lipopolysaccharide (LPS) derived from Porphyromonas gingivalis (P.g.), which causes periodontal disease, contributes to the development of non-alcoholic steatohepatitis (NASH). We investigated the role of Nrf2, an antioxidative stress sensor, in macrophages in the development of NASH induced by LPS from P.g. We generated macrophage-specific Nrf2 gene rescue mice (Nrf2-mRes), which express Nrf2 only in macrophages, using the cre/loxp system. Wild-type (WT) mice, whole body Nrf2-knockout (Nrf2-KO) mice, and Nrf2-mRes mice were fed a high-fat diet for 18 weeks, and LPS from P.g. was administered intraperitoneally for the last 6 weeks. Nrf2-KO mice developed severe steatohepatitis with liver inflammation and fibrosis compared with WT mice, and steatohepatitis was ameliorated in Nrf2-mRes mice. The mRNA expressions of Toll-like receptor (Tlr)-2, which activates inflammatory signaling pathways after LPS binding, and α-smooth muscle actin (αSma), which promotes hepatic fibrosis, were reduced in Nrf2-mRes mice compared with Nrf2-KO mice. The protein levels of LPS-binding protein in livers were increased in Nrf2-KO mice compared with WT mice; however, the levels were reduced in Nrf2-mRes mice despite similar numbers of F4/80 positive cells, which reflect macrophage/Kupffer cell infiltration into the livers. Nrf2 in macrophages ameliorates NASH through the increased hepatic clearance of LPS.