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Chestnut (Castanea crenata) inner shell extract (CIE), a curative herb in Korea, has diverse pharmacological effects against various diseases including pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease (COPD). However, its molecular mechanisms of anti-emphysematous effects are still not fully elucidated. In the present study, we elucidate the efficacy of CIE against emphysematous lesion progression in a cigarette smoke condensate (CSC)-instilled mice and CSC-stimulated H292 cell line. The mice are administered CSC via intranasal instillation at 7-day intervals for 1 month after 1 week of pretreatment with CIE. CIE (100 or 300 mg/kg) is administered by oral gavage for 1 month. CIE decreased the macrophage count in bronchoalveolar lavage fluid and the severity of emphysematous lesions in lung tissue. Additionally, CIE suppressed the phosphatidylinositol 3-kinase/protein kinase B/nuclear factor kappa B signal pathway and thereby downregulated matrix metalloprotease-9 expression, which was confirmed in CSC-stimulated H292 cells. Thus, CIE effectively inhibited CSC-induced macrophage-driven emphysema progression in airways; this inhibition was associated with the suppression of protease–antiprotease imbalance. Our results propose that CIE has the potential for the alleviation of COPD.

The inner shell of the chestnut (Castanea crenata) contains various polyphenols, which exert beneficial biological effects. Hence, we assessed the anti-inflammatory efficacy of a chestnut inner shell extract (CIE) in ovalbumin (OVA)-induced allergic asthma. We intraperitoneally injected 20 μg of OVA with 2 mg of aluminum hydroxide on days 0 and 14. On test days 21, 22, and 23, the mice were treated with aerosolized 1% (

In this study, we explored the potential beneficial effects of green tea extract (GTE) in a pathogenic Escherichia coli (F18:LT:STa:Stx2e)-induced colitis model. The GTE was standardized with catechin and epigallocatechin-3-gallate content using chromatography analysis. Ten consecutive days of GTE (500 and 1000 mg/kg) oral administration was followed by 3 days of a pathogenic E. coli challenge (1 × 109 CFU/mL). In vitro antibacterial analysis showed that GTE successfully inhibited the growth of pathogenic E. coli, demonstrating over a 3-fold reduction under time- and concentration-dependent conditions. The in vivo antibacterial effect of GTE was confirmed, with an inhibition rate of approximately 90% when compared to that of the E. coli alone group. GTE treatment improved pathogenic E. coli-induced intestinal injury with well-preserved epithelial linings and villi. In addition, the increased expression of annexin A1 in GTE-treated jejunum tissue was detected, which was accompanied by suppressed inflammation-related signal expression, including TNFA, COX-2, and iNOS. Moreover, proliferation-related signals such as PCNA, CD44, and Ki-67 were enhanced in the GTE group compared to those in the E. coli alone group. Taken together, these results indicate that GTE has an antibacterial activity against pathogenic E. coli and ameliorates pathogenic E. coli-induced intestinal damage by modulating inflammation and epithelial cell proliferation.

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.

Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies, however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.

The incidence of non-alcoholic fatty liver disease (NAFLD) increases in males aged &gt, 45 years, which indicates that androgens are associated with the development and/or progression of NAFLD, although excess dietary intake is the primary causative factor. However, it is uncertain how androgens are involved in the metabolic process of NAFLD, which is associated with the state of steatosis in hepatocytes. To investigate whether androgen receptor (AR) signaling influences NAFLD development, the state of steatosis was monitored in mouse livers and hepatocytes with or without androgens. As a result, hepatic lipid droplets, expression of AR, and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) increased in the presence of testosterone. Concurrently, the expression of LKB1, an upstream regulator of AMPK, was increased by testosterone treatment. We observed that the fluctuation of AMPK-ACC signaling, which plays an important role in lipogenesis, depends on the presence of testosterone and AR. Additionally, we demonstrated that testosterone bound AR was recruited to the promoter of the LKB1 gene and induced LKB1 expression. Our study highlights a novel mechanism by which testosterone modulates NAFLD development by inducing the mRNA expression of LKB1.

Background Melatonin has various biological activities that improve the health of an individual. We evaluated the effects of melatonin on inflammatory response in chronic obstructive pulmonary disease (COPD), focusing on the regulation of SIRT1 expression. Methods To investigate the effect of melatonin, we used cigarette smoke (CS)‐induced COPD mouse model and CS condensate (CSC)‐stimulated J774 macrophage cells. Results CSC‐stimulated J774 macrophages exhibited increased p65 acetylation with a reduction in SIRT1 expression. However, melatonin induced the enhancement of SIRT1 expression, which eventually decreased p65 acetylation in CSC‐stimulated J774 cells. Melatonin‐treated mice exhibited an enhancement in SIRT1 expression with the reduction in p65 acetylation, which decreased the level of inflammatory mediators induced by CS. Additionally, SIRT1 inhibitor treatment increased the level of inflammatory mediators, which was accompanied by an increase in p65 acetylation. However, cotreatment with melatonin and an SIRT1 inhibitor reduced the level of inflammatory mediators compared with that by treatment with the SIRT1 inhibitor alone, which was accompanied by elevation in SIRT1 expression and reduction in p65 acetylation. Conclusions Overall, the results indicated that melatonin has therapeutic effects against COPD, owing to its property to enhance SIRT1 expression.

Alismatis rhizoma (AR), the dried rhizome of Alisma orientale (Sam.) Juzep, is a well-known, traditional medicine that is used for the various biological activities including as a diuretic, to lower cholesterol and as an anti-inflammatory agent. The present study was carried out to investigate the potential toxicity of the Alismatis rhizoma aqueous extract (ARAE) following 90-day repeated oral administration to Sprague-Dawley rats. ARAE was administered orally to male and female rats for 90 days at 0 (control), 500, 1,000 and 2,000 mg/kg/day (n = 10 for male and female rats for each dose). Additional recovery groups from the control group and high dose group were observed for a 28-day recovery period. Chromatograms of ARAE detected main compounds with four peaks. Treatment-related effects including an increase in the red blood cells, hemoglobin, hematocrit, albumin, total protein, and urine volume were observed in males of the 2,000 mg/kg/day group (p < 0.05). However, the diuretic effect of ARAE was considered, a major cause of hematological and serum biochemical changes. The oral no-observed-adverse-effect level (NOAEL) of the ARAE was > 2,000 mg/kg/day in both genders, and no target organs were identified.

Water extract of guibi-tang (GB), a traditional Chinese, Japanese, and Korean herbal medicine, is used to treat memory impairment, insomnia, and peptic ulcers. The aim of this study was to investigate the protective effects of GB on pulmonary inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). C57BL/6 mice were used to develop a pulmonary inflammation model by exposing them to CS for 1 h per day for 7 days. LPS was intranasally administered to mice under mild anesthesia on day 5. GB was administered 1 h before CS exposure at doses of 50 or 100 mg/kg for 7 days. Our results showed that GB suppressed the CS and LPS induced elevation in inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), with significant reductions in protein, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels. Histological studies revealed that GB decreased the inflammatory cell infiltration into lung tissue caused by CS- and LPS-exposure. GB also significantly decreased the CS and LPS-induced expression of inducible nitric oxide synthase (iNOS) in the lung tissue. Taken together, GB effectively attenuated airway inflammation caused by CS and LPS. These results indicate that GB is a potential therapeutic herbal formula for pulmonary inflammatory disease.

Yijin-tang is an oriental traditional herb used to treat inflammatory diseases. In the present study, we investigated the protective effects of Yijin-tang water extract (YTE) using an ovalbumin- (OVA-) induced asthma model, focusing on the antioxidant and anti-inflammatory properties of the herb. BALB/c mice were intraperitoneally injected with OVA on days 0 and 14 and then challenged with OVA on days 21, 22, and 23. The animals were orally administered YTE (200 and 400 mg/kg) from days 18 to 23, and this was found to significantly decrease airway hyperresponsiveness and release of inflammatory cells, cytokines, and OVA-specific immunoglobulin E in mice with asthma. In addition, YTE was associated with a marked reduction in airway inflammation and mucus production in lung tissue of mice with asthma. Furthermore, YTE suppressed the expression of matrix metalloproteinase-9 and phosphorylation of ERK in the lungs, which in turn led to a reduction in inducible nitric oxide synthases and an elevation in reduced glutathione and heme oxygenase-1. In conclusion, YTE effectively suppressed allergic responses in mice with asthma and the effect was closely related to antioxidant and anti-inflammatory properties of the herb. Our results indicate that YTE may be a potential agent for the treatment of allergic asthma.

Although vitamin B6 is contained in various foods, its deficiency is one of the most common micronutrient deficiencies worldwide. Furthermore, patients with obesity and cardiovascular disease are more likely to have suboptimal vitamin B6 status than healthy people. Therefore, we investigated the effects of dietary vitamin B6 restriction on hepatic gene expression and function in obese mice. C57BL/6J male mice were fed a low-fat (LF) or high-fat (HF) diet in combination with sufficient (7 mg pyridoxine/kg diet) or insufficient (1 mg) amounts of vitamin B6 for 16 weeks. Analysis of microarray data revealed that expressions of 4000 genes were significantly altered by the experimental diets (LF7, LF1, HF7, and HF1). The effects of dietary fat content on gene expressions were markedly greater than vitamin B6 content. Only three differentially expressed genes (DEGs) were overlapped between the LF1/LF7 and HF1/HF7 comparison. In the LF1/LF7 comparison, 54 upregulated DEGs were enriched in gene ontology (GO) terms associated with the sterol metabolic process and 54 downregulated DEGs were enriched in GO terms associated with immune response. In HF1/HF7 comparison, 26 upregulated DEGs were enriched in GO terms associated with amino acid catabolic process. High-fat consumption downregulated gene expressions associated with vitamin B6-dependent pathways. In conclusion, our data suggest that obesity may differentially regulate vitamin B6-associated metabolic pathways in the body.

Scrophularia koraiensis Nakai (Scrophulariaceae) is a medicinal herb that grows in Korea and which has been widely used to treat fever, edema, neuritis and laryngitis. Hence, we evaluated the anti-inflammatory and antioxidant effects of the ethanol extract (SKE) of S. koraiensis Nakai in an ovalbumin (OVA)-induced mouse model. We injected 20 &mu, g of OVA with 2 mg of aluminum on day 0 and day 14 to induce allergic airway inflammation in six-week-old BALB/c mice, and mice were challenged with 1% OVA by nebulization for 1 h on days 21, 22, and 23. SKE was orally administered at 20 mg/kg and 40 mg/kg from day 18 to 23, and its effects were compared with those of montelukast treatment. SKE significantly reduced proinflammatory cytokines, inflammatory cell counts, immunoglobulin-E, and airway hyperresponsiveness during the OVA-induced allergic airway inflammation model, it also reduced airway inflammation and mucus production. In addition, SKE reduced the OVA-induced nuclear factor kappa B (NF-&kappa, B) phosphorylation in lung tissues while enhancing nuclear factor erythroid-derived 2-related factor (Nrf-2) and heme oxygenase-1 (HO-1) expression. In conclusion, SKE showed the protective effects on OVA-induced allergic airway inflammation via the suppression of NF-&kappa, B phosphorylation and the enhancement of the Nrf2/HO-1 signaling pathway. These results indicate that SKE is a potential therapeutic agent for allergic airway inflammation.

Silica dioxide nanoparticles (SiONPs) have been applied to several fields, such as drug delivery and gene therapy. However, SiONPs are a constituent of fine dust and can induce excessive inflammatory responses in the lungs via the airways. Silibinin, a major component of silymarin, has been known for its anti-oxidant and anti-inflammatory effects. In the present study, we explored the protective effects of silibinin against SiONPs-induced airway inflammation and explored its underlying mechanism of action, focusing on thioredoxin-interacting protein (TXNIP)/mitogen-activated protein kinases (MAPKs) in vitro and in vivo. In SiONPs-stimulated NCI-H292 airway epithelial cells, silibinin treatment effectively suppressed the elevation of the mRNA expression of tumor necrosis factor-&alpha, (TNF-&alpha, ), interleukin (IL)-6, and IL-1&beta, which was accompanied by the reduction in the expression of TXNIP, MAPKs, and activator protein-1 (AP-1). In SiONPs-treated mice, silibinin administration inhibited the increase in inflammatory cell counts and proinflammatory mediators, and it alleviated airway inflammation by SiONPs exposure. In addition, silibinin administration effectively suppressed the elevation of TXNIP/MAPKs/AP-1 signaling by SiONPs exposure. Taken together, silibinin effectively inhibited SiONPs-induced inflammatory responses, and this effect was closely related to the inhibition of TXNIP/MAPK/AP-1 signaling. These results suggested that silibinin might be useful for reducing pulmonary inflammation induced by SiONPs.

We investigated whether diallyl disulfide (DADS) has protective effects against 1,3-dichloro-2-propanol (1,3-DCP)-induced hepatotoxicity and oxidative damage in rats and HepG2 cells. DADS was administered to rats once daily for 7 days at doses of 30 and 60 mg/kg/day. One hour after the final DADS treatment, the rats were administered 90 mg/kg 1,3-DCP to induce acute hepatotoxicity. DADS treatment significantly suppressed the increase in serum aminotransferase levels induced by 1,3-DCP administration, and reduced histopathological alterations in the liver. DADS treatment reduced 1-3-DCP-induced apoptotic changes in the liver, as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry for caspase-3. DADS treatment competitively inhibited or reduced cytochrome p450 2E1 (CYP2E1) expression, which is involved in the metabolic activation of 1,3-DCP, and enhanced antioxidant properties. Furthermore, DADS treatment inhibited phosphorylation of mitogen-activated protein kinases (MAPKs) and apoptotic signaling. In in vitro experiments, MAPKs inhibitors reduced the expression of Bax/Bcl-2/Caspase 3 signaling, which effects were more significant in co-treated cells with DADS and MAPKs inhibitors. In conclusion, the protective effect of DADS against 1,3-DCP-induced hepatotoxicity may be related to blocking the metabolic activation of 1,3-DCP by suppressing CYP2E1 expression, inducing antioxidant enzyme activity, and reducing apoptotic activity by inhibiting phosphorylation of MAPKs.

This study investigated the potential toxicity of the Areca catechu water extract after 13-week repeated oral administration at 0, 166.7, 500, and 1500 mg/kg/day in rats. During the study period, clinical signs, mortality, body weight, food consumption, water consumption, urinalysis, estrous cycle, sperm count and motility, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 1500 mg/kg/day, both sexes exhibited an increase in the incidence of abnormal clinical signs, which included, decreased body weight gain and food consumption, and increased urine bilirubin, ketone bodies, specific gravity, and protein and kidney weight. An increase in liver weight and estrous cycle alterations was observed in females. Serum biochemical and histopathological investigations revealed an increase in the levels of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and the incidence of hepatic necrosis in females. At 500 mg/kg/day, an increase in the incidence of abnormal clinical signs including diarrhea and soiled perineal region, was observed in both sexes. No treatmentrelated effects were observed at 166.7 mg/kg/day. Under the present experimental conditions, the target organs were determined to be the liver, kidney, and female reproductive system in rats. The no-observedeffect level was considered to be 166.7 mg/kg/day in rats.

Cigarette smoke (CS) is the main etiological cause of chronic obstructive pulmonary disease, the prevalence of which has continuously increased in recent years. 4-Hydroxycinnamic acid (HA) is a plant phenolic acid that has anti-inflammatory activities. In this study, we explored the therapeutic effects of HA on airway inflammation caused by CS and lipopolysaccharide (LPS) in mice. The animals received 1 h of CS exposure for 7 days and intranasal instillation of LPS on day 4. HA (10 and 20 mg/kg) was administered to animals via oral gavage 1 h before CS exposure. HA treatment significantly decreased the accumulation of inflammatory cells and production of cytokines, including tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, caused by CS and LPS exposure. After histological examination, we observed that HA treatment significantly reduced the infiltration of inflammatory cells into lung tissue caused by CS and LPS exposure. Furthermore, HA-treated groups showed significantly decreased phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, and nuclear factor-κB, and activity of cytochrome c oxidase subunit-2 caused by CS and LPS. In conclusion, HA effectively suppresses the airway inflammatory response induced by CS and LPS exposure, and is closely associated with the downregulation of mitogen-activated protein kinases signaling.

Artemisia argyi is used as a health supplement, tea, and food source in Korea. This study aimed to evaluate the effect of Artemisia argyi (AA) and its active compound, dehydromatricarin A (DA), on the attenuation of airway inflammation in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). The C57BL/6 mice were administered AA (50 mg/kg or 100 mg/kg) and DA (10 mg/kg or 20 mg/kg) by oral gavage from day 0 to 7 days and LPS treated by intranasal instillation 48 hours before the sacrifice. The treatment of AA and DA markedly decreased inflammatory cells in the bronchoalveolar lavage fluid (BALF) compared with that in ALI-induced mice, which was accompanied by a significant reduction in the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in BALF. Furthermore, the administration of AA and DA clearly decreased inducible nitric oxide synthase (iNOS) expression and nuclear factor kappa B (NF-κB) phosphorylation in comparison with that in the ALI-induced mice. The histological examination of the lung tissue revealed that the administration of AA and DA suppressed the inflammatory cell infiltration into the peribronchial and alveolar lesions induced by LPS instillation. Collectively, our results indicated that AA and DA effectively decreased the airway inflammatory response induced by LPS instillation. Therefore, AA and DA may offer a potential therapy for airway inflammatory disease.

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.

// Na-Rae Shin 1, * , Ji-Won Park 2, * , In-Chul Lee 3 , Je-Won Ko 1 , Sung-Hyeuk Park 1 , Joong-Sun Kim 4 , Jong-Choon Kim 1 , Kyung-Seop Ahn 2 and In-Sik Shin 1 1 College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, Gwangju 500-757, Republic of Korea 2 Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea 3 Natural Product Research Center, Jeonbuk Branch, Korea Research Institute of Biosciences and Biotechnology, Jeongeup 580-185, Republic of Korea 4 Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan 619-953, Republic of Korea * These authors contributed equally to this work Correspondence to: In-Sik Shin, email: dvmmk79@gmail.com Kyung-Seop Ahn, email: ksahn@kribb.re.kr Keywords: melatonin, cigarette smoke, pulmonary fibrosis, TGF-β1, MAPK Received: August 01, 2017 Accepted: September 22, 2017 Published: October 09, 2017 ABSTRACT Cigarette smoke (CS) is the most important risk factor in the development of chronic obstructive pulmonary disease (COPD). Pulmonary fibrosis is an irreversible response and important feature of COPD. In this study, we investigated the effects of melatonin on fibrotic response in development of COPD using a CS and lipopolysaccharide (LPS) induced COPD model and cigarette smoke condensate (CSC)-stimulated NCI-H292 cells, a human mucoepidermoid cell line. Mice were exposed to CS for 1 h per day (8 cigarettes per day) from day 1 to day 7 and were treated intranasally with LPS on day 4. Melatonin (10 or 20 mg/kg) was injected intraperitoneally 1 h before CS exposure. Melatonin decreased the inflammatory cell counts in bronchoalveolar lavage fluid (BALF), with a reduction in transforming growth factor (TGF)-β1. Melatonin inhibited the expression of TGF-β1, collagen I and SMAD3 phosphorylation in lung tissue exposed to CS and LPS. In CSC-stimulated H292 cells, melatonin suppressed the elevated expression of fibrotic mediators induced by CSC treatment. Melatonin reduced the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation in CSC-stimulated H292 cells. In addition, cotreatment with melatonin and TGF-β1 inhibitors significantly limited fibrotic mediators, with greater reductions in the expression of TGF-β1, collagen I, SMAD3 and p38 phosphorylation than those of H292 cells treated with TGF-β1 inhibitor alone. Taken together, melatonin effectively inhibited fibrotic responses induced by CS and LPS exposure, which was related to the downregulation of TGF-β1. Therefore, our results suggest that melatonin may suppress the pulmonary fibrotic response induced by CS.

Diallyl disulfide (DADS) is a degradation product of allicin which is contained in garlic. This study investigated the protective effects of DADS against acetaminophen (AAP)-induced nephrotoxicity and the molecular mechanisms of nephroprotective effects in rats. AAP caused severe nephrotoxicity as evidenced by significant increases in renal tubular cell apoptosis, mitochondria-mediated apoptosis, and up-regulation of nuclear transcription factor kappa-B (NF-κB), cyclooxygenase-2 (Cox-2), and tumor necrosis factor-α (TNF-α) in the kidney with histopathological alterations. After AAP administration, glutathione content and activities of catalase, superoxide dismutase, and glutathione reductase were significantly decreased whereas malondialdehyde content was significantly increased, indicating that AAP-induced kidney injury was mediated through oxidative stress. In contrast, DADS pretreatment significantly attenuated AAP-induced nephrotoxic effects, including oxidative damage, histopathological lesions, and apoptotic changes in the kidney. DADS also attenuated AAP-induced up-regulation of NF-κB, Cox-2, and TNF-α in the kidney, and microsomal CYP2E1 expression in liver and kidney. These results indicated that DADS could prevent AAP-induced nephrotoxicity. The protective effects of DADS might be due to its ability to decrease metabolic activation of AAP by inhibiting CYP2E1 and its potent antioxidant, antiapoptotic, and antiinflammatory effects via inhibition of NF-κB.

This study investigated the protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute renal injury in male rats. We also investigated the effects of DADS on kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NCAL), which are novel biomarkers of nephrotoxicity in renal tissues, in response to AAP treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) AAP (1,000 mg/kg), (3) AAP&DADS, and (4) DADS (50 mg/kg/day). AAP treatment caused acute kidney injury evidenced by increased serum blood urea nitrogen (BUN) levels and histopathological alterations. Additionally, Western blot and immunohistochemistry analysis showed increased expression of KIM-1 and NCAL proteins in renal tissues of AAP-treated rats. In contrast, DADS pretreatment significantly attenuated the AAP-induced nephrotoxic effects, including serum BUN level and expression of KIM-1 and NCAL proteins. Histopathological studies confirmed the renoprotective effect of DADS. The results suggest that DADS prevents AAP-induced acute nephrotoxicity, and that KIM-1 and NCAL may be useful biomarkers for the detection and monitoring of acute kidney injury associated with AAP exposure.

Background Scrophularia buergeriana Miq. (Scrophulariaceae) (SB) has been used as an oriental medicine for the treatment of inflammatory diseases, such as neuritis and pharyngolaryngitis. Purpose We explored the therapeutic effects of S. buergeriana ethanol extract (SBE) on airway inflammation in ovalbumin (OVA)-induced asthmatic mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Methods Mice were intraperitoneally injected with OVA on days 0 and 14 to elevate the immune response. On days 21 to 23, the mice were challenged with OVA solution and SBE (20 and 40 mg/kg) was administered daily by oral gavage from days 18 to 23. RAW264.7 cells were pretreated with SBE 1 h before LPS stimulation. Results SBE administration effectively suppressed inflammatory cell infiltration, the expression of interleukin (IL)-5, IL-13, and IL-17, immunoglobulin E, and airway hyperresponsiveness in an OVA-induced allergic asthma model. A reduction in histological alterations, including airway inflammation and mucus hypersecretion, was observed. These effects of SBE were accompanied by a decrease in matrix metalloproteinase-9 (MMP-9) expression and nuclear factor kappa B (NF-κB) phosphorylation. These responses were observed in LPS-stimulated RAW264.7 cells. SBE treatment reduced the mRNA expression of tumor necrosis factor (TNF)-α, IL-6, and MMP-9, and NF-κB phosphorylation, in LPS-stimulated RAW264.7 cells. Conclusion Our results indicated that SBE effectively attenuated airway inflammation in an OVA-induced allergic asthma model. These properties of SBE were thought to be involved in the suppression of NF-κB phosphorylation, suggesting that the material has the potential to regulate the development of allergic asthma.

Background Although Eriobotrya japonica leaves have been studied as a raw material for various cosmetic products, little is known about the anti-oxidant, anti-inflammatory, and anti-melanogenic activities of Eriobotrya japonica leaf ethanol extract (EJEE). Methods This study was conducted to evaluate the anti-oxidant, anti-inflammatory, and anti-melanogenic activities of EJEE using different in vitro models. In addition, we investigated the potential irritation of EJEE to skin and eye using animal alternative tests. Results The total content of polyphenols, one of the active constituents of EJEE, was analyzed by high-performance liquid chromatography and found to contain 88.68 mg tannic acid equivalent/g. EJEE showed a concentration-dependent 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radical scavenging activity, and a superoxide dismutase-like activity. The anti-inflammatory effect of 0.5% (w/v) EJEE was demonstrated by a reduction in lipopolysaccharide-induced nitric oxide and tumor necrosis factor-alpha levels in RAW 264.7 cells. EJEE also significantly inhibited melanogenesis in melanocyte stimulating hormone-induced B16F1 cells. EJEE did not show any irritation in skin and eye in animal alternative test. Conclusions These results indicate that the EJEE possesses anti-oxidant, anti-inflammatory, and anti-melanogenic activities, while it did not induce toxicity or irritation in neither skin nor eye. Therefore, EJEE can be used as a cosmetic ingredient for skin improvement.

Dipsacus asperoides C. Y. Cheng et T. M. Ai (DA) has been used in China as a traditional medicine to treat lumbar and knee pain, liver dysfunction, and fractures. We explored the suppressive effect of DA on allergic asthma using an ovalbumin (OVA)-induced asthma model. In the asthma model, female Balb/c mice were sensitized to OVA on day 0 and 14 to boost immune responses and then exposed to OVA solution by using an ultrasonic nebulizer on days 21 to 23. DA (20 and 40 mg/kg) was administered to mice by oral gavage on days 18 to 23. Methacholine responsiveness was determined on day 24 using a plethysmography. On day 25, we collected bronchoalveolar lavage fluid, serum, and lung tissue from animals under anesthesia. DA treatment effectively inhibited methacholine responsiveness, inflammatory cell infiltration, proinflammatory cytokines such as interleukin (IL)-5 and IL-13, and immunoglobulin (Ig) E in OVA-induced asthma model. Reductions in airway inflammation and mucus hypersecretion, accompanied by decreases in the expression of inducible nitric oxide synthase (iNOS) and the phosphorylation of nuclear factor kappa B (NF-κB), were also observed. Our results indicated that DA attenuated the asthmatic response, and that this attenuation was closely linked to NF-κB suppression. Thus, this study suggests that DA is a potential therapeutic for allergic asthma.

Both melamine and cyanuric acid have low toxicity, but combined exposure to melamine and cyanuric acid (M + CA) was reported to cause unexpected toxicological synergy on kidney damage. In this study, we investigated the role of oxidative stress and apoptotic changes in the nephrotoxicity caused by M + CA in rats. M + CA treatment caused an increase in the kidney weight, serum blood urea nitrogen or creatinine levels in a dose-dependent manner. With severe morphological and histological changes in kidneys, M + CA markedly elevated lipid peroxidation and suppressed antioxidant enzyme activities. M + CA treatment induced apoptotic changes in renal tubular cells. Additionally, exposure to M + CA increased phosphorylation of mitogen-activated protein kinases (MAPKs) coincided with increased Bax level and decreased Bcl2 level, resulting in caspase-3 activation. In summary, oxidative stress and simultaneous MAPKs and mitochondrial/caspase activation may be related to renal tubular cell apoptosis caused by M + CA.

Copper nanoparticles (CuONPs) can pose risks to industrial workers. With increase of its applications especially in electronic fields, it is necessary to assess the toxicity of CuONPs, including pulmonary toxicity. In this study, we investigated the effect of CuONPs on human epithelial cell line H292. CuONPs treatment caused a significant increase in IL-6 and IL-8 mRNA expression and protein levels in H292 cells in a concentration-dependent manner. The mRNA expression and protein levels of MUC5AC were consistent with those of proinflammatory mediators. Additionally, CuONPs treatment increased phosphorylation of mitogen-activated protein kinases (MAPKs), Erk, JNK, and p-38 compared to that of control in a concentration-dependent manner. However, co-treatment with CuONPs and each MAPK inhibitor significantly decreased the phosphorylation of each MAPK, resulting in decreased mRNA expression and protein levels of proinflammatory mediators and MUC5AC compared to that in H292 cells only treated with CuONPs. In summary, CuONPs-induced inflammatory mediators and MUC5AC associated with MAPKs phosphorylation. Our results will provide useful information on CuONPs-induced pulmonary toxicity.

Garlic (Allium sativum) has traditionally been used as a medicinal food and exhibits various beneficial activities, such as antitumor, antimicrobial, hypolipidemic, antiarthritic, and hypoglycemic activities. The aim of this study was to explore the preventive effect of garlic oil (GO) and its organosulfur component diallyl disulfide (DADS) on cigarette smoke (CS)-induced airway inflammation. Mice were exposed to CS daily for 1 h (equivalent to eight cigarettes per day) for two weeks, and intranasally instilled with lipopolysaccharide (LPS) on day 12 after the initiation of CS exposure. GO and DADS were administered to mice by oral gavage, both at rates of 20 and 40 mg/kg, for 1 h before CS exposure for two weeks. In the bronchoalveolar lavage fluid, GO and DADS inhibited the elevation in the counts of inflammatory cells, particularly neutrophils, which were induced in the CS and LPS (CS + LPS) group. This was accompanied by the lowered production (relative to the CS + LPS group) of interleukin (IL)-1&beta, IL-6, and tumor necrosis factor-&alpha, Histologically, GO and DADS inhibited the CS- and LPS-induced infiltration of inflammatory cells into lung tissues. Additionally, GO and DADS inhibited the phosphorylation of extracellular signal-regulated kinase and the expression of matrix metalloproteinase-9 in the lung tissues. Taken together, these findings indicate that GO and DADS could be a potential preventive agent in CS-induced airway inflammation.

So-Cheong-Ryoung-Tang is a traditionally used herbal formula for the treatment of pulmonary diseases in China, Korea, and Japan. We investigated the protective effects of So-Cheong-Ryong-Tang water extract (SCWE) in cigarette smoke concentrate (CSC) stimulated human airway epithelial cell line NCI-H292 and mice exposed cigarette smoke (CS) and lipopolysaccharide (LPS). In the CSC-stimulated NCI-H292 cells, SCWE inhibited proinflammatory cytokines in a concentration-dependent manner, as evidenced by a reduction in their mRNA levels. Also, SCWE significant reduced inducible nitric oxide synthase (iNOS) expression and nuclear factor kappa B (NF-κB) phosphorylation in CSC-stimulated cells. The mice were exposed to CS for 1 h per day (a total of eight cigarettes per day) for 7 days and received LPS intranasally on day 5. The mice were administered a dose of SCWE (100 and 200 mg/kg) 1 h before CS exposure. In in vivo, SCWE decreased the inflammatory cell count and reduced the expression of the proinflammatory cytokines in the broncho-alveolar lavage fluid (BALF) compared with CS and LPS exposed mice. SCWE attenuated inflammatory cell infiltration in airway induced by CS and LPS exposure, and this decrease was accompanied by a reduction in the expression levels of iNOS and MMP-9 in lung tissue. The extract also inhibited the phosphorylation of inhibitor of kappa B alpha (IκBα) and NF-κB induced by CS and LPS exposure in lung tissue. These results suggest that SCWE may effectively inhibit airway inflammatory responses induced by CS and LPS exposure via the NF-κB pathway. Therefore, SCWE may be a potential treatment for airway inflammatory diseases, such as chronic obstructive pulmonary disease (COPD).

Silicon dioxide nanoparticles (SiONPs), which are metal oxide nanoparticles, have been used in a wide variety of applications. In this study, acute pulmonary responses were examined after the intranasal instillation of SiONPs in mice primed with or without lipopolysaccharide (LPS, intranasal, 5 &micro, g/mouse). The exposure to SiONPs increased the inflammatory cell counts and proinflammatory cytokines in the bronchoalveolar lavage fluid. SiONPs induced airway inflammation with increases in the phosphorylation of mitogen-activated protein kinases (MAPKs). The ratios of the inflammatory responses induced by the SiONPs were increased in the acute pulmonary disease model primed by LPS. Taken together, SiONPs exhibited toxicity to the respiratory system, which was associated with MAPK phosphorylation. In addition, the exposure to SiONPs exacerbated any existing inflammatory pulmonary diseases. These data showed the additive, as well as synergistic, interaction effects of SiONPs and LPS. We conclude that the exposure to SiONPs causes potential toxicity in humans, especially those with respiratory diseases.

Galgeun-tang water extract (GGWE) is used to treat various diseases such as the common cold, eczema and asthma in China and Korea. In this study, we investigated the anti-inflammatory effect of GGWE using a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced induced pulmonary inflammation mouse model. The mice were exposed to CS for a total of seven days (eight cigarettes per day for 1 h) and LPS was administered intranasally to mice on day 4. GGWE was administered by oral gavage at doses of 50 mg/kg or 100 mg/kg 1 h before exposure to CS. GGWE decreased inflammatory cell counts, and expression of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-&alpha, ) in bronchoalveolar lavage fluid (BALF) from mice exposed to CS and LPS. GGWE reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), as well as the phosphorylation of inhibitor of kappa-B subunit alpha (I&kappa, B&alpha, ) and nuclear factor kappa-B (NF-&kappa, B) in CS- and LPS-exposed mice. Histological examinations revealed that GGWE suppressed inflammatory cell infiltration into lung tissue compared to untreated CS- and LPS-exposed mice. In conclusion, GGWE effectively suppressed CS- and LPS-induced pulmonary inflammation. Our results indicate that GGWE may be used as a protective drug to control pulmonary inflammation diseases such as chronic obstructive pulmonary disease.

Benign prostate hyperplasia (BPH) is a male reproductive disease that has gained increasing importance in recent years. The present study investigated whether Pycnogenol® (PYC), a standardized French maritime pine bark extract, could prevent BPH induced by testosterone propionate (TP) in rats. Male Sprague-Dawley rats were randomly divided into five groups of six rats. One group was used as a normal control rats and the other groups received subcutaneous injections of TP for 4 weeks to induce BPH. In the two treatment groups, PYC (20 or 40 mg/kg) was administered daily for 4 weeks by oral gavage concurrently with the induction of TP. All rats were sacrificed at the scheduled termination time, the prostates were weighed, and histopathologic examinations were conducted. Dihydrotestosterone (DHT) levels in serum and the prostate were measured, and the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 proteins was investigated. BPH-treated animals showed increases in the relative weight of the prostate, higher concentrations of DHT in serum and the prostate, and higher expression of PCNA and Ki-67 in the prostate; in contrast, PYC-treated animals had significant reductions in these factors compared with the BPH animals. These findings indicated that PYC inhibited the development of BPH and that this was closely associated with a reduction in DHT concentration.