Na-Rae Shin

Protective effects of diallyl disulfide against acetaminophen-induced nephrotoxicity: A possible role of CYP2E1 and NF-κB.

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.

Comparative toxicity and biodistribution assessments in rats following subchronic oral exposure to copper nanoparticles and microparticles.

BackgroundCopper nanoparticles (Cu NPs) have great potential in electronics and biomedical fields because of their efficient thermodynamic and anti-microbial properties. However, their potential toxic effects and kinetic data following repeated exposure are still unclear.MethodsWe evaluated the physicochemical properties of Cu NPs (25xa0nm) and copper microparticles (Cu MPs, 14–25xa0μm). Comparative in vivo toxicity of Cu NPs and Cu MPs was evaluated by conducting a 28-day repeated oral dose study at equivalent dose levels of 0, 100, 200, and 400xa0mg/kg/day (vehicle, 1xa0% hydroxypropyl methylcellulose). We determined Cu levels in the blood, tissues, urine, and feces by using inductively coupled plasma mass spectrometry.ResultsThe solubility of Cu NPs and Cu MPs was 84.5 and 17.2xa0%, respectively, in an acidic milieu; however, they scarcely dissolved in vehicle or intestinal milieus. The specific surface area of Cu NPs and Cu MPs was determined to be 14.7 and 0.16xa0m2/g, respectively. Cu NPs exhibited a dose-dependent increase of Cu content in the blood and tested organs, with particularly high levels of Cu in the liver, kidney, and spleen. Only for liver and kidney increased Cu levels were found in Cu MPs-treated rats. Cu NPs caused a dose-related increase in Cu levels in urine, whereas Cu MPs did not affect the urine Cu levels. Extremely high levels of Cu were detected in the feces of Cu MPs-treated rats, whereas much lower levels were detected in the feces of Cu NPs-treated rats. A comparative in vivo toxicity study showed that Cu NPs caused damages to red blood cells, thymus, spleen, liver, and kidney at ≥200xa0mg/kg/days, but Cu MPs did not cause any adverse effects even at the highest dose.ConclusionsOverall, the in vivo repeated dose toxicity study of Cu NPs and Cu MPs demonstrated that large surface area and high solubility in physiological milieus could directly influence the toxicological responses and biodistribution of Cu particles when administered orally. Under these experimental conditions, the no-observed-adverse-effect levels of Cu NPs and Cu MPs were determined to be 100 and ≥400xa0mg/kg/day, respectively.

Protective effect and mechanism of action of diallyl disulfide against acetaminophen-induced acute hepatotoxicity

The aim of this study was to investigate the potential protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute hepatotoxicity and elucidate the molecular mechanisms underlying these protective effects in rats. Treatment with AAP caused acute hepatotoxicity manifested by elevated levels of aspartate aminotransferase and alanine aminotransferase with corresponding histopathological changes and high levels of oxidative stress in the livers. AAP treatment also caused hepatocellular apoptosis with phosphorylation of c-Jun-N-terminal protein kinase (JNK). In addition, AAP caused activation of nuclear factor kappaB (NF-κB) concurrent with induction of inflammatory mediators. In contrast, pretreatment with DADS effectively attenuated acute liver injury and oxidative stress caused by AAP. DADS pretreatment suppressed cytochrome P450 2E1 (CYP2E1) levels in a dose-dependent manner and inhibited elevation of CYP2E1 activity induced by AAP. DADS pretreatment suppressed the phosphorylation of JNK and attenuated hepatocellular apoptotic changes. In addition, DADS inhibited the nuclear translocation of NF-κB and subsequent induction of inflammatory mediators. Overall, these results indicate that DADS confers a protective effect against oxidative stress-mediated JNK activation and apoptotic changes caused by AAP in the rat livers. This may be due to its ability to inhibit CYP2E1, enhance antioxidant enzymes activities, and suppress NF-κB activation.

Protective effect of HwangRyunHaeDok-Tang water extract against chronic obstructive pulmonary disease induced by cigarette smoke and lipopolysaccharide in a mouse model

ETHNOPHARMACOLOGICAL RELEVANCEnHwangryunhaedok-tang is an oriental herbal formula treated to cure inflammation and gastric disorders in China, Japan, and Korea. We explored the protective effects of Hwangryunhaedok-tang water extract (HRWE) against airway pathophysiological changes caused by cigarette smoke (CS) and lipopolysaccharide (LPS) in a mouse.nnnMATERIALS AND METHODSnWe performed quantitative analyses of five marker components, namely geniposide, baicalin, coptisine, plamatine, and berberine, using high-performance liquid chromatography. Animals were received CS exposure (1h per day) for 7 days. LPS was administered intranasally on day 4. Mice were received HRWE at dose of 100 or 200mg/kg for 1h before CS exposure.nnnRESULTSnTreatment with HRWE significantly suppressed the increased inflammatory cell count induced by CS and LPS exposure. In addition, reduction in IL-6, TNF-α and IL-1β in broncho-alveolar lavage fluid (BALF) was observed after HRWE treatment. HRWE not only decreased inflammatory cell infiltration in lung, but also decreased the expression of iNOS, NF-κB and matrix metallopeptidase (MMP)-9 in lung tissues.nnnCONCLUSIONnThis study showed that HRWE can attenuate respiratory inflammation caused by CS and LPS exposure. Therefore, HRWE has potential for treating airway inflammatory disease.

Artemisia argyi attenuates airway inflammation in ovalbumin-induced asthmatic animals

ETHNOPHARMACOLOGICAL RELEVANCEnArtemisia argyi is a traditional herbal medicine in Korea and commonly called as mugwort. It is traditionally used as food source and tea to control abdominal pain, dysmenorrhea, uterine hemorrhage, and inflammation.nnnAIM OF THE STUDYnWe investigated the effects of A. argyi (TOTAL) and dehydromatricarin A (DA), its active component on ovalbumin (OVA)-induced allergic asthma.nnnMATERIALS AND METHODSnThe animals were sensitized on day 0 and 14 by intraperitoneal injection of OVA with aluminum hydroxide. On day 21, 22 and 23 after the initial sensitization, the animals received an airway challenge with OVA for 1h using an ultrasonic nebulizer. TOTAL (50 and 100mg/kg) or DA (10 and 20mg/kg) were administered to mice by oral gavage once daily from day 18-23. Airway hyperresponsiveness (AHR) was measured 24h after final OVA challenge.nnnRESULTnTOTAL and DA treated animals reduced inflammatory cell counts, cytokines and AHR in asthmatic animals, which was accompanied with inflammatory cell accumulation and mucus hypersecretion. Furthermore, TOTAL and DA significantly declined Erk phosphorylation and the expression of MMP-9 in asthmatic animals.nnnCONCLUSIONnIn conclusion, we indicate that Total and DA suppress allergic inflammatory responses caused by OVA challenge. It was considered that A. argyi has a potential for treating allergic asthma.

4-Hydroxycinnamic acid protects mice from cigarette smoke-induced pulmonary inflammation via MAPK pathways

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.

A standardized bark extract of Pinus pinaster Aiton (Pycnogenol®) attenuated chronic obstructive pulmonary disease via Erk-sp1 signaling pathway

ETHNOPHARMACOLOGICAL RELEVANCEnA standardized bark extract of Pinus pinaster Aiton (Pycnogenol®; PYC) used as an herbal medicine to treat various diseases in Europe and North America.nnnAIM OF THE STUDYnThis study evaluates the ability of PYC to inhibit chronic obstructive pulmonary disease (COPD) in the cigarette smoke extract (CSE)-stimulated human airway epithelial cell line NCI-H292 and in a cigarette smoke (CS) and lipopolysaccharide (LPS)-induced mouse model.nnnMETHODSnTo induce COPD, the mice intranasally received LPS on day 4 and were exposed to CS for 1h per day (total eight cigarettes per day) from days 1-7. The mice were administered PYC at a dose of 15mg/kg and 30mg/kg 1h before CS exposure.nnnRESULTSnIn the CSE-stimulated NCI-H292 cells, PYC significantly inhibited Erk phosphorylation, sp1 expression, MUC5AC, and pro-inflammatory cytokines in a concentration-dependent manner, as evidenced by a reduction in their mRNA levels. Co-treatment with PYC and Erk inhibitors markedly reduced the levels inflammatory mediators compared to only PYC-treatment. In the COPD mice model, PYC decreased the inflammatory cell count and the levels of pro-inflammatory cytokines in the broncho-alveolar lavage fluid compared with COPD mice. PYC attenuated the recruitment of inflammatory cells in the airways and decreased the expression levels of Erk phosphorylation and sp1. PYC also inhibited the expression of myeloperoxidase and matrix metalloproteinases-9 in lung tissue.nnnCONCLUSIONnOur results indicate that PYC inhibited the reduction in the inflammatory response in CSE-stimulated NCI-H292 cells and the COPD mouse model via the Erk-sp1 pathway. Therefore, we suggest that PYC has the potential to treat COPD.

Ameliorative effects of pine bark extract on cisplatin-induced acute kidney injury in rats

Abstract Objective: This study investigated the dose–response effects of pine bark extract (PBE, pycnogenol®) on oxidative stress-mediated apoptotic changes induced by cisplatin (Csp) in rats. Materials and methods: The ameliorating potential of PBE was evaluated after orally administering PBE at doses of 10 or 20u2009mg/kg for 10 days. Acute kidney injury was induced by a single intraperitoneal injection of Csp at 7u2009mg/kg on test day 5. Results: Csp treatment caused acute kidney injury manifested by elevated levels of serum blood urea nitrogen (BUN) and creatinine (CRE) with corresponding histopathological changes, including degeneration of tubular epithelial cells, hyaline casts in the tubular lumen, and inflammatory cell infiltration (interstitial nephritis). Csp also induced significant apoptotic changes in renal tubular cells. In addition, Csp treatment induced high levels of oxidative stress, as evidenced by an increased level of malondialdehyde, depletion of the reduced glutathione (GSH) content, and decreased activities of glutathione S-transferase, superoxide dismutase, and catalase in kidney tissues. On the contrary, PBE treatment lowered BUN and CRE levels and effectively attenuated histopathological alterations and apoptotic changes induced by Csp. Additionally, treatment with PBE suppressed lipid peroxidation, prevented depletion of GSH, and enhanced activities of the antioxidant enzymes in kidney tissue. Conclusions: These results indicate that PBE has a cytoprotective effect against oxidative stress-mediated apoptotic changes caused by Csp in the rat kidney, which may be attributed to both increase of antioxidant enzyme activities and inhibition of lipid peroxidation.

Ssanghwa-Tang, a traditional herbal formula, suppresses cigarette smoke-induced airway inflammation via inhibition of MMP-9 and Erk signaling

We investigated the effects of Ssanghwa-Tang water extract (STWE), a traditional herbal medicine, on airway inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Mice were exposed to CS for 1 h per day (8 cigarettes per day) from day 1 to day 7. On day 4, the mice were treated intranasally with LPS. STWE (50 or 100 mg/kg) was administered by oral gavage 1 h before the CS exposure. STWE markedly decreased the neutrophil and other inflammatory cell counts in bronchoalveolar lavage fluid, along with the reduction of proinflammatory mediators such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α. STWE significantly decreased inflammatory cell infiltration into lung tissue, induced by CS and LPS exposure. In addition, STWE reduced the expression level and activity of matrix metalloproteinase-9 (MMP-9) in the lung tissue, which was accompanied by a decrease in phosphorylation of extracellular signal-regulated kinase (Erk). STWE effectively inhibited the neutrophilic airway inflammation and MMP-9 expression induced by the CS and LPS exposure, which was closely related to the downregulation of Erk phosphorylation. These findings suggest that STWE has therapeutic potential for the treatment of airway inflammatory disorders such as chronic obstructive pulmonary disease.

Copper oxide nanoparticles induce collagen deposition via TGF-β1/Smad3 signaling in human airway epithelial cells

Abstract Use and application of nanoparticles has increased in recent years. Copper oxide nanoparticles (CuONPs) are one of the most common types of nanoparticles, and they are mainly used as catalysts and preservatives. However, limited toxicity data are available on the toxicity of CuONPs to the respiratory system. We investigated fibrotic responses induced by CuONPs in the respiratory tract and elucidated its underlying mechanism of action in vivo and in vitro experiments. In the mouse model, CuONPs exposure markedly increased transforming growth factor-β1 (TGF-β1) and collagen I expression and Smad3 phosphorylation, combined with elevation of inflammatory mediators including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). These alterations were also observed in histological analysis of lung tissue. CuONPs markedly increased inflammatory responses and collagen deposition, accompanied by the elevation of TGF-β1 and collagen I expression in lung tissue. In addition, CuONPs-treated H292 cells showed significantly increased mRNA and protein production of TGF-β1, collagen I, IL-6, and TNF-α; this response was markedly decreased by treatment of a TGF-β1 inhibitor (SB-431542). Taken together, CuONPs induced fibrotic responses in the respiratory tract, closely related to TGF-β1/Smad3 signaling. Therefore, our results raise the necessity of further investigation for the present state of its risk by providing useful information of the toxicity of CuONPs.