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Background: The maturation and patency of permanent vascular access are critical in patients requiring hemodialysis. Although numerus trials have been attempted to achieve permanently patent vascular access, little have been noticeable. Cilostazol, a phosphodiesterase-3 inhibitor, has been shown to be effective in peripheral arterial disease including vascular injury-induced intimal hyperplasia. We therefore aimed to determine the effect of cilostazol on the patency and maturation of permanent vascular access. Methods: This single-center, retrospective study included 194 patients who underwent arteriovenous fistula surgery to compare vascular complications between the cilostazol (n = 107) and control (n = 87) groups. Results: The rate of vascular complications was lower in the cilostazol group than in the control group (36.4% vs. 51.7%; p = 0.033), including maturation failure (2.8% vs. 11.5%; p = 0.016). The rate of reoperation due to vascular injury after hemodialysis initiation following fistula maturation was also significantly lower in the cilostazol group than in the control group (7.5% vs. 28.7%; p

Background: The study aimed to evaluate the inhibitory effect of tamarixetin on the production of inflammatory mediators in immunoglobulin E /antigen-induced mouse bone marrow-derived mast cells (BMMCs).Material and methods: Tamarixetin isolated from Inula japonica was infected into BMMCs. The inhibitory effect of tamarixetin were analyzed by quantifying β-hexosaminidase, eicosanoid generation, intracellular calcium measurement, and Western blot analysis.Results: Tamarixetin effectively decreased degranulation and the eicosanoid generation such as leukotriene C4 and prostaglandin D2 in BMMCs. To elucidate the mechanism involved, we investigated the effect of tamarixetin on the phosphorylation of signal molecules. Tamarixetin inhibited the phosphorylation of protein kinase B (Akt) and its downstream signal molecules including IκB kinase and nuclear factor-κB. Besides, tamarixetin downregulated the phosphorylation of cytosolic phospholipase A2 and p38 mitogen-activated protein kinase.Conclusion: In summary, tamarixetin inhibits degranulation and eicosanoid generation through the phospholipase Cγ1 as well as Akt pathways. It could be potential for the prevention of allergic inflammatory diseases in BMMCs.

Background The study aimed to evaluate the inhibitory effect of tamarixetin on the production of inflammatory mediators in immunoglobulin E /antigen-induced mouse bone marrow-derived mast cells (BMMCs). Material and methods Tamarixetin isolated from Inula japonica was infected into BMMCs. The inhibitory effect of tamarixetin were analyzed by quantifying β-hexosaminidase, eicosanoid generation, intracellular calcium measurement, and Western blot analysis. Results Tamarixetin effectively decreased degranulation and the eicosanoid generation such as leukotriene C4 and prostaglandin D2 in BMMCs. To elucidate the mechanism involved, we investigated the effect of tamarixetin on the phosphorylation of signal molecules. Tamarixetin inhibited the phosphorylation of protein kinase B (Akt) and its downstream signal molecules including IκB kinase and nuclear factor-κB. Besides, tamarixetin downregulated the phosphorylation of cytosolic phospholipase A2 and p38 mitogen-activated protein kinase.Conclusion: In summary, tamarixetin inhibits degranulation and eicosanoid generation through the phospholipase Cγ1 as well as Akt pathways. It could be potential for the prevention of allergic inflammatory diseases in BMMCs.

The purpose of this study is to classify the types of decoration techniques used in women’s Chima and Jeogori in traditional Hanbok catalogs from 2010 to 2020, and to analyze the frequency of each type. The method of this study is as follows. This study first investigated the transition of modern Hanbok and decorative techniques by analyzing and classifying such work in previous studies. Based on this, the technique of decorating the Jeogori and Chima that appeared in the traditional Hanbok catalog of the study period was analyzed. The results of the study are as follows. In the case of Jeogori, in the first half of 2010, the decorative technique of a relatively large size was used, and the decorativeness tended to be strong. However, in the late 2010s, the number of decorative techniques used in Jeogori has decreased, and the size of the decorative technique has become smaller and more concise, leading to a tendency to understated decoration. In the case of Chima, techniques to express natural texture by processing threads or fabrics themselves were mainly used rather than techniques to add decoration to the surface, and techniques to express various surface texture tended to develop toward the late 2010s. The change in the decoration technique of Jeogori and Chima appears to be a combination of social, cultural, and economic factors such as a change in consumption culture and a reduction in the wedding market.

The endoplasmic reticulum (ER) stress response is an adaptive mechanism that is activated upon disruption of ER homeostasis and protects the cells against certain harmful environmental stimuli. However, critical and prolonged cell stress triggers cell death. In this study, we demonstrate that Flightless-1 (FliI) regulates ER stress-induced apoptosis in colon cancer cells by modulating Ca2+ homeostasis. FliI was highly expressed in both colon cell lines and colorectal cancer mouse models. In a mouse xenograft model using CT26 mouse colorectal cancer cells, tumor formation was slowed due to elevated levels of apoptosis in FliI-knockdown (FliI-KD) cells. FliI-KD cells treated with ER stress inducers, thapsigargin (TG), and tunicamycin exhibited activation of the unfolded protein response (UPR) and induction of UPR-related gene expression, which eventually triggered apoptosis. FliI-KD increased the intracellular Ca2+ concentration, and this upregulation was caused by accelerated ER-to-cytosolic efflux of Ca2+. The increase in intracellular Ca2+ concentration was significantly blocked by dantrolene and tetracaine, inhibitors of ryanodine receptors (RyRs). Dantrolene inhibited TG-induced ER stress and decreased the rate of apoptosis in FliI-KD CT26 cells. Finally, we found that knockdown of FliI decreased the levels of sorcin and ER Ca2+ and that TG-induced ER stress was recovered by overexpression of sorcin in FliI-KD cells. Taken together, these results suggest that FliI regulates sorcin expression, which modulates Ca2+ homeostasis in the ER through RyRs. Our findings reveal a novel mechanism by which FliI influences Ca2+ homeostasis and cell survival during ER stress., Cancer: Protein enhances survival of tumor cells under stress A cytoskeletal protein that helps tumors avoid cell death offers a promising new drug target for fighting cancer. A team led by Jang Hyun Choi and Sun Sil Choi of the Ulsan National Institute of Science and Technology, South Korea, detailed how a protein called Flightless I (FliI) that normally regulates the remodeling of structural filaments in the cell can, in colorectal cancer cells, serve as a tumor promoter through its action on calcium levels. Typically, cells respond to chronic stress by altering calcium signaling to promote their own death. In tumors, however, FliI maintains normal calcium levels to enhance cell survival even in the face of chemotherapy and other stressful stimuli. Suppressing FliI activity could thus help sensitize cancer cells to other stress- and death-inducing drug regimens.

Transcriptome-based dose–response curves were recently applied to the phytodosimetry of gamma radiation in a dicot plant, Arabidopsis thaliana, as an alternative biological assessment of genotoxicity using DNA damage response (DDR) genes. In the present study, we characterized gamma ray-responsive marker genes for transcriptome-based phytodosimetry in a monocot plant, rice (Oryza sativa L.), and compared different phytodosimetry models between rice and Arabidopsis using gamma-H2AX, comet, and quantitative transcriptomic assays. The transcriptome-based dose–response curves of four marker genes (OsGRG, OsMutS, OsRAD51, and OsRPA1) were reliably fitted to quadratic or exponential decay equations (r2 &gt, 0.99). However, the single or integrated dose–response curves of these genes were distinctive from the conventional models obtained by the gamma-H2AX or comet assays. In comparison, rice displayed a higher dose-dependency in the comet signal and OsRAD51 transcription, while the gamma-H2AX induction was more dose-dependent in Arabidopsis. The dose-dependent transcriptions of the selected gamma-ray-inducible marker genes, including OsGRG, OsMutS, OsRAD51, and OsRPA1 in rice and AtGRG, AtPARP1, AtRAD51, and AtRPA1E in Arabidopsis, were maintained similarly at different vegetative stages. These results suggested that the transcriptome-based phytodosimetry model should be further corrected with conventional genotoxicity- or DDR-based models despite the high reliability or dose-dependency of the model. In addition, the relative weighting of each gene in the integrated transcriptome-based dose–response model using multiple genes needs to be considered based on the trend and amplitude of the transcriptional change.

The aim of this study was to evaluate the inhibitory effect of tamarixetin on the production of inflammatory mediators in IgE/antigen-induced mouse bone marrow-derived mast cells (BMMCs).The effects of tamarixetin on mast cell activation were investigated with regard to degranulation, eicosanoid generation, Ca2+ influx, and immunoblotting of various signaling molecules.Tamarixetin effectively decreased degranulation and the eicosanoid generation such as leukotriene CTaken together, this study suggests that tamarixetin inhibits degranulation and eicosanoid generation through the PLCγ1 as well as Akt pathways in BMMCs, which would be potential for the prevention of allergic inflammatory diseases.

Angiogenesis, which refers to the formation of new blood vessels from already existing vessels, is a promising therapeutic target and a complex multistep process involving many different factors. Pericytes (PCs) are attracting attention as they are considered to make significant contributions to the maturation and stabilisation of newly formed vessels, although not much is known about the precise mechanisms involved. Since there is no single specific marker for pericytes, in vivo models may complicate PC identification and the study of PCs in angiogenesis would benefit from in vitro models recapitulating the interactions between PCs and endothelial cells (ECs) in a three-dimensional (3D) configuration. In this study, a 3D in vitro co-culture microvessel model incorporating ECs and PCs was constructed by bottom-up tissue engineering. Angiogenesis was induced in the manner of sprout formation by the addition of a vascular endothelial cell growth factor. It was found that the incorporation of PCs prevented expansion of the parent vessel diameter and enhanced sprout formation and elongation. Physical interactions between ECs and PCs were visualised by immunostaining and it disclosed that PCs covered the EC monolayer from its basal side in the parent vessel as well as angiogenic sprouts. Furthermore, the microvessels were visualized in 3D by using a non-invasive optical coherence tomography (OCT) imaging system and sprout features were quantitatively assessed. It revealed that the sprouts in EC-PC co-culture vessels were longer and tighter than those in EC mono-culture vessels. The combination of the microvessel model and the OCT system analysis can be useful for the visualisation and demonstration of the multistep process of angiogenesis, which incorporates PCs.

Peroxisome proliferator-activated receptor &gamma, (PPAR&gamma, ) is a master regulator of adipose tissue biology. In obesity, phosphorylation of PPAR&gamma, at Ser273 (pSer273) by cyclin-dependent kinase 5 (CDK5)/extracellular signal-regulated kinase (ERK) orchestrates diabetic gene reprogramming via dysregulation of specific gene expression. Although many recent studies have focused on the development of non-classical agonist drugs that inhibit the phosphorylation of PPAR&gamma, at Ser273, the molecular mechanism of PPAR&gamma, dephosphorylation at Ser273 is not well characterized. Here, we report that protein phosphatase Mg2+/Mn2+-dependent 1A (PPM1A) is a novel PPAR&gamma, phosphatase that directly dephosphorylates Ser273 and restores diabetic gene expression which is dysregulated by pSer273. The expression of PPM1A significantly decreases in two models of insulin resistance: diet-induced obese (DIO) mice and db/db mice, in which it negatively correlates with pSer273. Transcriptomic analysis using microarray and genotype-tissue expression (GTEx) data in humans shows positive correlations between PPM1A and most of the genes that are dysregulated by pSer273. These findings suggest that PPM1A dephosphorylates PPAR&gamma, at Ser273 and represents a potential target for the treatment of obesity-linked metabolic disorders.

Methionine-S-sulfoxide reductase (MsrA) protects against high-fat diet-induced insulin resistance due to its antioxidant effects. To determine whether its counterpart, methionine-R-sulfoxide reductase (MsrB) has similar effects, we compared MsrB1 knockout and wild-type mice using a hyperinsulinemic-euglycemic clamp technique. High-fat feeding for eight weeks increased body weights, fat masses, and plasma levels of glucose, insulin, and triglycerides to similar extents in wild-type and MsrB1 knockout mice. Intraperitoneal glucose tolerance test showed no difference in blood glucose levels between the two genotypes after eight weeks on the high-fat diet. The hyperglycemic-euglycemic clamp study showed that glucose infusion rates and whole body glucose uptakes were decreased to similar extents by the high-fat diet in both wild-type and MsrB1 knockout mice. Hepatic glucose production and glucose uptake of skeletal muscle were unaffected by MsrB1 deficiency. The high-fat diet-induced oxidative stress in skeletal muscle and liver was not aggravated in MsrB1-deficient mice. Interestingly, whereas MsrB1 deficiency reduced JNK protein levels to a great extent in skeletal muscle and liver, it markedly elevated phosphorylation of JNK, suggesting the involvement of MsrB1 in JNK protein activation. However, this JNK phosphorylation based on a p-JNK/JNK level did not positively correlate with insulin resistance in MsrB1-deficient mice. Taken together, our results show that, in contrast to MsrA deficiency, MsrB1 deficiency does not increase high-fat diet-induced insulin resistance in mice.

Nepetin derived from the flowers of Inula japonica, Inulae flos, has been reported to exert several biological activities, including anti-inflammatory responses. In this study, we evaluated the anti-allergic property of nepetin with its molecular mechanisms in bone marrow-derived mast cells (BMMC) and mice. In this in vitro study, we investigated the inhibitory effects of nepetin on degranulation and generation of leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in IgE/antigen (Ag)-stimulated BMMC. The effect of nepetin on passive cutaneous anaphylaxis (PCA) reaction was also studied in mice. Nepetin reduced degranulation and LTC4 generation in BMMC. The IgE/Ag-mediated signaling pathway demonstrated that nepetin suppressed intracellular Ca2+ level and activation of PLCγ1 and cPLA2. However, MAPKs were not affected by nepetin in BMMC. In addition, nepetin treatment reduced PGD2 production and suppressed cyclooxygenase-2 protein expression via the inhibition of the Akt and nuclear factor-κB signaling pathways. With respect to the local allergic response in vivo, oral administration of nepetin suppressed mast cell-dependent PCA reaction in a dose-dependent manner. The results of this study suggest that nepetin might have an anti-allergic potential related to mast cell-mediated inflammatory diseases.

Background Probability of causation (PC) is a reasonable way to estimate causal relationships in radiation-related cancer. This study reviewed the international trend, usage, and critiques of the PC method. Because it has been used in Korea, it is important to check the present status and estimation of PC in radiation-related cancers in Korea. Methods Research articles and official reports regarding PC of radiation-related cancer and published from the 1980s onwards were reviewed, including studies used for the revision of the Korean PC program. PC has been calculated for compensation-related cases in Korea since 2005. Results The United States National Institutes of Health first estimated the PC in 1985. Among the 106 occupational diseases listed in the International Labor Organization Recommendation 194 (International Labor Office (ILO), ILO List of Occupational Diseases, 2010), PC is available only for occupational cancer after ionizing radiation exposure. The United States and United Kingdom use PC as specific criteria for decisions on the compensability of workers’ radiation-related health effects. In Korea, PC was developed firstly as Korean Radiation Risk and Assigned Share (KORRAS) in 1999. In 2015, the Occupational Safety and Health Research Institute and Radiation Health Research Institute jointly developed a more revised PC program, Occupational Safety and Health-PC (OSH-PC). Between 2005 and 2015, PC was applied in 16 claims of workers’ compensation for radiation-related cancers. In most of the cases, compensation was given when the PC was more than 50%. However, in one case, lower than 50% PC was accepted considering the possibility of underestimation of the cumulative exposure dose. Conclusions PC is one of the most advanced tools for estimating the causation of occupational cancer. PC has been adjusted for baseline cancer incidence in Korean workers, and for uncertainties using a statistical method. Because the fundamental reason for under- or over-estimation is probably inaccurate dose reconstruction, a proper guideline is necessary.

Imperatorin has been known to exert many biological functions including anti-inflammatory activity. In this study, we investigated the inhibitory effects of imperatorin on the production of inflammatory mediators in mouse bone marrow-derived mast cells (BMMC). Imperatorin inhibited degranulation and the generation of eicosanoids (leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)) in IgE/antigen (Ag)-stimulated BMMC. To elucidate the molecular mechanism involved in this process, we investigated the effect of imperatorin on intracellular signaling in BMMC. Biochemical analyses of the IgE/Ag-mediated signaling pathway demonstrated that imperatorin dramatically attenuated degranulation and the production of 5-lipoxygenase-dependent LTC4 and cyclooxygenase-2-dependent PGD2 through the inhibition of intracellular calcium influx/phospholipase Cγ1, cytosolic phospholipase A2/mitogen-activated protein kinases and/or nuclear factor-κB pathways in BMMC. These results suggest that the effects of imperatorin on inhibition of degranulation and eicosanoid generation through the suppression of multiple steps of IgE/Ag-mediated signaling pathways would be beneficial for the prevention of allergic inflammation.

Wound healing is a complex process orchestrated by the regeneration of the epithelium and the remodeling of the extracellular matrix through processes like collagen deposition. Galla Rhois has been widely used in traditional Korean medicine for its various pharmacological effects, including an anticoccidial effect, however, little is known about its healing activity. The purpose of this study was to determine the effects of Galla Rhois ethanol extract (GRE) on wound healing activities, including H2O2-induced oxidative stress, cell migration, and lactate dehydrogenase (LDH) release assays using human keratinocyte (HaCaT) and dermal fibroblasts (CCD-986SK). In addition, total soluble collagen deposition and collagen gene expression for Type I and III collagen were evaluated in CCD-986SK. Total tannin and flavonoid contents for GRE were measured. GRE induced a significant increase in the number and migration of cells, along with a decrease in cell death and LDH release. In addition, it also induced the over-expression of collagen Type I and III mRNA and caused increased synthesis of total soluble collagen. The contents of total tannin and flavonoid for GRE were 55.7% ([Formula: see text][Formula: see text]mg/g) and 62.9% ([Formula: see text][Formula: see text]mg/g), respectively. The results suggest that GRE can cause accelerated wound healing by increasing cell survival, proliferation, migration, and collagen synthesis along with a potential anti-oxidant property. This evidence provides novel insight into natural therapy for tissue injury.

Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically reduces methionine-R-sulfoxide to methionine. A recent genetic study showed that the MSRB3 gene is associated with autosomal recessive hearing loss in human deafness DFNB74. However, the precise role of MSRB3 in the auditory system and the pathogenesis of hearing loss have not yet been determined. This work is the first to generate MsrB3 knockout mice to elucidate the possible pathological mechanisms of hearing loss observed in DFNB74 patients. We found that homozygous MsrB3(-/-) mice were profoundly deaf and had largely unaffected vestibular function, whereas heterozygous MsrB3(+/-) mice exhibited normal hearing similar to that of wild-type mice. The MsrB3 protein is expressed in the sensory epithelia of the cochlear and vestibular tissues, beginning at E15.5 and E13.5, respectively. Interestingly, MsrB3 is densely localized at the base of stereocilia on the apical surface of auditory hair cells. MsrB3 deficiency led to progressive degeneration of stereociliary bundles starting at P8, followed by a loss of hair cells, resulting in profound deafness in MsrB3(-/-) mice. The hair cell loss appeared to be mediated by apoptotic cell death, which was measured using TUNEL and caspase 3 immunocytochemistry. Taken together, our data suggest that MsrB3 plays an essential role in maintaining the integrity of hair cells, possibly explaining the pathogenesis of DFNB74 deafness in humans caused by MSRB3 deficiency.

We previously demonstrated the alleviation of ovalbumin (OVA)-induced airway inflammation by Inulae flos. In the present study, the effects of britanin, a sesquiterpene compound isolated from Inulae flos, were evaluated in an in vivo animal model for anti-asthma activity through observation of airway hyperresponsiveness (AHR), eosinophil recruitment, Th2 cytokine and IgE levels, and lung histopathology. Britanin administration effectively reduced AHR induced by aerosolized methacholine, airway eosinophilia, Th2 cytokines in bronchoalveolar lavage fluids and the supernatant of cultured splenocytes compared with OVA-induced mice. Histological studies showed that increased inflammatory cell infiltration and mucus secretion were reduced by britanin administration. Thus, britanin may have therapeutic potential for treating allergic asthma.

Background: A Korean herbal medicine, KOTMIN13, composed of Inula japonica Thunberg, Trichosanthes kirilowii Maximowicz var. japonica kitamura, Peucedanum praeruptorum Dunn, and Allium macrostemon Bge, has been used for anti-allergic and anti-asthmatic treatment in oriental clinics, but its activity has not been investigated. Materials and Methods: To evaluate the anti-inflammatory activity of KOTMIN13 for in vitro study, LPS-stimulated RAW 264.7 cells were used to induce the production and expression of inflammatory mediators and its mechanisms. 12-O-Tetradecanoylphorobol-13 aceate (TPA)-induced ear edema and carrageenan-induced paw edema models were also used to evaluate the effect of KOTMIN13 on acute inflammation in vivo. Results: KOTMIN13 reduced the release of inflammatory mediators [nitric oxide, prostaglandin E2, interleukin (IL)-1β, and IL-6] and the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW 264.7 cells. Mechanism studies showed the attenuation of LPS-induced NF-κB activation by KOTMIN13 via IκBα degradation abrogation and a subsequent decrease in nuclear p65 levels. Activation of mitogen-activated protein kinases (ERK, JNK, and p38) was also suppressed. Furthermore, KOTMIN13 ameliorated the development of TPA-induced ear edema and carrageenan-induced paw edema in acute inflammatory edema mouse models. Conclusion: Our study demonstrates that KOTMIN13 inhibits inflammatory mediators through the inhibitions of NF-κB and MAPK activities in LPS-induced RAW 264.7 cells, as well as acute inflammation in edema models, indicating that KOTMIN13 is an effective suppressor for anti-inflammatory activities. SUMMARY KOTMIN13 decrease the production of No, PGE2, and proinflammatory cytokine (TNF-∝, IL-1β,IL-6).KOTMIN13 Suppressed the degradation of NF-kβ and IKβα and the phosorylation of MAP Kinases.Topical application of KOTMIN13 reduced mouse ear edema.Oral administration of KOTMIN13 decreased carrageenan-induced paw edema. Abbreviations used: NO: nitric oxide; PGE2: prostaglandin E2; iNOS: inducible NO synthase; COX-2: cyclooxygenase-2; TNF-α: tumor necrosis factor-α; IL: interleukin; NF-κB: nuclear factor kappaB; MAPK: mitogen-activated protein kinases; ERK: extracellular signal regulated kinase; JNK: c-jun N terminal kinase; TPA: 12-O-tetradecanoylphorbol-13-acetate

Methionine sulfoxide reductase B3 (MsrB3) is an oxidoreductase in the endoplasmic reticulum that catalyzes the stereospecific reduction of methionine-R-sulfoxide to methionine. Here, we report the critical role and mechanisms of MsrB3 in cell proliferation. The deletion of MsrB3 led to a significant decrease in cell proliferation in mouse embryonic fibroblast (MEF) cells. MsrB3-knockout MEF cells showed increased p53 protein levels, compared to wild-type MEF cells, which subsequently elevated the protein level of cyclin-dependent kinase inhibitor p21. In addition, MsrB3 deficiency enhanced the protein level of p27, another cell cycle regulator, and caused cell cycle arrest at the G1 stage. The inhibitory effect of MsrB3 deficiency on cell proliferation through the activation of p53-p21 and p27 pathways was also confirmed in primary human dermal fibroblasts. Collectively, the data suggest that MsrB3 is a regulator of cell growth through the p53-p21 and p27 pathways.

Methionine sulfoxide reductase A (MsrA) functions as a protein repair enzyme by catalyzing the stereospecific reduction of methionine-S-sulfoxide to methionine. We previously identified that MsrA deficiency inhibits normal cell growth via activation of the p53–p21 pathway. In this study, we report a critical role of MsrA in expression of heme oxygenase-1 (HO-1), a highly inducible enzyme that has an anti-proliferative effect mediated by up-regulation of p21. Down-regulation of MsrA induced HO-1 expression in mammalian cells with increased p21 levels, but MsrA overexpression did not affect HO-1 expression. MsrA depletion activated Nrf2 by increasing its expression and nuclear translocation. Nrf2 activation was associated with increased reactive oxygen species production. MsrA overexpression in MsrA-depleted cells led to the reduction of increased HO-1 expression, and suppressed nuclear accumulation of Nrf2. Taken together, the data suggest that MsrA attenuates HO-1 induction by inhibiting Nrf2 activation.

Aims: Methionine sulfoxide reductase A (MsrA) and methionine metabolism are associated with oxidative stress, a principal cause of ischemia/reperfusion (I/R) injury. Herein, we investigated the protective role of MsrA against kidney I/R injury and the involvement of MsrA in methionine metabolism and the trans-sulfuration pathway during I/R. Results: We found that MsrA gene-deleted mice (MsrA−/−) were more susceptible to kidney I/R injury than wild-type mice (MsrA+/+). Deletion of MsrA enhanced renal functional and morphological impairments, congestion, inflammatory responses, and oxidative stress under I/R conditions. Concentrations of homocysteine and H2S in the plasma of control MsrA−/− mice were significantly lower than those in control MsrA+/+ mice. I/R reduced the levels of homocysteine and H2S in both MsrA+/+ and MsrA−/− mice, and these reductions were significantly more profound in MsrA−/− than in MsrA+/+ mice. I/R reduced the expression and activities of cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), both of which are H2S-producing enzymes, in the kidneys. These reductions were more profound in the MsrA−/− mice than in the MsrA+/+mice. Innovation: The data provided herein constitute the first in vivo evidence for the involvement of MsrA in regulating methionine metabolism and the trans-sulfuration pathway under normal and I/R conditions. Conclusion: Our data demonstrate that MsrA protects the kidney against I/R injury, and that this protection is associated with reduced oxidative stress and inflammatory responses. The data indicate that MsrA regulates H2S production during I/R by modulating the expression and activity of the CBS and CSE enzymes. Antioxid. Redox Signal. 18, 2241—2250.

Methionine sulfoxide reductase A (MsrA) functions as a protein repair enzyme by catalyzing the stereospecific reduction of methionine-S-sulfoxide to methionine. We previously identified that MsrA deficiency inhibits normal cell growth via activation of the p53-p21 pathway. In this study, we report a critical role of MsrA in expression of heme oxygenase-1 (HO-1), a highly inducible enzyme that has an anti-proliferative effect mediated by up-regulation of p21. Down-regulation of MsrA induced HO-1 expression in mammalian cells with increased p21 levels, but MsrA overexpression did not affect HO-1 expression. MsrA depletion activated Nrf2 by increasing its expression and nuclear translocation. Nrf2 activation was associated with increased reactive oxygen species production. MsrA overexpression in MsrA-depleted cells led to the reduction of increased HO-1 expression, and suppressed nuclear accumulation of Nrf2. Taken together, the data suggest that MsrA attenuates HO-1 induction by inhibiting Nrf2 activation.

Background: The ethanol extract of KOTMIN13, composed of Inula japonica Flowers, Trichosanthes kirilowii Semen, Peucedanum praeruptorum Radix, and Allium macrostemon Bulbs, was investigated for its anti-asthmatic and anti-allergic activities. Methods: The anti-asthmatic effects of KOTMIN13 were evaluated on ovalbumin (OVA)-induced murine asthma model. Anti-allergic properties of KOTMIN13 in bone-marrow derived mast cells (BMMC) and passive cutaneous anaphylaxis (PCA) in vivo were also examined. Results: In asthma model, KOTMIN13 effectively suppressed airway hyperresponsiveness induced by aerosolized methacholine when compared to the levels of OVA-induced mice. KOTMIN13 treatment reduced the total leukocytes, eosinophil percentage, and Th2 cytokines in the bronchoalveolar lavage fluids in OVA-induced mice. The increased levels of eotaxin and Th2 cytokines in the lung as well as serum IgE were decreased by KOTMIN13. The histological analysis shows that the increased inflammatory cell infiltration and mucus secretion were also reduced. In addition, the degranulation and leukotriene C-4 production were inhibited in BMMC with IC50 values of 3.9 mu g/ml and 1.7 mu g/ml, respectively. Furthermore, KOTMIN13 treatment attenuated mast-mediated PCA reaction. Conclusions: These results demonstrate that KOTMIN13 has anti-asthmatic and anti-allergic effects in vivo and in vitro models.