Pathologic properties of SOD3 variant R213G in the cardiovascular system through the altered neutrophils function.

The SOD3 variant, SOD3R213G, results from substitution of arginine to glycine at amino acid 213 (R213G) in its heparin binding domain (HBD) and is a common genetic variant, reported to be associated with ischemic heart disease. However, little is understood about the role of SOD3R213G in innate immune function, and how it leads to dysfunction of the cardiovascular system. We observed pathologic changes in SOD3R213G transgenic (Tg) mice, including cystic medial degeneration of the aorta, heart inflammation, and increased circulating and organ infiltrating neutrophils. Interestingly, SOD3R213G altered the profile of SOD3 interacting proteins in neutrophils in response to G-CSF. Unexpectedly, we found that G-CSF mediated tyrosine phosphatase, SH-PTP1 was down-regulated in the neutrophils of SOD3R213G overexpressing mice. These effects were recovered by reconstitution with Wt SOD3 expressing bone marrow cells. Overall, our study reveals that SOD3R213G plays a crucial role in the function of the cardiovascular system by controlling innate immune response and signaling. These results suggest that reconstitution with SOD3 expressing bone marrow cells may be a therapeutic strategy to treat SOD3R213G mediated diseases.

SOD3 Variant, R213G, Altered SOD3 Function, Leading to ROS-Mediated Inflammation and Damage in Multiple Organs of Premature Aging Mice.

AIMS: Among the isoforms of superoxide dismutase, SOD3 is uniquely associated with the extracellular matrix (ECM) by virtue of its heparin-binding domain (HBD). Substitution of arginine by glycine at amino acid 213 (R213G) of its HBD was first identified in patients with heart failure, followed by many studies that focused on the role of this variant (SOD3(R213G)) in ischemic heart disease and cardiovascular disease. However, the biological significance of this mutation in a physiological context is largely unknown. RESULTS: As a first step, we generated SOD3(R213G) transgenic mice, in which the variant gene was driven by the ß-actin promoter allowing expression in all tissues. Unexpectedly, we found that SOD3(R213G) transgenic mice exhibited premature aging, including hair graying, abnormal gait, and a shortened life span. Specifically, the aged mice showed systemic inflammation and organ degeneration. In addition, aged SOD3(R213G) mice are susceptible to neutrophil-mediated inflammation. Among other functions, the neutrophils of SOD3(R213G) mice produce high amounts of reactive oxygen species, which would normally be controlled by SOD3 in ECM. INNOVATION: These findings showed for the first time that arginine 213 in the HBD of SOD3 is critical for maintaining proper organ function through moderating the normal innate immune response, which would otherwise lead to chronic inflammation and degenerative diseases in aged mice. CONCLUSION: Therefore, patients with this variant may be treated with SOD3 as a therapeutic strategy to prevent or cure these diseases.

Loss of extracellular superoxide dismutase induces severe IL-23-mediated skin inflammation in mice.

Psoriasis is a common chronic and complex autoimmune inflammatory skin disorder. The histological characteristics of psoriasis are epidermal hyperplasia, mononuclear leukocyte infiltration into the dermis, and increased angiogenesis. However, the mechanisms involved in the pathogenesis of psoriasis remain unclear. Extracellular superoxide dismutase (EC-SOD) has antichemotactic activities. Because immune cell infiltration is seen in psoriatic lesions and psoriasis patients express low levels of EC-SOD, we hypothesized that the lack of EC-SOD induces more severe IL-23-mediated psoriasis-like skin inflammation. To test this hypothesis, we determined whether the loss of EC-SOD causes more severe IL-23-induced skin inflammation. Ear skin after IL-23 administration was thicker in EC-SOD knockout (KO) mice compared with wild-type mice. In addition, infiltration of CD4(+) T cells, macrophages, and dendritic cells (DCs) into IL-23 injection sites was more elevated in EC-SOD KO mice. The expression of proinflammatory cytokines and chemokines was also more elevated in EC-SOD KO mice, and EC-SOD KO DCs expressed a higher level of MHCII. Finally, EC-SOD transgenic mice showed much less severe IL-23-induced skin inflammation. Therefore, EC-SOD may inhibit IL-23-induced psoriasis-like inflammation through the inhibition of immune cell infiltration and immune responses. These results suggest that EC-SOD could be a possible candidate for management of psoriasis.

Role of superoxide dismutase 3 in skin inflammation.

In 1982, a third SOD enzyme was discovered by Marklund and co-workers and named SOD3 on extracellular superoxide dismutase (EC-SOD), as it was shown to be the predominant form in extracellular fluids such as lymph, synovial fluid, and plasma. Many studies have focused on the anti-oxidative effect of SOD3 in the lung and vascular wall where it is highly expressed. Thus, the roles of SOD3 as an anti-oxidative enzyme in ROS-mediated lung inflammation and vascular disease such as ischemia and atherosclerosis, and its mechanism have been extensively studied. However, our studies revealed that the role of SOD3 in inflammation is not simply due to radical scavenging; it affects immune responses and signal initiation. Further, we found that SOD3 is expressed throughout the epidermis and dermis, and its levels were altered upon the progression of inflammation. Considering that skin is the primarily contact with the exogenous environment, including UV, pathogens, and chemicals, it is necessary to understand the role of SOD3 in the prevention or suppression of skin inflammation. Here, we address the emerging role of SOD3 in the suppression of skin inflammation and immune response.

Superoxide dismutase 3 controls adaptive immune responses and contributes to the inhibition of ovalbumin-induced allergic airway inflammation in mice.

AIMS: The extracellular superoxide dismutase 3 (SOD3) is an isoform of SOD. Extensive studies have been focused on role of SOD3 as an antioxidant. However, the role of SOD3 in the immune responses that contribute to the inhibition of allergic lung inflammation has not been investigated. RESULTS: Here, we report for the first time that SOD3 specifically inhibits dendritic cell maturation. Subsequently, SOD3 controls T cell activation and proliferation, and T helper 2 (Th2) and Th17 cell differentiation. As a consequence, the administration of SOD3 into mice alleviated Th2-cell-mediated ovalbumin (OVA)-induced allergic asthma. In addition, we demonstrated that SOD3 inhibits OVA-induced airway extracellular remodeling and Th2 cell trafficking. Through mass spectrometry analysis, the proteins interacting with SOD3 in the lung of asthma were identified. And it was revealed that signaling molecules, such as transforming growth factor (TGF) and epidermal growth factor (EGF) receptor, adhesion and adaptor molecules, kinases, phosphatases, NADPH oxidase, and apoptosis-related factor, were involved, which were altered by administration of SOD3. Relatively severe asthma was observed in SOD3 KO mice and was ameliorated by both the administration of SOD3 and adoptive transfer of SOD3-sufficient CD4 T cells. Moreover, the expression of endogenous SOD3 in the lung peaked early in OVA challenge and gradually decreased upon disease progression, while both SOD1 and SOD2 expression changed relatively little. INNOVATION AND CONCLUSION: Thus, our data suggest that SOD3 is required to maintain lung homeostasis and acts, at least in part, as a controller of signaling and a decision maker to determine the progression of allergic lung disease.

Protein kinase C-θ promotes Th17 differentiation via upregulation of Stat3.

Although protein kinase C-θ (PKC-θ)-deficient mice are resistant to the induction of Th17-dependent experimental autoimmune encephalomyelitis, the function of PKC-θ in Th17 differentiation remains unknown. In this article, we show that purified, naive CD4 PKC-θ(-/-) T cells were defective in Th17 differentiation, whereas Th1 and Th2 differentiation appeared normal. Activation of PKC-θ with PMA promoted Th17 differentiation in wild type (WT) but not PKC-θ(-/-) T cells. Furthermore, PKC-θ(-/-) T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation, and PMA markedly stimulated the expression of Stat3 in WT but not PKC-θ(-/-) T cells. In contrast, activation of Stat4 and Stat6, which are critical for Th1 and Th2 differentiation, was normal in PKC-θ(-/-) T cells. Forced expression of Stat3 significantly increased Th17 differentiation in PKC-θ(-/-) T cells, suggesting that reduced Stat3 levels were responsible for impaired Th17 differentiation, and that Stat3 lies downstream of PKC-θ. Constitutively active PKC-θ, or WT PKC-θ activated by either PMA or TCR cross-linking, stimulated expression of a luciferase reporter gene driven by the Stat3 promoter. PKC-θ-mediated activation of the Stat3 promoter was inhibited by dominant-negative AP-1 and IκB kinase-ß, but stimulated by WT AP-1 and IκB kinase-ß, suggesting that PKC-θ stimulates Stat3 transcription via the AP-1 and NF-κB pathways. Lastly, conditions favoring Th17 differentiation induced the highest activation level of PKC-θ. Altogether, the data indicate that PKC-θ integrates the signals from TCR signaling and Th17 priming cytokines to upregulate Stat3 via NF-κB and AP-1, resulting in the stimulation of Th17 differentiation.

Superoxide dismutase 3 suppresses hyaluronic acid fragments mediated skin inflammation by inhibition of toll-like receptor 4 signaling pathway: superoxide dismutase 3 inhibits reactive oxygen species-induced trafficking of toll-like receptor 4 to lipid rafts.

AIMS: Hyaluronic acid (HA) is a component of the extracellular matrix and has been extensively applied for cosmetic, therapeutic, and antiaging purposes. However, HA fragments (HAFs) cause adverse effects. Considering that UV-exposure produces HAF that accumulated on the skin, the role of HAF in skin inflammation and its precise mechanism needs to be clarified, and strategies for the prevention of skin inflammation are necessary. RESULTS: We found that extracellular superoxide dismutase (SOD), SOD3, suppresses HAF-mediated skin inflammation, while HAF mediated skin inflammation, macrophages and dendritic cells (DCs) dominantly infiltrate, up-regulating inflammatory cytokines and chemokines receptors. However, keratinocytes indirectly responded to HAF. Instead, epidermis containing keratinocytes were stimulated by secreted molecules from HAF-treated macrophages or DC and produced inflammatory molecules including chemokines, which, in turn, led to skin inflammation. This orchestrated inflammatory response was inhibited by SOD3. In addition, SOD3 inhibited DC maturation by suppressing the expression of major histocompatibility complex II, CD80, and CD86. Interestingly, these responses did not occur in Toll-like receptor 4 (TLR4) deficient mice. Similar to lipopolysaccharide (LPS), HAF promoted TLR4 translocation into the lipid rafts to initiate signaling. This trafficking was mediated, at least in part, by NAPDH oxidase-dependent reactive oxygen species (ROS) generation. Subsequently, nuclear factor kappa B (NFκB) subunit, p65, was recruited the promoters of genes encoding inflammatory molecules. This inflammatory machinery was blocked by SOD3. INNOVATION AND CONCLUSION: Thus, we propose that SOD3 might provide an effective strategy for the treatment of HAF-mediated skin inflammation.

Regulation of skin inflammation and angiogenesis by EC-SOD via HIF-1α and NF-κB pathways.

Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that breaks down superoxide anion into oxygen and hydrogen peroxide in extracellular spaces and plays key roles in controlling pulmonary and vascular diseases in response to oxidative stresses. We aimed to investigate the role of EC-SOD in angiogenesis and inflammation in chronic inflammatory skin disorders such as psoriasis. Overexpressed EC-SOD reduced expression of angiogenic factors and proinflammatory mediators in hypoxia-induced keratinocytes and in ultraviolet B-irradiated mice, whereas the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase-1 and anti-inflammatory cytokine interleukin-10 were increased. EC-SOD decreased new vessel formation, epidermal edema, and inflammatory cell infiltration in UVB-irradiated transgenic mice. Moreover, cells treated with recombinant human EC-SOD showed inhibited endothelial tube formation and cell proliferation. Overall, the antiangiogenic and anti-inflammatory effects of EC-SOD might be due to suppression of hypoxia-inducible factor-1α, protein kinase C, and nuclear factor-κB expression. Furthermore, EC-SOD expression in tissue from psoriasis patients was markedly decreased in psoriatic lesional and nonlesional skins from psoriasis patients in comparison to normal skin from healthy volunteers. Together, these results suggest that EC-SOD may provide a novel therapeutic approach to treating angiogenic and inflammatory skin diseases such as psoriasis.

PKC-θ is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection.

Protein kinase C theta (PKC-θ) is a key kinase in mediating T cell receptor (TCR) signals. PKC-θ activated by T cell receptor (TCR) engagement translocates to immunological synapses and regulates the activation of transcriptional factors NFκB, AP-1, and NFAT. These transcription factors then activate target genes such as IL-2. T cells deficient in PKC-θ display defects in T cell activation, survival, activation-induced cell death, and the differentiation into inflammatory T cells, such as Th2 and Th17 cells both in vitro and in vivo. Since these effector T helper cells are responsible for mediating autoimmunity, selective inhibition of PKC-θ is considered a treatment for prevention of autoimmune diseases and allograft rejection.

Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner.

The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS- or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.

Active principle of kimchi, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid, retards fatty streak formation at aortic sinus of apolipoprotein E knockout mice.

We examined the beneficial effects of an active principle in kimchi, 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), on atherogenesis in apolipoprotein E knockout (apoE KO) mice. ApoE KO mice were fed an atherogenic diet containing 1% cholesterol (control group) with an intraperitoneal injection of chemically synthesized HDMPPA (10 mg/kg/day) (HDMPPA group) for 8 weeks. The aortic sinus atherosclerotic lesion size in the HDMPPA group (n = 10) was significantly smaller (control vs. HDMPPA, 280,790 vs. 165,409 microm(2), P < .001). The level of reactive oxygen species (ROS) in the HDMPPA group was lower by 14%, compared with the control group (P < .05). Aortic NADPH oxidase activity was significantly lower in the HDMPPA group than in the control group. HDMPPA suppressed the mRNA expression of p47phox and rac-1 of NADPH oxidase by 27.2% and 46.0%, respectively, compared with values of the control group. In conclusion, HDMPPA in kimchi may attenuate atherosclerosis in apoE KO mice through retardation of ROS generation via down-regulating the mRNA expression of p47phox and rac-1, which are the components of NADPH oxidase.

Lipid-lowering effect of hot water-soluble extracts of Saururus chinensis Bail on rats fed high fat diets.

We evaluated the inhibition of low-density lipoprotein (LDL) oxidation inhibition by a hot water-soluble extract of Saururus chinensis Bail (HWSCB) in vitro and the lipid-lowering effects of HWSCB in rats fed high fat diet (HFD). HFDs were supplemented with 5% HWSCB (HFSCB5 group), 10% HWSCB (HFSCB10 group), or 1% tannic acid (Tannin group). The Tannin group served as a positive control for the study, based on tannic acid's known lipid-lowering effect and water-soluble characteristics. LDL oxidation was dose-dependently inhibited in the presence of HWSCB, and the effect of HWSCB was comparable to that of vitamin C. Significant reductions in triglyceride (P < .05) and cholesterol (P < .05) levels in the plasma and liver of the HFSCB5, HFSCB10, and Tannin groups were observed. High-density lipoprotein cholesterol was elevated (P < .05), but LDL was decreased in a dose-dependent manner for the HFSCB samples. These results were associated with a significant decrease in the atherogenic index for the HFSCB samples, especially for HFSCB10. In addition, fecal excretion of triglyceride with HWSCB supplementation was greater than with tannic acid supplementation. The findings of this study suggest that HWSCB may reduce plasma and hepatic lipids, especially triglyceride, in rats fed high fat diet.

Role of PKCdelta in IFN-gamma-inducible CIITA gene expression.

The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCdelta plays an important role in regulating IFN-gamma-inducible CIITA gene expression in macrophages. Inhibition of PKCdelta by either a PKCdelta inhibitor or a dominant negative (DN) mutant form of PKCdelta led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCdelta inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-gamma induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCdelta did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCdelta is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-gamma in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-gamma inducible CIITA promoter, the effect of PKCdelta on CIITA expression is mediated primarily by serine phosphorylation of Stat 1.

Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells.

Nucleotide-binding oligomerization domain-containing proteins (Nods) are intracellular pattern recognition receptors recognizing conserved moieties of bacterial peptidoglycan through their leucine-rich repeats domain. The agonists for Nods activate proinflammatory signaling pathways, including NF-kappaB pathways. The results from our previous studies showed that the activation of TLR4 and TLR2, leucine-rich repeat-containing pattern recognition receptors, were differentially modulated by saturated and n-3 polyunsaturated fatty acids in macrophages and dendritic cells. Here, we show the differential modulation of NF-kappaB activation and interleukin-8 (IL-8) expression in colonic epithelial cells HCT116 by saturated and unsaturated fatty acids mediated through Nods proteins. Lauric acid (C12:0) dose dependently activated NF-kappaB and induced IL-8 expression in HCT116 cells, which express both Nod1 and Nod2, but not detectable amounts of TLR2 and TLR4. These effects of lauric acid were inhibited by dominant negative forms of Nod1 or Nod2, but not by dominant negative forms of TLR2, TLR4, and TLR5. The effects of lauric acid were also attenuated by small RNA interference targeting Nod1 or Nod2. In contrast, polyunsaturated fatty acids, especially n-3 polyunsaturated fatty acids, inhibited the activation of NF-kappaB and IL-8 expression induced by lauric acid or known Nods ligands in HCT116. Furthermore, lauric acid induced, but docosahexaenoic acid inhibited lauric acid- or Nod2 ligand MDP-induced, Nod2 oligomerization in HEK293T cells transfected with Nod2. Together, these results provide new insights into the role of dietary fatty acids in modulating inflammation in colon epithelial cells. The results suggest that Nods may be involved in inducing sterile inflammation, one of the key etiological conditions in the development of many chronic inflammatory diseases.

Protein kinase C delta is essential to maintain CIITA gene expression in B cells.

Expression of MHC class II genes requires CIITA. Although the transactivation function of CIITA is well characterized, the signaling events that regulate CIITA expression are less understood. In this study, we report that CIITA expression in B cells depends on protein kinase Cdelta (PKCdelta). PKCdelta controls CIITA gene transcription mainly via modulating CREB recruitment to the CIITA promoter without affecting CIITA mRNA stability. Inhibition of PKCdelta by a pharmacological inhibitor or knocking down of endogenous PKCdelta expression by small interfering RNA reduced CREB binding to the CIITA promoter. The decrease of CIITA gene expression in the presence of the PKCdelta inhibitor was prevented by ectopically expressing a constitutively active form of CREB. In addition, histone acetylation of the CIITA promoter is regulated by PKCdelta since the PKCdelta inhibitor treatment or PKCdelta small interfering RNA resulted in decreased histone acetylation. Taken together, our study reveals that PKCdelta is an important signaling molecule necessary to maintain CIITA and MHC class II expression in B cells.

ERK and p38 MAPK signaling pathways negatively regulate CIITA gene expression in dendritic cells and macrophages.

The CIITA is a master regulator for MHC class II expression, but the signaling events that control CIITA expression remain poorly understood. In this study, we report that both constitutive and IFN-gamma-inducible expression of CIITA in mouse bone marrow-derived dendritic cells (DC) and macrophages, respectively, are regulated by MAPK signals. In DC, the inhibitory effect of LPS on CIITA expression was prevented by MyD88 deficiency or pharmacological MAPK inhibitors specific for MEK (U0126) and p38 (SB203580), but not JNK (SP600125). In macrophages, LPS inhibited IFN-gamma-inducible CIITA and MHC class II expression without affecting expression of IFN regulatory factor-1 and MHC class I. Blocking ERK and p38 by MAPK inhibitors not only rescued LPS-mediated inhibition, but also augmented IFN-gamma induction of CIITA. Moreover, the induction of CIITA by IFN-gamma was enhanced by overexpressing MAPK phosphatase-1 that inactivates MAPK. Conversely, CIITA expression was attenuated in the absence of MAPK phosphatase-1. The down-regulation of CIITA gene expression by ERK and p38 was at least partly due to decreased histone acetylation of the CIITA promoter. Our study indicates that both MAPK and phosphatase play an important role for CIITA regulation in DC and macrophages.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced activation of mitogen-activated protein kinase signaling pathway in Jurkat T cells.

The present study was performed to examine mitogen-activated protein kinase associated pathways in mediation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cell apoptosis in cultured Jurkat T cells. TCDD significantly decreased cell viability in a concentration-dependent manner (P<0.05 at 10-300 nM). TCDD (10 nM) also time-dependently decreased cell viability (P<0.05 at 12-48 hr). c-Jun NH2-terminal kinase was significantly phosphorylated with TCDD treatment in a time dependent manner. p38 Mitogen-activated protein kinase was not significantly changed with TCDD treatment. Extracellular signal-regulated protein kinase was significantly phosphorylated with TCDD treatment for 8 hr and gradually returned to baseline. TCDD induced up-regulation of ASK1 and C-Jun, which are up- and down-stream of JNK, respectively, and up-regulation of cytosolic cytochrome c and caspase-3. These results demonstrate that MAPK signaling pathways including JNK and ERK 1/2, are activated with the treatment of TCDD in Jurkat T cells, which suggest that MAPK pathways may be involved in TCDD-induced cell death.

Red pepper attenuates cholesteryl ester transfer protein activity and atherosclerosis in cholesterol-fed rabbits.

BACKGROUND: The current study was conducted to examine the effect of red pepper supplementation on cholesteryl ester transfer protein (CETP) activity, along with its anti-atherosclerotic effect in cholesterol-fed rabbits. METHODS: Rabbits were fed a 1% cholesterol diet for 12 weeks, including a 1% red pepper powder supplement. RESULTS: The red pepper supplemented group exhibited significantly lower CETP activity than the control group during the experimental period (P<0.05). The total cholesterol, triglyceride (TG), LDL-C, VLDL-C, and VLDL-TG levels and atherogenic index (AI) were all significantly lower in the red pepper group than in the control group (P<0.05), whereas the HDL-C level was significantly higher in the red pepper group than in the control group during the experimental period (P<0.05). Furthermore, the red pepper supplementation increased the fecal TG excretion (P<0.05). Based on a morphological examination, the red pepper supplemented group exhibited fewer fat droplet deposits than the control group. CONCLUSIONS: The current results suggest that red pepper attenuates atherosclerosis, plus plasma CETP would appear to be a risk marker of atherosclerosis in cholesterol-fed rabbits.

Cholesteryl ester transfer protein activity and atherogenic parameters in rabbits supplemented with cholesterol and garlic powder.

The current study was conducted to examine the effect of garlic supplementation on CETP activity, along with its anti-atherosclerotic effect in cholesterol-fed rabbits. Rabbits were fed a 1% cholesterol diet for 12 weeks, including a 1% garlic powder supplement. The garlic-supplemented group exhibited significantly lower CETP activity than the control group during the experimental period (P < 0.05). Among the atherogenic parameters, the total cholesterol, TG, LDL-C, VLDL-C, and atherogenic index were all significantly lower in the garlic group than in the control group during the experimental period (P < 0.05), whereas the HDL-C concentration was significantly higher in the garlic group than in the control group after 12 weeks (P < 0.05). Atherosclerotic lesion area in the aorta arch was also significantly lower in the garlic group (P < 0.05). In the morphological examination, the garlic-supplemented group exhibited far fewer fat droplet deposits than the control group. Furthermore, the garlic supplement also lowered the aortic and hepatic cholesterol, and triglyceride. Accordingly, the current results suggest that garlic exerts hypocholesterolemic and/or antiatherogenic and that plasma CETP activity might be a risk marker related with atherogenesis. As such, the inhibition of CETP activity may delay the progression of atherosclerosis, thereby supporting the atherogenicity of CETP and the inhibitory activity of garlic supplementation against CETP.

Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage.

Quercetin is a flavonoid molecule ubiquitous in nature and functions as an anti-oxidant and anti-inflammatory agent with little toxicity in vivo and in vitro. Dose- and time-dependent effect of quercetin has been investigated on proinflammatory cytokine expression and NO production, focusing on its effects on the MAP kinases and the NF-kappaB signal transduction pathways in LPS-stimulated RAW 264.7 cells by using RT-PCR and immunoblotting. Quercetin strongly reduced activation of phosphorylated ERK kinase and p38 MAP kinase but not JNK MAP kinase by LPS treatment. In addition, quercetin treatment inhibited NF-kappaB activation through stabilization of the NF-kappaB/IkappaB complex and IkappaB degradation and proinflammatory cytokines and NO/iNOS expression. Quercetin may exert its anti-inflammatory and immunomodulatory properties in the effect molecules such as proinflammatory cytokines and NO/iNOS by suppressing the activation of ERK and p38 MAP kinase, and NF-kappaB/IkappaB signal transduction pathways.