caveolin-1: a critical regulator of inflammation and fibrosis

Caveolin-1 (cav-1) has been reported to regulate apoptosis, lipid metabolism and endocytosis. In the present study, we demonstrate that cav-1 can act as a potent immunomodulatory molecule in murine macrophages and play an important role in the development of fibrosis. In murine alveolar and peritoneal macrophages, loss of function experiments using siRNA showed that down-regulating cav-1 expression increased lipopolysaccharide (LPS)-induced proinflammatory cytokine tumor necrosis factor-alpha (TNF-á) and interleukin-6 (IL-6) production but decreased anti-inflammatory cytokine interleukin-10 (IL-10) production. Gain of function experiments demonstrated that overexpression of cav-1 in RAW264.7 decreased LPS-induced TNF-á and IL-6 production and augmented IL-10 production. Cav-1 interacted with TLR4 as revealed by co-immunoprecipitation in peritoneal macrophages. Overexpressing cav-1 in RAW264.7 disrupted Toll like receptor 4 (TLR4) MyD88 and TRIF complex formation; regulated mitogen-activated protein kinase (MAPK) phosphorylation; and inhibited NF-êB activation. Furthermore, the anti-inflammatory modulation by cav-1 involved p38, since the administration of SB203580 significantly abrogated the effects of cav-1, and peritoneal macrophages isolated from MKK3 null mice did not demonstrate any modulation of cav-1. Interestingly, HO-1 translocated into caveolae after LPS stimulation. Carbon monoxide (CO), the gaseous byproduct of HO activity responsible for the anti-inflammatory effects of HO-1, did not regulate cytokines production in cav-1 null macrophages. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients, compared to controls. Transforming growth factor-â1 (TGF-â1), the well-known pro-fibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. Cav-1 was able to suppress TGF-â1-induced extracellular matrix (ECM) production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF and bleomycin (BLM)-instilled lung tissue samples, which was dramatically suppressed by adenovirus cav-1 infection. Moreover, JNK1 null fibroblasts showed reduced Smads cascades signaling, mimicking the effects of cav-1. We also demonstrated that cav-1 markedly ameliorated BLM-induced pulmonary fibrosis as evidenced by histological analysis, hydroxyproline content and immunoblot analysis. In summary, our data suggest that cav-1 acts as a potent immunomodulatory and anti-fibrotic effector molecule. Cav-1 may mediate the anti-inflammatory effects of HO-1/CO in immune cells involving the MKK3/p38 MAPK pathway. Cav-1 also plays a pivotal role in ECM regulation and the development of fibrosis, possibly through the MAPK and Smads pathway. This study suggests cav-1 as a novel therapeutic target for patients with fibrosis and inflammation

Risk Aversion, Prudence, and the Three-Moment Decision Model for Hedging

The linear two-moment mean-variance (MV) model has been widely used in finance and economic decision analysis as an approximation of Von Neumann-Morgenstern expected utility (EU) model. The introduction of third or higher moments not only can improve the accuracy of the approximation, but is also suitable to represent investors¡¯ skewness preference (prudence) with the latter supported by empirical evidence. The goal of this paper is to develop a general MVS model and compare it and the traditional MV model against the EU model in the setting of an individual producer hedging in the futures market. Results show: 1) the derived linear MVS model maintains the analytical convenience of MV model, 2) it can generate different results as MV, 3) it approximate EU better than MV, and 4) it is more flexible than MV.Risk and Uncertainty,

THE CROWDING OUT EFFECTS OF THE 2002 FARM BILL ON HEDGING: EVIDENCE FROM PACIFIC NORTHWEST GRAIN FARMS

The 2002 Food Security and Rural Investment (FSRI) Act introduced a price protection program called Counter Cyclical Payments (CCP) to major grain producers in the US. The CCP program is an addition to the Loan Deficiency Payment (LDP) and Direct Payment (DP) programs from the previous 1996 Federal Agriculture Improvement and Reform (FAIR) Act. At the same time, US federally subsidized crop revenue insurance programs also protect farmers from market and production risks. These government policy programs may crowd out the traditional price risk management role of hedging in commodity futures markets.Agricultural and Food Policy, Crop Production/Industries,

Production Risk and Crop Insurance Effectiveness: Organic Versus Conventional Apples

This paper empirically examines the income risks for Pacific Northwest apple growers, both conventional and organic. Current yield based apple production insurance, the Growers Yield Certification (GYC), and hypothesized revenue based insurance are also examined for their risk management effect on growers. Results show that organic apple production is more risky but has higher expected return than its conventional counterpart. The current GYC is subsidized and subsidized more for organic growers. However, the current low price selection levels prevent these programs from offering effective risk reducing effect, and they also prevent the hypothesized revenue insurance from showing its advantage over yield insurance as in the case of other major field crops.Risk and Uncertainty,

EVALUATING RISK MANAGEMENT STRATEGIES FOR NON-IRRIGATED SMALL GRAIN PRODUCERS

Risk management strategies (market and insurance based) are evaluated for selected small grain producers in the Pacific Northwest using expected utility maximization. Equivalent variation (EV) compares alternative risk management portfolios to cash sales under specified restrictions and conditions. Resulting EV's are strongly influenced by government payments, and hedging-based strategies are not used when counter cyclical payments are included in government programs. Optimum risk management portfolios include extensive coverage by insurance-based products only when such products have premiums that are heavily subsidized, or have premiums with no significant expense load.Risk and Uncertainty,

A-80426 suppresses CFA-induced inflammatory pain by suppressing TRPV1 activity via NFκB and PI3K pathways in mice

Objectives: Pain is associated with many circumstances, including inflammatory reactions, which arise from modification of the features of signaling pathways. α2-adrenergic receptor antagonists are widely utilized in narcosis. Here, the authors focused on the narcotic effect of A-80426 (A8) on Complete Freund's Adjuvant (CFA) injections-triggered chronic inflammation pain in WT and TRPV1-/- mice and explored whether its antinociceptive impact was modulated via Transient Receptor Potential Vanilloid 1 (TRPV1). Method: CFA with or without A8 was co-administered to the mice, which were categorized randomly into four groups: CFA, A8, control, and vehicle. Pain behaviors underwent evaluation through mechanical withdrawal threshold, abdominal withdrawal reflex, and thermal withdrawal latency of WT animals. Results: Quantitative polymerase chain reaction revealed that inflammation-promoting cytokines (IL-1β, IL-6, and TNF-α) were upregulated in Dorsal Root Ganglion (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT animals. A8 administration reduced the pain behaviors and production of pro-inflammatory cytokines; however, this effect was significantly reduced in TRPV1-/- mice. Further analysis showed that CFA treatment reduced the TRPV1 expression in WT mice and A8 administration increased its expression and activity. The co-administration of SB-705498, a TRPV1 blocker, did not influence the pain behaviors and inflammation cytokines in CFA WT mice; however, SB-705498 the effect of A8 in WT mice. In addition, the TRPV1 block decreased the NFκB and PI3K activation in the Dorsal Root Ganglia (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT mice. Conclusions: Together, A8 exerted a narcotic impact on CFA-supplemented mice via the TRPV1-modulated NFκB and PI3K pathway

Application of Blockchain Technology in the Governance of Executive Corruption in Context of National Audit

To reduce the impact of hidden corruption of the state-owned enterprise executives, first, this paper uses the difference-in-difference (DD) analysis method to build the DD model in the context of national audit. Second, the study analyzes the impact of the operating performance of the state-owned enterprises on the enterprise value. Third, it discusses the impact of the executive power of the state-owned enterprises on the hidden corruption, and uses blockchain technology with decentralization and high transparency, and information not be tampered with to analyze the degree of information transparency in state-owned enterprises, thereby enhancing the existing audit mode and improving the audit efficiency, and further predicting the trend of hidden corruption for finding the characteristics of corruption as early as possible, and timely governing the corruption behaviors. The research results show that the greater the power of state-owned enterprise executives is, the lower the transparency of information is, the less sound the supervision mechanism is, and the easier the hidden corruption of state-owned enterprise executives will breed. Only by using blockchain technology to enhance the audit mode, ensure data integrity, improve audit efficiency, and decrease audit risk, can the corruption of the executives of state-owned enterprises be effectively curbed