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Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-[alpha], IL-1[beta], IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1[beta], IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation. mitogen-activated protein kinase; adenosine 5'-monophosphate-activated protein kinase; reactive oxygen species

Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in subjects with diabetes is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3β-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3β inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis. [ABSTRACT FROM AUTHOR]

Rationale: Chronic obstructive lung disease (COPD) is a chronic progressive disease. Although smoking is the most important risk factor, 30% of patients with COPD are never-smokers, and environmental agents are also influential. The effects of air pollutants and meteorological factors on COPD exacerbations have not been studied extensively. Objectives: We aimed to investigate the air pollutants and meteorological factors that impact the incidence of COPD exacerbations. Methods: We obtained clinical data of COPD exacerbation cases from The National Health Insurance Service and merged it with 24-hour average values of air pollutants and meteorological factors from national databases. Patients who reside in eight metropolitan cities, where observatory stations are densely located, were selected for analysis. Results: In 1,404,505 patients with COPD between 2013 and 2018, 15,282 COPD exacerbations leading to hospitalization or emergency room visits were identified. Among the various air pollutants and meteorological factors, particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5), particulate matter ⩽10 μm in aerodynamic diameter (PM10), NO2, SO2, CO, O3, average temperature, and diurnal temperature range (DTR) were associated with COPD exacerbations. Generalized additive mode model analysis with cubic splines showed an inverted U-shaped relationship with PM2.5, PM10, CO, NO2, SO2, O3, DTR, and humidity, whereas it displayed a U-shaped pattern with the average temperature. Distinct patterns were found from 2015-2016 to 2017-2018. Conclusions: PM2.5, PM10, CO, NO2, O3, SO2, average temperature, humidity, and DTR affected the incidence of COPD exacerbations in various patterns, up to 10 lag days. [ABSTRACT FROM AUTHOR]