We used a large medical insurance claims database to identify three groups: chronic opioid (>180 therapeutic days, N=3726); acute opioid use (<10 therapeutic days, N=37,108); and a non-opioid group (N=337,366) who filled at least one insurance claim but none for opioids. Our results showed that, although chronic opioid users represented only 0.65% of the total population, they filed 4.56% of all insurance claims, used 45% of all opioid analgesics and had much more physical and psychiatric co-morbidity than the acute opioid or non-opioid samples. Women were substantially over-represented (>63%) in the chronic pain group and used a much greater share of all medical services than males especially as they grew older. Although our data suggest that chronic pain is optimally managed in a multidisciplinary patient- and gender-specific treatment plan, this was rarely the case with internists being the primary, and often only, physician seen. Moreover, our data suggest that opioids were often used for conditions in which they are generally not indicated (e.g. arthritis and headaches) or contraindicated by co-existing physical ailments (COPD). Finally, we conclude that adherence to the WHO analgesic ladder and other pain treatment guidelines was relatively infrequent: first, opioid extended release preparations which are ideally suited for chronic pain were used only in 1 in 4 patients; and, second, the selection of a weak (propoxyphene, codeine, tramadol) or strong opioid (e.g. morphine, oxycodone, etc.) seemed to be driven by numerous factors not necessarily related to the intensity or duration of pain.

The present work adopted a systems pharmacology-based approach to provide new insights into the active compounds and therapeutic targets of Bufei Yishen formula (BYF) for the treatment of chronic obstructive pulmonary disease (COPD). In addition, we established a rat model of cigarette smoke- and bacterial infection-induced COPD to validate the mechanisms of BYF action that were predicted in systems pharmacology study. The systems pharmacology model derived 216 active compounds from BYF and 195 potential targets related to various diseases. The compound-target network showed that each herbal drug in the BYF formula acted on similar targets, suggesting potential synergistic effects among these herbal drugs. The ClueGo assay, a Cytoscape plugin, revealed that most targets were related to activation of MAP kinase and matrix metalloproteinases. By using target-diseases network analysis, we found that BYF had great potential to treatment of multiple diseases, such as respiratory tract diseases, immune system, and cardiovascular diseases. Furthermore, we found that BYF had the ability to prevent COPD and its comorbidities, such as ventricular hypertrophy, in vivo. Moreover, BYF inhibited the inflammatory cytokine, and hypertrophic factors expression, protease-antiprotease imbalance and the collagen deposition, which may be the underlying mechanisms of action of BYF.

To develop a stable chronic obstructive pulmonary disease (COPD) model in rats. Sprague-Dawley rats were treated with cigarette-smoke inhalation (CSI) for 12 weeks, repetitive bacterial infection (RBI) for 8 weeks, or the combination of the two (CCR) for 12 weeks and followed up for the additional 20 weeks. Tidal volume (V T ), peak expiratory flow (PEF) and 50% V T expiratory flow (EF 50 ), histological changes in the lungs, and levels of the cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-10 in serum and bronchial alveolar lavage fluid (BALF) were examined at intervals during the 32 week study period. The right ventricular hypertrophy index (RVHI) was also determined at the same times. V T , PEF, and EF 50 were decreased in rats with COPD compared to the control. The expression of TNF-α, IL-8 and IL-10 increased in both serum and BALF with a similar trend. Bronchiole and arteriole wall thickness and the degree of bronchiole stenosis and alveolar size increased in COPD rats. RVHI was reduced gradually following the treatment. All of these changes were more pronounced in the CCR-treatment group than in the other groups. Our results have shown that CSI or RBI alone can induce COPD in rats, but that the combination of CSI with RBI induces a stable COPD that has more similarity to complications seen in patients with COPD. This combination may therefore provide a more appropriate model for study of human COPD.Key words pulmonary disease; chronic obstructive; animal model; pulmonary function; histological change; right ventricular hypertrophy index Chronic obstructive pulmonary disease (COPD) has been defined as a preventable and treatable pathologic condition characterized by partially reversible airflow limitation, 1) and is a major cause of morbidity and mortality throughout the world.2) Its prevalence among the Chinese population aged 40 or older is 8.2%.3) Development of COPD is slow and progressive in humans, with occasional exacerbations caused by an inflammatory response to triggering substances such as noxious gases, 1) bacteria 4-6) or viruses. [7][8][9][10][11] Four abnormalities are present in chronic, stable COPD: emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis.Tobacco smoking and bacterial infection are the most common and important risk factors for COPD, 1,12,13) and they have each been used to establish animal COPD models. [14][15][16] Animal models have also used other noxious gases [17][18][19] and Pneumocystis carinii infection 20) in COPD induction. Short term induction protocols (days) 17,21) have resulted in a pulmonary inflammatory infiltrate, increased mucus production, and pulmonary edema. Long term induction protocols (weeks or months) 15,[17][18][19] have produced, in addition to the inflammatory infiltrate, emphysema and pulmonary remodeling characterized by fibrosis, and thickened bronchiole and arterial walls. Problems with animal models are that most of them are of short duration and the COPD produced does not correspond to the late...

Platycodin D (PD) is the main active saponin of Platycodon grandiflorum (PG) and is reported to exhibit multiple biological effects, including anti-tumor, anti-inflammation, and anti-obesity properties. Although recently there have been many research reports on the chemical constituents of the plant's roots, only few works have been reported on the aerial parts of PG. In the present study, we report the first isolation of PD from the aerial parts of PG and its protective effect against acute alcohol-induced liver oxidative injury and inflammatory response in mice. In brief, the protective effect was evaluated by tracking biochemical markers, enzymatic antioxidants and proinflammatory cytokines in serum and liver tissue. The results indicated that PD pretreatment significantly decreased the levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (L-DLC) in serum and malondialdehyde (MDA) in liver. PD was also found to increase the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the liver (p < 0.05). In addition, PD markedly decreased the levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, which was caused by alcohol exposure (p < 0.05). In contrast, histopathological examinations revealed that PD pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and steatosis. Collectively, the present study clearly suggests that the protective effect exhibited by PD on alcohol-induced liver oxidative injury may occur via the alleviation of oxidative stress and inflammatory response.

BackgroundAcetaminophen (APAP) overdose-induced acute liver failure (ALF) is mainly resulted from uncontrolled oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, is essential for alleviating APAP-induced hepatotoxicity. Corilagin (Cori) is a natural polyphenol compound that possesses effective antioxidant activity; however, the protective effect of Cori on APAP-induced hepatotoxicity is still unknown. The current study aimed to explore whether Cori could mitigate hepatotoxicity caused by APAP and the underlying molecular mechanisms of action.MethodsCell counting kit-8 (CCK-8) assays, Western blotting analysis, dual-luciferase reporter assays, a mouse model, CRISPR/Cas9 knockout technology, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Cori exerts a protective effect on hepatotoxicity in HepG2 cells and in a mouse model.ResultsOur findings suggested that Cori efficiently decreased APAP-triggered the generation of reactive oxygen species (ROS) and cell death in HepG2 cells. Additionally, Cori significantly induced the expression of several antioxidant enzymes, and this induced expression was closely linked to the upregulation of Nrf2, inhibition of Keap1 protein expression, and promotion of antioxidant response element (ARE) activity in HepG2 cells. Moreover, Cori clearly induced the phosphorylation of AMP-activated protein kinase (AMPK), glycogen synthase kinase-3β (GSK3β), liver kinase B1 (LKB1) and acetyl-CoA carboxylase (ACC). Furthermore, Cori-mediated GSK3β inactivation, Nrf2 upregulation and cytoprotection were abolished by an AMPK inhibitor (Compound C) in HepG2 cells. Lastly, we found that Cori inhibited APAP-induced hepatotoxicity and mediated the expression of many antioxidant enzymes; these results were reversed in Nrf2 −/− HepG2 cells. In vivo, Cori significantly protected against APAP-induced ALF by reducing mortality and alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, attenuating histopathological liver changes, inhibiting myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and increasing the superoxide dismutase (SOD) content and GSH-to-GSSG ratio as well as suppressing c-jun N-terminal kinase (JNK) phosphorylation. However, Cori-induced reductions in mortality, AST and ALT levels, and histopathological liver changes induced by APAP were clearly abrogated in Nrf2-deficienct mice.ConclusionsThese findings principally indicated that Cori effectively protects against APAP-induced ALF via the upregulation of the AMPK/GSK3β-Nrf2 signaling pathway.