Effects of Coptis extract combined with chemotherapeutic agents on ROS production, multidrug resistance, and cell growth in A549 human lung cancer cells

Background: Non–small cell lung cancer is associated with high expression of multidrug resistance (MDR) proteins and low production of reactive oxygen species (ROS). Coptis extract (COP), a Chinese medicinal herb, and its major constituent, berberine (BER), have anticancer properties. This study aims to investigate the effects of COP and BER combined with chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX), on cell proliferation, ROS production, and MDR in A549 human non-small cell lung cancer cells. Methods: A549 cells were treated with different doses of COP and BER, combined with 5-FU, CPT, and TAX. Cell viability was measured by an XTT (2,3-bis-(2-methoxy-4- nitro-5-sulfophenyl)-2 H-tetrazolium-5-carboxanilide) assay. Intracellular ROS levels were determined by measuring the oxidative conversion of cell permeable 2′,7′-dichlorofluorescein diacetate to fluorescent dichlorofluorescein. MDR of A549 cells was assessed by rhodamine 123 retention assay. Results: Both COP and BER significantly inhibited A549 cell growth in a dose-dependent manner. Combinations of COP or BER with chemotherapeutic agents (5-FU, CPT, and TAX) exhibited a stronger inhibitory effect on A549 cell growth. In addition, COP and BER increased ROS production and reduced MDR in A549 cells. Conclusion: As potential adjuvants to chemotherapy for non–small cell lung cancer, COP and BER increase ROS production, reduce MDR, and enhance the inhibitory effects of chemotherapeutic agents on A549 cell growth

Omega-3 Polyunsaturated Fatty Acids Protect Neural Progenitor Cells against Oxidative Injury

The omega-3 polyunsaturated fatty acids (ω-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived mainly from fish oil, play important roles in brain development and neuroplasticity. Here, we reported that application of ω-3 PUFAs significantly protected mouse neural progenitor cells (NPCs) against H2O2-induced oxidative injury. We also isolated NPCs from transgenic mice expressing the Caenorhabditis elegans fat-1 gene. The fat-1 gene, which is absent in mammals, can add a double bond into an unsaturated fatty acid hydrocarbon chain and convert ω-6 to ω-3 fatty acids. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that a marked decrease in apoptotic cells was found in fat-1 NPCs after oxidative injury with H2O2 as compared with wild-type NPCs. Quantitative RT-PCR and Western blot analysis demonstrated a much higher expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes, in fat-1 NPCs. The results of the study provide evidence that ω-3 PUFAs resist oxidative injury to NPCs

Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice

Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n−6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n−6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n−6 AA and increased D6D activity can lead to enhanced n−6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention

Vitamin E succinate-conjugated F68 micelles for mitoxantrone delivery in enhancing anticancer activity

Mitoxantrone (MIT) is a chemotherapeutic agent with promising anticancer efficacy. In this study, Pluronic F68-vitamine E succinate (F68-VES) amphiphilic polymer micelles were developed for delivering MIT and enhancing its anticancer activity. MIT-loaded F68–VES (F68–VES/MIT) micelles were prepared via the solvent evaporation method with self-assembly under aqueous conditions. F68–VES/MIT micelles were found to be of optimal particle size with the narrow size distribution. Transmission electron microscopy images of F68–VES/MIT micelles showed homogeneous spherical shapes and smooth surfaces. F68–VES micelles had a low critical micelle concentration value of 3.311 mg/L, as well as high encapsulation efficiency and drug loading. Moreover, F68–VES/MIT micelles were stable in the presence of fetal bovine serum for 24 hours and maintained sustained drug release in vitro. Remarkably, the half maximal inhibitory concentration (IC(50)) value of F68–VES/MIT micelles was lower than that of free MIT in both MDA-MB-231 and MCF-7 cells (two human breast cancer cell lines). In addition, compared with free MIT, there was an increased trend of apoptosis and cellular uptake of F68–VES/MIT micelles in MDA-MB-231 cells. Taken together, these results indicated that F68–VES polymer micelles were able to effectively deliver MIT and largely improve its potency in cancer therapy

Mindfulness-based stress reduction combined with early cardiac rehabilitation improves negative mood states and cardiac function in patients with acute myocardial infarction assisted with an intra-aortic balloon pump: a randomized controlled trial

ObjectiveTo investigate the clinical effects of mindfulness-based stress reduction (MBSR) intervention combined with early cardiac rehabilitation (CR) on patients with acute myocardial infarction (AMI) assisted with an intra-aortic balloon pump (IABP).MethodsA total of 100 AMI patients with IABP assistance due to hemodynamic instability at Wuhan Asia Heart Hospital were enrolled in the study. The participants were divided into two groups using the random number table method (n = 50 each group). Patients receiving routine CR were assigned to the CR control group, while patients receiving MBSR plus CR were assigned to the MBSR intervention group. The intervention was performed twice a day until the removal of the IABP (5–7 days). Each patient's level of anxiety/depression and negative mood state were evaluated before and after intervention using the self-rating anxiety scale (SAS), self-rating depression scale (SDS), and profiles of mood state scale (POMS). The results of the control and intervention groups were compared. IABP-related complications and left ventricular ejection fraction (LVEF), measured with echocardiography, were also assessed and compared between the two groups.ResultsThe SAS, SDS, and POMS scores were lower in the MBSR intervention group than in the CR control group (P < 0.05). There were also less IABP-related complications in the MBSR intervention group. LVEF was significantly improved in both groups, but the degree of LVEF improvement was more significant in the MBSR intervention group than in the CR control group (P < 0.05).ConclusionsMBSR combined with early CR intervention can assist in alleviating anxiety, depression, and other negative mood states, reduce IABP-related complications, and further improve cardiac function in AMI patients with IABP assistance

Long-Term Telbivudine Treatment Results in Resolution of Liver Inflammation and Fibrosis in Patients with Chronic Hepatitis B

The long-term goal of chronic hepatitis B (CHB) treatment is improvement of liver disease and prevention of cirrhosis. The aim of this study was to assess whether prolonged telbivudine treatment improves liver inflammation and fibrosis. The primary objective was to evaluate the proportion of patients with absence/minimal inflammation (Knodell necroinflammatory score a parts per thousand currency sign3) on liver biopsy at Year 5. Fifty-seven patients aged 16-70 years with a clinical history of CHB and active viral replication (38 hepatitis B e antigen [HBeAg] positive and 19 HBeAg negative) were followed for 6 years: 33 received telbivudine 600 mg/day continuously for 5 years; 24 received lamivudine 100 mg/day for 2 years and then telbivudine for 3 years. Liver biopsies were taken pre-treatment and after 5 years of treatment. At baseline, mean (standard deviation) serum hepatitis B virus (HBV) DNA load was 8.5 (1.7) log(10) copies/mL, Knodell necroinflammatory score was 7.6 (2.9), and Ishak fibrosis score was 2.2 (1.1). After antiviral treatment (median duration: 261 weeks), liver histology improved with increased proportions of patients with absence/minimal liver inflammation (Knodell necroinflammatory score a parts per thousand currency sign3), from 16% (9/57) at baseline to 98% (56/57), and absence/minimal fibrosis (Ishak score a parts per thousand currency sign1), from 25% (14/57) at baseline to 84% (48/57). At Year 5, HBV DNA load was < 300 copies/mL for all patients; cumulative HBeAg loss and seroconversion rates were 88% and 77%, respectively. At Year 6, 95% of patients with abnormal baseline glomerular filtration rate (60-90 mL/min/1.73 m(2)) improved to normal GFR (> 90 mL/min/1.73 m(2)). Long-term telbivudine treatment with profound and durable viral suppression significantly improved liver histology, thus achieving the long-term goals of CHB treatment. FibroScan(A (R)) results after 5 and 6 years of treatment (in almost 20% of patients) were consistent with this information. Novartis and National Science and Technology Major Project (2012ZX10002003). ClinicalTrials.gov # NCT00877149.Novartis; National Science and Technology Major Project [2012ZX10002003]; Novartis Pharma AGSCI(E)[email protected]

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China

Background & Aims: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China.Methods: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n=29,478) according to the Roussel Uclaf Causality Assessment Method.Results: Most cases of DILI presented with hepatocellular injury (51.39%; 95% CI, 50.76–52.03), followed by mixed injury (28.30%; 95% CI, 27.73–28.87) and cholestatic injury (20.31%; 95% CI, 19.80–20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and anti-tuberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy’s Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI, 20.86–26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher.Conclusions: In a retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons—higher than that reported from western countries. Traditional Chinese medicines, herbal and dietary supplements, and anti-tuberculosis drugs were the leading causes of DILI in mainland Chin

Isotopic constraints on water balance of tundra lakes and watersheds affected by permafrost degradation, Mackenzie Delta region, Northwest Territories, Canada

&amp;lt;p&amp;gt;Widespread permafrost thaw in Canada's western Arctic has led to formation of shoreline retrogressive thaw slumps (SRTS), a process influential in modifying water and biogeochemical balances of tundra lakes. To investigate hydrological effects of SRTS, water sampling campaigns were conducted in 2004, 2005 and 2008 for paired lakes (pristine vs catchments disturbed by SRTS) in the upland region adjacent to the Mackenzie Delta, Northwest Territories, Canada. An isotope balance model to estimate evaporation/inflow, precipitation/inflow, water yield and runoff ratio was developed incorporating seasonal evaporative drawdown effects and a vapour mixing model to simulate gradients in Beaufort Sea marine air versus continental moisture sources. Site- specific water balance results reveal systematically higher evaporation/inflow and precipitation/inflow for lakes with active SRTS compared to undisturbed lakes, and typically higher ratios for lakes with stabilized versus active SRTS. For lake catchments, water yield is found to be higher for active SRTS sites compared to undisturbed and stabilized SRTS sites, suggesting that slumping is an initial but not a sustained source of water delivery to lakes. Catchments with history of wildfire are found to have lower water yields, attributed to reduced permafrost influence. Conceptually, we define a thaw trajectory whereby undisturbed sites, active SRTS, stabilized SRTS, and ancient- SRTS define progressive stages of permafrost thaw. We postulate that release of additional runoff is mainly due to permafrost thaw in active SRTS which also promotes lake expansion, talik formation, and subsurface connectivity. Eventual stabilization of slumps and reduced runoff is expected once permafrost thaw sources are exhausted, at which time lakes may become more reliant on replenishment by direct precipitation. The effect of snow catch in slumps appears to be subordinate to thawing based on eventual decline in runoff once thaw slumps stabilize. Improved, site-specific hydrologic understanding will assist ongoing research into carbon cycling and biogeochemical feedbacks.&amp;lt;/p&amp;gt; </jats:p