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BackgroundTemozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms.MethodsTMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ.ResultsExposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells.ConclusionsTaken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.

Early intraarticular injection of HA attenuates the progression of cartilage destruction in the ACLT knee, and the downregulation of the cystine/glutamate antiporter system [Formula: see text] was accompanied by the progression of OA.

ObjectiveThe relationship between chronic obstructive pulmonary disease (COPD) and diabetes remains incompletely understood. This study evaluated diabetes risk and post-diabetes outcomes in COPD patients with and without exacerbations.MethodsWe identified 4671 adults newly diagnosed with COPD exacerbations and 9342 adults newly diagnosed with COPD without exacerbations during 2000–2008 using Taiwan’s National Health Insurance Research Database. A comparison cohort of 18684 adults without COPD, matched by age and sex, was randomly selected from the same dataset for the control group. Diabetes events during 2000–2013 were ascertained from medical claims during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of diabetes associated with COPD with or without exacerbations were calculated. We conducted another nested cohort study of 395516 patients with diabetes hospitalization during 2002–2013 and calculated adjusted odds ratios (ORs) and 95% CIs of histories of COPD and COPD exacerbations associated with adverse events after diabetes admission.ResultsDuring the follow-up period, the incidences of diabetes for patients without COPD and for patients with COPD without or with exacerbations were 3.4, 4.1 and 7.4 per 1000 person-years, respectively (P < 0.0001). Increased risk of diabetes for patients with COPD without exacerbations (HR 1.09, 95% CI 1.02–1.17) and COPD with exacerbations (HR 2.18, 95% CI 1.88–2.52) was noted. Post-diabetes pneumonia (OR 3.28, 95% CI 3.13–3.43), intensive care admission (OR 1.32, 95% CI 1.26–1.39) and mortality (OR 2.06, 95% CI 1.88–2.25) were associated with COPD exacerbations.ConclusionPrevention and intervention strategies for diabetes and post-diabetes outcomes are needed for this susceptible population.

We present a patient with a history of clomipramine-induced serotonin syndrome 5 yr prior who developed serotonin syndrome after a single dose of meperidine. This report heightens appreciation of population at risk and also recognition of potential toxicity in meperidine.

We had previously demonstrated that excitatory amino acid glutamate plays a role in the progression and severity of knee osteoarthritis (OA), and early hyaluronic acid injection attenuates the OA progression by attenuation of knee joint glutamate level, which was also related to the cystine/glutamate antiporter system X (system X À C ) expression. System X À C uptakes cystine into chondrocytes for glutathione (GSH) synthesis, but the role of system X À C in OA is rarely addressed. Sulfasalazine (SSZ) is a system X À C inhibitor; SSZ was applied intra-articularly to study the function of system X À C in the development of OA in rats subjected to anterior cruciate ligament transection and medial meniscectomy (ACLT þ MMx). Moerover, the system X À C activator N-acetylcysteine (NAC) was also applied to verify the role of system X À C . The intra-articular injection of SSZ significantly attenuated knee swelling and cartilage destruction in the knees of ACLT þ MMx rats and this effect was blocked by NAC. The results showed that inhibition of system X À C function can attenuate ACLT þ MMx-induced cartilage destruction. In the present study, system X À C inhibitor SSZ was shown to reduce glutamate content in synovial fluid and GSH in chondrocytes. It was also showed SSZ could attenuate ACLT þ MMx-induced cartilage destruction, and treatment of NAC reversed the protective effect of SSZ. ß

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