RESUMO
BACKGROUND: The ability to treat glioblastoma (GBM) using the chemotherapeutic agent temozolomide (TMZ) has been hampered by the development of therapeutic resistance. In this study, we assessed the ability of the isoquinoline alkaloid berberine to alter GBM TMZ resistance using two different TMZ-resistant cell lines to mimic a physiologically relevant GBM experimental system. METHODS: By treating these resistant cell lines with berberine followed by TMZ, we were able to assess the chemosensitivity of these cells and their parental strains, based on their performance in the MTT and colony formation assays, as well as on the degree of detectable apoptosis that was detected in the strains. Furthermore, we used Western blotting to assess autophagic responses in these cell lines, and we extended this work into a xenograft mouse model to assess the in vivo efficacy of berberine. RESULTS: Through these experiments, our findings indicated that berberine enhanced autophagy and apoptosis in TMZ-resistant cells upon TMZ treatment in a manner that was linked with ERK1/2 signaling. Similarly, when used in vivo, berberine increased GBM sensitivity to TMZ through ERK1/2 signaling pathways. CONCLUSIONS: These findings demonstrate that berberine is an effective method of increasing the sensitization of GBM cells to TMZ treatment in a manner that is dependent upon the ERK1/2-mediated induction of autophagy, thus making berberine a potentially viable therapeutic agent for GBM treatment.
RESUMO
BACKGROUND AND PURPOSE: Tafamidis functions to delay the loss of function in transthyretin familial amyloid polyneuropathy (TTR-FAP), which is a rare inherited amyloidosis with progressive sensorimotor and autonomic polyneuropathy. This systematic literature review and meta-analysis evaluated the efficacy and safety of tafamidis in TTR-FAP patients, with the aim of improving the evidence-based medical evidence of this treatment option for TTP-FAP. METHODS: A systematic search of the English-language literature in five databases was performed through to May 31, 2018 by two reviewers who independently extracted data and assessed the risk of bias. We extracted efficacy and safety outcomes and performed a meta-analysis. Statistical tests were performed to check for heterogeneity and publication bias. RESULTS: The meta-analysis identified six relevant studies. The tafamidis group showed smaller changes from baseline in the Neuropathy Impairment Score-Lower Limbs [mean difference (MD)=-3.01, 95% confidence interval (CI)=-3.26 to -2.75, p<0.001] and the Norfolk Quality of Life-Diabetic Neuropathy total quality of life score (MD=-6.67, 95% CI=-9.70 to -3.64, p<0.001), and a higher modified body mass index (MD=72.45, 95% CI=69.41 to 75.49, p<0.001), with no significant difference in total adverse events [odds ratio (OR)=0.69, 95% CI=0.35 to 1.35, p=0.27]. The incidence of adverse events did not differ between tafamidis and placebo treatment except for fatigue (OR=0.13, 95% CI=0.02 to 0.72, p=0.02) and hypesthesia (OR=0.16, 95% CI=0.03 to 0.92, p=0.04). CONCLUSIONS: This systematic review and meta-analysis has demonstrated that tafamidis delays neurologic progression and preserves a better nutritional status and the quality of life. The rates of adverse events did not differ between the patients in the tafamidis and placebo groups. Tafamidis might be a safer noninvasive option for patients with TTR-FAP.
RESUMO
BACKGROUND: Tranexamic acid functions as an antifibrinolytic medication and is widely used to treat or prevent excessive blood loss in menorrhagia and during the perioperative period. The efficacy of tranexamic acid in reducing mortaligy and disability, and the occurrence of complications during treatment of cerebral hemorrhage remains controversial. OBJECTIVE: The objective of this systematic literature review and meta-analysis was to evaluate the efficacy and safety of tranexamic acid in patients with cerebral hemorrhage, aiming to improve the evidence-based medical knowledge of treatment options for such patients. METHODS: A systematic literature search was performed in English through 31 August 2018, with two reviewers independently extracting data and assessing risk of bias. We extracted efficacy and safety outcomes and performed a meta-analysis. Statistical tests were performed to check for heterogeneity and publication bias. RESULTS: In total, 14 randomized controlled trials with 4703 participants were included in the meta-analysis. Tranexamic acid did not improve mortality by day 90 (odds ratio (OR) 0.99; 95% confidence interval (CI) 0.84-1.18; p = 0.95) or day 180 (OR 1.01; 95% CI 0.51-2.01; p = 0.98) or overall death endpoints of different follow-up times (OR 0.82; 95% CI 0.62-1.08; p = 0.15), which was supported by sensitivity analysis of studies published during or after 2000 (OR 0.92; 95% CI 0.77-1.09; p = 0.33). A lower incidence of hematoma expansion (OR 0.54; 95% CI 0.37-0.80; p = 0.002) and less change in volume from baseline (mean difference (MD) - 1.98; 95% CI - 3.00 to - 0.97; p = 0.0001) were observed, but no change was seen in poor functional outcomes (OR 0.95; 95% CI 0.79-1.14; p = 0.55) in the tranexamic acid group. The risk of hydrocephalus (OR 1.21; 95% CI 0.90-1.62; p = 0.21), ischemic stroke (OR 1.43; 95% CI 0.87-2.34; p = 0.16), deep vein thrombosis (OR 1.25; 95% CI 0.75-2.08; p = 0.40), and pulmonary embolism (OR 0.97; 95% CI 0.59-1.58; p = 0.89) was similar, whereas the risk of combined ischemic events increased in the tranexamic acid group (OR 1.47; 95% CI 1.07-2.01; p = 0.02). CONCLUSIONS: Treatment with tranexamic acid could reduce rebleeding and hematoma expansion in cerebral hemorrhage without an increase in single ischemic adverse events, but it could increase the risk of combined ischemic events; however, the lack of improvement in mortality and the poor functional outcomes limit the value of clinical application. These findings indicate that the most pertinent issue is the risk-to-benefit ratio with tranexamic acid treatment in cerebral hemorrhage.