Anti-proliferation and apoptosis-inducing effects of dihydroartemisinin on SH-SY5Y cells and metabolomic analysis.

Background: In childhood, metastatic neuroblastoma (NB) is the most common extracranial solid tumor, but there are no appropriate drugs for its treatment. Dihydroartemisinin (DHA), a drug for malaria treatment, has therapeutic potential in several cancers; however, its mechanisms remain unclear. This study aimed to investigate the anti-proliferation effect of DHA on SH-SY5Y cells and to explore its mechanism in vitro. Methods: We used 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to measure the half-maximal inhibitory concentration (IC50) of DHA; western blot was used to determine protein levels; propidium iodide (PI) staining was used to determine apoptotic cells; JC-1 staining to measure mitochondrial membrane potential; and dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining was used to determine reactive oxygen species (ROS). Metabonomic analysis was performed by using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based untargeted metabolomics. Multivariate statistical analysis was performed to screen potential metabolites associated with DHA treatment in SH-SY5Y cells. Results: It was shown that DHA inhibited SH-SY5Y cell proliferation and increased poly (ADP-ribose) polymerase (PARP-1) and caspase 3 in a dose-dependent manner. In Further, DHA promoted ROS generation and γH2AX expression. In addition, a total of 125 proposed metabolites in SH-SY5Y cells and 45 vital metabolic pathways were identified through UHPLC-MS/MS-based untargeted metabolomic analysis. Conclusions: These data suggest that DHA could regulate taurine, linoleic acid, phenylalanine metabolism, and tryptophan metabolism, which are involved in the anti-proliferation effect of DHA in SH-SY5Y cells.

Development and validation of an UHPLC-Orbitrap-HRMS method for rapid determination of endogenous L-carnitine in patients on hemodialysis/peritoneal dialysis and its application to promote rational drug use.

Background: L-carnitine is an endogenous vitamin-like amino acid derivate which plays an essential role in energy metabolism and can be easily lost via dialysis. Deficiency of L-carnitine has great effects on many aspects of bodily functions. To determine the deficiency degree and adjust the supplementation dose, a rapid, sensitive, and specific method for the detection of endogenous L-carnitine in the plasma of dialysis patients using ultra-high performance liquid chromatography-Orbitrap high resolution mass spectrometry (UHPLC-Orbitrap-HRMS) was developed and validated. Methods: The plasma samples were processed by protein precipitation and centrifugation before analysis using UHPLC-Orbitrap-HRMS. Sample separation was achieved with a hydrophilic interaction liquid chromatography (HILIC) column, using an isocratic elution with a runtime of 5 min. The separated analytes were detected by positive ionization mode in full scan mode and targeted-single ion monitoring (t-SIM) mode. Mildronate was used as the internal standard (IS). Results: All the plasma could be detected in the range of 6.169 to 197.394 µM, with adequate accuracy, precision, and recovery. The method was validated in fortified validation with relative standard deviations (RSD) 5.15-8.74%. This method was applied to the analysis of 105 dialysis patients and 39 healthy participants, the results revealed that peritoneal dialysis patients without L-carnitine supplementation should pay more attention to L-carnitine monitoring, meanwhile, all the hemodialysis patients were advised to be routinely given a full dose of L-carnitine, no matter whether they had taken L-carnitine or not. Conclusions: This study developed a simple and rapid UHPLC-Orbitrap-HRMS method for detection of endogenous L-carnitine in dialysis patients, which could be useful to promote rational drug use.

[Immunotherapy and Pharmaceutical Care for Non-small-cell Lung Cancer Complicated with Hyperthyroidism:Report of One Case].

Based on our experience in treating one patients with non-small cell lung cancer complicated with hyperthyroidism,the following considerations in immunotherapy and pharmaceutical care are proposed:role of iodine contrast and contrast agent selection in patients with hyperthyroidism;selection of hemostatic agents and assessment of thrombosis risk in patients with hemoptysis caused by tumor invasion of bronchus;influence of glucocorticoid use on the treatment with programmed cell death-1(PD-1)inhibitor and the role of PD-1 inhibitors in patients with a history of hyperthyroidism;education methods for patients refuse to receive opioids.The participation of clinical pharmacists in the Multiple Disciplinary Team and the multi-dimensional pharmaceutical monitoring for patients can improve the safety and rationality of medications.

Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson's Disease and Diabetes.

Patients with diabetes mellitus have a higher risk of developing Parkinson's disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.

Thioredoxin-interacting protein induced α-synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease.

AIMS: Thioredoxin-interacting protein (TXNIP) is associated with activation of oxidative stress through inhibition of thioredoxin (Trx). However, some evidences point out that TXNIP acts as a scaffolding protein in signaling complex independent of cellular redox regulation. The autophagy-lysosomal pathway plays important roles in the clearance of misfolded proteins and dysfunctional organelles. Lysosomal dysfunction has been involved in several neurodegenerative disorders including Parkinson's disease (PD). Although researchers have reported that TXNIP inhibited autophagic flux, the specific mechanism is rarely studied. METHODS: In this study, we investigated the effects of TXNIP on autophagic flux and α-synuclein accumulation by Western blot in HEK293 cells transfected with TXNIP plasmid. Further, we explored the influence of TXNIP on DA neuron survival in substantia nigra by IHC. RESULTS: We found that TXNIP induced LC3-II expression, but failed to degrade p62, a substrate of autophagy. Also, TXNIP aggravated α-synuclein accumulation. We also found that TXNIP inhibited the expression of ATP13A2, a lysosomal membrane protein. Moreover, we found that overexpression of ATP13A2 attenuated the impairment of autophagic flux and α-synuclein accumulation induced by TXNIP. Furthermore, overexpression of TXNIP in substantia nigra resulted in loss of DA neuron. CONCLUSION: Our data suggested that TXNIP blocked autophagic flux and induced α-synuclein accumulation through inhibition of ATP13A2, indicating TXNIP was a disease-causing protein in PD.

Efficacy of proton pump inhibitors for patients with duodenal ulcers: A pairwise and network meta-analysis of randomized controlled trials.

BACKGROUND/AIM: To compare the efficacy and tolerance of different proton pump inhibitors (PPIs) in different doses for patients with duodenal ulcers. MATERIALS AND METHODS: An electronic database was searched to collect all randomized clinical trials (RCTs), and a pairwise and network meta-analysis were performed. RESULTS: A total of 24 RCTs involving 6188 patients were included. The network meta-analysis showed that there were no significant differences for the 4-week healing rate of duodenal ulcer treated with different PPI regimens except pantoprazle 40 mg/d versus lansoprazole 15 mg/d [Relative risk (RR) = 3.57; 95% confidence interval (CI) = 1.36-10.31)] and lansoprazole 30 mg/d versus lansoprazole 15 mg/d (RR = 2.45; 95% CI = 1.01-6.14). In comparison with H2receptor antagonists (H2RA), pantoprazole 40 mg/d and lansoprazole 30 mg/d significantly increase the healing rate (RR = 2.96; 95% CI = 1.78-5.14 and RR = 2.04; 95% CI = 1.13-3.53, respectively). There was no significant difference for the rate of adverse events between different regimens, including H2RA for a duration of 4-week of follow up. CONCLUSION: There was no significant difference for the efficacy and tolerance between the ordinary doses of different PPIs with the exception of lansoprazle 15 mg/d.

Description of two unknown females of Epeus Peckham & Peckham from China (Araneae: Salticidae).

The jumping spider genus Epeus Peckham & Peckham presently includes 15 species, mainly from South and Southeast Asia (World Spider Catalog 2015). Species of this genus have the cymbium of male palp flattened and elongated, with a basal apophysis retrolaterally, pointing postero-ventrally; tegulum with a tongue-like process; filiform embolus; and epigyne with long copulatory ducts with several loops.