Favorable neuroprotective effect of intra-arterial application of edaravone dexborneol in ischemic stroke rats.

OBJECTIVE: The aim of this study was to investigate the neuroprotective effects of intra-arterial administration of edaravone dexborneol in rats with acute ischemic stroke and determine the optimal dose. MATERIALS AND METHODS: Firstly, 120 male Sprague-Dawley rats (265-300 g) were selected to establish ischemic stroke models and were randomly divided into groups of sham-operation (Sham group), cerebral ischemia-reperfusion (IS group), permanent focal ischemia (PI group) and treatment (2MG group: 2 mg/kg, 4MG group: 4 mg/kg, 6MG group: 6 mg/kg) groups. There are 20 rats in each group, and ten rats in each group were randomly selected for Longa score and 2,3,5-triphenyl tetrazolium chloride staining to observe the changes in neurological function and the proportion of cerebral infarct volume in each group. Secondly, the remaining ten rats in each group were scored for Longa and tested for free radicals (hydroxyl radical; peroxynitrite; nitric oxide) and pro-inflammatory cytokines (interleukin 6; interleukin-1ß; tumor necrosis factor-α). We monitored changes in the indicators in each group of rats. RESULTS: There were no significant differences among the enrolled Sprague-Dawley rats concerning age, sex, and feeding conditions. Edaravone dexborneol could significantly reduce the cerebral levels of hydroxyl radical, interleukin 6, interleukin-1ß, tumor necrosis factor-α, and their behavioral scores of acute ischemic stroke rats after a single dose in the carotid artery. The results suggested that 4 mg/kg might be an appropriate dose. CONCLUSIONS: A single intra-arterial administration of edaravone dexborneol can improve neurobehavioral function and alleviate cerebral injury in acute ischemic stroke rats through anti-inflammatory and free radical scavenging effects.

Clinical Experience in the Diagnosis and Treatment of Adult Acute Necrotizing Encephalopathy.

PURPOSE: We report two cases diagnosed as acute necrotizing encephalopathy (ANE) with acute onset and various clinical manifestations. METHODS: The patients' data were obtained from the medical records of the Binzhou Medical University Hospital in Binzhou, China. The clinical symptoms, laboratory examination, neuroimaging, treatment, and prognosis of the 2 patients were collected and analyzed. RESULTS: We report 2 adult ANE patients with acute onset. The first symptom was fever, followed by symptoms and signs of damage to the central nervous system. The patients were infected with herpes simplex virus and influenza virus, respectively. The main manifestation on brain magnetic resonance imaging was a mixed-signal of a "three-layer structure" in the bilateral thalamus. The first patient died. Based on the experience of the diagnosis and treatment of the first patient, combined with a review of the literature, the second patient was immediately treated with glucocorticoid pulse therapy combined with gamma globulin injection. This patient's condition was controlled, and the prognosis was good. CONCLUSIONS: This study describes the clinical symptoms, laboratory examination, neuroimaging evidence, and treatment experience of ANE in adults. We believe that the progress of the disease may be controlled, and the prognosis may be improved if glucocorticoid pulse therapy combined with gamma globulin injection is used as soon as possible.

Hepatoprotective effect and metabonomics studies of radix gentianae in rats with acute liver injury.

CONTEXT: As a well-known traditional Chinese medicine for protecting the liver, the mechanism of Radix Gentianae (RG) remains unclear. OBJECTIVE: The hepatoprotective effect and metabonomics of RG were studied to explore the molecular and metabolic mechanisms of RG protecting the liver. MATERIALS AND METHODS: Sprague-Dawley rats were divided into control and model group (n = 10, orally given distilled water), intervention group (4 subgroups, n = 10, prophylactically and orally given 0.63, 2.5 and 5.6 g/kg RG and 0.2 g/kg bifendatatum for 7 d). On day 7 of the intervention, all rats except the control were injected intraperitoneally with 2.5% carbon tetrachloride vegetable oil solution (1.5 mL/kg) to induce liver injury. After 24 h of carbon tetrachloride injection, rat serum and liver tissue were collected for determining AST, ALT, TNF-α, MCP-1, IL-6, SOD, MDA, GSH, and GSH-PX. Rat serum was used for analysing endogenous metabolism by UPLC-Q-TOF-MS. RESULTS: Different doses of RG can significantly decrease the levels of AST, ALT, TNF-α, MCP-1, IL-6 and MDA, and increase the levels of SOD, GSH, and GSH-PX in rats with liver injury (p < 0.05; TNF-α, and IL-6, p < 0.05 only at 5.6 g/kg dose). Eight biomarkers of liver injury were obtained in serum metabonomics, involving five significant metabolic pathways. RG can improve steroid biosynthesis, linoleic acid metabolism, porphyrin and chlorophyll metabolism, and fatty acid biosynthesis. CONCLUSION: RG demonstrated a good ability to protect the liver and improving endogenous metabolism in rats with liver injury. This can help us understand the mechanism of RG and more clinical verifications were inspired.

Efficacy of bevacizumab combined with chemotherapy in the treatment of HER2-negative metastatic breast cancer: a network meta-analysis.

BACKGROUND: It is not known what combination of bevacizumab and chemotherapy agents is the best therapeutic regimen. Comparative study results among the efficacies of bevacizumab plus chemotherapy remain controversial in patients with HER2-negative metastatic breast cancer. METHODS: We searched Pubmed, Embase, and Cochrane Library Central Resister of Controlled Trials through were July 2019 for randomized controlled trials that evaluated the efficacy of bevacizumab plus chemotherapy in HER2-negative metastatic breast cancer. Data on included study characteristics, outcomes, and risk of bias were abstracted by two reviewers. RESULTS: A total of 16 RCT studies involving 5689 patients were included. The results showed that bevacizumab (Bev) - taxanes (Tax) - capecitabine (Cap) has highest-ranking and is probably more effective for prolonging progression-free survival (PFS) than Tax, Cap, Bev-Tax and Bev-Cap, which was no convincing differences among Bev-Cap-vinorelbine, Bev-Tax-everolimus, Bev-Tax-trebananib, Bev-exemestane, Bev-Cap-cyclophosphamide in Bev-containing regimens. For overall response rate (ORR), Bev-Tax-Cap is superior to Tax, Cap and Bev-Cap, while Bev-Tax-trebananib is superior to Cap. The cumulative probability ranking showed that Bev-Tax-Cap or Bev-Tax-trebananib may have best pathological response rate in HER2-negative metastatic breast cancer. CONCLUSION: Our results provide moderate quality evidence that bevacizumab-taxanes-capecitabine maybe the most effective bevacizumab plus chemotherapy on PFS and ORR in HER2-negative metastatic breast cancer, however it should be also considered that bevacizumab may add toxicity to chemotherapy and whether improve overall survival (OS) or not.

EGCG protects against homocysteine-induced human umbilical vein endothelial cells apoptosis by modulating mitochondrial-dependent apoptotic signaling and PI3K/Akt/eNOS signaling pathways.

Homocysteine (Hcy) induced vascular endothelial injury leads to the progression of endothelial dysfunction in atherosclerosis. Epigallocatechin gallate (EGCG), a natural dietary antioxidant, has been applied to protect against atherosclerosis. However, the underlying protective mechanism of EGCG has not been clarified. The present study investigated the mechanism of EGCG protected against Hcy-induced human umbilical vein endothelial cells (HUVECs) apoptosis. Methyl thiazolyl tetrazolium assay (MTT), transmission electron microscope, fluorescent staining, flow cytometry, western blot were used in this study. The study has demonstrated that EGCG suppressed Hcy-induced endothelial cell morphological changes and reactive oxygen species (ROS) generation. Moreover, EGCG dose-dependently prevented Hcy-induced HUVECs cytotoxicity and apoptotic biochemical changes such as reducing mitochondrial membrane potential (MMP), decreasing Bcl-2/Bax protein ratio and activating caspase-9 and 3. In addition, EGCG enhanced the protein ratio of p-Akt/Akt, endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) formation in injured cells. In conclusion, the present study shows that EGCG prevents Hcy-induced HUVECs apoptosis via modulating mitochondrial apoptotic and PI3K/Akt/eNOS signaling pathways. Furthermore, the results indicate that EGCG is likely to represent a potential therapeutic strategy for atherosclerosis associated with Hyperhomocysteinemia (HHcy).

Erratum to: Phosphocreatine protects against LPS-induced human umbilical vein endothelial cell apoptosis by regulating mitochondrial oxidative phosphorylation.

The original version of this article unfortunately contained a mistake. The arrow marks in Fig. 5 were incorrect. It is now corrected with this erratum. The correct version of Fig. 5 is given below. The authors apologise for this error and the inconvenience it has caused to the readers.

Phosphocreatine protects against LPS-induced human umbilical vein endothelial cell apoptosis by regulating mitochondrial oxidative phosphorylation.

Phosphocreatine (PCr) is an exogenous energy substance, which provides phosphate groups for adenosine triphosphate (ATP) cycle and promotes energy metabolism in cells. However, it is still unclear whether PCr has influenced on mitochondrial energy metabolism as well as oxidative phosphorylation (OXPHO) in previous studies. Therefore, the aim of the present study was to investigate the regulation of PCr on lipopolsaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs) and mitochondrial OXPHO pathway. PCr protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c (Cyt C), Ca(2+), reactive oxygen species and subsequent activation of caspases, and increasing Bcl2 expression, while suppressing Bax expression. More importantly, PCr significantly improved mitochondrial swelling and membrane potential, enhanced the activities of ATP synthase and mitochondrial creatine kinase (CKmt) in creatine shuttle, influenced on respiratory chain enzymes, respiratory control ratio, phosphorus/oxygen ratio and ATP production of OXPHO. Above PCr-mediated mitochondrial events were effectively more favorable to reduced form of flavin adenine dinucleotide (FADH2) pathway than reduced form of nicotinamide-adenine dinucleotid pathway in the mitochondrial respiratory chain. Our results revealed that PCr protects against LPS-induced HUVECs apoptosis, which probably related to stabilization of intracellular energy metabolism, especially for FADH2 pathway in mitochondrial respiratory chain, ATP synthase and CKmt. Our findings suggest that PCr may play a certain role in the treatment of atherosclerosis via protecting endothelial cell function.

MAPRS: An intelligent approach for post-prescription review based on multi-label learning.

Antimicrobial resistance (AMR) is a major threat to public health worldwide. It is a promising way to improve appropriate prescription by the review and stewardship of antimicrobials, and Post-Prescription Review (PPR) is currently the main tool used in hospitals. Existing methods of PPR typically focus on the dichotomy of antimicrobial prescription based on binary classification which, however, is usually a multi-label classification problem. Moreover, previous research did not explain the causes beneath the inappropriate antimicrobial used in the clinical setting, which could be practically important for problem location and decision improvement. In this paper, we collected antimicrobial prescriptions and related data from clean surgery in a hospital in northeastern China, and proposed a Multi-label Antimicrobial Post-Prescription Review System (MAPRS). MAPRS first uses NLP techniques to process unstructured data in prescriptions and explores the value of clinical record text for solving medical problems. Then, Classifier Chains are used to deal with multi-label problems and fused with machine learning algorithms to construct a classifier. At last, a SHAP explanation module is introduced to explain the inappropriate prescriptions. The experimental results show that MAPRS could achieve great performance in a challenging six-category multi-label task, with a subset accuracy of 90.7 % and an average AUROC of 94.3 %. Our results can help hospitals to perform intelligent prescription review and improve the antimicrobial stewardship.

Dexmedetomidine protects PC12 cells from oxidative damage through regulation of miR-199a/HIF-1α.

Background: Although dexmedetomidine (Dex) has a significant neuroprotective effect in various nerve-damage models, the exact mechanism of which Dex protects cells from oxidative damage is not fully clear. This article recommended the protective effect of Dex on oxidative damage in PC12 cells.Methods: The PC12 cells were incubated by hydrogen peroxide (H2O2) for 24 h and pre-treated by Dex for 30 min. Cell viability, apoptosis, HIF-1α expression and ROS level were detected by CCK-8, apoptosis assay, Western blot and ROS assay, respectively. The miR-199a expression was tested by qRT-PCR. Targeting relationship between miR-199a and HIF-1α was performed by dual luciferase activity assay. The activation of PI3K/AKT/mTOR and Wnt/ß-catenin pathways was tested by western blot.Results: Dex attenuated H2O2-induced oxidative damage, including the decline of cell viability, the raise of apoptosis and the generation of ROS in PC12 cells by down-regulating miR-199a expression. Moreover, Dex up-regulated HIF-1α expression via decreasing miR-199a level in PC12 cells and miR-199a targeted the 3'-UTR of HIF-1α. In addition, Dex activated PI3K/AKT/mTOR and Wnt/ß-catenin pathways by declining miR-199a level.Conclusions: This article illustrated the protective effect of Dex on oxidative damage in PC12 cells. Furthermore, Dex prevented PC12 cells from oxidative injury through the regulation of miR-199a/HIF-1α.

Comparisons of argatroban to lepirudin and bivalirudin in the treatment of heparin-induced thrombocytopenia: a systematic review and meta-analysis.

To prevent thromboembolic events associated with heparin-induced thrombocytopenia (HIT), patients usually are treated with argatroban, lepirudin, and bivalirudin. Here, we conducted a meta-analysis of studies to comparing the treatment of HIT with the following direct thrombin inhibitor: argatroban versus lepirudin and argatroban versus bivalirudin. We systematically searched PubMed, Embase, and Cochrane Library database for relevant studies. The clinical outcomes were thromboembolic complication and bleeding. A total of 589 articles were found and 9 of which were finally included in this meta-analysis. There were no significantly differences of thromboembolic complication between argatroban and hirudin analogues (lepirudin and bivalirudin) in the treatment of HIT (lepirudin: RR = 0.773, 95% CI = 0.449-1.331, P = 0.353; bivalirudin: RR = 0.768, 95% CI = 0.386-1.527, P = 0.452). Moreover, the incidence of clinical bleeding of argatroban was similar to hirudin analogues (lepirudin: RR = 0.755, 95% CI = 0.531-1.073, P = 0.117; bivalirudin: RR = 0.995, 95% CI = 0.673-1.472, P = 0.981). Current evidences show that argatroban has the similar effectiveness and safety with lepirudin and bivalirudin for defending against HIT.