The Promising Seesaw Relationship Between Activity and Stability of Ru-Based Electrocatalysts for Acid Oxygen Evolution and Proton Exchange Membrane Water Electrolysis.

The development of electrocatalysts that are not reliant on iridium for efficient acid-oxygen evolution is a critical step towards the proton exchange membrane water electrolysis (PEMWE) and green hydrogen industry. Ruthenium-based electrocatalysts have garnered widespread attention due to their remarkable catalytic activity and lower commercial price. However, the challenge lies in balancing the seesaw relationship between activity and stability of these electrocatalysts during the acid-oxygen evolution reaction (OER). This review delves into the progress made in Ru-based electrocatalysts with regards to acid OER and PEMWE applications. It highlights the significance of customizing the acidic OER mechanism of Ru-based electrocatalysts through the coordination of adsorption evolution mechanism (AEM) and lattice oxygen oxidation mechanism (LOM) to attain the ideal activity and stability relationship. The promising tradeoffs between the activity and stability of different Ru-based electrocatalysts, including Ru metals and alloys, Ru single-atomic materials, Ru oxides, and derived complexes, and Ru-based heterojunctions, as well as their applicability to PEMWE systems, are discussed in detail. Furthermore, this paper offers insights on in situ control of Ru active sites, dynamic catalytic mechanism, and commercial application of PEMWE. Based on three-way relationship between cost, activity, and stability, the perspectives and development are provided.

TREM-1-targeting LP17 attenuates cerebral ischemia-induced neuronal injury by inhibiting oxidative stress and pyroptosis.

Stroke ranks as the second leading cause of disability and death globally. Trigger receptors expressed on myeloid cells (TREM) -1 are responsible for the activation of the innate immune response and also play a critical role in inflammation. In this study, we reported the contribution of TREM-1 after ischemic damage in a rat middle cerebral artery occlusion (MCAO) model. This study also demonstrated that TREM-1 expression was upregulated following cerebral infarction in rats. TREM-1 inhibition was determined using its selective inhibitor, LP17, which indicated a neuroprotective effect on cerebral infarction damage. The findings revealed that inhibition of TREM-1 by administering LP17 improved cerebral damage and decreased ischemic areas and brain water contents. Moreover, LP17 decreased MCAO-induced microglial activation and neurodegeneration, evidenced by a reduction in the expression of microglial Iba-1 and FJ-B positive cells, and reversed neuronal loss. Besides, the contribution of LP17 to ischemic neuronal damage may be associated with a decrease in the production of pro-inflammatory cytokines, and enhanced production of anti-inflammatory cytokine IL-10. Both in vivo and in vitro studies showed that inhibiting TREM-1 attenuated ROS accumulation, lipid per-oxidation (LPO) contents such as malondialdehyde (MDA) and enhanced the superoxide dismutase (SOD) activity after ischemia. Inhibiting TREM-1 alleviated inflammation and pyroptosis found in MCAO rats. This was achieved through the inhibition of the levels of NLRP3, caspase-1, ASC (an apoptosis-associated speck-like protein containing a CARD) and gasdermin D. These results confirmed that inhibiting TREM-1 protects against ischemia-induced neuronal damage and alleviates microglial mediated neuro-inflammation by reducing oxidative stress and pyroptosis. Therefore, blocking TREM-1 expression provides an effective intervention for improving ischemic stroke.

The Value of the Score for the Targeting of Atrial Fibrillation (STAF) Screening in Acute Stroke Patients.

BACKGROUND AND PURPOSE: Recently, the score for the targeting of atrial fibrillation (STAF) was introduced to identify the risk of atrial fibrillation (AF) in stroke patients. In this study, we aim to evaluate the usefulness of the STAF score for AF screening in acute stroke patients. METHODS: Patients with acute ischemic stroke who were admitted to our stroke unit were prospectively enrolled from March 2011 to March 2013. Baseline National Institutes of Health Stroke Scale (NIHSS), left atrial dilatation, and vascular etiology were assessed to calculate the STAF score. Logistic regression analysis was used to examine the relationship between AF and STAF factors. Univariate analysis of AF and age, history of coronary heart disease and rheumatic heart disease, NIHSS, left atrial dilatation, and vascular etiology was performed. RESULTS: A total of 472 patients were enrolled in our analysis. AF was documented in 78 (16.53%) patients, of which 50% were paroxysmal. Multivariable analysis demonstrated that age, NIHSS, left atrial dilatation, and the absence of vascular etiology can each function as independent predictors for AF. In addition, all AF patients with a STAF ≥5 show a sensitivity of 76.92% and a specificity of 78.68%. The area under the receiver operating characteristic for all AF patients was .842 versus .763 for the paroxysmal AF (pAF) patients. In addition, a sensitivity of 81% (95% CI 73-92) and a ROC of .829 were for new-AF. CONCLUSIONS: The value of the STAF system for predicting the risk of pAF and new-AF in stroke patients is relatively limited.

Des-gamma-carboxy prothrombin (DCP) antagonizes the effects of gefitinib on human hepatocellular carcinoma cells.

BACKGROUND/AIMS: Des-gamma-carboxy prothrombin (DCP), an aberrant prothrombin produced by hepatocellular carcinoma (HCC) cells, is known as a marker for HCC. Recent studies indicated that high levels of DCP are associated with the malignant potential of HCC. In this study, we aimed to investigate the association of DCP with gefitinib treatment failure in HCC and whether DCP counteracts gefitinib-induced growth inhibition and apoptosis of HCC. METHODS: The experiments were performed in HCC cell lines HepG2 and PLC/PRF/5. The effects of gefitinib on HCC in the presence or absence of DCP were evaluated by the 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Apoptotic cells were identified by Annexin V-FITC/PI staining. Western blotting was performed to analyze the expressions of molecules related to the apoptotic caspase-dependent pathway and epidermal growth factor receptor (EGFR) pathway. RESULTS: Gefitinib inhibited HCC cell proliferation and induced apoptosis in HCC cells. The effects of gefitinib on HCC cells were antagonized by DCP. In the presence of DCP, HCC cells were resistant to the gefitinib-induced inhibition of proliferation and stimulation of apoptosis. DCP prevented the activation of the apoptotic caspase-dependent pathway induced by gefitinib. These antagonistic effects of DCP also arose from its ability to up-regulate EGFR, c-Met and hepatocyte growth factor (HGF) in HCC cells. CONCLUSION: DCP antagonized gefitinib-induced HCC cell growth inhibition by counteracting apoptosis and up-regulating the EGFR pathway. High levels of DCP might thus lead to low response rates or possibly no response to gefitinib in patients with HCC.

Acetyl-11-keto-ß-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, an active component of Boswellia serrata gum resin. We examined the effect of AKBA on human gastric carcinoma growth and explored the underlying molecular mechanisms. METHODS: Inhibition of cancer cell growth was estimated by colorimetric and clonogenic assays. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/PI staining and DNA ladder quantification. After three weeks of oral AKBA administration in nude mice bearing cancer xenografts, animals were sacrificed and xenografts removed for TUNEL staining and western blot analysis. RESULTS: AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity. This effect might be associated with its roles in cell cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Further analysis suggested that these effects might arise from AKBA's modulation of the aberrant Wnt/ß-catenin signaling pathway. Upon AKBA treatment, ß-catenin expression in nuclei was inhibited, and membrane ß-catenin was activated. In the same sample, active GSK3ß was increased and its non-active form decreased. Levels of cyclin D1, PCNA, survivin, c-Myc, MMP-2, and MMP-7, downstream targets of Wnt/ß-catenin, were inhibited. CONCLUSIONS: AKBA effects on human gastric carcinoma growth were associated with its activity in modulating the Wnt/ß-catenin signaling pathway. GENERAL SIGNIFICANCE: AKBA could be useful in the treatment of gastric cancers.

Des-γ-carboxy prothrombin (DCP) as a potential autologous growth factor for the development of hepatocellular carcinoma.

Des-γ-carboxy prothrombin (DCP) is a prothrombin precursor produced in hepatocellular carcinoma (HCC). Because of deficiency of vitamin K or γ-glutamyl carboxylase in HCC cells, the 10 glutamic acid (Glu) residues in prothrombin precursor did not completely carboxylate to γ-carboxylated glutamic acid (Gla) residues, leaving some Glu residues remained in N-terminal domain. These prothrombin precursors with Glu residues are called DCPs. DCP displays insufficient coagulation activity. Since Liebman reported an elevated plasma DCP in patients with HCC, DCP has been used in the diagnosis of HCC. Recently, its biological malignant potential has been specified to describe DCP as an autologous growth factor to stimulate HCC growth and a paracrine factor to integrate HCC with vascular endothelial cells. DCP was found to stimulate HCC growth through activation of the DCP-Met-JAK1-STAT3 signaling pathway. DCP might increase HCC invasion and metastasis through activation of matrix metalloproteinase (MMPs) and the ERK1/2 MAPK signaling pathway. DCP has also been found to play a crucial role in the formation of angiogenesis. DCP could increase the angiogenic factors released from HCC and vascular endothelial cells. These effects of DCP in angiogenesis might be related to activation of the DCP-KDR-PLC-γ-MAPK signaling pathway. In this article, we summarized recent studies on DCP in biological roles related to cancer progression and angiogenesis in HCC.

Plasma metabolomic profiling of patients with transient ischemic attack reveals positive role of neutrophils in ischemic tolerance.

BACKGROUND: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of patients with stroke. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of patients with TIA for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. METHODS: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse middle cerebral artery occlusion (MCAO)-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of patients with TIA were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. FINDINGS: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with potentially TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in patients with TIA that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. INTERPRETATION: TIA-induced potential ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils. FUNDING: National Natural Science Foundation of China (81974210), Science and Technology Planning Project of Guangdong Province, China (2020A0505100045), Natural Science Foundation of Guangdong Province (2019A1515010671), Science and Technology Program of Guangzhou, China (2023A03J0577), and Natural Science Foundation of Jiangxi, China（20224BAB216043).

Optimized Electronic Modification of S-Doped CuO Induced by Oxidative Reconstruction for Coupling Glycerol Electrooxidation with Hydrogen Evolution.

Glycerol (electrochemical) oxidation reaction (GOR) producing organic small molecule acid and coupling with hydrogen evolution reaction is a critical aspect of ensuring balanced glycerol capacity and promoting hydrogen generation on a large scale. However, the development of highly efficient and selective non-noble metal-based GOR electrocatalysts is still a key problem. Here, an S-doped CuO nanorod array catalyst (S-CuO/CF) constructed by sulfur leaching and oxidative remodeling is used to drive GOR at low potentials: It requires potentials of only 1.23 and 1.33 V versus RHE to provide currents of 100 and 500 mA cm-2, respectively. Moreover, it shows satisfactory comprehensive performance (at 100 mA cm-2, Vcell = 1.37 V) when assembled as the anode in asymmetric coupled electrolytic cell. Furthermore, we propose a detailed cycle reaction pathway (in alkaline environment) of S-doped CuO surface promoting GOR to produce formic acid and glycolic acid. Among them, the C-C bond breaking and lattice oxygen deintercalation steps frequently involved in the reaction pathway are the key factors to determine the catalytic performance and product selectivity. This research provides valuable guidance for the development of transition metal-based electrocatalysts for GOR and valuable insights into the glycerol oxidation cycle reaction pathway.

[Influence of Ammonium Sulfate and Ammonium Nitrate on the Properties of Ambient PM2.5 in Zhenjiang].

Recently, the contribution of inorganic salts (nitrates in particular) to the mass concentration of particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) has been increasing across China. However, it is urgent to understand how the increased inorganic salts affect the crucial properties of PM2.5. Here, we conducted continuous field observations at Zhenjiang Ecology and Environment Protection Bureau from January 1 to December 31, 2021. The mass concentrations of ammonium sulfate[(NH4)2SO4] and ammonium nitrate (NH4NO3) were calculated using different methods. The contributions of (NH4)2SO4 and NH4NO3 to the extinction coefficient, hygroscopic growth, and acidity of PM2.5 were discussed in detail. Our results demonstrated that the mean mass concentrations of (NH4)2SO4 and NH4NO3 during the study period were (6.5±4.5) and (15.0±13.3) µg·m-3, which contributed (20.5±18.2)% and (34.5±18.4)% to the mass concentration of PM2.5, respectively. The total extinction coefficient of PM2.5 was (224.5±194.2) Mm-1, in which NH4NO3 was the largest contributor[(40.1±20.9)%] followed by (NH4)2SO4[(19.1±10.8)%]. (NH4)2SO4 and NH4NO3 were also the dominant contributors to the hygroscopic growth of PM2.5. In particular, NH4NO3contributed from (53.8±13.4)% to (61.6±14.6)% to the aerosol water content of PM2.5 under pollution conditions. Thus, NH4NO3 was a key air pollutant to be targeted for further improving the visibility and air quality in Zhenjiang in the future. However, the reduction in the precursors of NH4NO3 would lead to an increase in aerosol acidity, particularly in the spring and winter seasons. Our results help us understand the evolution of air quality and the related impacts and also provide important information on air quality improvement in Zhenjiang in the future.

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C-terminal AAs 2-5 to mitogen-activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3-MKK3-p38 module assembly.

In this study, we explored the precise mechanisms underlying the receptor for advanced glycation end products (RAGE)-mediated neuronal loss and behavioral dysfunction induced by hyperglycemia. We used immunoprecipitation (IP) and GST pull-down assays to assess the interaction between RAGE and mitogen-activated protein kinase kinase 3 (MKK3). Then, we investigated the effect of specific mutation of RAGE on plasticity at hippocampal synapses and behavioral deficits in db/db mice through electrophysiological recordings, morphological assays, and behavioral tests. We discovered that RAGE binds MKK3 and that this binding is required for assembly of the MEKK3-MKK3-p38 signaling module. Mechanistically, we found that activation of p38 mitogen-activated protein kinase (MAPK)/NF-κB signaling depends on mediation of the RAGE-MKK3 interaction by C-terminal RAGE (ctRAGE) amino acids (AAs) 2-5. We found that ctRAGE R2A-K3A-R4A-Q5A mutation suppressed neuronal damage, improved synaptic plasticity, and alleviated behavioral deficits in diabetic mice by disrupting the RAGE-MKK3 conjugation. High glucose induces direct binding of RAGE and MKK3 via ctRAGE AAs 2-5, which leads to assembly of the MEKK3-MKK3-p38 signaling module and subsequent activation of the p38MAPK/NF-κB pathway, and ultimately results in diabetic encephalopathy (DE).

3D printed collagen/silk fibroin scaffolds carrying the secretome of human umbilical mesenchymal stem cells ameliorated neurological dysfunction after spinal cord injury in rats.

Although implantation of biomaterials carrying mesenchymal stem cells (MSCs) is considered as a promising strategy for ameliorating neural function after spinal cord injury (SCI), there are still some challenges including poor cell survival rate, tumorigenicity and ethics concerns. The performance of the secretome derived from MSCs was more stable, and its clinical transformation was more operable. Cytokine antibody array demonstrated that the secretome of MSCs contained 79 proteins among the 174 proteins analyzed. Three-dimensional (3D) printed collagen/silk fibroin scaffolds carrying MSCs secretome improved hindlimb locomotor function according to the Basso-Beattie-Bresnahan scores, the inclined-grid climbing test and electrophysiological analysis. Parallel with locomotor function recovery, 3D printed collagen/silk fibroin scaffolds carrying MSCs secretome could further facilitate nerve fiber regeneration, enhance remyelination and accelerate the establishment of synaptic connections at the injury site compared to 3D printed collagen/silk fibroin scaffolds alone group according to magnetic resonance imaging, diffusion tensor imaging, hematoxylin and eosin staining, Bielschowsky's silver staining, immunofluorescence staining and transmission electron microscopy. These results indicated the implantation of 3D printed collagen/silk fibroin scaffolds carrying MSCs secretome might be a potential treatment for SCI.

Decrease of tight junction integrity in the ipsilateral thalamus during the acute stage after focal infarction and ablation of the cerebral cortex in rats.

1. Whether damage to the blood-brain barrier (BBB) occurs in remote areas after a focal cortical lesion remains unknown. The present study investigated tight junction-related proteins and tight junction microstructure in the ipsilateral thalamus during the acute stage after middle cerebral artery occlusion (MCAO) and cortical aspiration lesion (CAL) in rats. 2. Thirty-six hypertensive and normotensive rats were subjected to MCAO or CAL; another 18 rats in each group were submitted to sham operation. Zonula Occluden (ZO)-1, occludin and albumin were detected by western blotting 12 and 24 h after surgery. Tight junction microstructure was evaluated using electron microscopy, whereas albumin location in the ipsilateral thalamus was determined using double immunostaining for albumin and occludin or albumin and neuronal nuclei (NeuN) 24 h after surgery. 3. Twenty-four hours after MCAO or CAL, occludin expression was reduced to 78.4% and 81.3%, respectively, compared with control. A reduction in ZO-1 expression in the ipsilateral thalamus (to 79%) was seen only after CAL (P < 0.05). Membrane contact at the tight junction was discontinuous in the ipsilateral thalamus in both MCAO and CAL rats. Albumin levels were 23.2% and 82.5% higher in the ipsilateral thalamus after MCAO and CAL, respectively (P < 0.05). The percentage of the albumin-positive area that coincided with the occludin-positive area in the MCAO and CAL groups was 76.8% and 64.6%, respectively, indicating that albumin was mainly localized around the microvessels. 4. The results of the present study suggest that tight junction integrity decreases during the acute stage in the ipsilateral thalamus after MCAO and CAL in rats.

Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis.

Purpose: Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of anti-diabetic drugs on fracture risk in type 2 diabetes mellitus (T2DM) patients. Methods: Embase, Medline, ClinicalTrials.gov, and Cochrane CENTRAL were searched for relevant trials. All data analyses were performed with STATA (12.0) and R language (3.6.0). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining data for the fracture effects of anti-diabetic drugs, including sodium-glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, meglitinides, α-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, and sulfonylureas. Results: One hundred seventeen eligible randomized controlled trials (RCTs) with 221,364 participants were included in this study. Compared with placebo, trelagliptin (RR 3.51; 1.58-13.70) increased the risk of fracture, whereas albiglutide (RR 0.29; 0.04-0.93) and voglibose (RR 0.03; 0-0.11) decreased the risk of fracture. Other medications were comparable in terms of their effects on fracture risk, and no statistical significance was observed. In terms of fractures, voglibose (0.01%) may be the safest option, and trelagliptin (13.64%) may be the worst. Sensitivity analysis results were consistent with those of the main analysis. No statistically significant differences were observed in the regression coefficients of age (1.03; 0.32-2.1), follow-up duration (0.79; 0.27-1.64), and sex distribution (0.63; 0.15-1.56). Conclusions: We found varied results on the association between the use of anti-diabetic drugs and fracture risk. Specifically, trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefit with statistical difference. Other drugs were comparable in terms of their effects on fracture risk. Some drugs (omarigliptin, sitagliptin, vildagliptin, saxagliptin, empagliflozin, ertugliflozin, rosiglitazone, pioglitazone, and nateglinide) may increase the risk of fracture, while others (such as dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide, linagliptin, alogliptin, canagliflozin, dapagliflozin, glipizide, gliclazide, glibenclamide, glimepiride, metformin, and insulin) may show benefits. The risk of fracture was independent of age, sex distribution, and the duration of exposure to anti-diabetic drugs. When developing individualized treatment strategies, the clinical efficacy of anti-diabetic drugs must be weighed against their benefits and risks brought about by individual differences of patients. Systematic Review Registration: This Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).

Integrated printed BDNF/collagen/chitosan scaffolds with low temperature extrusion 3D printer accelerated neural regeneration after spinal cord injury.

Recent studies have shown that 3D printed scaffolds integrated with growth factors can guide the growth of neurites and promote axon regeneration at the injury site. However, heat, organic solvents or cross-linking agents used in conventional 3D printing reduce the biological activity of growth factors. Low temperature 3D printing can incorporate growth factors into the scaffold and maintain their biological activity. In this study, we developed a collagen/chitosan scaffold integrated with brain-derived neurotrophic factor (3D-CC-BDNF) by low temperature extrusion 3D printing as a new type of artificial controlled release system, which could prolong the release of BDNF for the treatment of spinal cord injury (SCI). Eight weeks after the implantation of scaffolds in the transected lesion of T10 of the spinal cord, 3D-CC-BDNF significantly ameliorate locomotor function of the rats. Consistent with the recovery of locomotor function, 3D-CC-BDNF treatment could fill the gap, facilitate nerve fiber regeneration, accelerate the establishment of synaptic connections and enhance remyelination at the injury site.

Erratum to: Integrated printed BDNF/collagen/chitosan scaffolds with low temperature extrusion 3D printer accelerated neural regeneration after spinal cord injury.

[This corrects the article DOI: 10.1093/rb/rbab047.].

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial.

OBJECTIVE: To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy. METHODS: A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days. RESULTS: The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran-Mantel-Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999). CONCLUSION: The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org . Unique identifier: ChiCTR-IPR-16008642.

Memantine ameliorates tau protein deposition and secondary damage in the ipsilateral thalamus and sensory decline following focal cortical infarction in rats.

Previous studies have reported that memantine presents evidence of therapeutic benefits in several animal models of ischemic stroke and neurodegenerative diseases. However, the effect of memantine on secondary damage in the ipsilateral thalamus after focal cortical infarction remains undefined. Present study investigated whether memantine has a protective effect on secondary damage in the ipsilateral thalamus after focal cerebral infarction in rats. At 24 h after distal middle cerebral artery occlusion (MCAO), rats in the memantine and vehicle groups were intraperitoneal injected with memantine and isopycnic vehicle, respectively, was once daily administered for consecutive 7 days. Infarct size was evaluated through Nissl staining and sensory decline determined using adhesive removal test. Secondary thalamic damage was assessed using Nissl staining and immunofluorescence 8 days after MCAO. Immunoboltting was used to identify tau and apoptosis-associated proteins in the ipsilateral thalamus after MCAO. Results revealed that memantine ameliorated sensory decline compared to the vehicle controls. Subsequently, tau phosphorylated at threonine 231 (p-tau-231), glycogen synthase kinase3ßpY216 (GSK3ßpY216) and protein phosphatase 2A (PP2ApY307) were reduced by memantine, causing greater reduction in neuronal loss and inhibition of reactive astrogliosis in the ipsilateral ventroposterior thalamic nucleus (VPN) compared with the vehicle groups. In addition, increase in secondary damage-induced TUNEL-positive cells was blunted by memantine, as demonstrated by the significant reduction in expression of apoptosis-associated proteins. Our results suggest that memantine has a neuro-protective effect on secondary damage in the ipsilateral thalamus following MCAO by inhibiting the activity of GSK3ßpY216/PP2ApY307 and down regulating the levels of p-tau-231 protein.

Microplastics negatively impact embryogenesis and modulate the immune response of the marine medaka Oryzias melastigma.

Microplastic (MP) pollution is an emerging contaminant in aquatic environments worldwide. Nonetheless, the developmental toxicity of MPs in the early life stages of fish and the mechanisms involved are not yet fully understood. The present study investigated the effects of different concentrations of polystyrene (PS) MPs on the early development of the marine model fish the medaka Oryzias melastigma. Our results showed that waterborne exposure to PS MPs significantly delayed the hatching time, altered the heartbeat and decreased the hatching rate of embryos. Furthermore, the genes involved in cardiac development, encoding for embryo-hatching enzymes, as well as inflammatory responses were significantly upregulated. The transcriptome results showed that mainly the pathways involved in metabolism, immune response, genetic information processing and diseases were significantly enriched. These results demonstrate that PS MPs negatively impact embryogenesis and the immune response of O. melastigma.

[Efficacy, Prognosis and Safety of Decitabine Combined with Low-Dose Cytarabine in the Treatment of Elderly Patients with Relapsed/Refractory Acute Myeloid Leukemia].

OBJECTIVE: To investigate the efficacy, prognosis and safety of decitabine combined with low-dose CAG regimen in the treatment of elderly patients with acute myeloid leukemia （AML）. METHODS: The clinical data of 40 elderly patients with relapsed/refractory AML （69-85 years old） admitted to our hospital from January 2014 to August 2016 were analyzed retrospectively. 40 patients were divided into combination therapy group and CAG group according to different treatment methods. 20 patients of the combination therepy group were treated with decitabine combined with low-dose CAG （decitabine, 15 mg/m2, d 1; aclarithromycin, 10 mg/m2, d 3-6; Cytidine, 10 mg/m2, d 1-14; recombinant human granulocyte macrophage colony-stimulating factor （G-CSF） for injection, 200 µg/（m2·d）, d 1-14）. 20 patients of CAG group were treated by the standard CAG protocol （acralmycin 20 mg/m2, d 1-4; cytarabine for injection, 15 mg/m2, d 1-14; G-CSF 400 µg/（m2·d）, d 1-14）. One course of treatment lasted for 2 weeks, after 2 courses of continuous medication, the complete remission rate （CR）, overall remission rate （ORR）, overall survival （OS）, 1-year survival rate, hemoglobin, white blood cells, platelets improvement, and incidence of adverse reactions were compared. RESULTS: In combination therapy group the CR was 55.00% （11/20）, OR was 85.00% （17/20）, but in the CAG group CR was 30.00% （6/20）, and OR was 50.00% （10/20）. Till to February 2018, out of 40 patients 17 survived, 20 died, and 3 failed to be followed-up. The median follow-up time was 12 （2 to 35） months; the median survival time in the comtination therapy group was 13 （2-35） months, and the 1-year OS rate was 70.00%, and the median survival time of the CAG group was 10 （2-31） months, and the 1-year OS rate was 50.00%, without staistical significance between the 2 groups （P>0.05）. After treatment, the WBC and Plt counts in the combination therapy group were higher than those in the CAG group, but the Hb level was lower than that in the CAG group with statistically significant difference （P<0.05）. In the combination therapy group, the incidence of lung infection, nausea and vomiting was higher than that of the CAG group （65.00% vs 25.00%, 50.00% vs 20.00%）, with statistically significant difference （P<0.05）. CONCLUSION: Decitabine combined with low-dose CAG regimen is effective for the treatment of relapsed/refractory AML in the elderly. Compared with the standard CAG regimen, the long-term efficacy of this regimen is not different significantly, but its adverse reactions are increase, thus the preventive treatment should be given in time.