N-carbamylglutamate restores nitric oxide synthesis and attenuates high altitudeinduced pulmonary hypertension in Holstein heifers ascended to high altitude

Background: High-altitude pulmonary hypertension(HAPH) is a life-threating condition for animals in high altitude,and disturbance of endothelial nitric oxide(NO) synthesis contributes to its pathogenesis. N-carbamylglutamate(NCG), which enhances arginine synthesis, promotes endogenous synthesis of NO. In this study, we determined the effects of NCG on alleviating HAPH in Holstein heifers that ascended to Tibet(Lhasa, 3,658 m).Methods: Exp. 1, 2,000 Holstein heifers were transported from low elevation(1,027 m) to Lhasa. After being exposed to hypoxia for 1 yr, Holstein heifers were assigned to a healthy group(Control, n = 6) with mean pulmonary hypertension(mPAP) < 41 mmHg, and an HAPH affected group(HAPH, n = 6) with mPAP > 49 mmHg.Lung tissues were collected to evaluate histopathological changes and the expression of endothelial nitric oxide synthase(eNOS). Exp. 2, ten healthy heifers and 10 HAPH affected heifers were supplemented with NCG(20 g/d per heifer) for 4 wk. Physiological parameters were determined and blood samples were collected on d-1 and d 28 of the feeding trial.Results: Expression of e NOS in small pulmonary arteriole intima was higher in the healthy than HAPH group(P = 0.006), whereas HAPH group had significantly thicker media and adventitia than healthy group(all P < 0.05). The mRNA of eNOS and protein level of eNOS were higher in the lungs of heifers in the healthy group than in the HAPH group(both P < 0.001), whereas endothelin-1 protein levels were higher in HAPH group than in the healthy group(P = 0.025). NCG supplementation decreased mPAP and ammonia(both P = 0.001), whereas it increased the expression of eNOS, arginine, and plasma NO(all P < 0.05).Conclusions: The expression of eNOS was decreased in Holstein heifers with HAPH. NCG supplementation decreased m PAP through the restoration of eNOS and endogenous NO synthesis.

Effects of nanometer particles and water decoction of the Chinese medicine mixture of pinellia ternate and scorpion on P53 protein contents and apoptosis in the cerebral cortex and hippocampus of epileptic rats

BACKGROUND： Water decoction of the Chinese traditional medicine mixture of pinellia ternate and scorpion is an effective treatment for epilepsy. OBJECTIVE： To compare nanometer particles and effects of water decoction of Chinese traditional medicine mixture on P53 protein levels and apoptosis in the cerebral cortex and hippocampus of epileptic rats. DESIGN, TIME AND SETTING： This randomized, controlled molecular biology study was performed at the Key Laboratory of Child Neural Rehabilitation of Jiamusi University from October to December 2007. MATERIALS： Forty healthy male Wistar rats were used in this study. Convulsion rat models were established by intraperitoneal infusion of 35 mg/kg pentylenetetrazol, once a day, for 28 successive days. The Chinese traditional medicine mixture, comprising pinellia ternate, scorpion, centipede, bupleurum, peach pit and glycyrrhiza, was purchased from Beijing Tongrentang, China. The mixture was made into nanometer particles and water decoction. The apoptosis determination kit and P53 immunohistochemistry kit were bought from Boster, China. METHODS： Forty Wistar rats were randomly divided into four groups of ten rats per group, control, nanometer particle, water decoction and epileptic model groups. Rats in the nanometer particle and water decoction groups were respectively treated with 300 mg/kg Chinese herb nanometer particle suspension and water decoction by gavage, once a day, for 28 days. Rats in the epileptic model group were fed an equal volume of saline by gavage. Rats in the control group were only administered with the same volume of saline by gavage. MAIN OUTCOME MEASURES： Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling （TUNEL） and immunohistochemistry were used to respectively detect neuronal apoptosis and P53 protein expression in the rat brain cortex and hippocampus at 28 days following administration. RESULTS： The number of apoptotic neurons was lower in the nanometer particle and water decoction groups compared with the epileptic model group. The number of apoptotic cells and P53 protein expression in the rat cerebral cortex and hippocampus was greater in the epileptic model group compared with the control group （P 〈 0.05）, but lower in the nanometer particle and water decoction groups compared with the epileptic model group （P 〈 0.05）, and lower in the nanometer particle group compared with the water decoction group （P 〈 0.05）. CONCLUSION： Chinese traditional medicine mixture decreases neuronal apoptosis and P53 protein expression in epileptic rats. The effect of nanometer particles is significant compared with water decoction.

Changing Demand for Agro-products and Restructuring on Agro-production

Upon the analysis on the commodity natures and consumption features at different economic development periods, it is concluded that the commodity natures and consumption features of agricultural products display their evolvements by three phases. What＇s more, twice critical modification might arise, one is innovational, the other, transitional. In addition, the two key variables are discussed in the article that reflect economic index of agricultural products, the evolution rule of the weighted coefficient, production P and Quality Q. Sequentially, it is pointed out that the restructuring nature of agricultural production is to restructure the agricultural operation capability to adapt to the market, the target is to transform agricultural production to agricultural economy, and the principle abided by is benefit drive and market guide.

Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy

Tumor cells establish a robust self-defense system characterized by hypoxia,antioxidant overexpression,DNA damage repair,and so forth to resist radiotherapy.Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy.Therefore,we herein developed an engineering biomimetic nanosystem(M@HHPt)masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens(O_(2))and cisplatin prodrugs(Pt(Ⅳ))to target multiple tumor radioresistance hallmarks for enhanced radiotherapy.After administration,M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O_(2)and Pt(Ⅳ).O_(2)introduction induced hypoxia alleviation cooperated with Pt(Ⅳ)reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress.Moreover,the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments.Consequently,M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%.Overall,this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

“Three-in-one” strategy of trifluoromethyl regulated blood-brain barrier permeable fluorescent probe for peroxynitrite and antiepileptic evaluation of edaravone

Epilepsy,as a chronic neurological disease of the brain,is closely related to oxidative stress,and the peroxynitrite(ONOO-)significantly rise up in this event.Therefore,ONOO-is considered as a potential biomarker for early prediction of epilepsy.However,some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB).Meanwhile,“drug repurposing”is attracting a growing interest.Edaravone(EDA),as a first-line drug in the clinical treatment of cerebral ischemia,plays antioxidant roles in scavenging free radicals,promising potential antiepileptic activity.Thus,it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic brain.Hence,we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the fluorophore.Moreover,by the“three-in-one”strategy,the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore,shorten the response and increase lipophilicity.Consequently,DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of EDA.It opens up a new way for the design of BBB permeable fluorescent probes,and provides a convincing new method for the diagnosis and treatment of epilepsy.

一种“硫醇-色烯点击反应”的荧光探针的合成及应用

本文设计合成了一种基于硫醇-色烯点击反应的荧光探针CHMPC-Ac,用于半胱氨酸(Cys)、同型半胱氨酸(Hcy)和谷胱甘肽(GSH)的识别检测.这些生物硫醇因巯基的强亲核性而与探针的不饱和酮发生迈克尔加成反应,导致色烯分子开环等分子内级联反应,生成具有强荧光的香豆素衍生物,分别使荧光强度增强107、69和66倍.CHMPC-Ac具有灵敏度高(Cys:15 nM;Hcy:26 nM;GSH:22 nM)和响应快(Cys:20 s;Hcy:50 s;GSH:30 s)等优点,并已应用于HepG 2细胞和斑马鱼体内生物硫醇的识别检测.

Defect-related luminescent bur-like hydroxyapatite microspheres induced apoptosis of MC3T3-E1 cells by lysosomal and mitochondrial pathways

When orthopedic joints coated by hydroxyapatite(HA) were implanted in the human body, they release wear debris into the surrounding tissues. The generation and accumulation of wear particles will induce aseptic loosening. However, the potential bioeffect and mechanism of HA-coated orthopedic implants on bone cells are poorly understood. In this study, defect-related luminescent bur-like hydroxyapatite(BHA) microspheres with the average diameter of 7–9 μm which are comparable to that of the wear-debris particles from aseptically loosened HA implants or HA debris have been synthesized by hydrothermal synthesis and the MC3 T3-E1 cells were set as a cells model to study the potential bioeffect and mechanism of BHA microspheres. The studies demonstrated that BHA microspheres could be taken into MC3 T3-E1 cells via endocytosis involved in micropinocytosisand clathrin-mediated endocytosis process, and exert cytotoxicity effect. BHA microspheres could induce the cell apoptosis by intracellular production of reactive oxygen species(ROS), which led to not only an increase in the permeability of lysosome and release of cathepsins B, but also mitochondrial dysfunction and DNA damage. Our results provide novel evidence to elucidate their toxicity mechanisms and might be helpful for more reasonable applications of HA-based orthopaedic implants in the future.