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Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinaseⅡ

WU DAN ; HU QING-XUN ; ZHU DE-QIU ; ZHU YI-ZHUN

Chinese Journal of Pharmacology and Toxicology.2017;31(10):1025-1026. doi:10.3867/j.issn.1000-3002.2017.10.114

OBJECTIVE To determine the functional role of hydrogen sulfide (H2S) in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca2 +/calmodulin-dependent protein kinaseⅡ (CaMKⅡ) using wild type and CSE knockout mouse models. METHODS Continuous subcutaneous injection isoprenaline (7.5 mg·kg-1·d-1), once a day for 4 weeks to induce heart failure in Male C57BL/6 (6-8 weeks old) mice and CSE-/- mice. 150 μmol·L-1 H2O2 was used to induce oxidative stress in H9c2 cells. Echocardiograph was used to detect cardiac parameters. H&E stain and Masson stain was to observation histopathological changes. Western blot was used to detect protein expression and activity. The siRNA was used to silence protein expression. HPLC was used to detect H2S level. Biotin assay was used to detect the level of S- sulfhydration protein. RESULTS Treatment with S-propyl-L-cysteine (SPRC) or sodium hydrosulfide (NaHS), modulators of blood H2S levels, attenuated the development of heart failure in animals, reduced lipid peroxidation, and preserved mitochondrial function. The inhibition CaMKⅡ phosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds. Interestingly, CaMKⅡ activity was found to be elevated in CSE-/- mice as compared to wild type animals and the phosphorylation status of CaMKⅡ appeared to relate to the severity of heart failure. Importantly, in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein however, in CSE-/- mice S-sulfhydration was abolished following SPRC treatment. CONCLUSION A novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKⅡ is presented. SPRC mediated S-sulfhydration of CaMKII was found to inhibit CaMKⅡ activity and to preserve cardiovascular homeostasis.

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Enhanced anti-cancer effect of gambogic acid by gold nanorod-based delivery

WAN HONG-YE ; CHEN JIAN-LI ; YU XIAO-YAN ; ZHU XIAO-MING

Chinese Journal of Pharmacology and Toxicology.2017;31(10):1010-1010. doi:10.3867/j.issn.1000-3002.2017.10.093

OBJECTIVE Nanotechnology provides a novel strategy for the delivery of anticancer drugs. In this study, titanium dioxide coated gold nanorod (GNR/TiO2) nanostructures were used as the drug carrier for gambogic acid in order to improve its anticancer effect. METHODS Biocompatibility and cellular uptake of GNR/TiO2 nanostructures were studied in human glioblastoma U-87 MG cells. Cell viability was evaluated by ATP assay and calcein AM staining. LysoSensor Green DND-189 and Hoechst 33342 were used to analyze the intracellular location of GNR/TiO2 nanostructures. The in vitro anti-cancer effect of gambogic acid loaded nanoparticles was compared with free drug. RESULTS The results showed that GNR/TiO2 nanostructures are biocompatible, and they are localized at the intracel?lular acidic compartments of endosomes and lysosomes. The intracellular drug content delivered via GNR/TiO2 nanostructures was 6 fold higher than the free form, thus dramatically enhancing the anticancer effect of gambogic acid. Furthermore, mild photothermal therapy also showed synergistic effect with the drug. CONCLUSION Our study suggested that GNR/TiO2 nanostructures can be considered as a promising anticancer drug carrier.

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Neurotransmitter systems in mouse airways

ABEL W PETER ; KIEFFER M CAMERON ; TU YA-PING

Chinese Journal of Pharmacology and Toxicology.2017;31(10):1015-1016. doi:10.3867/j.issn.1000-3002.2017.10.101

OBJECTIVE The objective of this study was to characterize the neurotransmitter systems that cause constriction of murine airways. METHODS Murine precision cut lung slices (PCLS) and trachea were prepared, placed into perfusion chambers equipped with platinum electrodes and stimulated transmurally (1.0 ms, 50 V, 0.1- 30 Hz). To measure PCLS constriction, changes in airway luminal area in response to electric field stimulation (EFS) were captured as video images quantified using Image J software. For trachea, changes in isometric tension were recorded using Grass force transducers. Frequency response curves were generated in the absence and the presence of the inhibitors magnesium, atropine and capsaicin and responses analyzed and compared using a student' s t- test (P<0.05). RESULTS EFS caused airway constriction in a frequency-dependent manner that was best fit by a biphasic curve. Neuron-specific stimulation was verified by Mg2+ blockade. Maximum airway constriction to 30 Hz EFS in PCLS was (51.8±3.0)% while tracheal constriction averaged (551±80)mg. Interestingly, in PCLS the muscarinic receptor antagonist atropine (10 μmol · L- 1) blocked (99.5 ± 7.2)% of EFS induced constriction at 1 Hz, but only blocked (23.3±3.8)% of EFS induced constriction at 30 Hz and eliminated the first phase but not the second phase of the biphasic EFS response. Treatment with capsaicin to deplete sensory neurotransmitters significantly increased EFS constriction supporting the presence of sensory neurotransmitter systems in airways. CONCLUSION These data are consistent with parasympathetic constriction of airways by acetylcholine at lower EFS frequencies while higher frequencies release sensory dilator neurotransmitters. These data provide evidence for multiple nerve types innervating airways which may provide novel targets for treatment of lung disease.

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Protective effect and its mechanism of codonopsis pilosula polysaccharide on memory consolidation disorder induced by cycloheximide in mice

LI WEI ; LIU WEI-DA ; DUAN LI-YAO ; LI JIANG-MAN ; ZHANG DAN-SHEN

Chinese Journal of Pharmacology and Toxicology.2017;31(10):992-992. doi:10.3867/j.issn.1000-3002.2017.10.070

OBJECTIVE To investigate the protective effect of Codonopsis Pilosula Polysaccharide (CPPS) on improving of the memory consolidation disorder induced by Cycloheximide and its possible mechanisms in mice. METHODS The mice was divided into five groups, as normal control group, cycloheximid model group, piracetam positive control group, CPPS 300 mg · kg- 1 group, and CPPS 150 mg·kg-1 group. The mice respectively were given saline, piracetam, and CPPS for 15 d. The memory consolidation disorder model in mice was established by ip. Cyclohexylamine, and orally administered CPPS(300 mg·kg-1 or 150 mg·kg-1) every day. Then experimental groups were subjected Morris Water Maze test. Western blotting analysis were used to analysis the expression of CaMKⅡ/CREB signaling pathways. RESULTS Morris water maze experiment showed that cyclohexylamine can cause memory consolidation disorder(P<0.01), and giving piracetam and CPPS (300 mg · kg- 1) can improve spatial memory impairment in mice(P<0.05, P<0.01). Western blotting experiment results show that compared with normal control group, CaMKⅡ and CREB contents of brain in model group mice had significant decreased(P<0.001); Compared with model group, CaMK Ⅱ and CREB contents of brain tissue in piracetam and CPPS groups increased significantly(P<0.05,P<0.01,P<0.001). CONCLUSION Cyclo?heximide can induce the memory consolidation disorder, and its effect in mice related to CaMK/CREB signaling pathways. CPPS can improved this memory disorder by influence CaMKⅡ/CREB signaling pathways.

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Wudang cherry ameliorates urate underexcretion and renal dysfunction in hyperuricemic mice

ZHOU JIE ; LI FEI

Chinese Journal of Pharmacology and Toxicology.2017;31(10):991-991. doi:10.3867/j.issn.1000-3002.2017.10.068

OBJECTIVE To investigate effects of Wudang cherry on urate excretion and renal function and examined whether renal organic ion transporters were involved in potassium oxonate-induced hyperuricemic mice. METHODS The model of hyperuricemic mice was induced by intraperitoneal injection of potassium oxonate (250 mg·kg- 1) for 7 d. Water extracts of Wudang cherry at 500 mg·kg- 1 were orally administered to hyperuricemic mice for 7 d, benzbromarone (20 mg·kg- 1) and allopurinol (20 mg · kg- 1) were given as positive controls, vehicle control group was given equal normal saline. Serum and urine levels of uric acid were measured in hyperuricemic and normal mice. Simultaneously, the mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), organic anion transporters (mOAT1 and mOAT3), ATP- binding cassette, subfamily G, membrane 2 (mABCG2) and organic cation/carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2) in the kidney were analyzed by Western blot, RT-PCR, immunohistochemical and immuno?fluorescent assay, respectively. RESULTS Wudang cherry significantly reduced serum uric acid levels and increased urine uric acid levels in hyperuricemic mice. And it effectively reversed potassium oxonate-induced alterations in renal mURAT1, mGLUT9, mOAT1, mOAT3 and mABCG2 mRNA and protein levels, resulting in the enhancement of renal urate excretion in mice. Moreover, Wudang Cherry increased renal mOCT1, mOCT2, mOCTN1 and mOCTN2 mRNA and protein levels, and improved renal impairment in this model. CONCLUSION Wudang cherry processes uricosuric and nephroprotective actions by regulating renal organic ion transporters in hyperuricemic mice.

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Effect of Shenfu injection on microcirculation effect index in early-and middle-stage of cardiogenic shock rats

JIANG LI ; YU LAN-BIN ; YAN XIAO-JUN ; CHEN YU ; YAO RONG ; XU GUO-LIANG

Chinese Journal of Pharmacology and Toxicology.2017;31(10):990-990. doi:10.3867/j.issn.1000-3002.2017.10.067

OBJECTIVE Shenfu injection(SFI) is an effective treatment of cardiogenic shock, the pathology of the central link was microcirculation disturbance. However, whether the microcirculation status of the early- and mid-stage of cardiogenic shock has any difference is unclear. This study aimed to observe the effect of SFI on the microcirculatory disturbance in mesentery for early- and mid-stage of cardiogenic shock rat. METHODS The early- and mid-stage model of cardiogenic shock was estab?lished by ligating the ending or root of left anterior descending coronary arteries(LADCA). The rats were randomly divided into 9 groups, ie control group, early- stage model group, mid- stage model group, 3 early medicated groups and 3 mid medicated groups(the dosage was 1, 3.33, 10 mL·kg-1 SFI for cardiogenic shock rats of early- and mid-stage, respectively). Parameters in mesenteric microcircu?lation, such as velocity of RBCs in venules, diameters of venules, the count of leukocyte adhesion and vascular permeability which calculated by FITC-dextran leakage were observed through an Geneandi-M2 inverted intravital microscope and high-speed video camera system. RESULTS The cardiogenic shock induced by ligating the LADCA resulted in a number of responses in microcirculation, including a significant increase in the counts of adhesive leukocytes, narrowing of the vascular diameter, decrease in the velocity of RBCs and dextran efflux. All of the above parameters for early- stage cardiogenic shock rats were attenuated by the treatment with SFI, especially the dosage of 10 mL·kg-1. While SFI had no apparent time- effect on the vascular diameter and vascular permeability in mesentery for mid-stage cardiogenic shock rats. CONCLUSION The microcirculation status of the early- and mid-stage of cardiogenic shock rats were quite different. The efficacy of early treatment with SFI was more obvious than the mid administration, which could provide experimental and theoretical basis for the patients with cardiogenic shock in an earlier time.

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Progress in preventive effects of cordyceps sinensis on ischemic brain

BAI XUE ; ZHAO YU-QING ; LI CHAO-FENG ; TANG YI-BO ; LIU ZHEN-QUAN

Chinese Journal of Pharmacology and Toxicology.2017;31(10):985-986. doi:10.3867/j.issn.1000-3002.2017.10.061

Cerebral ischemia is due to cerebral blood supply disorders caused by ischemia and hypoxia resulting in localized ischemic brain necrosis or brain softening of the disease, leading to irreversible brain damage and subsequent loss of neuronal function is a serious threat to human health One of several diseases. For patients with cerebral ischemia, often the lack of effective and extensive treatment. In addition, cerebral ischemia with morbidity, morbidity and mortality are characterized by high, so by the medical profession at home and abroad attention. As a traditional Chinese medicine, cordyceps sinensis (CS) is a complex of ergot fungus, which is parasitized on the larvae of the bat-moth family. The compound is composed of cordycepin, cordyceps polysaccharide, cordyceps sinensis peptides, ergosterol, mannitol, fatty acids and trace elements such as a variety of ingredients, with a wide range of pharmacological effects. Over the years, domestic and foreign scholars on the pharmacological effects of cordyceps sinensis were more comprehensive study of its prevention and treatment of cerebral ischemia is also deepening, found that cordyceps sinensis on cerebral ischemia with anti-inflammatory, reduce oxidative damage and neuronal ischemia damage, reduce neuronal apoptosis, improve memory cognition, reduce thrombosis, inhibit NO production, enhance mitochondrial energy supply, scavenging free radicals and other prevention and treatment. But no relevant review. In this paper, the domestic and foreign literatures on the prevention and treatment of cerebral ischemia by cordyceps sinensis were summarized, analyzed and summarized in order to provide useful information for the research and further development of cordyceps sinensis.

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Bile salt derivatives with novel skeleton from sea lamprey function as putative pheromone

LI KE ; SCOTT M ANNE ; FISSETTE D SKYE ; RIEDY J JOSEPH ; LI WEI-MING

Chinese Journal of Pharmacology and Toxicology.2017;31(10):985-985. doi:10.3867/j.issn.1000-3002.2017.10.060

OBJECTIVE The invasive sea lamprey (Petromyzon marinus) has devastated the ecosystem of the Laurentian Great Lakes. Application of pheromones to manipulate adult sea lamprey behavior is among the options considered for alternative sea lamprey control techniques. The male sea lamprey sex pheromone is hypothesized to be possess multiple functions through actions of multiple components, some of which have yet to be characterized. Our objective is to isolate and characterize the bioactive components from water conditioned with sexually mature male sea lamprey. METHODS The water conditioned with sexually mature male sea lamprey was extracted by solid phase extraction and concentrated in vacuo. The compounds were isolated by liquid chromatography and elucidated by spectrometry and spectroscopy. Their biological activities were evaluated by electro-olfactogram recordings and two-choice maze behavioral assays. RESULTS Five novel bile salts, petromyzene A and B and petromyzone A-C, have been characterized. Petromyzene A and B featured either a unique, rearranged side chain or a rare cis-11,12-diol on the steroidal B-ring. Petromyzone A-C represented three novel highly oxidized sulfated bile alcohols possessing different hydroxylation, oxidation, and double bond patterns, which exemplify the chemical diversity of bile salts. These five bile salts were potent odorants that stimulated the adult sea lamprey olfactory epithelium in a concentration dependent manner and showed detection thresholds between 10–13 mol·L-1 and 10–11 mol·L-1(paired t-test, P<0.05). Experi?ments in the two-choice maze showed that all isolated compounds induced behavioral responses in ovulated females. CONCLUSION The five novel compounds are likely additional components of phero?mones released by sexually mature male sea lamprey, and may provide useful behavioral manipulation tools to be implemented with the integrated management of the destructive and invasive sea lamprey in the Laurentian Great Lakes.

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Protective action of aspirin and its against endothelial Nlrp3 inflammasome activation in response to LPS stimuli

ZHOU XING ; ZHONG YI-LIN ; WU YAN-JIAO ; HUANG YI ; CHEN YANG

Chinese Journal of Pharmacology and Toxicology.2017;31(10):984-984. doi:10.3867/j.issn.1000-3002.2017.10.059

OBJECTIVE Recent studies have demonstrated that the Nlrp3 inflammasome serve as a central role in the pathogenesis of cardiovascular diseases and endothelial dysfunction occurs in association with several cardiovascular risk factors. Given the demonstrated anti-inflammatory effects of aspirin, the present study was designed to test whether aspirin diminish NLRP3 inflammasome activation and prevent endothelium injury and associated coronary artery damage during LPS. METHODS Mouse carotid arterial endothelial cells (CAECs) were cultured and treated with 0.1-3 mmol·L-1 of aspirin in response to LPS (2 μg·mL-1) stimuli. After 24 h, the Nlrp3 inflammasome complexes consist of varied proteins were analyzed by WB. NO and T-AOC in the supernatant was detected by ELISA. Intracellular reactive oxygen species (ROS) generation for 24 h was observed by DCF fluorescence. The mice were treated with aspirin (12.5 mg·kg-1 per day, 62.5 mg·kg-1 per day, 125 mg·kg-1 per day) and dexametha?sone (0.0182 mg · kg- 1 per day) for 7 d. The level of IL- 1β,IL- 18 protein was detected by ELISA. RESULTS Immunofluorescence results showed the colocalization of Nlrp3 with ASC or caspase 1 decrease in a concentration- dependent manner. Meanwhile, the expression of Nlrp3 and caspase 1 protein was decreased with the concentration of aspirin, but no changes the expression of ASC protein. Nlrp3 protein levels in CAECs were 0.33- 0.8- fold and cle- caspase 1 protein levels in CAECs were 0.48-1-fold compared to those in LPS stimulation when treated with 0.1-3 mmol·L-1 aspirin for 24 h (P<0.01). Aspirin significantly antagonized the effect of LPS on NO (1.22-1.91-fold that of LPS stimulation, P<0.01) and T-AOC expression (1.02-1.90-fold that of LPS stimulation, P<0.01). As the different concentration of aspirin treated, the generation of ROS was 0.51-1.10-fold that of LPS stimulation (P<0.01). In vivo data shown the level of IL-1β, IL-18 protein from serum are in concordance with the level of Nlrp3 inflammasome activation. CONCLUSION We conclude that aspirin has anti- inflammatory properties, protecting CAECs from LPS-induced injury by inhibition of NLRP3 inflammasome activation through ROS pathway.

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Effects of methionine enkephalin on immune enhancement by reducing myeloid derived suppressor cells and reprogramming liver metabolism in colon cancer mice

XIANG MING ; TUO YA-LI ; CHENG QI ; XU QIAN-QIAN ; CAO HUI ; FU RONG

Chinese Journal of Pharmacology and Toxicology.2017;31(10):973-974. doi:10.3867/j.issn.1000-3002.2017.10.045

OBJECTIVE To investigate enhanced immune function of methionine encephalin (MENK) and its anti-tumor mechanism in CT26 colon cancer mouse model. METHODS 3×106 CT26 cells were implanted subcutaneously in BALB/c mice. Four days after, MENK was peritoneally administrated at the concentration of 20 mg·kg-1 for 14 d. The percentage of MDSCs in bone marrow, spleen, blood, tumor and liver were detected by flow cytometry. Non- esterified fatty acid (NEFA), triglycerides (TG) and total cholesterol (T-CHO) in liver homogenate were tested by a NEFA test kit, a TG test kit and a T- CHO test kit respectively. qRT- PCR and Western blot were used to measure mRNA and protein levels of inflammation-, glycometabolsim- and lipometabolsim-associated indexes in liver. RESULTS MENK decreased percentages of MDSCs in bone marrow, spleen, blood and tumor in colon cancer mice. MENK-treated mice displayed elevated ratio of CD4+T and CD8+T cells in spleen as well as increased T and B lymphocytes proliferation. Meanwhile, MENK also ameliorated liver damage reflected by lower levels of GPT and GOT in serum and reduced risks of cancer- associated index including inflammation, high lipid and high glucose. Furthermore, MENK lowered down the levels of NEFA, TG and T- CHO in liver homogenate. MENK treatment decreased expression of p- STAT3, increased expression of p-AKT, IRS1 and Glut4 at protein level as well as reduced lipogenesis-associated genes and elevated glycolysis-associated genes in liver of tumor bearing mice. Also, abated expression of genes associated with MDSCs generation (M-CSF, GM-CSF, IL-6, IL-1β) and migration (S100A9, KC) was observed within shrunken subcutaneous tumor by MENK intervention. CONCLUSION MENK has the ability to strength immune function against colon cancer by reducing MDSCs and improving liver metabolism.

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