- MPP(+) inhibits mGluR1/5-mediated long-term depression in mouse hippocampus by calpain activation. [Journal Article]
- EJEur J Pharmacol 2016 Nov 28
- Neurotoxins are harmful to nervous system and cause either neuronal cell death or impairment of synaptic activity, which contributes to Parkinson's disease or other neuronal disorders. Hippocampal sy...
Neurotoxins are harmful to nervous system and cause either neuronal cell death or impairment of synaptic activity, which contributes to Parkinson's disease or other neuronal disorders. Hippocampal synaptic plasticity was proposed as a cellular model for memory processing. In this study, we reported a novel effect of neurotoxin, 1-methyl-4-phenylpyridinium (MPP(+)), on metabotropic glutamate receptor 1/5 agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced hippocampal synaptic plasticity, and MPP(+) incubation blocked DHPG-induced hippocampal long-term depression (LTD) in Schaffer collateral-CA1 synapses. Our further findings indicated that, this blockage was reversed by pre-application of calpain inhibitor III, but not by cathepsin inhibitors. Biochemical analysis showed that MPP(+) treatment stimulated calpain activation, displayed by spectrin breakdown. Interestingly, the level and activity of protein tyrosine phosphatase 1B (PTP1B) were reduced after MPP(+) incubation and the decrease of PTP1B was prohibited by calpain inhibitor III. In addition, PTP1B inhibitor also blocked DHPG-induced LTD, mimicking the effect of MPP(+). In summary, our data implicated that MPP(+) activated calpain-dependent PTP1B degradation, which subsequently impaired hippocampal LTD. This novel effect of MPP(+) might partially explain the impairment of memory processing in the pathogenesis of PD.
- Tanshinone IIA induced cell death via miR30b-p53-PTPN11/SHP2 signaling pathway in human hepatocellular carcinoma cells. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25
- Tanshinone IIA, a multi-pharmaceutical compound from traditional Chinese herb, has been reported to have anti-hepatocarcinomic (HCC) properties through cell death induction. Apart from the typical p5...
Tanshinone IIA, a multi-pharmaceutical compound from traditional Chinese herb, has been reported to have anti-hepatocarcinomic (HCC) properties through cell death induction. Apart from the typical p53-dependent pathway, mechanisms of the anti-carcinogenic role of Tanshinone remain scarce. In an effort to explore the mechanism behind Tanshinone IIA, we detected the upstream of the p53 and the potential novel pathway. Tanshinone IIA dose-dependently initiated HepG2 cell apoptosis and cell cycle arrest at the G1 checkpoint. In the miR30 family, only the transcription of miR30b was downregulated by Tanshinone IIA, which subsequently upregulated both the genomic and protein levels of p53. Further, we screened that PTPN11 and Tp53 are the two critical genomes involved in the pharmacology of Tanshinone IIA. Building upon LASAGNA-search and kinetics binding assay, p53 was found to be a potential transcription factor for PTPN11. Concomitant with the expression of p53, Tanshinone IIA stimulated both PTPN11 and its encoded protein SHP2. Inhibition miR30b attenuated the Tanshinone IIA-induced cytotoxicity, level of p53 and PTPN11 in HepG2 cells. Finally, the apoptotic molecules such as Bax/Bcl2, cleavage caspase 3 and the cell cycle regulation factors including p21, cyclin D1, and CDK6 were changed by Tanshinone IIA. Several cytotoxic endpoints induced by Tanshinone IIA were also checked in Hep3B cells. This study confirmed that Tanshinone IIA may induce hepatoma cell death through the miR30b-p53- PTPN11/SHP2 pathway. With regard to the complicated tumorigenesis of HCC and the multi-targets of Tanshinone IIA, our results propose developing Tanshinone IIA for clinic therapy and the interference of HCC.
- Salicylic acid retention impairs aspirin reactivity in type 2 diabetes. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25
- High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain el...
High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B2/ 6-keto-prostaglandin（PG）F1α ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB2/6-keto-PGF1α ratio in female T2DM mice, while pretreatment with NaHCO3 caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB2/6-keto-PGF1α ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR.
- Enhanced legumain-recognition and NIR controlled released of cisplatin-indocyanine nanosphere against gastric carcinoma. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25; 794:184-192
- Cisplatin-therapy has faced limitations in the gastric cancer therapy. To settle the bottleneck, enhanced specificity and controlled-release property are choosen. We synthesize cisplatin and indocyan...
Cisplatin-therapy has faced limitations in the gastric cancer therapy. To settle the bottleneck, enhanced specificity and controlled-release property are choosen. We synthesize cisplatin and indocyanine green (ICG) loaded PLGA-(DSPE-PEG2000) nanoparticles, which is abbreviated as CINPs. And we conjugate the Gly-Cys-Gly-Ala-Ala-Asn-Leu (GCGAANL) heptapeptide upon the surface of CINPs, the product is abbreviated as ACINPs. ACINPs with nearly 110nm exhibit good monodispersity and size stability. The EE (efficiency of encapsulation) and LE (loading of encapsulation) of cisplatin loaded into ACINPs are optimized as 29.81% and 3.88%. MGC803 cells overexpressing the legumain and MKN28 cells, which negatively express the legumain as well as the normal stomach cells, are selected. In vitro studies have suggested ACINPs, compared with CINPs, could be recognized by MGC803 cells and efficiently killed the cancer cells, while be harmless to MKN28 cells, which indicates the specificity and safety of ACINPs. Under irradiation of 808nm NIR irradiation, ICG loaded in ACINPs could rapidly transform the light to heat up to 60℃. Nanoparticles compared with non-irraditaion group could be quickly disrupted and release the cisplatin which could enhance the controlled-release ability. Hence, the ACINPs exhibit great potential in avoiding the side effects and enhancing the therapy ability of cisplatin.
- Critical role of Toll-like receptors in pathophysiology of allergic asthma. [Journal Article]
- EJEur J Pharmacol 2016 Nov 26
- Allergic asthma is an airway disease, characterized by reversible bronchoconstriction, chronic inflammation of the airway, and thickness of smooth muscle in the respiratory tract. Asthma is orchestra...
Allergic asthma is an airway disease, characterized by reversible bronchoconstriction, chronic inflammation of the airway, and thickness of smooth muscle in the respiratory tract. Asthma is orchestrated by an excessive Th2-adaptive immune response, in which innate immunity plays a key role. Recently TLRs have received more and more attention as they are central to orchestrate the innate immune responses. TLRs are localized as integral membrane or intracellular glycoproteins with those on the cell surface sensing microbial antigens and the ones, localized in intracellular vesicles, sensing microbial nucleic acid species. Having recognized microbial antigens, TLRs conduct the immune response towards a pro- or anti-allergy response. As a double-edged sword, they could initiate either harmful or helpful responses by the immune system in case of allergic asthma. In the current review, we will describe the role of TLRs and their signaling pathways in allergic asthma.
- Na(+)/Ca(2+) exchanger 1 inhibition abolishes ischemic tolerance induced by ischemic preconditioning in different cardiac models. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25
- Ca(2+)-handling disturbances play an important role in the genesis of myocardial ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) is a powerful strategy to induce tolerance against s...
Ca(2+)-handling disturbances play an important role in the genesis of myocardial ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) is a powerful strategy to induce tolerance against subsequent ischemic episodes. IPC signaling pathways may be triggered by Ca(2+) ion. Since Na(+)/Ca(2+) exchanger 1 (NCX1) participates in modulating intracellular Ca(2+) homeostasis, here we further defined its role in I/R and investigated its potential involvement in IPC-induced cardioprotection. In isolated ventricular cardiomyocytes, perfused rat heart and H9c2 cardiomyoblasts, I/R produceda significant cellinjury, assessed by measuring extracellular lactate dehydrogenase (LDH) and, for the whole heart, also by estimating myocardialinfarct size area. Characterization of cell death revealed the involvement of apoptotic processes. Interestingly, I/R challenge induced NCX1 protein upregulation. In NCX1-transfected H9c2 cells, exchanger protein upregulation was accompanied by an increase in its reverse mode activity. The effects of I/R on extracellular LDH and infarct size area were drastically reduced by 1μM SN-6, a selective NCX1 inhibitor. Moreover, SN-6 also prevented I/R-induced increase of NCX1 reverse-mode activity and protein upregulation. These results suggested a deleterious role of NCX1 in I/R-induced cell damage. In both isolated cardiomyocytes and perfused heart, IPC followed by I/R afforded cardioprotection, reducing extracellular LDH release and limiting ischemic area extent. Interestingly, NCX1 blockade (1μM SN-6) completely abolished IPC protection against I/R, leading to exacerbation of cell injury, massive infarct size area and restoration of NCX1 protein expression. These findings suggest that NCX1 is deleterious in I/R, whereas it may be beneficial in promoting IPC-induced cardioprotection.
- Cyclic AMP (cAMP) confers drug resistance against DNA damaging agents via PKAIA in CML cells. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25; 794:201-208
- Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote o...
Cyclic adenosine monophosphate (cAMP) regulates many vital functions such as metabolism, proliferation, differentiation and death. Depending on cell types and stimulators, cAMP could either promote or attenuate cell death. cAMP signal can be transduced by protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). In CML cells, cAMP may suppress their proliferation and enhance their differentiation. However, the role of cAMP on DNA damaging agent toxicity and the mechanism involved has not been studied. In this study, we studied the effect of cAMP on the sensitivity of CML cells to DNA damaging agents. We observed that forskolin (FSK) and dibutyryl-cAMP (DBcAMP) decreased cisplatin and etoposide-induced cell death in K562 cells. Moreover, PKA activator prevented K562 cells from DNA damaging agent-induced cell death while EPAC activator had no effect. Furthermore, we found that the PKA subtype, PKAIA, was involved in cAMP-attenuated resistance in K562 cells. Taken together, our results suggest that increased cAMP level confers CML cells to acquire a novel mechanism against DNA damaging agent toxicity via PKAIA. Thus, PKAIA inhibitor may be helpful in overcoming the resistance to DNA damaging agents in CML cells.
- Protective effect of betulinic acid on early atherosclerosis in diabetic apolipoprotein-E gene knockout mice. [Journal Article]
- EJEur J Pharmacol 2016 Nov 25
- Atherosclerosis, a chronic and progressive disease, is a leading cause of endothelial dysfunction, diabetes mellitus, hypertension, and hypercholesterolemia. Betulinic acid (BA), a pentacyclic triter...
Atherosclerosis, a chronic and progressive disease, is a leading cause of endothelial dysfunction, diabetes mellitus, hypertension, and hypercholesterolemia. Betulinic acid (BA), a pentacyclic triterpene, has been reported to have a variety of biological effects, including anti-inflammatory and immunomodulatory properties. This study was designed to determine whether BA could prevent atherosclerosis in diabetic apolipoprotein-E gene knockout (ApoE KO) mice. The mice were treated with BA for 12 weeks to examine its beneficial effects on atherosclerosis in ApoE KO mice. Male ApoE KO mice and age-matched control group mice (C57BL/6Jms) were used as experimental systems and their systolic blood pressure, insulin resistance, and vascular inflammation were measured. BA-treated ApoE KO mice showed lowered systolic blood pressure. The metabolic parameter showed that BA decreased blood urea nitrogen, triglyceride, and total cholesterol levels. Blood glucose, insulin, glucose tolerance results, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were found to be better in BA-treated ApoE KO mice than untreated ApoE KO mice. Consistent with the change in lipid profiles, oil red O and H&E staining revealed that treatment with BA reduced atherosclerotic lesions such as roughened endothelial layers. BA ameliorated the reduction of endothelial nitric oxide synthase (eNOS) expression, leading to the inhibition of intracellular adhesion molecule 1 (ICAM-1) and endothelin 1 (ET-1) expression. These results suggest that BA may be useful in the treatment and prevention of early atherosclerosis via the attenuation of endothelial dysfunction in diabetic ApoE KO mice.
- The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant. [Journal Article]
- EJEur J Pharmacol 2016 Nov 24
- N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodyna...
N-arachidonoyl glycine (NAGLY), is the endogenous lipid that activates the G protein-couple receptor 18 (GPR18) with vasodilatory activity in resistance arteries. This study investigates its hemodynamic effects and mechanisms of vasorelaxation. Hemodynamic effects of NAGLY in rats were assessed using a Biopac system and its vascular responses were assessed using a wire myograph. NAGLY (1 mg/kg) decreased blood pressure by 69.4 ± 5.5% and reduced renal blood flow by 88 ± 12% and the effects were not sensitive to inhibition by O-1918 (3 mg/kg). In resistant vessels, NAGLY (1-30 µM) induced concentration- and endothelium-dependent vasorelaxation and the effect was inhibited by the nitric oxide synthase inhibitor, L-NAME (300 µM), a cGMP synthase inhibitor, ODQ (10 µM), the antagonists of "endothelial anandamide" receptor, rimonabant (3 µM) and O-1918 (10 µM) and the inhibitor of Na+/Ca2+ exchanger (NCX), KB-R7943 (10 µM). On the other hand, NAGLY-induced vasorelaxation was not affected by CID 16020046 (GPR55 antagonist), AM 251 (cannabinoid CB1 receptor antagonist), AM 630 (cannabinoid CB2 receptor antagonist), capsazepine (TRPV1 antagonist), indomethacin (cyclooxygenase inhibitor), TRAM34 (IKCa channel blocker), iberiotoxin (BKCa channel blocker) and GW9662 (PPARɤ antagonist). At low concentrations of carbachol, NAGLY potentiated carbachol-induced vasorelaxation. NAGLY is an endothelium-dependent vasodilator and hypotensive lipid. The vasorelaxation is predominantly via activation of nitric oxide-cGMP pathway and NCX and probably mediated by the "endothelial anandamide" receptor, while the hypotensive effect of NAGLY appears not to involve the anandamide receptor. NAGLY also potentiates carbachol-induced vasorelaxation, the mechanism of which might involve stimulation of NO release.
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- In vivo and vitro characterization of the effects of kisspeptin-13, endogenous ligands for GPR54, on mouse gastrointestinal motility. [Journal Article]
- EJEur J Pharmacol 2016 Nov 24
- Kisspeptin (KP), the endogenous ligand of GPR54, is a mammalian amidated neurohormone, which belongs to the RF-amide peptide family. However, in contrast with the related members of the RF-amide fami...
Kisspeptin (KP), the endogenous ligand of GPR54, is a mammalian amidated neurohormone, which belongs to the RF-amide peptide family. However, in contrast with the related members of the RF-amide family, little information is available regarding its role in the gastrointestinal motility. With regard to the recent data suggesting KP play an important role in food intake, and while gastrointestinal motility are closely related to it. Thus, in the present work, effects of central administration of KP-13, one of the endogenous active isoforms, on gastrointestinal motility were investigated. The results indicated that intracerebroventricular (i.c.v.) infused of KP-13 significantly facilitated gastrointestinal transit, bead expulsion and fecal pellet output, respectively, while has no effect on gastric emptying. The effects were significantly reversed by GPR54 antagonist 234, but not GnRH receptor antagonist Cetrorelix. However, i.p. injected of KP-13 or compound 5 (10mg/kg), a high metabolic stability kisspeptin analog, did not affect gastrointestinal transit, suggesting that KP-13 or compound 5 facilitated gastrointestinal transit through the activation of central GPR54. Then the gastrointestinal motility-enhancing effects were also presented after infusion of KP-13 into the hypothalamus. In vitro, KP-13 (10(-6)M) also modulated colonic contraction, but not in the stomach and small intestine. Similarly, KP-13 (10(-6)M)-induced contractions of circular and longitudinal colonic muscle were significantly attenuated by antagonist 234 (10(-6)M). In conclusion, all the results indicated that KP-13 promoted gastrointestinal motility through the activation of GPR54, which implicate that KP/GPR54 system might be a new target to treat gastrointestinal function disorder.