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1.
Chinese Pharmacological Bulletin ; (12): 317-323, 2024.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-1013634

ABSTRACT

Aim To investigate the effect of histamine H, receptor (HjR) on the immune responses in astrocytes induced by lipopolysaccharide (LPS) and the regulatory mechanism of its signaling pathway. Methods LPS was used to establish an in vitro astrocyte inflammation model. Rat primary astrocytes were divided into the control group, LPS group, LPS + Hj R agonist group (2-pyridylethlamine, Pyri), and HjR agonist group. Astrocytes were treated with Pyri 100 p,mol • L~ for 1 h, then stimulated with LPS at 100 p,g • L~ for 24 h. Cell viability was measured using the CCK-8 assay. The expression of GFAP and HjR was detected by immunofluorescence. Glial morphological changes were observed under a microscope. The levels of proinflammatory mediators (TNF-a and IL-6) were detected by ELISA. The protein expressions of p-Akt, Akt, p-NF-KB p65, and NF-KB p65 were detected by Western blot. Results Compared with the control group, more activated astrocytes with fewer cell processes and branches were observed in the LPS group. Besides, LPS enhanced the GFAP expression level, reduced the H,R expression level and stimulated the production of TNF-a and IL-6 from astrocytes. Pre treatment with Pyri for 1 h ameliorated the glial morphological changes stimulated by LPS, inhibited LPS-induced upregulation of GFAP level and the inflammatory factors secretion. In addition, LPS stimulated astrocytes showed a higher phosphorylation of Akt and NF-KB p65, which was also ameliorated by Pyri. Conclusions H, R agonist can inhibit LPS-induced astrocyte activation and inflammatory factor secretion, and the Akt/NF-KB signaling pathway may be an important pathway for the involvement of H,R in immune regulation.

2.
Cancer Chemother Pharmacol ; 84(1): 155-161, 2019 07.
Article in English | MEDLINE | ID: mdl-31087135

ABSTRACT

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of gemcitabine plus cisplatin concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma. METHOD: Patients with NPC were randomly assigned to the gemcitabine plus cisplatin (GP) group or fluorouracil plus cisplatin (PF) group. Primary end-point was disease-free survival (DFS); secondary endpoints: overall survival, distant metastasis-free survival (DMFS), locoregional relapse-free survival, and treatment-related adverse events. RESULTS: Seventy-six patients were prospectively enrolled and the median follow-up time was 41 months (9-61 months). Three-year DFS were similar between the GP and PF groups (73.7% vs. 60.5%, HR 0.66, 95% CI 0.30-1.44; P = 0.30). Distant metastasis was the most common failure form in PF compared with GP (P = 0.034). Three-year DMFS was significantly better in the GP group than PF group (89.5% vs. 71.1%, P = 0.045). Grade 3-4 gastrointestinal toxicities (vomiting and diarrhea) were significantly more common in the PF group; grade 3-4 neutropenia and thrombocytopenia were more common in the GP group. CONCLUSION: Gemcitabine plus cisplatin could be used as an alternative regimen in CCRT for nasopharyngeal carcinoma.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Neoplasms/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemoradiotherapy , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Young Adult , Gemcitabine
3.
J Physiol ; 566(Pt 2): 341-53, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-15878941

ABSTRACT

We previously showed that chronic exposure to interleukin (IL)-6 decreases contractile and sarcoplasmic reticular (SR) function assessed by postrest potentiation (PRP) via a nitric oxide (NO)-dependent mechanism in adult rat ventricular myocytes (ARVM). Cyclic GMP (cGMP) has been associated with NO-associated negative inotropic effects of IL-6 during acute exposure; however, its role in chronic cardiac effects of IL-6 remains unclear. The present study examined the roles of cGMP and peroxynitrite (ONOO-) in chronic IL-6-induced negative inotropy in ARVM. After ARVM were exposed to IL-6 for 2-24 h, intracellular cGMP contents were time dependently increased; this was mimicked by a NO donor and abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase (sGC), or Rp-8-Br-cGMP, an inhibitor of cGMP-dependent protein kinase G (PKG). Meanwhile, the IL-6-induced decrease in PRP at 2 h was blocked by ODQ or Rp-8-Br-cGMP. By contrast, ODQ or Rp-8-Br-cGMP only attenuated the inhibition of PRP induced by IL-6 after 24 h exposure. Furthermore, IL-6 time dependently increased superoxide anion production and ONOO- formation; the latter was abolished by 5,10,15,20-tetrakis-(4-sulphonatophenyl)-porphyrinato iron (III) (FeTPPS), an ONOO- decomposition catalyst. Interestingly, FeTPPS had no effect on the IL-6-elicited decrease in PRP at 2 h, but attenuated it after 24 h exposure. Moreover, inhibition of sGC/cGMP/PKG, but not ONOO- formation, abolished the IL-6-induced inhibition of kinetics of myocyte contraction during 24 h exposure. We conclude that while the sGC/cGMP/PKG pathway was the primary mechanism for chronic IL-6-induced negative inotropy at 2 h, both sGC/cGMP/PKG and ONOO-, at least in part, mediate the IL-6-induced inhibition of SR function after 24 h exposure.


Subject(s)
Cyclic GMP/physiology , Interleukin-6/pharmacology , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Peroxynitrous Acid/metabolism , Animals , Cell Separation , Cyclic GMP/metabolism , Depression, Chemical , Guanylate Cyclase/metabolism , Male , Rats , Rats, Sprague-Dawley , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/enzymology , Sarcoplasmic Reticulum/metabolism , Signal Transduction/drug effects , Stimulation, Chemical , Superoxides/metabolism
4.
J Physiol ; 566(Pt 2): 327-40, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-15845578

ABSTRACT

Interleukin (IL)-6 has been shown to decrease cardiac contractility via a nitric oxide synthase (NOS)-dependent pathway during acute exposure. We previously reported that IL-6 decreases contractility and increases inducible NOS (iNOS) in adult rat ventricular myocytes (ARVM) after 2 h exposure. The goal of this study was to investigate the cellular mechanism underlying this chronic IL-6-induced negative inotropy and the role of iNOS. Pretreatment for 2 h with 10 ng ml-1 IL-6 decreased the kinetics of cell shortening (CS) and contractile responsiveness to Ca2+o ([Ca2+]o from(0) to 2 mM) in ARVM. We first examined whether IL-6 reduced Ca2+ influx via L-type Ca2+ -channel current (ICa,L). Whole-cell ICa,L in ARVM was measured under conditions similar to those used for CS measurements, and it was found to be unaltered by IL-6. The sarcoplasmic reticular (SR) function was then assessed by examining postrest potentiation (PRP) and caffeine responsiveness of CS. Results showed that treatment with IL-6 for 2 h significantly decreased PRP, which was concomitant with a decrease in the phosphorylation of phospholamban. Following removal of IL-6, PRP and responsiveness to 10 mM caffeine were also reduced. Meanwhile, the IL-6-induced increase in nitric oxide (NO) production after 2 h (but not 1 h) was abolished by NG-monomethyl-l-arginine (l-NMMA) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; a selective inhibitor of iNOS). Furthermore, IL-6-elicited suppressions of PRP and responsiveness to caffeine and Ca2+o were abolished by L-NMMA and AMT. Thus, these results suggest that activation of iNOS mediates IL-6-induced inhibition of SR function in ARVM during chronic exposure.


Subject(s)
Interleukin-6/pharmacology , Myocytes, Cardiac/metabolism , Nitric Oxide Synthase/metabolism , Sarcoplasmic Reticulum/drug effects , Animals , Antibodies, Blocking/pharmacology , Blotting, Western , Caffeine/pharmacology , Calcium/pharmacology , Calcium-Binding Proteins/metabolism , Central Nervous System Stimulants/pharmacology , Down-Regulation/drug effects , Enzyme Activation/drug effects , In Vitro Techniques , Interleukin-6/antagonists & inhibitors , Male , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Nitric Oxide/biosynthesis , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type II , Phosphorylation , Rats , Rats, Sprague-Dawley , Sarcoplasmic Reticulum/enzymology
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