Liver Tissue-related Metabolic Mechanism of Different Infusion Volumes for Hemorrhagic Shock.

OBJECTIVES: To investigate the curative effects of various infusion volumes on liver-related metabolic mechanism in the treatment of hemorrhagic shock. METHODS: A severe hemorrhagic shock rabbit model was established in 30 rabbits. The rabbits were randomly divided into three groups： non-infusion group （A）, conventional infusion group （B）, and excessive infusion group （C） （n=10 in each group）. Taking group B as the control, groups A and C were observed for the damage of non-infusion and excessive infusion, respectively. The outcomes in the three groups and their relations with liver tissue metabolism changes were analyzed with gas chromatograph-mass spectrometer （GC-MS）. RESULTS: The mortality in groups A, B, and C group were 80%, 0%, and 70%, respectively. The liver tissue metabolic profile in group B showed statistically significant difference compared with that in groups A and B. In group C, the levels of 21 metabolites were lower than those in group B, and the levels of 8 metabolites were lower than those in group A. The relative contents of various metabolites were correlated with infusion volumes, and the succinic acid content was associated with death events （P<0.05）. CONCLUSIONS: The conventional infusion has significant curative effect on hemorrhagic shock. The metabolites of liver tissues with excessive infusion are generally decompensated and have longer survival time than those in non-infusion group, which may caused by the excessive infusion-induced blood volume increase after hemorrhagic shock. Tissue fluid dilution is an important cause of death.

Identifying the molecular targets of Salvia miltiorrhiza (SM) in ox-LDL induced macrophage-derived foam cells based on the integration of metabolomics and network pharmacology.

The identification of network targets is one of the core issues used to reveal the molecular mechanism of traditional Chinese medicine (TCM) and is also the grand challenge of modernization of TCM. In this study, a protein-protein interaction (PPI) network was constructed based on the integration of network pharmacology and metabolomics, which was used as an effective approach to elucidate the relationship between disease pathway proteins and the targets of active small-molecule compounds. The intermolecular transfer process of the drug effect of active compounds in Salvia miltiorrhiza (SM) was revealed and visualized using the PPI network. Our study indicates that PTGS2 was the most important disease protein regulated by the active compounds in SM. Furthermore, the drug targets that can be linked to PTGS2 were regarded as direct targets and the direct targets of the active compounds were identified, respectively. Western blot and co-immuno precipitation (Co-IP) were used to verify the results of the network analysis and reveal the intermolecular transfer process of the effect of Tan IIA. Biological validation revealed that Tan IIA-EDN1-PTGS2-anandamide was a major intervention way of Tan IIA on early atherosclerosis (AS). This work provides a new perspective for the discovery of drug targets and the specific approaches regulated by the active compounds in SM on disease pathway proteins, which is beneficial for understanding the mechanism of action of bioactive compounds and expanding their clinical applications.

Down-regulation of MAO-B activity and imidazoline receptors in rat brain following chronic treatment of morphine.

AIM: To study the regulation of monoamine oxidase-B (MAO-B) activity and imidazoline receptors (I-R) during long term treatment of morphine. METHODS: MAO-B activity was detected by high performance liquid chromatography; I-R was detected by [3H]idazoxan binding test. RESULTS: Idazoxan and morphine inhibited whole brain homogenate MAO-B activity in a dose-dependent manner, while agmatine, an endogenous imidazoline ligand, didn't affect the activity of MAO-B, and it had no effect on the inhibition of MAO-B activity by idazoxan or morphine. MAO-B activity of rats decreased markedly in all five brain regions detected (cerebral cortex, hippocampus, thalamus, cerebellum, and striatum) after chronic administration of morphine for 16 d (P < 0.01). Acute challenge with naloxone or idazoxan did not influence MAO-B activity in morphine chronically treated rats. Although agmatine itself did not affect MAO-B activity, co-administration of agmatine with morphine could reverse the effect of morphine on MAO-B activity. Chronic administration of morphine significantly decreased the density of [3H]idazoxan binding sites and increased the binding affinity in cerebral cortex and cerebellum (P < 0.05 or P < 0.01). CONCLUSION: MAO-B activity was relevant to the abstinent syndrome of morphine dependent rats, but not related to the effect of agmatine on morphine analgesia; influence of agmatine on the pharmacological effects of morphine was based on its activation of imidazoline receptors.

Influence of idazoxan on analgesia, tolerance, and physical dependence of morphine in mice and rats in vivo.

AIM: To study the influence of idazoxan (Ida), an antagonist of imidazoline receptors (I-R), on analgesia, tolerance, and physical dependence of morphine. METHODS: The effects of Ida on pain threshold and morphine analgesia were observed in mouse acetic acid writhing test and 55 degrees C hot plate test. The effect of Ida on morphine tolerance and physical dependence were observed in mouse tolerant model and in mice and rat models. RESULTS: Ida (3-9 mg/kg) significantly decreased the pain threshold by 120% in acetic acid writhing test and by 39% in 55 degrees C hot plate test of mice, respectively. It inhibited the analgesic effect of morphine in a dose-dependent manner. Ida promoted the development of tolerance to morphine in mice and induced the abstinence syndrome in morphine-dependent mice and rats similar to naloxone. CONCLUSION: I-R and its endogenous ligand agmatine might participate in the pain threshold and influence morphine analgesia as well as negatively regulate tolerance to and physical dependence on morphine.