Pharmacodynamic substances in Salvia miltiorrhiza for prevention and treatment of hyperlipidemia and coronary heart disease based on lipidomics technology and network pharmacology analysis.

In this study, untargeted lipidomics based on UPLC-Q/TOF-MS, network pharmacology and atomic force microscopy were used to explore the common biomarkers of hyperlipidemia and coronary heart disease, the therapeutic mechanism of the main components of Salvia miltiorrhiza as well as the action mechanism of key lipids. Firstly, the serum samples of 30 healthy people, 30 patients with coronary heart disease and 30 patients with hyperlipidemia were analyzed by using lipidomics technology to obtain biomarkers which can be used to link hyperlipidemia and coronary heart disease and to find potential targets; then, the key components and core targets of Salvia miltiorrhiza intervention in hyperlipidemia and coronary heart disease were analyzed by network pharmacology, the results were verified by atomic force microscopy. It showed that SMS2 might be the key target. And through network pharmacology and atomic force microscope analysis, it can be inferred that salvianolic acid A can combine with SMS2 to play a therapeutic role.

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which mediate glucose and lipid homeostasis by regulating the expression of a large number of transcription factors. Sphingomyelin synthase (SMS) is a key enzyme in the synthesis of sphingomyelin (SM), and its expression and activity have been reported to be associated with atherosclerosis (AS). Although there have been many functional PPAR and SMS studies on atherosclerosis in recent years, few have investigated the correlation between the activation of PPARδ and the activity of SMS. In his study, macrophage-induced foam cells were utilized to model important pathological changes that occur in AS. The influence of PPARδ agonism by GW501516 on SMS and its product molecule SM were measured. Results indicated that the activation of PPARδ was correlated in a positive manner with the activity of SMS2, and the content of SM was dose dependently increased by GW501516. Together, this study represents the first to suggest that PPARδ activation may be a potential risk of AS through enhancing activity of SMS2.

Docetaxel and cisplatin in patients with advanced or recurrent gastric cancer: a multicenter phase I/II study.

BACKGROUND: Because docetaxel and cisplatin are both active against gastric cancer and have different mechanisms of action, this combination may provide additive or synergistic effects against gastric cancer. This article presents a phase I study designed to determine the recommended dose of cisplatin combined with a fixed dose of docetaxel, and a subsequent phase II study that evaluated the clinical efficacy and feasibility of this combination regimen. METHODS: Patients enrolled in the study had to have histologically confirmed advanced or recurrent gastric cancer with measurable disease and adequate organ function, and to be aged 20 to 75 years, with a performance status (PS) of 0 to 2. In the phase I study, docetaxel was administered at a fixed dose of 60 mg/m(2) on day 1. Cisplatin was also administered on day 1, at dose levels of 60, 70, and 80 mg/m(2). Where dose-limiting toxicities were not observed in more than 33.3% of patients, three patients were accrued for each dose level. RESULTS: Recommended doses for the phase II evaluation were determined to be 60 mg/m(2) of docetaxel and 80 mg/m(2) of cisplatin. Although grade 3 or more severe leukopenia and neutropenia were observed in 71.4% and 82.1% of the patients, respectively, nonhematological toxicities were not severe. The overall response rate at the recommended dose level was 25.0% (7/28 patients), and the rate was 40% (6/15) for patients with liver metastases. The median survival time was 9.7 months and the 1-year survival rate was 39.3%. CONCLUSION: Although this study failed to demonstrate a high response rate, this regimen was feasible and might be of value in further investigations in respect to the relatively high response rate in patients with liver metastasis and the favorable survival.

Biosynthesis and localization of phosphatidyl-scyllo-inositol in barley aleurone cells.

A novel isomer of phosphatidylinositol (PI), phosphatidyl-scyllo-inositol, was characterized in the aleurone cells of barley seeds. In this investigation, the subcellular localization of scyllo-PI and the relative rates of biosynthesis and accumulation of [32P]phosphoric acid ([32Pi])-labeled scyllo- and myo-phosphoinositides in the plasma membrane and intracellular membrane pools were investigated. About 25% of the [32Pi]-labeled phospholipids were present in plasma membrane and 75% in intracellular membranes. Incorporation of [32Pi] into scyllo-PI was greater than into myo-PI in both the plasma membranes and intracellular membranes at all time points investigated, thus suggesting a higher rate of biosynthesis; however, the data do not preclude reduced breakdown of labeled scyllo-PI as a contributing factor. In vitro studies were conducted to investigate the presence of cytidinediphosphate diacylglycerol (CDP-DG):scyllo-inositol 3-phosphatidyltransferase (scyllo-PI synthase) and to optimize enzymatic activity. The inclusion of nonionic detergents (Brij 58 and Triton X-100) effected significant enhancement in the biosynthesis of scyllo-PI, whereas anionic, cationic, and zwitterionic detergents had little or no effect. This is the first evidence for CDP-DG:scyllo-inositol 3-phosphatidyltransferase activity.

The dual role of mRNA half-lives in the expression of the yeast ALG7 gene.

The yeast ALG7 gene functions by initiating the synthesis of the dolichol-linked oligosaccharide precursor and plays an important role in the control of protein N-glycosylation. The levels of ALG7 multiple transcripts are modulated by the physiological status of the cell and environmental cues, and deregulation of their abundance is deleterious to several cellular functions. Since ALG7 mRNAs are unstable, we investigated the role of these transcripts' half-lives in determining their steady-state levels. Using a temperature-sensitive RNA polymerase II mutant, we demonstrate that increased stability was the primary determinant of higher ALG7 mRNA abundance in response to glucose limitation or treatment with tunicamycin. In contrast, at the G1/G0 transition point, changes in the decay rates were inversely related to ALG7 transcript accumulation: the decreased abundance of ALG7 mRNAs following exit from the mitotic cycle was associated with lengthening of the decay rates, while their increased accumulation after growth stimulation correlated with decreased stability. This suggests that, depending on the circumstance, mRNA half-lives can either directly determine the level of ALG7 transcript accumulation or oppose regulatory changes at other control levels.

Characterization of phosphatidylinositol synthase and evidence of a polyphosphoinositide cycle in Plasmodium-infected erythrocytes.

Plasmodium knowlesi-infected erythrocytes possess a membranous cytidine 5'-diphospho-1,2-diacyl-sn-glycerol: myoinositol 3-phosphatidyl transferase (PI synthase) (EC 2.7.8.11) activity of 10 +/- 1.7 nmol min-1 per 10(10) infected cells. The activity was successfully solubilized with 40 mM n-octyl-beta-D-glucopyranoside in the presence of bivalent metal ions which were absolutely required for activity. The optimal pH was 8 and the apparent Ks for Mn2+ was 0.1 mM. Mg2+ allowed two-fold higher PI synthase activity, with an optimum above 100 mM. Calcium alone was ineffective while at 2 mM it inhibited solubilized PI synthase activity in the presence of 100 mM Mg2+. Enzymatic activity was fully dependent on CDP-diacylglycerol and inositol with apparent Km of 0.16 +/- 0.1 mM and 1 +/- 0.5 mM respectively. Affinity chromatography clearly showed CDP-diacylglycerol-dependent interactions of PI synthase with CDP-diacylglycerol Sepharose. However, elution of enzymatic activity in an active form was unsuccessful while SDS-PAGE of the eluate showed one apparent band. Incubations of Plasmodium falciparum-infected erythrocytes with 32P or [3H]inositol revealed de novo biosynthesis of phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate which appeared to predominate in the second half of the asexual cellular cycle. Ionomycin, a calcium ionophore, induced Li(+)-sensitive production of radioactive inositol phosphates, with neo-synthesized inositol 1,4,5-trisphosphate accumulation being the highest.

Phosphatidylethanolamine: ceramide-ethanolaminephosphotransferase activity in synaptic plasma membrane vesicles. Influence of some cations and phospholipid environment on transferase activity. Further proof of its location.

1. Synaptic plasma membrane vesicles (SPMV) from rat brain synthesized ceramide-phosphoethanolamine (SpE), an analogue of sphingomyelin (SpC) from phosphatidylethanolamine (PE) and ceramide. 2. This reaction was catalyzed by PE: ceramide-phosphotransferase. 3. The presence of PC did not modify the SpE synthesis and PI and PS at twice PE concentration seemed to be activators; only PG was an inhibitor at all concentrations. 4. Some cations (Mg2+, Mn2+) were without effect, while Ca2+ increased transferase activity, so was interesting to study. 5. Transferase was compared with sialidase (external enzyme). 6. Kinetics other than those already performed by us were undertaken in order to confirm its location.