Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway.

This study was designed to investigate the precancerous lesions of gastric carcinoma (PLGC)-reversing mechanisms of astragaloside IV (ASIV) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced PLGC rats. All rats were sacrificed after 10-week treatment. Gastric tissue was analyzed by using histopathology and electron microscope. To be fully evidenced, LDHA, p53, TIGAR, MCT1, MCT4, HIF-1α, CD147, and miRNA-34a were detected by Western blotting and Real-time Quantitative polymerase chain reaction (RT-qPCR). As histopathology and electron microscope showed, it can be clearly observed that the area of dysplasia was reduced in ASIV groups, indicating that MNNG-induced PLGC was markedly reversed by ASIV. Moreover, compared with model group, a significant decrease in gene expressions of LDHA, MCT1, MCT4, HIF-1α, CD147, and TIGAR was observed whereas miRNA-34a level was increased in ASIV groups. A significant up-regulation induced by MNNG in protein levels of LDHA, MCT1, MCT4, HIF-1α, and CD147 was attenuated in rats treated with ASIV. In contrast, the decreased expression of TIGAR was restored by ASIV. Interestingly, up-regulation of p53 expression induced by MNNG was further increased in ASIV groups. In brief, these results implied that abnormal glycolysis was relieved by ASIV via regulation of the expressions of LDHA, p53, TIGAR, MCT1, MCT4, HIF-1α, CD147, and miRNA-34a.

Selective reduction in the expression of UGTs and SULTs, a novel mechanism by which piperine enhances the bioavailability of curcumin in rat.

Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low bioavailability hinders the development of curcumin as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of curcumin, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which piperine enhances the bioavailability of curcumin, the dosage ratio (CUR: PIP) and pre-treatment with piperine were hypothesized as key factors for improving the bioavailability in this combination. Therefore, combining curcumin with piperine at various dose ratios (1:1 to 100:1) and pre-dosing with piperine (0.5-8 h prior to curcumin) were designed to investigate their contributions to the pharmacokinetic parameters of curcumin in rats and their effects on the expression of UGT and SULT isoforms. It was shown that the Cmax and AUC0-t of curcumin were slightly increased by 1.29 and 1.67 fold at a ratio of 20:1, while curcumin exposure was enhanced significantly in all the piperine pre-treated rats (0.5-8 h), peaking at 6 h (a 6.09-fold and 5.97-fold increase in Cmax and AUC0-t , p < 0.01), regardless of the unchanged t1/2 and Tmax . Also observed was a time-dependent inhibition of the hepatic expression of UGT1A6, 1A8, SULT1A1, 1A3, and the colonic expression of UGT1A6 that occurred within 6 h of piperine pre-treatment but was reversed at 8 h, which correlated with the changes in curcumin exposure. Similarly, the inhibitory effect of piperine on most of the UGTs and SULTs are time-dependent in Caco-2 and HepG2 cells. It is concluded that piperine pre-treatment time-dependently improves the bioavailability of curcumin through the reversible and selective inhibition of UGTs and SULTs. Copyright © 2016 John Wiley & Sons, Ltd.

Spatholobus suberectus inhibits lipogenesis and tumorigenesis in triple-negative breast cancer via activation of AMPK-ACC and K-Ras-ERK signaling pathway.

Background and aim: Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancer with a poor prognosis. Currently, there are no effective management strategies for TNBC. Earlier, our lab reported the percolation of Spatholobus suberectus for the treatment of breast cancer. Lipid metabolic reprogramming is a hallmark of cancer. However, the anti-TNBC efficiency of S. suberectus extract and its causal mechanism for preventing lipogenesis have not been fully recognized. Hence, the present study aimed to investigate the inhibitory role of S. suberectus extract on lipogenesis and tumorigenesis in TNBC in vitro and in vivo by activating AMPK-ACC and K-Ras-ERK signaling pathways using lipidomic and metabolomic techniques. Experimental procedure: Dried stems of S. suberectus extract inhibited lipogenesis and tumorigenesis and promoted fatty acid oxidation as demonstrated by the identification of the metabolites and fatty acid markers using proteomic and metabolomic analysis, qPCR, and Western blot. Results and conclusion: The results indicated that S. suberectus extract promotes fatty acid oxidation and suppresses lipogenic metabolites and biomarkers, thereby preventing tumorigenesis via the AMPK-ACC and K-Ras-ERK signaling pathways. On the basis of this preclinical evidence, we suggest that this study represents a milestone and complements Chinese medicine. Further studies remain underway in our laboratory to elucidate the active principles of S. suberectus extract. This study suggests that S. suberectus extract could be a promising therapy for TNBC.

Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen­activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin.

Type 2 diabetic mellitus (T2DM), which is characterized by insulin resistance (IR), hyperglycemia and hyperlipidemia, is a comprehensive dysfunction of metabolism. The insulin receptor (INSR)/phosphoinositide 3­kinase (PI3K)/AKT signaling pathway is well acknowledged as a predominant pathway associated with glucose uptake; however, the effect of streptozotocin (STZ) plus a high fat and sugar diet (HFSD) on the proteins associated with this pathway requires further elucidation. In order to explore this effect, a T2DM rat model was constructed to investigate T2DM pathogenesis and potential therapeutic advantages. Rats were randomly divided into control and model groups, including normal diet (ND) and HFSD types. ND types were administered intraperitoneal (IP) injections of STZ (35 mg/kg) or a combination of STZ and alloxan monohydrate (AON) (40 mg/kg), whereas HFSD types were composed of HFSD pre­given, post­given and simul­given groups, and were modeled as follows: IP or intramuscular (IM) injection of STZ (35 mg/kg) or a combination of STZ and AON (40 mg/kg). Results indicated that, compared with controls, blood glucose, insulin, homeostatic model assessment­insulin resistance and total triglyceride were significantly elevated in groups with HFSD and modeling agents (P<0.05 or P<0.01), whereas total cholesterol and low­density lipoprotein levels were significantly elevated in groups simultaneously administered HFSD and modeling agents (P<0.05 or P<0.01), in addition to downregulation of the expression of insulin signaling pathway proteins in the liver, including INSR, PI3K, AKT1, phosphatidylinositol-5-phosphate 4­kinase type­2α (PIP5Kα) and glucose transporter (GLUT)2, and increased expression of inflammatory factors, including p38, tumor necrosis factor (TNF)α and interleukin (IL)6. Furthermore, compared with other two HFSD types including pre­given and post­given group, the simul­given group that received IM injection with STZ exhibited decreased expression levels of major insulin signal pathway proteins INSR, PI3K, AKT1, PIP5Kα, GLUT2 or GLUT4 in the liver and pancreas (P<0.05 or P<0.01), whereas the opposite was observed in the skeletal muscle. In addition, the protein expression levels of phosphorylated­p38, p38, IL6 and TNFα in the simul­given group that received IM injection with STZ were increased (P<0.05 or P<0.01), and histopathology also indicated inflammation in pancreas and liver. The present findings suggest that a low dose of STZ may partially impair the ß cells of the pancreas, whereas long­term excess intake of HFSD may increase lipid metabolites, inhibit the insulin signaling pathway and activate the mitogen­activated protein kinase p38 signaling pathway. The combined action of STZ and AON may result in insulin resistance, which ultimately results in abnormalities in glucose and lipid metabolism. The present model, analogue to T2DM onset of humans, evaluated the medical effect on metabolic dysfunction and provides an insight into the underlining mechanism of IR.

Mechanism of YLTZ on glycolipid metabolism based on UPLC/TOF/MS metabolomics.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by dysfunction of glycolipid metabolism. YLTZ is used to treat hyperlipidemia, yet its hypolipidemic and hypoglycemic mechanism on T2DM are unknown. Thus, UPLC/TOF/MS was applied in this study to identify the potential bio-markers, and deduce the possible metabolic pathways. According to bio-indexes, the increased blood lipid levels, including TC, TG, LDL and FA, and the decreased HDL, the elevated glucose, reduced insulin level and impaired OGTT were observed in diabetic rat model. While YLTZ can decrease the lipid levels and glucose content, as well as increased insulin standards and improve OGTT. After data from UPLC/TOF/MS processed, 17 metabolites were obtained, including phospholipids (LPCs, PCs and PGP (18:1)), beta-oxidation production (HAA, VAG and CNE) and precursors (THA), bile acid (CA, CDCA and IDCA), hydrolysate of TG (MG (22:4)), glycometabolism (G6P), cholesterol-driven synthetics (ADO) and production of arachidonate acid (THETA). As a result, YLTZ was able to reduce LPCs, PCs, PGP (18:1), HAA, VAG, CNE, CA, ADO and THETA, as well as enhance MG (22:4) and G6P. After analyzing results, several metabolic pathways were deduced, which containing, cholesterol synthesis and elimination, FA beta-oxidation, TG hydrolysis, phospholipids synthesis, glycolysis, gluconeogenesis and inflammation. Consequently, YLTZ performed to prohibit the FA beta-oxidation, synthesis of cholesterol and phospholipids, gluconeogenesis and inflammation level, as well as promote TG hydrolysis, glycolysis and blood circulation. Hence, applying metabonomics in TCM research can uncover its pharmacological edges, elucidating comprehensively that YLTZ has capacity of hypolipidemic, hypoglycemic and promoting blood circulation, matching the effect of removing blood stasis, eliminating phlegm and dampness.