Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Dietary Choline Supplementation Attenuates High-Fat-Diet-Induced Hepatocellular Carcinoma in Mice.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Choline deficiency has been well studied in the context of liver disease; however, less is known about the effects of choline supplementation in HCC. OBJECTIVE: The objective of this study was to test whether choline supplementation could influence the progression of HCC in a high-fat-diet (HFD)-driven mouse model. METHODS: Four-day-old male C57BL/6J mice were treated with the chemical carcinogen, 7,12-dimethylbenz[a]anthracene, and were randomly assigned at weaning to a cohort fed an HFD (60% kcal fat) or an HFD with supplemental choline (60% kcal fat, 1.2% choline; HFD+C) for 30 wk. Blood was isolated at 15 and 30 wk to measure immune cells by flow cytometry, and glucose-tolerance tests were performed 2 wk prior to killing. Overall tumor burden was quantified, hepatic lipids were measured enzymatically, and phosphatidylcholine species were measured by targeted MS methods. Gene expression and mitochondrial DNA were quantified by quantitative PCR. RESULTS: HFD+C mice exhibited a 50-90% increase in both circulating choline and betaine concentrations in the fed state (P ≤ 0.05). Choline supplementation resulted in a 55% decrease in total tumor numbers, a 67% decrease in tumor surface area, and a 50% decrease in hepatic steatosis after 30 wk of diet (P ≤ 0.05). Choline supplementation increased the abundance of mitochondria and the relative expression of ß-oxidation genes by 21% and ∼75-100%, respectively, in the liver. HFD+C attenuated circulating myeloid-derived suppressor cells at 15 wk of feeding (P ≤ 0.05). CONCLUSIONS: Choline supplementation attenuated HFD-induced HCC and hepatic steatosis in male C57BL/6J mice. These results suggest a therapeutic benefit of choline supplementation in blunting HCC progression.

Metabolic products of soluble epoxide hydrolase are essential for monocyte chemotaxis to MCP-1 in vitro and in vivo.

Monocyte chemoattractant protein-1 (MCP-1)-induced monocyte chemotaxis is a major event in inflammatory disease. Our prior studies have demonstrated that MCP-1-dependent chemotaxis requires release of arachidonic acid (AA) by activated cytosolic phospholipase A(2) (cPLA(2)). Here we investigated the involvement of AA metabolites in chemotaxis. Neither cyclooxygenase nor lipoxygenase pathways were required, whereas pharmacologic inhibitors of both the cytochrome-P450 (CYP) and the soluble epoxide hydrolase (sEH) pathways blocked monocyte chemotaxis to MCP-1. To verify specificity, we demonstrated that the CYP and sEH products epoxyeiscosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs), respectively, restored chemotaxis in the presence of the inhibitors, indicating that sEH-derived products are essential for MCP-1-driven chemotaxis. Importantly, DHETs also rescued chemotaxis in cPLA(2)-deficient monocytes and monocytes with blocked Erk1/2 activity, because Erk controls cPLA(2) activation. The in vitro findings regarding the involvement of CYP/sEH pathways were further validated in vivo using two complementary approaches measuring MCP-1-dependent chemotaxis in mice. These observations reveal the importance of sEH in MCP-1-regulated monocyte chemotaxis and may explain the observed therapeutic value of sEH inhibitors in treatment of inflammatory diseases, cardiovascular diseases, pain, and even carcinogenesis. Their effectiveness, often attributed to increasing EET levels, is probably influenced by the impairment of DHET formation and inhibition of chemotaxis.

Danshen extracts decrease blood C reactive protein and prevent ischemic stroke recurrence: a controlled pilot study.

The efficacy of a danshen (Salvia miltiorrhiza) dripping pill (DDP) for secondary stroke prevention was evaluated in patients with ischemic cerebrovascular disease. The preparation also contained Panax notoginseng (sanqi) and Dryobalanops camphor. Patients who had suffered from ischemic stroke or a transient ischemic attack (TIA) within the previous 20 days were managed according to established guidelines, and were divided into groups to receive either DDP or non-DDP treatment according to their time of enrolment. Mortality, cerebrovascular events and any suspected adverse reactions during the 1-year follow-up were recorded and analysed. Hematological and hemorheological parameters were measured at the start of the study (baseline) and the end of the follow-up period. A total of 106 patients with ischemic stroke/TIA were enrolled, of which 52 were allocated to take DDP and 54 were in the control group. Recurrent stroke/TIA was observed in five patients (9.6%) with DDP and in 13 patients (24.1%) without DDP during the follow-up. Recurrence in the patient group taking DDP was lower than that in the control group (p<0.05). No significant differences in intracranial hemorrhage and mortality were detected between groups (p>0.05). Blood C reactive protein decreased significantly in patients with DDP compared with patients without DDP. These results indicate that DDP treatment may reduce the risk for stroke/TIA recurrence, and this reduction of risk may be associated with its antiinflammatory effects.

Defects in leukocyte-mediated initiation of lipid peroxidation in plasma as studied in myeloperoxidase-deficient subjects: systematic identification of multiple endogenous diffusible substrates for myeloperoxidase in plasma.

More than a decade ago it was demonstrated that neutrophil activation in plasma results in the time-dependent formation of lipid hydroperoxides through an unknown, ascorbate-sensitive pathway. It is now shown that the mechanism involves myeloperoxidase (MPO)-dependent use of multiple low-molecular-weight substrates in plasma, generating diffusible oxidant species. Addition of activated human neutrophils (from healthy subjects) to plasma (50%, vol/vol) resulted in the peroxidation of endogenous plasma lipids by catalase-, heme poison-, and ascorbate-sensitive pathways, as assessed by high-performance liquid chromatography (HPLC) with on-line electrospray ionization tandem mass spectrometric analysis of free and lipid-bound 9-HETE and 9-HODE. In marked contrast, neutrophils isolated from multiple subjects with MPO deficiency failed to initiate peroxidation of plasma lipids, but they did so after supplementation with isolated human MPO. MPO-dependent use of a low-molecular-weight substrate(s) in plasma for initiating lipid peroxidation was illustrated by demonstrating that the filtrate of plasma (10-kd MWt cutoff) could supply components required for low-density lipoprotein lipid peroxidation in the presence of MPO and H(2)O(2). Subsequent HPLC fractionation of plasma filtrate (10-kd MWt cutoff) by sequential column chromatography identified nitrite, tyrosine, and thiocyanate as major endogenous substrates and 17 beta-estradiol as a novel minor endogenous substrate in plasma for MPO in promoting peroxidation of plasma lipids. These results strongly suggest that the MPO-H(2)O(2) system of human leukocytes serves as a physiological mechanism for initiating lipid peroxidation in vivo.