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Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity. An approach using glucose tracers and labeling of proline metabolites is applied to assess compartmentalized NADPH fluxes. The results show that NADPH fluxes in the cytosol and mitochondria are independently regulated, with no evidence of a shuttle.

Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener 1 . It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel 2 , 3 . Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism. Dietary fructose enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer indirectly via metabolite transfer.

BackgroundProstate cancer (PCa) is the second most frequently diagnosed cancer among men worldwide. Many epidemiological studies have found an inverse association between increased tomato consumption and PCa risk. This study aims to determine the associations between consumption of various types of tomato products and PCa risk and to investigate potential dose–response relationships.MethodsWe conducted a systematic review and dose–response meta-analysis of dietary tomato in relation to PCa. Eligible studies were published before April 10, 2017 and were identified from PubMed, Web of Science, and the Cochrane Library. We estimated pooled risk ratios (RRs) and 95% confidence intervals (CI) using random and fixed effects models. Linear and nonlinear dose–response relationships were also evaluated for PCa risk.ResultsThirty studies related to tomato consumption and PCa risk were included in the meta-analysis, which summarized data from 24,222 cases and 260,461 participants. Higher total tomato consumption was associated with a reduced risk of PCa (RR = 0.81, 95% CI: 0.71–0.92, p = 0.001). Specifically, tomato foods (RR = 0.84, 95% CI: 0.72–0.98, p = 0.030) and cooked tomatoes and sauces (RR = 0.84, 95% CI: 0.73–0.98, p = 0.029) were associated with a reduced risk of PCa. However, no associations were found for raw tomatoes (RR = 0.96, 95% CI: 0.84–1.09, p = 0.487). There was a significant dose–response association observed for total tomato consumption (p = 0.040), cooked tomatoes and sauces (p < 0.001), and raw tomatoes (p = 0.037), but there was not a significant association with tomato foods (plinear = 0.511, pnonlinear = 0.289).ConclusionsOur data demonstrate that increased tomato consumption is inversely associated with PCa risk. These findings were accompanied with dose–response relationships for total tomato consumption and for cooked tomatoes and sauces. Further studies are required to determine the underlying mechanisms of these associations.

First-line therapy for advanced or metastatic prostate cancer (PCa) involves the removal of tumor-promoting androgens by androgen deprivation therapy (ADT), resulting in transient tumor regression. Recurrent disease is attributed to tumor adaptation to survive, despite lower circulating androgen concentrations, making the blockage of downstream androgen signaling a chemotherapeutic goal for PCa. Dietary intake of tomato and its predominant carotenoid, lycopene, reduce the risk for PCa, and preclinical studies have shown promising results that tomato and lycopene can inhibit androgen signaling in normal prostate tissue. The goal of this systematic review was to evaluate whether mechanistic evidence exists to support the hypothesis that tomato or lycopene interact with the androgen axis in PCa. Eighteen studies (n = 5 in vivo; n = 13 in vitro) were included in the final review. A formal meta-analysis was not feasible due to variability of the data; however, the overall estimated directions of effect for the compared studies were visually represented by albatross plots. All studies demonstrated either null or, more commonly, inhibitory effects of tomato or lycopene treatment on androgen-related outcomes. Strong mechanistic evidence was unable to be ascertained, but tomato and lycopene treatment appears to down-regulate androgen metabolism and signaling in PCa.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, accounting for 15% of all cancers in men worldwide. Asian populations consume soy foods as part of a regular diet, which may contribute to the lower PCa incidence observed in these countries. This meta-analysis provides a comprehensive updated analysis that builds on previously published meta-analyses, demonstrating that soy foods and their isoflavones (genistein and daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty articles were included for analysis of the potential impacts of soy food intake, isoflavone intake, and circulating isoflavone levels, on both primary and advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p = 0.018), and unfermented soy food (p < 0.001) intakes were significantly associated with a reduced risk of PCa. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with PCa risk. Neither soy food intake nor circulating isoflavones were associated with advanced PCa risk, although very few studies currently exist to examine potential associations. Combined, this evidence from observational studies shows a statistically significant association between soy consumption and decreased PCa risk. Further studies are required to support soy consumption as a prophylactic dietary approach to reduce PCa carcinogenesis.

Over 400 California sea lions ( Zalophus californianus ) died and many others displayed signs of neurological dysfunction along the central California coast during May and June 1998. A bloom of Pseudo-nitzschia australis (diatom) was observed in the Monterey Bay region during the same period. This bloom was associated with production of domoic acid (DA), a neurotoxin 1 that was also detected in planktivorous fish, including the northern anchovy ( Engraulis mordax ), and in sea lion body fluids. These and other concurrent observations demonstrate the trophic transfer of DA resulting in marine mammal mortality. In contrast to fish, blue mussels ( Mytilus edulus ) collected during the DA outbreak contained no DA or only trace amounts. Such findings reveal that monitoring of mussel toxicity alone does not necessarily provide adequate warning of DA entering the food web at levels sufficient to harm marine wildlife and perhaps humans.