The occurrence of altered brain glucose metabolism has long been suggested in both diabetes and Alzheimer’s diseases. However, the preceding mechanism to altered glucose metabolism has not been well understood. Glucose enters the brain via glucose transporters primarily present at the blood-brain barrier. Any changes in glucose transporter function and expression dramatically affects brain glucose homeostasis and function. In the brains of both diabetic and Alzheimer’s disease patients, changes in glucose transporter function and expression have been observed, but a possible link between the altered glucose transporter function and disease progress is missing. Future recognition of the role of new glucose transporter isoforms in the brain may provide a better understanding of brain glucose metabolism in normal and disease states. Elucidation of clinical pathological mechanisms related to glucose transport and metabolism may provide common links to the etiology of these two diseases. Considering these facts, in this review we provide a current understanding of the vital roles of a variety of glucose transporters in the normal, diabetic and Alzheimer’s disease brain.

Cancer causes considerable morbidity and mortality across the world. Socioeconomic, environmental, and lifestyle factors contribute to the increasing cancer prevalence, bespeaking a need for effective prevention and treatment strategies. Phytochemicals like plant polyphenols are generally considered to have anticancer, anti-inflammatory, antiviral, antimicrobial, and immunomodulatory effects, which explain their promotion for human health. The past several decades have contributed to a growing evidence base in the literature that demonstrate ability of polyphenols to modulate multiple targets of carcinogenesis linking models of cancer characteristics (i.e., hallmarks and nutraceutical-based targeting of cancer) via direct or indirect interaction or modulation of cellular and molecular targets. This evidence is particularly relevant for the lignans, an ubiquitous, important class of dietary polyphenols present in high levels in food sources such as flaxseed. Literature evidence on lignans suggests potential benefit in cancer prevention and treatment. This review summarizes the relevant chemical and pharmacokinetic properties of dietary polyphenols and specifically focuses on the biological targets of flaxseed lignans. The consolidation of the considerable body of data on the diverse targets of the lignans will aid continued research into their potential for use in combination with other cancer chemotherapies, utilizing flaxseed lignan-enriched natural products.

Cancer is a global issue, and it is expected to have a major impact on our continuing global health crisis. As populations age, we see an increased incidence in cancer rates, but considerable variation is observed in survival rates across different geographical regions and cancer types. Both breast and prostate cancer are leading causes of morbidity and mortality worldwide. Although cancer statistics indicate improvements in some areas of breast and prostate cancer prevention, diagnosis, and treatment, such statistics clearly convey the need for improvements in our understanding of the disease, risk factors, and interventions to improve life span and quality of life for all patients, and hopefully to effect a cure for people living in developed and developing countries. This concise review compiles the current information on statistics, pathophysiology, risk factors, and treatments associated with breast and prostate cancer.

Systemic cytotoxic chemotherapy remains the mainstay of metastatic breast cancer; however, prognosis and overall survival is unfavorable due to inadequate treatment response and/or unacceptable toxicity. Natural compounds and their active metabolites receive increasing attention as possible adjuvant therapy with cancer chemotherapeutics to improve treatment response, survival rates, and quality of life of breast cancer patients. This study investigated the combination of flaxseed lignans (Secoisolariciresinol and Enterolactone) with classic chemotherapeutic agents (Docetaxel, Doxorubicin, and Carboplatin) with different mechanisms of action to determine whether flaxseed lignans could enhance the cytotoxic effect of such drugs in the metastatic breast cancer cell lines, SKBR3 and MDA-MB-231. The experimental data suggests that flaxseed lignans significantly enhanced the ability of chemotherapeutic agents to cause cytotoxicity in SKBR3 and MDA-MB-231 breast cancer cells. A three compound combination study found that enterolactone and metformin together in combination with relatively low concentrations of chemotherapeutic drugs were able to significantly decrease cancer cell viability, compared to low concentrations of the individual chemotherapeutic drug alone. Our in vitro evaluation suggests a future direction in improving chemotherapeutic efficacy in breast cancer by adjuvant therapy with the flaxseed lignans.

PC cells susceptible to androgen deprivation therapy (ADT) and relapse of aggressive resistant cells are a principal cause of mortality. Cell metabolism plays a key role in cancer prevention, treatment and disease free survival. Naturally occurring polyphenolic lignans are capable of modulating serum and hepatic cholesterol levels. Diverse plant lignanoid constituents can be precursors of enterolactone (ENL) a mammalian lignan. Despite the information gathered throughout the years, the effects and mechanisms of action of bioactive lignans (LN) are not completely understood. As drug discovery efforts continue to move towards multi‐targeted and combination effects, ENL's drug‐like characteristics warrants further attention to fully grasp LN enriched products' and ENL analogs' potential use in the clinic. Additionally, a clinical trial concluded by our lab with an appropriate LN enriched product indicates that it can provide a clinically relevant dose without significant toxicities. Furthermore, dysregulated cells can exhibit endoplasmic reticulum (ER) stress. A link between LNs anti‐cancer effects might exist through the ability of FLNs to modulate ER stress and metabolism in dysregulated cells such as cancer. TGFβ mediated signaling is reported to be involved in the epithelial mesenchymal transition (EMT) of PC cells especially with metastases after ADT. Hypothesis: ENL's anti‐cancer effects in PC cells are a result of increased ER stress and decreased TGFβ. ENL alone did not cause cytotoxicity (sulforhodamine B) to non‐cancerous cells at 1000μM, but to cancerous cells at 50 – 200μM (LNCap, PC3, C4‐2, RWPE‐1, and 3T3‐L1). Binding assay (PolarScreen™ PPARγ‐competitor), transactivation assay (Cignal reporter), and uptake assay (2‐NBD glucose) revealed ENL as a PPARϒ partial agonist compared with controls Rosiglitazone (full agonist) and FMOC (partial agonist). ENL modulated metabolism markers (FASN, SREBPs, LDLR, PPARϒ, GLUT1, PKM2), reduced EMT markers (TGFβ) and increased ER stress markers (ATF4, CHOP, GADD34, GRP58). ENL reduced mitochondrial redox function (Alamar blue) and caused mitochondrial toxicity (Cell‐Glo ATP) in (non)glycolytic phenotype representing cells using glucose and galactose media. ENL sensitized select anticancer drugs; microtubule inhibitors (Cabazitaxel and Docetaxel), and AR / synthesis inhibitors (Enzalutamide and Abiraterone) to decrease cell viability (Calcein AM, colony forming assay) and cell motility (migration/invasion, cell adherent, wound healing assay) and increased apoptosis (Caspase 3/7 Assay). Microscopy using F‐actin stain (Phalloidin conjugate) revealed changes in cytoskeleton. There might be a novel target in the regulation of metabolism and cell motility, by ENL connecting PPARγ and TGFβ. ENL ↓metabolism, modulate ATP generation, ↑oxidative/ER stress, activate pro‐apoptotic factors leading to mitochondrial toxicity related cell death, and reduced cell motility. All these suggest that the combination of enterolactone with chemotherapy could be an efficacious therapeutic strategy for the treatment of prostate cancer. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .