The Role of Diet in the Onset of Depression: A Biochemical Connection Between Nutrition and Mental Health

Depression is a major clinical concern, having a complex onset and the presence of multiple, often unidentifiable causes. Depression affects millions of individuals worldwide, with a high prevalence in regions of the world with a Western-style diet as compared to regions with a Mediterranean diet. A Western-style diet consists of foods high in sugar, fat, and processed meats and grains, whereas the Mediterranean diet contains significantly more vegetables, fruits, lean meats, and whole grains. The link between diet and mental health disorders has implications for individuals of all ages who are hesitant to turn to medication. In addition to presenting a closer examination of the biochemical foundation of depression, this review focuses on the effects of factors such as food-related inflammation, nutrition, and probiotics in symptom development

Flaxseed Lignan Supplementation as Possible Adjuvant Therapy for Prostate and Breast Cancer

Dietary flaxseed lignans may have a chemopreventive and chemotherapeutic role against prostate and breast cancers. Flaxseed lignans, though, undergo an extensive first-pass effect and exist systemically primarily as glucuronide conjugates that are believed to be inactive. Their poor oral bioavailability (FO) likely explains the very modest benefit observed in human clinical studies. To fully realize the potential for lignan oral supplementation in prostate and breast cancer, pharmaceutical strategies are necessary to overcome the limitations imposed by poor FO. This dissertation involved proof-of-principle studies designed to first provide in vitro experimental evidence of flaxseed lignans on enhancing cytotoxicity of typical chemotherapeutic agents when used in combination, followed by the development of a pharmaceutical strategy to potentially exploit a role for lignans as adjuvant therapy against prostate cancer, and a human clinical trial to show oral safety and tolerability. Combination studies of lignans with chemotherapeutic agents were first conducted in prostate (PC3 and LNCap) and breast (SKBR3 and MDA-MB-231) cancer cell lines. SECO, the aglycone metabolite of the plant lignan, secoisolariciresinol diglucoside (SDG), was tested as it exhibits good FO but has had little investigation. As a major mammalian lignan converted from SECO, studies focused on enterolactone (ENL) and its glucuronic acid conjugate (ENL-Gluc). Typical chemotherapeutic agents with different mechanisms of action, including docetaxel, doxorubicin, cabazitaxel, MDV3100, and carboplatin were selected for combination experiments with lignans. A randomized, double-blind, placebo-controlled clinical trial in healthy older adults was conducted with oral supplementation of a standard flaxseed lignan-enriched complex (~38% SDG) equivalent to 600 mg SDG for 6-months, to assess efficacy, safety, and tolerability of flaxseed lignans. Finally, antibody directed enzyme prodrug therapy (ADEPT) system was generated by using anti-prostate specific membrane antigen (PSMA) antibody, D7 scFv as the carrier, and human β-glucuronidase (hβG) as the drug-converting enzyme. The binding affinity of fusion protein was assessed in purified PSMA as well as LNCap cells expressing cell surface PSMA. The enzymatic activity of D7-hβG fusion protein was determined using probe, 4-methylumberlliferone glucuronide, and prodrug, ENL-Gluc. C4-2 cells, expressing PSMA, were chosen to measure the conversion of ENL-Gluc into ENL by fusion protein in combination with docetaxel. In the in vitro combination studies, SECO and ENL enhanced sensitivity of cancer cells against therapeutic agents, in particular the ENL and docetaxel combination, while no obvious cytotoxicity was observed from ENL-Gluc. The in vivo assessment of flaxseed lignan-enriched product indicated no adverse side effects suggesting the safety and tolerability of flaxseed lignans for long-term oral exposure at a low pharmacological dose. Furthermore, plasma parent and total flaxseed lignans were significantly elevated in healthy older adults receiving lignan supplementation (n=19) compared with placebo (n=13), with large interindividual variation in systemic lignan levels observed. Interestingly, a significant reduction in systolic blood pressure (SBP) (from 155 mmHg to 140 mmHg) was observed in participants receiving treatment under the subcategory of SBP ³140 mmHg, while no change was observed in placebo group with SBP ³140 mmHg (n=6). Positive outcomes from in vitro and human clinical trial data supported investigations into an ADEPT strategy from which the fusion protein D7-hβG was successfully generated. The fusion protein displayed excellent binding against cell surface or purified PSMA, and favorable activity in production of active mammalian lignan, ENL, from ENL-Gluc. A slight decrease in the IC50 value was observed in the treatment group of D7-hβG with 100 µM ENL-Gluc plus docetaxel compared with docetaxel alone group in C4-2 cells. This proof-of-principle therapeutic strategy is the first attempt to expand the utility of flaxseed lignans as adjuvant therapy against prostate cancer. With the advantage of the safety and tolerability profile following convenient oral lignan consumption, this dissertation research warrants further evaluations of the ADEPT strategy as adjuvant therapy against prostate as well as breast cancer both in vitro and in vivo. In general, this dissertation provides science-based evidence to support the health benefits of flaxseed lignan-enriched product following oral consumption as a natural health product (NHP) which is required by Health Canada

Investigating the protective role of the natural hormone Melatonin, in reducing drug-induced cardiotoxicity in the therapy of chronic diseases

Heart failure (HF) is a highly complex disorder and a major end-point of cardiovascular diseases (CVD). The pathogenesis of HF is mostly unresolved but involves interplay between cardiac structural and electrical remodelling, metabolic alterations, cell death and altered gene expression. Mitochondrial dysfunction and HF are common complications of chronic treatment from diverse groups of drugs, in particular anticancer drugs such as doxorubicin (DOX). Treatment of animals and cardiomyocytes with cardiotoxic chemicals such as β-adrenergic receptor agonists (such as isoproterenol) induces cardiac dysfunction and HF. Previous work done by the group have identified the pineal hormone melatonin was protective against stress-induced cardiac arrhythmias and simulated heart failure in cardiomyocytes in vitro. Melatonin synthesis is also dramatically decreased with age and in patients with CVD. The aim of the present project was to better understand the pathogenesis of druginduced cardiac dysfunction and delineate the role of melatonin in cardioprotection in H9c2, a model rat cell line in vitro. Using the Seahorse XF analyser method, it was demonstrated that commonly used medication for chronic diseases such as amiodarone, amitriptyline, and statins all caused altered mitochondrial dysfunction. In addition, cardiotoxic chemicals (isoproterenol, hydrogen peroxide, DOX) altered oxidative phosphorylation and glycolysis in living cardiomyocyte-derived H9c2 cells; these deleterious metabolic changes were ameliorated by melatonin. Flowcytometry and Alamar Blue staining methods demonstrated that DOX robustly induced apoptosis in H9c2 cells (~30%) which was reversed by melatonin. Doxorubicin-induced stress in H9c2 cells dramatically altered gene expression in several key signalling pathways integral in cardiac function and disease. These included mitochondrial metabolism (UCP2, PPARɣ, Drp1, Mfn1, Parp 1, Parp2, Sirt3 and Cav3), apoptosis (Bcl2 and Bcl-xL), cardiac electrophysiology and arrhythmia (Scn5a, SERCA2a), calcium handling (SERCA2a) and cardiac remodelling (Myh7, ms1). Melatonin pre-treatment attenuated or completely blocked this DOX-induced alteration in gene expression in cardiomyocytes. In conclusion, the present result demonstrated for the first time that melatonin is cardioprotective against drug-induced cardiotoxicity and apoptosis via modifying diverse heart failure-related signalling pathways. This provides novel insight on the possible use of melatonin as an adjunct intervention in several therapies including anti-cancer

Effects of vitamin and mineral nutriture on systemic and visual function: A review

Vitamins and minerals are essential for all aspects of human function. There is, however, considerable controversy regarding the types and quantities of these nutrients needed to insure maximum performance. In this paper, basic nutritional concepts are reviewed, specific information is presented on selected vitamins and minerals, and the effects of vitamin and mineral nutriture on visual function is discussed. It is concluded that, apart from diseases associated with frank deficiencies or toxic levels, relatively little is known about how vitamin and mineral levels can contribute to optimum visual performance

Comparison of human and mouse AKR1C enzymes: implications for modeling human cancer

Human aldo-keto reductases (AKR) of the 1C subfamily have been implicated in the progression of prostate, breast and endometrial carcinomas as well as leukaemias due to their ability to modify key signaling molecules: steroid hormones and prostaglandins (PGs). In leukaemia, the AKR1C3 isoform has been identified as a novel therapeutic target since its PGD2 reductase activity prevents cell differentiation. Mice are ideal organisms for in vivo studies, using knock-out or over-expression strains. However, no mouse models for AKR1C enzymes have been generated to date since the functional conservation of these enzymes between human and mice is yet to be described. This study compared and characterised the phylogeny, substrate preference and tissue expression profile of the four human (AKR1C1,-1C2, -1C3 and -1C4) and the eight mouse (AKR1C6, -1C12, -1C13, -1C14, -1C18, -1C19, -1C20 and -1C21) isoforms. Despite being orthologues, AKR1C enzymes of mouse and humans have undergone significant divergence in number and sequence which was reflected in different substrate preference and tissue distribution. Mouse AKR1C isoforms lacked the PGD2 reductase activity but AKR1C6 was able to reduce PGE2 instead, an activity absent amongst human isoforms. Reduction of the key steroids androstenedione, 5$\alpha$-dihydrotestosterone, progesterone and estrone was performed by 4 of the murine isoforms. However, unlike humans, no AKR1C isoforms were detected in murine prostate, testes, uterus and haemopoietic progenitors. This study exposes significant lack of phylogenetic and functional conservation between human and murine AKR1C enzymes. Therefore, it is concluded that mice are not suitable to model the role of AKR1C in human carcinomas and leukemia. Additionally, the role of PGD2 in adult muscle differentiation was investigated using the mouse myoblast cell line C2C12. PGD2, but not PGE2 or PGF2$\alpha$, inhibited myotube formation in a dose dependent manner. Exposure to PGD2 disrupted the expression of myogenic regulators (MyoD and myogenin) during differentiation and suppressed cell fusion, $\alpha$-actin expression and creatine kinase activity. Inhibition of myogenesis was independent of PGD2 surface receptors DP1 and DP2 and activation of the peroxisome proliferator-activated receptor $\gamma$ (PPAR$\gamma$) suggesting a new form of signaling is involved. This discovery has implications in the interplay between inflammation, where high levels of PGD2 are secreted, and adult muscle regeneration, two processes that are intimately related

Methylene chloride

"September 2000.""Contract No. 205-1999-00024.""Update"--Cover."Prepared by Syracuse Reseach Corporation."Chemical manager(s)/author(s): Jewell D. Wilson, ATSDR, Division of Toxicology, Atlanta, GA; Margaret E. Fransen, Fernando Llados, Mona Singh, Gary L. Diamond, Syracuse Research Corporation, North Syracuse, NY.Also available via the World Wide Web (accessed 2003 July 1).Includes bibliographical references (p. 213-264)