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BACKGROUND Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. OBJECTIVE We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. METHODS Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. RESULTS In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P

Doxorubicin (Dox), a widely used chemotherapy drug, can also cause cardiotoxic effects leading to heart failure. The excessive oxidative stress caused by Dox results in the modification of a variety of cellular molecules, including phospholipids. In cardiomyocytes, Dox increases oxidation of a species of phospholipids, phosphatidylcholine, which has been associated with increased cell death. Oxidized phospholipids (Ox-PL) are involved in development and progression of various pathologies, including atherosclerosis, thrombosis, and tissue inflammation. Moreover, Ox-PL and excess iron are associated with ferroptosis, a form of regulated cell death. Neutralizing Ox-PL increases resistance to ischemia-reperfusion injuries which is linked to preservation of the mitochondrial membrane potential. This review aims to discuss the potential role of Ox-PL in Dox-induced pathology and supports the notion that a better understanding of the field could point to new strategies to prevent cardiotoxicity.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg−1·wk−1), or 3) SNT (40 mg·kg−1·day−1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Myocardial ischemia-reperfusion (I/R) injury increases the generation of oxidized phosphatidylcholines (OxPCs), which results in cell death. However, the mechanism by which OxPCs mediate cell death and cardiac dysfunction is largely unknown. The aim of this study was to determine the mechanisms by which OxPC triggers cardiomyocyte cell death during reperfusion injury. Adult rat ventricular cardiomyocytes were treated with increasing concentrations of various purified fragmented OxPCs. Cardiomyocyte viability, bioenergetic response, and calcium transients were determined in the presence of OxPCs. Five different fragmented OxPCs resulted in a decrease in cell viability, with 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PONPC) having the most potent cardiotoxic effect in both a concentration and time dependent manner (P < 0.05). POVPC and PONPC also caused a significant decrease in Ca2+ transients and net contraction in isolated cardiomyocytes compared to vehicle treated control cells (P < 0.05). PONPC depressed maximal respiration rate (P < 0.01; 54%) and spare respiratory capacity (P < 0.01; 54.5%). Notably, neither caspase 3 activation or TUNEL staining was observed in cells treated with either POVPC or PONPC. Further, cardiac myocytes treated with OxPCs were indistinguishable from vehicle-treated control cells with respect to nuclear high-mobility group box protein 1 (HMGBP1) activity. However, glutathione peroxidase 4 activity was markedly suppressed in cardiomyocytes treated with POVPC and PONPC coincident with increased ferroptosis. Importantly, cell death induced by OxPCs could be suppressed by E06 Ab, directed against OxPCs or by ferrostatin-1, which bound the sn-2 aldehyde of POVPC during I/R. The findings of the present study demonstrate that oxidation of phosphatidylcholines during I/R generate bioactive phospholipid intermediates that disrupt mitochondrial bioenergetics and calcium transients and provoke wide spread cell death through ferroptosis. Neutralization of OxPC with E06 or with ferrostatin-1 prevents cell death during reperfusion. Our study demonstrates a novel signaling pathway that operationally links generation of OxPC during cardiac I/R to ferroptosis. Interventions designed to target OxPCs may prove beneficial in mitigating ferroptosis during I/R injury in individuals with ischemic heart disease.NEW & NOTEWORTHY Oxidized phosphatidylcholines (OxPC) generated during reperfusion injury are potent inducers of cardiomyocyte death. Our studies have shown that OxPCs exert this effect through a ferroptotic process that can be attenuated. A better understanding of the OxPC cell death pathway can prove a novel strategy for prevention of cell death during myocardial reperfusion injury.

Background Repetitive Transcranial Magnetic Stimulation [rTMS] is increasingly being used to treat Major Depressive Disorder [MDD]. Given that not all patients respond to rTMS, it would be clinically useful to have reliable biomarkers that predict treatment response. Oxidized phosphatidylcholine [OxPC] and some oxylipins are important plasma biomarkers of oxidative stress and inflammation. Not only is depression associated with oxidative stress, but rTMS has been shown to have anti-oxidative effects. Objectives To investigate whether plasma oxolipidomics profiles could predict treatment response in patients with treatment resistant MDD. Methods Fourty-eight patients undergoing rTMS treatment for MDD were recruited along with nine healthy control subjects. Plasma OxPCs and oxylipins were extracted and analyzed through high performance liquid chromatography coupled with mass spectrometry. Patients with a Hamilton Depression Rating Scale score [Ham-D] ≤7 post-treatment were defined as having entered remission. Results Fifty-seven OxPC and 32 oxylipin species were identified in our subjects. MDD patients who entered remission following rTMS had significantly higher pre-rTMS levels of total and fragmented OxPCs compared to non-remitters and controls [one-way ANOVA, p0.05]. No differences in plasma oxylipins were found between remitters and non-remitters at baseline. Conclusion Certain categories of OxPCs may be useful predictive biomarkers for response to rTMS treatment in MDD. Given that elevated oxidized lipids may indicate higher levels of oxidative stress and inflammation in the brain, patients with this phenotype of depression may be more receptive to rTMS treatment.

This study outlines the first step toward creating the metabolite atlas of human calcified aortic valves by identifying the expression of metabolites and metabolic pathways involved at various stages of calcific aortic valve stenosis progression. Untargeted analysis identified 72 metabolites and lipids that were significantly altered (p < 0.01) across different stages of disease progression. Of these metabolites and lipids, the levels of lysophosphatidic acid were shown to correlate with faster hemodynamic progression and could select patients at risk for faster progression rate.

Summary: The LPA gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets categorized pathologically from both ATXâapolipoprotein B and ATXâapolipoprotein(a) were measureable in plasma. Lipoprotein(a) (Lp[a]), ATX, OxPL, and malondialdehyde epitopes progressively increased in immunostaining (p < 0.001 for all). Six species of OxPL and lysophosphatidic acid were identified after extraction from valve leaflets. The presence of a constellation of pathologically linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiologic factor in CAVS. Key Words: aortic valve stenosis, autotaxin, inflammation, Lp(a), oxidation-specific epitopes

Introduction: Calcific aortic valve stenosis (CAVS) is the most prevalent cardiac valvular pathology, leading to a high incidence of morbidity and mortality if left untreated. The exact pathophysiology of CAVS is largely undefined. Genetic studies have shown a strong correlation of the Lp(a) gene to developing CAVS. Lp(a) is known to be the carrier of plasma Oxidized Phosphatidylcholine and results in Lysophosphatidic acid (LPA) accumulation. The focus of the present study was to determine if OxPC and LPA in calcific human aortic valves relate with echocardiographic markers of CAVS. Methods: Aortic valves (n=98) were obtained from patients undergoing AVR. OxPC and LPA were extracted from pulverized aortic valves and analyzed using a targeted mass spectrometry approach. Lipid values are represented relative to an internal standard and normalized by homogenate and leaflet weights. The severity of calcification and aortic stenosis were measured anatomically by Echocardiographic calcification (ECC) score and hemodynamically by mean AV pressure gradient. Results: One-palmitoyl-2-(9-oxo)-nonanoyl- sn- glycero-3-phosphocholine (PONPC) was the most abundant OxPC among 58 OxPC molecules detected (49.3±3.8ng), in AV tissue. When valves were graded by ECC score, scores of 1 (no calcification) had observably attenuated amounts of mean total OxPC’s (135.3±39.3ng) compared to those with a score of 4 (severe calcification) (310.1±34.8 ng). Total valvular OxPC increased linearly with increased ECC score. Total non-fragmented OxPC’s were also significantly lower in valves with ECC scores of 1 and 2 compared to a score of 4 ( P =0.03). Six LPA species were also identified with 16:0 and 18:1 being the most prevalent. Mean AV pressure gradient had a significant, positive correlation with Total LPA amounts (r 2 =0.580, p Conclusions: Our study is the largest lipidomics study of human aortic valve tissue demonstrating that OxPC and LPA molecules play a significant role in the etiology of CAVS and provides a novel therapeutic target for mitigating disease progression.

Aims Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and results OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a ‘natural’ murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr−/− mice, overexpressing a single-chain variable fragment of E06 (Ldlr−/−-E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P Conclusions OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.

Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed. Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK. We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity. Electronic supplementary material The online version of this article (10.1007/s00441-018-2905-z) contains supplementary material, which is available to authorized users.

Background: Dietary flaxseed lowers cholesterol in healthy subjects with mild biomarkers of cardiovascular disease (CVD). Objective: The aim was to investigate the effects of dietary flaxseed on plasma cholesterol in a patient population with clinically significant CVD and in those administered cholesterol-lowering medications (CLMs), primarily statins. Methods: This double-blinded, randomized, placebo-controlled trial examined the effects of a diet supplemented for 12 mo with foods that contained either 30 g of milled flaxseed [milled flaxseed treatment (FX) group; n = 58] or 30 g of whole wheat [placebo (PL) group; n = 52] in a patient population with peripheral artery disease (PAD). Plasma lipids were measured at 0, 1, 6, and 12 mo. Results: Dietaryflaxseed in PAD patients resulted in a 15% reduction in circulating LDL cholesterol as early as 1 mo into the trial (P = 0.05). The concentration in the FX group (2.1 6 0.10 mmol/L) tended to be less than in the PL group (2.5 6 0.2 mmol/L) at 6mo(P= 0.12), but not at 12 mo (P= 0.33). Total cholesterol also tended to be lower in the FX group than in the PL group at 1 mo (11%, P = 0.05) and 6 mo (11%, P = 0.07), but not at 12 mo (P = 0.24). In a subgroup of patients taking flaxseed and CLM (n = 36), LDL-cholesterol concentrations were lowered by 8.5% 6 3.0% compared with baseline after 12 mo. This differed from the PL + CLM subgroup (n = 26), which increased by 3.0% 6 4.4% (P = 0.030) to a final concentration of 2.2 6 0.1 mmol/L. Conclusions: Milled flaxseed lowers total and LDL cholesterol in patients with PAD and has additional LDLcholesterol‐lowering capabilities whenused in conjunction with CLMs. This trialwas registered at clinicaltrials.gov as NCT00781950. JN utrdoi: 10.3945/jn.114.204594.

Flaxseed contains ω-3 fatty acids, lignans, and fiber that together may provide benefits to patients with cardiovascular disease. Animal work identified that patients with peripheral artery disease may particularly benefit from dietary supplementation with flaxseed. Hypertension is commonly associated with peripheral artery disease. The purpose of the study was to examine the effects of daily ingestion of flaxseed on systolic (SBP) and diastolic blood pressure (DBP) in peripheral artery disease patients. In this prospective, double-blinded, placebo-controlled, randomized trial, patients (110 in total) ingested a variety of foods that contained 30 g of milled flaxseed or placebo each day over 6 months. Plasma levels of the ω-3 fatty acid α-linolenic acid and enterolignans increased 2- to 50-fold in the flaxseed-fed group but did not increase significantly in the placebo group. Patient body weights were not significantly different between the 2 groups at any time. SBP was ≈10 mm Hg lower, and DBP was ≈7 mm Hg lower in the flaxseed group compared with placebo after 6 months. Patients who entered the trial with a SBP ≥140 mm Hg at baseline obtained a significant reduction of 15 mm Hg in SBP and 7 mm Hg in DBP from flaxseed ingestion. The antihypertensive effect was achieved selectively in hypertensive patients. Circulating α-linolenic acid levels correlated with SBP and DBP, and lignan levels correlated with changes in DBP. In summary, flaxseed induced one of the most potent antihypertensive effects achieved by a dietary intervention.

Dietary intake of industrially hydrogenated trans fatty acids (TFA) has been associated with coronary heart disease. Dietary flaxseed can inhibit atherosclerosis induced by dietary cholesterol. The aim of this study was to determine whether supplementing the diet with flaxseed could protect against atherosclerosis induced by a diet enriched in TFA. Low-density lipoprotein receptor-deficient (LDLr−/−) mice were fed 1 of 14 experimental diets for 14 wk containing one of two fat sources [regular (pork/soy) or trans fat] at two concentrations (4 or 8%) and supplemented with or without dietary cholesterol (2%), whole ground flaxseed, or one of the components of flaxseed [α-linolenic acid (ALA), defatted fiber, or lignan]. Adding flaxseed to the diet partially mitigated the rise in circulating cholesterol levels induced by the cholesterol-enriched diet. Atherosclerosis was stimulated by TFA and/or cholesterol. Including milled flaxseed to an atherogenic diet significantly reduced atherosclerosis compared with the groups that consumed cholesterol and/or TFA. ALA was the only component within flaxseed that could inhibit the atherogenic action of cholesterol and/or TFA on its own. Dietary flaxseed protects against atherosclerotic development induced by TFA and cholesterol feeding through its content of ALA.

Dietary flaxseed has cardioprotective effects that may be achieved through its rich content of the omega-3 fatty acid, alpha linolenic acid (ALA). Because ALA can be stored in adipose tissue, it is possible that some of its beneficial actions may be due to effects it has on the adipose tissue. We investigated the effects of dietary flaxseed both with and without an atherogenic cholesterol-enriched diet to determine the effects of dietary flaxseed on the expression of the adipose cytokines leptin and adiponectin. Rabbits were fed one of four diets: a regular (RG) diet, or a regular diet with added 0.5% cholesterol (CH), or 10% ground flaxseed (FX), or both (CF) for 8 weeks. Levels of leptin and adiponectin expression were assessed by RT-PCR in visceral adipose tissue. Consumption of flaxseed significantly increased plasma and adipose levels of ALA. Leptin protein and mRNA expression were lower in CH animals and were elevated in CF animals. Changes in leptin expression were strongly and positively correlated with adipose ALA levels and inversely correlated with levels of en face atherosclerosis. Adiponectin expression was not significantly affected by any of the dietary interventions. Our data demonstrate that the type of fat in the diet as well as its caloric content can specifically influence leptin expression. The findings support the hypothesis that the beneficial cardiovascular effects associated with flaxseed consumption may be related to a change in leptin expression.

Background The aim of this study was to determine the individual oxidized phosphatidylcholine (OxPC) molecules generated during renal ischemia/ reperfusion (I/R) injury. Methods Kidney ischemia was induced in male Sprague–Dawley rats by clamping the left renal pedicle for 45 min followed by reperfusion for either 6h or 24h. Kidney tissue was subjected to lipid extraction. Phospholipids and OxPC species were identified and quantitated using liquid chromatography coupled to electrospray ionization tandem mass spectrometry using internal standards. Result We identified fifty-five distinct OxPC in rat kidney following I/R injury. These included a variety of fragmented (aldehyde and carboxylic acid containing species) and non-fragmented products. 1-stearoyl-2-linoleoyl-phosphatidylcholine (SLPC-OH), which is a non-fragmented OxPC and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PAzPC), which is a fragmented OxPC, were the most abundant OxPC species after 6h and 24 h I/R respectively. Total fragmented aldehyde OxPC were significantly higher in 6h and 24h I/R groups compared to sham operated groups (P = 0.03, 0.001 respectively). Moreover, levels of aldehyde OxPC at 24h I/R were significantly greater than those in 6h I/R (P = 0.007). Fragmented carboxylic acid increased significantly in 24h I/R group compared with sham and 6h I/R groups (P = 0.001, 0.001). Moreover, levels of fragmented OxPC were significantly correlated with creatinine levels (r = 0.885, P = 0.001). Among non-fragmented OxPC, only isoprostanes were elevated significantly in 6h I/R group compared with sham group but not in 24h I/R group (P = 0.01). No significant changes were observed in other non-fragmented OxPC including long chain products and terminal furans. Conclusion We have shown for the first time that bioactive OxPC species are produced in renal I/R and their levels increase with increasing time of reperfusion in a kidney model of I/R and correlate with severity of I/R injury. Given the pathological activity of fragmented OxPCs, therapies focused on their reduction may be a mechanism to attenuate renal I/R injury.

Epidemiological evidence has associated dietary trans fatty acids (TFA) with heart disease. TFA are primarily from hydrogenated fats rich in elaidic acid, but dairy products also contain naturally occurring TFA such as vaccenic acid. Our purpose in this study was to compare the effects of consuming a commercially hydrogenated vegetable shortening rich in elaidic TFA (18:1t9) or a butter rich in vaccenic TFA (18:1t11) in the absence and presence of dietary cholesterol on atherosclerosis. LDL receptor deficient (LDLr(-/-)) mice were fed 1 of 8 experimental diets for 14 wk with the fat content replaced by: regular (pork/soy) fat (RG), elaidic shortening (ES), regular butter (RB), vaccenic butter (VB), or an atherogenic diet containing 2% cholesterol with RG (CH+RG), ES (CH+ES), RB (CH+RB), or VB (CH+VB). Serum cholesterol levels were elevated with cholesterol feeding (P < 0.001), whereas serum triglyceride levels were higher only in the CH+RB (P < 0.001) and CH+VB (P < 0.001) groups compared with the other 6 groups. Serum cholesterol and triglyceride levels were significantly lower in the CH+VB group than in the CH+RB group (P < 0.001). Atherosclerosis was stimulated by dietary ES compared with RG (P = 0.021), but CH+ES did not stimulate atherosclerosis beyond CH+RG alone. In contrast, VB did not induce an increase in atherosclerotic plaque formation compared with the RG and RB diets and the CH+VB diet reduced atherosclerosis compared with the other diets containing cholesterol (P < 0.01). In summary, consuming a hydrogenated elaidic acid-rich diet stimulates atherosclerosis, whereas a vaccenic acid-rich butter protects against atherosclerosis in this animal model.

A series of functionalized polynorbornenes containing pendent ether- or ester-bridged poly(aromatic ether) chains were prepared. The ether-bridged norbornene complex was synthesized via cyclopentadienyliron-mediated nucleophilic aromatic substitution reactions. This methodology, combined with that of dicyclohexylcarbodiimide-mediated coupling, allowed for the formation of novel oligomeric aryl ether and ester substituted norbornene complexes. Photolytic demetallation gave the monomers in good yields. Structural identification of the exo and endo isomers of both the metallated and demetallated norbornene derivatives was accomplished using HH and CH COSY NMR techniques. Ring-opening metathesis polymerization (ROMP) of these monomers using RuCl3(hydrate) and (Cy3P)2Cl2Ru=CHPh allowed for the preparation of the functionalized polynorbornenes. Thermal analysis of the resulting polymeric materials demonstrated greater thermal stability as the number of aryl ether groups increased.Key words: aromatic ethers, cyclopentadienyliron, polynorbornene, ROMP, ruthenium catalysts.

Dietary flaxseed may have beneficial cardiovascular effects. An aged population has a higher incidence of cardiovascular disease, but they may react differently to flaxseed in the diet.To investigate the response, over a period of 4 weeks, of subjects aged 18-29 or 45-69 years to a diet containing the same amount of alpha-linolenic acid (ALA) (6 g) introduced in the form of ground flaxseed (30 g) or flaxseed oil.All subjects who received flaxseed oil showed a significant increase in plasma ALA and eicosapentaenoic acid (EPA) concentrations over the course of this study. Subjects who received ground flaxseed in the 18-29-year-old group showed a statistically significant increase in their plasma ALA levels, and although there was a trend in the same direction for the 45-69-year-old subjects, this did not achieve statistical significance. The diets induced no major changes in platelet aggregation, plasma total cholesterol, low-density lipoprotein or high-density lipoprotein cholesterol levels in any of the groups. Younger subjects showed a decrease in triglyceride (TG) values compared with older subjects. There were no significant side effects that caused compliancy issues.Subject age does not seem to be a major determining factor in influencing ALA absorption from a flaxseed-supplemented diet nor in the metabolism of ALA to EPA in the groups fed flaxseed oil. Concerns about side effects in older subjects administered a higher fiber load in a flaxseed-supplemented diet are not justified. However, younger but not older subjects showed a beneficial decrease in circulating TGs due to flaxseed supplementation.

Polyunsaturated fatty acids (PUFAs) have significant, cardioprotective effects against ischemia. Hempseed contains a high proportion of the PUFAs linoleic acid (LA) and α-linolenic acid (ALA), which may have opposing effects on postischemic heart performance. There are no reported data concerning the cardiovascular effects of dietary hempseed intake. A group of 40 male Sprague-Dawley rats were distributed evenly into four groups that were fed for 12 wk a normal rat chow supplemented with hempseed (5% and 10%), palm oil (1%), or a 10% partially delipidated hempseed that served as a control. Plasma ALA and γ-linolenic acid levels were significantly elevated in the rats that were fed a 5% or 10% hempseed-supplemented diet, but in heart tissue only ALA levels were significantly elevated in the rats fed these diets compared with control. After the dietary interventions were completed, postischemic heart performance was evaluated by measuring developed tension, resting tension, the rates of tension development and relaxation, and the number of extrasystoles. Hearts from rats fed a hempseed-supplemented diet exhibited significantly better postischemic recovery of maximal contractile function and enhanced rates of tension development and relaxation during reperfusion than hearts from the other groups. These hearts, however, were not protected from the occurrence of extrasystoles, nor were the increases in resting tension altered during ischemia or reperfusion as a function of any dietary intervention. Our data demonstrate that dietary hempseed can provide significant cardioprotective effects during postischemic reperfusion. This appears to be due to its highly enriched PUFA content.

A novel black tea decoction containing vanadate has successfully replaced insulin in a rat model of insulin-dependent diabetes but is untested in non-insulin-dependent diabetic animals. A tea-vanadate decoction (TV) containing 30 or 40 mg sodium orthovanadate was administered by oral gavage to two groups of Zucker diabetic fatty rats and a conventional water vehicle containing 30 or 40 mg of sodium orthovanadate to two others. In the latter group receiving the 30-mg dose, vanadate induced diarrhea in 50% of the rats and death in 10%. In contrast, TV-treated rats had no incidence of diarrhea and no deaths. Symptoms were more severe in both groups with higher vanadate doses, so these were discontinued. After ~16 weeks, the level of vanadium in plasma and tissue extracts was negligible in a further group of untreated rats but highly elevated after vanadate treatment. Vanadium levels were not significantly different between the TV-treated diabetic rats and the diabetic rats given vanadate in a water vehicle. Over the 115 days of the study, blood glucose levels increased from ~17 to 25 mmol/L in untreated diabetic rats. This was effectively lowered (to