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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.

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.

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.

Vanadium can induce potent hypoglycemic effects in type 1 and type 2 diabetes mellitus animals, but toxic adverse effects have inhibited the translation of these findings. Administration of vanadate in a black tea decoction has shown impressive hypoglycemic effects without evidence of toxicity in short-term studies. The purpose of this study was to investigate the hypoglycemic action and the toxic adverse effects of a tea/vanadate (T/V) decoction in diabetic rats over a 14-month treatment period. Streptozotocin-induced type 1 diabetes mellitus rats were orally gavaged with 40 mg sodium vanadate in a black tea decoction only when blood glucose levels were greater than 10 mmol/L. Glycemic status and liver and kidney function were monitored over 14 months. All of the diabetic rats in this treatment group (n = 25) required treatment with the T/V decoction at the start of the study to reduce blood glucose levels to less than 10 mmol/L. Diarrhea was uncommon among the T/V-treated animals during the first week of T/V treatment and was absent thereafter. There was no evidence of liver or kidney dysfunction or injury. From 2 to 6 months, fewer animals required the T/V treatment to maintain their blood glucose levels. After 9 months of treatment, none of the diabetic animals required any T/V to maintain their blood glucose levels at less than 10 mmol/L. Oral administration of a T/V decoction provides safe, long-acting hypoglycemic effects in type 1 diabetes mellitus rats. The typical glycemic signs of diabetes were absent for the last 5 months of the study.

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.

Hempseed contains a unique combination of both omega-3 and omega-6 polyunsaturated fatty acids. In other studies, supplementation of the diet with selected polyunsaturated fatty acids has induced significant, beneficial cardiovascular effects. The purpose of the present study is to determine if hempseed ingestion over an 8-week period may provide protection to rabbits against the deleterious effects associated with dietary cholesterol supplementation. Methods: Male albino New Zealand White rabbits were randomly divided into one of six groups: the control diet (RG), the control diet then supplemented with (wt/wt) 5% coconut oil (CO), or 10% hempseed (HP), or 0.5% cholesterol (OL), or with both 10% hempseed and 0.5% cholesterol (OLHP) or with 10% hempseed that was partially delipidated (SC). Each day the rabbits were fed 125 grams of the appropriate diet over an 8-week period. Fatty acid analysis of tissue and diets was determined using gas chromatography. Vascular function testing of aortic rings was done in order to assess the response of the tissue to both contraction and relaxation stimuli. Aortic atherosclerotic plaque was quantified. Results: Cholesterol supplementation to the diet induced significant aortic plaque development. Dietary hempseed did not generate protection. The aorta obtained from rabbits fed the cholesterol-supplemented chow also exhibited defects in their contractile responses to KCl and norepinephrine and in relaxation to sodium nitroprusside (SNP). The addition of hempseed to this diet did not generate any improvement in contractile responses but had a modest protective effect on the cholesterol-induced defects in SNP-induced relaxation. Conclusions: Our data demonstrate that dietary hempseed provides mildly beneficial effects against contractile dysfunction associated with atherosclerotic vessels in the cholesterol-fed rabbit.

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.

Diets rich in omega-3 polyunsaturated fatty acids are associated with decreased incidences of cardiovascular disease. The extent of incorporation and distribution of these beneficial fats into body tissues is uncertain. Rabbits were fed regular rabbit chow or a diet containing 10% ground flaxseed that is highly enriched with the omega-3 polyunsaturated fatty acid alpha-linolenic acid (ALA). The high-flaxseed diet resulted in an incorporation of ALA in all tissues, but mostly in the heart and liver with little in the brain. Docosahexaenoic and eicosapentaenoic acid levels were also selectively increased in some tissues, and the effects were not as large as ALA. Arachidonic acid and the ratio of omega-6/omega-3 fatty acids were decreased in all tissues obtained from the flax-supplemented group. Consumption of dietary flaxseed appears to be an effective means to increase ALA content in body tissues, but the degree will depend upon the tissues examined.

Epidemiological evidence has associated dietary trans-fatty acids (TFAs) with coronary heart disease. It is assumed that TFAs stimulate atherosclerosis, but this has not been proven. The purpose of this study was to determine the effects of consuming 2 concentrations of TFAs obtained from commercially hydrogenated vegetable shortening on atherosclerotic development in the presence or absence of elevated dietary cholesterol. Low-density lipoprotein receptor-deficient mice were fed 1 of 7 experimental diets for 14 weeks: low regular fat (LR), low trans-fat (LT), regular high fat, high trans-fat (HT), or a diet containing 2% cholesterol with low regular fat (C + LR), low trans-fat (C + LT), or high trans-fat (C + HT). The extent of lesion development was quantified by en face examination of the dissected aortae. Dietary cholesterol supplementation significantly elevated serum cholesterol levels. Surprisingly, this rise was partially attenuated by the addition of TFAs (C + LT and C + HT) in the diet. Serum triglyceride levels were elevated with the higher-fat diets and with the combination of trans-fat and cholesterol. Animals consuming TFAs in the absence of dietary cholesterol developed a significantly greater extent of aortic atherosclerotic lesions as compared with control animals (LT > LR and HT > regular high fat). Atherosclerotic lesions were more extensive after cholesterol feeding, but the addition of TFAs to this atherogenic diet did not advance atherosclerotic development further. In summary, TFAs are atherogenic on their own; but they do not stimulate further effects beyond the strongly atherogenic effects of dietary cholesterol.

Background and purpose: Increased plasma [homocysteine] is associated with stroke but its direct effects on the brain during a stroke are unknown. Since excitatory amino acids are important in inducing brain damage, we examined the effect of homocysteine on the release of various amino acids in the striatum of spontaneously hypertensive stroke-prone (SHSP) rats before and after a stroke. Methods: In vivo microdialysis was carried out in the striatum of anesthetized SHSP rats before and after signs of stroke. Animals were exposed to 20 and 200 μM homocysteine in the microdialysis solution and then the microdialysates were analyzed 30 min later for amino acid content. Brain cryosections were silver-stained to quantify infarcts in the non-ischemic and the damaged tissues in pre-stroke and post-stroke rats. Results: Both pre-stroke and post-stroke animals had similar levels of all amino acids in the striatum. Homocysteine did not alter amino acid release in rats prior to stroke but induced a significant increase in the release of all amino acids tested in the post-stroke rats. However, the increase was significantly greater with the excitatory amino acids glutamate and aspartate, and with tyrosine in post-stroke animals as compared to those in pre-stroke, normal animals. The mean pixel density of the gray matter of post-stroke animals was significantly decreased following homocysteine treatment indicating the presence of neurological damage. Conclusions: Homocysteine-induced neurological damage in post-infarct SHSP rats was associated with a hypersecretion of excitatory amino acids. Patients with hyperhomocysteinemia may be at risk for augmented brain damage from an ischemic infarct due to a selective activation of neuronal excitatory amino acids.

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.

Sodium orthovanadate suspended in a lichee black tea decoction effectively regulates blood glucose levels in rats with insulin-dependent, streptozotocin (STZ)-induced diabetes. The primary advantage of vanadate delivery with the tea decoction over conventional systems that use water suspensions of vanadate is a significant reduction in the toxic side effects of vanadate. It is unknown if the tea alters the bioavailability of vanadate. Male Sprague-Dawley rats were administered an intravenous injection of STZ to induce diabetes. Four days later, the diabetic rats were treated by oral gavage with 40 mg of Na-orthovanadate suspended in double-distilled, deionized water (V/H2O), tea/vanadate (TV) decoction, or were treated with the tea decoction alone. Vanadium concentrations were measured in blood and various tissues at 1 to 24 hours posttreatment using graphite furnace atomic absorption spectrophotometry. With the exception of bone, maximal vanadium concentration in plasma and tissue samples were observed 2 hours after ingestion, but steadily decreased after that. Plasma vanadium levels continued to decrease until 16 hours. In contrast, vanadium steadily accumulated in bone over the 24-hour period. Overall, rats treated with V/H2O contained similar or significantly higher concentrations of vanadium in all tissues compared with TV treatment. The pattern of vanadium accumulation was also similar over time in both treatment groups. Vanadium levels were highest in bone > kidney > liver > pancreas > lung > heart > muscle > brain in both TV- and V/H2O-treated animals. This study demonstrates that the accumulation of vanadium in diabetic rats is reduced when coadministered with a black tea decoction in comparison to administration of vanadium in water. However, this effect is unlikely to be of a magnitude to explain the full capacity of TV to reduce the toxic side effects of vanadate.

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

Oral administration of vanadate has a strong hypoglycemic effect but results in toxic side effects like life-threatening diarrhea. Tea is known to have potent antidiarrhea effects. We investigated the potential of suspending the vanadate in a tea decoction to reduce the diarrheatic action of vanadate. A concentrated extract of Lichee black tea was, therefore, added to sodium orthovanadate. Streptozotocin (STZ)-induced diabetic rats were orally gavaged with vanadate suspended in water or in the tea decoction, or with the tea extract alone. Blood glucose levels were assessed daily over 11 weeks with levels greater than 10 mmol/L warranting therapeutic intervention. Both the vanadate/water and vanadate/tea solutions acutely reduced blood glucose. The tea extract alone had no effect. The majority of vanadate/water-treated rats developed diarrhea and mortality rates approached 40%. Vanadate/tea-treated diabetic rats experienced no diarrhea or mortality and liver and kidney analyses (plasma ALT and creatinine, blood urea nitrogen [BUN], and urine-specific gravity) were normal. Animals treated with vanadate/tea retained blood glucose levels less than 10 mmol/L for an average of 24 consecutive days without subsequent treatments. Cataract formation was completely prevented. The mechanism of action of vanadate may have involved beta-cell stimulation because vanadate/tea-treated diabetic rats exhibited normal plasma insulin levels. In summary, because of its long-lasting effects, oral administration, and lack of side effects, vanadate/tea represents a potentially important alternative therapy for an insulin-deficient diabetic state.