Xylitol biosynthesis enhancement by Candida tropicalis via medium, process parameter optimization, and co-substrate supplementation.

The present study examines the impact of nitrogen sources (yeast extract, ammonium sulfate peptone, ammonium nitrate, urea, and sodium nitrate), salt solution (0.5 g/L MgSO4, 0.5 g/L KH2PO4, 0.3 g/L CaCl2), trace elements solution (0.1 g/L CuSO4, 0.1 g/L FeSO4, 0.02 g/L MnCl2, 0.02 g/L ZnSO4), operational parameters (temperature, aeration, agitation, initial pH and xylose concentration) and co- substrate supplementation (glucose, fructose, maltose, sucrose, and glycerol) on xylitol biosynthesis by Candida tropicalis ATCC 13803 using synthetic xylose. The significant medium components were identified using the Plackett Burman design followed by central composite designs to obtain the optimal concentration for the critical medium components in shaker flasks. Subsequently, the effect of operational parameters was examined using the One Factor At a Time method, followed by the impact of five co-substrates on xylitol biosynthesis in a 1 L bioreactor. The optimal media components and process parameters are as follows: peptone: 12.68 g/L, yeast extract: 6.62 g/L, salt solution (0.5 g/L MgSO4, 0.5 g/L KH2PO4, and 0.3 g/L CaCl2): 1.23 X (0.62 g/L, 0.62 g/L, and 0.37 g/L respectively), temperature: 30 °C, pH: 6, agitation: 400 rpm, aeration: 1 vvm, and xylose: 50 g/L. Optimization studies resulted in xylitol yield and productivity of 0.71 ± 0.004 g/g and 1.48 ± 0.018 g/L/h, respectively. Glycerol supplementation (2 g/L) further improved xylitol yield (0.83 ± 0.009 g/g) and productivity (1.87 ± 0.020 g/L/h) by 1.66 and 3.12 folds, respectively, higher than the unoptimized conditions thus exhibiting the potential of C. tropicalis ATCC 13803 being used for commercial xylitol production.

The predictive power of serum vitamin D for poor outcomes in COVID-19 patients.

Considering the high prevalence of vitamin D deficiency worldwide and its relationship with immune response to viral infections, this study attempted to identify the predictive power of serum vitamin D for poor outcomes among the COVID-19 patients. This retrospective cohort study included all patients with confirmed COVID-19 hospitalized between February 20, 2020, and April 20, 2020, at a designated COVID-19 hospital, located in Tehran province, Iran. General characteristics, medical history and clinical symptoms were recorded by trained physicians. Blood parameters including complete blood count, creatinine, lactate dehydrogenase, creatine phosphokinase, erythrocyte sedimentation rate, C-reactive protein and vitamin D were tested. This study included 290 hospitalized patients with COVID-19 (the mean age [SD]: 61.6 [16.9], 56.6% males), of whom 142 had vitamin D concentrations less than 20 ng/ml, defined as vitamin D deficiency. COVID-19 patients with vitamin D deficiency were more likely to die (Crude OR [95% CI]: 2.30 [1.25-4.26]), require ICU (2.06 [1.22-3.46]) and invasive mechanical ventilation (2.03 [1.04-3.93]) based on univariate logistic regression results. Although, after adjusting for potentials confounders such as gender and age, the association between vitamin D and need to invasive mechanical ventilation lost its significance, adjusted values for the risk of death and ICU requirement were still statistically significant. Vitamin D deficiency can be considered as a predictor of poor outcomes and mortality in COVID-19 patients. Therefore, checking serum 25 (OH) D on admission and taking vitamin D supplements according to the prophylactic or treatment protocols is recommended for all COVID-19 patients.

Maternal Intake of Dietary Fat Pre-Programs Offspring's Gut Ecosystem Altering Colonization Resistance and Immunity to Infectious Colitis in Mice.

SCOPE: The transgenerational impact of dietary fat remains unclear. Here, the role of maternal fat consumption as a modulator of gut microbial communities and infectious disease outcomes in their offspring is explored. METHODS AND RESULTS: C57BL/6 mice are fed isocaloric high-fat diets throughout breeding, gestation and lactation. Diets contained either milk fat (MF), olive oil (OO) or corn oil (CO), with or without fish oil. The pups born to maternally exposed mice are weaned on to chow and raised into adulthood. At 8 weeks, the offsprings are either euthanized for colonic 16S rRNA analysis or challenged with the enteric pathogen, Citrobacter rodentium. Maternal CO exposure resulted in unique clustering of bacterial communities in offspring compared with MF and OO. Diets rich in CO reduced survival in offspring challenged with C. rodentium. The addition of fish oil did not improve mortality caused by CO and worsened disease outcomes when combined with OO. Unlike the unsaturated diets, MF is protective with and without fish oil. CONCLUSIONS: Overall, these data reveal that maternal intake of fatty acids do have transgenerational impacts on their offspring's bacteriome and enteric infection risk. Based on this study, saturated fats should be included in maternal diets.

Fish oil supplementation reduces maternal defensive inflammation and predicts a gut bacteriome with reduced immune priming capacity in infants.

Habitual supplementation of fish oil is thought to provide benefits to the developing infant; however, the effects on infant microbial establishment and immune development are unknown. A 6-month observational cohort study was conducted where 47 out of 91 women self-administered dietary fish oil during breastfeeding. Infant stool and mothers' breast milk were collected each month over 6 months. Gas chromatography was used to quantify breast milk fatty acids and high-throughput sequencing was used to assess the infant fecal microbiota. Immune markers and parent-reported questionnaires were used to assess infant immunity and health up to 2 years. Our results reveal that fish oil supplementation decreased secretory immunoglobulin A and increased IL-10 production in lactating women along with increased breast milk eicosapentaenoic acid, and this corresponded to increased abundances of fecal Bifidobacterium and Lactobacillus spp. in their infants. Docosahexaenoic acid levels in breast milk aligned with decreases in infant gut bacterial richness and the predicted bacterial phenotypes suggested that fish oil lowers commensal traits involved in pathogen colonization resistance. Despite this, there were no differences in sickness incidence in toddlers. This study revealed that fish oil associates with decreases in breast milk defensive inflammatory responses and corresponds with infant fecal microbiota with anti-inflammatory potential.

Egg white consumption increases GSH and lowers oxidative damage in 110-week-old geriatric mice hearts.

The number of geriatrics with an advanced age is rising worldwide, with attendant cardiovascular disorders, characterized by elevated oxidative stress. Such oxidative stress is accelerated by an age-related loss of critical antioxidants like glutathione (GSH) and dietary solutions to combat this loss does not exist. While egg white is rich in sulphur amino acids (AAs), precursors for GSH biosynthesis, whether they can increase sulphur AA in vivo and augment GSH in the aged myocardium remain unclear. We hypothesized that egg white consumption increases GSH and reduces oxidative damage and inflammation in the geriatric heart. To this end, 101-102 week-old mice were given a AIN 76A diet supplemented with either 9% w/w egg white powder or casein for 8 weeks. Subsequent analysis revealed that egg white increased serum sulphur AA and cardiac GSH, while reducing the cysteine carrying transporter SNAT-2 and elevating glutamine transporter ASCT2 in the heart. Increased GSH was accompanied by elevated expression of GSH biosynthesis enzyme glutathione synthase as well as mitochondrial antioxidants like superoxide dismutase 2 and glutathione peroxidase 1 in egg white-fed hearts. These hearts also demonstrated lower oxidative damage of lipids (4-hydroxynonenal) and proteins [nitrotyrosine] with elevated anti-inflammatory IL-10 gene expression. These data demonstrate that even at the end of lifespan, egg whites remain effective in promoting serum sulphur AAs and preserve cardiac GSH with potent anti-oxidant and mild anti-inflammatory effects in the geriatric myocardium. We conclude that egg white intake may be an effective dietary strategy to attenuate oxidative damage in the senescent heart.

Therapeutic Potential of Fulvic Acid in Chronic Inflammatory Diseases and Diabetes.

Chronic inflammatory diseases like diabetes are on a rise in the Western world. Based on the tsunami of new cases every year, new therapeutic measures must be considered. A promising avenue might involve the attenuation of underlying inflammation through natural health products (NHPs). This is because most NHPs have a rich history in traditional medicine and might be considered safer under appropriate doses and conditions. However, the biggest impediment in NHP research is that rarely do these products come with verified health benefits or dosing schedules established through modern scientific research. Fulvic acid (FvA), one such NHP, comes from humic substances produced by microorganisms in soil. Traditional medicine and modern research claim FvA can modulate the immune system, influence the oxidative state of cells, and improve gastrointestinal function; all of which are hallmarks of diabetes. This minireview outlines the available peer-reviewed research on FvA and examines its anecdotal health claims. We show that although available research has been minimal, there is substantial evidence to pursue FvA research in preventing chronic inflammatory diseases, including diabetes.

Evidence for altered cell membrane lipid composition in postmortem prefrontal white matter in bipolar disorder and schizophrenia.

Brain imaging suggests that white matter abnormalities, including compromised white matter integrity in the frontal lobe, are shared across bipolar disorder (BD) and schizophrenia (SCZ). However, the precise molecular and cellular correlates remain to be elucidated. Given evidence for widespread alterations in cell membrane lipid composition in both disorders, we sought to investigate whether lipid composition is disturbed in frontal white matter in SCZ and BD. The phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were quantified in white matter adjacent to the dorsolateral prefrontal cortex in subjects with BD (n = 34), SCZ (n = 35), and non-psychiatric controls (n = 35) using high-pressure liquid chromatography. Individual fatty acid species and plasmalogens were then quantified separately in PE and PC fractions by gas liquid chromatography. PC was significantly lower in the BD group, compared to controls. The fatty acids PE22:0, PE24:1 and PE20:2n6 were higher, and PC20:4n6, PE22:5n6 and PC22:5n6 lower in the BD group, relative to the control group. PE22:1 was higher and PC20:3n6, PE22:5n6 and PC22:5n6 lower in the SCZ group, compared to the control group. These data provide evidence for altered lipid composition in white matter in both BD and SCZ. Changes in white matter lipid composition could ultimately contribute to dysfunction of frontal white matter circuits in SCZ and BD.

Dietary Lipid Type, Rather Than Total Number of Calories, Alters Outcomes of Enteric Infection in Mice.

Dietary lipids modulate immunity, yet the means by which specific fatty acids affect infectious disease susceptibility remains unclear. Deciphering lipid-induced immunity is critical to understanding the balance required for protecting against pathogens while avoiding chronic inflammatory diseases. To understand how specific lipids alter susceptibility to enteric infection, we fed mice isocaloric, high-fat diets composed of corn oil (rich in n-6 polyunsaturated fatty acids [n-6 PUFAs]), olive oil (rich in monounsaturated fatty acids), or milk fat (rich in saturated fatty acids) with or without fish oil (rich in n-3 PUFAs). After 5 weeks of dietary intervention, mice were challenged with Citrobacter rodentium, and pathological responses were assessed. Olive oil diets resulted in little colonic pathology associated with intestinal alkaline phosphatase, a mucosal defense factor that detoxifies lipopolysaccharide. In contrast, while both corn oil and milk fat diets resulted in inflammation-induced colonic damage, only milk fat induced compensatory protective responses, including short chain fatty acid production. Fish oil combined with milk fat, unlike unsaturated lipid diets, had a protective effect associated with intestinal alkaline phosphatase activity. Overall, these results reveal that dietary lipid type, independent of the total number of calories associated with the dietary lipid, influences the susceptibility to enteric damage and the benefits of fish oil during infection.

A high-fat diet rich in corn oil reduces spontaneous locomotor activity and induces insulin resistance in mice.

Over the last few decades, polyunsaturated fatty acid (PUFA), especially n-6 PUFA, and monounsaturated fatty acid content in 'Western diets' has increased manyfold. Such a dietary shift also parallels rising sedentary behavior and diabetes in the Western world. We queried if a shift in dietary fats could be linked to physical inactivity and insulin insensitivity in mice. Eight-week old female C57/Bl6 mice were fed either high-fat (HF) diets [40% energy corn oil (CO) or isocaloric olive oil (OO) diets] or chow (n=10/group) for 6 weeks, followed by estimation of spontaneous locomotor activity, body composition and in vivo metabolic outcomes. Although lean mass and resting energy expenditure stayed similar in both OO- and CO-fed mice, only CO-fed mice demonstrated reduced spontaneous locomotor activity. Such depressed activity in CO-fed mice was accompanied by a lower respiratory ratio, hyperinsulinemia and impaired glucose disposal following intraperitoneal glucose tolerance and insulin tolerance tests compared to OO-fed mice. Unlike the liver, where both HF diets increased expression of fat oxidation genes like PPARs, the skeletal muscle of CO-fed mice failed to up-regulate such genes, thereby supporting the metabolic insufficiencies observed in these mice. In summary, this study demonstrates a specific contribution of n-6 PUFA-rich oils like CO to the loss of spontaneous physical activity and insulin sensitivity in mice. If these data hold true for humans, this study could provide a novel link between recent increases in dietary n-6 PUFA to sedentary behavior and the development of insulin resistance in the Western world.

Immunomodulation by dietary long chain omega-3 fatty acids and the potential for adverse health outcomes.

Recommendations to consume fish for prevention of cardiovascular disease (CVD), along with the U.S. Food and Drug Administration-approved generally recognized as safe (GRAS) status for long chain omega-3 fatty acids, may have had the unanticipated consequence of encouraging long-chain omega-3 (ω-3) fatty acid [(eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] supplementation and fortification practices. While there is evidence supporting a protective role for EPA/DHA supplementation in reducing sudden cardiac events, the safety and efficacy of supplementation with LCω-3PUFA in the context of other disease outcomes is unclear. Recent studies of bacterial, viral, and fungal infections in animal models of infectious disease demonstrate that LCω-3PUFA intake dampens immunity and alters pathogen clearance and can result in reduced survival. The same physiological properties of EPA/DHA that are responsible for the amelioration of inflammation associated with chronic cardiovascular pathology or autoimmune states, may impair pathogen clearance during acute infections by decreasing host resistance or interfere with tumor surveillance resulting in adverse health outcomes. Recent observations that high serum LCω-3PUFA levels are associated with higher risk of prostate cancer and atrial fibrillation raise concern for adverse outcomes. Given the widespread use of supplements and fortification of common food items with LCω-3PUFA, this review focuses on the immunomodulatory effects of the dietary LCω-3PUFAs, EPA and DHA, the mechanistic basis for potential negative health outcomes, and calls for biomarker development and validation as rational first steps towards setting recommended dietary intake levels.

Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis.

Clinically, excessive ω-6 polyunsaturated fatty acid (PUFA) and inadequate ω-3 PUFA have been associated with enhanced risks for developing ulcerative colitis. In rodent models, ω-3 PUFAs have been shown to either attenuate or exacerbate colitis in different studies. We hypothesized that a high ω-6: ω-3 PUFA ratio would increase colitis susceptibility through the microbe-immunity nexus. To address this, we fed post-weaned mice diets rich in ω-6 PUFA (corn oil) and diets supplemented with ω-3 PUFA (corn oil+fish oil) for 5 weeks. We evaluated the intestinal microbiota, induced colitis with Citrobacter rodentium and followed disease progression. We found that ω-6 PUFA enriched the microbiota with Enterobacteriaceae, Segmented Filamentous Bacteria and Clostridia spp., all known to induce inflammation. During infection-induced colitis, ω-6 PUFA fed mice had exacerbated intestinal damage, immune cell infiltration, prostaglandin E2 expression and C. rodentium translocation across the intestinal mucosae. Addition of ω-3 PUFA on a high ω-6 PUFA diet, reversed inflammatory-inducing microbial blooms and enriched beneficial microbes like Lactobacillus and Bifidobacteria, reduced immune cell infiltration and impaired cytokine/chemokine induction during infection. While, ω-3 PUFA supplementation protected against severe colitis, these mice suffered greater mortality associated with sepsis-related serum factors such as LPS binding protein, IL-15 and TNF-α. These mice also demonstrated decreased expression of intestinal alkaline phosphatase and an inability to dephosphorylate LPS. Thus, the colonic microbiota is altered differentially through varying PUFA composition, conferring altered susceptibility to colitis. Overall, ω-6 PUFA enriches pro-inflammatory microbes and augments colitis; but prevents infection-induced systemic inflammation. In contrast, ω-3 PUFA supplementation reverses the effects of the ω-6 PUFA diet but impairs infection-induced responses resulting in sepsis. We conclude that as an anti-inflammatory agent, ω-3 PUFA supplementation during infection may prove detrimental when host inflammatory responses are critical for survival.

Diets rich in n-6 PUFA induce intestinal microbial dysbiosis in aged mice.

Controversies have emerged regarding the beneficial v. detrimental effects of dietary n-6 PUFA. The alteration of the intestinal microbiota, a phenomenon termed dysbiosis, occurs during several chronic inflammatory diseases, but has not been well studied in an aged population. With present 'Western' diets predominantly composed of n-6 PUFA, we hypothesised that PUFA-rich diets cause intestinal dysbiosis in an aged population. C57BL/6 mice (aged 2 years) were fed a high-fat (40% energy), isoenergetic and isonitrogenous diet composed of rapeseed oil, maize oil or maize oil supplemented with fish oil. We examined ileal microbiota using fluorescence in situ hybridisation and stained tissues by immunofluorescence for the presence of immune cells and oxidative stress. We observed that feeding high-fat diets rich in n-6 PUFA promoted bacterial overgrowth but depleted microbes from the Bacteroidetes and Firmicutes phyla. This corresponded with increased body mass and infiltration of macrophages and neutrophils. Fish oil supplementation (rich in long-chain n-3 PUFA like DHA and EPA) restored the microbiota and inflammatory cell infiltration and promoted regulatory T-cell recruitment. However, fish oil supplementation was associated with increased oxidative stress, evident by the increased presence of 4-hydroxynonenal, a product of lipid peroxidation. These results suggest that an n-6 PUFA-rich diet can cause dysbiosis and intestinal inflammation in aged mice. However, while fish oil supplementation on an n-6 PUFA diet reverses dysbiosis, the combination of n-6 and n-3 PUFA, like DHA/EPA, leads to increased oxidative stress, which could exacerbate gastrointestinal disorders in the elderly.

Cardiac proinflammatory pathways are altered with different dietary n-6 linoleic to n-3 alpha-linolenic acid ratios in normal, fat-fed pigs.

Although dietary fat has been associated with inflammation and cardiovascular diseases (CVD), most studies have focused on individuals with preexisting diseases. However, the role of dietary fatty acids on inflammatory pathways before the onset of any abnormality may be more relevant for identifying initiating factors and interventions for CVD prevention. We fed young male pigs one of three diets differing in n-6 and n-3 polyunsaturated fatty acids (PUFA) linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (ALA, 18:3n-3) for 30 days. Cardiac membrane phospholipid fatty acids, phospholipase A(2) (PLA(2)) isoform activities, and cyclooxygenase (COX)-1 and -2 and 5-lipoxygenase (5-LO) expression were measured. The low PUFA diet (% energy, 1.2% LA+0.06% ALA) increased arachidonic acid (AA) and decreased eicosapentaenoic acid (EPA) in heart membranes and increased Ca(2+)-independent iPLA(2) activity, COX-2 expression, and activation of 5-LO. Increasing dietary ALA while keeping LA constant (1.4% LA+1.2% ALA) decreased the heart membrane AA, increased EPA, and prevented proinflammatory enzyme activation. However, regardless of high ALA, high dietary LA (11.6% LA and 1.2% ALA) decreased EPA and led to a high heart membrane AA, and Ca(2+)-dependent cPLA(2) with a marked increase in nitrosative stress. Our results suggest that the potential cardiovascular benefit of ALA is achieved only when dietary LA is reduced concomitantly rather than fed with high LA diet. The increased nitrosative stress in the unstressed heart with high dietary LA suggests that biomarkers of nitrosative stress may offer a useful early marker of the effects of dietary fat on oxidative tissue stress.

Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary omega-6 polyunsaturated fatty acids.

Increased awareness of obesity has led to a dietary shift toward "heart-friendly" vegetable oils containing omega-6 polyunsaturated fatty acid (omega-6 PUFA). In addition to its beneficial effects, omega-6 PUFA also exhibits proinflammatory and prooxidative properties. We hypothesized that chronic dietary omega-6 PUFA can induce free radical generation, predisposing the cardiac mitochondria to oxidative damage. Male Wistar rats were fed a diet supplemented with 20% w/w sunflower oil, rich in omega-6 PUFA (HP) or normal laboratory chow (LP) for 4 weeks. HP feeding augmented phospholipase A(2) activity and breakdown of cardiolipin, a mitochondrial phospholipid. HP hearts also demonstrated elevated inducible nitric oxide synthase expression, loss of Mn superoxide dismutase, and increased mitochondrial nitrotyrosine levels. In these hearts, oxidative damage to mitochondrial DNA (mDNA) was demonstrated by 8-hydroxyguanosine immunopositivity, overexpression of DNA repair enzymes, and a decrease in the mRNA expression of specific respiratory subunits encoded by the mDNA. Functionally, at higher workloads, HP hearts also demonstrated a greater decline in cardiac work than LP, suggesting a compromised mitochondrial reserve. Our study, for the first time, demonstrates that consumption of a high fat diet rich in omega-6 PUFA for only 4 weeks instigates mitochondrial nitrosative damage and causes cardiac dysfunction at high afterloads.

Cardiac cell death in early diabetes and its modulation by dietary fatty acids.

Diabetes is a significant risk factor for cardiovascular diseases with the majority of these complications being attributed to coronary vascular pathology. However, both in humans and animal models of diabetes, an additional heart muscle specific disease in the absence of any vascular pathology has also been described. Even though diverse mechanisms have been suggested to explain the etiology of this diabetic heart disease, important roles of oxidative stress and cell death have been implicated behind this disorder. Apart from hyperglycemia, cardiac lipid overload is currently believed to be responsible for oxidative stress and cell death in the diabetic heart. Although lipotoxicity is considered a major player in precipitating cardiac cell death, most of the existing work revolves around saturated and monounsaturated fatty acids. Looking at the current western diet with its preponderance of omega-6 polyunsaturated fatty acids (PUFA), more emphasis should be placed on its role in the diabetic heart. In this review, we shall highlight the most intriguing and updated findings of the differential fatty acid classes including omega-6 PUFA and their established/probable roles on diabetic myocardial cell death.

Role of dietary fatty acids and acute hyperglycemia in modulating cardiac cell death.

OBJECTIVE: We examined the effect of dietary manipulation of palmitic acid (20% [w/w] palm oil [PO]) on cardiomyocyte apoptosis in the rat heart under normoglycemic and hyperglycemic conditions in vivo. We used 20% (w/w) sunflower oil (SO; a diet rich in omega-6 polyunsaturated fatty acids) as an isocaloric control. METHODS: Adult male Wistar rats were fed experimental diets containing normal laboratory chow (5% corn oil) or a high fat diet (AIN-76A with PO or SO) for 4 wk. Subsequently, to induce diabetes, rats were injected with streptozotocin (55 mg/kg, intravenously). After 4 d of diabetes, hearts were tested for evidence of lipotoxicity and cell death, and the serum for its related markers. RESULTS: Feeding PO and SO magnified palmitic and linoleic acid contents within lipoproteins and hearts respectively. Compared with SO, PO diabetic hearts demonstrated significantly higher levels of apoptosis, with an altered Bax:Bcl-2 ratio, augmented lipid peroxidation, and protein modification by formation of nitrotyrosine. Interestingly, SO-fed diabetic animals demonstrated an increase in serum lactate dehydrogenase and myocardial necrotic changes. CONCLUSION: In marked contrast to results obtained in vitro, PO feeding led to only a minor fraction of cardiomyocytes undergoing apoptosis and suggests that, in the intact heart, protective mechanisms could be triggered that dampen excessive apoptosis. Of greater clinical significance was the observation that "heart-friendly" vegetable oils such as SO, rich in omega-6 polyunsaturated fatty acids, could precipitate cardiac necrosis, and questions its beneficial role in the cardiovascular system, especially following diabetes.

Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA.

Diabetic patients are particularly susceptible to cardiomyopathy independent of vascular disease, and recent evidence implicates cell death as a contributing factor. Given its protective role against apoptosis, we hypothesized that dietary n-6 polyunsaturated fatty acid (PUFA) may well decrease the incidence of this mode of cardiac cell death after diabetes. Male Wistar rats were first fed a diet rich in n-6 PUFA [20% (wt/wt) sunflower oil] for 4 wk followed by streptozotocin (STZ, 55 mg/kg) to induce diabetes. After a brief period of hyperglycemia (4 days), hearts were excised for functional, morphological, and biochemical analysis. In diabetic rats, n-6 PUFA decreased caspase-3 activity, crucial for myocardial apoptosis. However, cardiac necrosis, an alternative mode of cell death, increased. In these hearts, a rise in linoleic acid and depleted cardiac glutathione could explain this "switch" to necrotic cell death. Additionally, mitochondrial abnormalities, impaired substrate utilization, and enhanced triglyceride accumulation could have also contributed to a decline in cardiac function in these animals. Our study provides evidence that, in contrast to other models of diabetic cardiomyopathy that exhibit cardiac dysfunction only after chronic hyperglycemia, n-6 PUFA feeding coupled with only 4 days of diabetes precipitated metabolic and contractile abnormalities in the heart. Thus, although promoted as being beneficial, excess n-6 PUFA, with its predisposition to induce obesity, insulin resistance, and ultimately diabetes, could accelerate myocardial abnormalities in diabetic patients.