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In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function. [ABSTRACT FROM AUTHOR]

Chemical cues play important roles in mediating ecological interactions. Oxylipins, oxygenated metabolites of fatty acids, are one signalling molecule type that influences the physiology and function of species, suggesting their broader significance in chemical communication within aquatic systems. Yet, our current understanding of their function is restricted taxonomically and contextually making it difficult to infer their ecological significance. Snails and leeches are ubiquitous in freshwater ecosystems worldwide, yet little is known about their oxylipin profiles and the factors that cause their profiles to change. As snails and leeches differ taxonomically and represent different trophic groups, we postulated oxylipin profile differences. For snails, we hypothesized that ontogeny (non-reproductive vs reproductive) and predation (non-infested vs leech-infested) would affect oxylipin profiles. Oxylipins were characterized from water conditioned with the snail Planorbella duryi and leech Helobdella lineata , and included three treatment types (snails, leeches, and leech-infested snails) with the snails consisting of three size classes: small (5–6 mm, non-reproductive) and medium and large (13–14 and 19–20 mm, reproductive). The two species differed in the composition of their oxylipin profiles both in diversity and amounts. Further, ontogeny and predation affected the diversity of oxylipins emitted by snails. Our experimental profiles of oxylipins show that chemical cues within freshwater systems vary depending upon the species emitting the signals, the developmental stage of the species, as well as from ecological interactions such as predation. We also identified some candidates, like 9-HETE and PGE 2 , that could be explored more directly for their physiological and ecological roles in freshwater systems. [Display omitted] • Snails and leeches had species-specific oxylipin profiles. • Ontogeny and predation affected the diversity of oxylipins emitted by snails. • Oxylipin profiles of small non-reproductive snails differed more versus other snails. • Leech-infested snails emitted less oxylipins than uninfested snails. • We identified candidate oxylipins to test their physiological and ecological roles. [ABSTRACT FROM AUTHOR]

Background: Ex vivo studies suggest that increased renal prostanoids can mediate effects of high-protein (HP) compared with low-protein (LP) diets on normal and diseased kidneys. However, a short-term HP feeding study in normal male rats failed to demonstrate higher renal prostanoids in vivo.Objectives: The aim of the present study was to investigate whether long-term HP feeding alters renal prostanoids in male and female mice, with and without kidney disease.Methods: Weanling normal mice (CD1) and mice with kidney disease (CD1-pcy/pcy mice) were fed standard diets with normal protein [NP, 20% of energy (%E)] or HP (35%E) for 13 wk. Renal disease was assessed by histomorphometric analysis of cysts and fibrosis, and measurement of serum urea nitrogen (SUN) and creatinine concentrations. Targeted analysis of renal oxylipins was performed by HPLC-MS/MS.Results: The HP diet increased kidney size and water content of normal kidneys, and worsened disease in CD1-pcy/pcy mice as indicated by higher (P < 0.05) kidney weights (8-31%), water content (8-10%), cyst volume (36-60%), fibrous volume (44-53%), and SUN (47-55%). Diseased compared with normal kidneys had higher (P < 0.05) concentrations of 6 of 11 prostanoids and lower (P < 0.05) concentrations of 33 of 54 other oxylipins. This is consistent with previously known effects of dietary HP and disease effects on the kidney. However, the HP diet did not alter renal prostanoids and other renal oxylipins in either normal or diseased kidneys (P < 0.05), despite having the expected physiological effects on normal and diseased kidneys. This study also showed that females have higher concentrations of renal prostanoids [9 of 11 prostanoids higher (P < 0.05) in females], but lower concentrations of other oxylipins [28 of 54 other oxylipins lower (P < 0.05) in females].Conclusions: The effects of HP diets on normal and diseased kidneys in CD1 and CD1-pcy/pcy mice are independent of renal oxylipin alterations. [ABSTRACT FROM AUTHOR]

Oxylipins and fatty acids may be novel therapeutic targets for cardiovascular disease. The objective was to determine if plasma oxylipins or fatty acids can influence the odds of cardiovascular/cerebrovascular events. In 98 patients (25 female, 73 male) with peripheral artery disease, the prevalence of transient ischemic attacks, cerebrovascular accidents, stable angina, and acute coronary syndrome was n = 16, 10, 16, and 24, respectively. Risk factors such as being male, diagnosed hypertension, diabetes mellitus, and hyperlipidemia were not associated with events. Plasma fatty acids and oxylipins were analyzed with gas chromatography and HPLC-MS/MS, respectively. None of 24 fatty acids quantified were associated with events. In contrast, 39 plasma oxylipins were quantified, and 8 were significantly associated with events. These 8 oxylipins are known regulators of vascular tone. For example, every 1 unit increase in Thromboxane B2/Prostaglandin F1α and every 1 nmol/L increase in plasma 16-hydroxyeicosatetraenoic acid, thromboxane B2, or 11,12-dihydroxyeicosatrienoic acid (DiHETrE) increased the odds of having had ≥2 events versus no event ( p < 0.05). The greatest predictor was plasma 8,9-DiHETrE, which increased the odds of acute coronary syndrome by 92-fold. In conclusion, specific oxylipins were highly associated with clinical events and may represent specific biomarkers and (or) therapeutic targets of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background and aims Oxylipins, including eicosanoids, are highly bioactive molecules endogenously produced from polyunsaturated fatty acids. Oxylipins play a key role in chronic disease progression. It is possible, but unknown, if oxylipin concentrations change with the consumption of functional foods or differ with subject age. Methods Therefore, in a parallel comparator trial, 20 healthy individuals were recruited into a younger (19–28 years) or older (45–64 years) age group (n = 10/group). Participants ingested one muffin/day containing 30 g of milled flaxseed (6 g alpha-linolenic acid) for 4 weeks. Plasma oxylipins were isolated through solid phase extraction, analyzed with HPLC-MS/MS targeted lipidomics, and quantified with the stable isotope dilution method. Results At baseline, the older group exhibited 13 oxylipins ≥ 2-fold the concentration of the younger group. Specifically, pro-inflammatory oxylipins 5-hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid were significantly greater in the older (1.1 ± 0.23 nM, 5.6 ± 0.84 nM, and 4.5 ± 0.58 nM, respectively) versus the younger group (0.34 ± 0.12 nM, 3.5 ± 0.33 nM, and 3.0 ± 0.24 nM, respectively) (p < 0.05). After 4 weeks of flaxseed consumption the number of oxylipins that were ≥ 2-fold higher in the older versus the younger group was reduced to 3. 5-Hydroxyeicosatetraenoic acid, 9,10,13-trihydroxyoctadecenoic acid, and 9,12,13-trihydroxyoctadecenoic acid decreased in the older group to concentrations equivalent to the younger group after flaxseed consumption. Conclusion These data suggest a potential role for oxylipins in the aging process and how nutritional interventions like flaxseed can beneficially disrupt these biological changes associated with inflammation and aging. [ABSTRACT FROM AUTHOR]

Host behavior may be modified by their parasites to increase the likelihood of transmission, but mechanisms underlying these interactions are not well understood. Hosts and parasites release chemical signaling molecules, like oxylipins, that may affect transmission. Oxylipins are oxygenated metabolites of fatty acids that function as signaling molecules and have essential physiological and functional roles. Yet, the limited taxonomic and contextual scope of these studies constrains our ability to understand their role in parasite‐modified behavior. We characterized oxylipins in field-collected File Ramshorn snails, Planorbella pilsbryi. We tested for differences in oxylipin profiles based on infection status (infected with the trematode Echinostoma trivolvis lineage a and uninfected) and parasite activity (high and low). Snail-conditioned water samples were produced by placing five snails into artificial spring water for four hours. Oxylipins were extracted from snail-conditioned water samples and quantified using high performance liquid chromatography-tandem mass spectrometry. Infected snails emitted 69 oxylipins in higher amounts, with 37 only released by this group. Within infected snails, 18 oxylipins were emitted in higher amounts in snails with increased parasite activity. Oxylipins emitted in higher amounts by infected snails with increased parasite activity were predominantly derived from the cytochrome P450 pathway. As infected snails emit different oxylipin profiles than uninfected snails, their production may play a role in altering transmission success. By characterizing the oxylipins produced by snails, and how they are altered by infection, we can test their physiological and ecological roles in freshwater systems. • We used HPLC/MS/MS to discover a potential mechanism of parasite-modified behavior. • Oxylipin profiles of trematode infected and uninfected snails dramatically differed. • Diversity and amount of oxylipins differed based on infection and parasite activity. • Alteration of oxylipins may be a mechanism of parasite-modified behavior. [ABSTRACT FROM AUTHOR]

Examines the effects of dietary soy protein on disease and insulin-like growth factor-binding proteins (IGF-I) in model rats. Delay in the progression of polycystic kidney disease; Role of IGF-I in cell growth and differentiation; Extraction of serum aliquots.

Many foods including edible oils contain 2-monochloropropane-1,3-diol (2-MCPD), a processing-induced chemical contaminant. Cardiotoxic effects have been shown to result from oral 2-MCPD exposure in rodents, but the underlying mechanisms of action remain poorly understood. We undertook a comprehensive multi-omics approach to assess changes at the transcriptomic, proteomic, and oxylipin levels in heart tissues from male F344 rats that were exposed to 0 or 40 mg/kg BW/day of 2-MCPD in the diet for 90 days, in a regulatory compliant rodent bioassay. Heart tissues were collected for RNA sequencing, quantitative PCR analysis, proteomic analysis via two-dimensional gel electrophoresis and mass spectrometry, and targeted lipidomic profiling by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Transcriptomic and proteomic data analyses revealed upregulation of immune/inflammatory response processes and downregulation of energy metabolism and cardiac structure and functions. Among differentially expressed gene–protein pairs, coronin-1A, a key leukocyte-regulating protein, emerged as markedly up-regulated. Oxylipin profiling highlighted a selective suppression of docosahexaenoic acid-derived metabolites, suggesting a disruption in cardioprotective lipid pathways. These findings suggest that 2-MCPD disrupts homeostasis through inflammatory activation and suppression of metabolic and cardiac function. This research provides insights into 2-MCPD's cardiotoxicity, emphasizing the need for further studies to support hazard characterization. [ABSTRACT FROM AUTHOR]

Investigates the effect of butyrate on cAMP receptor protein kinase (PKA) activity in young adult mouse colon cells isolated from transgenic mice bearing a temperature sensitive mutation of the SV40 large T antigen gene. Incubation of cells at 33 degrees centigrade with or without 1 mmol/L butyrate for 24 hours; Level of PKA I isozyme.

Examines the effects of diet and disease on phosphoinositide composition and metabolism in kidneys of mice with polycystic kidney disease (PKD). Phosphatidylinositol-phosphate (PIP) to phosphatidylinositol (PI) molar ratio; Modulation of renal phosphoinositide signal transduction in mice with PKD due to dietary protein level and lipid composition alterations.

Pharmacological and dietary approaches to reducing high blood lipids in the general population decrease cardiovascular disease risk. Patients with chronic kidney disease (CKD) often display elevated blood lipids, and reducing cholesterol levels with statin drugs reduces cardiovascular disease in patients with moderate CKD, similar to the effects in the general population. Benefits to kidney disease itself appear to be marginal, if present. Studies with omega-3 fatty acids indicate that both cardiovascular and kidney disease progression may be slowed by dietary omega-3 fatty acids in CKD patients, but long-term studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

High protein (HP) diets are often used as a means to reduce obesity, but their long-term effects remain unclear. In vitro studies suggest the involvement of a subset of oxylipins in the tissue response to HP diets. To examine the role of these bioactive lipids in vivo, normal adult male Sprague Dawley rats were provided isocaloric diets with LP (low protein, 8% protein by weight), NP (normal protein, 14%) or HP (50%) diets for 2 weeks, and targeted lipidomic analysis of oxylipins in kidney (cortex and medulla), liver and serum was performed by HPLC-MS/MS. The main group of oxylipins affected by the HP diet was the oxylipins derived from linoleic acid (LA), many of which were elevated in kidney (particularly the medulla) and liver, but reduced in serum of rats provided the HP compared to NP or LP diets. A smaller proportion of other n-6 fatty acid derived oxylipins were lower in kidney and higher in liver, and none were affected in serum, by HP feeding. Few n-3 oxylipins were affected by protein level. In liver only, the oxylipin product to substrate ratios of the soluble epoxide hydrolase enzyme were higher in LP fed rats. Differences between cortex and medulla oxylipins suggest relatively higher cortex activity of 5- and 8-lipoxygenase and cytochrome P450 hydroxylase, and higher medulla cyclooxygenase and 12- and 15-lipoxygenase activity. Further studies are needed to elucidate the physiological effects of the changes in these novel oxylipins in response to short-term dietary HP. [ABSTRACT FROM AUTHOR]

There is much data on the effects of dietary n-3 fatty acids on tissue fatty acid compositions, but comparable comprehensive data on their oxygenated metabolites (oxylipins) is limited. The effects of providing female and male rats with diets high in α-linolenic acid (ALA), EPA or DHA for 6 weeks on oxylipins and fatty acids in kidney, liver and serum were therefore examined. The oxylipin profile generally reflected fatty acids, but it also revealed unique effects of individual n-3 fatty acids that were not apparent from fatty acid data alone. Dietary ALA increased renal and serum DHA oxylipins even though DHA itself did not increase, while dietary EPA did not increase DHA oxylipins in kidney or liver, suggesting that high EPA may inhibit this conversion. Oxylipin data generally corroborated fatty acid data that indicated that DHA can be retroconverted to EPA and that further retroconversion to ALA is limited. Dietary n-3 fatty acids decreased n-6 fatty acids and their oxylipins (except linoleic acid and its oxylipins), in order of effectiveness of DHA > EPA > ALA, with some exceptions: several arachidonic acid oxylipins modified at carbon 15 were not lower in all three sites, and EPA had a greater effect on 12-hydroxy-eicosatetraenoic acid and its metabolites in the liver. Oxylipins were predominantly higher in males, which was not reflective of fatty acids. Tissue-specific oxylipin profiles, therefore, provide further information on individual dietary n-3 fatty acid and sex effects that may help explain their unique physiological effects and have implications for dietary recommendations. [ABSTRACT FROM AUTHOR]

Consumption of different PUFAs (polyunsaturated fatty acids) can induce functional changes in blood vessels via endothelial cells, which interact with dietary factors in the circulation. The basement membrane that separates the endothelium from the smooth muscle cells of the medial layer can also influence the functional state of endothelial cells. However, the effect of basement membrane on the endothelial response to dietary PUFAs in relation to growth state (e.g. proliferation versus quiescence) has never been investigated. We therefore compared the viability (CCK kit) and proliferation (bromodeoxyuridine incorporation) of EA.hy926 endothelial cells grown on Matrigel or collagen versus non-coated plates. EA.hy926 viability and proliferation were also assessed after treatment with 0–150 μM of PUFAs [linoleic acid (LA), arachidonic acid (AA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. Our study showed that only cells grown on Matrigel-coated plates reached quiescence after becoming confluent with a decreased level of MCM2 and p-cyclin D1 (T286), increased levels of p27kip1 and a low level of apoptosis and senescence. AA, EPA and DHA decreased the viability and proliferation of subconfluent cells grown on plastic dishes in a dose-dependent manner, while the presence of Matrigel made the cells resistant to these adverse effects. Confluent cell viability was less sensitive to higher concentrations of AA, EPA and DHA than subconfluent cells, and a significant increase in caspase-3 cleavage was only observed in confluent cells treated with DHA. Higher concentrations of AA, EPA and DHA suppressed DNA synthesis by both subconfluent and confluent cells, while precursor C18 PUFAs (LA and ALA) had no negative effects on viability and proliferation. Our study is the first to show that extracellular matrix and growth state are important factors in the EA.hy926 cell response to PUFAs, and that the mechanisms by which individual PUFAs operate may be growth state-dependent. [ABSTRACT FROM AUTHOR]

Generation of oxylipins (oxygenated metabolites of fatty acids) by lipoxygenases may be responsible for the beneficial effects of 20- and 22-carbon n-3 fatty acids on adipose tissue dysfunction in obesity, but the potential actions of oxylipins derived from 18-carbon fatty acids, which are generally at higher levels in the diet, are unknown. We therefore compared the effects of select lipoxygenase-derived oxylipins produced from α-linolenic acid (ALA, C18:3 n-3), linoleic acid (LA, C18:2 n-6), and arachidonic acid (AA, C20:4 n-6) on key adipocyte functions that are altered in obesity. Individual oxylipins were added to the culture medium of differentiating 3T3-L1 preadipocytes for 6 days. Lipid accumulation was subsequently determined by Oil Red O staining, while Western blotting was used to measure levels of proteins associated with lipid metabolism and characteristics of adipocyte functionality. Addition of all oxylipins at 30 nM was sufficient to significantly decrease triglyceride accumulation in lipid droplets, and higher levels completely blocked lipid production. Our results establish that lipoxygenase-derived oxylipins produced from 18-carbon PUFA differentially affect multiple adipocyte processes associated with lipid storage and adipokine production. However, these effects are not due to the oxylipins blocking adipocyte maturation and thus globally suppressing all adipocyte characteristics. Furthermore, these oxylipin species decrease the lipid content of adipocytes regardless from which precursor fatty acid or lipoxygenase they were derived. Consequently, adipocyte characteristics can be altered through the ability of oxylipins to selectively modulate levels of proteins involved in both lipid metabolism and adipokine production. [ABSTRACT FROM AUTHOR]

Chloropropanols have been identified as processing-induced food contaminants that occur as by-products of the manufacturing of refined food oils and hydrolyzed vegetable protein. There has been a paucity of research on the 2-monochloropropane-1,3-diol (2-MCPD) isomer, thus forming a data gap for regulatory risk assessment. Previous studies suggest 2-MCPD causes adverse cardiotoxic, nephrotoxic, and myotoxic effects, but were inconclusive for hazard identification; thus a dose-response OECD TG-408 -compliant study was conducted by Health Canada. Our study profiled the effects of 2-MCPD on oxylipins and oxidized phosphatidylcholines, using HPLC-MS/MS, in heart, kidney, serum, and skeletal muscle of male and female F344 rats orally exposed to 2-MCPD (40 mg/kg BW/d) for 90 days. Cardiac n-3 polyunsaturated fatty acid-derived oxylipins, particularly DHA-derived oxylipins, were lower with 2-MCPD exposure, coincident with cardiac lesions. Lipoxygenase-derived oxylipins were decreased in the serum with a greater effect in the male 2-MCPD treatment group. Few oxylipin alterations were seen in the kidney and there was an absence of alterations in the tibialis anterior. Oxidized phosphatidylcholines and isoprostanes were not altered in this study, indicating that oxidative stress was not elevated by 2-MCPD. These findings add to the weight of the evidence for 2-MCPD toxicity and support the use of serum oxylipins as potential biomarkers of 2-MCPD exposure. • Oxylipin profiles were altered in heart, kidney, and serum of rats exposed to the food contaminant 2-MCPD. • DHA-derived oxylipins were lower in 2-MCPD-exposed hearts, indicating a pro-inflammatory response signature. • 2-MCPD-induced cardiac inflammation was independent of oxidative stress lipid biomarkers (OxPC & isoprostanes). • The oxylipin alterations discovered in the heart provide evidence of their critical role in cardiotoxicity. [ABSTRACT FROM AUTHOR]

1.5 million new HIV infections occurred in 2021, suggesting new prevention methods are needed. Inflammation increases the risk for HIV acquisition by attracting HIV target cells to the female genital tract (FGT). In a pilot study, acetylsalicylic acid (ASA/Aspirin) decreased the proportion of FGT HIV target cells by 35 %. However, the mechanism remains unknown. Women from Nairobi, Kenya took low-dose ASA (81 mg) daily for 6-weeks. Free oxylipins in the plasma were quantified by high-performance liquid chromatography-tandem mass spectroscopy. Oxylipins from 9 fatty acid substrates were detected, with more than one analyte from 4 substrates reduced post-ASA. Summary analysis found ASA downregulated cyclooxygenase and lipoxygenase but not cytochrome P450 activity with a lower n-6/n-3 oxylipin profile, reflecting reduced inflammation post-ASA. Inflammation is associated with increased lipoxygenase activity and HIV risk. Our data suggests ASA reduces inflammation through downregulation of oxylipins. Understanding how ASA reduces inflammation may lead to novel HIV prevention approaches. [Display omitted] • Analysis of oxylipins derived from multiple fatty acids. • Characterization of oxylipin metabolites in a Kenyan population. • Summary analysis of oxylipin metabolism by enzyme. • Validation of ASA detection in plasma prior to analysis. [ABSTRACT FROM AUTHOR]

Oxylipins are oxygenated derivatives of polyunsaturated fatty acids, generated by COX, LOX and CYP enzymes, that regulate various aspects of endothelial cell physiology. Although 15-LOX and its products are positively associated with atherosclerosis, the relevant mechanisms have not been explored. The current study examined the effects of PD146176 (PD), a putative 15-LOX inhibitor, on EA.hy926 endothelial cell functions in the growing and confluent states. The effects of PD on endothelial cell oxylipin production (profiled by LC/MS/MS), cell viability, proliferation, eNOS activity, ICAM-1 and VE-cadherin levels were assessed. The contribution of signaling pathways relevant to endothelial function (p38 MAPK, Akt, PPARα) were also investigated. PD treatment for 30 min did not block formation of individual 15-LOX oxylipins, but 20 μM PD stimulated the accumulation of total LOX and COX products, while reducing several individual CYP products generated by epoxygenase. At 20 μM, the accumulated total oxylipins were primarily LOX-derived (86%) followed by COX (12%) and CYP (2%). PD altered cell functions by upregulating p38 MAPK and PPARα and downregulating Akt in a dose-dependent fashion. These observations suggest a link between PD-induced changes in oxylipins and altered endothelial cell functions via specific signaling pathways. In conclusion, the results of this study imply that PD does not function as a 15-LOX inhibitor in EA.hy926 endothelial cells, and instead inhibits CYP epoxygenase. These findings suggest that the cellular function changes induced by PD may be contingent upon its ability to modulate total oxylipin production, particularly by the LOX and CYP families. • PD146176 (PD) does not block formation of individual oxylipins by 15-LOX. • 30 min PD treatment stimulates total oxylipin production by LOX and COX families. • LOX-derived oxylipins are more abundant than from COX and CYP after PD treatment. • 20 μM PD blocks total oxylipin production by CYP epoxygenases after 30 min. • PD146176 modulates endothelial cell function through p38 MAPK, PPARα and Akt. [ABSTRACT FROM AUTHOR]

Pulses (beans, peas, and lentils) have been consumed for at least 10 000 years and are among the most extensively used foods in the world. A wide variety of pulses can be grown globally, making them important both economically as well as nutritionally. Pulses provide protein and fibre, as well as a significant source of vitamins and minerals, such as iron, zinc, folate, and magnesium, and consuming half a cup of beans or peas per day can enhance diet quality by increasing intakes of these nutrients. In addition, the phytochemicals, saponins, and tannins found in pulses possess antioxidant and anti-carcinogenic effects, indicating that pulses may have significant anti-cancer effects. Pulse consumption also improves serum lipid profiles and positively affects several other cardiovascular disease risk factors, such as blood pressure, platelet activity, and inflammation. Pulses are high in fibre and have a low glycemic index, making them particularly beneficial to people with diabetes by assisting in maintaining healthy blood glucose and insulin levels. Emerging research examining the effect of pulse components on HIV and consumption patterns with aging populations indicates that pulses may have further effects on health. In conclusion, including pulses in the diet is a healthy way to meet dietary recommendations and is associated with reduced risk of several chronic diseases. Long-term randomized controlled trials are needed to demonstrate the direct effects of pulses on these diseases. [ABSTRACT FROM AUTHOR]

Background: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. Methods: Over a six-week period, 81 wild-type C57Bl/6 female mice (8–12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. Results: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. Conclusion: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model. [ABSTRACT FROM AUTHOR]

Long-term consumption of high-protein (HP) diets at 35% of energy is postulated to negatively influence bone health. Previous studies have not comprehensively examined the biochemical, physical, and biomechanical properties of bone required to arrive at this conclusion. Our objective in this study was to examine the long-term effect of a HP diet on bone metabolism, mass, and strength in rats. Adult female Sprague-Dawley rats (n = 80) were randomized to receive for 4, 8, 12, or 17 mo a normal-protein (NP) control diet (15% of energy) or a HP diet (35% of energy). Diets were balanced for calcium because the protein sources were rich in calcium. At each time point, measurements included weight, body composition, and bone mass using dual-energy X-ray absorptiometry, mechanical strength at the mid-diaphysis of femur and tibia, microarchitecture of femurs using microcomputerized tomography and serum osteocalcin, carboxy-terminal cross)inks of type I collagen (CTX), insulin-like growth factor-1 (IGF-1), leptin, and adiponectin. Effects of diet, time, and their interaction were tested using factorial ANOVA. The HP diet resulted in lower body weight, total body, and abdominal fat and higher lean mass. Serum leptin and adiponectin were greater in HP-fed than in NP-fed rats, but IGF-1 did not differ between the groups. Whereas the HP diet resulted in higher relative bone mineral content )g/kg) in the femur, tibia, and vertebrae, serum osteocalcin and CTX and bone internal architecture and biomechanical strength were unaffected. In conclusion, HP diets at 35% of energy lower body fat content without hindering the mechanical and weight-bearing properties of bone. [ABSTRACT FROM AUTHOR]

We recently demonstrated that (n-3) PUFA trigger the induction of apoptosis in the colon by enhancing phospholipid oxidation and mitochondrial Ca2+ accumulation. To further elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, a 2 × 2 experiment was designed using both wild type (control) and manganese-dependent superoxide dismutase (SOD2) heterozygous knockout mice (SOD2+/-), which exhibit increased mitochondrial oxidative stress. Mice were fed diets differing only in the type of fat [corn oil or fish oil containing (n-3) PUFA] at 15% by weight for 4 wk. Dietary (n-3) PUFA treatment enhanced (22%) apoptosis in colonic crypts. In addition, SOD2 haploinsufficiency enhanced (20%) apoptosis, which was further increased (36%) by (n-3) PUFA feeding. Dietary lipid source and genotype interactively modulated nitrotyrosine levels (P=0.027) and inflammation (P=0.032). These findings demonstrate that the proapoptotic effects of (n-3) PUFA are enhanced in oxidatively stressed SOD2+/- mice. Thus, (n-3) PUFA appear to promote an oxidation-reduction imbalance in the intestine, which may directly or indirectly trigger apoptosis and thereby reduce colon cancer risk. [ABSTRACT FROM AUTHOR]

The article discusses a 2021 study on the influence of oxylipins on muscle growth, inflammation and repair in select muscles in young rats. It states that rat soleus (SO) have a higher number and greater mass of oxylipins compared with red gastrocnemius (RG) and white gastrocnemius (WG) muscles, and that oxylipins generally reflect diet effects on polyunsaturated fatty acids (PUFA) in all muscles with notable exceptions. Also noted are the higher oxylipins in female SO and RG.

Background: Omega-3 fatty acids, including DHA and α-linolenic acid (ALA), are proposed to improve metabolic health by reducing obesity-associated inflammation. Their effects are mediated in part by conversion to oxylipins. ALA is relatively understudied, and direct comparisons to other omega-3 fatty acids are limited.Objectives: We compared the effects of equal doses of ALA and DHA on plasma oxylipins and markers of metabolic health in women with obesity.Methods: We carried out a randomized, double-blind, crossover clinical trial where women aged 20-51 with a BMI of 30-51 kg/m2 were supplemented with 4 g/day of ALA or DHA for 4 weeks in the form of ALA-rich flaxseed oil or DHA-rich fish oil. The primary outcome, the plasma oxylipin profile, was assessed at Days 0 and 28 of each phase by HPLC-MS/MS. Plasma fatty acids, inflammatory markers, and the monocyte glucose metabolism were key secondary outcomes. Data were analyzed using a mixed model.Results: Compared to the baseline visit, there were higher plasma levels of nearly all oxylipins derived from DHA (3.8-fold overall; P < 0.001) and EPA (2.7-fold overall; P < 0.05) after 28 days of fish-oil supplementation, while there were no changes to oxylipins after flaxseed-oil supplementation. Neither supplement altered plasma cytokines; however, adiponectin was increased (1.1-fold; P < 0.05) at the end of the fish-oil phase. Compared to the baseline visit, 28 days of flaxseed-oil supplementation reduced ATP-linked oxygen consumption (0.75-fold; P < 0.05) and increased spare respiratory capacity (1.4-fold; P < 0.05) in monocytes, and countered the shift in oxygen consumption induced by LPS.Conclusions: Flaxseed oil and fish oil each had unique effects on metabolic parameters in women with obesity. The supplementation regimens were insufficient to reduce inflammatory markers but adequate to elicit increases in omega-3 oxylipins and adiponectin in response to fish oil and to alter monocyte bioenergetics in response to flaxseed oil. This trial was registered at clinicaltrials.gov as NCT03583281. [ABSTRACT FROM AUTHOR]

Saskatoon berry (SKB) may have the potential to counter reno‐cardiac syndrome owing to its antioxidant capacity. Here, we investigated the renal and cardiovascular effects of SKB‐enriched diet in a rat model of reno‐cardiac disease. Two groups of wild‐type rats (+/+) and two groups of Hannover Sprague‐Dawley (Han:SPRD‐Cy/+) rats were given either regular diet or SKB diet (10% w/w total diet) for 8 weeks. Body weight, kidney weight, kidney water content, and left ventricle (LV) weight were measured. Blood pressure (BP) was measured by the tail‐cuff method. Echocardiography was performed to assess cardiac structure and function. Serum creatinine and malondialdehyde (MDA) were also measured. Han:SPRD‐Cy/+ rats had significantly higher kidney weight, kidney water content, LV weight, BP, and creatinine compared with wild‐type rats (+/+). The SKB diet supplementation did not reduce kidney weight, kidney water content, BP, and LV weight in Han:SPRD‐Cy/+ rats. The SKB diet also resulted in higher systolic BP in Han:SPRD‐Cy/+rats. Han:SPRD‐Cy/+rats showed cardiac structural remodeling (higher LV wall thickness) without any cardiac functional abnormalities. Han:SPRD‐Cy/+ rats also had significantly higher creatinine whereas the concentration of MDA was not different. The SKB diet supplementation reduced cardiac remodeling and the concentration of MDA without altering the concentration of creatinine in Han:SPRD‐Cy/+ rats. In conclusion, Han:SPRD‐Cy/+ rats developed significant renal disease, high BP, and cardiac remodeling by 8 weeks without cardiac functional impairment. The SKB diet may be useful in preventing cardiac remodeling and oxidative stress in Han:SPRD‐Cy/+rats. Practical applications: Saskatoon berry (SKB) is widely consumed as fresh fruit or processed fruit items and has significant commercial value. It may offer health benefits due to the presence of bioactives such as anthocyanins. SKB has very good culinary flavors, and it is an economically viable fruit crop in many parts of the world. The disease‐modifying benefits of SKB are mainly ascribed to the antioxidant nature of its bioactive content. Polycystic kidney disease is a serious condition that can lead to renal and cardiac abnormalities. Here, we showed that SKB supplementation was able to mitigate cardiac remodeling and lower the level of a marker of oxidative stress in an animal model of reno‐cardiac syndrome. Our study suggests that SKB possesses beneficial cardioprotective properties. Further evidence from human studies may help in increasing the consumption of SKB as a functional food. [ABSTRACT FROM AUTHOR]

Endothelial cells, which help to maintain vascular homeostasis, can be functionally modulated by polyunsaturated fatty acids. Previously, we reported that docosahexaenoic acid (DHA) reduced the viability of confluent EA.hy926 endothelial cells with caspase-3 activation. This study therefore examined the molecular mechanism by which DHA affects the viability of confluent cells, with a focus on the interaction between caspase-9, caspase-8, caspase-3, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) by Western blotting. Our results revealed that DHA induces apoptosis of confluent cells through both intrinsic and extrinsic pathways, which requires activation of p38 MAPK, and involves activation of JNK, caspase-9, caspase-8 and caspase-3 with the exception that cleavage of caspase-8 was incomplete and truncated BID was not detected at the maximum time (8 h) examined. Apoptosis induced by high levels of DHA in healthy endothelial cells is achieved through positive feedback loops linking these MAPKs to multiple caspases, as well as negative feedback from p38 MAPK to JNK. However, only p38 MAPK is crucial in apoptosis induction in comparison with JNK or any other caspase examined. This study has expanded the knowledge on the molecular mechanism of DHA-induced apoptosis in human endothelial cells and has also implied the differential roles of MAP kinases and caspases in apoptosis. Unlabelled Image • DHA induces apoptosis in confluent EA.hy926 cells. • DHA treatment leads to partial cleavage of caspase-8 (p43 subunit). • DHA-induced apoptosis does not involve participation of cleaved BID. • DHA upregulates multiple caspases via p38 MAPK and JNK. • p38 MAPK, instead of caspase-8, -9, -3 or JNK, is critical in apoptosis regulation. [ABSTRACT FROM AUTHOR]

Background: Differences in health effects of dietary α-linolenic acid (ALA) and DHA are mediated at least in part by differences in their effects on oxylipins.Objectives: Time course and sex differences of plasma oxylipins in response to ALA- compared with DHA-rich supplements were examined.Methods: Healthy men and women, aged 19-34 y and BMI 18-28 kg/m2, were provided with capsules containing ∼4 g/d of ALA or DHA in a randomized double-blind crossover study with >6-wk wash-in and wash-out phases. Plasma PUFA and oxylipin (primary outcome) concentrations at days 0, 1, 3, 7, 14, and 28 of supplementation were analyzed by GC and HPLC-MS/MS, respectively. Sex differences, supplementation and time effects, and days to plateau were analyzed.Results: ALA supplementation doubled ALA concentrations, but had no effects on ALA oxylipins after 28 d, whereas DHA supplementation tripled both DHA and its oxylipins. Increases in DHA oxylipins were detected as early as day 1, and a plateau was reached by days 5-7 for 11 of 12 individual DHA oxylipins and for total DHA oxylipins. Nine individual DHA oxylipins reached a plateau in females with DHA supplementation, compared with only 4 in males. A similar time course and sex difference pattern occurred with EPA and its oxylipins with DHA supplementation. DHA compared with ALA supplementation also resulted in higher concentrations of 4 individual arachidonic acids, 1 linoleic acid, and 1 dihomo-γ-linolenic acid oxylipin, despite not increasing the concentrations of these fatty acids, further demonstrating that oxylipins do not always reflect their precursor PUFA.Conclusions: DHA compared with a similar dose of ALA has greater effects on both n-3 and n-6 oxylipins in young, healthy adults, with differences in response to DHA supplementation occurring earlier and being greater in females. These findings can help explain differences in dietary effects of ALA and DHA.This study was registered at clinicaltrials.gov as NCT02317588. [ABSTRACT FROM AUTHOR]

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 < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ-treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase-1 and the ratio of BCL2-associated X protein to B-cell lymphoma-extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways.Conclusion: In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ-mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective. [ABSTRACT FROM AUTHOR]

Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA α-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion. We find that ALA treatment leads to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production. Although ALA is known to be converted to longer-chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins. In contrast, we observed profound increases in oxylipins directly derived from ALA. Lipoxygenase products of linoleic acid were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. These results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those used by the long-chain omega-3 fatty acids EPA and DHA. Thus, there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Cystic kidney diseases are characterized by multiple renal cysts and are the leading cause of inherited renal disease. Oxylipins are bioactive lipids derived from fatty acids formed via cyclooxygenase, lipoxygenase and cytochrome P450 activity, and are important regulators of renal health and disease. Oxylipins are altered in nephronophthisis, a type of cystic kidney disease. To further investigate and to determine whether other cystic renal diseases share these abnormalities, a targeted lipidomic analysis of renal oxylipins was performed in orthologous models of autosomal dominant polycystic kidney disease 1 ( Mx1Cre + Pkd1 flox/flox mouse) and 2 ( Pkd2 ws25/− mouse), autosomal recessive polycystic kidney disease (PCK rat) and nephronophthisis ( jck/jck mouse). Kidney cyclooxygenase oxylipins were consistently higher in all diseased kidneys, even in very early stage disease. On the other hand, cytochrome P450 epoxygenase derived oxylipins were lower only in the autosomal recessive polycystic kidney disease and nephronophthisis models, while lipoxygenase and cytochrome P450 hydroxylase derived oxylipins were lower only in nephronophthisis. Sex effects on renal oxylipin alterations were observed but they did not always coincide with sex effects on disease. For oxylipins with sex effects, arachidonic acid derived oxylipins formed via cyclooxygenases and lipoxygenases were higher in females, while oxylipins from other fatty acids and via cytochrome P450 enzymes were higher in males. The consistent and unique patterns of oxylipin alterations in the different models indicates the importance of these bioactive lipids in cystic renal diseases, suggesting that pharmacological agents (e.g. cyclooxygenase inhibitors) may be useful in treating these disorders, for which effective treatment remains elusive. [ABSTRACT FROM AUTHOR]

Oxylipins are a group of fatty acid metabolites generated via oxygenation of polyunsaturated fatty acids and are involved in processes such as inflammation, immunity, pain, vascular tone, and coagulation. As a result, oxylipins have been implicated in many conditions characterized by these processes, including cardiovascular disease and aging. The best characterized oxylipins in relation to cardiovascular disease are derived from the ω-6 fatty acid arachidonic acid. These oxylipins generally increase inflammation, hypertension, and platelet aggregation, although not universally. Similarly, oxylipins derived from the ω-6 fatty acid linoleic acid generally have more adverse than beneficial cardiovascular effects. Alternatively, most oxylipins derived from 20- and 22-carbon ω-3 fatty acids have anti-inflammatory, antiaggregatory, and vasodilatory effects that help explain the cardioprotective effects of these fatty acids. Much less is known regarding the oxylipins derived from the 18-carbon ω-3 fatty acid α-linolenic acid, but clinical trials with flaxseed supplementation have indicated that these oxylipins can have positive effects on blood pressure. Normal aging also is associated with changes in oxylipin levels in the brain, vasculature, and other tissues, indicating that oxylipin changes with aging may be involved in age-related changes in these tissues. A small number of trials in humans and animals with interventions that contain either 18-carbon or 20- and 22-carbon ω-3 fatty acids have indicated that dietary-induced changes in oxylipins may be beneficial in slowing the changes associated with normal aging. In summary, oxylipins are an important group of molecules amenable to dietary manipulation to target cardiovascular disease and age-related degeneration. [ABSTRACT FROM AUTHOR]

Questions remain regarding the potential negative effects of dietary high protein (HP) on kidney health, particularly in the context of obesity in which the risk for renal disease is already increased. To examine whether some of the variability in HP effects on kidney health may be due to source of protein, obese fa/fa Zucker rats were given HP (35% of energy from protein) diets containing either casein, soy protein, or a mixed source of animal and plant proteins for 12 weeks. Control lean and obese rats were given diets containing casein at normal protein (15% of energy from protein) levels. Body weight and blood pressure were measured, and markers of renal structural changes, damage, and function were assessed. Obesity alone resulted in mild renal changes, as evidenced by higher kidney weights, proteinuria, and glomerular volumes. In obese rats, increasing the protein level using the single, but not mixed, protein sources resulted in higher renal fibrosis compared with the lean rats. The mixed-protein HP group also had lower levels of serum monocyte chemoattractant protein-1, even though this diet further increased kidney and glomerular size. Soy and mixed-protein HP diets also resulted in a small number of damaged glomeruli, while soy compared with mixed-protein HP diet delayed the increase in blood pressure over time. Since obesity itself confers added risk of renal disease, an HP diet from mixed-protein sources that enables weight loss but has fewer risks to renal health may be advantageous. [ABSTRACT FROM AUTHOR]

Monocytes play a large role in chronic inflammatory conditions such as obesity, atherosclerosis and infection. Marine-derived omega-3 fatty acids such as docosahexaenoic acid (DHA) beneficially alter immune function and attenuate chronic inflammation in part by modifying gene expression. Comparisons with plant-derived omega-3 α-linolenic acid (ALA) on immune cell gene expression and function are limited. Transcriptome analysis was performed on THP-1 human monocytes treated with ALA, DHA or vehicle for 48 hr using fold change analysis, principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), variable importance analysis (VIP), and ingenuity pathway analysis (IPA). Candidate genes were validated by qPCR. Functional assays evaluated the transcriptomic predictions. Expression of candidate transcripts identified in THP-1 cells were examined in PBMC from clinical trial (OXBIO; NCT 03583281) participants consuming ALA- or DHA-rich oil supplements. ALA and DHA-treated monocytes presented distinct transcriptomic profiles as per VIP and PLS-DA. Both fatty acids were predicted to reduce cellular cholesterol content, while ALA would uniquely increase response to infection and chemotactic signals. Functional assays revealed ALA and DHA decreased cholesterol content. DHA significantly decreased the response to infection and chemotaxis, but ALA had no effect. Candidate transcripts responded similarly in PBMC from n-3 PUFA supplemented women with obesity. ALA and DHA differentially alter the transcription profiles and functions associated with the response to infection, chemotaxis, and cholesterol metabolism in mononuclear immune cells. Thus, they may uniquely affect related disease processes contributing to obesity, atherosclerosis, and the response to infection. [Display omitted] • ALA and DHA treatment decrease cholesterol metabolism genes in THP-1 monocytes. • ALA increases expression of genes related to chemotaxis and response to infection. • OXBIO participants Immune cells have similar transcription patterns as THP-1 cells. • ALA and DHA uniquely affect processes associated with obesity and atherosclerosis. [ABSTRACT FROM AUTHOR]

Rationale for dietary advice in polycystic kidney disease (PKD) is based in part on animal studies that have examined non-orthologous models with progressive development of cystic disease. Since no model completely mimics human PKD, the purpose of the current studies was to examine the effects of dietary soy protein (compared to casein) or oils enriched in omega-3 fatty acids (fish or flax oil compared to soy oil) on early disease progression in two orthologous models of PKD. The models studied were Pkd2WS25/- mice as a model of autosomal dominant PKD, and PCK rats as a model of autosomal recessive PKD. After 13 weeks of feeding, dietary fish (but not flax) oil resulted in larger kidneys and greater kidney water content in female Pkd2WS25/- compared to control mice. After 12 weeks of feeding male PCK compared to control rats, both fish and flax compared to soy oil resulted in enlarged kidneys and livers, greater kidney water content and higher kidney cyst area in diseased rats. Dietary soy protein compared to casein had no effects in Pkd2WS25/- compared to control mice. In PCK rats, kidney and liver histology were not improved, but lower proteinuria and higher urine pH suggest that soy protein could be beneficial in the long term. Therefore, in contrast to studies in non-orthologous models during the progressive development phase, these studies in orthologous PKD models do not support dietary advice to increase soy protein or oils enriched in omega-3 oils in early PKD. [ABSTRACT FROM AUTHOR]

The blood–brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14-cis-eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n – 6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell™ inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2), an eicosanoid known to facilitate opening of the blood–brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein-labeled dextran from apical to basolateral medium. ARA-mediated permeability was attenuated by specific cyclooxygenase-2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA-mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA. [ABSTRACT FROM AUTHOR]

Obesity is increasing worldwide, and high-protein (HP) diets are widely used for weight loss. However, the overall safety of HP diets is not well established in obese individuals, who make up a significant proportion of the population. To evaluate the health effects of an HP diet in obesity, obesity-prone (OP) Sprague-Dawley rats were given high-fat diets for 12 weeks to induce obesity. Following this, for 8 more weeks, these rats were given either a normal-protein (NP) (15% of energy) or an HP (35% of energy) diet ad libitum, or the NP diet at a restricted level to achieve body weights similar to those of the HP group (pair-weighted (PW) group). Obesity-resistant (OR) control rats were also given the NP diet throughout the feeding period. The HP-OP group had higher food intake but lower body weight, improved glucose handling, and lowered serum haptoglobin compared with the NP-OP group. These benefits were also observed in PW-OP rats. In addition, PW-OP rats had less fat accumulation when compared with NP-OP rats, and an improved Lee index, lower liver size, and lower serum alanine aminotransferase when compared with HP-OP rats. On the other hand, kidney size, proteinuria, and serum homocysteine were increased in HP-OP rats compared with NP-OP rats, whereas PW-OP rats did not experience these effects. These results indicate that in obese rats, more benefits are obtained via dietary restriction with an NP diet and without some of the potentially detrimental effects of an HP diet. [ABSTRACT FROM AUTHOR]

Dietary conjugated linoleic acid (CLA) reduces indicators of early renal disease progression and the associated elevated cyclooxygenase (COX) levels in young obese rats with obesity-associated nephropathy (OAN). Therefore, renal function and injury and COX and its metabolites were assessed in obese fa/fa Zucker rats with more advanced renal disease. Obese rats at 16 weeks of age were provided with either cis (c)9, trans (t)11 ( fa/fa -9,11) or t10,c12 ( fa/fa -10,12) CLA for 8 weeks, and compared to lean (lean-CTL) and obese ( fa/fa -CTL) rats provided the control diet without CLA. Obese rats displayed significantly reduced renal function and increased renal injury compared to lean rats. In the obese rat groups, glomerular hypertrophy was reduced in both CLA-supplemented groups. While all other measures of renal function or injury were not different in fa/fa -9,11 compared to fa/fa -CTL rats, the fa/fa -10,12 rats had greater renal hypertrophy, glomerular fibrosis, fibrosis, tubular casts and macrophage infiltration compared to the fa/fa -CTL and fa/fa -9,11 groups. The fa/fa -10,12 group also had elevated levels of renal COX1, which was associated with increased levels of two oxylipins produced by this enzyme, 6-keto-prostaglandin F 1α , and thromboxane B 2 . Renal linoleic acid and its lipoxygenase products also were lower in obese compared to lean rats, but CLA supplementation had no effect on these or any other lipoxygenase oxylipins. In summary, supplementation with c9,t11 CLA did not improve more advanced OAN and t10,c12 CLA worsened the renal pathology. Altered production of select COX1 derived oxylipins was associated with the detrimental effect of the t10,c12 isomer. [ABSTRACT FROM AUTHOR]

Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD- Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD- cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression. [ABSTRACT FROM AUTHOR]

Obesity-related glomerulopathy (ORG) is a unique and emerging condition that can lead to renal failure. Early detection, aided by an earlier diagnostic marker, would improve patient outcomes; this could be facilitated by an accurate model. Such a model would be useful to examine interventions like dietary fatty acids, which are known to influence renal diseases in later stages. In this study, obese-prone rats were provided high-fat (55% of energy) diets for 12 weeks to generate a model of diet-induced obesity. The rats were subsequently provided dietary oils with various levels of alpha-linolenic acid (ALA) and linoleic acid (LA) for 8 weeks, as follows: (g ALA:LA per 100 g oil): canola/flax (20:18), canola (8:18), soy (9:53), high-oleic canola/canola (5:16), high-oleic canola (2:15), lard/soy (1:8), and safflower (0.2:73). The model developed obesity, glomerulomegaly, proteinuria, and scarce glomerular damage with an indolent course. Morphometry and histology revealed glomerulomegaly as the first renal structural alteration. The utility of this marker as a predictor for the presence of ORG and renal injury was evidenced by its correlation to visceral adiposity ( p < 0.0001, r = 0.44), proteinuria ( p < 0.0001, ρ = 0.55), change in proteinuria ( p = 0.0092, ρ = 0.42), and glomerular damage ( p < 0.0001, ρ = 0.48). Renal triglyceride ALA:LA was strongly correlated with dietary ALA:LA ( p < 0.0005, ρ = 0.96), and inversely associated with mean glomerular volume ( p = 0.02, ρ = -0.82). The diet-induced obese model accurately represents early ORG, and implicates glomerulomegaly as an early surrogate diagnostic marker. Early intervention with ALA-rich dietary oils slowed glomerular enlargement; these findings warrant further clinical investigation to promote optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients. [ABSTRACT FROM AUTHOR]

Analysis of oxylipins derived from fatty acids may provide insight into the biological effects of dietary lipids beyond their effects on tissue fatty acid profiles. We have previously observed that diets with higher amounts of e-linolenic acid (ALA; 18:3n3) are associated with reduced obesity-related glomerulopathy (ORG). Therefore, to examine the renal oxylipin profile, the effects of dietary linoleic acid (LA; 18:2n6) and ALA on oxytipins and renal phospholipid fatty acid composition, and the relationship between oxylipins and ORG, diet-induced obese rats displaying ORG were fed 8 different diets for 8 wk as follows (oil/oil = combination of two oils) [shown as ALA/LA (in g) per 100 g oil]: canola/flax (20/18), canola (8/18), soy (9/53), high-oleic canola/canola (5/16), high-oleic canola (2/15), lard/soy (1/8), and safflower (0.2/73). Targeted lipidomic analysis by HPLC-tandem mass spectrometry revealed that LA and ALA oxylipins comprised 60% of the total renal oxylipin profile examined. Of the >60 oxylipins screened, only those derived either directly or indirectly from ALA were associated with less glomerulomegaly, indicative of reduced ORG progression. Both the amount and ratio of dietary LA and ALA influenced renal polyunsaturated fatty acids (PUFAs); in contrast, only fatty acid amount altered oxylipins derived from these fatty acids, but there was no apparent competition by LA or ALA on their formation. Dietary LA incorporation into renal phospholipids was higher than for ALA, but ALA oxylipin:ALA ratios were higher than the analogous LA ratios for select lipoxygenase reactions. This indicates that the effect of dietary ALA on renal oxylipins exceeded what was reflected in renal PUFA composition, In conclusion, dietary LA and ALA have differential effects on renal oxylipins and PUFAs, and ALA-derived oxylipins are associated with renoprotection in this model of ORG. [ABSTRACT FROM AUTHOR]

Abstract: A mixture of dietary conjugated linoleic acid (CLA) isomers reduces inflammation and mitigates disease progression in the Han:SPRD-cy rat model of chronic kidney disease. Since cyclooxygenase (COX) activities and prostanoid levels are higher in diseased kidneys in this rat, and dietary CLA can inhibit COX2 and prostanoid production in other tissues, the effects of dietary CLA were investigated. Kidney homogenates from normal and diseased Han:SPRD-cy rats were analyzed for prostanoid levels under various conditions: endogenous levels, steady-state levels (60-min incubations) and produced by COX isoforms. Thromboxane B2 (TXB2; TXA2 metabolite), 6-keto-prostaglandin F1α (6-keto-PGF1α; PGI2 metabolite) and PGE2 levels under these conditions were two- to ninefold higher in diseased kidneys. Dietary CLA resulted in ∼32%–53% lower levels of prostanoids produced by total COX and COX2 activities in normal and diseased kidneys and partially mitigated alterations in COX2 protein levels associated with disease. The COX1 protein and activity were higher in renal disease, resulting in increased production of TXB2 and 6-ketoPGF1α, but not PGE2. Dietary CLA had no effect on COX1, however. Disease resulted in up to twofold higher ratios of TXB2/6-ketoPGF1α, TXB2/PGE2 and 6-ketoPGF1α /PGE2, and dietary CLA partially mitigated these increases under several conditions. Elevated levels of renal membrane associated cytosolic phospholipase A2 in diseased kidneys also were reduced by 50% with CLA feeding. The effects of CLA feeding on COX2 protein levels and activity indicate that the beneficial effect of dietary CLA in this renal disorder is mediated in part via effects on COX2-derived prostanoids. [Copyright &y& Elsevier]

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γ agonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoylcoenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism. [ABSTRACT FROM AUTHOR]

In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD. [ABSTRACT FROM AUTHOR]

Despite evidence of potential antiobesity effects of high-protein (HP) diets, the impact of consuming diets with protein levels at the upper limit of the acceptable macronutrient distribution range (AMDIR) on kidney health is unknown. To test whether HP diets affect renal health, whole plant and animal proteins in proportions that mimicked human diets were given to pigs, because their kidneys have a similar anatomy and function to those of humans. Adult female pigs received either normal-protein (NP) or HP 115 or 35% of energy from protein, respectivelyl isocaloric diets for either 4 018 mo. The higher protein in the HP diet was achieved by increasing egg and dairy proteins. Although there were initial differences in body weight and composition, after 8 mo these were similar in pigs consuming the NP and HP diets. The HP compared with NP diet, however, resulted in enlarged kidneys at both 4 and 8 mo. Renal and glomerular volumes were 60-70% higher by the end of the study. These enlarged kidneys had greater evidence of histological damage, with 55% more fibrosis and 30% more glomerulosclerosis. Renal monocyte chemoattractant protein-i levels also were 22% higher in pigs given the HP diet. Plasma homocysteine levels were higher in the HP pigs at 4 mo and continued to be elevated by 35% at 8 mo of feeding. These findings suggest that long-term intakes of protein at the upper limit of the AMDR from whole protein sources may compromise renal health. [ABSTRACT FROM AUTHOR]

Conjugated linoleic acid (CLA) slows the progression of disease in models of chronic kidney disease. Because obesity is associated with nephropathy and increased renal cyclooxygenase (COX) levels, the effects of dietary CLA on kidney function, morphology, and COX protein levels in the kidneys of young obese (fa/fa) Zucker rats, a model of metabolic syndrome, were examined. In study 1,6-wk-old fa/fa and lean Zucker rats were given a mixture of CLA isomers (1.5% CLA, wt:wt) or the control diet (CTL) with no CLA for 8 wk. To examine specific isomer effects, study 2 used the same model with the following diets: 0.4% (g/g) cis-9, trans-11 (c9,t11) CLA; 0.4% trans-10, cis-12 (t10,c12) CLA; a combination of these 2 isomers (0.4% each); or CTL diets with no CLA. In study 1, fa/fa rats given the CLA mixture had 11% smaller kidney weights and 28% smaller glomeruli, and feed intake and body weight did not differ from the CTL rats. In study 2, diet also did not affect body weights, but fa/fa rats given a diet containing t10, c12 CLA had 7% lower kidney weights, 20% smaller glomeruli, and 39% lower COX-2 protein levels than CTL rats. In conclusion, dietary t10, C12 CLA reduces the enlargement of glomeruli in young obesity-associated nephropathy and is associated with lower protein levels of renal COX-2. Long-term studies with CLA supplementation are required to determine whether these changes would lead to reduction in development of renal disease associated with obesity. [ABSTRACT FROM AUTHOR]

Background/Aims: Several dietary interventions, including those involving conjugated linoleic acid (CLA), slow progression of polycystic kidney disease (PKD) when initiated in the early stages of disease in Han:SPRD-cy rats. However, in humans, kidney disease is often undetected until extensive renal injury has developed. The objective of this study therefore was to determine whether initiating dietary CLA intervention in advanced PKD would slow disease progression. Methods: Adult male Han:SPRD-cy rats with advanced kidney disease were fed diets with or without 1% CLA for 16 weeks. Disease progression was assessed by serum urea, proteinuria, and creatinine clearance, and morphological and immunohistochemical measurements for pathologic change. Results: Renal injury was lower in the PKD rats given CLA compared to those given the control diet as indicated by a reduction in inflammation (42% less), fibrosis (28% less), oxidative damage (30% less) and proliferating cells (35% less). Diet had no effect on body, kidney, or liver weight, serum urea, serum creatinine, creatinine clearance, proteinuria, or cyst volume. Conclusions: Late dietary intervention with CLA reduced some disease-associated pathologies, but did not alter renal function in adult Han:SPRD-cy rats. The long-term anti-inflammatory, antioxidant, and antiproliferative benefits of CLA in advanced kidney disease remain to be determined. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: With the rising incidence of obesity and the metabolic syndrome, obesity-associated nephropathy also has increased. One of the earliest pathologies in the development of this nephropathy is glomerular hyperfiltration and hypertrophy. Dietary soy protein (SP) ameliorates disease progression in several models of renal disease, and vegetable sources of protein, as compared to animal sources of protein, alter renal hemodynamics. Therefore, the effect of dietary SP on early renal disease and prostanoid production was examined in the obese fa/fa Zucker rat. Rats, 6 weeks of age, were given diets containing 17% protein from either SP or egg white (EW) for 8 weeks. Feed consumption and body and kidney weights were significantly greater in fa/fa rats as compared to lean rats. The fa/fa rats also had 139% more proteinuria and kidneys with 43% larger glomeruli. SP feeding did not alter body weights or proteinuria but did result in 6% lower kidney weights (g/100 g body weight) and 16% smaller glomeruli in fa/fa rats. Cyclooxygenase activity as determined by 6-keto prostaglandin F1α (6-keto PGF1α) synthesis was lower in fa/fa rats given SP-based diets as compared to those given EW-based diets. Ratios of renal thromboxane (TX) B2/6-keto PGF1α and PGE2/6-keto PGF1α were higher, while TXB2/PGE2 levels were not different in rats given SP diets as compared to those given EW diets, also indicating that dietary SP reduced renal 6-keto PGF1α levels. These findings suggest that attenuation of early glomerular hypertrophy in young obese fa/fa rats by dietary SP may be mediated by the lower levels of 6-keto PGF1α since this would be expected to reduce glomerular hyperfiltration. [Copyright &y& Elsevier]