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A novel treatment for lupus nephritis: Lignan precursor derived from flax

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Abstract

Flaxseed has renoprotective effects in animal and human lupus nephritis. We have recently extracted the lignan precursor (secoisolariresinol diglucoside) (SDG) to determine if this more palatable derivative of flaxseed would exert renoprotection similar to the whole flaxseed in the aggressive MRL/lpr lupus mouse model. 131 MRL/lpr mice were randomly assigned to saline gavage, 600, 1,200 and 4,800 microg lignan gavage groups. At 7 weeks, 6 animals underwent platelet aggregating factor (PAF) lethal challenge and 40 were studied with urine collection to determine the levels of secoisolariresinol, enterodiol and enterolactone in the gavaged animals. A baseline study of 10 saline gavaged animals took place at 6 weeks. 25 animals in the saline gavage, 600 and 1200 microg lignan groups were studied at 14 and 22 weeks for GFR, spleen lymphocyte S-phase and organ weight studies. Metabolic studies indicated that secoisolariresinol is the major metabolite absorbed and the lowest lignan dose provides a lengthening in survival for the PAF lethal challenge. Body weight, fluid and water intake studies demonstrated that the lignan was well tolerated. Changes in proteinuria, GFR and renal size showed a time- and dose-dependent protection for the lignan precursor. Cervical lymph node size and spleen lymphocyte cells in the S-phase demonstrated modest dose-dependent reductions in the lignan gavaged groups. SDG was converted in the gut to secoisolariresinol, which was absorbed and well tolerated by the MRL/lpr mice. Renoprotection was evidenced, in a dose-dependent fashion, by a significant delay in the onset of proteinuria with preservation in GFR and renal size. This study suggests that SDG may have a therapeutic role in lupus nephritis.

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... The type of estrogenic effect depends on both the relative potency of the compound and the time of exposure [3,5] . Additionally, phytoestrogens exert antioxidant, antitumor, anti-breast and prostate cancers, anti-diabetic, cardiovascular diseases, menopausal symptoms, osteoporosis and some other activities [4][5][6][7][8] . ...
... The Table 2 below elucidated the proximate nutrients content of whole flaxseed. [24,25] Alpha Linolenic Acid (Omega-3) 1,710 mg Linoleic Acid (Omega- 6) 480 mg Oleic Acid (Omega-9) 540 mg Lignin Fiber 1,003 mg Mucilage 200.6 mg Lignan 13.6 mg ...
... SDG was found to prevent the development of diabetes type I and II [33,87] and improve renal function in lupus nephritis [6] . Thus, dietary SDG has the potential to decrease the incidence of several chronic diseases that result in significant morbidity and mortality in industrialized countries. ...
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... The type of estrogenic effect depends on both the relative potency of the compound and the time of exposure (Adlercreutz, 1995;Prasad et al., 2000). Additionally, phytoestrogens exert antioxidant, antitumor, anti- breast and prostate cancers, anti-diabetic, cardiovascular disease, menopausal symptoms, osteoporosis and some other activities ( Clark et al., 2000;Matthew et al., 2005;Mazur et al., 1998). ...
... SDG was found to prevent the development of diabetes I and II (Prasad, 1997(Prasad, , 2002) and improve renal function in lupus nephritis ( Clark et al., 2000). Thus, dietary SDG has the potential to decrease the incidence of several chronic diseases that result in significant morbidity and mortality in industrialized countries. ...
... Plasma enterodiol and enterolactone were not associated with risk of colorectal cancer after adjustment for known colorectal cancer risk factors. These findings do not support the hypothesis that high plasma enterodiol or enterolactone concentrations are associated with reduced risk of colorectal cancer (Serraino and Thompson, 1992), and they may have a therapeutic role in lupus nephritis ( Clark et al., 2000). ...
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The relationship between phytochemicals and degenerative diseases has attracted the attention of those industries engaged in functional food, nutraceutical and pharmaceutical production. Lignans are essential class of natural products and second class of phytoestrogens, they have attracted considerable interest due to their fascinating biological activities. Secoisolariciresinol Diglucoside (SDG), the major lignan of flaxseed has gained significant importance in nutritional and functional foods due to its substantial biological activities. For a lot of first-time author established a novel method for the synthesis of SDG from highly available precursors. In addition, author determines the antioxidant, antidiabetic, antiinflammatory, and antibacterial properties using several in vitro and in vivo methods. The book elucidates in details all information that readers need and fulfill the desire of scientist in an easy and fantastic way.
... Decreased lymph node hyperplasia, fatty accumulation, proteinuria and blood urea N Increased survival Decreased serum levels of anti-DNA antibodies and kidney immune complexes Improved glomerulonephritis and nephric vasculitis 2 % green tea-enriched diet (158) Human primary epidermal keratinocytes (170) BALB/c mice Reduced serum levels of TNF-α, IL-6, and IL-1β and improved survival after 9 h of LPS challenge 25 mg lucerne sprout ethyl acetate extract/kg BW by oral administration (169) Inhibited IL-6 and TNF-α production in LPS-primary macrophages 50 μg/ml NZB/W F 1 mice Decreased splenomegaly and proteinuria 0·01 % enriched diet (168) (177) Improved renal function, decreasing serum creatinine, plasma lipids, blood viscosity and increasing complement C3 l 30 g ground flaxseed/d (176) MRL/lpr Decreased proteinuria and improved renal function 600, 1200 and 4800 µg by oral administration (175) Improved survival Delayed and decreased proteinuria and splenic lymphocyte proliferation Attenuated glomerular filtration and lymphoproliferation 15 % flaxseed-enriched diet (174) Diarylheptanoids and arylalkanones Curcumin Curcuma longa L. Patients with SLE Modulated Th17/Treg balance of CD4 + T cells by reducing Th17 response and IL-17A production and increasing Treg differentiation and TGF-β1 production 0·1 and 1 µg/ml (178) Decreased proteinuria levels and systolic blood pressure 22·1 mg three times/d (181) MRL/lpr Delayed onset of anti-RNP, anti-Sm, ANA and anti-dsDNA autoantibodies and proteinuria Decreased salivary gland infiltration and lymphadenopathy 5 mg/ml in water (179) NZB/W F 1 mice Decreased proteinuria, serum levels of IgG1, IgG2a and anti-dsDNA and IgG glomeruli immune complex deposition Reduced TNF-α and MCP-1 in kidney and FOXP3 in spleen 1 % enriched diet (180) ...
... A flaxseed-supplemented diet in a lupus mouse model improved renal damage and decreased splenic lymphocyte proliferation (174) . Similarly, oral administration with SDG from flaxseed showed dose-dependent protective effects in the kidney, with similar effects to those previously noted for dietary supplementation with flaxseed (175) . In a randomised cross-over trial, flaxseed supplementation over 17 weeks was well tolerated by patients with lupus nephritis and exerted significant positive effects on renal function (176) . ...
Article
Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease characterised by multiple organ involvement and a large number of complications. SLE management remains complicated owing to the biological heterogeneity between patients and the lack of safe and specific targeted therapies. There is evidence that dietary factors can contribute to the geoepidemiology of autoimmune diseases such as SLE. Thus, diet therapy could be a promising approach in SLE owing to both its potential prophylactic effects, without the side effects of classical pharmacology, and its contribution to reducing co-morbidities and improving quality of life in patients with SLE. However, the question arises as to whether nutrients could ameliorate or exacerbate SLE and how they could modulate inflammation and immune function at a molecular level. The present review summarises preclinical and clinical experiences to provide the reader with an update of the positive and negative aspects of macro- and micronutrients and other nutritional factors, including dietary phenols, on SLE, focusing on the mechanisms of action involved.
... Both SDG and its metabolites, EL and ED, were demonstrated to possess antioxidant activity in lipid and aqueous systems at relatively low concentrations (10). Besides, SDG was also reported to represent a potential treatment for renal disorders (12) and inhibit the development of type-1 and type-2 diabetes (13,14). ...
Article
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A simplified and efficient method is developed for the large-scale purification of the secoisolariciresinol diglucoside (SDG) from defatted flaxseed after aqueous ethanol extraction. Extractant from defatted flaxseed with aqueous ethanol is hydrolyzed with basic solution, concentrated under vacuum, subjected to Sephadex LH-20 column chromatography, and eluted with aqueous ethanol of different concentrations. Elution is monitored by a UV detector at 280 nm, and fractions containing SDG are pooled, concentrated, and applied to a second column chromatography under the same conditions. Elution with water results in a better resolution of SDG [94.5% by high-performance liquid chromatography (HPLC)] than that with pure ethanol or 50% (v/v) aqueous ethanol. HPLC-photodiode array detection-mass spectrometry and NMR are applied to identify SDG and to determine the purity of the eluted fraction. This simplified purification scheme avoids toxic organic solvent used in the common silica gel separation process and, thus, increases the safety of the process.
... Mais d'autres caractéristiques pourraient jouer un rôle, par exemple sa capacité à agir comme antioxydant, en particulier pour la prévention de l'apparition de cancers et de maladies cardiaques. Également étudiée, la prévention de diabète de type 1 et 2 [3,32], et celle du lupus [8]. Dans un autre domaine, la différenciation de kératinocytes et la stimulation de synthèse de collagène ont été observées in vitro [34,35]. ...
... Flaxseed has recently undergone extensive study at Agriculture Canada and elsewhere [11][12][13][14][15] because it contains high amounts of ␣-linolenic acid [11,[15][16][17] and a potent phytoestrogen precursor, secoisolariciresinol diglucoside (SDG), which leads to production of mammalian lignans in humans (facultative organisms in the GI tract produce enterodiol and enterolactone, which are absorbed and achieve high plasma concentrations). The chief phytoestrogen, SDG, has been extracted by Agriculture Canada [18]. ...
Article
Phytoestrogens offer a possible alternative to hormone replacement therapy. Flax seed contains large quantities of a phytoestrogen precursor, secoisolariciresinol diglucoside (SDG), as well as large quantities of alpha-linolenic acid; these factors may be protective against vascular disease. We have previously shown that the rise in blood pressure during mental stress is a strong predictor of atherosclerosis progression. 35 postmenopausal women with vascular disease, 62 +/- 8 years of age, were treated in a random-sequence double-blind Latin square crossover study comparing three strains of flax seed: Flanders (low in lignan and high in alpha-linolenic acid), Linola 989 (high in lignan and low in alpha-linolenic acid) and AC Linora (intermediate in both lignan and alpha-linolenic acid). Compared to the pre-treatment baseline diet, all three strains of flax significantly reduced blood pressure during mental stress induced by a frustrating cognitive task (Stroop color-word interference task) (p = 0.004). Linola 989, the strain highest in lignan and lowest in alpha-linolenic acid, was associated with the least increase in peripheral resistance during stress, the greatest reduction in plasma cortisol during stress and the smallest increase in plasma fibrinogen during mental stress. Flax phytoestrogens ameliorate certain responses to stress and thus may afford protection against atherosclerosis; this hypothesis should be tested in clinical trials.
... One of the major lignan precursors derived from flaxseed, SDG, has been shown to have antioxidant activity in animals [50][51][52]. In addition, Clark et al have shown that chronic oral administration of SDG (the lignan precursor also extracted from flax) for 22 weeks in MRL/lpr mice delayed the onset of proteinuria and preserved GFR and kidney weight in a time-and dose-dependent manner [53]. This study further suggests that SDG in flaxseed exerts renal protective effects similar to the whole flaxseed in this mouse model of lupus nephritis. ...
Article
Evidence is emerging that varying the type or source of dietary protein intake can have beneficial effects on chronic renal disease. Consumption of soybean and soy-based food products, as the source of plant protein, can retard the development and progression of chronic renal disease. We studied the obese spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat, a model of obesity and type II diabetes mellitus that consistently develops nephropathy resembling diabetic nephropathy. We specifically sought to determine whether changing the source of protein intake from animal protein, casein, to plant protein in the form of either soy protein concentrate or flaxseed protein in the diet has a different impact on renal function and nephropathy in this model. Male obese SHR/N-cp rats were randomly assigned to one of three diets containing either 20% casein, 20% soy protein concentrate, or 20% flaxseed meal. Except for the protein source, all three diets were identical and contained similar amounts of protein, fat, carbohydrates, minerals, and vitamins. All animals were maintained on these diets for 6 months. At the end of the study, blood sampling and 24-hour urine collections were performed for renal functional measurements, and the kidneys were harvested and examined for histologic evaluation. All three groups had similar amounts of food intake and body weight gain and exhibited fasting hyperglycemia and hyperinsulinemia. Plasma glucose levels did not differ among the three groups, but plasma insulin concentration was significantly lower in rats fed flaxseed meal than those fed either casein or soy protein concentrate. Mean plasma creatinine, creatinine clearance, and urinary urea excretion also did not differ significantly between the three groups. By contrast, urinary protein excretion was significantly lower (P < 0.01) in rats fed flaxseed than in rats fed either casein or soy protein concentrate. Morphologic analysis of renal structural lesions showed that the percentage of abnormal glomeruli with mesangial expansion and the tubulointerstitial score (an index of severity of tubulointerstitial damage) were significantly reduced in rats fed flaxmeal compared to those fed casein or soy protein concentrate. We conclude that dietary protein substitution with flaxseed meal reduces proteinuria and glomerular and tubulointerstitial lesions in obese SHR/N-cp rats and that flaxseed meal is more effective than soy protein in reducing proteinuria and renal histologic abnormalities in this model. The reduction in proteinuria and renal injury was independent of the amount of protein intake and glycemic control. Which dietary component(s) present in flaxseed meal is (are) responsible for the renal protective effect remains to be determined.
... Flaxseed and SDG are suggested to protect against renal diseases (reviewed by Ranich, Bhathena & Velasquez, 2001). Renal function in animal models or in humans has been shown to improve with flaxseed treatment (Hall et al., 1993; Clark et al., 2001; Velasquez et al., 2003) or SDG (Clark et al., 2000). ...
Article
Flaxseed is the richest plant source of the lignan secoisolariciresinol diglucoside (SDG). In flaxseed, SDG exists in an oligomeric structure with 3-hydroxy-3-methyl glutaric acid (HMGA) forming a phenolic complex together with p-coumaric acid and ferulic acid glucosides and herbacetin diglucoside (HDG). Epidemiological and animal studies indicate protective effects of flaxseed and SDG towards hormone-dependent cancers and cardiovascular diseases, and reducing effect toward cholesterol levels in blood. Knowledge about the structural features and properties of the phenolic complex are required to further understand bioavailability, bioconversion and bioactivity of flaxseed lignans in humans and animals, the biosynthesis in flaxseed, as well as if it may affect technology and quality of food products containing flaxseed or the phenolic complex. A new fast and simple high-performance liquid chromatographic (HPLC) method was developed for analysing secoisolariciresinol diglucoside (SDG), p-coumaric acid glucoside and ferulic acid glucoside, based on direct hydrolysis of defatted flaxseed flour using alkali. Variations in SDG, p-coumaric acid glucoside and ferulic acid glucoside content were reported in flaxseed samples and bread products containing flaxseed. The composition and properties of flaxseed phenolic complex were studied by reversed-phase liquid chromatography and gel filtration fractionation. Results indicate that the phenolic glucosides exist in oligomers with variable molecular sizes. A complicated linkage pattern and/or possibly interactions with other components may contribute to the observed complexity. SDG and the phenolic complex showed similar hydrogen-donating abilities to ferulic acid but higher than α-tocopherol in the DPPH inhibition metod, suggesting that SDG was the only active antioxidant in the phenolic complex. Contradicting results were obtained on the effect of SDG on levels of Vitamin E and cholesterol in two rat studies.
... 186 Limited research suggests that flaxseed may be renoprotective in individuals with lupus nephritis and warrants further investigation. 187,188 Other measures may provide additional benefits without doing harm. Even though research has failed to show a reduction in vascular events with vitamin therapy, folic acid plus B vitamins may be worthwhile in SLE patients. ...
Article
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Women with systemic lupus erythematosus (SLE) develop cardiovascular disease (CVD) earlier and at a more accelerated rate compared to women without SLE. Many women with SLE are unaware of their increased risk despite years spent in the health care system, thus giving the atherogenic process time to accrue damage. Research has not explained fully why women with SLE are unaware of their increased risk for CVD or why awareness does not correspond to risk-educing behaviors. Stage theories of behavior like the Precaution Adoption Process Model (PAPM) propose that health behavior change proceeds through qualitatively different stages, and people at one stage face similar barriers before they can progress to the next. The Common Sense Model (CSM), a self-regulatory model of health behavior, explains the emotional and cognitive processes involved in progression from one stage to the next and the formation of a personal risk/illness representation. Combining the PAPM and CSM helps understand the relationship between risk perception and adoption of risk reducing behaviors. The specific aims of this study were to assess in women with SLE: (1) general knowledge of heart disease compared to women without SLE; (2) awareness of increased CVD risk and CVD risk factors; and (3) personal and healthcare system factors that influence awareness of increased CVD risk and adoption of risk reducing behaviors. Sixty women with SLE, 18 years of age or older, were recruited to participate in this descriptive study. Data included demographic information, self-report questionnaires (perceived CVD risk, CVD risk factors, depression, physical activity), body measures (height, weight, waist circumference, blood pressure), and blood samples for physiologic markers of traditional and novel CVD risk factors (glucose, insulin, lipoprotein lipids, creatinine, C-reactive protein, homocysteine, antiphospholipid antibodies). The Beck Depression Inventory-Primary Care and the Physical Activity Disability Survey were used to determine depression and activity level respectively. General knowledge of heart disease was assessed using the American Heart Association (AHA) National Survey on women�s awareness of heart disease. Logistic regression was used to categorize participants into subgroups according to perceived risk and identify important factors that influenced their PAPM stage categorization. Women with SLE in this study were more aware of women�s leading cause of death than United States women who responded to the 2006 AHA survey (73% v 57%), but fewer than 25% perceived themselves at increased CVD risk. Age was a significant predictor (p=0.05) for awareness of increased risk; younger age correlated with increased awareness. Most women received information about heart disease from public media. On average, women had 4 CVD risk factors, but they perceived they had only 2. The number of perceived risk factors predicted adoption of risk reducing behaviors (p=0.03). Women in this study with SLE underestimated their CVD risk factors and did not personalize their increased CVD risk. Healthcare providers� identification and discussion of CVD risk factors in women with SLE may enhance their risk awareness and the adoption of risk reducing behaviors. This information may contribute to the development of stage-matched interventions, a potentially more effective and efficient approach than a generic program of risk-reduction, especially in individuals with SLE who face the additional burden of a chronic illness.
... They make the cell permeable, which helps in the protection of cells against invading bacterial toxins, infections, and viruses (Javed, 1999). The αlinolenic acid in flaxseed can reduce the risk of cardiovascular disease (CVD) osteoporosis, rheumatoid arthritis, and cancer (Adlercreutz, 2007;Kettler, 2001;Spence et al., 2003;Clark et al., 2000;Prasad et al., 1998). Omega-3 fatty acids present in flaxseed help in reducing blood triglycerides, blood pressure, platelet reactivity, neutrophil activity, and increase blood HDL cholesterol thereby helping in lowering CVD risk (Gorder et al., 1986;Cunnane et al., 1993;Li et al., 1999). ...
Article
Full-text available
Flaxseed is one of the most important oilseed crops for industrial as well as food, feed, and fiber purposes. Almost every part of the flaxseed plant is utilized commercially, either directly or after processing. The stem yields good quality fiber having high strength and durability. The seed provides oil rich in omega-3, digestible proteins, and lignans. In addition to being one of the richest sources of α-linolenic acid oil and lignans, flaxseed is an essential source of high quality protein and soluble fiber and has considerable potential as a source of phenolic compounds. Flaxseed is emerging as an important functional food ingredient because of its rich contents of α-linolenic acid (ALA), lignans, and fiber. Lignans appear to be anti-carcinogenic compounds. The omega-3s and lignan phytoestrogens of flaxseed are in focus for their benefits for a wide range of health conditions and may possess chemo-protective properties in animals and humans. This paper presents a review of literature on the nutritional composition of flaxseed, its health benefits, and disease-prevention qualities, utilization of flaxseed for food, feed, and fiber, and processing of flaxseed.
... Previous researches indicated that SDG could prevent mammary, colonic, and prostate cancer [4][5][6][7][8] and have a beneficial effect on tumour [9,10] and atherosclerosis [11]. Positive results were also found on lupus nephritis [12,13], hypertension [14,15], diabetes [16,17] and other diseases after SDG intake. Although SDG can be found in many food products, flaxseed appears to be the richest source, with values more than 100 times higher than those of the other foods. ...
Article
The optimal conditions for the extraction of lignans from flaxseed were determined. A second-order regression for rotation-orthogonal composite design was used to investigate the effects of three independent variables, namely ethanol concentration (%), extraction temperature (°C), and extraction time (h) on the response, the acquired ratio of lignans. The independent variables were coded at five levels and their actual values selected on the basis of results of single-factor experiment. The second-order regression for rotation-orthogonal composite design consisted of 23 experimental points and 9 replications at the central point. Data were analyzed using MATLAB software. The results indicated that acquired ratio of lignans might be beyond 8% at a probability of 95% in the range of ethanol concentration: 56.6–83.4%, extraction time: 26.7–27.9h, extraction temperature: 38.7–40.1°C. And the optimal extraction conditions were ethanol concentration of 70%, extraction time of 28h and extraction temperature of 40°C according to the analysis of response surface. In this condition, the experimental acquired ratio of lignans was 8.975% (w/w; lignans/defatted flaxseed powder), which is close to the predicted value (9.316%).
... Mais d'autres caractéristiques pourraient jouer un rôle, par exemple sa capacité à agir comme antioxydant, en particulier pour la prévention de l'apparition de cancers et de maladies cardiaques. Également étudiée, la prévention de diabète de type 1 et 2 [3,32], et celle du lupus [8]. Dans un autre domaine, la différenciation de kératinocytes et la stimulation de synthèse de collagène ont été observées in vitro [34,35]. ...
Article
Les graines du lin contiennent des teneurs très élevées en composés phénoliques, les lignanes, en particulier en sécoisolaricirésinol diglucoside (SDG). Ses propriétés antioxydantes et de liaison aux récepteurs oestrogéniques pourraient expliquer ses activités biologiques en rapport avec la prévention de certains cancers et des maladies cardiovasculaires. On observe cependant des résultats contradictoires parmi les études épidémiologiques publiées à ce jour. Toutefois, malgré la qualification de phytoestrogène du SDG, il n’a jamais été observé de stimulation de croissance de cellules cancéreuses. La connaissance du devenir des lignanes ingérés et de leurs interactions possibles avec notre métabolisme, en particulier hormonal, progresse. La récente disponibilité de produit purifié permet maintenant d’en étudier les effets in vitro.
... They make the cell permeable, which helps in the protection of cells against invading bacterial toxins, infections, and viruses (Javed, 1999). The αlinolenic acid in flaxseed can reduce the risk of cardiovascular disease (CVD) osteoporosis, rheumatoid arthritis, and cancer (Adlercreutz, 2007;Kettler, 2001;Spence et al., 2003;Clark et al., 2000;Prasad et al., 1998). Omega-3 fatty acids present in flaxseed help in reducing blood triglycerides, blood pressure, platelet reactivity, neutrophil activity, and increase blood HDL cholesterol thereby helping in lowering CVD risk (Gorder et al., 1986;Cunnane et al., 1993;Li et al., 1999). ...
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... The beneficial effects of omega-3 fatty acids on human health are well established (Conners 2000;Simopoulos 2003). The ALA reduces the risk of cardiovascular disease (CVD), osteoporosis, rheumatoid arthritis and cancer (Prasad et al. 1998;Clark et al. 2000;Spence et al. 2003;Aldercreutz 2007). There is, thus, an increasing interest in enriching the omega-3 fatty acid content of meat. ...
Article
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A 42-day study was conducted to evaluate the effect of ground full-fat flaxseed supplementation on growth performance, carcass characteristics, α-linolenic acid (ALA), linoleic acid (LA) and organoleptic characteristics of broiler meat. A total of 200 one-day-old broiler chicks were randomly allocated to five experimental groups and were fed isoenergetic and isonitrogenous diets containing flaxseed at 0%, 2.5%, 5.0%, 7.5% and 10%. Flaxseed supplementation did not affect the weekly body weight of broiler chicks during the first three weeks, but thereafter it reduced significantly with increasing levels of flaxseed in the diets. Birds fed on 10% flaxseed showed a reduction of 10.08% in body weight as compared to the control group. Diets containing 5.0–7.5% flaxseed resulted in significantly lower weight gain, higher feed conversion ratio, energy efficiency ratio and lower protein efficiency ratio as compared to control and 2.5% flaxseed diets. The carcass characteristics data indicated a little variation in the evisceration rate and giblet among treatment groups, but the breast yield was significantly higher in control than flaxseed groups. The protein, fat and ash content of broiler meat were not affected with the level of flaxseed in the diets. However, the inclusion of flaxseed in the diets significantly increased the ALA in the breast and thigh tissues with no difference in the organoleptic quality of meat. Keywords: flaxseed; broiler; growth performance; α-linolenic acid
... Previous researches indicated that SDG could prevent mammary, colonic, and prostate cancer [4][5][6][7][8] and have a beneficial effect on tumour [9,10] and atherosclerosis [11]. Positive results were also found on lupus nephritis [12,13], hypertension [14,15], diabetes [16,17] and other diseases after SDG intake. Although SDG can be found in many food products, flaxseed appears to be the richest source, with values more than 100 times higher than those of the other foods. ...
... Faxseed SDG has a therapeutic role in animal and human lupus nephritis. SDG significant delays the onset of proteinuria with preservation in GFR and renal size in a dose-dependent fashion [56]. Purified SDG during early life of a young rat animal sensitize bone strength due to low endogenous levels of sex hormones but having no negative effects on bone strength and bone health, as measures of bone mass in adulthood [57,58]. ...
Article
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Lignans are a group of phytonutrients which are widely distributed in the plant kingdom. Flaxseed is the richest source of providing lignan precursor such as secoisolariciresinol diglucoside (SDG). This article reviews the studies relevant to experimental models in animals and humans demonstrating the possible nutraceutical actions of SDG to prevent and alleviate lifestyle-related diseases. A local and international web-based literature review for this project was carried out to provide information relating to the study. The major key word "SDG" was selected to gather information using the electronic databases pertaining to the current state of flaxseed lignans composition, bioactive compounds, metabolism and to find out their role in terms of chemopreventive action. The extraction methods vary from simple to complex depending on separation, fractionation, identification and detection of the analytes. The majority of studies demonstrate that SDG interferes with the development of different types of diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress, immunity, atherosclerosis, hemopoietic, liver necrosis and urinary disorders due to its various biological properties including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic and neuroprotective effects. Moreover, SDG has a defending mediator against various cancers by modulating multiple cell signaling pathways. As discussed in this review, SDG has shown therapeutic potential against a number of human diseases and can be recommended for discerning consumers.
... They make the cell permeable, which helps in the protection of cells against invading bacterial toxins, infections, and viruses (Javed 1999). The α-linolenic acid in flaxseed can reduce the risk of cardiovascular disease (CVD) osteoporosis, rheumatoid arthritis, and cancer (Aldercreutz 2007;Kettler 2001;Spence et al. 2003;Clark et al. 2000;Prasad et al. 1998). Omega-3 fatty acids present in flaxseed help in reducing blood triglycerides, blood pressure, platelet reactivity, neutrophil activity, and increase blood HDL cholesterol thereby helping in lowering CVD risk (Gorder et al. 1986;Cunnane et al. 1993;Li et al. 1999). ...
Article
In the present study, effects of chemical (ethanol, HCl and sulphuric acid) pretreatment on various dehulling parameters of flaxseed (cv. Garima) including yield, hull, hullability, extraction rate and embryo (dehulled flaxseed) recovery were studied. Pretreated flaxseed, at 3.1 to 3.6 % moisture range (p > 0.05) were dehulled for 60 s in a laboratory model rice polisher/dehulling machine at 2,000 rpm followed by aspiration (hull separation) using a laboratory model aspirator. The study revealed that chemical pre-dehulling treatment of flaxseed plays a significant role in the embryo recovery of flaxseed. Both ethanol and HCl pre-dehulling treatment enhanced but sulphuric acid pretreatment reduced the embryo recovery of flaxseed. Moreover, HCL and Sulphuric acid deteriorated the quality of hull obtained during dehulling, hence may not be considered for flaxseed dehulling. The study showed the maximum embryo recovery from ethanol pretreated flaxseed, hence ethanol pre-dehulling treatment with 2 h tempering time may be considered for effective flaxseed dehulling.
... (Hall et al.,1993). Clark et al. (2000) concluded that dietary phytoestrogens have a beneficial role in chronic renal disease. Flaxseed has been shown to limit or reduced proteinuria and renal pathological lesion associated with progressive renal failure. ...
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of Tukhm-e-Katan (Linum usitatissimum L.). Int J Adv Pharm Med Bioallied Sci. 2017; 2017:111.
... SDG has been shown to be effective in several preclinical models of diseases in which oxidative stress and inflammation play a prominent role in pathogenesis, including heart disease [2][3][4] and diabetes [5,6]. In addition, SDG showed positive effects in cancer [4,7,8], liver [9,10], and kidney inflammation as well as in obesity and the metabolic syndrome [10,11]. Importantly, diverse SDG formulations have also been safely used in human clinical trials [4,10,12,13]. ...
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Background Secoisolariciresinol diglucoside (SDG), the main lignan in flaxseed, is known for its beneficial effects in inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes. SDG might be an attractive natural compound that protects against neuroinflammation. Yet, there are no comprehensive studies to date investigating the effects of SDG on brain endothelium using relevant in vivo and in vitro models. Methods We evaluated the effects of orally administered SDG on neuroinflammatory responses using in vivo imaging of the brain microvasculature during systemic inflammation and aseptic encephalitis. In parallel, the anti-inflammatory actions of SDG on brain endothelium and monocytes were evaluated in vitro blood-brain barrier (BBB) model. Multiple group comparisons were performed by one-way analysis of variance with Dunnet’s post hoc tests. ResultsWe found that SDG diminished leukocyte adhesion to and migration across the BBB in vivo in the setting of aseptic encephalitis (intracerebral TNFα injection) and prevented enhanced BBB permeability during systemic inflammatory response (LPS injection). In vitro SDG pretreatment of primary human brain microvascular endothelial cells (BMVEC) or human monocytes diminished adhesion and migration of monocytes across brain endothelial monolayers in conditions mimicking CNS inflammatory responses. Consistent with our in vivo observations, SDG decreased expression of the adhesion molecule, VCAM1, induced by TNFα, or IL-1β in BMVEC. SDG diminished expression of the active form of VLA-4 integrin (promoting leukocyte adhesion and migration) and prevented the cytoskeleton changes in primary human monocytes activated by relevant inflammatory stimuli. Conclusion This study indicates that SDG directly inhibits BBB interactions with inflammatory cells and reduces the inflammatory state of leukocytes. Though more work is needed to determine the mechanism by which SDG mediates these effects, the ability of SDG to exert a multi-functional response reducing oxidative stress, inflammation, and BBB permeability makes it an exciting potential therapeutic for neuroinflammatory diseases. SDG can serve as an anti-inflammatory and barrier-protective agent in neuroinflammation.
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В сообщении 1 рассмотрены проблемы эпидемиологии, патогенеза, морфологии и клиники волчаночного гломерулонефрита. In the report 1 epidemiology, pathogenesis, morphology and clinic lupus nephritis are discussed.
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Secoisolariciresinol (SECO ) is the major lignan found in flaxseed (Linum usitatissimum L.) and is present in a polymer that contains secoisolariciresinol diglucoside (SDG ). SECO, SDG and the polymer are known to have a number of health benefits, including reduction of serum cholesterol levels, delay in the onset of type II diabetes and decreased formation of breast, prostate and colon cancers. The health benefits of SECO and SDG may be partially attributed to their antioxidant properties. To better understand their antioxidant properties, SECO and SDG were oxidized using 2,2'-azobis(2-amidinopropane), an in vitro model of radical scavenging. The major lignan radical-scavenging oxidation products and their formation over time were determined. SDG was converted to four major products, which were the result of a phenoxyl radical intermediate. One of these products, a dimer of SDG, decomposed under the reaction conditions to form two of the other major products, and . SECO was converted to five major products, two of which were also the result of a phenoxyl radical intermediate. The remaining products were the result of an unexpected alkoxyl radical intermediate. The phenol oxidation products were stable under the reaction conditions, whereas two of the alcohol oxidation products decomposed. In general, only one phenol group on the lignans was oxidized, suggesting that the number of phenols per molecule may not predict radical scavenging antioxidant ability of lignans. Finally, SECO is a superior antioxidant to SDG, and it may be that the additional alcohol oxidation pathway contributes to its greater antioxidant ability.
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Flaxseed derivatives, including both oil and flax lignan, modify progression of renal injury in animal models, including Han:SPRD-cy polycystic kidney disease (PKD). Gender is a significant factor in the rates of progression of many forms of human renal disease, but the role of gender in the response to nutrition intervention in renal disease is unexplored. In this study, male and female Han:SPRD-cy rats or normal littermates were fed either corn oil (CO) or flax oil (FO) diets, with or without 20 mg/kg of the diet flax lignan secoisolaricinoresinol dyglycoside (SDG). Renal injury was assessed morphometrically and biochemically. Renal and hepatic PUFA composition was assessed by GC and renal PGE2 release by ELISA. FO preserved body weight in PKD males, with no effect in females. SDG reduced weight in both normal and PKD females. FO reduced proteinuria in both male and female PKD. FO reduced cystic change and renal inflammation in PKD males but reduced cystic change, fibrosis, renal inflammation, tissue lipid peroxides, and epithelial proliferation in PKD females. SDG reduced renal inflammation in all animals and lipid peroxides in PKD females. A strong interaction between SDG and FO was observed in renal FA composition of female kidneys only, suggesting increased conversion of C18 PUFA to C20 PUFA. FO reduced renal release of PGE2 in both genders. Gender influences the effects of flaxseed derivatives in Han:SPRD-cy rats. Gender-based responses to environmental factors, such as dietary lipid sources and micronutrients, may contribute to gender-based differences in disease progression rates.
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The aim of this paper is to review the literature on life story work in health and social care practice. Life story work as an intervention has been used with a number of health and social care clients, such as children people with learning disabilities, older people on medical wards and with older people who have dementia. It may help challenge ageist attitudes and assumptions, be used as a basis for individualized care, improve assessment, assist in transitions between different care environments, and help to develop improved relationships between care staff and family carers. However, to date there has been no attempt to collate the findings from published accounts. A systematic search of the literature on life story work was conducted in February 2004, using nursing, medical and social science databases and a combination of thesaurus and free text search terms. This revealed over 1000 publications; the use of carefully constructed inclusion and exclusion criteria identified 51 relevant items. Fourteen were subsequently selected and reviewed using a set of reflective critical appraisal questions. A range of methodological approaches has been adopted to explore the use of life story work with no one specific methodology prevailing. The work has been most frequently used with older people and people with a learning disability and life story books are the most common approach. Staff perceptions of life story work have been explored, but patient and carer views are less frequently reported. The findings of the studies are discussed in broad themes, offering some tentative recommendations for using life story work in practice. Evidence on the use of life story work is immature, leading to the recommendation for more research. Although appraising literature from a range of approaches is complex, there are some potentially far-reaching benefits of life story work in health and social care practice.
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The effects of dietary flaxseed (FS), and defatted flaxseed meal (FLM) on serum and tissue fatty acid profiles were investigated. Pregnant Sprague-Dawley rats were fed AIN-93 based diets balanced in calories, fat, nitrogen, and fiber. Diets contained 0, 20%, 40% FS or 13% or 26% FLM by weight. The control, FS and FLM diets differed in linoleic acid to alpha-linolenic acid (ALA) fatty acid ratio. These diets were fed continuously during gestation, suckling period and 8 weeks post-weaning (F(1)). FS fatty acids were bioavailable and metabolized by pregnant and F(1) rats. ALA and eicosapentaenoic acid increased; linoleic and arachidonic acid decreased; and docosahexaeonic acid was unchanged in serum, 'gastric milk' and liver of FS and FLM-fed pregnant and F(1) rats. FS more than FLM, changed fatty acids profiles, but FLM and 40% FS significantly reduced serum cholesterol. Dietary 40% FS may have increased oxidative stress as evidenced by a reduction in liver vitamin E.
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Flaxseed (FS) being rich in alpha-linolenic acid may alter the immune parameters. Therefore, we assessed the impact of FS and defatted flaxseed meal (FLM) on fatty acid composition, cell subsets, proliferation and IL-2 production by splenic lymphocytes. Pregnant female Sprague-Dawley rats were fed diets containing 0% FS and FLM, 20 or 40% FS, 13 or 26% FLM during gestation or gestation, lactation and 8 week post-weaning period. FS and FLM resulted in up to 8.3 fold and 4.6 fold increase in splenic ALA among pregnant rats, 4.5 fold and 1.2 fold increase in splenic ALA among F(1) generation rats. Splenic linoleic acid (LA) and arachidonic acid (AA) were 18 and 40% lower in 40% FS fed pregnant rats, and AA was 15% lower in all the other groups. Among F(1) rats, splenic LA and AA were 16 and 48% lower in 40% FS group, and AA was 18% lower in 20% FS and 26% FLM groups. Concanavalin A and phytohemagglutinin mediated proliferation of spleen cells were 60 and 52% lower in 40% FS fed pregnant and F(1) generation rats, respectively. No significant changes were observed in the cell subsets or IL-2 production by splenic cells from different groups.
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Person-centered care is increasingly regarded as being synonymous with best quality care. However, the concept and its precise meaning is a subject of debate and reliable and valid measurement tools are lacking. This article describes the development and initial testing of a new self-report assessment scale, the Person-centered Care Assessment Tool (P-CAT), which measures the extent to which long-term aged care staff rate their settings to be person-centered. A preliminary 39-item tool generated from research literature, expert consultations and research interviews with aged care staff (n = 37), people with early onset dementia (n = 11), and family members (n = 19) was distributed to a sample of Australian aged care staff (n = 220) and subjected to item analysis and reduction. Psychometric evaluation of the final 13-item tool was conducted using statistical estimates of validity and reliability. The results showed that the P-CAT was shown to be valid and homogeneous by factor, item and content analyses. Cronbach's alpha was satisfactory for the total scale (0.84), and the three subscales had values of 0.81, 0.77, and 0.31 respectively. Test-retest reliability were evaluated (n = 26) and all analyses indicated satisfactory estimates. This study provides preliminary evidence in support of the psychometric properties of the P-CAT when used in an Australian sample of long-term aged care staff. The tool contributes to the literature by making it possible to study person-centered care in relation to health outcomes, organizational models, characteristics and levels of staffing, degrees of care needs among residents, and impact of interventions.
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Despite the availability of health and social care services designed to support people in their own homes, older people often underuse or refuse these services. It is now acknowledged that this phenomenon contributes to older people being admitted to hospital and long-term care in circumstances that could be avoided. To understand how the uptake of supportive and preventative services can be improved, the first author, supervised by the second and third authors, developed a constructivist inquiry to explore what factors enhance or bar service use. This article describes how narratives were used not only to help identify decision- and choice-making influences, but also as a way of enhancing the hermeneutic processes associated with constructivism.
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This chapter discusses the ethnopharmacological properties, phytochemistry, and culture conditions of the Linum species. Flax fibers of Linum usitatissimum are separated from the shoots of this crop plant and are stronger than cotton fibers. Flaxseed is used in treatment of cardiac disorders, cancer, arthritis, wounds, abscesses, diabetes, and digestive disorders. The formulated products of flaxseed have gastroprotective effects and possess, inter alia, antibacterial, radioprotective, and nephroprotective properties. The presence of ellagic acid, catechin, chlorogenic acid, gallic acid, kaempferol, umbelliferone, caffeic acid, coumaric acid, epicatechin, and rutin in L. usitatissimum has also been determined by ultra‐performance liquid chromatography in six flaxseed cultivars. The suspension cultures of L. mucronatum were induced in darkness at 25∘C and analyzed for estimation of lignans. During the course of estimation, the 6‐methoxypodophyllotoxin was found as a major compound and its identity confirmed by spectral data analysis.
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This article aims to describe the content of person-centred care as described by people with dementia, family members and staff in residential aged care. Person-centred care is increasingly being regarded as synonymous with best quality aged care; however, studies exploring stakeholders' experiences of person-centred care are few. A qualitative explorative design was employed using conversational research interviews and content analysis. Research interviews were conducted in 2007 and 2008 with staff working in aged care (n = 37), people with early onset dementia (n = 11), and family members of patients with dementia (n = 19) and were analysed using content analysis. The findings indicated that the core category of person-centred care was promoting a continuation of self and normality. Five content categories emerged as contributing to promoting a continuation of self and normality: knowing the person; welcoming family; providing meaningful activities; being in a personalised environment; and experiencing flexibility and continuity. This study describes person-centred care as it is understood by people with dementia, their family members and staff in residential aged care, and as such it contributes with inside perspectives to current understandings of person-centred care, perspectives that have been largely lacking. Relevance to clinical practice.  The findings of this study are clinically relevant and ready to be operationalised and applied in clinical aged care. The categories can be used as a topic guide for discussions in aged care organisations on the quality of current care and as elements indicating how to increase the person-centredness of care provided.
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While established therapies are successful in many patients with systemic lupus erythematosus (SLE), there is still a great need for more effective and safer treatments, particularly with respect to the long-term outcomes and quality of life. New data continues to emerge regarding unproven but widely employed therapies, such as intravenous gammaglobulin and plasmapheresis, while several immunosuppressive and immunomodulatory agents originally developed for use in other diseases are being evaluated for their potential in SLE, in particular, the agent mycophenolate mofetil that in one study showed promising results in the treatment of lupus nephritis. Appropriately, a large number of entirely new therapies for SLE are currently being tested in animal models and in human clinical trials. These include the hormonal agent dehydroepiandrosterone, which has gone through extensive clinical trials with positive results. A number of biological agents, such as monoclonal antibodies targeting B lymphocytes (rituximab), various "second signal" inhibitors (including CTLA4-Ig), and anti-IL10 have also been tested in humans, with varying results. The B-cell toleragen LJP394 is being evaluated for its ability to prevent nephritis flares. In addition, a range of "alternative" treatments including herbs and nutritional supplements are available to the general public. Thus, while the proper evaluation of new treatments for SLE remains a formidable challenge, the prospects are excellent for more successful treatments in the not too distant future.
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Introduction: Type 2 diabetes (T2D) cases continue to rise dramatically despite efforts to get people to exercise and eat with a view to health and combatting the cluster of 7 issues (elevated waist circumference, hyperglycaemia, hypertension, dyslipidemia, pro-thrombotic state, increased oxidation (including low density lipoprotein (LDL)) and the pro-inflammatory state associated with pre- and post-onset T2D. Background: There are numerous medications available to deal with these seven major issues. However, each medication currently available manages a maximum of two cluster members at a time. Consequently, polypharmacy is frequently required to manage the cluster of seven. Polypharmacy brings with it high financial costs for numerous medications, the risk of poor compliance (particularly so in older patients), side effects and drug interactions. Thus, there is a search for new agents that reduce the high costs and risks of polypharmacy while at the same time combatting three or more of the cluster of seven. There is very limited evidence to suggest that one or more lignans may efficaciously and safely, in the short and long term, manage at least three of the cluster of seven, pre- and post-T2D onset, thus reducing polypharmacy. However, multi-centre, large, clinical trials are required before any definitive conclusions about these lignans can be reached regarding its safe and efficacious polypharmacy reduction potential, both long and short term, in pre- and post-onset T2D management. Conclusion: It is concluded that some lignans appear to have the potential to manage at least three members of the cluster of seven in pre- or post-T2D onset and hence reduce polypharmacy but much more investigation is required to confirm if such is the case. At the moment there is not enough evidence that any of the lignans will, in the long or short term, safely and efficaciously manage the cluster of seven via polypharmacy reduction.
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Flaxseed's oil and lignan, secoisolariciresinol diglucoside (SDG), are implicated in attainment of health and treatment of renal injury and osteoporosis. To test for these benefits, weanling Han:SPRD-cy rats (n=171) with or without kidney disease were randomized to diets made with either corn oil or flaxseed oil and with or without SDG for 12 weeks. In females, weight was lower with the SDG diet. In males fed flaxseed oil, lean mass was higher and fat % was lower. In both sexes, fat % was lower in diseased rats. Bone mineral content (BMC) and density were higher in rats fed flaxseed oil and lower in diseased rats, additionally; BMC was lower in SDG-supplemented females. The benefit of flaxseed oil on body composition is sex specific but the effect on bone mass is not. Lastly, reduced weight due to early rat kidney disease is not due to loss of lean body mass.
Article
The flaxseed lignans secoisolariciresinol (SECO) and its diglucoside secoisolariciresinol diglucoside (SDG) are reported to have a number of health benefits associated with their consumption that have in part been attributed to their antioxidant properties. In this study the relative antioxidant capacity of the flaxseed lignans vs. BHT was determined in two model systems. First, an antioxidants stoichiometric value was determined for SECO and SDG in a liposomal system as a mimic of lipid peroxidation. Stoichiometric values for SECO (1.5) and SDG (1.2) vs. BHT (2.0) were measured from the lag time for the formation of conjugated dienes; all values were significantly different (P<0.01). Second, the ability of flaxseed lignans to prevent oxidative degradation of canola oil was determined. Samples were stored at room temperature and analyzed at 30-d intervals over 120 d using a Rancimat™ analyzer. The lignans prevented degradation of canola oil, as measured by induction time, in a concentration-dependent manner. Although SECO demonstrated a trend for better protection than either SDG or polymer containing SDG, they were not significantly different (P>0.01). There was also no significant difference between SECO or SDG and BHT, suggesting flaxseed lignans may be good alternatives to minimize rancidity in oil-based food products.
Article
Microwave-assisted extraction (MAE) of secoisolariciresinol diglucoside (SDG) from defatted flaxseed hull (DFH) was studied. The effects of pre-soaking methods and extraction parameters (ethanol concentration (0–100%, v/v), microwave energy input (50–390 W), liquid to solid ratio (5:1 to 40:1, mL g−1) and irradiation time (10–330 s)) on the SDG yield were investigated. Response surface methodology (RSM) was applied to optimise the MAE conditions as irradiation time 90.5 s, ethanol concentration 40.9% (v/v), liquid to solid ratio 21.9:1 (mL g−1) and microwave power 130 W. The SDG recovery from DFH with MAE was 11.7 g SECO kg−1 DFH (on dry-weight basis), which was significantly higher than that of stirring extraction (10.0 g SECO kg−1 DFH) and Soxhlet extraction (7.60 g SECO kg−1 DFH). Compared with stirring extraction and Soxhlet extraction, MAE showed its superiority in improving SDG yield and saving time and energy. Copyright © 2007 Society of Chemical Industry
Chapter
Introduction Potential Dangers of Herb and Supplement Use in Patients with Kidney Disease Potentiation of Glucose/Electrolyte Abnormalities Pharmacokinetic Interactions Potential Benefits of Herbs in Patients with Kidney Disease Miscellaneous Uses Conclusions References
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Flaxseed has been used in the treatment of many medical conditions due to its anti-inflammatory effects. Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that is, at times, punctuated by involvement of the kidneys. Flaxseed is a promising new treatment for this chronic disease. Various animal studies were undertaken utilizing the MRL/lpr mouse model. These mice develop a lymphoproliferative syndrome similar to SLE. In various studies, a synthetically derived lignan and a flaxseed rich diet were shown to improve clinically relevant outcomes of proteinuria and creatinine clearance in the mouse model. More recently, it was demonstrated that a purified form of flaxseed lignan was also effective in treating these mice. The first human study had the aim of determining what doses of flaxseed were tolerable among patients with SLE. The optimal dose of 30g per day was determined. Subsequently, a two-year randomized crossover trial assessed the effects of this dose on patients with lupus nephritis. 23 patients started the study; however, only nine adequately completed the study. The dropout and non-compliance was attributed to the significant side effect of increased laxation. The purified form of flaxseed noted above, has not been studied in humans. Future studies should be focused on determining an appropriate dosing regimen in humans and determining if this treatment has a possible clinical application.
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A review, with 69 refs., of properties and biol. activity of omega-3 acids produced from linseed oil. An innovative technol. for prodn. of Et esters of polyunsatd. fatty acids was presented.
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The study was designed to search the efficacy of the oil blend, composed of sesame, canola, walnut, and wheat germ oils against diabetic nephropathy (DN). In the present study the notion that a vegetable oil blend (VOB) minimizes oxidative damage, reduces renal injury, and preserves renal architecture was tested. Male wistar rats received VOB (2 ml/ kg⁻¹) for 56 days after diabetes induction (streptozotocin 55 mg kg⁻¹). Biochemical evidences in serum and renal tissue had been used to evaluate the impact on kidney injury and supported with histopathological examination. A significant increase in blood glucose, blood urea nitrogen (BUN), N-acetyl-β-D-glucosaminidase (NAG), and proteinuria levels with a concomitant decrease in glomerular filtration rate (GFR) were noted in diabetic rats. Oxidative damage indices such as 8-hydroxy-2′-deoxyguanosine (8-OHdG), transforming growth factor-beta1 (TGF-β1), malonaldehyde (MDA) and glutathione (GSH) were found higher in diabetic group with diminished glutathione reductase (GR) and superoxide dismutase (SOD) antioxidant enzymes level. Histological examination also revealed significant alterations, including glomerulosclerosis and interstitial fibrosis in diabetic group. Administration of VOB significantly modulated abnormalities in markers of renal dysfunction and tubular damage. Further oxidative damage and renal histological changes were recovered in the treatment group. In conclusion, our findings strongly suggest that renoprotective effect of VOB on nephrotic damage is attributable to its potential antidiabetic and antioxidant capabilities. There is still work to be done on a longer-term investigation or a clinical trial.
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Untreated 16-week-old MRL/MpJ-lpr/lpr (lpr) mice, when compared to congenic MRL/MpJ-+/+ (+/+) mice, are characterized by a systemic lupus erythematosus syndrome, including severe glomerulonephritis, proteinuria and reduction of renal function. We hypothesized that platelet activating factor (PAF), a potent chemotactic and proinflammatory phospholipid mediator synthesized and released by circulating cells, glomerular mesangial and renal medullary interstitial cells, may play a role in the development of renal injury in lupus mice. We assessed renal PAF synthesis in lpr as well as +/+ mice and the effect of treatment with a PAF receptor blocking agent. Treatment with the PAF receptor antagonist L659,989 for four weeks, starting at 12 weeks of age, significantly reduced acute glomerular infiltration and proliferation, and prevented chronic glomerular histological changes; proteinuria and serum creatinine levels were also significantly reduced in treated mice. Renal PAF production was increased in lpr when compared to +/+ mice, and treatment with L659,989 restored renal PAF synthesis to the control levels. Our results support the hypothesis that PAF can be one of the mediators of glomerular injury characteristic of murine lupus nephritis, and indicate the possible therapeutic utility of PAF receptor antagonists in immunologic renal diseases.
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A retrospective study of factors influencing survival in 1,103 patients with systemic lupus erythematosus (SLE) was carried out at 9 university centers diverse in geographic, socioeconomic, and racial characteristics. The mortality and disease characteristics of the patients at study entry varied widely among centers. The survival rates from the time patients with a diagnosis of SLE were first evaluated at the participating center was 90% at 1 year, 77% at 5 years, and 71% at 10 years. Patients with a serum creatinine >3 mg/dl at study entry had the lowest survival rates: 48%, 29%, and 12% at 1, 5, and 10 years, respectively. Survival rate also correlated independently with the entry hematocrit, degree of proteinuria, number of preliminary American Rheumatism Association criteria for SLE satisfied, and source of funding of medical care. When data were corrected for socioeconomic status, race/ethnic origin did not significantly influence survival. Survival rates varied widely at different participating institutions, generally due to differences in disease severity. Place of treatment was independently associated with survival only in the second year after study entry. Disease duration before study entry did not account for the differences in disease severity.
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A menhaden oil diet, rich in eicosapentaenoic acid, protected female NZBxNZW/F1 mice from autoimmune nephritis. Only 15% of mice treated with the diet from weaning had died with severe renal disease at 19 months, versus 98% of controls on a beef tallow diet. The menhaden oil also protected these mice from renal disease when instituted at 4 and 5 months of age and, under these conditions, levels of anti-native DNA antibodies were similar in both dietary groups. Our data suggest that the menhaden oil diet may act primarily to reduce inflammation via the ability of eicosapentaenoic acid to alter the production of prostaglandins and leukotrienes.
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The principal causes of death of 68 patients with lupus glomerulonephritis were reviewed. Renal failure (40%), vascular events (25%), and infections (16%) were the predominant causes. Diffuse proliferative glomerulonephritis was associated with an increased frequency of renal failure. A bimodal pattern of early deaths due to active lupus and sepsis and late deaths from vascular events was found superimposed on a constant rate of death from renal failure.
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The hypothesis that corticosteroid therapy is responsible for the striking improvement in survival of patients with systemic lupus erythematosus (SLE) was investigated with two approaches: Of 250 published papers on SLE, 52 were chosen for the first analysis because they included sufficient information on diagnostic criteria and survival but were not limited to patients selected for a particular target organ. From each article percent survival by series, average duration to death, and 1 and 5 year survival curves were abstracted. Each statistic showed linear improvement in survival since the 1930s without a significant change (P greater than 0.10) in slope for the time period following the introduction of corticosteroids. The second analysis examined the effect of corticosteroid therapy on 142 patients with SLE followed at the Massachusetts General Hospital between 1922 and 1966. Although the steroid use was conservative, the patients' survival, from year of entry, was comparable to the 52 abstracted series. A prognostic index was used to stratify patients admitted in the steroid era (after 1950) for life table analysis of survival with and without steroids. Steroids had no discernible effect on overall survival in low and medium risk groups. Use of steroids was associated with improved survival among high rish patients (P less than 0.05).
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The changing pattern of mortality in systemic lupus erythematosus (SLE) led to an examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit. During the follow-up 11 patients died; six patients died within the first year after diagnosis (group I) and five patients died an average of 8.6 years (from 2.5 to 19.5 years) after diagnosis (group II). In those who died early, the SLE was active clinically and serologically, and nephritis was present in four. Their mean prednisone dose was 53.3 mg/day. In four patients a major septic episode contributed to their death. In those who died late in the course of the disease, only one patient had active lupus and none had active lupus nephritis. Their mean prednisone dose was 10.1 mg/day taken for a mean of 7.2 years. In none was sepsis a contributing factor to their death. All five of these patients had had a recent myocardial infarction at the time of death; in four, ti was the primary cause of death. Mortality in SLE follows a bimodal pattern. Patients who die early in the course of their disease, die with active lupus, receive large doses of steroids and have a remarkable incidence of infection. In those who die late in the course of the disease, death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.
Article
To investigate the role of thromboxane A2 (TxA2) in murine lupus, we assessed the effects of the specific thromboxane receptor antagonist GR32191 on immune complex glomerulonephritis in MRL-lpr/lpr mice. Forty mg/kg/day GR32191 was given by twice daily subcutaneous injection for eight weeks beginning at 12 weeks of age. This dose completely blocked the renal vasoconstriction produced by the thromboxane agonist U46619. After eight weeks of treatment, both glomerular filtration rate (GFR) (8.9 +/- 0.6 vs. 6.8 +/- 1.1 ml/min/kg; P less than 0.05) and PAH clearance (CPAH) (37.4 +/- 2.5 vs. 29.9 +/- 3.3 ml/min/kg; P less than 0.05) were significantly higher in mice given GR32191 compared to vehicle treated animals. Administration of GR32191 also reduced proteinuria from 18.1 +/- 11.6 to 3.7 +/- 1.3 mg/24 hours (P less than 0.05). In GR32191 treated MRL-lpr/lpr mice, renal hemodynamic function and proteinuria were not significantly different from congenic MRL-+/+ controls. Thromboxane receptor blockade had striking affects on renal histomorphology reducing both hyaline thrombi in glomeruli (P = 0.022) and interstitial inflammation (P = 0.006). Glomerular crescents and severity of vasculitis also tended to be reduced in mice receiving the thromboxane receptor antagonist. The overall histopathologic score in mice given GR32191 was significantly lower than vehicle treated animals (4.7 +/- 0.5 vs. 8.4 +/- 1.5; P = 0.016). These effects of GR32191 were associated with decreased excretion of thromboxane B2 (TxB2) in urine (292 +/- 37 vs. 747 +/- 155 pg/24 hr; P less than 0.005) as well as a modest reduction in glomerular deposits of IgG (semiquantitative score 2.6 +/- 0.2 vs. 3.5 +/- 0.2; P less than 0.02). Thus, chronic thromboxane receptor blockade markedly altered the course of renal disease in MRL-lpr/lpr mice, suggesting that TxA2 is an important mediator of renal dysfunction and injury in this murine model of lupus nephritis.
Article
Platelet-activating factor (PAF) has been suggested recently to play an important role in immune glomerulonephritis, favoring the formation of immune deposits in glomeruli and contributing to the local inflammatory reaction. Here we sought to investigate whether urinary PAF excretion was modified in New Zealand Black x New Zealand White mice a model of genetically determined immune complex disease which mimics systemic lupus in humans and whether changes in PAF urinary excretion values correlated with the extent of proteinuria. To clarify the possible "in vivo" relevance of these findings we evaluated whether PAF receptor antagonist has any influence on the evolution of renal disease and survival of these mice. Our results showed that: 1) in lupus mice urinary PAF excretion increased progressively with age in New Zealand Black x White; 2) the increase in PAF excretion correlated with the severity of proteinuria; and 3) the chronic administration of a PAF receptor antagonist [L-659,989 [(+/- )-trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5- (3,4,5-trimethoxyphenyl)tetrahydrofuran]] starting from 26 weeks of age significantly delayed the onset of proteinuria and prolonged survival.
Article
Mammalian lignans such as enterolactone and enterodiol, which are produced in the colon from precursors in foods, have been suggested as playing a role in the cancer-protective effect of vegetarian diets. Despite this, very little is known regarding the amount that is produced from different food products. Therefore, the objective of this study was to determine the production of mammalian lignans from 68 common plant foods by using the technique of in vitro fermentation with human fecal microbiota, which simulates colonic fermentation. Results showed a wide range (21-67,541 microgram(s)/100 g sample) in the amount of lignans produced. On the average as a group, the oilseeds produced the highest amounts (20,461 +/- 12,685), followed by the dried seaweeds (900 +/- 247), whole legumes (562 +/- 211), cereal brans (486 +/- 90), legume hulls (371 +/- 52), whole grain cereals (359 +/- 81), vegetables (144 +/- 23), and fruits (84 +/- 22). The vegetables produced the second highest concentration of lignans (1,546 +/- 280) when the data were expressed on a moisture-free basis. Flaxseed flour and its defatted meal were the highest producers of lignans (mean 60,110 +/- 7,431). Lignan production with the in vitro method related well to the urinary lignan excretion observed in rats and humans. The data should be useful in the estimation of lignan production from a given diet and in the formulation of high-lignan-producing diet for the purpose of reducing the cancer risk.
Article
Various derivatives and isosteres of neolignans of the 2,5-diaryl tetrahydrofuran type have been synthesized as antagonists of platelet-activating factor (PAF). A detailed analysis of their structure-activity relationship (SAR) has revealed a clear preference for an asymmetrical molecular configuration with a high degree of stereo and chiral specificity associated with greater potency. The trans-2S,5S enantiomers are generally 10-200 times more potent in vitro than their corresponding cis or trans-2R,5R isomers. A similar stereochemical preference is indicated by the recently reported PAF antagonist MK-287 which has undergone clinical evaluation. An azido derivative L-662,025 has been characterized as a photolabile irreversible antagonist of PAF for the investigation of solubilized and partially purified PAF binding proteins from cell membranes. The biological justification for concomitant inhibition of both PAF receptor and 5-lipoxygenase in inflammation is well recognized. The feasibility of developing such dual-functional agents has been demonstrated by a group of dithiolane analogs of neolignans and several derivatives of futoenone.
Article
The effect of platelet-activating factor (PAF) on glomerular permeability to macromolecules was investigated in the isolated kidneys from normal male Sprague-Dawley rats perfused at constant pressure. Compared with basal values, infusion of PAF (10 nM final concentration) into the isolated kidneys induced a progressive and significant increase in protein excretion (6.7 +/- 2.7 vs. 40.7 +/- 10.4 micrograms/min, P less than 0.01), completely reversible 20 min after PAF infusion was discontinued (8.5 +/- 1.3 micrograms/min). In additional experiments, during PAF infusion the fractional clearance of small neutral dextrans (radius 24-48 A), defined as the ratio of the clearance of neutral dextrans to the clearance of creatinine, was comparable to preinfusion values, whereas fractional clearance of large dextrans (greater than 50 A) was significantly elevated (P less than 0.005) above preinfusion values. The specific PAF receptor antagonist L 652731 completely prevented the increased fractional clearance of large dextrans induced by PAF. Finally, lowering Ca2+ concentration in the perfusion medium from 2.5 to less than 0.1 mM markedly reduced proteinuria in isolated kidneys exposed to PAF (80.0 +/- 10.3, 42.8 +/- 3.1, and 22.0 +/- 7.6 micrograms/min, respectively, for 2.5, 1.25, and less than 0.1 mM). These results indicate that in isolated perfused kidneys 1) PAF-induced proteinuria is a functional phenomenon reversible on discontinuing PAF infusion, 2) PAF modifies glomerular size-selective properties by increasing transmural passage of large dextran molecules, and 3) PAF-induced change in glomerular permselective properties is dependent on Ca2+ concentration in the extracellular medium.
To investigate the physiologic significance of enhanced renal thromboxane production in murine lupus nephritis, we measured renal hemodynamics and eicosanoid production in MRL-lpr/lpr mice from 8 to 20 weeks of age. Over this age range, MRL-lpr/lpr mice develop an autoimmune disease with nephritis similar to human systemic lupus erythematosus (SLE). In these studies, glomerular filtration rate (GFR) and PAH clearance (CPAH) decreased progressively with age in MRL-lpr/lpr mice, but not in controls. This impairment of renal hemodynamics was associated with increased renal thromboxane production, as well as increased excretion of both thromboxane B2 (TxB2) and 2,3-dinor TxB2 in urine. There was an inverse correlation between renal thromboxane production in MRL-lpr/lpr mice and both GFR and CPAH. Furthermore, there were positive correlations between thromboxane production by the kidney and both the severity of renal histopathology and serum anti-DNA antibody levels measured in individual animals. Enhanced urinary excretion of TxB2 and the development of renal dysfunction also coincided temporally with the appearance of increased levels of interleukin 1 beta (IL-1 beta) mRNA in renal cortex. Acute administration of the specific thromboxane receptor antagonist GR32191 to MRL-lpr/lpr mice restored GFR to normal in early stages of the autoimmune disease. However, in animals with more advanced nephritis, the effect of acute thromboxane receptor blockade on renal hemodynamics was less marked. We conclude that thromboxane A2 is an important mediator of reversible renal hemodynamic impairment in murine lupus, especially in the early phase of disease.
Article
The formation of arachidonic acid derived eicosanoids, including thromboxane A2 and leukotriene B4, as well as platelet-activating factor (1-O-alkyl-2-acetyl-glycerophosphocholine), has been implicated in various renal pathophysiologies. Alteration of the fatty acid composition of membrane phospholipids in platelets, the glomerulus, and inflammatory cells, and of 1-O-alkyl-2-acyl-glycerophosphocholine (platelet-activating factor precursor) can be attained by dietary lipid modifications (e.g., consumption of fish oil containing n - 3 polyunsaturated fatty acids). These changes have been associated with an attenuation in renal disease progression and modifications in the synthesis and actions-interactions of eicosanoids, cytokines, and platelet-activating factors.
Article
A prospective, double blind, cross over study assessing the effects of a low fat, high marine oil diet in 27 patients with active systemic lupus erythematosus has been performed. The patients were given 20 g daily of MaxEPA (eicosapentaenoic acid) or 20 g of olive oil (placebo) in matching capsules added to a standardised isoenergetic low fat diet. When individual outcome measures of the 17 patients who completed the full 34 week study were considered 14 who were receiving MaxEPA achieved useful or ideal status, whereas 13 receiving placebo were rated as worse or no change. The difference between the two types of capsule was statistically significant. No major side effects were noted, and it is suggested that dietary modification with additional marine oil may be a useful way of modifying disease activity in systemic lupus erythematosus.
Article
Platelet activating factor (PAF) is present in urine from humans and experimental animals in normal conditions. Very little is known about changes in PAF urinary excretion under pathologic conditions and no data are available about the origin of PAF in the urine. In the present study we explored the possibility that immunologic renal disease is associated with an increase in PAF urinary excretion using gas chromatography-mass spectrometry technique. To clarify the renal or extrarenal origin of urinary PAF we evaluated whether exogenously administered PAF (1-[1', 2'-3H]alkyl) is filtered through the glomerulus and excreted in the urine. The results show that: 1) urine from mice with lupus nephritis in the early phase of the disease contained amounts of PAF comparable to those excreted in normal mouse urine, 2) PAF levels increased when animals started to develop high grade proteinuria, 3) after intravenous injection of [3H] PAF in nephritic mice, a negligible amount of [3H] ether lipid, corresponding to [3H]1-alkyl -2-acyl-3-phosphocholine (alkyl-2-acyl-GPC), was recovered from the 24 h urine extract.
Article
Seventeen patients with moderately active SLE participated in a double-blind, crossover study on the effect of MaxEPA, using olive oil as the control substance. During the first 3 months, 8/17 on Max EPA but only 2/17 on the control substance clinically and serologically improved (p = 0.05), but at 6 months there was no difference. The beneficial effect (if any) of MaxEPA on the disease was short-lived.
The biologically active 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet-activating factor; PAF) is inactivated in plasma mainly by a specific PAF acetylhydrolase (1-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine acetylhydrolase; EC 3.1.1.48). In the present study, PAF was released in detectable amounts (5.4 +/- 2.9 ng/ml; mean +/- 1 SD) in the plasma of 8 out of 10 patients with systemic lupus erythematosus (SLE) during the most active phases of the disease. PAF was never detectable in the plasma of patients with inactive SLE or of healthy subjects. PAF acetylhydrolase activity was markedly reduced in sera of 10 patients with active SLE as compared to 7 patients with inactive SLE, 16 patients with rheumatoid arthritis (RA), 5 patients with nephrotic syndrome (NS) and 15 healthy subjects. A kinetic study of the enzyme in patients with active SLE suggested an overall reduced activity rather than an intrinsic defect of the enzyme. PAF acetylhydrolase in sera of patients with active SLE shared with that of healthy subjects the same substrate specificity, sensitivity to enzymatic and chemicophysical treatments and association to low-density lipoprotein (LDL), acting as carrier of PAF acetylhydrolase in plasma. However, the protein concentration of LDL was significantly reduced in patients with active SLE as compared to patients with inactive SLE, RA and NS and to healthy subjects, thereby suggesting that the reduction of PAF acetylhydrolase activity in active SLE might be due at least in part to a carrier defect related to the activity of the disease. In addition, experiments in which serum of patients with active SLE and serum of healthy subjects were mixed in different combinations indicated the absence of factors inhibiting PAF acetylhydrolase activity in SLE patients.
Article
The influence of dietary fat on autoimmunity in lupus-prone (NZB x NZW)F1 mice has been demonstrated. In defining further the effects of dietary lipid on the immune system of this strain, female weanling mice were placed on four diets differing in quantity and type of fat. Their immunologic response was then studied by a variety of tests at 4 and 7 mo of age. Few differences were seen among the four groups at 4 mo of age. At 7 mo of age, however, the mice receiving diets high in saturated and unsaturated fats had a reduced mitogenic response to T cell mitogens and an enhanced response to the B cell mitogen LPS. Immunoglobulin levels and delayed hypersensitivity responses did not show any consistent differences among the diet groups. At 7 mo, however, mice receiving diets high in unsaturated fat demonstrated hyperresponsiveness to injected sheep red blood cells as measured by the hemolytic plaque technique. In addition, peritoneal leukocytes from the same diet group exhibited an increased response to bromelain-treated autologous erythrocytes which was decreased after treatment with anti-Thy-1 antiserum and complement. Phagocytosis by peritoneal macrophages was significantly decreased in the animals fed high-fat diets, particular high saturated fat. Similarly, natural killer cell activity was markedly reduced in the mice with a high intake of saturated lipid, a finding which correlated with the in vitro production of interferon. These results indicate that diets high in fat influence immune responses and thus can affect the onset and severity of autoimmune disease. A low-fat diet can reduce the development of disease by maintaining normal immune responses. The data also suggest that unsaturated fat may influence T helper cell activity and therefore antibody production, whereas saturated fats may affect cellular immune responses which are dependent on membrane contact.
Article
The effect of dietary fish oil (Omega-3 fatty acids--eicosapentenoic acid [EPA] and docosahexaenoic acid [DHA] on several mechanisms involved in immune, inflammatory and atherosclerotic vascular disease was determined in 12 subjects with systemic lupus erythematosus (SLE) and nephritis. These out-patients supplemented their usual diet for five weeks with daily doses of 6 g of fish oil, followed by a five-week washout period, then five weeks of 18 g of fish oil daily. The platelet EPA content rose six-fold with the lower and 15-fold with the higher dose of fish oil, and similar changes occurred to the platelet DHA content. The platelet arachidonic acid incorporation was reduced by 16 and 20%, respectively. These changes were associated with a reduction in collagen-induced platelet aggregation and an increase in red cell flexibility and a decrease in whole blood viscosity. Prostacyclin (PGI2) production was unaffected by the fish oil, but PGI3 formation correlated with its administration and dosage. Neutrophil leukotriene B4 release was reduced 78 and 42%, respectively, by the low and higher doses of fish oil. The higher fish oil dose induced a 38% decrease in triglyceride and a 39% reduction in VLDL cholesterol associated with a 28% rise in HDL, cholesterol. The fish oil had no effect on immune complex or anti-DNA antibody titer, albuminuria, intraplatelet serotonin or [14C]-serotonin release from platelets. We conclude that in patients with lupus nephritis, dietary supplementation with fish oil affects the mechanisms involved in inflammatory and atherosclerotic vascular disease.
MRL lpr/lpr (MRL/l) mice exhibit a disease similar to systemic lupus erythematosus (SLE) in humans. To investigate the influence of antihypertensive treatment on this disease, four groups of MRL/l mice were treated with the angiotensin-converting enzyme inhibitor captopril (n = 25), with the sympathetic blocker bretylium (n = 15), and with cyclophosphamide (n = 10). Thirty-five mice did not receive any treatment and served as controls. Survival rate, blood pressure, incidence of proteinuria and hematuria, renal pathology, lymphoid hyperplasia and dermatitis were studied. The survival at the age of 36 weeks was significantly improved by captopril as compared to controls (60 vs. 25%, p = 0.035). The cyclophosphamide group showed no mortality at that time and the bretylium group did not differ from the control group. Captopril and bretylium reduced systolic blood pressure significantly while cyclophosphamide was without effect. Captopril and cyclophosphamide diminished significantly the glomerular damage with less proliferative changes and a decreased incidence of proteinuria. The bretylium-treated animals also exhibited an improved renal pathology index but they did not differ from the controls with respect to proteinuria and hematuria. Lymphoid hyperplasia and dermatitis were decreased only by captopril and cyclophosphamide. It is concluded that captopril improves survival in SLE disease of MRL/l mice, counteracting lymphoid hyperplasia, renal disease, dermatitis and decreasing arterial blood pressure.
Article
Previous studies have shown that dietary marine lipids containing large quantities of n-3 polyunsaturated fatty acids, administered to (New Zealand black X New Zealand white)F1 and MRL-lpr/lpr mice before the development of renal disease, reduce the severity of glomerulonephritis in mice of these strains. The present study demonstrated that delayed administration of a marine lipid diet, 25% menhaden oil (MO) by weight, until after the onset of overt renal disease, also resulted in significant improvement in rates of mortality, proteinuria, and histologic evidence of glomerular injury, compared with control animals fed a diet that contained mostly saturated fatty acids, 25% beef tallow. The MO diet also reduced the histologic severity of renal disease in male BXSB/MpJ and male MRL-lpr/lpr mice. In contrast, necrotizing vasculitis was more frequent in small and medium-sized renal arteries of the MRL-lpr/lpr mice fed MO than in those fed beef tallow (33.4% versus 7.6%, respectively).
Article
Over 20 years 42 of 138 patients with systemic lupus erythematosus "died"--that is, suffered actual death or went into terminal renal failure, or both; data from 41 were available for analysis. In most patients the causes of death were multiple. Twenty seven patients went into terminal renal failure, of whom 25 were offered dialysis treatment. Three regained renal function later, 12 survived on dialysis or with functioning kidney allografts--almost all with inactive lupus--but 13 died after starting dialysis, most within a few weeks or months. The principal causes were active lupus or infection. In those patients with renal failure after rapid deterioration in renal function (n = 14) there were nine deaths, while of 10 patients with a slow evolution into renal failure, only four died. Four patients with impaired and 10 with normal renal function died, again most often from complications of lupus or from infection. Vascular disease was a major cause of death in seven patients, all but two of whom were young; of 15 postmortem examinations, eight showed severe coronary artery atheroma, and three surviving patients required coronary bypass operations. Analysis of the timing of death or entry into renal failure showed that in 12 out of 13 patients who died within two years of onset the lupus was judged to be active, while this was true in only eight out of 19 patients who died later. Six of the seven vascular deaths occurred later than two years from onset, while only nine of 26 renal "deaths" occurred before two years; deaths from infections (n = 13) were distributed equally. Despite this and aggressive treatment of active disease, the principal cause of actual death was uncontrolled lupus.
Article
A method is described for determining glomerular filtration rate (GFR) in conscious unrestrained rats without extracellular volume expansion. The glomerular marker used was 14C-labeled inulin infused in the minimal fluid volume of 1 microliter/h by intraperitoneally implanted osmotic minipumps. The workability, reproducibility, and precision of the technique was evaluated in sham-operated (sham) and uninephrectomized (UNI-NX) rats for 6 days. In six sham-operated rats the clearance of [14C]-inulin calculated from the plasma value obtained in a blood sample taken at 10 A.M. before food consumption was (means +/- SE): day 1 after pump implantation: 1.38 +/- 0.05; day 2: 1.27 +/- 0.05; day 3: 1.46 +/- 0.16; day 4: 1.45 +/- 0.15; day 5: 1.33 +/- 0.08; day 6: 1.38 +/- 0.11 ml/min. In six UNI-NX rats the corresponding values were: day 1: 0.88 +/- 0.04; day 2: 0.79 +/- 0.05; day 3: 0.91 +/- 0.03; day 4: 0.91 +/- 0.03; day 5: 0.83 +/- 0.06; day 6: 0.87 +/- 0.05 ml/min. When determined on day 2, 3, or 6 at 6 P.M., i.e., at the end of the food consumption period, [14C]inulin clearance was increased in all animals compared with the value determined at 10 A.M. in the fasted state. The use of implanted osmotic minipumps for delivering a glomerular marker such as [14C]inulin allows the determination of GFR in conscious unrestrained rats with normal fluid balance conditions. This method appears to be particularly appropriate for studying the influence of the intake and composition of food on GFR in physiological conditions.
Article
Accelerated coronary artery disease and myocardial infarction in young patients with systemic lupus erythematosus is well documented; however, the prevalence of coronary involvement is unknown. Accordingly, 26 patients with systemic lupus were selected irrespective of previous cardiac history to undergo exercise thallium-201 cardiac scintigraphy. Segmental perfusion abnormalities were present in 10 of the 26 studies (38.5 percent). Five patients had reversible defects suggesting ischemia, four patients had persistent defects consistent with scar, and one patient had both reversible and persistent defects in two areas. There was no correlation between positive thallium results and duration of disease, amount of corticosteroid treatment, major organ system involvement or age. Only a history of pericarditis appeared to be associated with positive thallium-201 results (p less than 0.05). It is concluded that segmental myocardial perfusion abnormalities are common in patients with systemic lupus erythematosus. Whether this reflects large-vessel coronary disease or small-vessel abnormalities remains to be determined.
Article
Prostaglandins and related compounds are active mediators of inflammation, but data concerning their role in the pathogenesis of the glomerulonephritis of New Zealand Black x New Zealand White (NZB x NZW) F1 mice are conflicting. Dietary eicosapentaenoic acid (EPA, C20:5), a fatty acid analogue of arachidonic acid (C20:4), has been shown to impair platelet aggregation in humans, apparently through inhibition of the synthesis of prostaglandins and thromboxanes from arachidonic acid. We report here the effects of a diet high in EPA on the development of renal disease and survival in female NZB x NZW F1 mice. Animals from 4--5 wk of age were fed diets containing 25% lipid, supplied either as beef tallow or menhaden oil, with fatty acid analysis of less than 0.05 and 14.4% EPA, respectively. In the first experiment, by 13.5 mo of age, mice on the beef tallow diet had all (9/9) developed proteinuria and the majority (6/9) had died, with renal histologic examination revealing severe glomerulonephritis. In contrast, none of 10 menhaden oil-fed animals had developed proteinuria, and all were alive at this time (P less than 0.005 for both proteinuria and survival). In a second experiment using 50 mice in each dietary group, 56% of the beef tallow group vs. none of the menhaden oil group had developed proteinuria at 9 mo of age (P less than 0.005). Native DNA binding at 6 mo of age was 23.9 +/- 14.7 vs. 10.1 +/- 9.7% in the beef and menhaden oil groups, respectively (P less than 0.01). Weights were similar in all groups, and there was no evidence of essential fatty acid deficiency in any group. These results demonstrate that a diet high in EPA protects NZB x NZW F1 mice from the development of glomerulonephritis.
Article
Flaxseed is rich in alpha-linolenic acid (alpha-LA) which has anti-atherogenic properties, and lignans which are platelet activating factor (PAF)-receptor antagonists. These constituents of flaxseed, and its beneficial effects in the MRL/lpr lupus mouse prompted us to perform this dosing study in lupus nephritis patients. Nine patients were enrolled, eight of whom completed the study. After the baseline studies, patients were given 15, 30, and 45 g of flaxseed/day sequentially at four week intervals, followed by a five-week washout period. Compliance, disease activity, blood pressure, plasma lipids, rheology, PAF-induced platelet aggregation, renal function, and serum immunology were assessed. Flaxseed-sachet count and a significant increase of serum alpha-LA indicated good compliance for 15 and 30 g doses. Total and LDL cholesterol, and blood viscosity were significantly reduced with 30 g and to a lesser extent 45 g doses. PAF-induced platelet aggregation was inhibited by all doses. There was a significant decline in serum creatinine with 30 and 45 g, and a concomitant increase in creatinine clearance with increasing flaxseed dose. Proteinuria was reduced with 30 g and to a lesser extent with 45 g of flaxseed. Complement C3 was significantly elevated by all three doses. CD11b expression on neutrophils, a measure of C3bi receptors, was significantly reduced with the 30 g dose. In conclusion, 30 g flaxseed/day was well tolerated and conferred benefit in terms of renal function as well as inflammatory and atherogenic mechanisms important in the pathogenesis of lupus nephritis.
Article
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by nephritis, in which mortality is largely influenced by the severity of renal involvement. As there are evidences that thromboxane (TX)A2 plays an important role in the pathogenesis of lupus nephritis, we decided to assess the effects of long-term suppression of TXA2 synthesis on the progression of the disease, by designing a study of TXA2-synthase inhibition having adequate size to detect an effect on mortality as the primary end-point. Thus, we randomized 362 NZBxNZW mice (11-week-old at entry) to one of the following treatments: a TXA2 synthase inhibitor, FCE 22178 (300 mg/kg daily), saline or cyclophosphamide (5 mg/mouse weekly x 4 weeks) used as reference treatment. The TXA2 synthase inhibitor suppressed TXA2 biosynthesis, as reflected by urinary TXB2 and 2,3-dinor-TXB2 excretion (by 78% and 90%, respectively) and significantly reduced mortality (death rate: 34% vs. 61% in controls, at 37 weeks, P < 0.01). A significant reduction in proteinuria (9 +/- 1.6 vs. 17.3 +/- 2.4 mg/24 hr in FCE 22178 vs. saline, P < 0.01) and glomerular lesions was observed up to 30 weeks but not at 37 weeks. In contrast, cyclophosphamide prevented the development of proteinuria and histologic lesions, and reduced mortality to 8% at 37 weeks. Renal plasma flow and glomerular filtration rate were lower (by 29% and 52%, respectively) in 37-week-old as compared to young NZBxNZW mice. These parameters were further depressed by cyclophosphamide (by 48% and 45% vs. age-matched controls, respectively, P < 0.01) but were not altered significantly by FCE 22178.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
A diet supplemented with flaxseed, rich in alpha-linolenic acid and plant lignans (the latter, potent platelet-activating factor receptor antagonists), was tested in a murine model of lupus nephritis. MRL/lpr female mice (n = 25) were fed 15% flaxseed diet for 14 weeks commencing at 10 weeks of age. As controls, 30 MRL/lpr mice received a standard rodent diet without flaxseed. Isotope-glomerular filtration rate (14C-inulin clearance) was measured at 9, 16, and 24 weeks of age. Proteinuria was assessed at 2-week intervals. Spleen lymphocyte proliferation, quantitated by DNA analysis, was evaluated using flow cytometry at 9, 13, 19, and 21 weeks of age. Mortality was recorded throughout the study. Glomerular filtration rate at 16 weeks was greater in flaxseed-fed mice (0.15 +/- 0.03 mL/min) compared with controls (0.06 +/- 0.04 mL/min; P = 0.01). The onset of proteinuria (Albustix, Ames Division, Miles Laboratories, Rexdale, Ontario, Canada; > or = 2+) was delayed by 4 weeks in the flax-treated mice. The percentage of flaxseed-fed mice with proteinuria was lower than the control mice up to 21 weeks of age (39% v 58%; P = 0.01). Spleen lymphocyte proliferation (percentage of cells in S-phase) at 13 weeks of age was significantly higher in the control group (22.9 +/- 5.0, P = 0.01) but not in the flaxseed group (17.2 +/- 4.9) compared with baseline (9 weeks of age) values (13.0 +/- 3.5). Mortality was lower in the flaxseed-fed mice versus the control mice (assessed by Mantel-Haenszel (log-rank) test; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Our objective was to determine the effects of fish oil on renal function, symptoms, and serum lipids in patients with lupus nephritis. A double-blind, randomized crossover trial of fish oil versus placebo (olive oil) was done on 26 patients with confirmed systemic lupus; 21 completed the study. Intervention was fish oil or placebo, 15 g/day, for one year followed by a 10 week wash-out period, and then the reverse treatment for one year. At baseline and six month intervals, we measured platelet membrane fatty acids, indices of renal function, a disease activity index, serum lipid levels, blood pressure, serum viscosity and red cell flexibility. We found that platelet membrane phospholipids were uniformly affected by fish oil supplementation (P < 0.001) but with significant carry-over effects despite a 10 week wash-out period. Glomerular filtration rate and serum creatinine were not affected. A non-significant reduction in mean (SE) 24-hour proteinuria occurred, from 1424.1 mg (442.7) on placebo to 896.7 mg (352.2) on fish oil (P = 0.21). Fish oil lowered serum triglycerides from 1.89 (0.25) mmol/liter to 1.02 (0.11) mmol/liter (P = 0.004). VLDL cholesterol decreased markedly whether patients initially received fish oil or placebo (P = 0.004). The size of the reduction was affected by the order of treatment (P = 0.03), but parallel comparisons were significant before the crossover (P = 0.0006). With the possible exception of bleeding time, no other treatment effects were shown with fish oil. However, treatment order effects were seen in urinary IgG excretion (P = 0.03), whole blood viscosity (P < 0.0001), red cell flexibility (P = 0.004), and bleeding time (P = 0.06). In conclusion, one year of dietary supplementation with fish oil in patients with stable lupus nephritis did not improve renal function or reduce disease activity, but did alter some lipid parameters. Hitherto unreported carry-over effects and treatment order effects caused by the olive oil created a risk of type II error, and bear methodologic consideration in the design of future studies.
  • Correia P
  • Clark WF