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Carob Pod Insoluble Fiber Exerts Anti-Atherosclerotic Effects in Rabbits through Sirtuin-1 and Peroxisome Proliferator-Activated Receptor- Coactivator-1
Abstract
The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ⋅ kg(-1) ⋅ d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed with the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ⋅ kg(-1) ⋅ d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-α (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-β (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of SIRT1 and PGC-1α (160% and 121% of the control group, respectively; P < 0.05) vascular expression. In summary, we demonstrated for the first time, to our knowledge, that administration of IFC reduces the development of atherosclerosis in rabbits. This effect seems to be related to an improvement in endothelial function and a reduction of inflammation and fibrosis, most probably as a consequence of the reduction of serum concentrations of cholesterol and triglycerides. Increased expression of aortic SIRT1 and PGC-1α could play an important role in the observed effects of IFC in rabbits with dyslipidemia.
... Among them the fruit of carob tree, (Ceratonia siliqua L.), may be a good candidate since several studies have reported that it exerts beneficial effects improving the glycemic status [18][19][20][21], the lipid profile [22][23][24][25][26], and attenuating the cardiovascular alterations associated with MetS [23,27,28]. Its therapeutic effects are attributed to several bioactive compounds that are present not only in the pulp but also in the pod and the seeds of the carob fruit. ...
... Likewise, other authors have reported that treatment with carob pod affects neither body weight, nor fat mass in vivo [27]. However, it exerts a strong delipidating effect in vitro on adipocyte cultures [31] and in vivo reduces liver triacylglycerol levels in obese rats [45] and in rabbits with hypercholesterolemia [28]. ...
... In addition, the decreased blood pressure in CSAT+ ® -treated mice may also be explained by the decreased vascular contraction of aorta segments in response to the vasoconstrictor AngII. Likewise, other authors have reported a beneficial effect of a carob pod extract in vascular function in hypercholesterolemic rabbits that is demonstrated by an increased relaxation of aorta segments to Ach and by a decreased response to the vasoconstrictor KCl [28]. Like in the study by Valero et al. we also found a significant reduction in the mRNA levels of several proinflammatory cytokines and a decreased expression of the pro-fibrotic marker TGF-1β in arterial tissue, which means that the improved vascular function is associated with decreased vascular fibrosis and inflammation. ...
The incidence of metabolic syndrome (MetS) is increasing worldwide which makes necessary the finding of new strategies to treat and/or prevent it. The aim of this study was to analyze the possible beneficial effects of a carob fruit extract (CSAT+®) on the cardiometabolic alterations associated with MetS in mice. 16-week-old C57BL/6J male mice were fed for 26 weeks either with a standard diet (chow) or with a diet rich in fats and sugars (HFHS), supplemented or not with 4.8% of CSAT+®. CSAT+® supplementation reduced blood glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-c), insulin, and interleukin-6 (IL-6). In adipose tissue and skeletal muscle, CSAT+® prevented MetS-induced insulin resistance, reduced macrophage infiltration and the expression of pro-inflammatory markers, and up-regulated the mRNA levels of antioxidant markers. Supplementation with CSAT+® prevented MetS-induced hypertension and decreased the vascular response of aortic rings to angiotensin II (AngII). Moreover, treatment with CSAT+® attenuated endothelial dysfunction and increased vascular sensitivity to insulin. In the heart, CSAT+® supplementation reduced cardiomyocyte apoptosis and prevented ischemia-reperfusion-induced decrease in cardiac contractility. The beneficial effects at the cardiovascular level were associated with a lower expression of pro-inflammatory and pro-oxidant markers in aortic and cardiac tissues.
... Mechanisms underlying the observed effect include the antagonism activity of carob bioactive molecules on α-adrenoceptor and muscarinic receptors, as well as the calcium channel blockage by these molecules 33 . Valero-Munoz et al. 131 evaluated the effects of an insoluble carob pod dietary fiber supplementation (1 g/kg) in the diet on alterations associated with atherosclerosis in dyslipidimec rabbit model. Animals fed the high fat diet in addition to carob insoluble fiber for 8 weeks, presented a reduction in the aortic lesion size and normal values of acetylcholine and endothelial nitric oxide synthase expression, compared to the mice with dyslipidemia. ...
... They also observed a reduction in the expression of many aortic proteins, like the plasminogen activator inhibitor-1, the TNF-α, the vascular cell adhesion molecule-1 (VCAM-1), the transforming growth factor-b and collagen I. Moreover, the authors also observed that carob fiber has the capacity to enhance vascular expression of sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and decrease both serum cholesterol and triglycerides levels 131 . In this regard, as mentioned previously, different parts of C. siliqua tree have the capacity to lower hypercholesterolemia, more particularly the blood level of LDL-C. ...
... Similar results have been found in previous reports showing the ability of cocoa flavanols to attenuate cardiac fibrosis during myocardial ischemia [36] and in pressure overloadinduced heart failure [37] model mice. In addition, the supplementation with carob extracts decreased the expression of the pro-fibrotic marker TGFβ1 and arterial vascular fibrosis in mice fed with a high fat/high sucrose diet [24] and in rabbits with dyslipidaemia [38]. Altogether, these results strongly support the protective effect of the CCB rich-diet against myocardial fibrosis, which could have significant therapeutic benefits in the treatment of DCM. ...
... Enhanced SIRT1 levels due to the flavonoid effect have been observed in other studies using pure flavonoids, such as daidzein [46], curcumin [47], or naringenin [48]. Therefore, the reduced oxidative stress and increased antioxidant activity induced by the mix of flavonoids presented in CCB could be mediated by the sirtuin pathway, as proven in in vitro and in vivo studies [38,46,47,49]. Interestingly, several studies have identified other sirtuins (mainly SIRT3 and SIRT6) to provide beneficial effects in cardiovascular diseases and energy metabolism [50]. ...
Diabetic cardiomyopathy (DCM) is one of the main causes of mortality among diabetic patients, with oxidative stress and inflammation major contributors to its development. Dietary flavonoids show strong antioxidant and anti-inflammatory activities, although their potential additive outcomes in combination with antidiabetic drugs have been scarcely explored. The present study investigates the cardioprotective effects of a cocoa–carob blend (CCB) diet, rich in flavonoids, alone or in combination with metformin, in the development of DCM. Zucker diabetic fatty rats (ZDF) were fed with a CCB rich-diet or a control diet, with or without metformin for 12 weeks. Glucose homeostasis, cardiac structure and function, and oxidative and inflammatory biomarkers were analysed. CCB improved glucose homeostasis, and mitigated cardiac dysfunction, hypertrophy, and fibrosis in ZDF rats. Mechanistically, CCB counteracted oxidative stress in diabetic hearts by down-regulating NADPH oxidases, reducing reactive oxygen species (ROS) generation and modulating the sirtuin-1 (SIRT1)/ nuclear factor E2-related factor 2 (Nrf2) signalling pathway, overall improving antioxidant defence. Moreover, CCB suppressed inflammatory and fibrotic reactions by inhibiting nuclear factor kappa B (NFκB) and pro-inflammatory and pro-fibrotic cytokines. Noteworthy, several of these effects were further improved in combination with metformin. Our results demonstrate that CCB strongly prevents the cardiac remodelling and dysfunction observed in diabetic animals, highlighting its potential, alone or in adjuvant therapy, for treating DCM.
... For example, PGC-1α has been found to be an essential regulator of oxidative stress in cardiac cells [14,15], as evidenced by the development of cardiac dysfunction in PGC-1α knockout mice [16]. On the other hand, current research revealed anti-atherosclerotic effects of PGC-1α [17,18], which was due at least in part to an improvement in endothelial dysfunction [19]. However, the functional role of PGC-1α in the progression of hypertension remains unknown. ...
... significantly inhibited in Ad-PGC-1α-infected mice compared with Lacz-infected mice. Of note, it was demonstrated that PGC-1α expression was positive associated with the maximal response to Ach [18], suggesting PGC-1α may play a crucial role in regulating NO generation and vascular relaxation and thus the development of hypertension. In the present study, our results showed that overexpression of PGC-1α restored DOCA-salt-induced the decrease in NO generation, as demonstrated not only by cGMP concentration but also by nitrite production. ...
Increasing evidences have accumulated that endothelial dysfunction is involved in the pathogenesis of hypertension. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) has been identified as an essential factor that protects against endothelial dysfunction in vascular pathologies. However, the functional role of PGC-1α in hypertension is not well understood. Using an adenovirus infection model, we tested the hypothesis that PGC-1α overexpression retards the progression of hypertension in deoxycorticosterone acetate (DOCA)-salt mice model through preservation of the function of endothelium. We first demonstrated that PGC-1α expression not only in conductance and resistance arteries but also in endothelial cells was decreased after DOCA-salt treatment. In PGC-1α adenovirus-infected mice, the elevation of blood pressure in DOCA-salt mice was attenuated, as determined using tail-cuff measurement. Furthermore, PGC-1α overexpression inhibited the decrease in nitric oxide (NO) generation and the increase in superoxide anion (O2 (-)) production in DOCA-salt-treated mice, in parallel with improved endothelium-dependent relaxation. Rather than affecting endothelial NO synthase (eNOS) total expression and phosphorylation, PGC-1α significantly inhibited eNOS uncoupling, as evidenced by increased eNOS homodimerization, BH4 levels, GTP-cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expression and heat-shock protein (Hsp)90-eNOS interaction. Our findings demonstrate that PGC-1α overexpression preserves eNOS coupling, enhances NO generation, improves endothelium-dependent relaxation and thus lowers blood pressure, suggesting that up-regulation of PGC-1α may be a novel strategy to prevent and treat hypertension.
© 2015 Authors.
... Regarding TC, LDL-C, and LDL/HDL ratio, a significant decrease in these indices compared to the hypercholesterolemic group treated with saline was found only in the groups treated with simvastatin or carob/simvastatin combined. Many studies showed the lipid-lowering effect of carob-only regimens [16][17][18][19][24][25][26][27][28]. The possible explanations why we did not prove this effect are the usage of different animals, the dosage of carob pulp, and the duration of the treatment. ...
Dyslipidemia and obesity are recognized as two of the major global health issues and main risk factors for coronary heart disease and cerebrovascular disease. In recent years, carob has shown certain antioxidant and anti-dyslipidemic potential. In this study, Wistar rats were fed with a standard and cholesterol-enriched diet and treated orally with carob extract and simvastatin for four weeks. After sacrifice, blood samples were collected for biochemical analysis, and liver tissue was taken for histological and immunohistochemical assessment. Weight gain was significantly higher in groups fed with cholesterol-fortified granules; total cholesterol was found to be significantly lower in the hypercholesterolemic groups treated with simvastatin and simvastatin/carob combined regimens compared with hypercholesterolemic animals treated with saline (p < 0.05). The same was true for low-density lipoprotein cholesterol and the LDL/HDL ratio (p < 0.05). Adiponectin was remarkably higher in animals treated with simvastatin compared to all other groups (p < 0.05). Leptin was significantly lower in groups treated with carob and simvastatin compared to the hypercholesterolemic group treated with saline (p < 0.05). Carob/simvastatin co-administration reduced hepatocyte damage and improved liver morphology. A study confirmed the anti-dyslipidemic, anti-obesity, and hepatoprotective potential of carob pulp alone or in combination with simvastatin in the treatment of high-fat diet-fed rats.
... Many in vivo and clinical studies have shown that carob pulp and fiber can reduce plasma insulin levels, lowering LDL-and increasing HDL-cholesterol levels in both healthy and hypercholesterolemic subjects by consuming 10-15 g daily. These benefits could be due not only to the possible cholesterol clearance in the intestinal lumen by the fiber but also to the phenolic compounds, which seem to act in the inhibition of inflammation by increasing the expression of SIRT1 and activating the peroxisome proliferator-1-alpha receptor [48][49][50][51][52][53]. ...
Rice, tiger nut and carob are Mediterranean products suitable for developing new foods, such as fermented beverages, due to their nutritional properties. These crops have a high carbohydrate content, are gluten and lactose-free and have a low allergenicity index. The development of fermented beverages from these crops can contribute to the Sustainable Development Goals by promoting human health and sustainable production and consumption. A narrative review of the nutritional value and potential functional activity of fermented beverages made from these crops was carried out. This literature review of existing studies on fermented and non-fermented beverages highlights their composition, production methodology, and health benefits. Fermented beverages made from these crops are high in fiber, essential fatty acids, vitamins (group B), and minerals. Fermentation increases the bioaccessibility of these nutrients while decreasing possible anti-nutritional factors. These fermented beverages offer several health benefits due to their antioxidant effects, modulating the intestinal microbiota and reducing the incidence of chronic degenerative diseases such as metabolic syndrome. Therefore, fermented rice, tiger nut and carob beverages can improve the Spanish diet by offering improved nutritional value and beneficial health effects. Additionally, these local crops promote sustainability, making them an appropriate choice for developing new fermented beverages.
... Carob has a great antioxidant capacity due to its phenolic content. Many studies reported that carob exhibits anti-atherosclerotic, antiinflammatory, antidiabetic and cholesterol-lowering properties (Ruiz-Roso et al., 2010;Tetik et al., 2011;Valero-Munoz et al., 2014;Roman et al., 2017). Altıner and Hallaç (2020) stated that the usage of carob in pasta formulation enriched the ash, protein and dietary fiber levels of pasta. ...
A COMPARATIVE PHENOTYPE AND GENOTYPE STUDY OF THE ANTIBIOTIC
RESISTANCE SALMONELLA SPECIES ISOLATED FROM CHICKEN MEAT IN BAKU,
AZERBAIJAN AND TYLER, TEXAS, USA
Asaf M.Omarov1, Ali Azghani2, Siala Rustamova3, Saida Aliyeva4, Javid Mammadov5
1Khazar University, Life Sciences department, Baku, Azerbaijan
2 The University of Texas at Tyler, Biology department, Tyler, The USA
3Veterinary Scientific Research Institute, Baku, Azerbaijan
4. The ADA University, Baku, Azerbaijan
5 Javid Mammadov, Baku, Azerbaijan Poultry Company
INTRODUCTION
The modern intensive integrated livestock production systems require regular antibiotics used at farms to
maintain animal health and production. The use of antibiotics in food animal production has been implicated
as a contributing factor to the emergence of drug resistance in human foodborne pathogens(Davies & Wray,
1997). Certain antibiotics, when given in low, subtherapeutic doses, are known to improve feed conversion
efficiency (more output, such as muscle or milk, for a given amount of feed) and may promote greater
growth, most likely by affecting gut flora (By Christopher D. Reinhardt, 2013). The regular and
irresponsible use of antibiotics in modern veterinary practices is associated with the emergence of different
multidrug-resistant (MDR) bacteria. These MDR pathogens of animal origin may be disseminated to humans
via the wider environment including food products, sewage, and agricultural system. Salmonella is an
important pathogen highly associated with poultry products such as eggs and chicken meat(Velasquez et al.,
2018)
Salmonella organisms may become resistant to antimicrobials by modifying or inactivating the antimicrobial
agent, modifying the antimicrobial target, the action of the efflux pumps, or cell membrane permeability.
(Hawe et al., 2022; Mulvey et al., 2006) Genomic events constitute a central process in the mobilization of
genetic elements and associated mobile antibiotic resistance antibiotic resistance-encoding genes in different
settings (Burrus & Waldor, 2004). The movement of bacteria from the environment to animals and humans
(and vice-versa) contributes to an increase in the mobilome (mobile gene pool) (Kav et al., 2012). These
genetic exchanges have been significantly reported among human and animal guts (Devirgiliis et al., 2011).
Material and Methods
The fresh chicken meat was collected from retail markets in the city of Tyler, Texas, and Baku, Azerbaijan.
The samples were processed in Dr. Azghani’s Laboratory at the University of Texas at Tyler and the
Laboratory of Khazar University, Baku Azerbaijan.
TSB, TSA, Mueller-Hinton Agar, and MacConkey Agar were used for Salmonella spp. isolation and
counting CFU. Difco Salmonella O antiserum Poly A – I and Vi serum was used as a screening test, PCR
(16S) was implemented for conformation. QIAamp ® DNA Mini and Blood kit was used for DNA
extraction. Cefotaxime 30ug, Imipenem 10ug, Colistin 10ug, Amoxicillin+Clavulanic acid 20ug/10ug,
Aztreonam 30ug, Chloramphenicol 30ug, Sulfamethoxazole+Trimethoprim 23.75ug/1.25ug, Ciprofloxacin
5ug, Gentamicin 10ug antibiotic discs were used for phenotypical identification to AMR ability to isolated
Salmonella spp. 16S, blaIMP blaNDM-1 mcr-1 aadB genes are considered a gene of interest, Cyber green
Super Mix was used for the recognition AMR genes.
International Congress on Natural & Medical Sciences
Proceedings book
www.egekongreleri.org | iksad47@gmail.com | September 02-04, 2022 / Ege University, Izmir, Türkiye 18
Results
1. AMR Salmonella spp. was detected in both countries
2. Mobile genetics elements were separated from isolated Salmonella spp.
3. Bacteria isolated from Azerbaijan and Tyler (the USA) demonstrated different phenotypes and genotypes
AMR ability
4. Different mobile genetic elements were detected based on phenotype antibiotic resistance variation in
Salmonella spp.
5. Various resistance to unique antibiotics were dissimilar for these countries
... Furthermore, fiber consumption hampers triglyceride absorption, which lowers serum concentrations. [22] Macho-Gonzalez et al. [80] explored that carob fiber extract (CFE) reduces postprandial lipemia levels in rats by inhibiting pancreatic lipase activity that leads to reduced fat digestion and absorption along with enhanced fecal excretion of fat. The carob beans are a rich source of dietary fiber as well as phenolic compounds both are responsible for antihyperlipidemia activity. ...
Carob (Ceratonia siliqua) is one of Asia and Africa's popular nutritional and medicinal crops. This unique plant has an outstanding functional properties and nutritional profile. Carob has high sugar content, drought resistance and is very economical. Carob fruit consists of pulp and seed that are rich sources of different bioactive components. Carob has wide applications in various industries (food, pharmaceuticals and cosmetics) as an anti-oxidant, thickener, stabilizer, lactic acid production and emulsions. The trend of moving towards natural products further highlights the use of carob in different fields due to its excellent nutritional and therapeutic profile. Carob bean gum is widely used in the food industry. The current review has highlighted the nutritional composition, bioactive profile, functional properties, and recent findings on the subject.
... Carob has a great antioxidant capacity due to its phenolic content. Many studies reported that carob exhibits anti-atherosclerotic, antiinflammatory, antidiabetic and cholesterol-lowering properties (Ruiz-Roso et al., 2010;Tetik et al., 2011;Valero-Munoz et al., 2014;Roman et al., 2017). Altıner and Hallaç (2020) stated that the usage of carob in pasta formulation enriched the ash, protein and dietary fiber levels of pasta. ...
In the study, it was aimed to examine the effect of height, body weight, push-ups, pull-ups in the pull-ups
and weightless, 8 and 16 kg weight climbing times, and the relationship between ascent and descent times
and Body Mass Index (BMI) of the study groups that trained two different rope climbing techniques.The
study model was planned as a pre-post-test quasi-experimental with two experimental groups. A total of 60
male volunteers [Compression Technique (ST), N=30 and Ladder Technique (MT) N=30] individuals were included in the study.In education; Five weeks, three days a week, 50 minutes of technical rope climbing
training was carried out, and the relationship between the effect of different strength intensities on climbing
times and BMI was examined.In the quasi-experimental planned study, the homogeneity of the groups was
ensured according to the pre-test values, and the ST and MT teaching and training program was applied for
five weeks.In the measurements taken before the study and at the end of the five-week study; height, body
weight, push-ups, pull-ups in the pull-ups and weightless, 8 to 16 kg climbing times were measured.Before
processing the obtained data, the entered data was checked in order to work with a complete and correct data
set. In the processing of the data, it was examined whether the research variables had a normal distribution.
For this, skewness, kurtosis coefficients, histogram graph and Q-Q plot were used.The homogeneity
assumption was checked with the Levene test to examine whether the groups were evenly distributed in the
hypotheses in which the mean differences in the pre-test values were examined.Since the distribution was
normal, Pearson correlation analysis was used for the relationship between T-Test variables and BMI in prepost-
test comparisons.As a result of the analyzes made; It was determined that both techniques of climbing
significantly increased arm strength, the relationship between climbing and descending times of climbing
and BMI was positively correlated with unweighted ascent-descent time in MT, and negatively correlated
with 8-16 kg ascent-downhill times; It was determined that there was a negative correlation between ST and
unweighted and 8 kg ascent and descent times, and a positive correlation between 16 kg weight ascent and
descent times.
Keywords: Rope, Climbing, Body Mass Index, Arm Strength, Weight, Duration
... Carob has a great antioxidant capacity due to its phenolic content. Many studies reported that carob exhibits anti-atherosclerotic, antiinflammatory, antidiabetic and cholesterol-lowering properties (Ruiz-Roso et al., 2010;Tetik et al., 2011;Valero-Munoz et al., 2014;Roman et al., 2017). Altıner and Hallaç (2020) stated that the usage of carob in pasta formulation enriched the ash, protein and dietary fiber levels of pasta. ...
AMR Salmonella spp. was detected in both countries. Mobile genetics elements were separated from isolated Salmonella spp. Bacteria isolated from Azerbaijan and Tyler (the USA) demonstrated different phenotypes and genotypes AMR ability. Different mobile genetic elements were detected based on phenotype antibiotic resistance variation in
Salmonella spp. Various resistance to unique antibiotics were dissimilar for these countries
... Comparing with control group, in test group, a blood cholesterol lowering effect was observed [102]. Commercial non-soluble, polyphenol-rich fi ber was supplemented to male rabbits, resulting improvement is cardiovascular system functioning, especially expression of protective proteins in aorta [103]. ...
Carob has been used by humans since antiquity. Its major use is food, but traditional medicines
of many nations used it for treatments of various health disorders. The fruits (pods or kibbles)
were the main source for nutrition and medicinal uses, but decoctions and extracts were prepared
from other parts of the tree, especially leaves. Modern science has analyzed most of the chemical
compositions of the different parts, and among the phytochemicals that were found, antioxidants
play very important roles in Carob nutritional and medicinal activities. So, in addition to having strong
antioxidant activity and due to it, these natural products, their extracts, and foods that contain them,
have anticancer, neuroprotective, hepatoprotective, antiaging, skin care, antidiabetic, and others.
Phenolics and carbohydrates are the strongest antioxidants, but some volatile compounds have
the same activity, to some extent. However, this review will present Carob antioxidants, their major
nutritional and medicinal activities, and suggest future horizons for their use in human wellbeing.
... Carob gum as soluble fiber has the potent to lower plasmatic blood cholesterol value [57]. Moreover, Carob fibers hypocholesterol agent derivative was patented [58]. ...
... Carob powder, the ground powder of deseeded roasted carob pods, improved the lipid profile makers in rats fed on a hyperlipidemic diet in a concentration-dependent manner (Hassanein et al. 2015). Carob pulp, with its enriched composition of insoluble dietary fibers, reduced serum levels of cholesterol and triglycerides and also minimized several structural and functional markers for the development of atherosclerosis in rabbits (Valero-Muñoz et al. 2014). A patented dietary food supplement recommended for promoting cardiovascular functions is a combined formulation of carob insoluble fibers and n-3 fatty acids (Haber et al. 2006). ...
Ceratonia siliqua (Carob); is a Mediterranean legume globally recognized for its commercial value, being used as a cold beverage, in bakery and confectionary products. It is widely used as a Cocoa substitute not only due to its richness in sugar but rather the absence of caffeine and theobromine stimulant action. Both fruit pulp and seeds are of potential nutritive and medicinal values. The pulp comprises a high sugar content dominantly sucrose as well as polyphenols viz. phenolic acids, flavonoids and tannins. Seeds potential usage is attributed to its locust bean gum (LBG), commercially and pharmaceutically used as gelling and stiffening agent. Carob syrup is a traditional product native to the Mediterranean region, enriched in D-pinitol sugar of anti-diabetic effect. Considering the diversity of carob active constituents’ classes, a myriad of biological effects is recorded to include antioxidant, anticancer, antimicrobial and anti-hyperlipidemic effects. This book chapter presents up to date information on carob usage and chemistry while providing insight on research questions or applications yet to be addressed.
... Animal experiments in rabbits indicated that insoluble dietary fiber from carob pod could reduce development of atherosclerosis. The results suggested that increased expression of aortic sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α may play a key role for the beneficial effects of carob fiber in dyslipidemia [48,49]. These effects are attributed to the presence of a large amount of insoluble dietary fiber (cellulose and hemicellulose) and/or polyphenols in carob fiber. ...
Abstract Polysaccharides in carob fruit, including carob bean gum (also known as carob gum, locust bean gum) and carob fiber, are widely used in industries such as food, pharmaceuticals, paper, textile, oil well drilling and cosmetics. Carob bean gum is a galactomannan obtained from the seed endosperm of carob tree and the fiber is obtained by removing most of soluble carbohydrates in carob pulp by water extraction. Both the gum and fiber are beneficial to health for many diseases such as diabetes, bowel movements, heart disease and colon cancer. This article reviewed the composition, properties, food applications and health benefits of polysaccharides from carob fruit.
... This species is also used for extracting sugars for making syrup or bioethanol, and carob fruit is mainly used for animal feed (Kotrotsios, Christaki, Bonos, Florou-Paneri, & Spais, 2011). Carob flour is also a good source of dietary fibre, and it has been shown to have therapeutic potential for several diseases, including reducing low-density-lipoprotein cholesterol in hypercholesterolemic patients, regulating blood glucose levels, benefits for the body weight and improving digestion and lipid utilisation (Valero-Muntildoz, Martín-Fernández, Ballesteros, Lahera, & de las Heras, 2014). Therefore, whole carob fruit flour could be a novel ingredient with great potential to be used for developing gluten-free, functional food products, such as extruded products. ...
Rice and legumes have great potential in the development of novel gluten-free snacks that are healthier than traditional snacks. Novel gluten-free extruded foods (composed of rice: 50–80%, beans: 20–40% and carob: 5–10%) were analysed and the extrusion effects regarding organic acids, tocopherols, phenolic compounds and bioactive properties were evaluated. The total concentration of organic acids was not significantly affected by extrusion, while tocopherols showed a significant reduction. Extrusion did not produce an increase of the total phenolic content. For the bioactivity assays, commercial extruded rice, carob and most of the extruded samples showed anti-proliferative activity, which was higher than in the non-extruded samples, while for the anti-inflammatory activity, the extrusion process did not show a significant effect. Regarding the antimicrobial activity, low potential was observed with extruded and non-extruded samples showing high values of MIC and MBC as the microorganisms tested were multi-resistant isolated clinical strains.
... l foods and plant supplements (Kraus, 2015. Öztürk, 2012. Carob pod, also called "carcao", is indicated in the diet of obese subjects (Petkova et al., 2017. Tounsi et al., 2017. Furthermore, some experiments conducted on guinea pigs have detected the cancellation of the physiological effects that lead to atherosclerosis (Sánchez-Segado et al., 2012. Valero-Munoz et al., 2014). ...
This research evaluates the degree of consumer acceptance, and or preference, for the carob, a substitute product for cocoa in the production of chocolate. It also assesses its potential as a “functional food” for celiacs, diabetics and for those intolerant to caffeine. In order to assess the degree of consumer preference for the consumption of chocolate made using carob, sensory analysis coupled with face-to-face surveys of 192 Sicilian consumers, who ate chocolate on a regular basis, were conducted, from March to May 2017. The data were processed using bivariate association analysis. 12.7% of the subjects described the aftertaste of chocolate made using carob as unpleasant and the aftertaste of chocolate made using cocoa, as pleasant or very pleasant. However, 7.1% declared that the aftertaste of the chocolate containing cocoa as unpleasant, defining the aftertaste of the carob, as pleasant or very pleasant. Some subjects also expressed a liking for both types of chocolate, declaring that they were pleasant (16.7%) or very pleasant (38.9%). Chocolate made using carob flour offers several potential health benefits compared to traditional chocolate and could find use as a functional food. This has social and economic implications for agriculture and for the cultivation of carobs. The scientific studies on this transformed product are very few. No previous research has conducted a sensory analysis on such a large sample of subjects. This research work could help to encourage the consumption of a “new chocolate” and consequently lead to the production of carob chocolate by those companies that use the fruit for other purposes. © 2019, SRAC - Romanian Society for Quality. All rights reserved.
... SIRT1 plays an essential role in the genesis of aldosterone-induced renal injury which is directly related to hypertension. One of the best-characterized targets of SIRT1 is PGC1α [44] since PGC1α activates NRF1 to promote mitochondrial biogenesis. It has been proposed that SIRT1 might be able to modulate the creation of new mitochondria during tissue repair in cases of cardiac injury [45]. ...
Background
Aldosterone plays a key role in the development of endothelial dysfunction and hypertension. The regulation of biogenesis and fusion/fission processes of vascular mitochondria has not been examined in aldosterone-induced hypertension. Thereby, we sought to explore in greater depth the role of aldosterone in mitochondrial biogenesis and fusion/fission processes in hypertension and the associated increases in oxidative stress.
Methods
Male Wistar rats received aldosterone (1mg/Kg/day) + 1% NaCl as drinking water for 3 weeks.
Results
Systolic blood pressure was elevated (p<0.05) in aldosterone-treated rats. eNOS and p-eNOS Ser1177 protein expression was down regulated (p<0.05) and NADPH oxidase subunit p22phox expression was increased (p<0.05) in aldosterone-treated rats. Expression of mitochondrial biogenesis proteins SIRT1, PGC1α, PPARγ, and TFAM decreased (p<0.05) in aldosterone-treated rats. Protein expression of vascular DRP1, OMA1 and S-OPA1 up regulated (p<0.05) in aldosterone-treated rats. MFN1 and L-OPA1 (p<0.05) decreased in aldosterone-treated animals.
Conclusion
The results showed that, in aldosterone-treated rats, hypertension is likely associated with increased oxidative stress in the aorta and with changes in the regulation of two key mitochondrial processes such as biogenesis and fusion/fission processes. The overall mitochondrial alterations observed in the study may play a role in aldosterone-derived vascular oxidative stress and hypertension.
... These effects may be attributed to the high content of lignins and polyphenols, especially tannins [166]. Similar results were observed in studies on rats and rabbits [168][169][170]. ...
Cocoa originates from the beans of the cocoa tree (Theobroma cacao L.). It is an important commodity and the main ingredient in chocolate manufacture. Its value and quality are related to complex flavors and to its distinct sensory properties. The increasing demand for cocoa and its rising price urges the research for cocoa substitutes. A potential substitute for cocoa is carob. Carob is the fruit of an evergreen tree (Ceratonia siliqua L.) cultivated in the Mediterranean area, well known for its valuable locust bean gum and also for carob powder and syrup that are obtained from carob pulp. Cocoa beans and carob pods contain various phytochemicals including polyphenols, proteins and amino acids, fatty acids, carbohydrates and fiber. Phytochemicals represent an important source of nutrients and compounds that are beneficial to human health. In this review, phytochemicals in cocoa beans and carob pods and their impact on human health are reviewed. The bioactive compounds that are present in carob, in conjunction with the cocoa-like flavors and unique sensory properties that are enhanced by carob powder roasting, underline carob’s potential to substitute cocoa in various food products. These food applications are discussed in this review.
... Multiple pharmacological activities have been reported on pods of C. siliqua including antidiabetic (Rtibi et al., 2016a), antibacterial (Meziani et al., 2015), antifungal and cytotoxic (Dhaouadi et al., 2014), anti-oxidant (Kumazawa et al., 2002;Rached et al., 2016), antiproliferative (Roseiro et al., 2013), neuroprotective (Ahmed, 2010), human neutrophil myeloperoxidase inhibitor, scavenger of reactive oxygen species (Rtibi et al., 2015a), gastroprotective (Rtibi et al., 2015b), hepatoprotective Temiz et al., 2015) and antiatherosclerotic effects (Valero-Muñoz et al., 2014). ...
p class="Abstract">The study was conducted to provide the ethnopharmacological bases of the crude extract of seed pods of Ceratonia siliqua in the gastrointestinal spasm, diarrhea and emesis. In segregated rabbit jejunum, it showed dose-dependent (0.01-10 mg/mL) relaxation of spontaneous as well as carbachol (1 µM)-induced contraction. Pre-treatment of segregated rat ileum with C. siliqua , significantly (p<0.0001) suppressed the carbachol (1 µM)-induced contraction similar to atropine (1 µM). These results indicated that C. siliqua possesses spasmolytic activity through possible blockage of muscarinic receptor in jejunum preparations. Furthermore, the crude extract inhibited the castor oil-induced diarrhea, charcoal meal propulsion in mice and copper sulfate-induced retches in chicks in a dose-dependent manner (100, 200, 300 mg/kg). These in vitro and in vivo results indicate that C. siliqua possesses the spasmolytic and antidiarrheal activities mediated possibly through blockage of muscarinic receptors. Thus, this study provides a rationale for its folkloric use.
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... This might be due to presence of an insoluble dietary fiber which comprised of 80 % insoluble polyphenol in the carob pod extract 59 . This leads to improvement of endothelial function and reduction of inflammation and fibrosis and hence reduction of serum cholesterol and T.Gs consequently 60 . ...
Drugs used for treatment of cancerous diseases by mean of chemotherapy are often limited due to their severe undesirable side effects in multiple organs. Cyclophosphamide (CYP) belongs to class of the cytotoxic bifunctional alkylating agents. In the current study, it was revealed that CYP caused significant (P˂0.05) elevation in levels of different biochemical measurements. Carob extract exhibited beneficial effect through lowering of all elevated parameters. Furthermore, CYP caused decline in total antioxidant capacity (TAC) level in association with elevation of lipid peroxidation (LPO) level and significantly (P˂0.05) in liver tissue. Carob extract restored TAC and lowered LPO level. CYP caused several histopathological alterations in the hepatocytes and carob extract minimized severity of these alterations. The similarity index percent (SI %) in the native electrophoretic protein, lipoprotein and calcium moiety of protein patterns was represented by lowest values (87.50, 66.67 and 70.59, respectively) with the CYP-treated group. The SI % values increased in all carob treated groups. In all electrophoretic isoenzymes, the SI % value was represented by the lowest value (60.00, 66.67, 66.67 and 53.33 respectively with catalase (CAT), peroxidase (GPx), α- and β-esterase (EST) patterns) in CYP-treated group. While in all carob treated groups, the SI % value reached the highest value (100.00). Furthermore, CYP induced cleavage of the genomic DNA and the carob extract maintained the DNA integrity. The study concluded that carob showed ameliorative effect against alterations induced by CYP at biochemical, histopathological and molecular levels in liver tissue of rats.
... The major phenolic compounds found in carob kibble contains mainly gallic acid (free form) and gallotannins (polymeric forms) with major contribution of former up to 42% of total phenolics (Owen et al., 2003). Fiber and polyphenol-rich preparations from carob kibble have potential to combat with various metabolic disorders such as hypercholesterolemia as it decreases low density lipoprotein (LDL), regulates level of glucose in blood, and improves digestion and lipid utilization (Gruendel et al., 2007;Koebnick & Zunft, 2004;Nasar-Abbas et al., 2016;Ruiz-Roso, Quintela, de la Fuente, Haya, & P erez-Olleros, 2010;Valero-Muntildoz, Martin-Fernandez, Ballesteros, Lahera, & de las Heras, 2014). ...
... In fact, the carob fibre can be used to minimize the lipid oxidation in cookies; in a similar way that tocopherol does (Haber 2002). Several studies have also reported a cholesterol attenuation activity of this carob fibre (Ruiz-Roso et al. 2010;Zunft et al. 2003), an anti-atherosclerotic effect of carob pod insoluble fibre in rabbits (Valero-Muñoz et al. 2014) and even a carob pod treatment for acute-onset diarrhea has been proposed (Loeb et al. 1989). Added to that, carob is also rich in D-pinitol, a compound that can lower blood glucose and has anti-inflammatory effects (Tetik et al. 2011). ...
Carob flour is a product rich in fibre obtained from by-products of the locust bean gum extraction processing. The flour is commercialised with different degrees of roasting in order to improve its organoleptic characteristics. In this study, carob flour with three different roasting degrees was used to replace rice flour (15%) in gluten-free cakes and cookies. The influence of this replacement was studied on the psychochemical characteristics and acceptability of the final products. The incorporation of carob flour increased the viscosity of cake batters and increased the solid elastic-like behaviour of the cookie doughs, indicating a stronger interaction among the formula ingredients. The inclusion of carob flour, with a low time of roasting, did not lead to any significant differences in the specific volume and hardness of the cakes, but reduced cake staling and the thickness and width of the cookies. Darker colours were obtained when carob flour was incorporated into the product. The acceptability of cakes was only reduced with the addition of highly roasted carob flour, while in the case of cookies there was a decline in the acceptability of all carob flour cookies, which was mostly perceived with the highest roasting degree, something mainly attributed to the bitter taste of the products.
... Carob powder could be a potential candidate in diet regimen of obese and overweight persons. Valero-Munoz et al. observed that carob pod fibers suppressed physiological events that led to atherosclerosis in rabbits with dyslipidemia [96]. They observed that the expression of SIRT1 and PGC-1a, proteins with a key role in the vascular and metabolic system, were enhanced, proposing a new mechanism of action of carob components. ...
The contribution of natural products to the drug-discovery pipeline has been remarkable since they have served as a rich source for drug development and discovery. Natural products have adapted, during the course of evolution, optimum chemical scaffolds against a wide variety of diseases, including cancer and diabetes. Advances in high-throughput screening assays, assisted by the continuous development on the instrumentation’s capabilities and omics, have resulted in charting a large chemical and biological space of drug-like compounds, originating from natural sources. Herein, we attempt to integrate the information on the chemical composition and the associated biological impact of carob fruit in regards to human health. The beneficial and health-promoting effects of carob along with the clinical trials and the drug formulations derived from carob’s natural components are presented in this review.
... Flour made by beating the seeded pods has been utilized in breakfast foods (Smith and others 2012;Tsatsaragkou and others 2014a). Due to the unique composition of carob powder, its incorporation into food products can significantly increase the dietary fiber and polyphenol contents without any significant increase in the fat content (Makris and others 2007;USDA 2009;Durazzo and others 2014). Since allergenicity is one of the major concerns associated with any new food ingredient, the carob protein was not found to be allergenic in peanut-allergic children aged 4 to 14 y (Fiocchi and others 1999). ...
Carob (Ceratonia siliqua L.) is well known for its valuable locust bean gum obtained from the carob seeds. Separation of seeds from the pod leaves behind the carob kibble which is a good source of dietary fiber, sugars, and a range of bioactive compounds such as polyphenols and pinitol. Bioactive compounds present in carob kibble have been found to be beneficial in the control of many health problems such as diabetes, heart diseases, and colon cancer due to their antidiabetic, antioxidant, and anti-inflammatory activities. Carob kibble has substantial potential to be used as a food ingredient. This article focuses on the composition, health benefits, and food applications of carob kibble.
Carob is botanically called as Ceratonia siliqua and belongs to the Legumes family. The
fruit is derived from hermaphrodite trees and hard in shape. The carob contains high
sugar contents in pulp, fat in seed and minerals like potassium, calcium, and phosphorus
are present in pods. Polyphenols and antioxidants are abundant in leaves and
pods. It can be used for enhancing human health due to its high nutritional profile.
Carob gum is used in the pharmaceutical industry in the form of pomades, anti-celiac
ingredients, pills, and dental paste. The clinical carob can aid as an anti-cancer,
anti-reflux,
anti-diabetic,
anti-diarrheal,
anti-hyperlipidemia,
anti-bacterial,
anti-microbial,
and anti-fungal.
Nowadays, carob seeds are being used as an alternative to cocoa
powder in food items whereas the leaves, pods, and seeds of carob are also historically
used as food for animal feed. However, these parts of carob are available in
markets with reasonable prices. Carob production, though with a rising contribution,
contributes to the local economy. In this sense, we can incorporate knowledge on the
chemical properties and the biological effect of carob fruits on human health. In this
study, the supportive and health-promoting
impacts of carob are discussed along with
the clinical testing obtained from natural constituents of carob. In addition, further
studies can be performed to extract and separate polyphenols and antioxidant potential
for the development of functional that play a valuable role in pharmaceutical and
food sectors.
This study aimed to develop nutritious, gluten-free bread with high quality characteristics using a mixture of chickpea, carob and rice flours as substitutes of wheat flour. To optimize the bread formulation, a Box-Behnken experimental design was conducted to evaluate the effect of the corresponding flour blend addition, proofing time and water amount addition on the physicochemical, technological and sensory properties of the obtained formulated bread. The optimized formulation was calculated to contain 70% of mixture flour and 100% of water, with a proofing time of 40 minutes. This formulation produced bread with greater specific volume (3.73±0.37 cm³/g) and less baking loss (22.98±0.94%) than those of control (+) bread (2.93±0.21 cm³/g and 31.65±0.72%, respectively). Findings proved that the mixture flour based on chickpeas, carob and rice represents a good alternative to make gluten-free bread with acceptable baking properties.
Le caroubier est un arbre méditerranéen qui est très utilisé en médecine traditionnelle et en alimentation pour son
fruit et ses graines. Les feuilles et les écorces constituent donc des sous-produits mais elles ne sont pas très
valorisées. L’objectif principal de cette étude est de distinguer les différents éléments botaniques de la feuille et
de l’écorce puis d’étudier qualitativement et quantitativement leurs composants chimiques. Il s’agit donc d’une
étude descriptive comparative par une étude macroscopique et microscopique de la coupe transversale et de la
poudre suivie d’un screening tri-phytochimique et d’un dosage spectrophotométrique des polyphénols et des
flavonoïdes de la feuille et de l’écorce du caroubier. Ces deux parties renferment des poils tecteurs et des fibres
scléreuses péricycliques mais seule l’écorce contient des cellules scléreuses, le screening phytochimique a
confirmé la présence des stérols des saponosides ainsi que des polyphénols avec 37,32 mg/g dont 24,20 mg/g de
flavonoïdes dans les feuilles et de 28,54mg/g dont 5,76mg/g de flavonoïdes dans l’écorce. Ces résultats très
encourageants doivent être complétés par des études chimiques, biologiques et cliniques plus approfondies afin de
permettre un sage thérapeutique.
The global prevalence of dyslipidemia (elevated plasma levels of total cholesterol, LDL-Cholesterol, triglycerides, and lower plasma levels of HDL-Cholesterol) is constantly on the rise. Lately, carob pulp has been recognized as an effective natural product for the treatment of dyslipidemia. The two main components of the carob pulp, polyphenols, and insoluble fiber are believed to have beneficial effects on lipid metabolism. Studies on humans and animals confirmed its lipid-lowering effects. Several mechanisms have been proposed to explain this phenomenon, namely by affecting three organ systems: 1) gastrointestinal tract, 2) liver and 3) adipose tissue. Also, carob products have antioxidative, anti-inflammatory, and vascular-protective activity.
This study aimed to develop nutritious, gluten-free bread with high quality characteristics using a mixture of chickpea, carob and rice flours as substitutes of wheat flour. To optimize the bread formulation, a Box-Behnken experimental design was conducted to evaluate the effect of the corresponding flour blend addition, proofing time and water amount addition on the physicochemical, technological and sensory properties of the obtained formulated bread. The optimized formulation was calculated to contain 70% of mixture flour and 100% of water, with a proofing time of 40 minutes. This formulation produced bread with greater specific volume (3.73±0.37 cm3/g) and less baking loss (22.98±0.94%) than those of control (+) bread (2.93±0.21 cm3/g and 31.65±0.72%, respectively). Findings proved that the mixture flour based on chickpeas, carob and rice represents a good alternative to make gluten-free bread with acceptable baking properties.
Phenolic compounds are linked to a number of health benefits, including antioxidant, antibacterial, antiglycaemic, antiviral, anticarcinogenic, anti-inflammatory and vasodilatory properties. To improve a great loss of phenolics during extrusion, researchers have investigated incorporating functional ingredients into the extrusion input mixture. Other reasons for the addition of active ingredients are the re-use of by-products from food technology, decreasing the calorie content of extruded food, inhibition of starch digestion, and the colour change of the gluten-free products. The paper presents 28 examples of new designs for extrusion based on rice, corn, cassava, sorghum, and lentil flours and on other crops, together with the analyses of phenolics. The present results show the highest total phenolic content in sorghum among cereals, and lentil flour and orange peel powder among mixtures for extrusion to prepare extrudates. The highest content of total flavonols was found in the mixture containing corn and freeze-dried red and purple potatoes.
Carob tree ( Ceratonia siliqua L.) is one of the most widespread medicinal plants in the Mediterranean area. Traditionally, it was cultivated for its ethnopharmacological benefits and, more especially, for the seeds, which served as unit of measurement of jewelers “carat.” Hence, in the last half-century, numerous studies reported a wide range of phytoconstituents contained in all parts of Ceratonia siliqua such as phenolic compounds, flavonoids, tannins, anthocyanins, alkaloids, glycosides, proteins and minerals. This review article unveils the phytochemical constituents, bioactivity and pharmacological studies of Ceratonia siliqua . Recent studies have shown that the extracts of this plant exhibit an antioxidant, antidiarrheal, antibacterial, antifungal, anti-inflammatory, antidiabetic activities and also hepatoprotective and antiproliferative effects. In this review, we provide a summary of the most interesting data related to bioactivity and therapeutic potential of Ceratonia siliqua in a way to suggest possible future studies that may use Ceratonia siliqua as an undeniable natural alternative for neurodegenerative diseases treatment.
The objective of this study was to evaluate carob pods and their effect on growth performance, antioxidant activities, carcass and caecal characteristics and equilibrium modification of the caecal microbiota population of growing NZW rabbits. Eighty weaned rabbits (initial body weight: 625.00 ± 26.46 g) were randomly allocated into four dietary groups of 20 rabbits each until 90 days of age. Dietary groups were as follows: C (basal diet with no supplementation), CP1 (basal diet + 2.5% carob pods), CP2 (basal diet + 5% carob pods) and CP3 (basal diet + 10% carob pods). Rabbits given the CP2 diet had significantly higher daily and final body weights compared with the other experimental groups. The increase in inclusion rate of carob pods significantly decreased feed intake, whereas carob pods at 5% in the CP2 group recorded the best value of feed conversion ratio. Rabbits in the CP3 group showed the worst slaughter weight and carcass dressing percentage weight. No significant effect was found on meat protein and ash contents. Cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides decreased significantly (p < 0.05) in rabbits treated with carob pods compared with the control. Because of high content of the antioxidant compounds in CP2 and CP3 groups, the activities of glutathione peroxidase, glutathione S-transferase, catalase and superoxide dismutase increased, whereas the concentration of thiobarbituric acid-reactive substance decreased significantly. Rabbits given the CP2 diet had a significantly higher volatile fatty acid concentration and a lower pH in content of the caecum compared to the other groups. The data of microbial analysis for C group showed a significant increase in Escherichia coli and Clostridium counts. Lactobacillus and Bacillus counts increased significantly more in the CP2 and CP3 groups than in the other groups. In conclusion, 5% of carob pods in the diet stimulated the performance of growing rabbits, and thus, it has potential as an unconventional feed resource for rabbits without any adverse effects.
Unlabelled:
SirT1 is a class III histone deacetylase that has been implicated in metabolic and reactive oxygen species control. In the vasculature it has been shown to decrease endothelial superoxide production, prevent endothelial dysfunction and atherosclerosis. However, the mechanisms that mediate SirT1 antioxidant functions remain to be characterized. The transcription factor FoxO3a and the transcriptional coactivator peroxisome proliferator activated receptor γ-coactivator 1α (PGC-1α) have been shown to induce the expression of antioxidant genes and to be deacetylated by SirT1.
Aims:
Here we investigated SirT1 regulation of antioxidant genes and the roles played by FoxO3a and PGC-1α in this regulation.
Results:
We found that SirT1 regulates the expression of several antioxidant genes in bovine aortic endothelial cells, including Mn superoxide dismutase (MnSOD), catalase, peroxiredoxins 3 and 5 (Prx3, Prx5), thioredoxin 2 (Trx2), thioredoxin reductase 2 (TR2), and uncoupling protein 2 (UCP-2) and can be localized in the regulatory regions of these genes. We also found that knockdown of either FoxO3a or PGC-1α prevented the induction of antioxidant genes by SirT1 over-expression. Furthermore, SirT1 increased the formation of a FoxO3a/PGC-1α complex as determined by co-immunoprecipitation (IP) assays, concomitantly reducing H2O2-dependent FoxO3a and PGC-1α acetylation. Data showing that FoxO3a knockdown increases PGC-1α acetylation levels and vice versa, suggest that SirT1 activity on FoxO3a and PGC-1α may be dependent of the formation of a FoxO3a/PGC-1α complex.
Innovation:
A unifying mechanism for SirT1 activities is suggested.
Conclusion:
We show that SirT1 regulation of antioxidant genes in vascular endothelial cells depends on the formation of a FoxO3a/PGC-1α complex.
Objective:
Cellular senescence influences organismal aging and increases predisposition to age-related diseases, in particular cardiovascular disease, a leading cause of death and disability worldwide. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and function, oxidative stress, and insulin resistance. Senescence is associated with telomere and mitochondrial dysfunction and oxidative stress, implying a potential causal role of PGC-1α in senescence pathogenesis.
Approach and results:
We generated a PGC-1α(+/-)/apolipoprotein E(-/-) mouse model and showed that PGC-1α deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1α disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas. Further, angiotensin II, a major hormonal inducer of vascular senescence, induces prolonged lysine acetylation of PGC-1α and releases the PGC-1α-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1α S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1α by angiotensin II interrupts the PGC-1α-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence.
Conclusions:
PGC-1α is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1α in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis.
Atherosclerosis is a chronic inflammatory disease that is based on the interaction between inflammatory cell subsets and specific cells in the arterial wall. SIRT1 deacetylates histone and non-histone proteins and has been implicated in protective effects of caloric restriction on lifespan and metabolic pathways in yeast, nematodes, and mice. In the vasculature of rodents, SIRT1 mediates vasodilatation through the release of endothelial nitric oxide synthase-derived nitric oxide and scavenges reactive oxygen species. Using a genetic loss-of-function approach, SIRT1 has been shown to interfere with crucial steps of endothelial activation and atherogenesis by suppressing NFκB signaling: Partial SIRT1 deletion in ApoE-/- mice prevented expression of endothelial adhesion molecules thereby hampering the extravasation of circulating monocytes. In monocyte-derived macrophages SIRT1 deletion reduced the expression of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor 1 (Lox-1) resulting in reduced foam cell formation and atherosclerosis. Moreover, it was reported that SIRT1 regulates the activity of liver X-receptor, thereby promoting ABCA1-driven reverse cholesterol transport in plaque-resident macrophages slowing foam cell formation. Finally, SIRT1 suppressed the expression of endothelial tissue factor, and thus exerted anti-thrombotic properties during induced carotid thrombosis in mice. These findings indicate protective effects of SIRT1 in atherogenesis and thrombosis at an experimental level and highlight the opportunity to translate this concept from bench to bedside. Indeed, SIRT1 activators are available and have been shown to exert beneficial effects at the preclinical level in obesity and type 2 diabetes mellitus (T2DM). SIRT1 activators are currently being evaluated in phase II clinical trials in patients with T2DM. The concept of SIRT1 activation appears a promising strategy for novel therapeutic approaches in patients with atherothrombosis.
Recently, insoluble fibre from carob pulp has been found to affect blood lipids in animals in a similar manner as soluble dietary fibre.
To investigate whether a carob pulp preparation containing high amounts of insoluble fibre has a beneficial effect on serum cholesterol in humans.
Volunteers (n = 58) with hypercholesterolemia were recruited to participate in a randomised, double- blind, placebo-controlled and parallel arm clinical study with a 6 week intervention phase. All participants consumed daily both, bread (two servings) and a fruitbar (one serving) either with (n = 29) or without (n = 29) a total amount of 15 g/d of a carob pulp preparation (carob fibre). Serum concentrations of total, LDL and HDL cholesterol and triglycerides were assessed at baseline and after week 4 and 6.
The consumption of carob fibre reduced LDL cholesterol by 10.5 +/- 2.2% (p = 0.010). The LDL:HDL cholesterol ratio was marginally decreased by 7.9 +/- 2.2 % in the carob fibre group compared to the placebo group (p = 0.058). Carob fibre consumption also lowered triglycerides in females by 11.3 +/- 4.5% (p = 0.030). Lipid lowering effects were more pronounced in females than in males.
Daily consumption of food products enriched with carob fibre shows beneficial effects on human blood lipid profile and may be effective in prevention and treatment of hypercholesterolemia.
Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances.
High blood pressure (BP) is considered a major risk factor for cardiovascular disease. Among lifestyle factors, diet plays a key role in the prevention and control of high BP. Therefore, it is important to elucidate which dietary components can exert beneficial effects on BP through modulation of endothelial function (EF) or by other mechanisms. In this paper we review the role of nutrients, foods, particularly nuts, and dietary patterns on BP control.
Because nuts are low in sodium and contain significant amounts of mono- and polyunsaturated fatty acids, fiber, minerals such as magnesium, potassium and calcium, and antioxidants, they have been suggested as potentially protective foods against hypertension. Limited evidence from prospective studies and clinical trials suggests that nut consumption has a beneficial effect on both BP and EF. However, BP changes were a secondary outcome in nut feeding trials and no study used ambulatory BP monitoring as the standard for BP measurements.
Further clinical trials, ideally using ambulatory BP monitoring, are needed to establish the potential protective effect of nut consumption on hypertension and vascular reactivity.
SIRT1 is a NAD (+) -dependent class III histone deacetylase (HDAC) that mediates the effects of caloric restriction on lifespan and metabolic pathways in various organisms. It deacetylates both histone and non-histone proteins, and targets proteins with diverse cellular and tissue functions. In the vasculature of rodent models SIRT1 mediates vasodilatation via eNOS-derived nitric oxide (NO) and scavenging reactive oxygen species (ROS). Recent studies demonstrated further protective roles of SIRT1 in vascular biology and atherosclerosis. In endothelial cells and macrophages SIRT1 has anti-inflammatory functions by downregulating the expression of various pro-inflammatory cytokines by interfering with the NF-kB signaling pathway. Deacetylation of RelA/p65-NF-kB by SIRT1 in macrophages also suppresses the expression of Lox-1, a scavenger receptor for oxidized low-density lipoproteins (oxLDL), thereby preventing macrophage foam cell formation. Moreover, SIRT1 has been shown to regulate the activity of Liver X-receptor (LXR), thereby promoting ABCA1-driven reverse cholesterol transport in plaque macrophages. Finally, SIRT1 suppresses the expression of endothelial tissue factor (coagulation factor III) and hence exerts anti-thrombotic properties. These findings indicate atheroprotective effects of SIRT1 in atherogenesis and highlight the need for translational research from bench-to-bedside. Indeed, SIRT1 activators are available for experimental research and undergo clinical testing. Taken together, these studies suggest SIRT1 activation as a promising therapeutic approach in atherosclerosis. Further studies are necessary to better understand the exact role of SIRT1 in the protagonist cells orchestrating atherogenesis and to identify the specificity, target effects and putative off-target effects of these promising SIRT1 activators.
Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-kappaB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-kappaB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation.
Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis.
Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-κB signalling pathway.
Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation.
Recently, polyphenols have been found to affect blood lipids in animals in a similar manner as soluble dietary fibre. The aim was to assess whether an insoluble dietary fiber very rich in polyphenols has a beneficial effect on serum lipids in humans. In a double-blind randomized placebo-controlled clinical study with parallel arms, 88 volunteers with hypercholesterolemia were randomly assigned to consume daily either, fiber with insoluble 84% polyphenols 4 g twice a day (n = 43) or placebo (n = 45). Serum total, LDL and HDL cholesterol and triglycerides were assessed at baseline and after 4 weeks. The insoluble polyphenols consumption reduced the total cholesterol by 17.8 +/- 6.1% (p < 0.05), LDL cholesterol by 22.5 +/- 8.9% (p < 0.001), LDL: HDL cholesterol ratio by 26.2 +/- 14.3% (p < 0.001) and triglycerides by 16.3 +/- 23.4% (p < 0.05) at the end of the study compared with baseline. No significant differences were found during the study time in the placebo group for the lipid profile. The consumption of fiber very rich in insoluble polyphenols shows beneficial effects on human blood lipid profile and may be effective in prevention and treatment of hyperlipemia.
To assess the association between the intake of dietary fibre and carotid intima-media thickness (IMT) in a Mediterranean population at high cardiovascular risk.
Baseline cross-sectional assessment of 457 men and women (average age 67 years) from two different Spanish centres of the PREDIMED trial. A previously validated food frequency questionnaire (137 food items) was administered by trained dieticians in a face-to-face interview. Mean common carotid IMT was measured using B-mode ultrasound imaging of the right and left carotid arteries by four certified sonographers who used a common protocol. Anthropometric and blood pressure measurements were performed and samples of fasting blood were obtained. Participants were categorized into four groups (roughly quartiles: < or =21; >21 to < or =25; >25 to < or =31 and >31 g/day) of energy-adjusted intake of dietary fibre. Multiple linear regression models were used to adjust for age, sex, centre, smoking, body mass index, diabetes, blood pressure, lipid levels and statin use.
In the crude analyses, energy-adjusted fibre intake showed a significant inverse correlation with IMT (r=-0.27, P<0.001). In multivariate analyses, a modest, though statistically significant (P=0.03) inverse association between energy-adjusted fibre intake and IMT was also found. The multivariate-adjusted difference in average IMT was -0.051 mm (95% confidence interval: -0.094 to-0.009, P=0.02) for participants whose intake was >35 g/day, (n=47) when compared with those whose intake was <25 g/day (n=224).
Our results suggest that high fibre intake is inversely associated with carotid atherosclerosis.
The development of atherosclerosis is a complex, multi-step process, which is at least in part controlled by the functional state of the vascular endothelium. It is generally believed that the functional state of the endothelium is influenced by a broad set of cardiovascular risk factors and that endothelial dysfunction is the stereotypic cellular response to a broad range of different stimuli on the background of a poorly defined genetic predisposition.1
That such a concept represents an over-simplification has become evident through studies demonstrating maternal–foetal transmission of the atherosclerotic risk2 and ‘atherosclerotic programming’ of cells derived from mice with a pro-atherosclerotic phenotype.3 Such programming is the consequence of epigenetic modifications like DNA methylation or histone acetylation, processes that are controlled by several different enzyme families.
One of these enzymes, SIRT1, a class III histone deacetylase (HDAC), has gained considerable interest as a mediator of longevity induced by caloric restriction.4 Also in the vascular system, SIRT1 has been …
*Corresponding author. Tel: +49 69 6301 6995; fax: +49 69 6301 7668. E-mail address: r.brandes{at}em.uni-frankfurt.de
Hazardous environmental and genetic factors can damage endothelial cells to induce atherosclerotic vascular disease. Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective.
Human umbilical vein endothelial cells (HUVECs) were used to study the effects of oxidized low-density lipoprotein (LDL) on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effects of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE(-/-)) mice to obtain SIRT1-Tg/apoE(-/-) mice for the analysis of atherogenesis in the presence of endothelial overexpression of SIRT1. SIRT1 expression in HUVECs was increased by the treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, the SIRT1 expression in mouse aortas. In SIRT1-Tg mice, high fat-induced impairment in endothelium-dependent vasorelaxation was improved compared with that of wild-type littermates. This was accompanied by an upregualtion of aortic endothelial nitric oxide synthase expression in the SIRT1-Tg mice. The SIRT1-Tg/apoE(-/-) mice had less atherosclerotic lesions compared with apoE(-/-) controls, without affecting blood lipids and glucose levels.
These results suggest that endothelium-specific SIRT1 overexpression likely suppresses atherogenesis via improving endothelial cell survival and function.
We compared the impact of hypercholesterolaemia and mixed dyslipidaemia on vascular function, vascular structure and fibrinolytic balance in rabbits. To this end, vascular reactivity was studied in aortic rings from rabbits fed a control diet, a diet containing 0.5% cholesterol+14% coconut oil (mixed dyslipidaemia) or a diet containing 1% cholesterol (hypercholesterolaemia) for 12-14 weeks. Morphometric analysis of aorta was also performed and plasminogen activator inhibitor-1 (PAI-1) as well as tissue-type plasminogen activator (t-PA) plasma activities were measured. Both diets induced a similar increase in cholesterol plasma levels, although triacylglycerols (triglycerides) were increased in animals with mixed dyslipidaemia. Hypercholesterolaemia was associated with intimal thickening, reduction in acetylcholine-induced relaxation ( P <0.05) and increased vasoconstriction induced by acetylcholine+ N (G)-nitro-L-arginine methyl ester (L-NAME) when compared with controls ( P <0.05). These effects were more marked ( P <0.05) in animals with mixed dyslipidaemia. Incubation with ifetroban, a thromboxane A(2)/prostaglandin H(2) receptor antagonist, increased acetylcholine-induced relaxation ( P <0.05) and reduced acetylcholine+L-NAME contraction ( P <0.05) in both diet groups. In contrast, the presence of PD 145, an endothelin (ET)(A)/ET(B) receptor antagonist, exerted these effects only in rabbits with mixed dyslipidaemia. Both hypercholesterolaemia and mixed dyslipidaemia induced a similar increase in PAI-1 and a similar decrease in t-PA plasma activities. These data suggest that hypertriglyceridaemia can increase the deleterious effects of hypercholesterolaemia on endothelial function and vascular structure. This additional harmful effect exerted by triacylglycerols on endothelial function could, in part, be mediated by ET.
Several epidemiologic studies found weak protective relations between dietary fiber intake and the risk of cardiovascular disease events. However, few of the studies addressed possible mechanisms of the effect.
In the present study, we estimated relations between the progression of atherosclerosis and the intake of selective dietary fiber fractions. Mediation of the relations by serum lipids was also investigated.
Participants who were free of heart disease and aged 40-60 y were recruited into the cohort (n = 573; 47% women). The intima-media thickness (IMT) of the common carotid arteries was measured ultrasonographically at the baseline examination and at 2 follow-up examinations (n = 500), dietary intakes were assessed with six 24-h recalls (3 at baseline and 3 at the first follow-up examination), and blood samples were analyzed at baseline and at both follow-up examinations.
A significant inverse association was observed between IMT progression and the intakes of viscous fiber (P = 0.05) and pectin (P = 0.01). Correction for measurement error increased the magnitude of these estimated effects. The ratio of total to HDL cholesterol was inversely related to the intakes of total fiber (P = 0.01), viscous fiber (P = 0.05), and pectin (P = 0.01). The magnitude of the association between IMT progression and the intakes of viscous fiber and pectin was attenuated by adjustment for serum lipids.
The intake of viscous fiber, especially pectin, appears to protect against IMT progression. Serum lipids may act as a mediator between dietary fiber intake and IMT progression.
The aim of the present study was to evaluate the effect of the aldosterone receptor antagonist eplerenone on endothelial function, oxidative stress, and structural alterations present in spontaneously hypertensive rats (SHR). To carry out the study, male SHR (18 weeks old) were treated with two doses of eplerenone (30 and 100 mg/kg/day) for 10 weeks. A group of n = 8 untreated SHR was used as a control-vehicle group, and a group of Wistar Kyoto rats (n = 8) was used as a reference of normotensive conditions. Systolic arterial pressure (SAP) was measured by the tail-cuff method. Endothelium-dependent and -independent relaxations, as well as endothelial nitric oxide synthase (eNOS) and the subunit p22phox of NAD(P)H oxidase mRNA expressions, were studied in aorta from SHR untreated or treated with eplerenone. Media/lumen ratio was also calculated in aortic preparations. In addition, levels of reduced glutathione (GSH), oxidized glutathione (GSSG), and malonyl dialdehyde (MDA) were evaluated in liver homogenates. Treatment with eplerenone reduced (p < 0.05) SAP and normalized aortic media/lumen ratio and acetylcholine relaxations. Both doses of the drug enhanced (p < 0.05) eNOS and reduced p22phox mRNA expressions. Similarly, eplerenone increased (p < 0.05) hepatic GSH/GSSG ratio, and reduced (p < 0.05) hepatic MDA levels in a comparable manner. Consequently, it could be concluded that aldosterone participates in the functional and structural vascular alterations of SHR through the diminution of nitric oxide availability and an enhancement of vascular and systemic oxidative stress.
Ghrelin is an orexigenic hormone that may affect substrate utilization in humans. Ghrelin is influenced by macronutrients, but the effects of insoluble dietary fiber and polyphenols are unknown. We investigated the effects of a polyphenol-rich insoluble dietary fiber preparation from carob pulp (carob fiber) on postprandial ghrelin responses and substrate utilization. Dose-dependent effects of the consumption of carob fiber were investigated in a randomized, single-blind, crossover study in 20 healthy subjects, aged 22-62 y. Plasma total and acylated ghrelin, triglycerides, and serum insulin and nonesterified fatty acids (NEFA) levels were repeatedly assessed before and after ingestion of an isocaloric standardized liquid meal with 0, 5, 10, or 20 g of carob fiber over a 300-min period. The respiratory quotient (RQ) was determined after consumption of 0 or 20 g of carob fiber. Carob fiber intake lowered acylated ghrelin to 49.1%, triglycerides to 97.2%, and NEFA to 67.2% compared with the control meal (P < 0.001). Total ghrelin and insulin concentrations were not affected by consumption of a carob fiber-enriched liquid meal. Postprandial energy expenditure was increased by 42.3% and RQ was reduced by 99.9% after a liquid meal with carob fiber compared with a control meal (P < 0.001). We showed that the consumption of a carob pulp preparation, an insoluble dietary fiber rich in polyphenols, decreases postprandial responses of acylated ghrelin, triglycerides, and NEFA and alters RQ, suggesting a change toward increased fatty acid oxidation. These results indicate that carob fiber might exert beneficial effects in energy intake and body weight.
We have recently shown that a polyphenol-rich insoluble dietary fibre preparation from carob pulp (Ceratonia siliqua L; carob fibre) decreased postprandial acylated ghrelin, TAG and NEFA during an acute liquid meal challenge test. However, delayed effects of carob fibre consumption are unknown. Therefore, a randomized controlled crossover study in nineteen healthy volunteers consuming foods with or without 50 g carob fibre was conducted. On the subsequent day (day 2), glucose, TAG, total and acylated ghrelin as well as insulin, NEFA and leptin were assessed at baseline and at timed intervals for 300 min after ingestion of standardized bread. Consumption of carob fibre-enriched foods did not affect fasting concentrations of glucose, TAG, total ghrelin, NEFA, insulin and leptin. Fasting acylated ghrelin was increased on the day subsequent to carob fibre consumption compared with control (P = 0.046). After consumption of the standard bread on day 2, glucose response (P = 0.029) was increased, and TAG (P = 0.033) and NEFA (P < 0.001) responses were decreased compared with control. Postprandial responses of total and acylated ghrelin, insulin and leptin on day 2 were unaffected by carob fibre consumption the previous day. In conclusion, an increase in total and acylated plasma ghrelin accompanied by enhanced lipid metabolism after carob fibre consumption suggests higher lipid utilization and suppressed lipolysis on the day subsequent to carob fibre consumption. However, elevated glucose levels after carob fibre consumption need to be addressed in future studies.
Reduced caloric intake decreases arterial blood pressure in healthy individuals and improves endothelium-dependent vasodilation in obese and overweight individuals. The SIRT1 protein deacetylase mediates many of the effects of calorie restriction (CR) on organismal lifespan and metabolic pathways. However, the role of SIRT1 in regulating endothelium-dependent vasomotor tone is not known. Here we show that SIRT1 promotes endothelium-dependent vasodilation by targeting endothelial nitric oxide synthase (eNOS) for deacetylation. SIRT1 and eNOS colocalize and coprecipitate in endothelial cells, and SIRT1 deacetylates eNOS, stimulating eNOS activity and increasing endothelial nitric oxide (NO). SIRT1-induced increase in endothelial NO is mediated through lysines 496 and 506 in the calmodulin-binding domain of eNOS. Inhibition of SIRT1 in the endothelium of arteries inhibits endothelium-dependent vasodilation and decreases bioavailable NO. Finally, CR of mice leads to deacetylation of eNOS. Our results demonstrate that SIRT1 plays a fundamental role in regulating endothelial NO and endothelium-dependent vascular tone by deacetylating eNOS. Furthermore, our results provide a possible molecular mechanism connecting the effects of CR on the endothelium and vascular tone to SIRT1-mediated deacetylation of eNOS.
• calorie restriction
• vasorelaxation
• silent information regulator 2
• resveratrol
• deacetylation
The nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase Sir2 regulates life-span in various species. Mammalian homologs of Sir2 are called sirtuins (SIRT1-SIRT7). In an effort to define the role of sirtuins in vascular homeostasis, we found that among the SIRT family, SIRT1 uniquely regulates angiogenesis signaling. We show that SIRT1 is highly expressed in the vasculature during blood vessel growth, where it controls the angiogenic activity of endothelial cells. Loss of SIRT1 function blocks sprouting angiogenesis and branching morphogenesis of endothelial cells with consequent down-regulation of genes involved in blood vessel development and vascular remodeling. Disruption of SIRT1 gene expression in zebrafish and mice results in defective blood vessel formation and blunts ischemia-induced neovascularization. Through gain- and loss-of-function approaches, we show that SIRT1 associates with and deacetylates the forkhead transcription factor Foxo1, an essential negative regulator of blood vessel development to restrain its anti-angiogenic activity. These findings uncover a novel and unexpected role for SIRT1 as a critical modulator of endothelial gene expression governing postnatal vascular growth.
New Findings
What is the central question of this study?
Does PGC‐1α play a key role in vascular alterations induced by cholesterol+coconut oil diet in rabbits?
What is the main finding and its importance?
Vascular expression of PGC‐1α, SIRT1 and PPARγ were reduced in atherosclerotic rabbits. Furthermore, PGC‐1α correlated with processes involved in atherosclerosis (endothelial dysfunction, oxidative stress and inflammation). Reduction of PGC‐1α seems to play an important role in the molecular alterations during the development of atherosclerosis.
Peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) is emerging as a novel factor that plays a critical role in integrating signalling pathways in the control of cellular and systemic metabolism. We investigated the role of vascular expression of PGC‐1α and related factors, such as sirtuin 1 (SIRT1), peroxisome proliferator‐activated receptor γ (PPARγ) and adiponectin, during the atherosclerotic process. Endothelial function, vascular superoxide anion production and inflammatory mediators were also evaluated. This study was carried out in male New Zealand rabbits fed a diet containing 0.5% cholesterol and 14% coconut oil for 8 weeks. Animals developed mixed dyslipidaemia and atherosclerotic lesions, which were associated with endothelial dysfunction, aortic overproduction of superoxide anions and inflammation. Expression of PGC‐1α, SIRT1, PPARγ and adiponectin was reduced ( P < 0.05) in aorta from atherosclerotic rabbits. Levels of PGC‐1α were correlated negatively ( P < 0.05) with total cholesterol levels, aortic superoxide anion production and tumour necrosis factor‐α expression, and positively ( P < 0.05) with maximal relaxation in response to acetylcholine. The observed results suggest that PGC‐1α could be considered to be a link between the main atherosclerotic processes (endothelial dysfunction, oxidation and inflammation) and alterations of other factors involved in vascular wall integrity, such as SIRT1, PPARγ and adiponectin.
Increased oxidative stress in vascular cells is implicated in the pathogenesis of atherosclerosis. Reactive oxygen species (ROS) induce vascular inflammation via the proinflammatory cytokine/NF-kappa B pathway. Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1 alpha) is an important regulator of intracellular ROS levels. However, no studies have examined the effects of PGC-1 alpha on this process. We investigated the effects of PGC-1 alpha on inflammatory molecule expression and activity of the redox-sensitive transcription factor, NF-kappa B, in vascular cells. PGC-1 alpha expressed in human aortic smooth (HASMCs) and endothelial cells (HAECs) is upregulated by AMP-activated protein kinase activators, including metformin, rosiglitazone and alpha-lipoic acid. Tumor necrosis factor-alpha (TNF-alpha), a major proinflammatory factor in the development of vascular inflammation, stimulates intracellular ROS production through an increase in both mitochondrial ROS and NAD(P)H oxidase activity. Adenovirus-mediated overexpression of the PGC-1 alpha gene in HASMCs and HAECs leads to a significant reduction in intracellular and mitochondrial ROS production as well as NAD(P)H oxidase activity. Consequently, NF-kappa B activity and MCP-1 and VCAM-1 induced by TNF-alpha are suppressed. Our data support the possibility that agents stimulating PGC-1 alpha expression in the vasculature aid in preventing the development of atherosclerosis.
Numerous trials have demonstrated that cholesterol-lowering therapy leads to marked reductions in cardiovascular and overall mortality and in the need for coronary revascularization. Angiographic regression trials have shown that cholesterol lowering can reduce progression and, in some instances, achieve regression of coronary atherosclerotic lesions. However, recent studies have contradicted the traditional view that the clinical course of coronary artery disease is closely linked to the severity of coronary artery stenosis. It is now apparent that stenoses responsible for myocardial infarction or unstable angina are typically mild rather than severe. These observations suggest that regression may not be the principal mechanism by which cholesterol lowering affects cardiovascular risk. Two mechanisms-plaque stabilization and improved endothelial function-have been examined in this regard. Basic studies suggest that cholesterol lowering favorably alters those features of atherosclerosis that promote plaque stability. Recent clinical studies have clearly established that aggressive lipid-lowering therapy improves endothelial function and reduces myocardial ischemia in patients with hypercholesterolemia.
The effects of angiotensin (AT) 1 receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P,0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P,0.05) this response in hypercholester- olemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P,0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.566% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P,0.05) intimal lesion to 2.460.7% and 2.760.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT1 receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT 1 receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis. (Hypertension. 1999;34(part 2):969-975.)
Background and aim:
To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways.
Methods and results:
Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats.
Conclusion:
Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats.
The effects of the addition of 100 g kg−1 of psyllium husk (PSY), cellulose (CEL) or natural carob fibre (NCF) to a semi-synthetic diet on fat (FD) and nitrogen (NF) digestibility coefficients, metabolic nitrogen utilisation (MNU), net nitrogen utilisation (NNU) and total serum cholesterol and triglyceride levels, were studied in male ‘Wistar’ rats. No significant differences were observed between the three fibres with respect to the weight increase of the animals or MNU. Significant differences were recorded for the FD of the NCF group (0.91±0.01) compared to the CEL group (0.95±0.01), as well as on ND (0.88±0.00 NCF group, 0.88±0.00 PSY group and 0.95±0.00 CEL group) and NNU. None of these indexes showed differences between the groups PSY and NCF. For the serum cholesterol levels, there were no significant differences between the non-hypercholesterolaemic groups fed PSY, CEL or NCF; in those in which hypercholesterolaemia was induced (cholesterol and bile bovine 8.3 g kg−1), significantly lower values were found in the NCF group (166±17 mg dl−1 ) than in the PSY group (343±61 mg dl −1) and in the CEL group (386±48 mg dl−1).© 1999 Society of Chemical Industry
Consumption of oats has long been known to lower plasma total and low-density lipoprotein (LDL) cholesterol levels, an effect usually attributed to the soluble fibers β-glucans. On the basis of this cholesterol-lowering effect, oats are ascribed cardiovascular health-promoting properties. However, besides cholesterol levels, effects of oats on parameters relating to atherosclerosis development have not been extensively investigated. Since oxidation of lipoproteins and inflammation are characteristics of atherosclerosis in addition to lipid accumulation in the vessel wall, micronutrients in oats (phytochemicals) with antioxidative and anti-inflammatory properties may contribute to an atheroprotective action. Here, we summarize evidence on antiatherogenic properties of oats obtained from in vitro assays, animal experiments, and human studies. Possible effects involving anti-inflammatory and antioxidative actions, as well as preservation of endothelial function, are considered in addition to those related to reduction of plasma cholesterol. Since results of in vitro assays with isolated oat components are difficult to compare with effects of whole oats in humans and experimental animals, more observational studies with isolated oat components or fractions of oats are warranted. Also, there is a lack of epidemiological studies focusing on effects of oat intake on the cardiovascular disease panorama.
Consumption of oats has long been known to lower plasma total and low-density lipoprotein (LDL) cholesterol levels, an effect usually attributed to the soluble fibers β-glucans. On the basis of this cholesterol-lowering effect, oats are ascribed cardiovascular health-promoting properties. However, besides cholesterol levels, effects of oats on parameters relating to atherosclerosis development have not been extensively investigated. Since oxidation of lipoproteins and inflammation are characteristics of atherosclerosis in addition to lipid accumulation in the vessel wall, micronutrients in oats (phytochemicals) with antioxidative and anti-inflammatory properties may contribute to an atheroprotective action. Here, we summarize evidence on antiatherogenic properties of oats obtained from in vitro assays, animal experiments, and human studies. Possible effects involving anti-inflammatory and antioxidative actions, as well as preservation of endothelial function, are considered in addition to those related to reduction of plasma cholesterol. Since results of in vitro assays with isolated oat components are difficult to compare with effects of whole oats in humans and experimental animals, more observational studies with isolated oat components or fractions of oats are warranted. Also, there is a lack of epidemiological studies focusing on effects of oat intake on the cardiovascular disease panorama.
Sir2 (silent information regulator-2), an NAD(+)-dependent histone deacetylase, is highly conserved in organisms ranging from archaea to humans. Yeast Sir2 is responsible for silencing at repeated DNA sequences in mating-type loci, telomeres and rDNA, and plays critical roles in DNA repair, stress resistance and longevity.The phenomenon of human aging is known to be a critical cardiovascular risk factor. Senescence of endothelial cells has been proposed to be involved in vascular dysfunction and atherogenesis. Recent studies have demonstrated that mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homologue of Sir2, regulates vascular angiogenesis, homeostasis and senescence. This review focuses on SIRT1 as a potential therapeutic target against atherosclerosis.
This study investigated and compared the effects of particle size reduction on the cholesterol-lowering activities of carrot insoluble fiber-rich fraction (IFF) and plant cellulose. Our results demonstrated that micronization treatment effectively pulverized the particle sizes of these insoluble fibers to different microsizes. Feeding the micronized insoluble fibers, particularly the micronized carrot IFF, significantly (p < 0.05) improved their abilities in lowering the concentrations of serum triglyceride (18.6-20.0%), serum total cholesterol (15.5-19.5%), and liver lipids (16.7-20.3%) to different extents by means of enhancing (p < 0.05) the excretion of lipids (124-131%), cholesterol (120-135%), and bile acids (130-141%) in feces. These results suggested that particle size was one of the crucial factors in affecting the characteristics and physiological functions of insoluble fibers. Therefore, particle size reduction by micronization might offer the industry an opportunity to improve the physiological functions of insoluble fibers, particularly the carrot IFF, in health food applications.
Carob pod fiber containing 44.4% highly polymerized tan nins was fed to rats in a purified diet in order to study its effect upon the concentration of cholesterol and lipids in the plasma and liver, and the fecal excretion of sterols and bile acids. The Carob fiber complex reduced significantly the protein utilization, probably by non-specific binding of protein by carob tannins. Rats fed diets containing 5 and 15% fiber ex creted the same amount of sterols but 3 and 5 times more bile acids, respectively, than did rats fed the fiber-free diet. The concentration of bile acids in the feces, however, remained unchanged due to the increased weight of the feces in rats fed fiber-containing diets. Bacterial degradation of cholesterol was reduced strongly in these two groups. Supplementation of the diet with cholesterol increased the fecal sterol and bile acid excre tions in rats fed fiber-free diets, but these excretions were even more in creased in the 5 and 10% fiber groups. The concentration of the bile acids in the feces was unchanged in the three groups that received cholesterol. In vitro studies demonstrated that carob fiber adsorbed appreciable quanti ties of bile salts. A diet containing at least 10% fiber was required to reduce the elevation of liver cholesterol and total lipid levels from dietary choles terol, but it did not prevent the increase of the plasma cholesterol level. Our data suggest that carob fiber has an influence on cholesterol turnover by decreasing the absorption of bile acids and cholesterol but the latter only in the case of cholesterol-fed rats. J. Nutr. 109: 685-692, 1979.
Although fiber has been increasingly recognized as an important dietary constituent, controversy and confusion still exist about the physiologic effects of fiber. Specifically, the independent ability of dietary fiber to lower serum lipid levels is controversial. The purpose of this article is to review available evidence regarding the impact of soluble fibers on serum lipid levels. Soluble fibers appear to have a greater potential to alter serum lipid levels than do insoluble fibers. Significant reduction in the level of serum total cholesterol by soluble fiber was found in 68 of the 77 (88%) human studies reviewed. Of the studies measuring low-density lipoprotein cholesterol, 41 of 49 (84%) reported significant reductions. No significant changes were reported in 43 of the 57 (75%) studies that reported high-density lipoprotein cholesterol and/or in 50 of the 58 (86%) studies that measured triglyceride levels.
Numerous trials have demonstrated that cholesterol-lowering therapy leads to marked reductions in cardiovascular and overall mortality and in the need for coronary revascularization. Angiographic regression trials have shown that cholesterol lowering can reduce progression and, in some instances, achieve regression of coronary atherosclerotic lesions. However, recent studies have contradicted the traditional view that the clinical course of coronary artery disease is closely linked to the severity of coronary artery stenosis. It is now apparent that stenoses responsible for myocardial infarction or unstable angina are typically mild rather than severe. These observations suggest that regression may not be the principal mechanism by which cholesterol lowering affects cardiovascular risk. Two mechanisms---plaque stabilization and improved endothelial function-have been examined in this regard. Basic studies suggest that cholesterol lowering favorably alters those features of atherosclerosis that promote plaque stability. Recent clinical studies have clearly established that aggressive lipid-lowering therapy improves endothelial function and reduces myocardial ischemia in patients with hypercholesterolemia.
The effects of dietary soluble fibers on blood cholesterol are uncertain.
This meta-analysis of 67 controlled trials was performed to quantify the cholesterol-lowering effect of major dietary fibers.
Least-squares regression analyses were used to test the effect on blood lipids of pectin, oat bran, guar gum, and psyllium. Independent variables were type and amount of soluble fiber, initial cholesterol concentration, and other important study characteristics.
Soluble fiber, 2-10 g/d, was associated with small but significant decreases in total cholesterol [-0.045 mmol L(-1).g soluble fiber(-1) (95% CI: -0.054, -0.035)] and LDL cholesterol [-0.057 mmol.L(-1).g(-1) (95% CI: -0.070, -0.044)]. The effects on plasma lipids of soluble fiber from oat, psyllium, or pectin were not significantly different. We were unable to compare effects of guar because of the limited number of studies using 2-10 g/d. Triacylglycerols and HDL cholesterol were not significantly influenced by soluble fiber. Lipid changes were independent of study design, treatment length, and background dietary fat content.
Various soluble fibers reduce total and LDL cholesterol by similar amounts. The effect is small within the practical range of intake. For example, 3 g soluble fiber from oats (3 servings of oatmeal, 28 g each) can decrease total and LDL cholesterol by approximately 0.13 mmol/L. Increasing soluble fiber can make only a small contribution to dietary therapy to lower cholesterol.
The healthy endothelium usually provides an anticoagulant, vasodilatory and anti-inflammatory spectrum of functions that are central in vascular homeostasis. Dysfunction of the endothelium is a common feature of all phases of atherosclerosis. Hypercholesterolemia provokes many aspects of endothelial dysfunction before and during the development of atheroma. For example, a high cholesterol diet leads to the formation of a fatty streak and the recruitment and binding of blood leukocytes to the artery wall. This process requires expression by the endothelial cells of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). In rabbits that are fed an atherogenic diet, the aortic endothelium, which usually expresses little VCAM-1, shows foci of VCAM-1 expression soon after initiating this diet. Furthermore, lowering plasma cholesterol by diet or drugs down-regulates the expression of VCAM-1 and reduces the density of inflammatory cells in the atherosclerotic plaque. Hypercholesterolemia also attenuates normal vasodilatation to several stimuli such as exercise and acetylcholine. In healthy subjects, the vascular endothelium produces the vasodilator nitric oxide. In atherosclerosis, however, nitric oxide bioavailability is impaired. As a result, atherosclerotic coronary arteries commonly display a vasoconstrictor response when challenged with acetylcholine. Lipid lowering appears to favorably influence endothelial vasomotor and inflammatory functions in ways that may benefit patients with coronary artery disease. Continued probing of the basic mechanisms of endothelial dysfunction and its treatment may lead to new therapies that offer clinical benefits in patients with atherosclerosis, including reductions in coronary events.
Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. In westernized societies, it is the underlying cause of about 50% of all deaths. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. Progress in defining the cellular and molecular interactions involved, however, has been hindered by the disease's aetiological complexity. Over the past decade, the availability of new investigative tools, including genetically modified mouse models of disease, has resulted in a clearer understanding of the molecular mechanisms that connect altered cholesterol metabolism and other risk factors to the development of atherosclerotic plaque. It is now clear that atherosclerosis is not simply an inevitable degenerative consequence of ageing, but rather a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis.
Responses to both an endothelium-dependent (acetylcholine 10(-9)-10(-5) mol/l) and an endothelium-independent vasodilator (sodium nitroprusside 10(-10)-10(-6) mol/l) were studied in aortic rings from rabbits fed or not with a diet containing 0.5% cholesterol plus 14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg/kg/day). Morphometric and ultrastructure analyses were also performed. Rabbits fed the dyslipidemic diet presented higher plasma cholesterol and triglyceride concentrations than controls (P < 0.05). This was associated with intima-media thickening and, consequently, aortic stenosis (29 +/- 3%) since vessel cross-sectional area did not change. Endothelial cells presented numerous alterations in dyslipidemic rabbits. Atorvastatin treatment only reduced plasma levels in dyslipidemic rabbits (P < 0.05), which were nevertheless higher than those of controls. In addition, it prevented the reduction in acetylcholine relaxation in hypercholesterolemic animals. Atorvastatin administration also enhanced the response to acetylcholine in rabbits fed a control diet. Likewise, atorvastatin treatment reduced lesion area and consequently increased aortic lumen in dyslipidemic rabbits but did not modify media thickening. It also prevented the majority of the ultrastructural changes observed in endothelial cells. In conclusion, chronic atorvastatin treatment exerts a protective role in vascular function, structure and ultrastructure even in the presence of high cholesterol and triglyceride plasma levels.
Fibric acid derivatives are a class of hypolipidaemic drugs used in the treatment of patients with hypertriglyceridaemia, mixed hyperlipidaemia and diabetic dyslipidaemia. Fibrate therapy results in a significant decrease in serum triglycerides and an increase in high-density lipoprotein (HDL) cholesterol levels. The latest drugs of this class are also effective in lowering low-density (LDL) cholesterol levels and can change the distribution of LDL towards higher and larger particles. The effects of fibrates on lipid metabolism are mostly mediated through the activation of peroxisome proliferator-activated receptors (PPARalpha). A number of angiographic and clinical trials have confirmed that fibrates can slow the progression of atherosclerotic disease and decrease cardiovascular morbidity and mortality. Recently published data suggest that the ability of fibrates to prevent atherosclerosis is not related only to their hypolipidaemic effects but also to other 'pleiotropic effects', such as their anti-inflammatory, antioxidant and antithrombotic effects, as well as their ability to improve endothelial function. Interestingly, fibrates may favourably influence the thrombotic/fibrinolytic system. In fact, most of these drugs can significantly decrease plasma fibrinogen levels and inhibit tissue factor expression and activity in human monocytes and macrophages. Some studies have shown that fibrates can improve carbohydrate metabolism in patients with dyslipidaemia, including diabetic patients. Among fibrates only fenofibrate can significantly decrease serum uric acid levels by increasing renal urate excretion. Fibrates, with the possible exception of gemfibrozil, can significantly increase serum creatinine and homocysteine levels. Finally, a reduction in serum alkaline phosphatase and gamma glutamyltranspeptidase (gammaGT) activity is a well-documented effect of therapy with fibrates. The fibrates are generally well-tolerated drugs with few side-effects. The most important side-effect is myositis, which is observed in patients with impaired renal function or when statins are given concomitantly.
Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effects, such as vasodilation, suppression of smooth muscle cell growth, and inhibition of inflammatory responses. Many of these effects are largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits oxidation of low-density lipoprotein. A defect in the production or activity of nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium-dependent vasodilation. Accumulating evidence suggests that endothelial dysfunction is an early marker for atherosclerosis and can be detected before structural changes to the vessel wall are apparent on angiography or ultrasound. Many of the risk factors that predispose to atherosclerosis can also cause endothelial dysfunction, and the presence of multiple risk factors has been found to predict endothelial dysfunction. A number of clinical trials have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve endothelial dysfunction in patients with coronary risk factors beyond what could be attributed to their impact on plasma lipids. Studies have elucidated several possible mechanisms by which statin therapy may improve endothelial dysfunction, including upregulation of nitric oxide production or activity and reduction of oxidative stress.
Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
Mitochondrial production of oxidants contributes to a variety of pathological conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. We postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha), a major regulator of oxidative metabolism and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells.
We show that PGC-1alpha is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1alpha show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1alpha levels by siRNA reduces the expression of mitochondrial detoxification proteins.
These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addition, they suggest that PGC-1alpha could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metabolism of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.
Many complex biological programs are controlled at the level of gene transcription by DNA binding transcription factors. Recent studies have revealed a novel mode of regulation by coactivator proteins, best illustrated by the PGC-1 family of coactivators. These factors are highly responsive to a variety of environmental cues, from temperature to nutritional status to physical activity, and they coordinately regulate metabolic pathways and biological processes in a tissue-specific manner. Notably, the PGC-1 coactivators play a critical role in the maintenance of glucose, lipid, and energy homeostasis and are likely involved in the pathogenic conditions such as obesity, diabetes, neurodegeneration, and cardiomyopathy. These actions also raise new opportunities for the development of novel therapeutics.
Fibres with a range of abilities to perturb cholesterol homeostasis were used to investigate how the serum cholesterol-lowering effects of insoluble dietary fibres are related to parameters of intestinal cholesterol absorption and hepatic cholesterol homeostasis in mice. Cholestyramine, chitosan and cellulose were used as examples of fibres with high, intermediate and low bile acid-binding capacities, respectively. The serum cholesterol levels in a control group of mice fed a high fat/high cholesterol (HFHC) diet for 3 weeks increased about 2-fold to 4.3 mm and inclusion of any of these fibres at 7.5 % of the diet prevented this increase from occurring. In addition, the amount of cholesterol accumulated in hepatic stores due to the HFHC diet was reduced by treatment with these fibres. The three kinds of fibres showed similar hypocholesterolaemic activity; however, cholesterol depletion of liver tissue was greatest with cholestyramine. The mechanisms underlying the cholesterol-lowering effect of cholestyramine were (1) decreased cholesterol (food) intake, (2) decreased cholesterol absorption efficiency, and (3) increased faecal bile acid and cholesterol excretion. The latter effects can be attributed to the high bile acid-binding capacity of cholestyramine. In contrast, incorporation of chitosan or cellulose in the diet reduced cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. The present study provides strong evidence that above all satiation and satiety effects underlie the cholesterol-lowering properties of insoluble dietary fibres with moderate or low bile acid-binding capabilities.
Many biological programs are regulated at the transcriptional level. This is generally achieved by the concerted actions of several transcription factors. Recent findings have shown that, in many cases, transcriptional coactivators coordinate the overall regulation of the biological programs. One of the best-studied examples of coactivator control of metabolic pathways is the peroxisome proliferator-activated receptor coactivator 1 (PGC-1) family. These proteins are strong activators of mitochondrial function and are thus dominant regulators of oxidative metabolism in a variety of tissues. The PGC-1 coactivators themselves are subject to powerful regulation at the transcriptional and posttranslational levels. Recent studies have elucidated the function of the PGC-1 coactivators in different tissues and have highlighted the implications of PGC-1 dysregulation in diseases such as diabetes, obesity, cardiomyopathy, or neurodegeneration.
Increased oxidative stress in vascular cells is implicated in the pathogenesis of atherosclerosis. Reactive oxygen species (ROS) induce vascular inflammation via the proinflammatory cytokine/NF-kappaB pathway. Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) is an important regulator of intracellular ROS levels. However, no studies have examined the effects of PGC-1alpha on this process. We investigated the effects of PGC-1alpha on inflammatory molecule expression and activity of the redox-sensitive transcription factor, NF-kappaB, in vascular cells. PGC-1alpha expressed in human aortic smooth (HASMCs) and endothelial cells (HAECs) is upregulated by AMP-activated protein kinase activators, including metformin, rosiglitazone and alpha-lipoic acid. Tumor necrosis factor-alpha (TNF-alpha), a major proinflammatory factor in the development of vascular inflammation, stimulates intracellular ROS production through an increase in both mitochondrial ROS and NAD(P)H oxidase activity. Adenovirus-mediated overexpression of the PGC-1alpha gene in HASMCs and HAECs leads to a significant reduction in intracellular and mitochondrial ROS production as well as NAD(P)H oxidase activity. Consequently, NF-kappaB activity and MCP-1 and VCAM-1 induced by TNF-alpha are suppressed. Our data support the possibility that agents stimulating PGC-1alpha expression in the vasculature aid in preventing the development of atherosclerosis.
The importance of pleiotropic effects of statins on endothelial function and inflammatory markers was investigated in patients with dysglycaemia and coronary artery disease (CAD).
Thirty-nine patients were randomized to simvastatin 80 mg daily (S80; n = 20) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10; n = 19) for 6 weeks, aiming at similar cholesterol reduction. Endothelial function, evaluated by brachial artery flow-mediated vasodilatation (FMD) and the effect of endothelin receptor blockade, serum lipids, and inflammatory markers were evaluated at baseline and follow-up. At follow-up, low-density lipoprotein cholesterol decreased from 3.1 (2.8-3.4) (median and quartiles) to 1.5 mmol/L (1.4-1.7) and from 3.0 (2.5-3.4) to 1.3 mmol/L (1.1-1.8), in the S80 and E10/S10 groups, respectively. In the entire study group, FMD increased from 4.3% (3.4-6.1) at baseline to 5.5% (3.4-6.6) at follow-up, while C-reactive protein decreased from 3.1 (1.7-7.6) to 2.3 mg/L (0.9-6.5). The changes in FMD and C-reactive protein from baseline to follow-up were not significantly different between patients on S80 and E10/S10 groups. Endothelin blockade enhanced endothelium-dependent vasodilatation both at baseline and follow-up.
Lipid lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers in patients with dysglycaemia and CAD.