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Bergamot leaf extract treats cardiorenal metabolic syndrome and associated pathophysiological factors in rats fed with a high sugar fat diet
Abstract
Bergamot citrus (Citrus bergamia Risso et Poiteau), have been used as a strategy to prevent or treat comorbidities associated with metabolic syndrome parameters, such as cardiorenal metabolic syndrome (CRMS). The aim was to test the effect of bergamot leaf extract on CRMS and associated pathophysiological factors in rats fed with a high sugar-fat diet. Animals were divided into two experimental groups with control diet (Control, n = 30) and high sugar-fat diet (HSF, n = 30) for 20 weeks. Once CRMS was detected, animals were redivided to begin the treatment with Bergamot Leaf Extract (BLE) by gavage (50mg/Kg) for 10 weeks: control diet + placebo (Control, n = 09), control diet + BLE (Control + BLE, n = 09), HSF diet + placebo (HSF, n = 09), HSF + BLE (n = 09). Evaluation included nutritional, metabolic and hormonal analysis; and renal and cardiac parameters. HSF groups presented obesity, dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, insulin resistance. BLE showed protection against effects on hypertriglyceridemia, insulin resistance, renal damage, and structural and functional alterations of the heart. Conclusion: Bergamot leaf extract shows potential as a therapeutic to treat CRMS in animals fed with a high sugar-fat diet.
... Equally, the polyphenol content in fruit and leaves is very similar and can be even higher in leaves respect to fruit (Baron et al. 2021). Since there are only in vitro studies evaluating its antioxidant and anti-inflammatory capacity, this study becomes extremely relevant to evaluate the effect of BLE in different skeletal muscles in rats with MetS (Baron et al. 2021;Siqueira et al. 2022). Thus, the aim of this study was to elucidate the antioxidant and anti-inflammatory activity of bergamot leaf extract in skeletal muscles in an experimental model of metabolic syndrome. ...
... The bergamot leaves were harvested in a farm located in Reggio Calabria, Italy, and the dry extract was obtained at H&AD (Herbal & Antioxidant Derivatives S.r.l.) located in Localit a Chiusi, 89032 Bianco (RC), Italy (www.head-sa.com). The processes involved in the extraction were described and published by our research group (Siqueira et al. 2022). The administration was carried out daily by gavage, at a concentration of 50 mg/kg of weight, and the extract was diluted in filtered water (Musolino et al. 2020). ...
... the results of a previously published article by our group, investigating the effects of bergamot polyphenols in animals with cardiorenal metabolic syndrome (Siqueira et al. 2022). Mirarchi et al. (2022) observed that the incubation with PF derived from the fruit reduced intracellular lipid content in human hepatocytes, inferring that it may be due to an increase in beta-oxidation (Mirarchi et al. 2022). ...
Metabolic Syndrome (MetS), inflammation and oxidative stress contribute to impairment of skeletal muscle function. Bergamot (Citrus bergamia) leaf extract (BLE) has shown protective effects against comorbidities associated with MetS through its anti-inflammatory and antioxidant effects. The aim of this work was to elucidate the antioxidant and anti-inflammatory activity of BLE in skeletal muscles in an experimental model of MetS. Once metabolic syndrome was diagnosed, animals were divided into groups receiving different treatments for 10 weeks, including control diet (n = 10), control + BLE (n = 10), High Sugar-fat diet (HSF) (n = 10), HSF + BLE (n = 10). Evaluation included nutritional, metabolic and hormonal analyses, along with measurements of inflammatory status and oxidative stress in soleus and extensor digitorum longus (EDL) muscles. BLE showed positive metabolic effects, with a reduction of plasma triglycerides and insulin resistance and an increase in high-density lipoprotein cholesterol, and protective activity against oxidative stress and inflammation in Soleus and EDL muscles in animals with MetS.
... BLE was diluted in filtered water and administered at a concentration of 50 mg/kg of body weight. The extract preparation and the dose were established according to literature data (Siqueira et al., 2022). After the 30-week, the animals were submitted to 8 h of fasting, and then were anesthetized with thiopental (120 mg/kg/IP). ...
... This can be confirmed by plasmatic decreased in blood glucose, triglycerides, insulin, leptin, and insulin resistance. These results agree with studies carried out with the fruit of bergamot and with a study by our group with BLE (Rondanelli et al., 2021;Siqueira et al., 2022). ...
Low-grade chronic inflammation in obesity is associated with leptin resistance. In order to alleviate this pathological condition, bioactive compounds capable of attenuating oxidative stress and inflammation have been researched, and bergamot (Citrus bergamia) presents these properties. The aim was to evaluate the effect of bergamot leaves extract on leptin resistance in obese rats. Animals were divided into 2 groups: control diet (C, n = 10) and high sugar-fat diet (HSF, n = 20) for 20 weeks. After detecting hyperleptinemia, animals were divided to begin the treatment with bergamot leaves extract (BLE) for 10 weeks: C + placebo (n = 7), HSF + placebo (n = 7), and HSF + BLE (n = 7) by gavage (50mg/Kg). Evaluations included nutritional, hormonal and metabolic parameters; adipose tissue dysfunction; inflammatory, oxidative markers and hypothalamic leptin pathway. HSF group presented obesity, metabolic syndrome, adipose tissue dysfunction, hyperleptinemia and leptin resistance compared to control group. However, the treated group showed a decrease in caloric consumption and attenuation of insulin resistance. Moreover, dyslipidemia, adipose tissue function, and leptin levels showed an improvement. At the level of the hypothalamus, the treated group showed a reduction of oxidative stress, inflammation and modulation of leptin signaling. In conclusion, BLE properties were able to improve leptin resistance through recovery of the hypothalamic pathway.
Diabetic cardiomyopathy (DCM) is the leading cause of death worldwide, and oxidative stress was discovered to serve an important role in the pathophysiology of the condition. An imbalance between free radicals and antioxidant defenses is known to be associated with cellular dysfunction, leading to the development of various types of cardiac disease. Nuclear factor-erythroid-2-related factor 2 (NRF2) is a transcription factor that controls the basal and inducible expression levels of various antioxidant genes and other cytoprotective phase II detoxifying enzymes, which are ubiquitously expressed in the cardiac system. Kelch-like ECH-associated protein 1 (Keap1) serves as the main intracellular regulator of NRF2. Emerging evidence has revealed that NRF2 is a critical regulator of cardiac homeostasis via the suppression of oxidative stress. The activation of NRF2 was discovered to enhance specific endogenous antioxidant defense factors, one of which is antioxidant response element (ARE), which was subsequently illustrated to detoxify and counteract oxidative stress-associated DCM. The NRF2 signaling pathway is closely associated with the development of various types of cardiac disease, including ischemic heart disease, heart failure, myocardial infarction, atrial fibrillation and myocarditis. Therefore, it is hypothesized that drugs targeting this pathway may be developed to inhibit the activation of NRF2 signaling, thereby preventing the occurrence of DCM and effectively treating the disease.
Immunomodulatory approaches are defined as all interventions that modulate and curb the immune response of the host rather than targeting the disease itself with the aim of disease prevention or treatment. A better understanding of the immune system continues to offer innovative drug targets and methods for immunomodulatory interventions. Cardiorenal syndrome is a clinical condition that defines disorders of the heart and kidneys, both of which communicate with one another through multiple pathways in an interdependent relationship. Cardiorenal syndrome denotes the confluence of heart-kidney relationships across numerous interfaces. As such, a dysfunctional heart or kidney has the capacity to initiate disease in the other organ via common hemodynamic, neurohormonal, immunological, and/or biochemical feedback pathways. Understanding how immunomodulatory approaches are implemented in diabetes-induced cardiovascular and renal diseases is important for a promising regenerative medicine, which is the process of replacing cells, tissues or organs to establish normal function. In this article, after a brief introduction on the immunomodulatory approaches in diseases, we will be reviewing the epidemiology and classifications of cardiorenal syndrome. We will be emphasizing on the hemodynamic factors and non-hemodynamic factors linking the heart and the kidneys. In addition, we will be elaborating on the immunomodulatory pathways involved in diabetes-induced cardiorenal syndrome namely, RAS, JAK/STAT, and oxidative stress. Moreover, we will be addressing possible therapeutic approaches that target the former pathways in an attempt to modulate the immune system.
The aim of the study is to compare the qualitative and semi-quantitative profile of the polyphenol fraction purified from the leaf (BLPF) and fruit (BFPF) of bergamot (Citrus bergamia), and to evaluate their antioxidant and anti-inflammatory activity. The analytical qualitative profile was carried out by LC-ESI/MS using three different approaches: targeted (searching analytes already reported in bergamot extract), semi-targeted (a selective search of 3-hydroxy-3-methylglutarate [HMG] derivatives involved in the cholesterol reducing activity of BPF) and untargeted. A total number of 108 compounds were identified by using the three approaches, 100 of which are present in both the extracts thus demonstrating a good qualitative overlapping of polyphenols between the two extracts. The antioxidant activity was higher for BLPF in respect to BFPF but when normalized in respect to the polyphenol content they were almost overlapping. Both the extracts were found to dose dependently inhibit cell inflammation stimulated with IL-1α. In conclusion, the comparison of the qualitative and quantitative profile of polyphenols as well as of the antioxidant and anti-inflammatory activity of bergamot leaf and fruit well indicates that leaf is a valid source of bergamot polyphenol extraction and an even richer source of polyphenol in respect to the fruit.
Background
Non-alcoholic fatty liver disease (NAFLD) is defined by the abundance of lipid droplets (LDs) in hepatocytes. While historically considered simply depots for energy storage, LDs are increasingly recognized to impact a wide range of biological processes that influence cellular metabolism, signaling, and function. While progress has been made toward understanding the factors leading to LD accumulation (i.e. steatosis) and its progression to advanced stages of NAFLD and/or systemic metabolic dysfunction, much remains to be resolved.
Scope of review
This review covers many facets of LD biology. We provide a brief overview of the major pathways of lipid accretion and degradation that contribute to steatosis and how they are altered in NAFLD. The major focus is on the relationship between LDs and cell function and the detailed mechanisms that couple or uncouple steatosis from the severity and progression of NAFLD and systemic comorbidities. The importance of specific lipids and proteins within or on LDs as key components that determine whether LD accumulation is linked to cellular and metabolic dysfunction is presented. We discuss emerging areas of LD biology and future research directions that are needed to advance our understanding of the role of LDs in NAFLD etiology.
Major conclusions
Impairments in LD breakdown appear to contribute to disease progression, but inefficient incorporation of fatty acids (FAs) into LD-containing triacylglycerol (TAG) and the consequential changes in FA partitioning also affect NAFLD etiology. Increased LD abundance in hepatocytes does not necessarily equate to cellular dysfunction. While LD accumulation is the prerequisite step for most NAFLD cases, the protein and lipid composition of LDs are critical factors in determining the progression from simple steatosis. Further defining the detailed molecular mechanisms linking LDs to metabolic dysfunction is important for designing effective therapeutic approaches targeting NAFLD and its comorbidities.
Obesity has been recognized as a major risk factor for chronic kidney disease, but the underlying mechanism remains elusive. Here, we investigated the mechanism whereby long-term high-fat diet (HFD) feeding induces renal injury in mice. The C57BL/6 mice fed HFD for 16 weeks developed obesity, diabetes, and kidney dysfunction manifested by albuminuria and blood accumulation of BUN and creatinine. The HFD-fed kidney showed marked glomerular and tubular injuries, including prominent defects in the glomerular filtration barrier and increased tubular cell apoptosis. Mechanistically, HFD feeding markedly increased triglyceride and cholesterol contents in the kidney and activated lipogenic pathways for cholesterol and triglyceride synthesis. HFD feeding also increased oxidative stress and induced mitochondrial fission in tubular cells, thereby activating the pro-apoptotic pathway. In HK-2 and mesangial cell cultures, high glucose, fatty acid, and TNF-α combination was able to activate the lipogenic pathways, increase oxidative stress, promote mitochondrial fission, and activate the pro-apoptotic pathway, all of which could be attenuated by an inhibitor that depleted reactive oxygen species. Taken together, these observations suggest that long-term HFD feeding causes kidney injury at least in part as a result of tissue lipid accumulation, increased oxidative stress, and mitochondrial dysfunction, which promote excess programmed cell death.
Background/aims:
Considering the importance of inflammation on obesity-related disorders pathogenesis, including cardiac dysfunction, the interest in natural anti-inflammatory therapeutic strategies has emerged. The lycopene is a carotenoid presents in tomato and red fruits that displays anti-inflammatory properties. In this sense, we will evaluate the anti-inflamma-
tory effect of tomato-oleoresin supplementation on obesity- related cardiac dysfunction by modulating myocardial calcium kinetic.
Methods:
Male Wistar rats were initially randomized into 2 experimental groups: (Control, n= 20) or high sugar- fat diet (HSF, n=20) for 20 weeks. At week 20th, once detected the cardiac dysfunction (cardiac remodeling, systolic and diastolic dysfunction) by echocardiography in HSF group, animals were randomly divided to begin the treatment with tomato-oleoresin, performing 4 groups: Control (n= 10); Control + tomato tomato-oleoresin supplementation (Control + Ly, n= 10); HSF (n= 10) or HSF + tomato tomato-oleoresin supplementation (HSF + Ly, n= 10). Tomato oleoresin was mixed with maize oil equivalent to 10mg lycopene/kg body weight (BW) per day and given orally, by gavage, every morning for a 10-week period. It was analyzed cardiac inflammatory parameters by the enzyme-linked immunosorbent assay (ELISA) and in vivo (echocardiography) and in vitro (studying isolated papillary muscles from the left ventricle) cardiac function. The groups were compared by Two-Way analysis of variance (ANOVA).
Results:
The HSF diet induced cardiac dysfunction (FS(%) C: 60.4±1.3; C+Ly: 60.9±1.3; HSF: 51.7±1.3; HSF+Ly: 59.4±1.4) and inflammation (TNF-α: C:1.88±0.41; C+Ly: 1.93±1.01; HSF: 4.58±1.99; HSF+Ly: 2.03±0.55; IL-6: C:0.58±0.16; C+Ly: 0.40±0.16; HSF: 2.00±0.45; HSF+Ly: 0.53±0.26; MCP-1: C:0.31±0.08; C+Ly: 0.43±0.22; HSF: 1.54±0.32; HSF+Ly: 0.50±0.16). Tomato-oleoresin supplementation improved cardiac remodeling and dysfunction, cardiac inflammation and myocardial calcium kinetic.
Conclusion:
the anti-inflammatory effect of tomato-oleoresin supplementation treated the obesity-induced cardiac dysfunction by modulating myocardial calcium handling.
Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus and induces the transcription of enzymes involved in counteracting oxidative stress, endobiotic and xenobiotic metabolism, regulators of inflammation, and others. Different natural compounds, including food and plant-derived components, were shown to be able to activate Nrf2, mediating an antioxidant response. Some of these compounds were tested in stroke experimental models showing several beneficial actions. In this review, we focused on the studies that evidenced the positive effects of natural bioactive compounds in stroke experimental models through the activation of Nrf2 pathway. Interestingly, different natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response associated with the beneficial effects against stroke. According to several studies, the combination of different bioactive compounds can lead to a better neuroprotection. In conclusion, natural bioactive compounds may represent new therapeutic strategies against stroke.
Metabolic syndrome (MS) is a condition that includes obesity, insulin resistance, dyslipidemias among other, abnormalities that favors type 2 Diabetes Mellitus (T2DM) and cardiovascular diseases development. Three main diet-induced metabolic syndrome models in rats exist: High carbohydrate diet (HCHD), high fat diet (HFD), and high carbohydrate-high fat diet (HCHHFD). We analyzed data from at least 35 articles per diet, from different research groups, to determine their effect on the development of the MS, aimed to aid researchers in choosing the model that better suits their research question; and also the best parameter that defines obesity, as there is no consensus to determine this condition in rats. For the HCHD we found a mild effect on body weight gain and fasting blood glucose levels (FBG), but significant increases in triglycerides, fasting insulin, insulin resistance and visceral fat accumulation. HFD had the greater increase in the parameters previously mentioned, followed by HCHHFD, which had a modest effect on FBG levels. Therefore, to study early stages of MS a HCHD is recommended, while HFD and HCHHFD better reproduce more severe stages of MS. We recommend the assessment of visceral fat accumulation as a good estimate for obesity in the rat.
The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models—the diacylglycerol (DAG) model and the ceramide model—have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.
There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical “proof of concept” study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice.
Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.
Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future.
The kidney is an important organ in the maintenance of body homeostasis. Dietary compounds, reactive metabolites, obesity, and metabolic syndrome (MetS) can affect renal filtration and whole body homeostasis, increasing the risk of chronic kidney disease (CKD) development. Gamma oryzanol ( γ Oz) is a compound with antioxidant and anti-inflammatory activity that has shown a positive action in the treatment of obesity and metabolic diseases. Aim . To evaluate the effect of γ Oz to recover renal function in obese animals by high sugar-fat diet by modulation of adiponectin receptor 2/PPAR- α axis Methods . Male Wistar rats were initially randomly divided into 2 experimental groups: control and high sugar-fat diet (HSF) for 20 weeks. When proteinuria was detected, HSF animals were allocated to receive γ Oz or maintain HSF for more than 10 weeks. The following were analyzed: nutritional and biochemical parameters, systolic blood pressure, and renal function. In the kidney, the following were evaluated: inflammation, oxidative stress, and protein expression by Western blot. Results . After 10 weeks of γ Oz treatment, γ Oz was effective to improve inflammation, increase antioxidant enzyme activities, increase the protein expression of adiponectin receptor 2 and PPAR- α , and recover renal function. Conclusion . These results permit us to confirm that γ Oz is able to modulate PPAR- α expression, inflammation, and oxidative stress pathways improving obesity-induced renal disease.
Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.
Systems medicine has a mechanism-based rather than a symptom- or organ-basedapproach to disease and identifies therapeutic targets in a nonhypothesisdrivenmanner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecularprofiles suggests alterations ofNRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.
Background:
The high consumption of fat and sugar contributes to the development of obesity and co-morbidities, such as diabetes, and cardiovascular and kidney diseases. Different strategies have been used to prevent these diseases associated with obesity, such as changes in eating habits and/or the addition of dietary components with anti-inflammatory and anti-oxidant properties, such as gamma-oryzanol (γOz) present mainly in bran layers and rice germ.
Methods:
Animals were randomly divided into four experimental groups and fed ad libitum for 20 weeks with control diet (C, n = 8), control diet + γOz (C + γOz, n = 8), high-sugar and high-fat diet (HSF, n = 8), and high-sugar and high-fat diet + γOz (HSF + γOz, n = 8). HSF groups also received water + sucrose (25%). The dose of γOz was added to diets to reach 0.5% of final concentration (w/w). Evaluation in animals included food and caloric intake, body weight, plasma glucose, insulin, triglycerides, uric acid, HOMA-IR, glomerular filtration rate, protein/creatinine ratio, systolic blood pressure, and Doppler echocardiographic.
Results:
Animals that consumed the HSF diet had weight gain compared to group C, increased insulin, HOMA, glucose and triglycerides, there were also atrial and ventricular structural alterations, deterioration of systolic and diastolic function, decreased glomerular filtration rate, and proteinuria. Gamma-oryzanol is significantly protective against effects on body weight, hypertriglyceridemia, renal damage, and against structural and functional alteration of the heart.
Conclusion:
Gamma-oryzanol shows potential as a therapeutic to prevent Cardiorenal Metabolic Syndrome.
Abstract Obesity has been pointed out as an important cause of kidney diseases. Due to its close association with diabetes and hypertension, excess weight and obesity are important risk factors for chronic kidney disease (CKD). Obesity influences CKD development, among other factors, because it predisposes to diabetic nephropathy, hypertensive nephrosclerosis and focal and segmental glomerulosclerosis. Excess weight and obesity are associated with hemodynamic, structural and histological renal changes, in addition to metabolic and biochemical alterations that lead to kidney disease. Adipose tissue is dynamic and it is involved in the production of "adipokines", such as leptin, adiponectin, tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β and angiotensin-II. A series of events is triggered by obesity, including insulin resistance, glucose intolerance, dyslipidemia, atherosclerosis and hypertension. There is evidence that obesity itself can lead to kidney disease development. Further studies are required to better understand the association between obesity and kidney disease.
Overnutrition and sedentary lifestyle result in overweight or obesity defined as abnormal or excessive fat accumulation that may impair health. According to the WHO, the worldwide prevalence of obesity nearly doubled between 1980 and 2008. In 2008, over 50% of both men and women in the WHO European Region were overweight, and approximately 23% of women and 20% of men were obese. Comprehensive diagnostic and therapeutic approaches should include nutritional treatment to favor the best metabolic and nutritional outcome, as well as to induce potential disease-specific benefits from selected nutritional regimens. Obesity is usually accompanied by an increased muscle mass. This might explain why obesity, under particular circumstances such as cancer or high age, might have protective effects, a phenomenon named the ‘obesity paradox’. However, loss of muscle mass or function can also occur, which is associated with poor prognosis and termed ‘sarcopenic obesity’. Therefore, treatment recommendations may need to be individualized and adapted to co-morbidities. Since obesity is a chronic systemic disease it requires a multidisciplinary approach, both at the level of prevention and therapy including weight loss and maintenance. In the present personal review and position paper, authors from different disciplines including endocrinology, gastroenterology, nephrology, pediatrics, surgery, geriatrics, intensive care medicine, psychology and psychiatry, sports medicine and rheumatology, both at the basic science and clinical level, present their view on the topic and underline the necessity to provide a multidisciplinary approach, to address this epidemic.
Berry fruits are recognized, worldwide, as “superfoods” due to the high content of
bioactive natural products and the health benefits deriving from their consumption. Berry leaves are
byproducts of berry cultivation; their traditional therapeutic use against several diseases, such as
the common cold, inflammation, diabetes, and ocular dysfunction, has been almost forgotten
nowadays. Nevertheless, the scientific interest regarding the leaf composition and beneficial
properties grows, documenting that berry leaves may be considered an alternative source of bioactives.
The main bioactive compounds in berry leaves are similar as in berry fruits, i.e., phenolic acids and
esters, flavonols, anthocyanins, and procyanidins. The leaves are one of the richest sources of
chlorogenic acid. In various studies, these secondary metabolites have demonstrated antioxidant,
anti-inflammatory, cardioprotective, and neuroprotective properties. This review focuses on the
phytochemical composition of the leaves of the commonest berry species, i.e., blackcurrant, blackberry,
raspberry, bilberry, blueberry, cranberry, and lingonberry leaves, and presents their traditional
medicinal uses and their biological activities in vitro and in vivo.
Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.
Plant polyphenols exert anti-inflammatory activity through both anti-oxidant effects and modulation of pivotal pro-inflammatory genes. Recently, Citrus bergamia has been studied as a natural source of bioactive molecules with antioxidant activity, but few studies have focused on molecular mechanisms underlying their potential beneficial effects. Several findings have suggested that polyphenols could influence cellular function by acting as activators of SIRT1, a nuclear histone deacetylase, involved in the inhibition of NF-κB signaling. On the basis of these observations we studied the anti-inflammatory effects produced by the flavonoid fraction of the bergamot juice (BJe) in a model of LPS-stimulated THP-1 cell line, focusing on SIRT1-mediated NF-κB inhibition. We demonstrated that BJe inhibited both gene expression and secretion of LPS-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) by a mechanism involving the inhibition of NF-κB activation. In addition, we showed that BJe treatment reversed the LPS-enhanced acetylation of p65 in THP-1 cells. Interestingly, increasing concentrations of Sirtinol were able to suppress the inhibitory effect of BJe via p65 acetylation, underscoring that NF-κB-mediated inflammatory cytokine production may be directly linked to SIRT1 activity. These results suggest that BJe may be useful for the development of alternative pharmacological strategies aimed at reducing the inflammatory process.
Background/Aims
The aim of this study was to evaluate whether supplementation of high doses of cholecalciferol for two months in normotensive rats results in increased systolic arterial pressure and which are the mechanisms involved. Specifically, this study assesses the potential effect on cardiac output as well as the changes in aortic structure and functional properties.
Methods
Male Wistar rats were divided into three groups: 1) Control group (C, n = 20), with no supplementation of vitamin D, 2) VD3 (n = 19), supplemented with 3,000 IU vitamin D/kg of chow; 3) VD10 (n = 21), supplemented with 10,000 IU vitamin D/kg of chow. After two months, echocardiographic analyses, measurements of systolic arterial pressure (SAP), vascular reactivity, reactive oxygen species (ROS) generation, mechanical properties, histological analysis and metalloproteinase-2 and -9 activity were performed.
Results
SAP was higher in VD3 and VD10 than in C rats (p = 0.001). Echocardiographic variables were not different among groups. Responses to phenylephrine in endothelium-denuded aortas was higher in VD3 compared to the C group (p = 0.041). Vascular relaxation induced by acetylcholine (p = 0.023) and sodium nitroprusside (p = 0.005) was impaired in both supplemented groups compared to the C group and apocynin treatment reversed impaired vasodilation. Collagen volume fraction (<0.001) and MMP-2 activity (p = 0.025) was higher in VD10 group compared to the VD3 group. Elastin volume fraction was lower in VD10 than in C and yield point was lower in VD3 than in C.
Conclusion
Our findings support the view that vitamin D supplementation increases arterial pressure in normotensive rats and this is associated with structural and functional vascular changes, modulated by NADPH oxidase, nitric oxide, and extracellular matrix components.
Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome.
Obesity is characterised by chronic low-grade inflammation, and lycopene has been reported to display anti-inflammatory effects. However, it is not clear whether lycopene supplementation modulates adipokine levels in vivo in obesity. To determine whether lycopene supplementation can regulate adipokine expression in obesity, male Wistar rats were randomly assigned to receive a control diet (C, n 6) or a hyperenergetic diet (DIO, n 12) for 6 weeks. After this period, the DIO animals were randomised into two groups: DIO (n 6) and DIO supplemented with lycopene (DIO+L, n 6). The animals received maize oil (C and DIO) or lycopene (DIO+L, 10 mg/kg body weight (BW) per d) by oral administration for a 6-week period. The animals were then killed by decapitation, and blood samples and epididymal adipose tissue were collected for hormonal determination and gene expression evaluation (IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-α, leptin and resistin). There was no detectable lycopene in the plasma of the C and DIO groups. However, the mean lycopene plasma concentration was 24 nmol in the DIO+L group. Although lycopene supplementation did not affect BW or adiposity, it significantly decreased leptin, resistin and IL-6 gene expression in epididymal adipose tissue and plasma concentrations. Also, it significantly reduced the gene expression of MCP-1 in epididymal adipose tissue. Lycopene affects adipokines by reducing leptin, resistin and plasma IL-6 levels. These data suggest that lycopene may be an effective strategy in reducing inflammation in obesity.
According to current clinical trials, albumin excretion is an early indicator of cardiovascular damage. While proteinuria is considered as a marker of kidney function, albuminuria indicates cardiovascular risk first of all. Sensitivity of the previous laboratory tests does not meet the clinical requirements, and the error of urine collection makes the results misleading. For that reason recent guidelines suggest to calculate albumin/creatinine (ACR) and protein/creatinine (PCR) measured from the first morning urine. For the clinical diagnosis of albuminuria the sensitive immunoturbidimetric assays are suggested. Albumin dipsticks are not recommended for the measurement of albuminuria. Wide-range urinary protein reagents are also available with high sensitivity, while serum reagents are not applicable (Biuret). The traceability of calibrator to a reference material is a critical requirement. Proteinuria and albuminuria of a patient should be monitored in the same laboratory, using a fixed method and cut-off value. Albumin/creatinine value should be reported together with gender-dependent reference range.
Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography–mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme.
British Journal of Cancer (2002) 86, 774–778. DOI: 10.1038/sj/bjc/6600197 www.bjcancer.com
© 2002 Cancer Research UK
Bergamot (Citrus bergamia) is cultivated in Southern Italy almost exclusively to produce the prized essential oil, top note in several perfumes. The juice of bergamot, until recently poorly studied, is the object of a growing scientific interest due to its claimed activity to treat metabolic syndrome. The aim of this investigation was a detailed characterization of bergamot juice polyphenolic fraction (BPF) based on a UPLC-DAD-MS analysis complemented by preparative chromatographic separations, followed by NMR characterization of the isolated compounds. The combination of these techniques efficiently covered different classes of secondary metabolites, leading to the identification of 39 components, several of which had never been reported from bergamot. One of them, bergamjuicin (35), is a new flavanone glycoside, whose structure has been determined by MS and NMR techniques. The reported results could provide a guide for future routine analyses of BPF, a material of great nutraceutical and industrial interest.
Obesity, especially of the abdominal type, is a health problem that constitutes metabolic syndrome and increases the incidence of various diseases, including diabetes, hypertension, dyslipidemia, atherosclerosis, and cancer. Various mechanisms linking obesity to these associated diseases have been postulated. One candidate is oxidative stress, which has been implicated in vascular complications of diabetes and in pancreatic -cell failure in diabetes. Notably, obese people without diabetes also display elevated levels of systemic oxidative stress. In addition, levels of oxidative stress are increased in the adipose tissue in obese mice. Treating obese mice with antioxidant agents attenuates the development of diabetes. In 3T3-L1 adipocytes, increases in reactive oxygen species (ROS) occur with lipid accumulation; the addition of free fatty acids elevates ROS generation further. Thus, adipose tissue represents an important source of ROS; ROS may contribute to the development of obesity-associated insulin resistance and type 2 diabetes. Moreover, the levels of oxidative stress present in several other types of cells or tis-sues, including those in the brain, arterial walls, and tumors, have been implicated in the pathogenesis associated with hypertension, atherosclerosis, and cancer. The increased levels of systemic oxidative stress that occur in obesity may contribute to the obesity-associated development of these diseases.
Excess visceral adiposity contributes to inappropriate activation of the renin-angiotensin-aldosterone system despite a state of volume expansion and of salt retention that contributes to subclinical elevations of pro-oxidant mechanisms. These adverse effects are mediated by excess generation of reactive oxygen species (ROS) and diminished antioxidant defense mechanisms. Excess tissue (i.e., skeletal muscle, liver, heart) free oxygen radicals contribute to impairments in the insulin-dependent metabolic signaling pathways that regulate glucose utilization/disposal and systemic insulin sensitivity. The generation of ROS is required for normal cell signaling and physiological responses. It is a loss of redox homeostasis that results in a proinflammatory/profibrotic milieu that promotes impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. These maladaptive processes are increasingly recognized as important in the progression of hypertension in the cardiorenal metabolic phenotype. There is increasing evidence to support a critical role for Ang II signaling through the AT(1)R and aldosterone actions through the MR in conjunction with an altered redox-mediating impaired endothelial, cardiac and renal function in this metabolic phenotype. There are emerging clinical data that indicate that therapies that target the renin angiotensin-aldosterone system (RAAS) also attenuate oxidative stress, and improve endothelial, cardiac and renal functions, which collectively contribute to reductions in hypertension.
Decades ago, discussion of an impending global pandemic of obesity was thought of as heresy. But in the 1970s, diets began to shift towards increased reliance upon processed foods, increased away-from-home food intake, and increased use of edible oils and sugar-sweetened beverages. Reductions in physical activity and increases in sedentary behavior began to be seen as well. The negative effects of these changes began to be recognized in the early 1990s, primarily in low- and middle-income populations, but they did not become clearly acknowledged until diabetes, hypertension, and obesity began to dominate the globe. Now, rapid increases in the rates of obesity and overweight are widely documented, from urban and rural areas in the poorest countries of sub-Saharan Africa and South Asia to populations in countries with higher income levels. Concurrent rapid shifts in diet and activity are well documented as well. An array of large-scale programmatic and policy measures are being explored in a few countries; however, few countries are engaged in serious efforts to prevent the serious dietary challenges being faced.
Abstract—The development,of congestive heart failure (CHF) is associated with left ventricular (LV) dilation and myocardial remodeling. However, fundamental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMPs) have been demonstrated,to play a significant role in tissue remodeling,in a number,of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progression of CHF is associated with early changes in MMP expression and zymographic,activity. LV and myocyte function, collagen content, and MMP expression and zymographic activity were serially measured during
Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m², but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m² were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and 2.16, respectively compared to a ratio of five. Albuminuria and eGFR were multiplicatively associated with all-cause mortality, without evidence for interaction. Similar associations were observed for cardiovascular mortality. Findings in cohorts with dipstick data were generally comparable to those in cohorts measuring albumin-to-creatinine ratios. Thus, lower eGFR and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors.
The 3-hydroxy-3-methylglutaryl neohesperidosides of hesperetin (brutieridin, 1) and naringenin (melitidin, 2) were isolated and detected from the fruits of bergamot (Citrus bergamia). The structures of these compounds were determined by spectroscopic and chemical methods.
Patients with chronic kidney disease (CKD) show a high cardiovascular morbidity and mortality. This seems to be consequence of the cardiovascular risk factor clustering in CKD patients. Non traditional risk factors such as oxidative stress and inflammation are also far more prevalent in this population than in normal subjects. Renal disease is associated with a graded increase in oxidative stress markers even in early CKD. This could be consequence of an increase in reactive oxygen species as well as a decrease in antioxidant defence. This oxidative stress can accelerate renal injury progression. Inflammatory markers such as C reactive protein and cytokines increase with renal function deterioration suggesting that CKD is a low-grade inflammatory process. In fact, inflammation facilitates renal function deterioration. Several factors can be involved in triggering the inflammatory process including oxidative stress. Statin administration is accompanied by risk reduction in all major vascular events in patients with CKD that are considered high-risk patients. These beneficial effects seem to be consequence of not only their hypolipidemic effect but especially their pleitropic actions that involve modulation of oxidative stress and inflammation.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
This chapter outlines the role of Nrf2 in the activation of antioxidation enzyme via antioxidant responsive element/electrophile responsive element (ARE/EpRE). The role is studied using experiments on mice and those involving the cell culture system. The experiments suggest that kelch-like ECH-associated protein 1 (Keap 1) and Nrf2 comprise the primary sensor in the cellular response to oxidative stress. The cytoplasmic protein Keap 1 interacts with Nrf2 and inhibits its translocation to nucleus. Electrophiles and ROS disrupt the binding between Nrf2 and Keap 1, such that activated Nrf2 can translocate to the nucleus, Nrf2 forms a heterodimer with a small Maf protein and activates gene transcription via ARE/EpRE. In macrophages exposed to oxidative stress agents, Nrf2 also plays a major role in the transcriptional activation of genes encoding A170, HO-1, and xCT.
Citrus bergamia Risso et Poiteau fruits have been traditionally utilized, in Calabria (Italy), as a popular remedy for their hypolipidemic properties. C. bergamia juice total phenol content (2474.35+/-38 microg/mL) was evaluated by the Folin-Ciocalteu method; moreover, HPLC analysis led to the identification of naringin (520 ppm), neoeriocitrin (370 ppm), and neohesperidin (310 ppm). The present study was designed to investigate the hypolipidemic effects of C. bergamia juice and its protective effect on liver of hyperlipidemic rats. Chronic administration of C. bergamia (1 mL/rat/day) provoked a significant reduction in serum cholesterol, triglycerides, and low-density lipoprotein (LDL) levels and an increase in high-density lipoprotein (HDL) levels; moreover, histopathological observations showed, in rats submitted to C. bergamia treatment, a protection of hepatic parenchyma. In addition, fecal neutral sterols and fecal bile acid excretion was found to be increased after C. bergamia treatment. These results suggest that the hypocholesterolemic effect of C. bergamia may be mediated by the increase in fecal neutral sterols and total bile acids excretion. In addition to the hypolipidemic effect, the juice shows radical scavenging activity in the diphenylpicrylhydrazyl (DPPH) test; probably the two effects are related. These observations suggest that the positive intake of C. bergamia may reduce the risk of some cardiovascular diseases through its radical scavenging function and hypocholesterolemic action.
Vitamin D induces increased systolic arterial pressure via vascular reactivity and mechanical properties
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