Resveratrol In Rats Research Articles

Resveratrol inhibited colorectal cancer progression by reducing oxidative DNA damage by targeting the JNK signaling pathway

Recent evidence has proved that resveratrol as a natural polyphenol has great anti-cancer and anti-proliferative effects in cancer cells. In this study, we aimed to examine the protective effects of resveratrol in rats with 1,2-dimethylhydrazine (DMH)-induced colorectal cancer and investigate the potential underlying molecular mechanisms. Male Wistar rats were classified into different groups, including Group 1 without any intervention, group 2 as resveratrol-received rats (8 mg/kg), Group 3 as DMH-received rats, and Group 4, as DMH and resveratrol-received rats. DNA damage, DNA repair, the expression levels and activities of antioxidants, and JNK signaling were evaluated in colon tissues. We found that DNA damage and DNA repair were significantly suppressed and induced, respectively, in DMH + resveratrol groups. The expression levels and activities of antioxidants were increased in DMH + resveratrol groups. Lipid and protein peroxidation were significantly suppressed in DMH + resveratrol groups. In addition, resveratrol also modulated JNK signaling in DMH + resveratrol groups. Our findings demonstrated that resveratrol effectively reversed DMH-mediated oxidative stress and DNA damage by targeting the JNK signaling pathway.

Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling

Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538–0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface.

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain–machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

Resveratrol could attenuate prostatic inflammation in rats with Oestradiol-induced chronic prostatitis.

To evaluate the effect of resveratrol in rats with chronic prostatitis, 24 rats were randomly divided into the negative control, vehicle-treated and resveratrol groups. The rats in the vehicle-treated group and the resveratrol group were injected subcutaneously with 17-β-oestradiol (0.25mg/kg) daily for 6weeks while the rats in the control group were injected with equivalent normal saline. From the 45th day, the rats in the resveratrol group were given resveratrol (10mg/kg) by gavage per day while the rest rats were given normal saline. After 55days, all the rats were sacrificed and the prostatic tissue was removed. Morphological changes were examined by light microscope after H&E staining. The expressions of IL-6, IL-8 and TNF-α were determined through ELISA and immunohistochemical staining. As a result, significant inflammatory cell infiltration and fibroblastic hyperplasia were observed in prostatic stroma in the vehicle-treated group compared with the negative control group, as well as the high expression of IL-6, IL-8 and TNF-α. After resveratrol treatment, inflammatory cell infiltration and fibroblastic hyperplasia were shown prominently reduced. Meanwhile, the expression of IL-6, IL-8 and TNF-α was significantly suppressed. For conclusion, resveratrol could attenuate the prostatic inflammation and downregulate the expression of IL-6, IL-8 and TNF-α in rat with oestradiol-induced chronic prostatitis.

Pulmonary administration of resveratrol/hydroxypropyl-β-cyclodextrin inclusion complex: in vivo disposition and in vitro metabolic study

Until today, the clinical application of phytochemicals is still limited largely due to poor oral bioavailability. Pulmonary administration is considered as an attractive alternative to oral delivery as it can improve the pharmacokinetic properties of compounds with extensive metabolism. In this study, resveratrol was selected as a study model to evaluate the feasibility of pulmonary administration in the delivery of phytochemicals, aiming to promote their therapeutic potential. The pharmacokinetic investigation on resveratrol was conducted in rats. Compared with oral delivery, resveratrol in rats after pulmonary administration showed superior absorption and bioavailability (92.95%). Directed delivery of resveratrol to lungs also showed potential usefulness in the treatment of lung diseases as drugs rapidly accumulated in lung tissues and concentrations were more than 100 times those of oral delivery at early time points. The metabolic study was carried out using rat microsomes and showed that metabolic activity of lung was much lower than that of liver. The overall results indicate that pulmonary administration is an effective strategy for both systemic and local delivery of resveratrol.

Effects of Maternal Resveratrol on Maternal High-Fat Diet/Obesity with or without Postnatal High-Fat Diet

To examine the effects of maternal resveratrol in rats borne to dams with gestational high-fat diet (HFD)/obesity with or without postnatal high-fat diet. We first tested the effects of maternal resveratrol intake on placenta and male fetus brain in rats borne to dams with gestational HFD/obesity. Then, we assessed the possible priming effect of a subsequent insult, male offspring were weaned onto either a rat chow or a HFD. Spatial learning and memory were assessed by Morris water maze test. Blood pressure and peripheral insulin resistance were examined. Maternal HFD/obesity decreased adiponectin, phosphorylation alpha serine/threonine-protein kinase (pAKT), sirtuin 1 (SIRT1), and brain-derived neurotrophic factor (BDNF) in rat placenta, male fetal brain, and adult male offspring dorsal hippocampus. Maternal resveratrol treatment restored adiponectin, pAKT, and BDNF in fetal brain. It also reduced body weight, peripheral insulin resistance, increased blood pressure, and alleviated cognitive impairment in adult male offspring with combined maternal HFD and postnatal HFD. Maternal resveratrol treatment restored hippocampal pAKT and BDNF in rats with combined maternal HFD and postnatal HFD in adult male offspring dorsal hippocampus. Maternal resveratrol intake protects the fetal brain in the context of maternal HFD/obesity. It effectively reduced the synergistic effects of maternal HFD/obesity and postnatal HFD on metabolic disturbances and cognitive impairment in adult male offspring. Our data suggest that maternal resveratrol intake may serve as an effective therapeutic strategy in the context of maternal HFD/obesity.

Resveratrol Prevents Right Ventricle Remodeling and Dysfunction in Monocrotaline-Induced Pulmonary Arterial Hypertension with a Limited Improvement in the Lung Vasculature.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that is characterized by an increase in pulmonary vascular pressure, leading to ventricular failure and high morbidity and mortality. Resveratrol, a phenolic compound and a sirtuin 1 pathway activator, has known dietary benefits and is used as a treatment for anti-inflammatory and cardiovascular diseases. Its therapeutic effects have been published in the scientific literature; however, its benefits in PAH are yet to be precisely elucidated. Using a murine model of PAH induced by monocrotaline, the macroscopic and microscopic effects of a daily oral dose of resveratrol in rats with PAH were evaluated by determining its impact on the lungs and the right and left ventricular function. While most literature has focused on smooth muscle cell mechanisms and lung pathology, our results highlight the relevance of therapy-mediated improvement of right ventricle and isolated cardiomyocyte physiology in both ventricles. Although significant differences in the pulmonary architecture were not identified either micro- or macroscopically, the effects of resveratrol on right ventricular function and remodeling were observed to be beneficial. The values for the volume, diameter, and contractility of the right ventricular cardiomyocytes returned to those of the control group, suggesting that resveratrol has a protective effect against ventricular dysfunction and pathological remodeling changes in PAH. The effect of resveratrol in the right ventricle delayed the progression of findings associated with right heart failure and had a limited positive effect on the architecture of the lungs. The use of resveratrol could be considered a future potential adjunct therapy, especially when the challenges to making a diagnosis and the current therapy limitations for PAH are taken into consideration.

Resveratrol loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles for tail vein injection II: pharmacokinetics, tissue distribution and bioavailability

There are many kinds of biological activities of resveratrol itself, but its clinical application is limited by its poor solubility in water and low bioavailability. Therefore, we have prepared glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles (GL-HSA-RESNPs). The purpose of this study was to investigate the bioavailability, pharmacokinetics and tissue distribution of resveratrol in rats after single-dose tail vein injection administration of GL-HSA-RESNPs. A sensitive and reliable high performance liquid chromatography (HPLC) method was established to verify the content of resveratrol in rat plasma and organs. The C max value after GL-HSA-RESNPs administration was significantly higher than that of resveratrol suspension (933 ± 76.64 ng/mL vs. 618 ± 42.54 ng/mL, p < .01). The T max value obtained after GL-HSA-RESNPs administration was significantly shorter than that after resveratrol suspension administration (0.17 ± 0.01 h vs. 0.25 ± 0.01 h, p < .001). The bioavailability of GL-HSA-RESNPs was 4.25 times higher than that of the pure resveratrol. The concentration of resveratrol in the main organs of rats treated with the GL-HSA-RESNPs was higher than that in rats treated with the pure resveratrol. Rats treated with GL-HSA-RESNPs had the highest concentration of resveratrol in their liver. It is indicated that GL-HSA-RESNPs is a promising liver-targeted delivery system that improves the in vivo bioavailability of resveratrol.

Neurological recovery and antioxidant effects of resveratrol in rats with spinal cord injury: a meta-analysis

Objective:To critically assess the neurological recovery and antioxidant effects of resveratrol in rat models of spinal cord injury.Data sources:Using “spinal cord injury”, “resveratrol” and “animal experiment” as the main search terms, all studies on the treatment of spinal cord injury in rats by resveratrol were searched for in PubMed, EMBASE, MEDLINE, Web of Science, Science Direct, China National Knowledge Infrastructure, Wanfang, VIP, and SinoMed databases by computer. The search was conducted from their inception date to April 2017. No language restriction was used in the literature search.Data selection:The methodological quality of each study was assessed by the initial Stroke Therapy Academic Industry Roundtable recommendations. Two reviewers independently selected studies according to the title, abstract and full text. The risk of bias in the included studies was also evaluated. Meta-analyses were performed with Review Manager 5.3 software.Outcome measures:Neurological function was assessed by the Basso, Beattie, and Bresnahan scale score, inclined plane score and Gale’s motor function score. Molecular-biological analysis of antioxidative effects was conducted to determine superoxide dismutase levels, malondialdehyde levels, nitric oxide synthase activity, nitric oxide levels, xanthine oxidase and glutathione levels in spinal cord tissues.Results:The methodological quality of the 12 included studies was poor. The results of meta-analysis showed that compared with the control group, resveratrol significantly increased the Basso, Beattie, and Bresnahan scale scores after spinal cord injury (n = 300, mean difference (MD) = 3.85, 95% confidence interval (CI) [2.10, 5.59], P < 0.0001). Compared with the control group, superoxide dismutase levels were significantly elevated (n = 138, standardized mean difference (SMD) = 5.22, 95% CI [2.98, 7.45], P < 0.00001), but malondialdehyde levels were significantly diminished (n = 84, SMD = –3.64, 95% CI [–5.84, –1.43], P = 0.001) in the spinal cord of the resveratrol treatment group.Conclusions:Resveratrol promoted neurological recovery and exerted antioxidative effects in rat models of spinal cord injury. The limited quality of the included studies reduces the application of this meta-analysis. Therefore, more high-quality studies are needed to provide more rigorous and objective evidence for the pre-clinical treatment of spinal cord injury.

Amelioration of Acetaminophen-Induced Hepatotoxicity in Rat by Co-Administration of Quercetin and Resveratrol in Rats

Amelioration of Acetaminophen-Induced Hepatotoxicity in Rat by Co-Administration of Quercetin and Resveratrol in Rats

Effects of Ganoderma, Rhodiola and grape seed extracts on the glucuronidation and oral bioavailability of resveratrol in rats

Herb extracts were shown to inhibit the activity of UDP-glucuronosyltransferases (UGTs) in vitro. However, the actual in vivo effect of the inhibitory ability on oral bioavailability is yet verified. In this study, resveratrol (RES) was used as a model drug to study the effect of three Chinese herb extracts, Ganoderma, Rhodiola and grape seed, on the in vitro and in vivo inhibition of glucuronidation and the in vivo bioavailability of RES. Overall, although herb extracts might show inhibition on glucuronidation of RES in vitro and in vivo, the inhibition of glucuronidation did not necessarily mean to improve the in vivo bioavailability of RES.

Protective effects of resveratrol improve cardiovascular function in rats with diabetes.

Resveratrol is a flavonoid with a stilbene structure that is able to suppress acute pulmonary thromboembolism-induced pulmonary artery hypertension. Furthermore, it possesses anti-cancer and antioxidant properties, is able to regulate blood lipids and increase life expectancy. In the present study, it was evaluated whether the protective effect of resveratrol was able to improve cardiovascular function in rats with diabetes. The effects of resveratrol on blood glucose, body weight, heart/body weight ratio, plasma triglyceride levels, heart rate, aspartate transaminase (AST)/alanine transaminase (ALT) ratio and total plasma insulin were evaluated. Levels of inflammation and oxidative stress were also evaluated using ELISA kits, and the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphorylated (p)-p38 protein were evaluated via western blot analysis. The results demonstrated that administration of resveratrol in rats with diabetes-related myocardial infarction (DRMI) significantly reduced blood glucose, body weight, plasma triglyceride levels, heart rate and AST/ALT ratio (all P<0.01) and significantly increased total plasma insulin (P<0.01). Furthermore, resveratrol significantly reduced levels of inflammation factors (P<0.01) and malondialdehyde, a marker for oxidative stress, in rats with DRMI (P<0.01). Resveratrol significantly increased the expression of eNOS (P<0.01) and suppressed the expression of VEGF and p-p38 (both P<0.01) in rats with DRMI. These results suggest that treatment with resveratrol is able to improve cardiovascular function via inhibition of eNOS and VEGF, and suppression of p38 phosphorylation in rats with DRMI.

Negative correlation between serum uric acid and kidney URAT1 mRNA expression caused by resveratrol in rats.

This study established a hyperuricemic rat model to elucidate the effect of resveratrol on the transport of UA in the kidney. Hyperuricemia was induced in rats through daily oral gavage of a potassium oxonate and UA mixture over 3 weeks. Our results revealed that resveratrol significantly reduced the serum UA levels but not creatinine, c-creative protein, alanine aminotransferase, or aspartate aminotransferase levels in these rats. Furthermore, renal URAT1 and OAT1 mRNA expression were significantly higher in the rats treated with allopurinol than in those with no treatment. Therefore, allopurinol not only inhibited UA production but also mediated renal URAT1 and OAT1 expression. The correlation analysis revealed that UA levels correlated negatively with renal IL-6 mRNA expression in rats treated with allopurinol. Moreover, URAT1 showed strong immunoreactivity in the distal convoluted tubule of rats treated with allopurinol or resveratrol and in hyperuricemic treated with allopurinol. Finally, in the rats treated with resveratrol, UA levels correlated negatively with renal URAT1 mRNA expression; thus, resveratrol reduced URAT1 mRNA expression under high UA levels, thereby reducing UA reabsorption in renal cells. Resveratrol contributes to URAT1 expression, which is potentially useful in therapeutic strategies aimed at treating hyperuricemia.

Are miRNA-103, miRNA-107 and miRNA-122 Involved in the Prevention of Liver Steatosis Induced by Resveratrol?

The aim of the present study was to determine whether the reduction in liver fat previously observed in our laboratory in a cohort of rats which had been fed an obesogenic diet was mediated by changes in the expression of microRNA (miRNA)-103-3p, miRNA-107-3p and miRNA-122-5p, which represent 70% of total miRNAs in the liver, as well as in their target genes. The expression of the three analysed miRNAs was reduced in rats treated with resveratrol. A reduction in sterol-regulatory element binding protein 1 (SREBP1) and an increase in carnitine palmitoyltransferase 1a (CPT1a) were observed in resveratrol-treated rats. No changes were found in fatty acid synthase (FAS). In cultured hepatocytes, SREBP1 protein was increased after the transfection of each miRNA. FAS protein expression was decreased after the transfection of miRNA-122-5p, and CPT1a protein was down-regulated by the over-expression of miRNA-107-3p. This study provides new evidences which show that srebf1 is a target gene for miRNA-103-3p and miRNA-107-3p, fasn a target gene for miRNA-122-5p and cpt1a a target gene for miRNA-107-3p. Moreover, the reduction in liver steatosis induced by resveratrol in rats fed an obesegenic diet is mediated, at least in part, by the increase in CPT1a protein expression and activity, via a decrease in miRNA-107-3p expression.

The Influence of Energy of Consciousness Healing Treatment on Low Bioavailable Resveratrol in Male Sprague Dawley Rats

Resveratrol is a natural dietary antioxidant polyphenol that believed to be effective in improving overall health. The biological activity of resveratrol is limited by its poor absorption and first-pass metabolism that lead to have very low plasma concentrations following oral administration. Therefore, the present study was performed to determine the effects of The Trivedi Effect®-Energy of Consciousness Healing Treatment by a renowned Biofield Energy Healer, Alice Branton on resveratrol and rats through the measurement of plasma concentrations after oral administration of resveratrol. The test item, resveratrol was divided into two parts. One part was denoted as the control, while the other part was defined as the Biofield Energy Treated sample. Additionally, one group of animals also received Biofield Energy Treatment under similar conditions. Resveratrol oral formulations were administrated by oral gavage at a dose of 150 mg/kg in groups viz. G1 (untreated resveratrol), G2 (Biofield Treated resveratrol) and G3 (Biofield Treated animals received untreated resveratrol) group. The results showed that resveratrol had a very low oral plasma exposure of 91.71 ng/mL in control group. The Biofield Treatment significantly enhanced the relative oral exposure (AUC0–t) of resveratrol by 23.35% in G2 group compared to the control group. The Biofield Treatment also improved plasma peak concentration (Cmax) of resveratrol by 125% and 28.5% in G2 and G3 groups, respectively compared with the control group. Plasma concentrations of resveratrol in G1 was declined with a rapid elimination half-life (T1/2, 1.48 hours), followed by sudden increases in plasma concentrations 12 to 24 hours after the test item administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of resveratrol. The oral elimination T1/2 of resveratrol in G2 and G3 were 4.67 and 9.0 hours, respectively as compared to the G1. The apparent oral plasma clearance of resveratrol decreased significantly by 54%, and 17.5% in G2 group and G3 group, respectively as compared to the control group. The mean residence time (MRTlast) of resveratrol significantly increased in G2 group (6.45 hours) and G3 group (7.70 hours), as compared to the control group. These data demonstrates greater bioavailability and total plasma level of resveratrol in rats which might be translated into better in vivo biological activity. Hence, The Trivedi Effect®-Energy of Consciousness Healing Treatment could be considered as an innovative strategy which opens new avenues to overcome poorly absorbed nutraceuticals/pharmaceuticals and can also improve the therapeutic performance of orally active molecules.

Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo

BackgroundPolydatin and resveratrol are extractives of radix or rhizoma of Polygonum cuspidatum, and as the glycoside forms, it is a natural precursor of resveratrol. PurposeIn this study, we aimed to explore the mutual transformation between polydatin and resveratrol in rats, and to compare the antioxidative effect of them in vivo. Study designIn this study, we analyzed the serum molar concentration of polydatin and resveratrol after oral administration in rats and evaluated the anti-oxidative stress effects of them using a mouse model. MethodsRats were orally administered polydatin or resveratrol and the concentration of them in serum were analyzed by high performance liquid chromatography (HPLC). Their antioxidative effect was compared in mice with oxidative stress cardiomyopathy induced by doxorubicin (DOX). ResultsThe results showed that polydatin and resveratrol could mutually transform in vivo, the molar concentration of polydatin in serum was always averagely 3.35 and 4.28 times as much as resveratrol after oral administration of polydatin and resveratrol at 200 mg/kg, respectively. Both polydatin and resveratrol could significantly decrease the content of malonydialdehyde (MDA), promote the activities of total superoxide dismutase (T-SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in plasma, and increase the content of glutathione (GSH) in myocardial tissue. The effect of polydatin surpassed resveratrol, particularly embodied in increasing the activities of T-SOD and CAT, and the content of GSH. ConclusionIt illustrates that polydatin is the main substance in serum after intragastric administration with polydatin or resveratrol, and the mutual transformation between polydatin and resveratrol keeps balance; they both have the ability of antioxidative stress in vivo, and polydatin has a better effect than resveratrol, which hints that polydatin may be a substitute for resveratrol in antioxidant for clinical use.

The Cardioprotective Effects of Resveratrol in Rats with Simultaneous Type 2 Diabetes and Renal Hypertension

This study aimed at examining the cardioprotective effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. Eight groups (8-10 each) of male Sprague-Dawley rats, including a control, a diabetic, a renal hypertensive, a sham, a simultaneously hypertensive-diabetic receiving vehicle, and 3 simultaneously hypertensive-diabetic receiving resveratrol at 5, 10 or 20 mg/kg/day were used. After 4 weeks of treatment, blood pressure and glucose, and serum markers of oxidative stress were measured, and animals' hearts were used for isolated studies. Resveratrol prevented the increase of systolic blood pressure, serum malondialdehyde, fasting blood glucose, infarct size, coronary resistance, and coronary effluent creatine kinase-MB. Moreover, it prevented the decrease of serum superoxide dismutase and glutathione reductase, heart rate, left ventricular developed pressure, rate of increase of ventricular pressure, and rate of decrease of ventricular pressure. In conclusion, our findings show that resveratrol alleviates cardiac dysfunction in diabetic-hypertensive rats by virtue of antioxidant, antihypertensive, and coronary vasodilating activities.

Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage

AimsTo investigate the effect of resveratrol (RES) on methotrexate (MTX)-induced testicular damage. Main methodsRES (10mg/kg/day) was given for 8days orally and MTX (20mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat. Key findingsMTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-α level and expression of nuclear factor-κB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18±0.08 and 20.5±3.6μM, respectively. RES also significantly enhanced cytotoxicity of MTX. SignificanceThus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism.

Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats.

The role of oxygen radicals are known for the pathogenesis of kidney damage. The aim of the present study was to investigate the antioxidative effects of melatonin, quercetin, and resveratrol on streptozotocin (STZ)-induced diabetic nephropathy in rats. A total of 35 male Wistar rats were divided into 5 groups as follows: control, diabetes mellitus (DM), DM + melatonin, DM + quercetin, and DM + resveratrol. All the injections started on the same day of single-dose STZ injection and continued for 30 days. At the end of this period, kidneys were removed and processed for routine histological procedures. Biochemical parameters and morphological changes were examined. In DM group, blood glucose levels were significantly increased, whereas body weights were decreased compared with the control group. Significant increases in blood urea nitrogen and tissue malondialdehyde (MDA) levels and decreases in superoxide dismutase and catalase activities were detected in DM group. Administration of melatonin, quercetin, and resveratrol significantly reduced these values. Melatonin was more efficient in reducing MDA levels than other antioxidants (p < 0.05). STZ-induced histopathological alterations including epithelial desquamation, swelling, intracytoplasmic vacuolization, brush border loss and peritubular infiltration. Additionally, basement membrane thickening and sclerotic changes were observed in glomerulus. Transforming growth factor-β1 positive cells were also increased. Melatonin, quercetin, and resveratrol significantly reduced these histopathological changes. Our results indicate that melatonin, quercetin, and resveratrol might be helpful in reducing diabetes-induced renal damage.

Chemopreventive effects of resveratrol in a rat model of cerulein-induced acute pancreatitis

In the past decades, a greater understanding of acute pancreatitis has led to improvement in mortality rates. Nevertheless, this disease continues to be a health care system problem due to its economical costs. Future strategies such as antioxidant supplementation could be very promising, regarding to beginning and progression of the disease. For this reason, this study was aimed at assessing the effect of exogenous administration of resveratrol during the induction process of acute pancreatitis caused by the cholecystokinin analog cerulein in rats. Resveratrol pretreatment reduced histological damage induced by cerulein treatment, as well as hyperamylasemia and hyperlipidemia. Altered levels of corticosterone, total antioxidant status, and glutathione peroxidase were significantly reverted to control levels by the administration of resveratrol. Lipid peroxidation was also counteracted; nevertheless, superoxide dismutase enzyme was overexpressed due to resveratrol pretreatment. Related to immune response, resveratrol pretreatment reduced pro-inflammatory cytokine IL-1β levels and increased anti-inflammatory cytokine IL-10 levels. In addition, pretreatment with resveratrol in cerulein-induced pancreatitis rats was able to reverse, at least partially, the abnormal calcium signal induced by treatment with cerulein. In conclusion, this study confirms antioxidant and immunomodulatory properties of resveratrol as chemopreventive in cerulein-induced acute pancreatitis.