MicroRNA-21 modulates brown adipose tissue adipogenesis and thermogenesis in a mouse model of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. METHODS: Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. RESULTS: MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpß) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. CONCLUSIONS: Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.

Polycystic ovary syndrome (PCOS) is a common hormone disorder in premenopausal women, often linked to obesity and abnormal brown fat tissue activity. Women with PCOS have elevated male hormones, which are responsible for many metabolic problems. Our study focuses on understanding the role of microRNA-21 (miR-21) in the energy balance and brown fat tissue activity in a PCOS mouse model. We studied female mice with and without miR-21, treating them with a male hormone. We measured body composition and energy expenditure. We also analyzed the levels of specific genes and proteins related to fat tissue and energy production. Our findings showed that mice lacking miR-21 had less weight gain in response to male hormones, without fat or brown fat tissue mass changes. They also had reduced energy production, changed eating habits, and altered expression of genes related to fat tissue and energy production. In conclusion, our study suggests that miR-21 in brown fat tissue may regulate the energy imbalance caused by male hormones in PCOS. Adjusting miR-21 levels in brown fat tissue could be a new way to address the metabolic issues associated with PCOS.

Vitamin D3 potentiates the nephroprotective effects of vildagliptin-metformin combination in a rat model of metabolic syndrome.

The current study was conducted to investigate the nephroprotective effects of vildagliptin-metformin combination in an experimental model of fructose/salt-induced metabolic syndrome (MetS). A major aim was to evaluate the potential capacity of vitamin D3 to potentiate the pleiotropic nephroprotective effects of vildagliptin-metformin combination. MetS was induced in adult male Wistar rats by adding fructose (10%) to everyday drinking water and salt (3%) to the diet for 6 weeks. Along with the same concentrations of fructose/salt feeding, MetS rats were then treated orally with either vildagliptin (10 mg/kg/day)-metformin (200 mg/kg/day) combination, vitamin D3 (10 µg/kg/day), or the triple therapy for a further 6 weeks. The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia, and impaired glucose tolerance. At the end of the 12-week experimental period, MetS rats displayed significantly deteriorated renal function, enhanced intrarenal oxidative stress and inflammation together with exaggerated renal histopathological damages and interstitial fibrosis. The study has corroborated antioxidant, anti-inflammatory, and antifibrotic effects of vildagliptin-metformin combination, vitamin D3, and the triple collaborative therapy, conferring renoprotection in the setting of MetS. Due attention has been paid to the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5' adenosine monophosphate-activated protein kinase activation as novel therapeutic targets to optimize renoprotection. The apparent potentiating effect, evoked upon coadministration of vitamin D3 with vildagliptin-metformin combination, may provide a cornerstone for further clinical investigations.

Histological and imunohistochemical alterations of hippocampus and prefrontal cortex in a rat model of Alzheimer like-disease with a preferential role of the flavonoid "hesperidin".

Alzheimer's disease (AD) is a chronic age-related neurodegenerative disease characterized by degeneration of the central cholinergic neurons, inflammation and oxidative stress in the basal forebrain, prefrontal cortex and hippocampus. Hesperidin (Hesp) is one of the flavonoids havinganti-inflammatory and anti-oxidative properties in some neurodegerative brain lesions. To investigate the possible neuroprotective role of Hespin an AD-like rat model induced experimentally by Scopolamine (Scop). Forty adult male Sprague Dawley rats were randomly allocated into four groups. Group I-(Control), group II-(Hesp) (supplemented orally with 100 mg/kg Hesp for 28 days), group III-(AD) (injected i.p with 1 mg/kg Scop for 9 days) and group IV-(Hesp/AD). At the end of the experiment, behavioral (Y-maze test) and biochemical analysis were carried out along with histological, immunohistochemical and morphometric studies of the hippocampus and prefrontal cortex. AD rats displayed memory impairment in the behavioural paradigm with a concomitant increase of serum TNF-α and IL-1ß, while IL-10 decreased significantly. Also, there was a rise of amyloid beta-42 (Aß-42), acetylcholinesterase (AChE) activity and malondialdehyde (MDA) together with a decrease of reduced glutathione (GSH) in hippocampal and prefrontal homogenate. In addition, sections of the hippocampus and prefrontal cortex revealed obvious histopathological changes, overexpression of p-Tau protein and glial fibrillary acidic protein (GFAP) with a decrease in the expression of synaptophysin (SYN). Contradictorily, pre-treatment with Hesp offset the spatial memory deficits, redox imbalance, Aß-42 and AChE over activity as well as preserved the histological architecture and attenuated the raised p-Tau protein and GFAP while upregulated SYN immuoreactivity of AD rats. Collectively, our results highlight the potential mitigating role of Hesp in AD-like state in rats and this may presumably raise the possibility of its future implementation as a prophylactic remedy against AD in humans.

Fetuin-A exerts a protective effect against experimentally induced intestinal ischemia/reperfusion by suppressing autophagic cell death.

Intestinal tissue is highly susceptible to ischemia/reperfusion injury in many hazardous health conditions. The anti-inflammatory and antioxidant glycoprotein fetuin-A showed efficacy in cerebral ischemic injury; however, its protective role against intestinal ischemia/reperfusion remains elusive. Therefore, this study investigated the protective role of fetuin-A supplementation against intestinal structural changes and dysfunction in a rat model of intestinal ischemia/reperfusion. We equally divided 72 male rats into control, sham, ischemia/reperfusion, and fetuin-A-pretreated ischemia/reperfusion (100 mg/kg/day fetuin-A intraperitoneally for three days prior to surgery and a third dose 1 h prior to the experiment) groups. After 2 h of reperfusion, the jejunum was dissected and examined for spontaneous contractility. A jejunal homogenate was used to assess inflammatory and oxidative stress enzymes. Staining of histological sections was carried out with hematoxylin, eosin and Masson's trichrome stain for evaluation. Immunohistochemistry was performed to detect autophagy proteins beclin-1, LC3, and p62. This study found that fetuin-A significantly improved ischemia/reperfusion-induced mucosal injury by reducing the percentage of areas of collagen deposition, increasing the amplitude of spontaneous contraction, decreasing inflammation and oxidative stress, and upregulating p62 expression, which was accompanied by beclin-1 and LC3 downregulation. Our findings suggest that fetuin-A treatment can prevent ischemia/reperfusion-induced jejunal structural and functional changes by increasing antioxidant activity and regulating autophagy disturbances observed in the ischemia/reperfusion rat model. Furthermore, fetuin-A may provide a protective influence against intestinal ischemia/reperfusion complications.

Potamogeton perfoliatus L. Extract Attenuates Neuroinflammation and Neuropathic Pain in Sciatic Nerve Chronic Constriction Injury-Induced Peripheral Neuropathy in Rats.

Sciatic nerve injury is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous systems. In our previous work, Potamogeton perfoliatus L. displayed anti-inflammatory, antipyretic and analgesic properties, predominantly via the inhibition of COX-2 enzyme and attenuation of oxidative stress. Herein, we extended our investigations to study the effects of the plant's extract on pain-related behaviors, oxidative stress, apoptosis markers, GFAP, CD68 and neuro-inflammation in sciatic nerve chronic constriction injury (CCI) rat model. The levels of the pro-inflammatory marker proteins in sciatic nerve and brainstem were measured with ELISA 14 days after CCI induction. Pretreatment with the extract significantly attenuated mechanical and cold allodynia and heat hyperalgesia with better potential than the reference drug, pregabalin. In addition, CCI lead to the overexpression of prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), tumor necrosis alpha (TNFα), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and NADPH oxidase-1 (NOX-1) and decreased the catalase level in sciatic nerve and brainstem. The observed neuro-inflammatory changes were accompanied with glial cells activation (increased GFAP and CD68 positive cells), apoptosis (increased Bax) and structural changes in both brainstem and sciatic nerve. The studied extract attenuated the CCI-induced neuro-inflammatory changes, oxidative stress, and apoptosis while it induced the expression of Bcl-2 and catalase in a dose dependent manner. It also decreased the brainstem expression of CD68 and GFAP indicating a possible neuroprotection effect. Taking together, P. perfoliatus may be considered as a novel therapy for neuropathic pain patients after performing the required clinical trials.

Vitamin D3 potentiates the nephroprotective effects of metformin in a rat model of metabolic syndrome: role of AMPK/SIRT1 activation and DPP-4 inhibition.

The current study aimed to investigate the molecular mechanisms of metformin and vitamin D3-induced nephroprotection in a metabolic syndrome (MetS) rat model, evaluating the capacity of vitamin D3 to potentiate metformin action. MetS was induced by 10% fructose in drinking water and 3% salt in the diet. After 6 weeks, serum lipid profile and uric acid were measured, an oral glucose tolerance test (OGTT) was performed, and kidney function was investigated. In conjunction with the same concentrations of fructose and salt feeding, MetS rats with significant weight gain, dyslipidemia, hyperuricemia, and dysglycemia were treated orally with metformin (200 mg/kg), vitamin D3 (10 µg/kg), or both daily for 6 weeks. At the end of the study period, anthropometrical parameters were recorded, OGTT was reperformed, urine and blood samples were collected, and tissue samples were harvested at sacrifice. MetS rats showed dramatically declined renal function, enhanced intrarenal oxidative stress and inflammation, and extravagant renal histopathological damage with interstitial fibrosis. Metformin and vitamin D3 significantly reversed all the aforementioned deleterious effects in MetS rats. The study has verified the nephroprotective effects of metformin and vitamin D3 in MetS, accentuating the critical role of AMP-activated protein kinase/sirtuin-1 activation and dipeptidyl peptidase-4 inhibition. Given the synergistic effects of the combination, vitamin D3 is worth being investigated as an additional therapeutic agent for preventing MetS-induced nephropathy.

Renoprotective effects of vitamin D3 supplementation in a rat model of metabolic syndrome.

PURPOSE: The study aimed to investigate the potential nephroprotective effects of vitamin D3 in metabolic syndrome (MetS) and the molecular basis of the underlying mechanisms of its action. METHODS: MetS was induced in adult male Wistar rat s by adding fructose (10%) to every day drinking water and salt (3%) to the diet. Six weeks after fructose/salt consumption, fasting serum lipid profile and uric acid levels were determined, an oral glucose tolerance test (OGTT) was performed and kidney function was checked. MetS rats were then treated orally with vitamin D3 (10 µg/kg/day) for 6 weeks. At the end of the study period (12 weeks), the OGTT test was reperformed, anthropometrical parameters were measured, urine, blood and tissue samples were collected and the animals were euthanised. RESULTS: The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia and impaired glucose tolerance. After 12 weeks, MetS rats displayed markedly declined renal function alongside with extravagant renal histopathological damages and interstitial fibrosis. Furthermore, significantly enhanced renal oxidative stress and inflammation were manifested. Vitamin D3 supplementation in MetS rats significantly reversed all the above-mentioned deleterious effects. CONCLUSION: The study has indeed provided mounting evidence of the promising therapeutic potential of vitamin D3 against development and progression of MetS-induced nephropathy. A new insight has been introduced into the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5'adenosine monophosphate-activated protein kinase activation in the renoprotective effects of vitamin D3.

Thymus algeriensis and Thymus fontanesii exert neuroprotective effect against chronic constriction injury-induced neuropathic pain in rats.

We have previously demonstrated that the Thymus algeriensis and Thymus fontanesii extracts have powerful anti-inflammatory, antipyretic, and analgesic effects against acute pain models. We profiled their chemical composition and found many phenolic acids, flavonoids, and phenolic diterpenes. In this work, we investigated their antioxidant properties on HaCaT cells exposed to UVA-induced oxidative stress and examined their effects against chronic neuropathic pain and the underlying mechanisms. Through a rat chronic constriction injury (CCI) model, we induced chronic neuropathic pain by placing 4 loose ligatures around the right sciatic nerve for 14 days. Thermal and mechanical hyperalgesia in addition to cold and dynamic allodynia were tested on the day before surgery and on the 7th and 14th post-surgery days. Key markers of the nitrosative and oxidative stresses, in addition to markers of inflammation, were measured at day 14 post surgery. Histopathological examination and immunostaining of both synaptophysin and caspase-3 of sciatic nerve and brain stem were also performed. Results of this study showed that T. algeriensis extract suppresses UVA oxidative stress in HaCaT cells via activation of the Nrf-2 pathway. Both extracts attenuated hyperalgesia and allodynia at 7- and 14-days post-surgery with more prominent effects at day 14 of surgery. Their protective effects against neuropathic pain were mediated by inhibiting NOX-1, iNOS, by increasing the enzyme activity of catalase, and inhibition of inflammatory mediators, NF-κB, TNF-α, lipoxygenase, COX-2 enzymes, and PGE2. Furthermore, they improved deleterious structural changes of the brainstem and sciatic nerve. They also attenuated the increased caspase-3 and synaptophysin. The data indicate that both extracts have neuroprotective effects against chronic constriction injury-induced neuropathic pain. The observed protective effects are partially mediated through attenuation of oxidative and nitrosative stress and suppression of both neuroinflammation and neuronal apoptosis, suggesting substantial activities of both extracts in amelioration of painful peripheral neuropathy.

CoQ10 exerts hepatoprotective effect in fructose-induced fatty liver model in rats.

BACKGROUND: Excess dietary sugar is associated with deleterious metabolic effects, liver injury, and coenzyme-Q10 (CoQ10) deficiency. This study investigates the ability of CoQ10 to protect against fructose-induced hepatic damage. METHODS: Rats were fed tap water or 30% fructose for 12 weeks with or without CoQ10 (10 mg/kg, po). An additional group of rats were allowed to feed on either water or 30% fructose for 12 weeks, followed by four weeks of treatment with either the vehicle or CoQ10. RESULTS: Fructose-fed rats showed lower CoQ10 levels, increased systolic pressure, increased body weight, higher liquid consumption, decreased food intake and hyperglycemia. Fructose-fed rats also showed deteriorated serum and liver lipid profiles, impaired liver function tests and oxidative status, and lower expression of adiponectin receptor 1 and 2 along with higher GLUT-2 levels. Furthermore, following fructose treatment, tyrosine kinase-PI3K pathway was inhibited. Additionally, there was an increase in the levels of apoptotic markers and serum visfatin and a decrease in the levels of adiponectin and soluble receptor of the advanced glycated end product. Consequently, several histopathological changes were detected in the liver. Concurrent or three months post-exposure administration of CoQ10 in fructose rats significantly reversed or attenuated all the measured parameters and hepato-cytoarchitecture alterations. CONCLUSION: This study suggests CoQ10 supplement as a possible prophylaxis or treatment candidate for fructose-induced liver injury.

Haematoxylon campechianum Extract Ameliorates Neuropathic Pain via Inhibition of NF-κB/TNF-α/NOX/iNOS Signalling Pathway in a Rat Model of Chronic Constriction Injury.

: In this study, the phytochemical composition and the possible prophylactic effects of an aqueous ethanol extract of Haematoxylon campechianum flowers (HCF) on peripheral neuropathic pain in a chronic constriction injury (CCI) rat model are investigated. Rats with induced CCI were subjected to neuropathic pain behaviour tests and evaluated by chemical, thermal, and mechanical sensation tests and functional recovery of the brain stem and sciatic nerve at 7- and 14-day intervals. The effect of the extract on acute pain and inflammation is also investigated. The extract exerted both peripheral and central analgesic and anti-inflammatory properties in addition to antipyretic effects that are clear from targeting COX, LOX and PGE. It was found that CCI produced significant thermal and mechanical hyperalgesia, cold allodynia and deleterious structural changes in both sciatic nerve and brain stem. Treatments with HCF extract significantly improved cold and thermal withdrawal latency, mechanical sensibility and ameliorated deleterious changes of sciatic nerve and brain stem at different dose levels. The extract also ameliorated oxidative stress and inflammatory markers in brain stem and sciatic nerve. It suppressed the apoptotic marker, p53, and restored myelin sheath integrity. The effects of HCF extract were more potent than pregabalin. Fifteen secondary metabolites, mainly gallotannins and flavonoids, were characterized in the extract based on their retention times and MS/MS data. The identified phenolic constituents from the extract could be promising candidates to treat neuropathic pain due to their diverse biological activities, including antioxidant, anti-inflammatory and neuroprotective properties.

Vitamin D3 potentiates the renoprotective effects of vildagliptin in a rat model of fructose/salt-induced insulin resistance.

Insulin resistance (IR) seemingly plays a role in chronic kidney disease (CKD). The present study has elucidated the crucial interplay of oxidative stress, inflammatory, apoptotic and profibrotic signaling pathways, linking IR to CKD. The study aimed at investigating the pleiotropic nephroprotective effects of either vildagliptin or vitamin D3 in a fructose/salt-induced IR rat model, highlighting the potential molecular mechanisms underlying their action. Another interesting target was to evaluate the potential capacity of vitamin D3 to potentiate the nephroprotective effects of vildagliptin. Indeed, a state of impaired fasting glucose, IR and compensatory hyperinsulinemia, constellating with significant weight gain, atherogenic dyslipidemia and hyperuricemia was established 6 weeks after fructose/salt consumption. IR rats were then treated orally with vildagliptin (10 mg/kg/day), vitamin D3 (10 µg/kg/day) or their combination for a further 6 weeks. By the end of the 12th week, untreated IR rats displayed significantly declined renal function with parallel interwined renal oxidative stress, inflammatory, apoptotic and profibrotic changes, renal histopathological damages and markedly enhanced collagen fiber deposition. Vildagliptin and vitamin D3 reversed hyperuricemia and exerted a plethora of renal anti-oxidant, anti-inflammatory, anti-apoptotic and anti-fibrotic effects. Our study has introduced a new insight into the role of dipeptidyl peptidase-4 inhibition and silent information regulator 1/5'adenosine monophosphate-activated protein kinase activation in the nephroprotective effects of either agent, elucidating their possible crosstalk with renin angiotensin aldosterone system downregulation. Considering the superadditive renoprotective effects evoked by the combination, vitamin D3 is worth being further investigated as an additional therapeutic agent for preventing IR-induced nephropathy.

Therapeutic prospects of hydroxytyrosol on experimentally induced diabetic testicular damage: potential interplay with AMPK expression.

Male reproductive dysfunction represents one of the overlooked consequences of diabetes that still deserve more scientific attention. We designed this study to explore the therapeutic potential of hydroxytyrosol (HT) on diabetic testicular damage and to investigate its relationship with adenosine monophosphate-activated protein kinase (AMPK) expression. In this context, 30 adult male Wistar rats were utilized and subdivided into control, diabetic and HT-treated diabetic groups. Testicular sections were prepared for histopathological examination and immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine, Sertoli cell vimentin, myoid cell α-SMA, androgen receptors and caspase-3. We also assessed oxidative enzymatic and lipid peroxidation biochemical profiles, sperm count, morphology and motility. Real-time PCR of AMPK expression in tissue homogenate was performed. We observed that HT restored testicular histopathological structure and significantly reduced oxidative DNA damage and the apoptotic index. The HT-treated group also exhibited significantly higher Sertoli cell vimentin, myoid cell α-SMA and androgen receptor immune expression than the diabetic group. A rescue of the oxidative enzymatic activity, lipid peroxidation profiles, sperm count, morphology and motility to control levels was also evident in the HT-treated group. Significant upregulation of AMPK mRNA expression in the HT-treated group clarified the role of AMPK as an underlying molecular interface of the ameliorative effects of HT. We concluded that HT exhibited tangible antioxidant and antiapoptotic impacts on the testicular cytomorphological and immunohistochemical effects of experimentally induced diabetes. Furthermore, AMPK has an impactful role in the molecular machinery of these effects.

Salix tetrasperma Roxb. Extract Alleviates Neuropathic Pain in Rats via Modulation of the NF-κB/TNF-α/NOX/iNOS Pathway.

Patients with neuropathic pain experience chronic painful tingling, burning, and prickling sensations accompanied with hyperalgesia and/or allodynia. In this study, 38 secondary metabolites of a methanol extract from Salix tetrasperma flowers were identified by liquid chromatography-mass spectrometry (HPLC-MS/MS). The extract showed substantial anti-inflammatory, central and peripheral anti-nociceptive, antipyretic, and antioxidant activities in vitro and in different animal models. In the chronic constriction injury (CCI) rat model, the extract was able to attenuate and significantly relieve hyperalgesia and allodynia responses in a dose dependent manner and restore the myelin sheath integrity and Schwann cells average number in the sciatic nerve. The enzyme-linked immunosorbent assay (ELISA) showed that the extract significantly reduced the expression of various pro-inflammatory biomarkers including nuclear factor kabba B (NF-κB), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the oxidative stress biomarker NADPH oxidase 1 (NOX1), in brain stem and sciatic nerve tissues. These findings were supported by in vitro enzyme inhibition assays (COX-1, COX-2 and 5-LOX). Moreover, the extract significantly reduced p53 expression in the brain stem tissue. These findings support the use of S. tetrasperma in folk medicine to alleviate pain. It could be a promising natural product for further clinical investigations to treat inflammation, nociceptive pain and chronic neuropathic pain.

Synergistic therapeutic effects of Vitis vinifera extract and Silymarin on experimentally induced cardiorenal injury: The pertinent role of Nrf2.

BACKGROUND: Cardiorenal crosstalk has gained growing scientific curiosity recently. Clinical observations have approved that heart and kidney performances are intimately interrelated; acute or chronic dysfunction of either is inevitably mirrored on the other. This coexistence usually has the poor prognosis and worsened outcome. METHODS: We designed this study to explore therapeutic potentials of combined Vitis vinifera and Silymarin extracts on histopathological alterations of experimentally induced cardiorenal injury model. Moreover, to examine the pertinent role of Nrf2 in their bio-molecular actions. Sixty adult male Wistar albino rats were utilized, further subdivided into control, doxorubicin (DXR), DXR + Silymarin, DXR + Aqueous Vitis, DXR + Ethanolic Vitis, DXR + Ethanolic Vitis + Silymarin. Left ventricle and renal cortex sections from all groups were processed for histopathological examination, biochemical estimation of serum Urea, Creatinine, BUN, lipid profile and hs-CRP and real-time PCR of Nrf2 expression in cardiac and renal tissue homogenate were performed. RESULTS: Our results proved that combined ethanolic extract of Vitis vinifera and Silymarin restored normal renal and cardiac histomorphology. Significant improvement of Creatinine, BUN, lipid profile and hs-CRP cardiac and renal biochemical indicators confirmed our results. Moreover, significant elevation of mRNA expression levels of Nrf2 proved that combined Vitis vinifera and Silymarin action was directly related to the redox-sensitive regulator pathway. CONCLUSIONS: We concluded that synergistic therapeutic effect of Vitis vinifera extract and Silymarin on experimental cardiorenal injury model owes principally to promoting activation of the Keap1/Nrf2 signaling pathway.