curcumin and Ischemia

Accumulating evidence has suggested that curcumin may protect against cerebral ischemia-reperfusion injury (CIRI). However, biological mechanisms vary across studies, limiting the clinical applicability of these findings. We performed a meta-analysis on publications evaluating curcumin administration in rat models of CIRI. Furthermore, we sought to test the hypothesis that curcumin alleviates CIRI through diminishing oxidation and inflammation. We searched PubMed, Embase, Web of Science, and Cochrane from the starting date of each database to May 2022 for experimental rat studies exploring the use of curcumin after ischemia reperfusion. Included articles were assessed for bias using SYRCLE's risk of bias tool. Data were aggregated by a random effects model. Curcumin administration significantly reduced neurological deficit score (20 studies; pooled mean difference [MD] = -1.57; 95% CI, -1.78 to -1.36, P < .00001), infarct volume (18 studies; pooled MD = -17.56%; 95% CI, -20.92% to -14.20%; P < 0.00001), and brain water content (8 studies, pooled MD = -11.29%, 95% CI: -16.48%, -6.11%, P < .00001). Compared with control, the levels of superoxide dismutase, glutathione, and glutathione peroxidase were significantly higher, whereas the levels of reactive oxygen species, malondialdehyde, interleukin-1β, interleukin-6, interleukin-8, and nuclear factor kappa B were significantly lower (P < .05). Subgroup analysis raised the possibility that intervention affections differed by curcumin's dose. To our knowledge, this is the first meta-analysis of curcumin's neuroprotection and mechanisms in rat CIRI models. Our analysis suggests the neuroprotective potential of curcumin in CIRI via antioxidant activity and anti-inflammatory effect. More research is required to further confirm the effectiveness and safety of curcumin on ischemic stroke therapy.

Topics: Animals; Antioxidants; Brain Ischemia; Curcumin; Inflammation; Ischemia; Neuroprotective Agents; Oxidative Stress; Rats; Reperfusion Injury

Ischemia/reperfusion (I/R) injury is a term used to describe phenomena connected to the dysfunction of various tissue damage due to reperfusion after ischemic injury. While I/R may result in systemic inflammatory response syndrome or multiple organ dysfunction syndrome, there is still a long way to improve therapeutic outcomes. A number of cellular metabolic and ultrastructural alterations occur by prolonged ischemia. Ischemia increases the expression of proinflammatory gene products and bioactive substances within the endothelium, such as cytokines, leukocytes, and adhesion molecules, even as suppressing the expression of other "protective" gene products and substances, such as thrombomodulin and constitutive nitric oxide synthase (e.g., prostacyclin, nitric oxide [NO]). Curcumin is the primary phenolic pigment derived from turmeric, the powdered rhizome of Curcuma longa. Numerous studies have shown that curcumin has strong antiinflammatory and antioxidant characteristics. It also prevents lipid peroxidation and scavenges free radicals like superoxide anion, singlet oxygen, NO, and hydroxyl. In our study, we highlight the mechanisms of protective effects of curcumin against I/R injury in various organs.

Topics: Curcumin; Humans; Ischemia; Reperfusion Injury

Chronic kidney disease (CKD) and acute kidney injury (AKI) are global health problems that affect over 850 million people, twice the number of diabetic individuals around the world. Diabetes mellitus (DM) is known to increase the susceptibility to AKI. Plants and foods, such as curcumin, are traditionally used as treatments for various diseases due to its wide range of bioactive compounds that exert antioxidative, anti-inflammatory, antimicrobial and anticancer properties. The aim of this study is to evaluate the effect of curcumin in diabetic rats with AKI. Adult male Wistar rats, weighing between 250 and 290 g, were randomized into four groups: Citrate (citrate buffer, i.v., single dose, on Day 1 of the protocol); DM (streptozotocin (STZ), 65 mg/k, single dose, i.v., on Day 1); DM + I/R (DM rats that, on Day 26, had the renal pedicle clamped for 30 min on both sides); DM + I/R + Curcumin (DM + I/R rats submitted to curcumin treatment). Results showed that IR worsened renal function and oxidative stress in DM rats, but the DM + IR + Curcumin group showed an increase in inulin clearance and a decrease in serum creatinine and in NGAL, in addition to an improvement in renal hemodynamics. These effects were accompanied by a reduction in oxidative and nitrosative metabolites and an increase in the thiol antioxidant reserve when curcumin was administered to the DM + IR group.

Topics: Acute Kidney Injury; Animals; Antioxidants; Citrates; Curcumin; Diabetes Mellitus, Experimental; Humans; Ischemia; Kidney; Male; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury

Medical improvements are needed to prevent ischemia-reperfusion injury in thoracoabdominal aortic surgery. The aim of this study was to determine the antioxidant effects of thymoquinone, silymarin, and curcumin against ischemia-reperfusion injury associated with abdominal aorta.. Twenty-five Wistar albino rats were included in the study. Sham, control, and treatment (thymoquinone, silymarin, and curcumin) groups were set in equal numbers. Ischemia-reperfusion was applied by clamping (120 minutes) and de-clamping (60 minutes) the infrarenal aorta of all groups, except the sham group. Before reperfusion, thymoquinone, silymarin, and curcumin were given intraperitoneally to the treatment groups. After reperfusion, blood samples were taken from the right ventricle. Total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were studied in serum samples and histopathological examination was performed on the gastrocnemius muscle.. There was a significant difference in TOS and OSI values between the control and sham groups. Both values were found higher in the control group than in the sham group (P<0.05). OSI values were found to be lower in the thymoquinone group compared to the control group (P<0.05). All three parameters were found to be lower in the silymarin group than in the control group (P<0.05). TAS and TOS levels were found to be higher in the curcumin group than in the control group (P<0.05). There was no histopathological difference between the groups.. Silymarin and thymoquinone administration decreases oxidative stress in experimental aortic ischemia-reperfusion injury. Antioxidant effect of curcumin was lower than silymarin and thymoquinone.

Topics: Animals; Antioxidants; Aorta, Abdominal; Curcumin; Ischemia; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Silymarin

To evaluate the effect of curcumin on renal function, hemodynamics, and renal oxidative profile of rats with chronic kidney disease (CKD) subjected to renal ischemia-reperfusion injury (IRI).. Wistar rats, 250-300 g, distributed in four groups: Sham (n = 5), CKD simulation; CKD (n = 5), 5/6 renal ablation for CKD induction; CKD + IRI (n = 5), CKD and renal pedicle clamping for 30 minutes; and CKD + IRI+curcumin (n = 5), CKD + IRI, curcumin administration 30 mg/kg/day, orally, for 10 days. Renal function (inulin clearance, urine flow, plasma creatinine), hemodynamics (blood pressure), and oxidative profile (peroxides, TBARS, and urine nitrate, non-protein soluble thiols in renal tissue) were evaluated.. The CKD + IRI + curcumin group showed increased inulin clearance and reduced plasma creatinine, decreased RVR and increased RBF, decreased oxidative metabolites in urine and increased thiols in renal tissue when compared with the CKD + IRI group.. The treatment with curcumin preserved renal function and hemodynamics of animals with acute CKD, improving oxidative profile, with reduction of oxidants and preservation of antioxidant reserve.

Topics: Acute Kidney Injury; Animals; Creatinine; Curcumin; Inulin; Ischemia; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Reperfusion; Sulfhydryl Compounds

The pathogenesis of ischemic cerebrovascular disease has revealed that ischemia-reperfusion (I/R) injury often leads to aggravation of metabolic oxidative stress and blood-brain barrier (BBB) destruction, eventually causing secondary brain tissue damage. Accumulated reactive oxygen species (ROS) in focal ischemia activate mitochondria-mediated apoptosis and damage the BBB by degrading tight junction proteins (TJPs). Herein, we report macrophage-derived exosomes (Ex) loaded with curcumin (cur) as a multifunctional biomimetic delivery vehicle (Ex-cur) for targeting ischemic brain tissue and alleviating cerebral I/R injury by inhibiting ROS-mediated mitochondrial apoptosis in a transient cerebral ischemia rat model. The design principle relies on unique features of macrophage-derived exosomes and the natural ingredient cur. Specifically, cur can be entrapped within exosomes when incubated with murine macrophage RAW264.7 cells, and its stability is subsequently significantly improved. The resultant Ex-cur can target ischemic regions by leveraging the targeting migration capability of Ex driven by inflammation. Accumulated Ex-cur in ischemic regions is experimentally proven to be highly effective at reducing ROS accumulation by virtue of the antioxidant properties of cur. Using Ex-cur to down-regulate ROS accumulation in lesions, we alleviate BBB damage and suppress mitochondria-mediated neuronal apoptosis, which is confirmed by a series of relevant protein analysis. These findings demonstrate good therapeutic efficacy of Ex-cur for treating I/R injury, providing experimental evidence for the potential clinical benefits of Ex-cur for other modes of neuroprotection.

Topics: Animals; Apoptosis; Brain; Curcumin; Exosomes; Ischemia; Mice; Mitochondria; Rats; Reactive Oxygen Species; Reperfusion Injury

Ovarian torsion must be diagnosed and treated as early as possible. The aim of the present study was to investigate the effects of intraperitoneal administration of nanocurcumin on ischemia-reperfusion injury in ovaries.. Thirty-five (35) healthy female Wistar rats weighing approximately 250 g were randomized into seven experimental groups (n=5): Group SSG - The rats underwent only laparotomy. Group I: A 3-hour ischemia only. Group I/R: A 3-hour ischemia and 3-hour reperfusion. Group I/C: A 3-hour ischemia only, and 1 mg/kg intraperitoneal administration of curcumin 2.5 hours after induction of ischemia. Group I/R/C: A 3-hour ischemia, 3-hour reperfusion, and 1 mg/kg intraperitoneal administration of curcumin 2.5 hours after induction of ischemia. Group I/NC: A 3-hour ischemia only and 1 mg/kg intraperitoneal administration of nanocurcumin 2.5 hours after induction of ischemia. Group I/R/C: A 3-hour ischemia, 3-hour reperfusion and 1 mg/kg intraperitoneal administration of nanocurcumin 2.5 hours after induction of ischemia.. Nanocurcumin-treated animals showed significantly improved development of ischemia and reperfusion tissue injury compared to those in the other groups (p<0.05). Significant higher values of SOD, tGSH, GPO, GSHRd and GST were observed in I/R/NC animals compared to those in the other groups (p<0.05). The damage indicators (NOS, MDA, MPO and DNA damage level) were significantly lower in I/R/NC animal compared to those of other groups (p<0.05).. Intraperitoneal administration of nanocurcumin can be helpful in minimizing ischemia-reperfusion injury in ovarian tissue exposed to ischemia.

Topics: Administration, Cutaneous; Animals; Antioxidants; Curcumin; Disease Models, Animal; Female; Humans; Injections, Intraperitoneal; Ischemia; Nanoparticles; Ovary; Rats; Rats, Wistar; Reperfusion Injury

The transplantation of isolated pancreatic islets is a promising treatment for diabetes. Curcumin has been used for its pharmacologic effects, such as antidiabetic and anti-inflammatory activities. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative THC treatment can attenuate ischemic damage and apoptosis before islet transplantation.. Islets isolated from Balb/c mice were randomly divided into 2 groups and cultured in medium supplemented with or without THC. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor-α, interferon-β, and interleukin-1β, islet cell viability, function, and apoptotic status were determined. Proteins related to apoptosis were analyzed using INS-1 cell after streptozocin treatment.. There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with THC showed 1.3-fold higher glucose-induced insulin secretion than the islets cultured in the medium without THC. After treatment with a cytokine cocktail, glucose-induced insulin release, and NO of the islets were significantly improved in THC-treated islets compared with islets not treated with THC. Apoptosis was significantly decreased, and B-cell lymphoma-2 was elevated in the THC-treated group. The streptozocin-treated INS-1 cell produced significantly higher levels of and B-cell lymphoma-2-associated X protein, caspase-3, and caspase-9 than INS-1 treated with THC.. These results suggest that preoperative THC administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with apoptosis.

Topics: Animals; Antioxidants; Apoptosis; Curcumin; Cytokines; Ischemia; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred BALB C

Neovascularization is impaired in diabetes mellitus, which leads to the development of peripheral arterial disease and is mainly attributed to the dysfunction of endothelial progenitor cells (EPCs). Previous studies proved the promotional effect of curcumin on neovascularization in wound healing of diabetes. Thus, we hypothesize that curcumin could promote neovascularization at sites of hindlimb ischemia in diabetes and might take effect via modulating the function of EPCs.. Streptozotocin-induced type 1 diabetic mice and nondiabetic mice both received unilateral hindlimb ischemic surgery. Curcumin was then administrated to the mice by lavage for 14 days consecutively. Laser Doppler perfusion imaging was conducted to demonstrate the blood flow reperfusion. Capillary density was measured in the ischemic gastrocnemius muscle. In addition, angiogenesis, migration, proliferation abilities, and senescence were determined in EPCs isolated from diabetic and nondiabetic mice. Quantitative PCR was then used to determine the mRNA expression of vascular endothelial growth factor (VEGF) and angiopoetin-1 (Ang-1) in EPCs.. Curcumin application to type 1 diabetic mice significantly improved blood reperfusion and increased the capillary density in ischemic hindlimbs. The in-vitro study also revealed that the angiogenesis, migration, and proliferation abilities of EPCs and the number of senescent EPCs were reversed by curcumin application. Quantitative PCR confirmed the overexpression of VEGF-A and Ang-1 in EPCs after curcumin treatment.. Curcumin could enhance neovascularization via promoting the function of EPCs in a diabetic mouse hindlimb ischemia model.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetic Foot; Endothelial Progenitor Cells; Hindlimb; Ischemia; Male; Mice; Neovascularization, Physiologic

To investigate the neuroprotective effect of chronic curcumin supplementation on the rat forebrain prior to ischemia and reperfusion.. Forebrain ischemia was induced by bilateral common carotid artery occlusion for 1/2 hour, followed by reperfusion for 72 hours. Older rats were divided into five groups: Group I received 300 mg/kg oral curcumin for 21 days before ischemia and 300 mg/kg intraperitoneal curcumin after ischemia; Group II received 300 mg/kg intraperitoneal curcumin after ischemia; Group III received 300 mg/kg oral curcumin for 21 days before ischemia; Group IV had only ischemia; Group V was the sham-operated group. The forebrain was rapidly dissected for biochemical parameter assessment and histopathological examination.. In forebrain tissue, enzyme activities of superoxide dismutase, glutathione peroxidase, and catalase were significantly higher in Group I than Groups II or III (p < 0.05) while xanthine dehydrogenase and malondialdehyde enzyme activities and concentrations of interleukin-6 and TNF-alpha were significantly lower in Group I when compared to Groups II and III (p < 0.05). A significant reduction in neurological score was observed after 24 and 72 hours in the curcumin-treated groups compared with the ischemic group. We also found a marked reduction in apoptotic index after 72 hours in the groups receiving curcumin. Significantly more TUNEL-positive cells were observed in the ischemic group compared to those treated with curcumin.. We demonstrated the neuroprotective effect of chronic curcumin supplement on biochemical parameters, neurological scores and apoptosis following ischemia and reperfusion injury in rats.

Topics: Animals; Apoptosis; Catalase; Curcumin; Glutathione Peroxidase; Interleukin-6; Ischemia; Male; Malondialdehyde; Neuroprotective Agents; Prosencephalon; Rats; Reperfusion Injury; Stroke; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Xanthine Dehydrogenase

Seventy-five compounds, including 21 new compounds (1-21), were isolated from the root bark of Cudrania tricuspidata. The structures of the isolated compounds were elucidated by interpretation of their spectroscopic data. All isolated compounds were evaluated for their neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cell death, and nine compounds had activities with EC50 values of 1.9-30.2 μM. The 75 isolated compounds along with 34 previously reported xanthones were tested also for neuroprotective effects against the 1-methyl-4-phenylpyridinium ion (MPP(+)) and oxygen glucose deprivation (OGD)-induced cell death. Three compounds were active against MPP(+)-induced cell death with EC50 values of 0.2-10.3 μM, and 23 compounds were active in the OGD model with EC50 values of 2.9-35.5 μM.

Topics: Animals; Cell Death; Disease Models, Animal; Glucose; Ischemia; Moraceae; Neuroprotective Agents; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Plant Bark; Plant Roots; Republic of Korea; Xanthones

BACKGROUND The prevalence of peripheral arterial disease (PAD) is increasing worldwide. Currently, there is no effective treatment for PAD. Curcumin is an ingredient of turmeric that has antioxidant, anti-inflammation, and anticancer properties. In the present study we investigated the potential effect of curcumin in protecting against ischemic limb injury. MATERIAL AND METHODS We used an established hindlimb ischemia mouse model in our study. Curcumin was administrated through intraperitoneal (I.P.) injection. Immunohistochemical staining and ELISA assays were performed. Treadmill training was used to evaluate skeletal muscle functions of animals. RESULTS Our experiments using in vivo treadmill training showed that curcumin treatment improved the running capacity of animals after ischemic injury. Histological analysis revealed that curcumin treatment significantly reduced the skeletal muscle damage and fibrosis associated with ischemic injury. In order to determine the cellular and molecular mechanisms underlying curcumin-mediated tissue protection, immunohistochemical staining and ELISA assays were performed. The results showed that curcumin treatment led to less macrophage infiltration and less local inflammatory responses as demonstrated by decreasing TNF-α, IL-1, and IL-6 levels. Further immunofluorescent staining of tissue slides indicated that curcumin treatment inhibited the NF-κB signaling pathway. Finally, curcumin can inhibit NF-kB activation induced by LPS in macrophages. CONCLUSIONS Our study results show that curcumin treatment can ameliorate hindlimb injury following ischemic surgery, which suggests that curcumin could be used for PAD treatment.

Topics: Animals; Anti-Inflammatory Agents; Curcumin; Disease Models, Animal; Hindlimb; Immunomodulation; Interleukin-1; Interleukin-6; Ischemia; Macrophages; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; NF-kappa B; Peripheral Arterial Disease; Random Allocation; Signal Transduction; Tumor Necrosis Factor-alpha

A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.

Topics: Animals; Antioxidants; Cell Survival; Chemokine CCL2; Curcumin; Diabetes Mellitus, Experimental; Endocytosis; Female; Hindlimb; Hydrogen Peroxide; Interferon-gamma; Intracellular Space; Ischemia; Kinetics; Lipopolysaccharides; Macrophage Activation; Mice; Microspheres; Muscles; NIH 3T3 Cells; Oxygen; Particle Size; Perfusion; Peripheral Arterial Disease; Polymers; Reactive Oxygen Species; Sulfides

The aim of this study was to investigate the angiogenic effects of curcumin on an ischemia and lung cancer model. To induce ischemia combined with lung cancer models, unilateral femoral arteries of C57BL/6 mice were disconnected on one side of the mouse and Lewis lung carcinoma (LLC) cells were xenografted on the opposite side. Angiogenic effects and underlying mechanisms associated with curcumin were investigated. Molecular target(s), signaling cascades and binding affinities were detected by Western blot, two-dimensional gel electrophoresis (2-DE), computer simulations and surface plasmon resonance (SPR) techniques. Curcumin promoted post-ischemic blood recirculation and suppressed lung cancer progression in inbred C57BL/6 mice via regulation of the HIF1α/mTOR/VEGF/VEGFR cascade oppositely. Inflammatory stimulation induced by neutrophil elastase (NE) promoted angiogenesis in lung cancer tissues, but these changes were reversed by curcumin through directly reducing NE secretion and stimulating α1-antitrypsin (α1-AT) and insulin receptor substrate-1 (IRS-1) production. Meanwhile, curcumin dose-dependently influenced endothelial cells (EC) tube formation and chicken embryo chorioallantoic membrane (CAM) neovascularization. Curcumin had opposite effects on blood vessel regeneration under physiological and pathological angiogenesis, which was effected through negative or positive regulation of the HIF1α/mTOR/VEGF/VEGFR cascade. Curcumin had the promise as a new treatment modality for both ischemic conditions and lung cancer simultaneously in the clinic.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Blotting, Western; Carcinoma, Lewis Lung; Cell Movement; Cell Proliferation; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Computer Simulation; Curcumin; Electrophoresis, Gel, Two-Dimensional; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Immunoprecipitation; In Vitro Techniques; Ischemia; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface Plasmon Resonance; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

We aimed to investigate the effects of curcumin on ischemia/ reperfusion (IR) injury of the liver and distant organs resulting from liver blood flow arrest.. Totally 40 rats, divided into four groups, each included 10 rats were used. Group I as only laparatomy, Group II laparatomy and curcumin application, Group III hepatic IR; and Group IV as hepatic IR and curcumin application group. Ischemia was generated by hepatoduedonal ligament clamping for 30 minutes and then reperfusion is started. Curcumin capsules were opened and appropriate dose had been created within weighing scales. After calculations, the powder was diluted with saline. Fifteen minutes before the ischemia, curcumin was applied via oral gavage. Blood samples were taken from the animals for biochemical analysis at 60th minutes of the experiment in the first and second groups; 30 minutes after beginning reperfusion in the third and forth groups. Simultaneously, liver, lung and kidney tissues were sampled for biochemical and histopathological examinations.. Plasma malondialdehyde levels were found to be higher (p < 0.001), but total antioxidant activity values were not different in IR group compared with IR + curcumin group (p > 0.05). Biochemical and histopathological evaluation of tissue samples revealed that there were no differences in total antioxidant activity, total oxidant activity and histopathologic scores in IR + curcumin group compared with values of IR group (p > 0.05).. Curcumin did not reduce the effects of hepatic ischemia reperfusion injury on the liver and distant organs including kidneys and lungs significantly.

Topics: Animals; Antioxidants; Curcumin; Disease Models, Animal; Ischemia; Kidney; Lipid Peroxidation; Liver; Lung; Male; Malondialdehyde; Organ Specificity; Rats; Rats, Wistar; Reperfusion Injury

Oxidative damage plays a critical role in many diseases of the central nervous system. This study was conducted to determine the molecular mechanisms involved in the putative anti-oxidative effects of curcumin against experimental stroke. Oxygen and glucose deprivation/reoxygenation (OGD/R) was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular expression of NAD(P)H: quinone oxidoreductase1 (NQO1) induced by OGD was counteracted by curcumin post-treatment, which paralleled attenuated cell injury. The reduction of phosphorylation Akt induced by OGD was restored by curcumin. Consequently, NQO1 expression and the binding activity of nuclear factor-erythroid 2-related factor 2 (Nrf2) to antioxidant response element (ARE) were increased. LY294002 blocked the increase in phospho-Akt evoked by curcumin and abolished the associated protective effect. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 60 minutes. Curcumin administration significantly reduced infarct size. Curcumin also markedly reduced oxidative stress levels in middle cerebral artery occlusion (MCAO) rats; hence, these effects were all suppressed by LY294002. Taken together, these findings provide evidence that curcumin protects neurons against ischemic injury, and this neuroprotective effect involves the Akt/Nrf2 pathway. In addition, Nrf2 is involved in the neuroprotective effects of curcumin against oxidative damage.

Topics: Animals; Animals, Newborn; Antioxidants; Brain; Brain Ischemia; Cell Nucleus; Cells, Cultured; Chromones; Curcumin; Enzyme Inhibitors; Glucose; Ischemia; Male; Morpholines; NAD(P)H Dehydrogenase (Quinone); Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Oxygen; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley

Mesenteric ischemia/reperfusion injury induces a systemic response and releases harmful substances that may affect distant organs such as the lung, liver and kidney. We designed this study to determine if curcumin has protective effects against mesenteric ischemia/reperfusion injury and mesenteric ischemia/reperfusion-induced intestinal and distant organ injury.. Forty Wistar-Albino rats were divided into four groups as: sham, control, ischemia/reperfusion, and ischemia/reperfusion+curcumin. The ischemia/reperfusion and ischemia/reperfusion+curcumin groups were subjected to mesenteric arterial ischemia for 30 minutes and reperfusion for 1 hour. The control and ischemia/reperfusion+curcumin groups were administered curcumin (200 mg/kg, single dose) via oral gavage 15 min before the injury insult. Blood and pulmonary, hepatic and kidney tissue specimens were obtained to measure serum malondialdehyde and total antioxidant capacity, tissue levels of total antioxidant capacity, total oxidative status, and oxidative stress index. In addition, intestine, pulmonary, hepatic, and kidney tissue specimens were obtained for the evaluation of histopathological changes.. The histopathological injury scores of the intestine and distant organs were significantly higher in the ischemia/reperfusion group; these injuries were prevented by curcumin in the ischemia/reperfusion+curcumin group. In the ischemia/reperfusion group, a significant increase in serum malondialdehyde levels was determined, which was prevented with curcumin pretreatment in the ischemia/reperfusion+curcumin group. Total antioxidant capacity levels were significantly supported by curcumin pretreatment in the control and ischemia/reperfusion+curcumin groups.. This study demonstrated that curcumin ameliorates histopathological damage in the intestine and distant organs against mesenteric ischemia/reperfusion injury.

Topics: Animals; Antioxidants; Curcumin; Intestines; Ischemia; Kidney; Liver; Lung; Malondialdehyde; Mesentery; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It regulates genes involved in angiogenesis, but is inactivated rapidly by normoxia. Ad-HIF-1α-Trip was constructed by transforming Pro402, Pro564, and Asn803 in HIF-1α to alanine in order to delay degradation and create a constitutive transcriptional activator. In this study, we investigated whether Ad-HIF-1α-Trip could induce functional mature angiogenesis and the possible mechanisms involved. We found that Ad-HIF-1α-Trip increased the expression of multiple angiogenic genes in cultured HMVEC-Ls, including VEGF, PLGF, PAI-1, and PDGF. In a rabbit model of acute hind limb ischemia, Ad-HIF-1α-Trip improved tissue perfusion and collateral vessels, as measured by contrast-enhanced ultrasound (CEU), CT angiography, and vascular casting. Ad-HIF-1α-Trip also produced more histologically identifiable capillaries, which were verified by immunostaining, compared with controls. Interestingly, inhibition of CBP/p300 by curcumin prevented HIF-1α from inducing the expression of several angiogenic genes. The present study suggests that Ad-HIF-1α-Trip can induce mature angiogenesis and improve tissue perfusion in ischemic rabbit skeletal muscle. CBP/p300, which interacts with the transactivation domains of HIF-1α, is important for HIF-1α-induced transcription of angiogenic genes.

Topics: Amino Acid Substitution; Angiogenic Proteins; Angiography; Animals; Cells, Cultured; Collateral Circulation; Curcumin; Endothelial Cells; Gene Expression; Genetic Therapy; Hindlimb; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemia; Male; Microvessels; Muscle, Skeletal; Neovascularization, Physiologic; p300-CBP Transcription Factors; Rabbits; Regional Blood Flow; Transduction, Genetic

Topics: Angiogenesis Inhibitors; Animals; Curcumin; Ischemia; Melanoma; Mice; Neovascularization, Pathologic; Spices; Wound Healing

The JNK/c-Jun cell death pathway is a major pathway responsible for the loss of oxidative stress-damaged auditory neurons.. Implantation of patients with residual hearing accentuates the need to preserve functioning sensorineural elements. Although some auditory function may survive electrode insertion, the probability of initiating an ongoing loss of auditory neurons and hair cells is unknown. Cochlear implantation can potentially generate oxidative stress, which can initiate the cell death of both auditory neurons and hair cells.. Dissociated cell cultures of P4 rat auditory neurons identified the apoptotic pathway initiated by oxidative stress insults (e.g., loss of trophic factor support) and characterized this pathway by arresting translation of pathway-specific mRNA with antisense oligonucleotide treatment and with the use of pathway specific inhibitors. The presence or absence of apoptosis-specific protein and changes in the level of neuronal survival measured the efficacy of these interventional strategies.. These in vitro studies identified the JNK/c-Jun cascade as a major initiator of apoptosis of auditory neurons in response to oxidative stress. Neurons pretreated with c-jun antisense oligonucleotide and exposed to high levels of oxidative stress were rescued from apoptosis, whereas neurons in treatment control cultures died. Treatment of oxidative-stressed cultures with either curcumin, a MAPKKK pathway inhibitor, or PD-098059, a MEK1 inhibitor, blocked loss of neurons via the JNK/c-Jun apoptotic pathway.. Blocking the JNK/c-Jun cell death pathway is a feasible approach to treating oxidative stress-induced apoptosis within the cochlea and may have application as an otoprotective strategy during cochlear implantation.

Topics: Animals; Animals, Newborn; Antibodies; Antineoplastic Agents; Apoptosis; Cell Culture Techniques; Cisplatin; Cochlear Implantation; Curcumin; Cytoskeletal Proteins; Hair Cells, Auditory; Immunohistochemistry; Ischemia; Oligonucleotides, Antisense; Oxidative Stress; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Spiral Ganglion; Transcription Factor AP-1

Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4- to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.

Topics: Alkaloids; Animals; Benzophenanthridines; Blotting, Western; Curcumin; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Female; Heart; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; HSC70 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Hypoxia; Imidazoles; Immunohistochemistry; Infant; Infant, Newborn; Ischemia; Male; MAP Kinase Signaling System; Membrane Proteins; Myocardium; Phenanthridines; Protein Kinase C; Pyridines; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Time Factors

Chronic renal allograft nephropathy is associated with both immune and ischemic injury which may act synergistically to promote an inflammatory response. The immunosuppressant mycophenolic acid and the polyphenolic agents curcumin and quercetin possess properties that might ameliorate such injury. We studied the effects of these agents in models of ischemic renal injury and skin allograft rejection.. Ischemic acute tubular necrosis was produced in rats by renal pedicle occlusion with contralateral nephrectomy. Animals were treated with mycophenolic acid, quercetin and curcumin, or a combination of agents. Animals were killed on days 2 and 7 after operation and tissue samples were collected. Renal tubular apoptosis and cellular proliferation were assessed by immunohistochemistry. Expression of the cytokines RANTES and AIF were evaluated by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).. Treatment with the polyphenolic compounds alone or in combination with mycophenolic acid was associated with less tubular damage, attenuation of renal inflammation, and prolongation of skin graft survival. A combination of agents decreased serum creatinine on day 2 from 4.5 to 0.9 mg./dl. (p< or =0.01) and at day 7 from 3.8 to 0.6 mg./dl. (p< or =0.01). Treatment with the polyphenolic compounds inhibited apoptosis at day 2. By RT-PCR, RANTES and AIF were detected at high levels on days 2 and 7. Treatment with these agents alone or in combination strongly attenuated this increased expression.. The combination of mycophenolic acid with curcumin and quercetin reduces renal injury and facilitates repair. These agents may have a role in therapeutic regimens that are both immunosuppressive and renoprotective.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CCL5; Curcumin; Gene Expression Regulation; Graft Rejection; Immunohistochemistry; Immunosuppressive Agents; Ischemia; Kidney; Male; Mycophenolic Acid; Nephritis; Quercetin; Rats; Rats, Sprague-Dawley; Skin Transplantation

Topics: Animals; Curcumin; Drug Synergism; Flavonoids; Graft Rejection; Immunosuppressive Agents; Ischemia; Kidney; Male; Mycophenolic Acid; Quercetin; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Skin Transplantation

Nonimmune renal injury plays an important role in acute and chronic rejection by triggering an injury response through cytokine and chemokine release. Bioflavonoids are agents with potential immunosuppressive and renoprotective properties. We studied the effects of quercetin and curcumin, two bioflavonoids, on ischemia-reperfusion in the rat.. Rats underwent 30 min of left renal pedicle occlusion with simultaneous right nephrectomy and were pretreated with quercetin or curcumin. Serial serum creatinine was measured, and renal expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1), and allograft inflammatory factor (AIF) was quantified by polymerase chain reaction.. Pretreatment with quercetin or curcumin resulted in preservation of histological integrity, with a decrease in tubular damage and interstitial inflammation. On day 2 after ischemia-reperfusion, quercetin pretreatment decreased the mean serum creatinine level from 6.5+/-1.4 to 3.3+/-0.5 mg/dl (P=0.06). On day 7, the creatinine level for control animals was 7.5+/-1.5 mg/dl, which was significantly decreased by pretreatment with quercetin, curcumin, or both together (creatinine levels: 1.6+/-1.3, 1.8+/-0.2, and 2.0+/-0.4 mg/dl, respectively; all P<0.05 vs. untreated). By semiquantitative polymerase chain reaction, RANTES, MCP-1, and AIF were detected at high levels in kidneys on day 2 but not in normal kidneys. Pretreatment with quercetin or curcumin strongly attenuated this expression.. Quercetin and curcumin reduce ischemia-reperfusion injury and its inflammatory sequelae. The bioflavonoids hold promise as agents that can reduce immune and nonimmune renal injury, the key risk factors in chronic graft loss.

Topics: Animals; Chemokine CCL2; Chemokine CCL5; Curcumin; Gene Expression; Ischemia; Kidney; Male; Quercetin; Rats; Rats, Inbred F344; Reperfusion Injury