curcumin and Diabetic-Nephropathies

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and is an enormous burden on both patients and society. There is an urgent need for effective alternative therapeutic strategies for the treatment of DN, as medical treatment is currently limited. The anti-inflammatory, antioxidative, anti-apoptotic, and anti-fibrosis properties of curcumin, a polyphenol curcuminoid, have been demonstrated in research on diabetic nephropathy. The clinical and preclinical trials and mechanisms by which curcumin affects DN have been discussed in this review. A deeper understanding of the pharmacological effects of curcumin on diabetic nephropathy may provide new therapies to improve the development and occurrence of diabetic nephropathy.

Topics: Anti-Inflammatory Agents; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; Diarylheptanoids; Humans; Polyphenols

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. Considering DKD is the main cause of end-stage renal disease (ESRD) in developed countries, extensive research is currently investigating the matrix of DKD pathophysiology. Hyperglycemia, inflammation and oxidative stress (OS) are the main mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-β, NF-κB, MCP-1, VCAM-1, ICAM-1) and the activation of diverse pathways (e.g., PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state with impairment of the antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations in the renal filtration unit. Hitherto, a wide spectrum of pre-clinical and clinical studies shows the beneficial use of NRF2-inducing strategies, such as NRF2 activators (e.g., Bardoxolone methyl, Curcumin, Sulforaphane and their analogues), and other natural compounds with antioxidant properties in DKD treatment. However, limitations regarding the lack of larger clinical trials, solubility or delivery hamper their implementation for clinical use. Therefore, in this review, we will discuss DKD mechanisms, especially oxidative stress (OS) and NRF2/KEAP1/ARE involvement, while highlighting the potential of therapeutic approaches that target DKD via OS.

Topics: Antioxidants; Curcumin; Diabetic Nephropathies; Humans; Intercellular Adhesion Molecule-1; Interleukin-1; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; NF-kappa B; Oleanolic Acid; Oxidative Stress; Quality of Life; Reactive Oxygen Species; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Curcumin is a polyphenolic compound derived from turmeric that has potential beneficial properties for cardiovascular and renal diseases and is relatively safe and inexpensive. However, the application of curcumin is rather problematic due to its chemical instability and low bioavailability. The experimental results showed improved chemical stability and potent pharmacokinetics of one of its analogs - (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66). There are several advantages of C66, like its synthetic accessibility, structural simplicity, improved chemical stability (in vitro and in vivo), presence of two reactive electrophilic centers, and good electron-accepting capacity. Considering these characteristics, we reviewed the literature on the application of C66 in resolving diabetes-associated cardiovascular and renal complications in animal models. We also summarized the mechanisms by which C66 is preventing the release of pro-oxidative and pro-inflammatory molecules in the priming and in activation stage of cardiomyopathy, renal fibrosis, and diabetic nephropathy. The cardiovascular protective effect of C66 against diabetes-induced oxidative damage is Nrf2 mediated but mainly dependent on JNK2. In general, C66 causes inhibition of JNK2, which reduces cardiac inflammation, fibrosis, oxidative stress, and apoptosis in the settings of diabetic cardiomyopathy. C66 exerts a powerful antifibrotic effect by reducing inflammation-related factors (MCP-1, NF-κB, TNF-α, IL-1β, COX-2, and CAV-1) and inducing the expression of anti-inflammatory factors (HO-1 and NEDD4), as well as targeting TGF-β/SMADs, MAPK/ERK, and PPAR-γ pathways in animal models of diabetic nephropathy. Based on the available evidence, C66 is becoming a promising drug candidate for improving cardiovascular and renal health.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Inflammation; Kidney; Oxidative Stress

In spite of much awareness, diabetes mellitus continues to remain one of major reasons for mortality and morbidity rate all over the globe. Free radicals cause oxidative stress which is responsible for causing diabetes. The recent advancements in elucidation of ARE/keap1/Nrf2 pathway can help in better understanding of diabetes mellitus. Various clinical trials and animal studies have shown the promising effect of Nrf2 pathway in reversing diabetes by counteracting with the oxidative stress produced. The gene is known to dissociate from Keap1 on coming in contact with such stresses to show preventive and prognosis effect. The Nrf2 gene has been marked as a molecular player in dealing with wide intracellular as well as extracellular cellular interactions in different diseases. The regulation of this gene gives some transcription factor that contain antioxidant response elements (ARE) in their promoter region and thus are responsible for encoding certain proteins involved in regulation of metabolic and detoxifying enzymes.

Topics: Animals; Antioxidant Response Elements; Antioxidants; Clinical Trials as Topic; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypoglycemic Agents; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Protein Binding; Reactive Oxygen Species; Signal Transduction

Curcuma caesia has shown positive results in treating number of diseases, but till date no work was reported on its activity in diabetic neuropathy. So, the present review aims at exploring several hypothesis which can be proposed to explain further its utility in diabetic neuropathy by its antioxidant property, anti-inflammatory, CNS depressant effect, antibacterial and antifungal property. For finding the accurate and exact detail, a thorough review of all the available research and review article was done. A number of book chapters and encyclopaedias were taken into consideration to find out the origin, botany and genetics. The databases were searched using different keywords like antioxidant, inflammation, turmeric, diabetic neuropathy.. After getting data on pathogenesis of diabetic neuropathy, it has been found out that its role as antioxidant will reduce the level of oxidative stress which is the main reason for the occurrence of the present complication. Apart this, the anti-inflammatory activity will further prevent the inflammation of neurons and antibacterial effect will inhibit the spread of infection. Combining all the factors together, the plant can be utilized in the treatment of diabetic neuropathy.. Curcuma caesia can be proved as a useful approach in the treatment of diabetic neuropathy.

Topics: Antioxidants; Curcuma; Curcumin; Diabetic Nephropathies; Humans; Hyperglycemia; Inflammation Mediators; Microglia; Oxidative Stress; Plant Extracts

Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti-inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end-products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions.

Topics: Biological Availability; Cell Proliferation; Curcumin; Diabetic Nephropathies; Diarylheptanoids; Glycation End Products, Advanced; Humans; Oxidative Stress; Signal Transduction

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies.

Topics: Animals; Anticarcinogenic Agents; Antioxidant Response Elements; Antioxidants; Curcumin; Cysteine Proteinase Inhibitors; Diabetic Nephropathies; Enzyme Inhibitors; Humans; Isothiocyanates; Leupeptins; Molecular Targeted Therapy; NF-E2-Related Factor 2; Oxidative Stress; Resveratrol; Rutin; Signal Transduction; Stilbenes; Sulfoxides; Trace Elements; Zinc

Diabetic nephropathy (DN) is currently well established as the most common cause of end-stage renal disease in most parts of the world. Notwithstanding the expanding basic and clinical research in this field, the pathogenesis remains far from clear and hence the treatment of DN remains suboptimal. There is a critical need for the development of newer therapeutic strategies including alternative and complementary therapies. One of the natural products that was extensively studied in cancer and other chronic disease states such as diabetes is curcumin, an active ingredient in turmeric, a spice extensively used in India. In this manuscript, we present a critical review of the experimental and clinical evidence that supports the use of curcumin and its analogs in DN as well as the various proposed mechanisms for its biological actions in health and disease states.

Topics: Animals; Cinnamomum zeylanicum; Curcumin; Diabetic Nephropathies; Humans; Proteinuria

To assess the renal protective effects of curcumin administration on diabetic rats/mice.. Databases were searched electronically and conference papers searched manually for search terms to find relevant studies. Articles were assessed independently by two reviewers. Review Manager 5.1 was used for data analysis.. Fourteen randomized controlled experiments were included. Meta-analysis demonstrated that blood sugar levels and kidney weight to body weight ratios in the model group were higher than those in the normal group, and the curcumin group had significantly lower mesangial area to glomerular area ratios compared with the model group, and also lower levels of urinary protein, blood urea nitrogen and serum creatinine.. Curcumin shows protective effects on the kidneys of rats/mice with diabetes.

Topics: Animals; Curcumin; Diabetic Nephropathies; Disease Models, Animal; Drugs, Chinese Herbal; Humans; Mice; Randomized Controlled Trials as Topic; Rats

Diabetic nephropathy is characterized by a plethora of signaling abnormalities. Recent trials have suggested that intensive glucose-lowering treatment leads to hypoglycemic events, which can be dangerous. Curcumin is the active ingredient of turmeric, which has been widely used in many countries for centuries to treat numerous diseases. The preventive and therapeutic properties of curcumin are associated with its antioxidant and anti-inflammatory properties. Here, we highlight the renoprotective role of curcumin in diabetes mellitus (DM) with an emphasis on the molecular basis of this effect. We also briefly discuss the numerous approaches that have been undertaken to improve the pharmacokinetics of curcumin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; Humans; Molecular Structure; Signal Transduction

Chronic kidney disease (CKD) is a worldwide public health problem, and proteinuria may accelerate the progression of CKD, being oxidative stress a common mechanism in nondiabetic or diabetic proteinuric kidney disease. This study was designed to evaluate the effect of the dietary supplementation with curcumin (CUR) on the redox status and the nuclear factor erythroid 2-related factor 2 (Nrf2) activation in patients with nondiabetic or diabetic proteinuric CKD.. Randomized double-blind placebo-controlled clinical trial.. A total of 101 Mexican patients from the National Institute of Cardiology "Ignacio Chavez", with nondiabetic or diabetic proteinuric CKD (proteinuria ≥ 1 g protein/24 hours), aged 20 to 70 years; 60% were male, and 51% were diabetic.. Patients with nondiabetic proteinuric CKD received placebo (n = 26) or CUR 320 mg/day (n = 24) for 8 weeks, and patients with diabetic proteinuric CKD were intervened with placebo (n = 23) or CUR 320 mg/day (n = 28) for the same period.. Anthropometrical, clinical, and biochemical characteristics, as well as oxidative stress markers, antioxidant enzyme activities and Nrf2 activation were evaluated at baseline and after intervention.. The intervention with CUR did not improve proteinuria, estimated glomerular filtration rate, or lipid profile. However, in plasma, CUR attenuated lipid peroxidation in individuals with nondiabetic proteinuric CKD (P<.05) and enhanced the antioxidant capacity in subjects with diabetic proteinuric CKD (P<.05). No effect of CUR was observed on the antioxidant enzymes activities or Nrf2 activation.. Dietary supplementation with CUR has the potential to reduce oxidative stress in Mexican patients with nondiabetic or diabetic proteinuric CKD. Studies with higher doses of CUR and longer follow-up are granted to confirm our findings.

Topics: Adult; Aged; Body Mass Index; Curcuma; Curcumin; Diabetic Nephropathies; Dietary Supplements; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Male; Mexico; Middle Aged; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Proteinuria; Renal Insufficiency, Chronic; Young Adult

Curcumin has a therapeutic potential in treating diabetic kidney disease (DKD) while potential mechanisms underlining this beneficial effect remain to be elucidated. In the present study, curcumin intervention was performed in patients with Type II diabetes mellitus (T2DM) by oral intake of curcumin at the dose of 500 mg/day for a period of 15-30 days. Nephritic excretion of urinary micro-albumin (U-mAlb) and blood metabolic indexes were assessed before and after this intervention. In addition, the lipid oxidation index, malondialdehyde (MDA) in plasma and the status of anti-oxidative Nrf2 system in blood lymphocytes were measured. The effect of curcumin on inflammation was assessed by measuring plasma lipopolysaccharide (LPS) content and inflammatory signaling protein in blood lymphocytes. A self-comparison method was used for assessing statistical significances of these measurements. Here we show that curcumin intervention markedly attenuated U-mAlb excretion without affecting metabolic control of participated patients. In addition, curcumin reduced plasma MDA level with enhanced the Nrf2 system specifically regulated protein, NAD(P)H quinone oxidoreductase 1 (NQO-1) together with other anti-oxidative enzymes in patients' blood lymphocytes. Furthermore, we observed reduced plasma LPS content and increased IκB, an inhibitory protein on inflammatory signaling in patient's lymphocytes after curcumin administration. Finally, several gut bacterials important for maintaining gut barrier integrity and function were upregulated by curcumin.In conclusion, short-term curcumin intervention ablates DKD progress with activating Nrf2 anti-oxidative system and anti-inflammatory efficacies in patients with T2DM.

Topics: Aged; Aged, 80 and over; Albuminuria; Curcumin; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Inflammation; Lipopolysaccharides; Lymphocytes; Male; Middle Aged; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Signal Transduction

End-stage renal disease (ESRD) due to type 2 diabetic nephropathy is a very common condition which is increasing in prevalence, and is associated with high global levels of mortality and morbidity. Both proteinuria and transforming growth factor-β (TGF-β) may contribute to the development of ESRD in patients with diabetic nephropathy. Experimental studies indicate that turmeric improves diabetic nephropathy by suppressing TGF-β. Therefore, this study investigated the effects of turmeric on serum and urinary TGF-β, interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α), as well as proteinuria, in patients with overt type 2 diabetic nephropathy.. A randomized, double-blind and placebo-controlled study was carried out in the Diabetes Clinic of the Outpatient Department of Shiraz University of Medical Sciences on 40 patients with overt type 2 diabetic nephropathy, randomized into a trial group (n = 20) and a control group (n = 20). Each patient in the trial group received one capsule with each meal containing 500 mg turmeric, of which 22.1 mg was the active ingredient curcumin (three capsules daily) for 2 months. The control group received three capsules identical in colour and size containing starch for the same 2 months.. Serum levels of TGF-β and IL-8 and urinary protein excretion and IL-8 decreased significantly comparing the pre- and post-turmeric supplementation values. No adverse effects related to turmeric supplementation were observed during the trial.. Short-term turmeric supplementation can attenuate proteinuria, TGF-β and IL-8 in patients with overt type 2 diabetic nephropathy and can be administered as a safe adjuvant therapy for these patients.

Topics: Administration, Oral; Curcuma; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dietary Supplements; Double-Blind Method; Female; Humans; Interleukin-8; Male; Middle Aged; Phytotherapy; Proteinuria; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin's anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin's biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.

Topics: Aldehyde Reductase; Anti-Inflammatory Agents; Antioxidants; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; Humans; Inflammation Mediators; Phosphatidylinositol 3-Kinases

High blood glucose in diabetic patients often causes cardiovascular diseases (CVDs) that threats to human life. Curcumin (Cur) is known as an antioxidant agent, possesses anti-inflammatory activity, and prevents CVDs. However, the clinical application of curcumin was limited due to its low bioavailability. This study aimed to investigate the ameliorative effects of chitosan-encapsulated curcumin (CEC) on heart and kidney damages in streptozotocin-induced type-1 diabetes C57BL/6 mice model. The results showed that Cur- and CEC-treatments downregulated the blood sugar and total cholesterol level as well as enhanced insulin secretion. However, blood pressure, triglycerides content, and very low-density lipoprotein-cholesterol content were not changed. Histochemistry analysis revealed that both curcumin and chitosan-encapsulated curcumin ameliorated cell hypertrophy and nucleus enlargement in the left ventricular of heart and reduced fibrosis in the kidney, especially after the chitosan-encapsulated curcumin treatment. Our study suggested that chitosan can effectively enhance the protective effect of curcumin on the heart and kidney damages in type-1 diabetes mice model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chitosan; Curcumin; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Models, Animal; Heart; Kidney; Male; Mice; Mice, Inbred C57BL; Streptozocin

B6, an analog of curcumin, is a compound isolated from a traditional Chinese medicine Turmeric. In this paper, we aimed to explore the efficacy of B6 on diabetic nephropathy and the related mechanisms.. The effects of B6 were studied on fast-blood glucose, serum creatinine, urea nitrogen, urine albumen/24 h, pathological changes of main organs, the levels of ACE2 and ACE2 mRNA in the rat model of diabetes induced by streptozotocin.. The results showed that B6 treatment could reduce serum creatinine, urea nitrogen, urine albumen/24 h, decrease the level of AngII, improve the renal pathological changes in diabetic rats and increase the levels of ACE2 and ACE2 mRNA.. These results suggested B6 could protect the renal function of diabetic rats. This study provided scientific basis for the further researches and clinical applications of B6.

Topics: Angiotensin-Converting Enzyme 2; Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Streptozocin

Diabetic cardiomyopathy is an independent cardiac injury that can develop in diabetic individuals. Our previous study showed that C66, a curcumin analogue, protects against diabetes-induced cardiac damage. The present study sought to reveal the underlying mechanisms of C66-mediated cardioprotection.. Neither C66 treatment nor JNK2 knockout affected body weight or plasma glucose levels. Cardiac inflammation, fibrosis, oxidative stress, and apoptosis were increased in WT diabetic compared to WT control mice, all of which were attenuated by C66 treatment. However, these pathological and molecular changes induced by diabetes were eliminated in JNK2. Our results indicate that C66 ameliorates diabetic cardiomyopathy by inhibiting JNK2 relative pathways.

Topics: Animals; Apoptosis; Curcumin; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Fibrosis; Humans; Inflammation; Mice; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 9; Oxidative Stress; Phosphorylation

Siwei Jianghuang Decoction Powder (SWJH) documented originally in the Four Medical Tantras-Blue Glaze exhibited beneficial effects on diabetic nephropathy (DN) via combined synergistically action of multiple formula components including Curcumae longae Rhizoma, Berberidis dictyophyllae Cortex, Phyllanthi Fructus and Tribuli Fructus. This study investigated the effects of SWJH on DN in db/db mice and possible underlying mechanisms. The ten weeks old db/db mice treated with SWJH by intra-gastric administration once a day for 8 weeks. After 8 weeks, body weight, water and food intake of mice were recorded. The level of fasting blood glucose (FBG) was measured. Serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin (UMAlb), serum uric acid (UA) and urinary albumin excretion (UAE) were detected. An enzyme-linked immunosorbent assay was performed to test serum vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Real-time PCR and Western blot analysis were used to test mRNA and protein expression of hypoxia inducible factor-1α (HIF-1α), VEGF and TGF-β1 in kidney tissue. SWJH treatment significantly reduced the levels of FBG, Scr, BUN, UMAlb, UA and UAE and retarded renal fibrosis. SWJH treatment further significantly reduced serum TGF-β1 level and downregulated the expression of HIF-1α, VEGF and TGF-β1 at both mRNA and protein levels. Principal component analysis and partial least squares regression and hierarchical cluster analysis demonstrated that SWJH treatment significantly ameliorated renal damage in DN mice. These consequences suggested that SWJH formulations were effective in the treatment of DN through regulating the HIF-1α, VEGF and TGF-β1 overexpression.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Creatinine; Curcuma; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Eating; Hypoxia-Inducible Factor 1, alpha Subunit; Medicine, Tibetan Traditional; Mice; Plant Extracts; Transforming Growth Factor beta1; Uric Acid; Vascular Endothelial Growth Factor A

Hyperglycemia-induced inflammation and fibrosis have important roles in the pathogenesis of diabetic nephropathy and cardiomyopathy. With inflammatory cytokines and signaling pathways as important mediators, targeting inflammation may be an effective approach to new avenue for treating diabetic complications. J17, a molecule with structural similarities to curcumin, exhibited good anti-inflammatory activities by inhibiting LPS-induced inflammatory response in macrophages. However, its ability to alleviate hyperglycemia-induced injury via its anti-inflammatory actions remained unclear. Thus, we reported that J17 exerts significant inhibitory effects on hyperglycemia-induced inflammation and fibrosis in NRK-52E cells, H9C2 cells and a streptozotocin-induced diabetic mouse model. We also found that the anti-inflammatory and anti-fibrosis activities of J17 are associated with the inhibition of the P38 and AKT signal pathway, respectively. In vivo oral administration of J17 suppressed hyperglycemia-induced inflammation, hypertrophy and fibrosis, thereby reducing key markers for renal and cardiac dysfunction and improving in fibrosis and pathological changes in both renal and cardiac tissues of diabetic mice. The results of this study indicated that J17 can be potentially used as a cardio- and reno-protective agent and that targeting the P38 and AKT pathways may be an effective therapeutic strategy for diabetic complications.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Cell Line; Curcumin; Cytokines; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Diabetic Nephropathies; Fibrosis; Inflammation Mediators; Kidney; Male; Mice, Inbred C57BL; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin; Time Factors

To investigate the protective effect of curcumin analogue L6H4 on the kidney from the type 2 diabetic rats.. The levels of the 24 h urinary protein, FBG, TG, Scr and BUN were elevated significantly in diabetic group(. L6H4 exerts the protective effect on kidneys of type 2 diabetic rats by reducing expression of TGF-β1, inhibiting secretion of Col-IV and FN, relieving the deposition of the extracellular matrix.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Collagen Type IV; Creatinine; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Extracellular Matrix; Fibronectins; Kidney; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1; Triglycerides; Uric Acid

Topics: Animals; Caspase 1; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Extracellular Matrix; Glomerular Mesangium; Inflammasomes; Interleukin-1beta; Male; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

The progression of diabetic nephropathy (DN) is accelerated by smoking. The current study investigated the ability of curcumin to protect the kidneys against damage from oxidative stress induced by diabetes mellitus (DM) and nicotine (NC). A total of 24 male Wistar rats were divided into four groups of six rats each. DM was induced by a single intraperitoneal injection of streptozotocin 60 mg/kg body weight. DM rats were treated with or without NC in the absence or presence of curcumin for 8 weeks. As compared with the controls, DM rats exhibited reduced serum levels of high density lipoprotein, superoxide dismutase and glutathione peroxidase, and decreased renal mRNA expression levels of synaptopodin, connexin 43 and erythropoietin (EPO), which were further suppressed by NC and restored to normal levels by curcumin treatment. Additionally, DM rats exhibited increases in their lipid profiles (cholesterol, triacylglycerol and phospholipids), oxidative markers (malondialdehyde, γ‑glutamyltranspeptidase and nitric oxide), kidney function markers (urea and creatinine) and the mRNA expression levels of vimentin, desmin, SREBP‑1, iNOS and TGF‑β1. These effects were further enhanced by NC, but counteracted by curcumin treatment. Kidneys from DM rats displayed glomerular hypertrophy, sclerosis and tubulo‑interstitial changes represented by tubular lipid deposition, interstitial mononuclear cell infiltration and fibroplasia. Pancreatic islets exhibited cellular vacuolation, morphological irregularity and damaged or reduced in size β‑cells. These renal and pancreatic changes became more severe following NC treatment and were ameliorated by curcumin. Therefore, NC‑induced DN progression may predominantly operate by increasing oxidative stress, reducing the levels of antioxidants, suppressing EPO levels, and causing perturbations to gap junction and podocyte structure. Curcumin may ameliorate the damaging effects of DM and NC on the kidney through normalization of the mRNA expression levels of several genes important in the progression of DN.

Topics: Animals; Antioxidants; Biomarkers; Blood Chemical Analysis; Connexins; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Male; Nicotine; Oxidative Stress; Podocytes; Rats; Transcriptome

The purposes of this study were to investigate whether curcumin can weaken diabetic nephropathy by modulating both oxidative stress and renal injury from Wnt signaling mediation. Wnt5a/β-catenin depression and induction of superoxide synthesis are associated with high glucose (HG) induced transforming growth factor (TGF)-β1 and fibronectin expression in mesangial cells. Curcumin resumes HG depression of Wnt/β-catenin signaling and alleviates HG induction of superoxide, TGF-β1 and fibronectin expression in renal mesangial cell. Exogenous curcumin alleviated urinary total proteinuria and serum superoxide level in diabetic rats. Based on laser-captured microdissection for quantitative real-time polymerase chain reaction, it was found that diabetes significantly increased TGF-β1 and fibronectin expression in line with depressed Wnt5a expression. Curcumin treatment reduced the TGF-β1 and fibronectin activation and the inhibiting effect of diabetes on Wnt5a/β-catenin expression in renal glomeruli. Immunohistochemistry showed that curcumin treatment significantly reduced 8-hydroxy-2'-deoxyguanosine, TGF-β1 and fibronectin, and was in line with the restoration of the suppressed Wnt5a expression immunoreactivities in glomeruli of diabetic rats. Curcumin alleviated extracellular matrix accumulation in diabetic nephropathy by not only preventing the diabetes-mediated superoxide synthesis but also resuming downregulation of Wnt/β-catenin signaling. These findings suggest that regulation of Wnt activity by curcumin is a feasible alternative strategy to rescue diabetic renal injury.

Topics: Animals; Cells, Cultured; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Delivery Systems; Male; Rats; Rats, Wistar; Superoxides; Wnt Signaling Pathway

Diabetic nephropathy is a serious complication of type 2 diabetes mellitus, and delaying the development of diabetic nephropathy in patients with diabetes mellitus is very important. In this study, we investigated inflammation, oxidative stress, and lipid metabolism to assess whether curcumin ameliorates diabetic nephropathy.. Animals were divided into three groups: Long-Evans-Tokushima-Otsuka rats for normal controls, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats for the diabetic group, and curcumin-treated (100 mg/kg/day) OLETF rats. We measured body and epididymal fat weights, and examined plasma glucose, adiponectin, and lipid profiles at 45 weeks. To confirm renal damage, we measured albumin-creatinine ratio, superoxide dismutase (SOD), and malondialdehyde (MDA) in urine samples. Glomerular basement membrane thickness and slit pore density were evaluated in the renal cortex tissue of rats. Furthermore, we conducted adenosine monophosphate-activated protein kinase (AMPK) signaling and oxidative stress-related nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling to investigate mechanisms of lipotoxicity in kidneys.. Curcumin ameliorated albuminuria, pathophysiologic changes on the glomerulus, urinary MDA, and urinary SOD related with elevated Nrf2 signaling, as well as serum lipid-related index and ectopic lipid accumulation through activation of AMPK signaling.. Collectively, these findings indicate that curcumin exerts renoprotective effects by inhibiting renal lipid accumulation and oxidative stress through AMPK and Nrf2 signaling pathway.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression; Inflammation; Kidney; Kidney Glomerulus; Lipid Metabolism; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Superoxide Dismutase

Diabetic nephropathy is the leading cause of end-stage renal disease. Previously we reported that C66, a novel analogue of curcumin with a very high bioavailability, ameliorated diabetic nephropathy in mice, with little known about the mechanism. The present study aimed to define the mechanism by which C66 ameliorates diabetic nephropathy.. Our aim was to discover whether C66 acts through the activation of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2), which governs the antioxidant response. Streptozotocin-induced Nrf2 (also known as Nfe2l2)-knockout and wild-type (WT) diabetic mice were treated with C66. To determine whether the actions of C66 on NRF2 are mediated by microRNA (miR)-200a, WT diabetic mice were treated with C66 in the presence or absence of an in vivo miR-200a inhibitor (locked nucleic acid-modified anti-miR-200a [LNA-200a]) for 6 months. To determine whether miR-21 downregulation provided an NRF2-independent basis for C66 protection, Nrf2-knockout diabetic mice were treated with either C66 or an inhibitor of miR-21 (locked nucleic acid-modified anti-miR-21 [LNA-21]).. Deletion of Nrf2 partially abolished diabetic nephropathy protection by C66, confirming the requirement of NRF2 for this protection. Diabetic mice, but not C66-treated diabetic mice, developed significant albuminuria, renal oxidative damage and fibrosis. C66 upregulated renal miR-200a, inhibited kelch-like ECH-associated protein 1 and induced NRF2 function, effects that were prevented by LNA-200a. However, LNA-200a only partially reduced the protection afforded by C66, suggesting the existence of miR-200a/NRF2-independent mechanisms for C66 protection. C66 was also found to inhibit diabetes induction of miR-21. Both C66 and LNA-21 produced similar reductions in miR-21, albuminuria and renal fibrosis.. The present study indicates that in addition to upregulating NRF2 by increasing miR-200a, C66 also protects against diabetic nephropathy by inhibiting miR-21.

Topics: Animals; Blood Pressure; Blotting, Western; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Heterozygote; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; NF-E2-Related Factor 2

Curcumol has recently attracted special attention due to its potential activities in many chronic disorders. Moreover, the traditional role of turmeric [Curcuma longa L. (Zingiberaceae)] in suppression of hyperglycemia is of great interest.. The present work explores the potential acute and subchronic antihyperglycemic, antinociceptive, and in vivo antioxidant effects of curcumol in alloxan-diabetic mice.. Bio-guided fractionation, column-chromatography, and GC-MS were utilized to identify the most active compound of turmeric (curcumol). Turmeric (25, 50, and 100 mg/kg), the curcumol rich fraction (CRF) (7 mg/kg), and curcumol (20, 30, and 40 mg/kg) were assessed for their acute (6 h) and subchronic (8 d) antihyperglycemic potentials and antinociceptive effects (8 weeks) were measured, using hot-plate and tail-flick latencies and von-Frey filaments method and in vivo antioxidant effects in alloxan-diabetic mice.. The most-active turmeric fraction was found to be rich in curcumol (45.5%) using GC-MS analysis method. The results proved that the highest dose levels of turmeric extract and curcumol exerted remarkable hypoglycemic activity with 41.4 and 39.3% drop in the mice glucose levels after 6 h, respectively. Curcumol (40 mg/kg) was found to be 9.4% more potent than turmeric extract (100 mg/kg) in subchronic management of diabetes. Curcumol also showed a significant improvement of peripheral nerve function as observed from the latency and tactile tests.. The antioxidant potential of curcumol may cause its ability to ameliorate diabetes and diabetes-related complications.. Curcumol, a natural metabolite with a good safety-profile, showed results comparable with tramadol in reversing diabetes-induced tactile allodynia and hyperalgesia.

Topics: Alloxan; Analgesics; Animals; Antioxidants; Biomarkers; Blood Glucose; Curcuma; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Gas Chromatography-Mass Spectrometry; Hyperalgesia; Hypoglycemic Agents; Male; Mice; Pain Threshold; Phytotherapy; Plants, Medicinal; Reaction Time; Rhizome; Sesquiterpenes; Time Factors

Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation.

Topics: Acetylation; Animals; Chromatin Immunoprecipitation; Curcumin; Diabetic Nephropathies; Histones; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; p300-CBP Transcription Factors; Real-Time Polymerase Chain Reaction

Curcumin has been observed to exhibit an anti-fibrotic effect in the liver, lung and gallbladder. However, the mechanisms underlying the cytoprotective effects of curcumin remain to be elucidated. The epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in the kidney is considered to contribute to the renal accumulation of matrix proteins associated with diabetic nephropathy. The EMT is also closely associated with the progression of renal interstitial fibrosis and oxidative stress. This process may occur through abrogation of high glucose (HG)-induced oxidative stress via activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in kidney tubular epithelial cells. In the present study, the effect of curcumin on HG-induced EMT in the NRK-52E normal rat kidney tubular epithelial cell line was investigated, and whether the effect of curcumin was mediated by the induction of Nrf2 and HO-1 expression was examined. The present study revealed that curcumin was able to prevent events associated with EMT, including the downregulation of E-cadherin and the increased expression of α-smooth muscle actin. Further analysis revealed that the expression levels of Nrf2 and HO-1 protein were elevated to a greater extent in the curcumin pretreated NRK-52E cells compared with those of the control. Notably, knockdown of Nrf2 with small interfering RNA prevented the curcumin-induced elevation in expression of HO-1 and the associated anti-fibrotic effects. In conclusion, the present findings suggested that curcumin may be significant in cellular antioxidant defense, through the activation of Nrf2 and HO-1, thereby protecting the NRK-52E cells from HG-induced EMT.

Topics: Animals; Curcumin; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Glucose; Heme Oxygenase (Decyclizing); Humans; Kidney Tubules; NF-E2-Related Factor 2; Oxidative Stress; Rats; Signal Transduction

Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Blood Glucose; Blood Urea Nitrogen; Captopril; Creatinine; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Kidney; Lipids; Male; Oxidative Stress; Peptidyl-Dipeptidase A; Rats; Rats, Wistar

Our previous studies have confirmed that the sphingosine kinase 1 (SphK1)-sphingosine 1-phosphate (S1P) signaling pathway in the kidney under diabetic conditions is closely correlated with the pathogenesis of diabetic nephropathy (DN). The activation of SphK1-S1P pathway by high glucose (HG) can increase the expression of fibronectin (FN), an important fibrotic component, in glomerular mesangial cells (GMCs) by promoting the DNA-binding activity of transcription factor AP-1. However, the mechanism responsible for the sustained activation of SphK1-S1P pathway remains unclear. Given the binding motifs for AP-1 within the first intron of the SphK1 gene, we speculated that the activated AP-1 in the kidney under HG condition possibly regulates SphK1 expression in a positive feedback manner, thereby promoting the sustained activation of SphK1-S1P pathway and mediating the pathological progression of DN. Here, we observed the effect of AP-1 on SphK1 expression in GMCs and explored the molecular mechanism involved in the sustained activation of SphK1-S1P pathway. We found two consensus binding motifs for AP-1 in the promoter sequences and non-coding region downstream of the transcriptional initiation of the rat SphK1 gene by chromatin immunoprecipitation assay. The treatment of GMCs with both HG and S1P significantly increased the protein expression of c-Jun and c-Fos, and obviously enhanced the phosphorylation of c-Jun at Ser63 and Ser73, and c-Fos at Ser32. Knockdown of c-Jun and c-Fos with siRNAs substantially inhibited the expression of SphK1 and FN, whereas overexpression of c-Jun and c-Fos significantly increased the expression of SphK1 and FN. Curcumin treatment greatly decreased the levels of c-Jun, c-Fos, SphK1, and FN in the kidney tissues of diabetic rats. SiRNAs targeting SphK1 and S1P2 receptor respectively inhibited the phosphorylation of c-Jun (ser63 and ser73) and c-Fos (ser32), as well as FN expression under both normal and HG conditions. Our data demonstrated that the activated SphK1-S1P signaling pathway in GMCs under diabetic conditions is closely associated with AP-1 to form a positive feedback loop. This positive feedback loop functions as an important molecular basis for the sustained activation of SphK1-S1P pathway and increased FN expression that lead to the initiation and progression of DN.

Topics: Animals; Binding Sites; Cells, Cultured; Curcumin; Diabetes Mellitus; Diabetic Nephropathies; DNA-Binding Proteins; Enzyme Inhibitors; Fibronectins; Glucose; JNK Mitogen-Activated Protein Kinases; Lysophospholipids; Male; Mesangial Cells; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-fos; Rats; Receptors, Lysosphingolipid; RNA Interference; RNA, Small Interfering; Signal Transduction; Sphingosine; Sweetening Agents; Transcription Factor AP-1

To determine the effect of curcumin on diabetic nephropathy in db/db mice and its possible mechanism.. Ten female db/db mice were randomly divided into 2 groups: one was treated with curcumin at 200 mg/(kg.d) and the other was a placebo group. Five age-matched db/m mice were grouped as the controls. In the curcumin group, curcumin was administered to db/db mice for 18 weeks. At the end of the experiment, the blood glucose and albumin were measured, and the kidney tissue sections were stained with PAS to observe the pathological changes. The expression of collagen IV and FN in the kidney was detected by immunohitochemistry staining. Western blot was used to detect the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and IκB in the kidney.. Compared with db/m mice, the weight and blood glucose of db/db mice were markedly increased, accompanied with heavy proteinuria, glomerulus hypertrophy, mesangial area expansion, thickening of basement membrane and ECM deposition. The phosphorylation of STAT3 was upregulated and the degradation of IκB was increased. Compared with the db/db mice, curcumin significantly decreased the urinary albumin, inhibited the phosphorylation of STAT3 and the degradation of IκB, and reduced the expression of collagen IV and FN in the kidney.. Curcumin can obviously decrease albuminuria and attenuate glomerular sclerosis in diabetic db/db mice by inhibiting phosphorylation of STAT3 and degradation of IκB.

Topics: Albuminuria; Animals; Blood Glucose; Collagen Type IV; Curcumin; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fibronectins; I-kappa B Proteins; Kidney; Mice; Phosphorylation; Proteinuria; STAT3 Transcription Factor

Inflammation is involved in the development and/or progression of diabetic nephropathy (DN). Curcumin has been reported for its anti-inflammation activity in DN. However, the mechanisms involved in the renoprotective effects of curcumin have not been clearly demonstrated. In this study, we hypothesized that curcumin affected high glucose (HG)-induced inflammation profiles in vivo and in vitro and then prevented renal injury in diabetic rats via reversing cav-1 Tyr(14) phosphorylation that influenced TLR4 activation. Streptozotocin (STZ)-induced diabetic rats received vehicle or curcumin for twelve weeks and podocytes were treated with HG in the presence or absence of curcumin in vitro. To further evaluate the effect of cav-1 phosphorylation at Tyr(14) on HG-induced podocyte inflammation response and TLR4 activation, a recombinant plasmid GFP-Cav-1 Y14F with a mutated phosphorylation site of cav-1, was transfected into cultured podocytes. In vivo, curcumin improved histological abnormalities and fibrosis of a diabetic kidney, inhibited renal inflammatory gene expression and reduced cav-1 phosphorylation at Tyr(14) and the expression of TLR4. Pretreatment of podocytes with curcumin reduced HG-stimulated production of proinflammatory cytokines, TLR4 and the phosphorylation of cav-1. But immunohistochemistry in rat kidney showed that the elevation of TLR4 expression is more evident in the renal interstitum than in the glomerulus where podocytes are located, and the possibility that the anti-inflammatory effects of curcumin on other cells in the kidney may be mediated through the same molecular pathways as in podocytes. Our study suggests that curcumin treatment ameliorates DN via inhibition of inflammatory gene expression by reversing caveolin-1 Tyr(14) phosphorylation that influenced TLR4 activation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Caveolin 1; Cells, Cultured; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Diet, Diabetic; Humans; Kidney; Male; Mutation; Phosphorylation; Podocytes; Protein Engineering; Rats; Rats, Wistar; Toll-Like Receptor 4; Tyrosine

Macrophage infiltration contributes to the pathogenesis of diabetic renal injury. However, the regulatory mechanisms between macrophage infiltration and epithelial cell activation are still unclear. Our previous study found that C66, a novel curcumin analog, was able to inhibit inflammatory cytokine expression in vitro and in vivo. This study further elucidated whether C66 can prevent glucose-induced renal epithelial activation and inflammatory macrophage infiltration by a MAPK/NF-κB medicated mechanism. Our data show that pretreatment with C66 not only significantly reduced high glucose (HG)-induced over-expressions of VCAM-1, ICAM-1 and MCP-1, but also remarkably inhibited NF-κB activation, MAPKs phosphorylation, and subsequently macrophage adhesion in renal epithelial NRK-52E cells. Furthermore, we find that MAPKs, especially JNK, play important roles in HG-induced NF-κB activation, which regulates the over-expression of adhesion molecules in HG-stimulated NRK-52E cells. A molecular docking predicted that C66 may target JNK2, which leads to its anti-inflammatory actions. In vivo, administration of C66 or JNK special inhibitor SP600125 at 5 mg/kg markedly decreased diabetes-induced renal adhesion molecule expression, NF-κB activation, inflammatory cell infiltration, and pathological indexes in the kidneys of diabetic mice. These findings provide a perspective on the renoprotective effects of C66 in diabetes, and outline a novel therapeutic strategy of JNK inhibition for the treatment of diabetic nephropathy.

Topics: Animals; Anthracenes; Cell Line; Chemokine CCL2; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Gene Expression Regulation; Intercellular Adhesion Molecule-1; Male; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; NF-kappa B; Phosphorylation; Vascular Cell Adhesion Molecule-1

Curcumin, a kind of plant polyphenolic compound, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). Podocyte can respond to various injuries including mechanical stress secondary to DN. Our previous study showed that podocyte miR-124 expression was up-regulated accompanied with podocytic adhesive capacity damage in vitro and in vivo. We hypothesized, in the present research that curcumin would ameliorate podocyte adhesion damage under mechanical stress by inhibiting miR-124 expression.. Gene expression of miR-124 was measured by real-time PCR and protein expression of integrin α3 was measured by Western blotting in STZ-induced uninephrectomized diabetic rats and cultured podocytes under mechanical stress treated with curcumin respectively. Western blot and luciferase reporter assays were used to detect the effects of miR-124 overexpression on the Itga3 expression in podocytes.. Gene expression of miR-124 was upregulated and α3 was downregulated in renal cortex of diabetic rats and cultured podocytes under mechanical stress which were ameliorated by curcumin treatment significantly. Transient co-transfection of miR-124 mimics with luciferase expression plasmids resulted in a significant repression of luciferase activity in podocytes. Mechanistically, Itga3 may be a regulation target of miR-124.. These results provide a novel idea that curcumin prevents against podocytic adhesive capacity damage under mechanical stress by inhibitting miR-124

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Adhesion; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Humans; Male; MicroRNAs; Plasmids; Podocytes; Rats; Rats, Wistar; Stress, Mechanical

There is increasing evidence indicating that inflammatory processes are involved in the development and progression of diabetic complications. However, effective anti-inflammatory treatments for patients who have diabetic complications have yet been practically identified. Curcumin is a main component of Curcuma longa with numerous pharmacological activities. Previously, we synthesized a novel curcumin analogue (B06) that exhibited an improved pharmacokinetic and enhanced anti-inflammatory activity compared to curcumin. The present study aimed to test the hypothesis that B06 may reduce high-glucose-induced inflammation and inflammation-mediated diabetic complications. In vitro, pretreatment with B06 at a concentration of 5 μM significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages. This anti-inflammatory activity of B06 is associated with its inhibition of c-Jun N-terminal kinase/nuclear factor κB activation. In vivo, despite that B06 administration at 0.2 mg · kg(-1) · d(-1) for 6 weeks did not affect the blood glucose profile of diabetic rats, the B06-treated animals displayed significant decreases in inflammatory mediators in the serum, kidney, and heart and renal macrophage infiltration. This was accompanied with an attenuation of diabetes-induced structural and functional abnormalities in the kidney and heart. Taken together, these data suggest that the novel derivative B06 might be a potential therapeutic agent for diabetic complications via an anti-inflammatory mechanism and support the potential application in diabetic complication therapy via anti-inflammatory strategy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bromobenzenes; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Glucose; Heart; Inflammation; Inflammation Mediators; Interleukin-6; JNK Mitogen-Activated Protein Kinases; Kidney; Macrophages, Peritoneal; Male; Mice; Mice, Inbred ICR; Myocardium; NF-kappa B; Pentanones; Protective Agents; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Diabetic kidney disease has been associated with the presence of lipid deposits. We assumed that curcumin, a polyphenol, would attenuate the tissue dyslipidemic condition through activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppression of sterol regulatory element-binding protein (SREBP)-1c in the kidney and would prevent renal progression in experimental type 1 diabetic rats. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in male Sprague-Dawley rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic and diabetic treated with curcumin (100 mg/kg/day) by gavage for 8 weeks. We found that curcumin decreased plasma triglyceride and the amount of renal triglyceride significantly. Furthermore, treatment of diabetic rats with curcumin increased the phosphorylation of AMPK and prevented the increased renal expression of SREBP-1c and, as a result, decreased the expression of acetyl CoA carboxylase and fatty acid synthase as well as adipose differentiation-related protein, a marker of cytoplasmic droplets. We also demonstrate that curcumin significantly suppressed the increased expression of transforming growth factor β, vascular endothelial growth factor and extracellular matrix proteins such as type IV collagen and fibronectin. In addition, curcumin treatment increased nephrin expression to near-normal levels in diabetic rats. These results demonstrated that curcumin protects against the development of diabetic nephropathy through the AMPK-SREBP pathway and the reduction of renal triglyceride accumulation which could be a possible mechanism by which curcumin preserves renal function in diabetes.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Extracellular Matrix Proteins; Fatty Acid Synthases; Kidney; Male; Membrane Proteins; Perilipin-2; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Streptozocin; Transforming Growth Factor beta; Triglycerides; Vascular Endothelial Growth Factors

Curcumin, a major polyphenol from the golden spice Curcuma longa commonly known as turmeric, has been recently discovered to have renoprotective effects on diabetic nephropathy (DN). However, the mechanisms underlying these effects remain unclear. We previously demonstrated that the sphingosine kinase 1-sphingosine 1-phosphate (SphK1-S1P) signaling pathway plays a pivotal role in the pathogenesis of DN. This study aims to investigate whether the renoprotective effects of curcumin on DN are associated with its inhibitory effects on the SphK1-S1P signaling pathway. Our results demonstrated that the expression and activity of SphK1 and the production of S1P were significantly down-regulated by curcumin in diabetic rat kidneys and glomerular mesangial cells (GMCs) exposed to high glucose (HG). Simultaneously, SphK1-S1P-mediated fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) overproduction were inhibited. In addition, curcumin dose dependently reduced SphK1 expression and activity in GMCs transfected with SphK(WT) and significantly suppressed the increase in SphK1-mediated FN levels. Furthermore, curcumin inhibited the DNA-binding activity of activator protein 1 (AP-1), and c-Jun small interference RNA (c-Jun-siRNA) reversed the HG-induced up-regulation of SphK1. These findings suggested that down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis.

Topics: Animals; Antioxidants; Cells, Cultured; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Fibronectins; Gene Expression; Glucose; JNK Mitogen-Activated Protein Kinases; Kidney; Lysophospholipids; Male; Mesangial Cells; Phosphotransferases (Alcohol Group Acceptor); Rats; Rats, Sprague-Dawley; Signal Transduction; Sphingosine; Transcription Factor AP-1; Transforming Growth Factor beta1

Inflammation is involved in the development and/or progression of many diseases including diabetic complications. Investigations on novel anti-inflammatory agents may offer new approaches for the prevention of diabetic nephropathy. Our previous bioscreening of synthetic analogues of curcumin revealed C66 as a novel anti-inflammatory compound against LPS challenge in macrophages. In this study, we hypothesized that C66 affects high glucose (HG)-induced inflammation profiles in vitro and in vivo and then prevents renal injury in diabetic rats via its anti-inflammatory actions.. Primary peritoneal macrophages (MPM), prepared from C57BL/6 mice, were treated with HG in the presence or absence of C66. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and the effects of C66 (0.2, 1.0 or 5.0 mg·kg(-1) ), administered daily for 6 weeks, on plasma TNF-α levels and expression of inflammatory genes in the kidney were assessed.. Pretreatment of MPMs with C66 reduced HG-stimulated production of TNF-α and NO, inhibited HG-induced IL-1β, TNF-α, IL-6, IL-12, COX-2 and iNOS mRNA transcription, and the activation of JNK/NF-kB signalling. In vivo, C66 inhibited the increased plasma TNF-α levels and renal inflammatory gene expression, improved histological abnormalities and fibrosis of diabetic kidney, but did not affect the hyperglycaemia in these diabetic rats.. The anti-inflammatory effects of C66 are mediated by inhibiting HG-induced activation of the JNK/NF-κB pathway, rather than by reducing blood glucose in diabetic rats. This novel compound is a potential anti-inflammatory agent and might be beneficial for the prevention of diabetic nephropathy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzylidene Compounds; Blood Glucose; Blotting, Western; Body Weight; Cell Culture Techniques; Cell Movement; Curcumin; Cyclohexanones; Cytokines; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Fibrosis; Glucose; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Organ Size; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction

We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-β1 activity-ERK1/2 pathway.. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-β1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-β1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin.. These results prove that curcumin produces dual blockade of both PKC-α and PKC-β1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.

Topics: Animals; Antioxidants; Curcumin; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Extracellular Matrix Proteins; Gene Expression Regulation; Isoenzymes; Kidney; Male; MAP Kinase Signaling System; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Phosphoproteins; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein Kinase Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Streptozocin

Curcumin has anti-inflammatory, anti-oxidant, and anti-proliferative properties, and depending upon the experimental circumstances, may be pro- or anti-apoptotic. Many of these biological actions could ameliorate diabetic nephropathy.. Mouse podocytes, cultured in basal or high glucose conditions, underwent acute exposure to curcumin. Western blots for p38-MAPK, COX-2 and cleaved caspase-3; isoelectric focusing for HSP25 phosphorylation; and DNase I assays for F- to G- actin cleavage were performed for in vitro analyses. In vivo studies examined the effects of dietary curcumin on the development of diabetic nephropathy in streptozotocin (Stz)-induced diabetes in DBA2J mice. Urinary albumin to creatinine ratios were obtained, high performance liquid chromatography was performed for urinary curcuminoid measurements, and Western blots for p38-MAPK and total HSP25 were performed.. Curcumin enhanced the phosphorylation of both p38MAPK and downstream HSP25; inhibited COX-2; induced a trend towards attenuation of F- to G-actin cleavage; and dramatically inhibited the activation of caspase-3 in vitro. In curcumin-treated DBA2J mice with Stz-diabetes, HPLC measurements confirmed the presence of urinary curcuminoid. Nevertheless, dietary provision of curcumin either before or after the induction of diabetes failed to attenuate albuminuria.. Apart from species, strain, early differences in glycemic control, and/or dosing effects, the failure to modulate albuminuria may have been due to a decrement in renal HSP25 or stimulation of the 12/15 lipoxygenase pathway in DBA2J mice fed curcumin. In addition, these studies suggest that timed urine collections may be useful for monitoring curcumin dosing and renal pharmacodynamic effects.

Topics: Actins; Albuminuria; Animals; Anti-Inflammatory Agents; Antioxidants; Caspase Inhibitors; Chromatography, High Pressure Liquid; Curcumin; Cyclooxygenase 2; Diabetic Nephropathies; Diet; HSP27 Heat-Shock Proteins; Kidney; Male; Mice; Mice, Inbred DBA; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plant Extracts; Podocytes; Signal Transduction

Diabetic nephropathy is a debilitating disease that leads to end-stage renal failure in the Western world. Hyperglycemia is the initiating factor in several chronic diabetic complications which mediates increased oxidative stress and eventually the increased production of vasoactive factors and extracellular matrix proteins. We hypothesized that curcumin, a potent antioxidant, might be beneficial in preventing the development of diabetic nephropathy because this compound has been shown to inhibit p300, a histone acetyltransferase that plays a role in regulating gene expression through its interaction with the transcription factor nuclear factor-kappaB.. To test this hypothesis, male Sprague-Dawley rats were injected with streptozotocin to induce diabetes. These animals were subsequently treated with curcumin for a period of 1 mo.. Real-time reverse transcriptase polymerase chain reaction analyses showed that diabetes-induced upregulation of vasoactive factors (endothelial nitric oxide synthase and endothelin-1), transforming growth factor-beta1 and extracellular matrix proteins (fibronectin and extradomain-B-containing fibronectin) in the kidneys. These changes were associated with increased oxidative stress, mesangial expansion, and p300 and nuclear factor-kappaB activity that were prevented with curcumin treatment.. These beneficial effects of curcumin were mediated through the inhibition of p300 and nuclear factor-kappaB.

Topics: Animals; Antioxidants; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; E1A-Associated p300 Protein; Endothelin-1; Extracellular Matrix Proteins; Kidney; Male; Mesangial Cells; NF-kappa B; Nitric Oxide Synthase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Topics: Animals; Curcumin; Diabetic Nephropathies; Dimethyl Sulfoxide; E1A-Associated p300 Protein; Ethanol; NF-kappa B; Pharmaceutical Vehicles; Phytotherapy; Rats

Curcumin has been used to treat cancer, diabetes and other pathologies. However, little is known regarding its role in altering post-translational modifications of histone H3. A recent report suggests that acute hyperglycaemia induces a global down-regulation of gene expression in human tissues and epigenetic regulation of gene expression could be a novel mechanism underlying the pathological processes of hyperglycaemia. The present study was undertaken to examine changes in histone modification by curcumin treatment which prevents development of type I diabetic nephropathy.. Male Sprague-Dawley rats were rendered diabetic using a single dose of streptozotocin (55 mg kg(-1), i.p.). Diabetic nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Post-translational modifications of histone H3, heat shock protein-27 (HSP-27) and mitogen-activated protein (MAP) kinase p38 expression were examined by western blotting.. Treatment of diabetic rats with curcumin significantly decreased blood urea nitrogen and creatinine and increased albumin; variables associated with the development of diabetic nephropathy. There were also increased levels of HSP-27 and MAP kinase (p38) in diabetic kidney. However, curcumin treatment prevented this increase in HSP-27 and p38 expression. Moreover, at nuclear level curcumin prevented the decrease in dephosphorylation and increases acetylation of histone H3.. Our results suggested that protection against development of diabetic nephropathy by curcumin treatment involved changes in post-translational modifications of histone H3, expression of HSP-27 and MAP kinase p38 in diabetic kidney.

Topics: Animals; Antioxidants; Blotting, Western; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Expression Regulation; Heat-Shock Proteins; Histones; Male; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Streptozocin

Chronic hyperglycaemia in diabetes leads to the overproduction of free radicals and evidence is increasing that these contribute to the development of diabetic nephropathy. Among the spices, turmeric (Curcuma longa) is used as a flavouring and colouring agent in the indian diet every day and is known to possess anti-oxidant properties. The present study was designed to examine the effect of curcumin, a yellow pigment of turmeric, on renal function and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. Four weeks after STZ injection, rats were divided into four groups, namely control rats, diabetic rats and diabetic rats treated with curcumin (15 and 30 mg/kg, p.o.) for 2 weeks. Renal function was assessed by creatinine, blood urea nitrogen, creatinine and urea clearance and urine albumin excretion. Oxidative stress was measured by renal malonaldehyde, reduced glutathione and the anti-oxidant enzymes superoxide dismutase and catalase. Streptozotocin-injected rats showed significant increases in blood glucose, polyuria and a decrease in bodyweight compared with age-matched control rats. After 6 weeks, diabetic rats also exhibited renal dysfunction, as evidenced by reduced creatinine and urea clearance and proteinuria, along with a marked increase in oxidative stress, as determined by lipid peroxidation and activities of key anti-oxidant enzymes. Chronic treatment with curcumin significantly attenuated both renal dysfunction and oxidative stress in diabetic rats. These results provide confirmatory evidence of oxidative stress in diabetic nephropathy and point towards the possible anti-oxidative mechanism being responsible for the nephroprotective action of curcumin.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Catalase; Curcuma; Curcumin; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Evaluation, Preclinical; Glutathione; Kidney; Malondialdehyde; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Survival Rate