curcumin and Diabetes-Mellitus--Type-1

Diabetes mellitus is one of the most prevalent chronic diseases in the world; one of its main characteristics is chronic hyperglycemia. Pharmacotherapy and other alternatives such as regular exercise are among the therapeutic methods used to control this pathology and participate in glycemic control, as well as the ingestion of plant extracts with antioxidant effects. Among the different plants used for this purpose, curcumin has potential to be used to attenuate the hyperglycemic condition triggered by diabetes mellitus (DM). Some prior studies suggest that this plant has antioxidant and hypoglycemic potential. This review aims to evaluate the antioxidant and hypoglycemic potential of curcumin supplementation in Type 1 DM (T1DM) and Type 2 DM (T2DM). The search considered articles published between 2010 and 2019 in English and Portuguese, and a theoretical survey of relevant information was conducted in the main databases of scientific publications, including the Virtual Health Library and its indexed databases, PubMed, LILACS (Latin American and Caribbean Literature on Health Sciences-Health Information for Latin America and the Caribbean-BIREME/PAHO/WHO), and Scientific Electronic Library Online (SciELO). The associated use of turmeric and physical exercise has demonstrated antioxidant, anti-inflammatory, and hypoglycemic effects, suggesting that these could be used as potential therapeutic methods to improve the quality of life and survival of diabetic patients.

Topics: Animals; Antioxidants; Blood Glucose; Combined Modality Therapy; Curcuma; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Supplements; Disease Models, Animal; Exercise Therapy; Humans; Hypoglycemic Agents; Plant Extracts; Quality of Life; Treatment Outcome

Oxidative stress and endoplasmic reticulum (ER) stress play crucial roles in pancreatic β cell destruction, leading to the development and progression of type 1 diabetes mellitus (T1DM). Curcumin, extracted from plant turmeric, possesses multiple bioactivities such as antioxidant, anti-inflammatory and anti-apoptosis properties and . However, it remains unknown whether curcumin improves ER stress to prevent β cells from apoptosis. In this study, we aim to investigate the role and mechanism of curcumin in ameliorating HO-induced injury in MIN6 (a mouse insulinoma cell line) cells. Cell viability is examined by CCK8 assay. Hoechst 33258 staining, TUNEL and flow cytometric assay are performed to detect cell apoptosis. The relative amounts of reactive oxygen species (ROS) are measured by DCFH-DA. WST-8 is used to determine the total superoxide dismutase (SOD) activity. Protein expressions are determined by western blot analysis and immunofluorescence staining. Pretreatment with curcumin prevents MIN6 cells from HO-induced cell apoptosis. Curcumin decreases ROS generation and inhibits protein kinase like ER kinase (PERK)-C/EBP homologous protein (CHOP) signaling axis, one of the critical branches of ER stress pathway. Moreover, incubation with curcumin activates silent information regulator 1 (SIRT1) expression and subsequently decreases the expression of CHOP. Additionally, EX527, a specific inhibitor of SIRT1, blocks the protective effect of curcumin on MIN6 cells exposed to HO. In sum, curcumin inhibits the PERK-CHOP pathway of ER stress mediated by SIRT1 and thus ameliorates HO-induced MIN6 cell apoptosis, suggesting that curcumin and SIRT1 may provide a potential therapeutic approach for T1DM.

Topics: Animals; Apoptosis; Curcumin; Diabetes Mellitus, Type 1; Endoplasmic Reticulum Stress; Insulin-Secreting Cells; Mice; Reactive Oxygen Species; Sirtuin 1; Transcription Factor CHOP

This experimental study examined the effects of curcumin-loaded iron oxide nanoparticles (CUR), photobiomodulation (PBM), and CUR + PBM treatments on mast cells (MC)s numbers and degranulation, inflammatory cells (macrophages, neutrophils), and wound strength in the last step of the diabetic wound repair process (maturation phase) in a rat model of type one diabetes mellitus (T1DM). T1DM was induced in 24 rats, and 1 month later, an excisional wound was created on each rat's back skin. The rats were then distributed into four groups: (1) untreated diabetic control group (UDCG); (2) rats treated with CUR (CUR); (3) rats exposed to PBM (890 nm, 80 Hz, 0.2 J/cm

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Humans; Low-Level Light Therapy; Magnetic Iron Oxide Nanoparticles; Rats; Rats, Wistar; Wound Healing

Cardiac inflammation is an important pathological process in diabetic cardiomyopathy (DCM). Curcumin is a natural compound found in the rhizome of Curcuma longa and has been shown to possess multifunctional bioactivities. In the present study, we identified a new curcumin-derived compound, JM-2, and investigated its therapeutic effects against DCM in mouse models of streptozotocin-induced type 1 diabetes mellitus (T1DM) and HFD-induced type 2 diabetes (T2DM). Treatment with JM-2 (10 mg/kg) prevented cardiac functional and structural deficits effectively and reduced cardiac inflammation and fibrosis. JM-2 administration attenuated DCM by inhibiting nuclear factor kappa-B (NF-κB) activation in the heart of both models. In addition, treatment with JM-2 completely prevented the increase in proinflammatory factors and macrophage infiltration in T1DM and T2DM mice. RNA-seq analysis showed that the anti-inflammatory activity of JM-2 was associated with the inhibition of NF-κB activation. In vitro, JM-2 suppressed high glucose (HG)-induced myocardial hypertrophy and fibrosis in H9c2 cells, accompanied by inhibition of HG-induced NF-κB activation. Collectively, our results showed that JM-2, a new curcumin analog, provides strong protection against DCM via inhibition of the NF-κB-mediated inflammation. In summary, our data suggest that the curcumin analog JM-2 may be a potential therapeutic agent for DCM.

Topics: Animals; Curcumin; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Mice; Myocytes, Cardiac; NF-kappa B

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the main pathogens that cause infections in diabetic individuals. In this paper, we report the outcomes of our investigation on the intradermal application of antimicrobial photodynamic therapy (PDT) with curcumin in an infection induced by MRSA ATCC 43300 strain in the ear of mice with Type 1 Diabetes Mellitus (T1DM). A solution containing 100 μg of curcumin was photoactivated ex vivo with a LED light (450 nm) delivering a fluency of 13.5 J/cm

Topics: Animals; Biomarkers; Curcumin; Diabetes Mellitus, Type 1; Inflammation Mediators; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Photochemotherapy; Pilot Projects; Skin Diseases, Bacterial; Staphylococcal Infections; Streptozocin

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biocompatible Materials; Cells, Cultured; Curcumin; Diabetes Mellitus, Type 1; Drug Liberation; Humans; Hyaluronic Acid; Hydrogels; Hypoglycemic Agents; Male; Materials Testing; Mice; Mice, Inbred BALB C; Molecular Structure; Peptides; Phenylalanine; Streptozocin; Wound Healing

Topics: Animals; Blood Glucose; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiotonic Agents; Curcumin; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Drug Therapy, Combination; Hypoglycemic Agents; Interleukin-6; Male; Myocardium; NF-kappa B; Oxidative Stress; Pioglitazone; PPAR gamma; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Type 1 diabetes is a chronic autoimmune disease of beta cells in the islets of Langerhans, which are responsible for making insulin. Even with insulin therapy, inflammatory complications will develop in the long term. The present study examines changes in serum levels of interleukin (IL)-6, IL-17, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, C-peptide, Insulin as well as fasting blood sugar (FBS) in control, diabetic and diabetic treated with curcumin groups. Thirty inbred C57BL /6 mice were randomly divided into three groups of 10 mice: group A consisted of healthy mice receiving citrate buffer, group B included a group of diabetic mice, and group C was a group of diabetic mice treated with curcumin. The cytokine levels were measured in the supernatant of stimulated splenocytes using enzyme -linked immunosorbent assay (ELISA). Radioimmunoassay was used to measure insulin and c-peptide levels. The FBS was measured by an automatic glucometer device. The levels of IL-6, IL-17, and IFN-γ, as well as FBS, was significantly decreased in the treated group with curcumin compared to the diabetic group mice (p<0.05). TNF-α levels were also low, but the difference was not significant. IL-10, plasma C-peptide, and insulin significantly increased in the supernatant of stimulated splenocytes of treated diabetic group than in the diabetic group (p<0/05). According to the results, this study supports the anti-diabetic and anti-inflammatory effects of curcumin; however, more studies are needed to investigate theeffects of curcumin and the dose-response relationship in this disease.

Topics: Animals; Anti-Inflammatory Agents; C-Peptide; Cells, Cultured; Curcumin; Cytokines; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Humans; Inflammation Mediators; Insulin; Mice; Mice, Inbred C57BL; Spleen

An important obstacle on the way of cell-based therapy is the risk of tumorigenicity in the patients benefit from these transplanted cells due to undifferentiated cells which participate in transplantation. Curcumin, the main compound of spice turmeric -as one of the natural products-was demonstrated to possess effective anti-cancer properties, with no significant effect on normal cells in dose and/or time-dependent manner. Furthermore many studies have been accomplished using curcumin for diabetes treatment. Therefore in this study we examined the efficacy of IPCs treated with curcumin in vivo.. Differentiation efficiency investigated by flowcytometry. RNA extraction and real-time PCR performed for important genes in IPC differentiation and tumorigenesis including Insulin, Nestin, Ngn3, Pdx1, P21, and P53. Finally we investigated the efficiency of these differentiated and treated cells in diabetic rats.. Our data indicates that nanocurcumin -in a specific dose-reduces the expression of Nestin with no significant effect on insulin expression in mRNA and protein level. Besides blood glucose level of diabetic rats which treated with DNC + cells, decreased from average 350 (mg/dI) to 100 (mg/dI). Checking out the pancreases of these rats, demonstrated that their endocrine segment was rebuilt. Moreover hematoxylin & eosin staining and IF results revealed that the Langerhans Islands were reformed.. IPCs' which treated with DNC were able to efficiently control the blood glucose level in diabetic rats which these cells were transplanted to them. Hence Curcumin has the potential to be employed in this kind of cell therapy.

Topics: Animals; Blood Glucose; Cell Differentiation; Cell- and Tissue-Based Therapy; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pancreas; Rats; Rats, Wistar

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

Management of diabetic wounds remains a major challenge in the medical field, mostly due to incompetent outcomes of treatments. Curcumin has been documented as anti-inflammatory, antioxidant, antimicrobial and antineoplastic agent in addition to wound healing activities. However, its poor aqueous solubility and impaired skin permeation handicap its topical pharmaceutical usage. Hydrogel loaded curcumin nanoparticle (Cur-NP/HG) could overcome this pitfall and enable extended topical delivery of curcumin. Rat model of diabetes mellitus (DM) type I was induced using single injection of 70mg/kg streptozotocin (STZ) followed by full thickness skin wound. Rats were divided into 4 groups. GpI: control non-diabetic, GpII: diabetic non-treated, GpIII: diabetic treated with topical curcumin hydrogel (Cur/HG) and GpIV: diabetic treated with topical Cur-NP/HG. Histological assessment of epidermal regeneration, dermo-epidermal junction, leukocyte infiltration and collagen deposition, in addition to immunohistochemical staining for vascular endothelial growth factor (VEGF) and aquaporin-3 (AQP3) were performed. Diabetic rat possessed impaired wound closure, persistence of inflammation and decreased collagen deposition as compared to non-diabetic control. Application of Cur/HG induced partial improvement of the healing process in diabetic rats. Cur-NP/HG treatment provoked obvious improvement of the healing process with complete re-epithelization, intact dermo-epidermal junction, reorganization of the dermis with significantly increased collagen deposition and VEGF and AQP3 expression. These results illustrated that Cur-NP/HG have effectively improved the healing process in diabetic skin wound with substantial differences in the wound healing kinetics compared to wounds that received Cur/HG.

Topics: Administration, Topical; Animals; Aquaporin 3; Collagen; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Epithelium; Hydrogels; Immunohistochemistry; Male; Nanoparticles; Rats; Regeneration; Skin; Vascular Endothelial Growth Factor A; Wound Healing

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiotonic Agents; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Synergism; Heart; Heme Oxygenase-1; Janus Kinases; Male; Membrane Proteins; Metformin; Myocardium; NF-E2-Related Factor 2; Rats; Rats, Wistar; STAT Transcription Factors; Treatment Outcome

Curcumin (cur) is a well known plant flavonoid with pleiotropic pharmacological activities. However, due to its poor bioavailability those therapeutic benefits are still out of reach for patient community. The main aim of our study was to prepare sustained release cur microparticles (CuMPs) with Poly (lactic-co-glycolic acid) (PLGA), an FDA approved biodegradable polymer and to assess their pharmacological potential in multiple low doses streptozotocin (MLD-STZ) induced type 1 diabetes mellitus (T1DM). CuMPs were formulated and characterized for size (12.71 ± 4.20 μm) and encapsulation efficiency (85.10 ± 2.33%) with 28% drug loading. In vitro release and in vivo pharmacokinetics studies showed promising results of sustained release of cur from CuMPs. With this here we report a strategy that single administration of CuMPs may fill the therapeutic window that is missing from free drug repeated administration and low bioavailability of cur. Moving forward with this concept, we compared the therapeutic effects of CuMPs (equivalent to 7.5 mg/kg cur with free cur orally (100 mg/kg) and intraperitoneally (7.5 mg/kg) administered daily in MLD-STZ challenged animals). CuMPs exhibited superior effects compared to daily administration free drug given either orally or i.p. in terms of lowering the blood glucose levels, improved glucose clearance as evident from results of i.p. glucose tolerance test (IPGTT). Interestingly, we observed a remarkable reduction in diabetes incidence in CuMPs groups (only one out of six animals i.e. 16.6%). Moreover, plasma and tissue levels of insulin indicated superior effect of CuMPs. In addition, immunohistochemical analysis of insulin in pancreatic β-cells further confirmed the improved therapeutic benefit with significant increase in insulin signal with CuMPs. Amelioration of oxidative stress and inflammation of CuMPs was observed as the molecular mechanism behind the observed superior pharmacological effects with CuMPs. Cumulatively, our sustained release CuMPs formulation may serve as a bridge in overcoming the poor pharmacokinetics issues associated with cur and may hasten the clinical translation of cur.

Topics: Animals; Blood Glucose; Curcumin; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Male; Mice; Microspheres; Oxidative Stress; Particle Size; Random Allocation; Rats; Rats, Sprague-Dawley

We examined the effects of photobiomodulation (PBM) independently and combined with curcumin on stereological parameters and basic fibroblast growth factor (bFGF), hypoxia-inducible factor-1α (HIF-1α), and stromal cell-derived factor-1α (SDF-1α) gene expressions in an excisional wound model of rats with type one diabetes mellitus (T1DM). T1DM was induced by an injection of streptozotocin (STZ) in each of the 90 male Wistar rats. One round excision was generated in the skin on the back of each of the 108 rats. The rats were divided into six groups (n = 18 per group): control (diabetic), untreated group; vehicle (diabetic) group, which received sesame oil; PBM (diabetic) group; curcumin (diabetic) group; PBM + curcumin (diabetic) group; and a healthy control group. On days 4, 7, and 15, we conducted both stereological and quantitative real-time PCR (qRT-PCR) analyses. The PBM and PBM + curcumin groups had significantly better inflammatory response modulation in terms of macrophages (P < .01), neutrophils (P < .001), and increased fibroblast values compared with the other groups at day 4 (P < .001), day 7 (P < .01), and day 15 (P < .001). PBM treatment resulted in increased bFGF gene expression on days 4 (P < .001) and 7 (P < .001), and SDF-1α gene expression on day 4 (P < .001). The curcumin group had increased bFGF (P < .001) expression on day 4. Both the PBM and PBM + curcumin groups significantly increased wound healing by modulation of the inflammatory response, and increased fibroblast values and angiogenesis. The PBM group increased bFGF and SDF-1α according to stereological and gene expression analyses compared with the other groups. The PBM and PBM + curcumin groups significantly increased the skin injury repair process to more rapidly reach the proliferation phase of the wound healing in T1DM rats.

Topics: Analysis of Variance; Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fibroblasts; Gene Expression Regulation; Low-Level Light Therapy; Macrophages; Neovascularization, Physiologic; Rats, Wistar; Wound Healing

The aim of the present study was to determine the effects of curcumin on antioxidants using a rat model of type 1 diabetes. Seven‑week‑old male Sprague‑Dawley rats were injected with Streptozotocin (STZ) intraperitoneally to induce this model, and then treated with 1.0% curcumin (weight ratio) mixed in their diet for 21 days. The present study included three groups: Control group (NC), diabetic rat model group (DC) and a curcumin treated group (Diab‑Cur). The results demonstrated that curcumin treatment markedly decreased the blood glucose levels, plasma malondialdehyde concentration and plasma activity of glutathione peroxidase (GSH‑Px) and catalase (CAT); however, it increased the plasma superoxide dismutase (SOD) and insulin levels. Curcumin treatment increased the expression of the CAT, GSH‑Px, HO‑1 and norvegicus NAD(P)H quinone dehydrogenase 1, and decreased the SOD1 expression, which, led to a diminished oxidative stress status. In addition, curcumin treatment significantly increased the protein expression of Keap1 in the Diab‑Cur group when compared with the DC group, decreased cytosolic concentrations of Nrf2 while increasing nuclear accumulation of Nrf2. The results provide evidence that oxidative stress in the STZ‑induced diabetic rat model may be attenuated by curcumin via the activation of the Keap1‑Nrf2‑ARE signaling pathway, as evidenced by a decrease in the blood glucose concentration and an increase in the transcription of several antioxidant genes.

Topics: Animals; Antioxidants; Biomarkers; Catalase; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Glutathione Peroxidase; Glycogen; Liver; Male; Malondialdehyde; Oxidative Stress; Rats; Superoxide Dismutase

Approaches to prevent selective and progressive loss of insulin-producing beta cells in Type 1 diabetes mellitus (T1DM) will help to manage this prevalent and devastating disease. Curcumin (CUR), a natural anti-inflammatory substance, suppresses diabetes-associated inflammation and cell death. However, very high doses need to be used because of poor oral bioavailability, making it difficult to translate the anti-inflammatory actions to clinical situations.. We have prepared biodegradable nanosystems encapsulating curcumin (nCUR), resulting in at least nine-fold improvement in oral bioavailability. Here, we tested the ability of nCUR to prevent streptozotocin (STZ)-induced inflammation and apoptosis in pancreatic islets and beta cells, in rats.. Non-fasted rats pretreated with 10 or 50 mg·kg. Together, these data indicate a potentially translatable dose of nCUR that is safe and efficacious in improving beta cell function, which could prevent T1DM.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Curcumin; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Inflammation; Insulin-Secreting Cells; Male; Nanostructures; Rats; Rats, Sprague-Dawley; Streptozocin; Structure-Activity Relationship

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is a lethal autoimmune disease caused by mutations in the Foxp3 gene scurfin (scurfy). Immunosuppressive therapy for IPEX patients has been generally ineffective and has caused severe side effects, however curcumin has shown immune regulation properties for inflammatory diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel diseases without side effects.. The aim of this study was to investigate whether curcumin would attenuate symptoms of IPEX in mouse model and would prolong its survival period.. C57BL/6 mice were separated into scurfy or wild-type litter mate groups by genotyping, and each group subsequently was separated into 2 subgroups that were fed a 1% curcumin containing or normal diet from the last day of breast-feeding. After weaning, pups were fed either a 1% curcumin containing or normal diet until all scurfy mice die for survival data. To elucidate immune cell proportions in spleen and lymph nodes, cells were analyzed by flowcytometry. Cellular cytokine production was accessed to investigate the effects of curcumin in T cell differentiation in vitro.. Scurfy mice fed a 1% curcumin diet survived 4.0-fold longer compared to scurfy (92.5 days) mice fed a normal diet (23 days). A curcumin diet decreased all of the Th1/Th2/Th17 cell populations and attenuated diverse symptoms such as splenomegaly in scurfy mice. In vitro experiments showed that curcumin treatment directly decreased the Th1/Th2/Th17 cytokine production of IFN-γ, IL-4, and IL-17A in CD4. Curcumin diet attenuated the scurfy-induced immune disorder, a model of IPEX syndrome, by inhibiting Th1/Th2/Th17 responses in mice. These results have implications for improving clinical therapy for patients with IPEX and other T cell related autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Curcumin; Diabetes Mellitus, Type 1; Diarrhea; Diet; Disease Models, Animal; Genetic Diseases, X-Linked; Immune System Diseases; Interleukin-17; Interleukin-4; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Th1 Cells; Th17 Cells; Th2 Cells

Introduction. Impaired wound-healing in diabetics can lead to life-threatening complications, such as limb amputation, associated in part with excessive matrix metalloproteinase- (MMP-) mediated degradation of collagen and other matrix constituents. In the current study, a novel triketonic chemically modified curcumin, CMC2.24, was tested for efficacy in healing of standardized skin wounds in streptozotocin-induced diabetic rats. Initially, CMC2.24 was daily applied topically at 1% or 3% concentrations or administered systemically (oral intubation; 30 mg/kg); controls received vehicle treatment only. Over 7 days, the diabetics exhibited impaired wound closure, assessed by gross and histologic measurements, compared to the nondiabetic controls. All drug treatments significantly improved wound closure with efficacy ratings as follows: 1% 2.24 > systemic 2.24 > 3% 2.24 with no effect on the severe hyperglycemia. In subsequent experiments, 1% CMC2.24 "normalized" wound-healing in the diabetics, whereas 1% curcumin was no more effective than 0.25% CMC2.24, and the latter remained 34% worse than normal. MMP-8 was increased 10-fold in the diabetic wounds and topically applied 1% (but not 0.25%) CMC2.24 significantly reduced this excessive collagenase-2; MMP-13/collagenase-3 did not show significant changes. Additional studies indicated efficacy of 1% CMC2.24 over more prolonged periods of time up to 30 days.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Blood Glucose; Case-Control Studies; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Male; Matrix Metalloproteinase 8; Rats; Rats, Sprague-Dawley; Wound Healing; Wounds and Injuries

What is the central question of this study? We sought to examine whether curcumin could ameliorate skeletal muscle atrophy in diabetic mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. What is the main finding and its importance? We found that curcumin ameliorated skeletal muscle atrophy in streptozotocin-induced diabetic mice by inhibiting protein ubiquitination without affecting protein synthesis. This favourable effect of curcumin was possibly due to the inhibition of inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type 1 diabetes mellitus. Skeletal muscle atrophy develops in patients with diabetes mellitus (DM), especially in type 1 DM, which is associated with chronic inflammation. Curcumin, the active ingredient of turmeric, has various biological actions, including anti-inflammatory and antioxidant properties. We hypothesized that curcumin could ameliorate skeletal muscle atrophy in mice with streptozotocin-induced type 1 DM. C57BL/6 J mice were injected with streptozotocin (200 mg kg(-1) i.p.; DM group) or vehicle (control group). Each group of mice was randomly subdivided into two groups of 10 mice each and fed a diet with or without curcumin (1500 mg kg(-1) day(-1)) for 2 weeks. There were significant decreases in body weight, skeletal muscle weight and cellular cross-sectional area of the skeletal muscle in DM mice compared with control mice, and these changes were significantly attenuated in DM+Curcumin mice without affecting plasma glucose and insulin concentrations. Ubiquitination of protein was increased in skeletal muscle from DM mice and decreased in DM+Curcumin mice. Gene expressions of muscle-specific ubiquitin E3 ligase atrogin-1/MAFbx and MuRF1 were increased in DM and inhibited in DM+Curcumin mice. Moreover, nuclear factor-κB activation, concentrations of the inflammatory cytokines tumour necrosis factor-α and interleukin-1β and oxidative stress were increased in the skeletal muscle from DM mice and inhibited in DM+Curcumin mice. Curcumin ameliorated skeletal muscle atrophy in DM mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type 1 DM.

Topics: Animals; Antioxidants; Body Weight; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Gene Expression; Insulin; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Oxidative Stress; Signal Transduction; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases; Ubiquitination

One of the major obstacles needed to be overcome before using cell therapy for clinical purposes is the high probability of tumor formation in patients who receive the transplants, as undifferentiated stem cells (SCs) have the potential to form teratomas/teratocarcinoma in xenotransplants. In this study the ability of dendrosomal nanocurcumin (solublized curcumin using a biodegradable non-toxic nano-carrier) to affect undifferentiated/hazardous cell, and hence increasing the safety of cell therapy (particularly in diabetes type I) by mesenchymal stem cells (MSCs) was examined. The results showed that after completion of differentiation of human mesenchymal stem cells (hMSCs) into insulin producing cells (IPCs), the expression level of insulin increases, although there remains a minority of undifferentiated cells which still express nestin (gene which is expressed in progenitor stem cells of IPCs). It indicates the emergence of a heterogeneous population containing undifferentiated and differentiated cells. Furthermore our data demonstrated that the expression level of p53 decreases during differentiation of hMSCs into IPCs which implies a more favorable microenvironment for tumor formation following the transplantation of such a heterogeneous population. After treatment with dendrosomal nanocurcumin, nestin expression eliminated, however no significant effect on the expression and secretion of insulin was observed. Together our data shows that dendrosomal nanocurcumin have the ability to affect residual undifferentiated stem cells after the completion of differentiation of MSCs induced to differentiate into IPCs; while it exerts no significant harmful effect on the survival and function of differentiated cells. With regard to the obtained results in this study, exploiting dendrosomal nanocurcumin, after completion of induced differentiation of stem cells and prior to the transplantation step, can be suggested as a very efficient, safe and cost-effective method to eliminate the residual undifferentiated stem cells in cell therapy practices in order to considerably decrease the risk of tumor development following transplantation.

Topics: Adult; Cell Differentiation; Cell- and Tissue-Based Therapy; Curcumin; Diabetes Mellitus, Type 1; Female; Humans; Male; Mesenchymal Stem Cells

Type 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic β cells. The only possible cure for T1DM is to control autoimmunity against β cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down-regulate the T cell response that destroys pancreatic β cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factor for proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for β cell death.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen Presentation; Antioxidants; Cells, Cultured; Curcumin; Dendritic Cells; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Interferon-gamma; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; NF-kappa B; T-Box Domain Proteins; Th1 Cells; Transcriptional Activation

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.

Topics: Animals; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Fibrosis; Glutathione Peroxidase; Heart Ventricles; Hemodynamics; Hyperglycemia; Lipid Peroxidation; Male; Myocytes, Cardiac; Oxidative Stress; Protein Kinase Inhibitors; Protein Kinases; Rats; Rats, Sprague-Dawley

Matrix metalloproteinases (MMPs) are essential for the degradation and turnover of components of the extracellular matrix (ECM) and, when pathologically elevated, mediate connective tissue loss (including bone destruction) in various inflammatory and other diseases. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of Doxycycline are FDA-approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. Because the C-11/ C-12 diketonic moiety of the tetracyclines is primarily responsible, through zinc-binding, for MMP inhibition, we have uniquely modified curcumin as a "core" molecule, since it contains a similar enolic system and is known to have beneficial effects in diseases where connective-tissue loss occurs. Specifically we have developed new congeners which exhibit improved zinc-binding and solubility, and potent reduction of excessive MMP levels and activity. We now describe a series of curcuminoid bi- and tri-carbonylmethanes in which all of these properties are substantially improved. An N-phenylaminocarbonyl derivative of bis-demethoxycurcumin (CMC2.24) was selected as the "lead" substance because it showed superior potency in vitro (i.e., the lowest IC(50)) against a series of neutral proteases (MMPs) associated with tissue erosion. Moreover, CMC2.24 administered to diabetic rats orally (30mg/kg), reduced the secretion of pathologically-excessive levels of MMP-9 to normal in cultured peritoneal macrophages with no evidence of toxicity. Thus, this (and other similar novel) compound(s) may be useful in various diseases of connective-tissue loss.

Topics: Animals; Cell Line; Cells, Cultured; Curcumin; Diabetes Mellitus, Type 1; Drug Design; Humans; Macrophages, Peritoneal; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Rats; Rats, Sprague-Dawley

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

This study examined the hypothesis that curcumin supplementation decreases blood levels of IL-6, MCP-1, TNF-alpha, hyperglycemia, and oxidative stress by using a cell-culture model and a diabetic rat model. U937 monocytes were cultured with control (7 mM) and high glucose (35 mM) in the absence or presence of curcumin (0.01-1 microM) at 37 degrees C for 24 h. Diabetes was induced in Sprague-Dawley rats by injection of streptozotocin (STZ) (i.p., 65 mg/kg BW). Control buffer, olive oil, or curcumin (100 mg/kg BW) supplementation was administered by gavage daily for 7 weeks. Blood was collected by heart puncture with light anesthesia. Results show that the effect of high glucose on lipid peroxidation, IL-6, IL-8, MCP-1, and TNF-alpha secretion was inhibited by curcumin in cultured monocytes. In the rat model, diabetes caused a significant increase in blood levels of IL-6, MCP-1, TNF-alpha, glucose, HbA(1), and oxidative stress, which was significantly decreased in curcumin-supplemented rats. Thus, curcumin can decrease markers of vascular inflammation and oxidative stress levels in both a cell-culture model and in the blood of diabetic rats. This suggests that curcumin supplementation can reduce glycemia and the risk of vascular inflammation in diabetes.

Topics: Animals; Blood Glucose; Chemokine CCL2; Curcumin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucose; Glycated Hemoglobin; Humans; Interleukin-6; Interleukin-8; Male; Monocytes; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; U937 Cells

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