curcumin and Sepsis

Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host immune response to an infection. Curcumin is a yellow polyphenol derived from the rhizome of Curcuma longa with anti-inflammatory and antioxidant properties scientifically proven, a condition that allowed its use as a tool in the treatment of sepsis. Thus, the purpose of this article was to systematically review the evidence on the impact of curcumin's anti-inflammatory effect on experimental sepsis.. For this, the PubMed, MEDLINE, EMBASE, Scopus, Web of Science, and LILACS databases were used, and the research was not limited to a specific publication period. Only original articles in English using

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcumin; Mice; Oxidative Stress; Rats; Sepsis

Primary and secondary immunodeficiencies cause an alteration in the immune response which can increase the rate of infectious diseases and worsened prognoses. They can also alter the immune response, thus, making the infection even worse. Curcumin is the most biologically active component of the turmeric root and appears to be an antimicrobial agent. Curcumin cooperates with various cells such as macrophages, dendritic cells, B, T, and natural killer cells to modify the body's defence capacity. Curcumin also inhibits inflammatory responses by suppressing different metabolic pathways, reduces the production of inflammatory cytokines, and increases the expression of anti-inflammatory cytokines. Curcumin may also affect oxidative stress and the non-coding genetic material. This review analyses the relationships between immunodeficiency and the onset of infectious diseases and discusses the effects of curcumin and its derivatives on the immune response. In addition, we analyse some of the preclinical and clinical studies that support its possible use in prophylaxis or in the treatment of infectious diseases. Lastly, we examine how nanotechnologies can enhance the clinical use of curcumin.

Topics: Communicable Diseases; Curcumin; Cytokines; Humans; Immunity; Sepsis

Sepsis is a complex disease that begins with an infectious disorder and causes excessive immune responses. Curcumin is considered as an active component of turmeric that can improve the condition in sepsis due to its anti-inflammatory and antioxidant properties. PubMed, Embase, Google Scholar, Web of Science, and Scopus databases were searched. Searching was not limited to a specific publication period. Only English-language original articles, which had examined the effect of curcumin on sepsis, were included. At first, 1,098 articles were totally found, and 209 articles were selected after excluding duplicated data; 46 articles were remained due to the curcumin effects on sepsis. These included 23 in vitro studies and 23 animal studies. Our results showed that curcumin and various analogs of curcumin can have an inhibitory effect on sepsis-induced complications. Curcumin has the ability to inhibit the inflammatory, oxidative coagulation factors, and regulation of immune responses in sepsis. Despite the promising evidence of the therapeutic effects of curcumin on the sepsis complication, further studies seem necessary to investigate its effect and possible mechanisms of action in human studies.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcuma; Curcumin; Drug Evaluation, Preclinical; Humans; Phytotherapy; Sepsis; Signal Transduction

The intention of this article is to review endotoxin, host response to endotoxin, clinical significance of endotoxemia, past failed therapies targeting endotoxin, current therapeutic efforts in this area and the authors' opinion on the future of such therapy.. Endotoxin or lipopolysaccharide is implicated in the activation of cytokine release with the potential to lead to severe sepsis. Therapies targeting endotoxin are very appealing and remain a matter of study and debate. Antiendotoxin antibody studies did not show consistent benefit to warrant its approval for use. Lipid A analog, phospholipid emulsion, and ethyl pyruvate are currently being evaluated for potential clinical use. Polymyxin B as an antiendotoxin strategy has an unacceptable toxicity profile for routine use as an intravenous agent and its use in plasmapheris is too cumbersome. Curcumin and lipopolysaccharide binding peptides, although having a potentially desirable effect on ameliorating endotoxin toxicity, remain to be shown effective in clinical trials. The development of a vaccine against endotoxin carries promise.. The benefits of therapies targeting endotoxin remain to be elucidated. Clinical trials targeting populations with documented endotoxemia are more likely to provide an adequate test of this therapeutic approach. Prophylaxis of high-risk populations should also be considered.

Topics: Antibodies, Bacterial; Antimicrobial Cationic Peptides; Bacterial Vaccines; Cathelicidins; Curcumin; Emulsions; Endotoxemia; Endotoxins; Humans; Incidence; Lipopolysaccharides; Phospholipids; Pyruvates; Sepsis

Sepsis is the final common pathway to death for severe infectious diseases worldwide. The present trial aimed to investigate the effects of nano-curcumin supplementation on hematological indices in critically ill patients with sepsis. Fourteen ICU-admitted patients were randomly allocated into either nano-curcumin or placebo group for 10 days. The blood indices, serum levels of inflammatory biomarker and presepsin as well as nutrition status, and clinical outcomes were assessed before the intervention and on days 5 and 10. White blood cells, neutrophils, platelets, erythrocyte sedimentation rate (ESR), and the levels of interleukin-8 significantly decreased in the nano-curcumin group compared to the placebo after 10 days of intervention (p = .024, p = .045, p = .017, p = .041, and p = .004, respectively). There was also a marginal meaningful decrease in serum presepsin levels in the intervention group compared to the placebo at the end of the study (p = .054). However, total lymphocyte count showed a significant increase in the nano-curcumin group compared to the placebo at the end-point (p = .04). No significant differences were found in the level of lymphocyte and the ratios of neutrophil/lymphocyte and platelet/lymphocyte between the study groups. Moreover, no significant between-group differences were observed for other study outcomes, post-intervention. Collectively, nano-curcumin may be a useful adjuvant therapy in critically ill patients with sepsis. However, further trials are suggested to examine the effects of nano-curcumin in the management of sepsis and its complications. PRACTICAL APPLICATIONS: Curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5- dione) or diferuloylmethane is widely used in medicine due to its several biological properties. Recent evidence has shown that curcumin possesses multiple pharmacological activities including immune-modulatory, antioxidant, anti-inflammatory, anti-cancer, and anti-microbial effects. In this study, it was observed that nano-curcumin at a dose of 160 mg for 10 days, without side effects, reduced some inflammatory factors and regulated the immune responses in sepsis patients. For the first time, this trial was conducted to determine the effect of nano-curcumin on hematological indices and the serum levels of presepsin and IL-8.

Topics: Antioxidants; Critical Illness; Curcumin; Dietary Supplements; Humans; Lipopolysaccharide Receptors; Peptide Fragments; Sepsis

Sepsis is a severe reaction and excessive immune response to infection, which can lead to organ dysfunction, and death. This study aimed to investigate the protective effect of nano-curcumin (NC) on inflammatory biomarkers, endothelial function, oxidative stress indices, biochemical factors, nutritional status, and clinical outcomes in patients with sepsis. In the present double-blind placebo-controlled randomized clinical trial, 40 ICU-admitted patients were randomly allocated into either NC or placebo group for 10 days. Both nano-curcumin (160 mg) and placebo were administered

Topics: bcl-2-Associated X Protein; Biomarkers; Critical Illness; Curcumin; Dietary Supplements; Humans; Leukocytes, Mononuclear; Nutritional Status; Oxidative Stress; Sepsis; Toll-Like Receptor 4

Sepsis-induced cardiomyopathy is the leading cause of death in sepsis and is characterized by reversible myocardial depression. However, the specific mechanisms responsible for myocardial injury in sepsis are not known. The present study used bioinformatic analysis to explore the possible mechanisms of sepsis-induced myocardial injury and the therapeutic potential of curcumin.. The GSE125042 microarray gene expression matrix was obtained from the Gene Expression Omnibus database, which includes 10 septic cardiomyocyte samples from cecum ligation perforation constructs and 10 sham-operated groups cardiomyocyte samples. Background correction and matrix data normalization were performed using the robust multiarray average algorithm. Differentially expressed genes (DEGs) screening was performed using the Limma R package expression matrix, and whole gene analysis was performed using the weighted gene co-expression network analysis R package to construct gene networks and identify modules. Enrichment analysis and gene set enrichment analysis was performed on the genes to be selected. Construct cellular and animal models of myocardial injury in sepsis were assessed and the effects of curcumin on a rat or cardiac myocytes were observed.. A total of 2876 DEGs were screened based on the GSE125042 chip, of which 1424 genes were upregulated and 1452 genes were down regulated. WGCNA analysis of the whole genes was also performed and a total of 20 gene modules were generated. Among them, the selected TLR1 gene was present in the most strongly correlated Brown module. Enrichment analysis of the upregulated DEGs with the Brown module showed that they were significantly enriched in biological processes related to ribosomal protein complex generation, cellular components related to phagocytic vesicles and molecular functions related to Toll-like receptor binding, affecting cardiomyocyte survival as a target for molecular intervention in septic cardiomyopathy. Animal experiments showed that curcumin reduced inflammation levels, improved cardiac function and increased survival in rats with septic myocardial injury. Cellular experiments showed that curcumin increased the survival rate of lipopolysaccharide-treated cardiomyocytes and down regulated TLR1 expression and inhibited NF-κB phosphorylation in cells in a dose-dependent manner. Molecular docking analysis revealed that curcumin interacted with TLR1 by hydrogen bonding and could be stably bound to inhibit the biological function of TLR1.. Our study shows that curcumin attenuates myocardial injury in sepsis by inhibiting TLR1 expression, which provides a molecular theoretical basis for clinical treatment.

Topics: Animals; Apoptosis; Curcumin; Heart Injuries; Molecular Docking Simulation; Myocytes, Cardiac; Rats; Sepsis; Toll-Like Receptor 1

We aimed to design RGD-anchored liposomes encapsulating an antipyroptosis drug that could efficiently target macrophages and relieve the rate of cytokine release syndrome, providing a new strategy for sepsis treatment, especially sepsis-induced acute renal injury.. Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by host response disorders due to infection. Sepsis has a high incidence and remains one of the leading causes of death worldwide.. Macrophage-mediated pyroptosis plays an important role in the occurrence and development of cytokine release syndrome and organ injury caused by sepsis. Curcumin can inhibit inflammasome assembly and slow the progression of pyroptosis by scavenging intracellular reactive oxygen species, but it has poor water solubility and low bioavailability. The emergence of drug-delivery nanosystems has overcome this problem, but there is still a lack of research on how to accurately deliver antipyroptotic drugs to innate immune cells and subsequently hinder pyroptosis.. We constructed a curcumin-loaded RGD-modified liposome (RGD-lipo/Cur) and demonstrated that RGD-lipo/Cur could effectively target macrophages.. In vitro, RGD-lipo/Cur reduced the upregulation of caspase-1, caspase-3, NLRP3, IL-1β and GSDMD, inhibiting pyroptosis, reducing oxidative stress, and attenuating the proinflammatory cytokine cascade.. RGD-lipo/Cur was considered to have great potential for sepsis treatment.

Topics: Aspartic Acid; Curcumin; Cytokine Release Syndrome; Humans; Inflammasomes; Oligopeptides; Pyroptosis; Sepsis

Acute inflammatory diseases, such as sepsis, are life-threatening illnesses. Regulating the α7 nicotinic acetylcholine receptor (α7 nAchR)-mediated signaling may be a promising strategy to treat sepsis. Diarylheptanoids have long been found to exhibit anti-inflammatory properties. However, the possible mechanism of diarylheptanoids has rarely been investigated. In this study, we isolated and synthesized 49 diarylheptanoids and analogues and evaluated their anti-inflammatory activities. Among them, compounds 28 and 40 markedly blocked lipopolysaccharide (LPS)-induced production of nitric oxide (NO), interleukin-1β (IL-1β) and interleukin-6 in murine RAW264.7 cells. Furthermore, compounds 28 and 40 also effectively attenuated LPS-induced sepsis, acute lung injury, and cytokines release in vivo. Mechanistically, compounds 28 and 40 significantly induced phosphorylation of janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling and suppression of nuclear factor-κB (NF-κB) pathway. Furthermore, blocking α7 nAchR could effectively abolish compounds 28 and 40-mediated activation of JAK2-STAT3 signaling as well as inhibition of NF-κB activation and NO production in LPS-exposed RAW264.7 cells. Collectively, our findings have identified a new diarylheptanoid, compound 28, as an agonist of α7 nAchR-JAK2-STAT3 signaling, which can be potentially developed as a valuable candidate for the treatment of sepsis, and provide a new lead structure for the development of anti-inflammatory agents targeting α7 nAchR-JAK2-STAT3 signaling.

Topics: Animals; Anti-Inflammatory Agents; Diarylheptanoids; Janus Kinase 2; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Sepsis; STAT3 Transcription Factor

Topics: Animals; Carnitine O-Palmitoyltransferase; Curcumin; Fatty Acids; Gene Knock-In Techniques; HEK293 Cells; Humans; Lipopolysaccharides; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Oxidation-Reduction; Phagocytes; Sepsis; STAT3 Transcription Factor

Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy.. After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was performed, and inflammatory markers were detected.. Myocardial systolic function was severely compromised in parallel with the accumulation of reactive oxygen species and enhanced cardiomyocyte apoptosis in mice with sepsis. These adverse changes were markedly reversed in response to THC treatment in septic mice as well as in LPS-treated H9c2 cells. Mechanistically, THC inhibited the release of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, by upregulating mitogen-activated protein kinase phosphatase 1, to block the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK). Additionally, THC enhanced the levels of antioxidant proteins, including nuclear factor-erythroid 2-related factor 2, superoxide dismutase 2, and NAD(P)H quinone oxidoreductase 1, while decreasing gp91. Our findings indicate that THC exhibited protective potential against septic cardiomyopathy by reducing oxidative stress and inflammation through the regulation of JNK/ERK signaling. The findings of this study provide a basis for the further evaluation of THC as a therapeutic agent against septic cardiomyopathy.

Topics: Animals; Cardiomyopathies; Curcumin; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Oxidative Stress; Sepsis

Epidemic modeling has been a key tool for understanding the impact of global viral outbreaks for over two decades. Recent developments of the COVID-19 pandemic have accelerated research using compartmental models, like SI, SIR, SEIR, with their appropriate modifications. However, there is a large body of recent research consolidated on homogeneous population mixing models, which are known to offer reduced tractability, and render conclusions hard to quantify. As such, based on our recent work, introducing the heterogeneous geo-spatial mobility population model (GPM), we adapt a modified SIR-V (susceptible-infected-recovered-vaccinated) epidemic model which embodies the idea of patient relapse from R back to S, vaccination of R and S patients (reducing their infectiousness), thus altering the infectiousness of V patients (from

Topics: Acute Lung Injury; Adherens Junctions; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antigens, CD; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; beta Catenin; Brain Ischemia; Cadherins; Carcinogenesis; Catalysis; Cell Line; Cells, Cultured; Curcuma; Curcumin; Dioxoles; Disease Models, Animal; Endothelial Cells; Epithelial Cells; Heme Oxygenase (Decyclizing); Humans; Inflammasomes; Intestinal Diseases; Intestinal Mucosa; Ischemic Stroke; Kidney Neoplasms; Lignans; Lung; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NAD(P)H Dehydrogenase (Quinone); Nanostructures; NF-E2-Related Factor 2; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phytotherapy; Plant Extracts; Pneumonia; PPAR gamma; Proto-Oncogene Proteins c-akt; Pyroptosis; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reperfusion Injury; Respiratory Distress Syndrome; Sepsis; Sesamum; Signal Transduction; Silybin; Silybum marianum; Silymarin; Sirtuin 3; Titanium; Transfection; Treatment Outcome; White Matter

Sepsis is the leading condition associated with acute kidney injury (AKI) in the hospital and intensive care unit (ICU), sepsis-induced AKI (S-AKI) is strongly associated with poor clinical outcomes. Curcumin possesses an ability to ameliorate renal injury from ischemia-reperfusion, but it is still unknown whether they have the ability to reduce S-AKI. The aim of this study was to investigate the protective effects of curcumin on S-AKI and to assess its therapeutic potential on renal function, inflammatory response, and microcirculatory perfusion.. Male Sprague-Dawley (SD) rats underwent cecal ligation and puncture (CLP) to induce S-AKI and immediately received vehicle (CLP group) or curcumin (CLP+Cur group) after surgery. At 12 and 24h after surgery, serum indexes, inflammatory factors, cardiac output (CO), renal blood flow and microcirculatory flow were measured.. Serum levels of creatinine (Scr), cystatin C (CysC), IL-6 and TNF-α were significantly lower in the CLP+Cur group than those in the CLP group (P < 0.05). Treatment with curcumin improved renal microcirculation at 24h by measurement of contrast enhanced ultrasound (CEUS) quantitative parameters [peak intensity (PI); half of descending time (DT/2); area under curve (AUC); P < 0.05]. In histopathological analysis, treatment with curcumin reduced damage caused by CLP.. Curcumin can alleviate S-AKI in rats by improving renal microcirculatory perfusion and reducing inflammatory response. Curcumin may be a potential novel therapeutic agent for the prevention or reduction of S-AKI.

Topics: Acute Kidney Injury; Animals; Creatinine; Curcumin; Disease Models, Animal; Inflammation; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Renal Circulation; Sepsis; Time Factors

To study the effect of curcumin on enterocyte apoptosis and its protective effect on intestinal mucosal barrier in septic rats.. Eighty-seven 3-month male Sprague-Dawley (SD) rats were divided into Sham group, model group and curcumin group by random number table method, with 29 rats in each group. The septic rat model was reproduced by cecal ligation and puncture (CLP). 4 mL dimethyl sulfoxide solution were intraperitoneally injected in both Sham group and model group, 200 mg/kg curcumin dissolved by 4 mL dimethyl sulfoxide solution were intraperitoneally injected in curcumin group 10 minutes after operation. The blood samples (15 rats in each group) were collected 2, 12, 24 hours after operation, and the levels of serum procalcitonin (PCT), tumor necrosis factor-α (TNF-α), D-lactic acid and diamine oxidas (DAO) were tested by enzyme linked immunosorbent assay (ELISA). The ileum tissues were collected 12 hours, 24 hours after operation in three groups, water content was tested by weighting, pathologic structure was observed by light microscope, the enterocyte apoptosis was tested by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling method (TUNEL). The 7-day survival rate was observed in three groups (14 rats in each group).. The serum levels of PCT, TNF-α, D-lactic acid and DAO were higher in model group at 2, 12, 24 hours after operation than those in Sham group, PCT, TNF-α levels were significantly higher in model group than those in Sham group 2 hours after operation [PCT (μg/L): 1.89±0.17 vs. 0.10±0.02, TNF-α (ng/L): 216.51±1.47 vs. 85.25±8.20, both P < 0.01], D-lactic acid, DAO levels were significantly higher in model group than those in Sham group 12 hours after operation [D-lactic acid (mg/L): 40.53±7.76 vs. 11.29±1.28, DAO (ng/L): 1 120.40±302.35 vs. 330.02±81.28, both P < 0.01]. Compared with model group, the levels of serum PCT, TNF-α, D-lactic acid and DAO were lower in curcumin group 2, 12, 24 hours after operation, the statistical difference appeared from 12 hours after operation [PCT (μg/L): 5.37±0.44 vs. 8.67±0.64, TNF-α (ng/L): 211.12±4.31 vs. 313.30±18.46, D-lactic acid (mg/L): 29.74±1.41 vs. 40.53±7.76, DAO (ng/L): 810.71±201.41 vs. 1 120.40±302.35, all P < 0.05], curcumin group had lower water content in ileum tissues 12 hours, 24 hours after operation [(68.34±0.68)% vs. (70.55±0.87)%, (69.41±0.59)% vs. (71.69±0.87)%, both P < 0.05]. The pathologic structures of intestinal villus were normal in Sham group, however, in model group intestinal villus were atrophic, edematous and shorten 12 hours after operation, it was further exacerbated 24 hours after operation. Compared with model group, the pathologic structures of intestinal villus in curcumin group were relived 12 hours, 24 hours after operation. The number of apoptotic enterocytes were significantly increased in model group compared with Sham group 24 hours after operation (cells: 25.48±6.10 vs. 4.00±2.04, P < 0.05), and the number of apoptotic enterocytes was lower in curcumin group than that in model group at the same time (cells: 15.48±3.75 vs. 25.48±6.10), the difference was statistically significant (both P < 0.05). Seven-day survival rate was significantly lower in curcumin than that in model group [42.9% (6/14) vs. 50.0% (7/14)], however, the difference was not statistically significant (P > 0.05).. Curcumin can protect the intestinal mucosal barrier by inhibiting enterocyte apoptosis in septic rats.

Topics: Animals; Apoptosis; Curcumin; Enterocytes; Male; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Curcumin; Cytokines; Inflammation; Kidney; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Protective Agents; Sepsis; Signal Transduction; Sirtuin 1

To investigate the protective effects of curcumin on LPS-induced septic acute kidney injury and to explore its underlying molecular mechanisms.. A mouse model of septic acute kidney injury (AKI) was given an intraperitoneal injection of lipopolysaccharide (LPS), followed by administration of variable levels of curcumin (intragastric). And NRK cells were used as the kidney cell model for all in vitro studies.. Curcumin significantly decreased the levels of serum Scr, BUN, and Cyc c and reduced kidney injury in LPS-induced AKI mice. Kidney tissues of LPS-induced AKI mice showed an increase in PVT1, ED-1, TNF-α, IL-1β, IL-6, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN expression levels; however, treatment with curcumin significantly reduced this effect. Curcumin increased the survival rate NRK cells exposed to LPS-induced inflammation in vitro. Moreover, NRK cells that overexpressed PVT1 had lower survival rates than WT NRK cells obtained from mice that received curcumin treatment after treating with LPS. Additionally, curcumin reduced the LPS-induced increase in Bax, cleaved-caspase3/caspase 3, p-IkBα/IkBα, p-p65/p65, p-JNK/JNK, and p-c-JUN/c-JUN protein expression, and increased Bcl2 protein expression in NRK cells. However, the extent of these changes was low in NRK cells that overexpressed PVT1.. Curcumin decreased PVT1 expression in LPS-induced septic acute kidney tissues and reduced LPS-induced septic acute kidney injury in mice. This might be related to the inhibition of the JNK/NF-κB pathway by curcumin through suppression of lncRNA PVT1.

Topics: Acute Kidney Injury; Animals; Cell Line; Curcumin; Female; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Sepsis

Curcumin alleviates septic acute kidney injury (SAKI); however, the underlying mechanism remained unclear. To explore this, SAKI cell model and mice model were conducted by using LPS and cecal ligation and puncture (CLP), respectively. Cell counting kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA) assays indicated that LPS reduced the viability, but upregulated the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, whereas Curcumin pretreatment had no effect on viability, but reduced the levels of TNF-α and IL-6. Further assays showed that Curcumin partly attenuated the LPS-induced injury as the viability was enhanced, TNF-α and IL-6 expressions and cell apoptosis rates were reduced. Western blot analysis indicated that Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, p-65-NF-κB and cell apoptosis pathways were activated by LPS but suppressed by Curcumin. Mice SAKI model further indicated that the serum Cystatin C (Cys-C), creatinine (Cr) and blood urea nitrogen (BUN) were increased within 24 h of model construction while those indicators were decreased at 48 h. Pretreated with Curcumin, NF-κB inhibitor (PDTC) or JAK2 inhibitor (AG-490) could weaken the renal histological injury and the increased serum Cys-C, Cr and BUN, IL-6 and TNF-α induced by CLP. Moreover, PDTC, AG-490 and Curcumin all significantly reversed the previously increased expressions of p-JAK2/STAT3, p-p65 and proapoptotic proteins in the mice with AKI. The present study revealed that Curcumin attenuated SAKI through inhibiting NF-κB and JAK2/STAT3 signaling pathways, and proposed that Curcumin could be a potential therapeutic agent for treating SAKI.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cecum; Cell Line; Cell Survival; Curcumin; Humans; Inflammation; Janus Kinase 2; Ligation; Lipopolysaccharides; Male; Mice, Inbred C57BL; NF-kappa B; Punctures; Sepsis; Signal Transduction; STAT3 Transcription Factor

To detect antioxidant and antiinflammatory efficacy of Curcumin (Cur) on lung tissue in rats with sepsis.. Totally 32 rats were divided into 4 groups; the rats in Group 1 (control group) had abdominal incision under sterile conditions following anesthesia and the abdomen was sutured. Abdominal incision was performed in the rats in Group 2 (Cur group) under sterile conditions following anesthesia and the abdomen was closed. Cur was given to this group after dissolving within dimethylsulphoxide as 100 mg/kg through oral gavage and started for 3 d before surgical procedure. Group 3 (CLP group) had caecal ligation and punction (CLP) under sterile conditions to create sepsis following anesthesia and the abdomen was sutured. CLP was performed in the rats in Group 4 (CLP + Cur group) under sterile conditions following anesthesia to create a sepsis model and the abdomen was closed. Cur was also given to this group after dissolving within dimethylsulphoxide as 100 mg/kg through oral gavage and started for 3 d before surgical procedure. All the rats were sacrificed through blood aspiration from the heart under sterile conditions following anesthesia and lung tissues were removed after 24 h following the surgical procedures. The tissue samples were homogenizated for biochemical analyses; and malondialdehyde (MDA), nitric okxide (NO), myeloperoxidase (MPO), superoxidedysmutase (SOD) nd catalase (CAT) were analyzed through spectrophotometric method, immunhistochemical iNOS staining was performed to assess the inflammation; and histopathological differences between the groups were evaluated.. A statistically significant decrease was detected in the CLP + Cur group when compared with the CLP group of which Cur was not given in terms of MDA, MPO and NO levels (P < 0.05) whereas a statistically significant elevation was fpund in the CLP + Cur group when compared with the CLP group in terms of SOD and CAT levels (P < 0.05).. The study outcomes revealed that supplementation of Cur presents an antioxidant effect by reducing the free radical level and increasing the antioxidant enzyme levels; and an antiinflammatory effect by reducing iNOS level.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcumin; Humans; Lung; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

An overactive Toll-like receptor (TLR) signaling complex is a significant pathogenic factor of acute and chronic inflammatory diseases. The natural product curcumin is reported to inhibit the TLR4 co-receptor, MD2 (myeloid differentiation protein 2), but its low in vivo bioavailability limits its therapeutic potential. We developed new curcumin analogs (MACs) with removal of the β-diketone moiety and substituted residues in benzene rings, and identify these as potential MD2 inhibitors with improved inhibition potency and stability over that of curcumin. Specifically, MAC 17 and 28 showed the highest anti-inflammatory activity, with >90% inhibition of LPS-stimulated cytokine secretion from macrophages, and protected against LPS-induced acute lung injury and sepsis. The MACs inhibited the TLR4-MD2 signaling complex through competition with LPS for binding on MD2, likely at Arg

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Curcumin; Cytokines; Lipopolysaccharides; Lymphocyte Antigen 96; Macrophages, Peritoneal; Mice; Sepsis; Toll-Like Receptor 4

Sepsis is characterized by the extensive release of cytokines and other mediators. It results in a dysregulated immune response and can lead to organ damage and death. Curcumin has anti-inflammatory properties and immunoregulation functions in various disorders such as sepsis, cancer, rheumatoid arthritis, cardiovascular diseases, lung fibrosis, gallstone formation, and diabetes. This paper investigates the effects of curcumin on immune status and inflammatory response in mice subjected to cecal ligation and puncture (CLP). Inflammatory tissue injury was evaluated by histological observation. Magnetic microbeads were used to isolate splenic CD4

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Cells, Cultured; Curcumin; Disease Models, Animal; Forkhead Transcription Factors; Humans; Immunomagnetic Separation; Immunosuppression Therapy; Inflammation; Interleukin-10; Kidney; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Sepsis; T-Lymphocytes, Regulatory

Aberrant activation of the NLRP3 inflammasome contributes to the onset and progression of various inflammatory diseases, making it a highly desirable drug target. In this study, we screened a series of small compounds with anti-inflammatory activities and identified a novel NLRP3 inflammasome inhibitor, AI-44, a curcumin analogue that selectively inhibited signal 2 but not signal 1 of NLRP3 inflammasome activation. We demonstrated that AI-44 bound to peroxiredoxin 1 (PRDX1) and promoted the interaction of PRDX1 with pro-Caspase-1 (CASP1), which led to the suppression of association of pro-CASP1 and ASC. Consequently, the assembly of the NLRP3 inflammasome was interrupted, and the activation of CASP1 was inhibited. Knockdown of PRDX1 significantly abrogated the inhibitory effect of AI-44 on the NLRP3 inflammasome. Importantly, AI-44 alleviated LPS-induced endotoxemia in mice via suppressing NLRP3 inflammasome activation. Taken together, our work highlighted PRDX1 as a negative regulator of NLRP3 inflammasome activation and suggested AI-44 as a promising candidate compound for the treatment of sepsis or other NLRP3 inflammasome-driven diseases.

Topics: Animals; Anti-Inflammatory Agents; Caspase 1; Curcumin; Disease Models, Animal; Female; Humans; Inflammasomes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Multiprotein Complexes; Peroxiredoxins; RNA, Small Interfering; Sepsis; Signal Transduction; THP-1 Cells

Many traditional Chinese medicines (TCM), such as Eucommia ulmoides Oliv., Gynostemma pentaphyllum (Thunb.) Makino, and Curcuma longa L., have been reported to have various immune-modulatory effects.. To determine the effects of extracts from these three TCM on type 1 T help (Th1)- and Th2-cytokine responses and human leukocyte antigen (HLA)-DR expression in peripheral blood mononuclear cells (PBMCs) obtained from septic patients.. Lipopolysaccharide (LPS)-stimulated PBMCs of healthy controls and septic patients were cultured for 48 hs with or without 0.05/0.1 mg/ml of TCM extract. HLA-DR expression in monocytes was detected using flow cytofluorimetry. The interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin (IL)- 2, IL-5, IL-10, and IL-13 levels in supernatants were measured with a human enzyme-linked immunosorbent assay.. Treatment with either 0.05 or 0.1 mg/ml of C. longa L. extract significantly restored the percentage of HLA-DR-positive monocytes, which was decreased by LPS in control and patient groups. Treatment with 0.05 or 0.1 mg/ml E. ulmoides Oliv. and C.longa L. extract decreased IL-10 production from LPS-stimulated PBMCs of controls and patients. In patients with sepsis, C. longa L. extract decreased IL-10 production to a greater degree than did E. ulmoides Oliv extract. Although IFN-γ, TNF-α, or IL-13 productions from LPS-stimulated PBMCs were influenced by E. ulmoides Oliv., G. pentaphyllum (Thunb.) Makino, or C. longa L. in control or sepsis groups in this study, only the influence of IL-10 was consistent in both control and sepsis groups.. By enhancing monocyte HLA-DR expression and decreasing IL-10 production, C. longa L. might help restore inflammatory responses in septic patients to eradicate pathogens.

Topics: Aged; Case-Control Studies; Cells, Cultured; Curcuma; Cytokines; Eucommiaceae; Female; Gynostemma; HLA-DR Antigens; Humans; Immunologic Factors; Male; Middle Aged; Monocytes; Phytotherapy; Plant Extracts; Plants, Medicinal; Sepsis; Th1 Cells; Th1-Th2 Balance; Th2 Cells

To investigate the protective effect of curcumin on hepatocytes in rats with sepsis.. Eighty healthy male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, Xuebijing group and curcumin group (20 rats in each group) according to the random number table method. The animal model of sepsis was established by cecal ligation and puncture (CLP). In the sham operation group, the cecum was removed only after the operation. The rats in Xuebijing group and curcumin group were injected with 4 mL/kg Xuebijing, 100 mg/kg curcumin intraperitoneally at 0, 8 and 16 hours after operation (diluted with normal saline to 4 mL/kg) respectively; Sham operation group and sepsis group were injected with the same volume of normal saline. Five rats in each group were sacrificed at 2, 6, 12 and 24 hours after operation, the blood sample was collected, and liver tissues were harvested. The levels of serum procalcitonin (PCT), tumor necrosis factor-α (TNF-α) and interleukin (IL-6, IL-1β) were measured by enzyme linked immunosorbent assay (ELISA), the pathological changes of liver tissues were observed by hematoxylin-eosin (HE) staining, and apoptosis index (AI) was measured by TdT-mediated dUTP nick end labeling (TUNEL) method.. The degree of hepatocyte injury in sepsis group increased gradually with time, the apoptotic cells gradually increased, and the AI of liver cells increased to 24 hours; serum levels of PCT, TNF-α, IL-6 and IL-1β were significantly higher than those in the sham operated group at 2 hours after operation and gradually increased to peak at 12 hours. The injury degree of liver tissue in Xuebijing group and curcumin group was significantly lighter than that in sepsis group, and the number of apoptotic cells were significantly decreased; the AI of hepatocytes and serum levels of PCT, TNF-α, IL-6 and IL-1β were significantly lower than those of sepsis group from 2 hours [AI: (11.89±1.34)%, (11.56±0.96)% vs. (23.59±2.00)% at 2 hours, (28.95±1.40)%, (30.35±1.20)% vs. (52.05±1.31)% at 24 hours; PCT (μg/L): 1.27±0.18, 1.13±0.19 vs. 2.41±0.21 at 2 hours, 5.07±0.45, 5.09±0.42 vs. 8.68±0.58 at 12 hours; TNF-α (ng/L): 127.93±9.53, 124.73±7.47 vs. 217.28±14.24 at 2 hours, 171.03±8.58, 168.68±6.95 vs. 314.13±14.39 at 12 hours; IL-6 (ng/L): 132.15±9.27, 136.14±8.42 vs. 153.35±12.64 at 2 hours, 211.65±8.52, 213.37±8.96 vs. 298.11±12.35 at 12 hours; IL-1β (ng/L): 33.59±1.49, 35.05±1.00 vs. 61.84±3.21 at 2 hours; 81.76±2.80, 84.06±3.42 vs. 132.24±2.58 at 12 hours, all P < 0.05]. There was no significant difference in the above indexes between Xuebijing group and curcumin group.. Curcumin can inhibit the inflammatory response of hepatocytes in sepsis rats and reduce the apoptosis of hepatocytes, which can protect hepatocytes from sepsis.

Topics: Animals; Curcumin; Hepatocytes; Interleukin-1beta; Male; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

Curcumin has been reported to have anti-inflammatory, antioxidant and hypoglycaemic properties, besides reducing mortality in sepsis.. This study evaluates the biological activities of a curcumin dispersion formulated by spray-drying in experimental sepsis.. Male Wistar rats were subjected to sepsis by caecal ligation and puncture (CLP), controls were sham operated. The animals were treated with curcumin dispersion (100 mg/kg, p.o.) or water for 7 days prior to CLP and at 2 h after surgery. One group was used to analyze curcumin absorption through HPLC; another had the survival rate assessed during 48 h; and from a third group, blood was collected by decapitation to analyze metabolic and inflammatory parameters.. The plasma curcumin levels reached 2.5 ng/mL at 4 h, dropped significantly (p < 0.001) at 6 h (1.2 ng/mL), and were undetectable at 24 h in both groups. Curcumin temporarily increased the survival rate of the septic rats by 20%. Moreover, it attenuated glycaemia (p < 0.05) and volemia (p < 0.05) alterations typically observed during sepsis, and decreased the levels of the proinflammatory cytokines IL-1β and IL-6 in plasma (p < 0.001) and peritoneal lavage fluid (p < 0.05) of septic rats. Serum HSP70 levels were decreased (p < 0.01) at 24 h after CLP.. Our results show that the curcumin dispersion dose employed was not detrimental to the septic rats. In fact, it temporarily increased their survival rate, improved important metabolic parameters, reduced proinflammatory cytokines and HSP70 production.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Blood Glucose; Blood Volume; Cecum; Curcumin; Cytokines; Disease Models, Animal; Dosage Forms; Down-Regulation; Drug Compounding; HSP70 Heat-Shock Proteins; Hypoglycemic Agents; Inflammation Mediators; Ligation; Male; Nitrates; Punctures; Rats, Wistar; Sepsis; Time Factors

The present study investigates curcumin effect against sepsis-induced chronic lung injury (CLI) of male albino rats. Rats were grouped into four groups such rats undergoing a sham cecal ligature puncture (CLP), rats undergoing CLP, rats undergoing CLP and treated with saline and rats undergoing CLP and treated with curcumin (100 mg/kg bwt). After 45 days of treatment, bronchoalveolar fluid (BALF), blood and lung tissues were collected from the each animal. The total protein content, wet and dry (W/D) weight of lung tissues and some inflammatory cells in the BALF were measured. Histopathological analysis was carried out to investigate the alteration of the cellular architecture of lung tissues. Lipid peroxidation malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) levels were determined. Cytokines such as interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and macrophage inhibitory factor (MIF) were measured in the BALF. Curcumin administration significantly reduced CLP-induced inflammation and pulmonary edema. Curcumin treatment is significantly reduced MPO activity, and inflammatory cell accumulation in the BALF and also protein level, MDA, SOD, and W/D ratio were significantly reduced in the lung tissues. Also, curcumin reduced the expression of IL-A, TNF-a and MIF levels in the lung tissues. Histopathological study revealed the significant reduction of CLP-induced CLI in the curcumin-treated male albino rats. Taking all these data together, it is concluded that curcumin can act as a suitable therapeutic agent against CLP-induced CLI of male albino rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Bronchoalveolar Lavage Fluid; Cecum; Curcumin; Interleukin-8; Intramolecular Oxidoreductases; Lipid Peroxidation; Lung; Lung Injury; Macrophage Migration-Inhibitory Factors; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Acute inflammatory diseases, including acute lung injury and sepsis, remain the most common life-threatening illness in intensive care units worldwide. Cinnamamide has been incorporated in several synthetic compounds with therapeutic potentials including anti-inflammatory properties. However, the possible mechanism and direct molecular target of cinnamamides for their anti-inflammatory effects were rarely investigated. In this study, we synthesized a series of cinnamamides and evaluated their anti-inflammatory activities. The most active compound, 2i, was found to block LPS-induced MD2/TLR4 pro-inflammatory signaling activation in vitro and to attenuate LPS-caused sepsis and acute lung injury in vivo. Mechanistically, we demonstrated that 2i exerts its anti-inflammatory effects by directly targeting and binding MD2 in Arg90 and Tyr102 residues and inhibiting MD2/TLR4 complex formation. Taken together, this work presents a novel MD2 inhibitor, 2i, which has the potential to be developed as a candidate for the treatment of sepsis, and provides a new lead structure for the development of anti-inflammatory agents targeting MD2.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Cinnamates; Cytokines; Drug Discovery; Interleukin-6; Lipopolysaccharides; Lymphocyte Antigen 96; Macrophages; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Models, Molecular; RAW 264.7 Cells; Sepsis; Survival Analysis; Toll-Like Receptor 4

To observe the protective effect of different doses of curcumin on hepatocytes of rats with sepsis.. 100 healthy male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, and low, medium, high dose curcumin intervention groups (L-cur, M-cur, H-cur groups), with 20 rats in each group. The animal model of sepsis was reproduced by cecal ligation and puncture (CLP) method, and in the sham operation group the cecum was just taken out and returned. In the L-cur, M-cur, H-cur groups curcumin was immediately injected after CLP with a dose of 50, 100, 150 mg/kg, respectively, and the rats in sham operation group and sepsis group were given the same amount of normal saline. Five rats in each group were sacrificed at 2, 6, 12, 24 hours after operation, and the hepatic tissues and blood samples were obtained. The pathological changes in hepatic tissues were observed under a microscope, and hepatocytes apoptosis and apoptosis index (AI) of hepatocytes were determined with transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) method, and the levels of serum procalcitonin (PCT), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined with enzyme linked immunosorbent assay (ELISA) method.. Microscopic examination showed that the damage degree of hepatic tissues was significantly increased in sepsis group; the number of apoptotic cells and damage degree of hepatic tissues were increased gradually over time. The damage degree of hepatic tissues in curcumin groups was lessened as compared with sepsis group, especially in M-cur group. There were no significant changes in AI and serum PCT, TNF-α, and IL-1β levels at any of the time points tested in the sham operation group. The AI, serum PCT, TNF-α, and IL-1β levels in the sepsis group were significantly higher than those in the sham operation group from 2 hours after operation on [AI: (23.59±2.00)% vs. (2.02±0.13)%, PCT (μg/L): 2.41±0.21 vs. 0.81±0.01, TNF-α (ng/L): 217.28±14.24 vs. 80.02±2.26, IL-1β (ng/L): 61.84±3.21 vs. 25.78±1.29, all P < 0.05], and they showed a gradually increasing tendency. AI reached peak value at 24 hours after operation [(52.05±1.31)%]; PCT, TNF-α and IL-1β reached the peak values at 12 hours after operation [(8.68±0.58) μg/L, (314.13±14.39) ng/L, (132.24±2.58) ng/L, respectively]. Curcumin intervention significantly reduced the levels of AI, TNF-α, PCT and IL-1β in hepatocytes of septic rats, especially in M-cur group [AI: (11.56±0.96)% vs. (23.59±2.00)% at 2 hours, (30.35±1.20)% vs. (52.05±1.31)% at 24 hours; PCT (μg/L): 1.13±0.19 vs. 2.41±0.21 at 2 hours, 5.09±0.42 vs. 8.68±0.58 at 12 hours; TNF-α (ng/L): 124.73±7.47 vs. 217.28±14.24 at 2 hours, 168.68±6.95 vs. 314.13±14.39 at 12 hours; IL-1β (ng/L): 35.05±1.00 vs. 61.84±3.21 at 2 hours, 84.06±3.42 vs. 132.24±2.58 at 12 hours; all P < 0.05].. Curcumin can inhibit the inflammatory reaction of hepatocytes of rats, prevent apoptosis, and protect the hepatocytes of rats with sepsis. The concentration of curcumin with the most significant effect is 100 mg/kg, which is the medium dosage.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Calcitonin; Curcumin; Disease Models, Animal; Hepatocytes; Inflammation; Interleukin-1beta; Liver; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Tumor Necrosis Factor-alpha

In many liver disorders, oxidative stress-related inflammation and apoptosis are important pathogenic components, finally resulting in acute liver failure. Erythropoietin and its analogues are well known to influence the interaction between apoptosis and inflammation in brain and kidney. The study is to clarify the effect of curcumin, a natural plant phenolic food additive, on lipopolysaccharides (LPS)-induced acute liver injury of mice with endotoxemia and associated molecular mechanism from inflammation, apoptosis and oxidative stress levels. And curcumin, lowered serum cytokines, including Interleukin 1beta (IL-1β), Interleukin 6 (IL-6) and tumor necrosis factor (TNF-α), and improved liver apoptosis through suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibiting Cyclic AMP-responsive element-binding protein (CREB)/Caspase expression, and decreased oxidative stress-associated protein expression, mainly involving 2E1 isoform of cytochrome P450/nuclear factor E2-related factor 2/reactive oxygen species (CYP2E/Nrf2/ROS) signaling pathway, as well as liver nitric oxide (NO) production in LPS-induced mice. Moreover, curcumin regulated serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), accelerated liver antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-px) levels, and inhibited activation of the mitogen-activated protein kinases/c-Jun NH2-terminal kinase (P38/JNK) cascade in the livers of LPS-induced rats. Thus, curcumin treatment attenuates LPS-induced PI3K/AKT and CYP2E/Nrf2/ROS signaling and liver injury. Strategies to inhibit inflammation and apoptosis signaling may provide alternatives to the current clinical approaches to improve oxidative responses of endotoxemia.

Topics: Animals; Apoptosis; Curcumin; Hepatic Stellate Cells; Inflammation; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Liver Failure; Male; Mice, Inbred C57BL; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; RNA, Messenger; Sepsis; Signal Transduction

Lipopolysaccharide (LPS) is one of the most powerful proinflammatory factor and can induce acute pulmonary inflammation even lung injury after inhalation or systemic administration. LPS induces sepsis and multiple organ damage. Curcumin (diferuloylmethane), a major component of turmeric, exhibits protection against LPS-induced acute lung injury (ALI). We aimed to investigate effects of intranasal curcumin on LPS-induced ALI in mice where curcumin (10 mg/kg, intranasal (i.n.) was given an hour before LPS exposure. After 24 h of intranasal LPS instillation, a marked increase in neutrophil recruitment and myeloperoxidase (MPO) activity was noted which were significantly ameliorated in curcumin treatment group. Oxidative stress markers like nitric oxide (NO), malondialdehyde (MDA) level and evans blue capillary leakage assay also revealed suppression after curcumin treatment; interestingly, levels of anti-oxidative enzymes such as superoxide dismutase (SOD) and catalase were upregulated. Inflammatory cytokine, tumour necrosis factor alpha (TNF-α) level was significantly attenuated by curcumin. Hence, intranasal curcumin could be a novel therapeutic strategy for LPS-induced ALI by directly targeting the lungs and enhancing anti-oxidant levels.

Topics: Acute Lung Injury; Administration, Intranasal; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Capillary Permeability; Catalase; Curcumin; Disease Models, Animal; Lipopolysaccharides; Lung; Malondialdehyde; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitrites; Oxidative Stress; Random Allocation; Respiratory Distress Syndrome; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

A novel class of asymmetric mono-carbonyl analogs of curcumin (AMACs) were synthesized and screened for anti-inflammatory activity. These analogs are chemically stable as characterized by UV absorption spectra. In vitro, compounds 3f, 3m, 4b, and 4d markedly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 in a dose-dependent manner, with IC50 values in low micromolar range. In vivo, compound 3f demonstrated potent preventive and therapeutic effects on LPS-induced sepsis in mouse model. Compound 3f downregulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 MAPK and suppressed IκBα degradation, which suggests that the possible anti-inflammatory mechanism of compound 3f may be through downregulating nuclear factor kappa binding (NF-κB) and ERK pathways. Also, we solved the crystal structure of compound 3e to confirm the asymmetrical structure. The quantitative structure-activity relationship analysis reveals that the electron-withdrawing substituents on aromatic ring of lead structures could improve activity. These active AMACs represent a new class of anti-inflammatory agents with improved stability, bioavailability, and potency compared to curcumin. Our results suggest that 3f may be further developed as a potential agent for prevention and treatment of sepsis or other inflammation-related diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Crystallography, X-Ray; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Molecular; Molecular Structure; Sepsis; Structure-Activity Relationship

Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor α and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg(90) and Tyr(102). Subsequently, L48H37 was shown to suppress LPS-induced mitogen-activated protein kinase phosphorylation and nuclear factor κB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.

Topics: Animals; Curcumin; Cytokines; Diarylheptanoids; Endotoxins; Humans; Lipopolysaccharides; Lymphocyte Antigen 96; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Primary Cell Culture; Protein Binding; Sepsis; Shock, Septic; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA

Sepsis is a significant public healthcare problem, affecting millions of people worldwide each year, killing one in four, and increasing in incidence. Thus, advanced therapeutic strategies are required to treat sepsis patients. Curcumin (Cur) is a promising anti-inflammatory agent for various inflammatory disorders. However, the therapeutic efficacy of Cur is limited due to poor aqueous solubility, rapid degradation, and low bioavailability. The aims of this study were to evaluate the therapeutic potential of Cur-loaded solid lipid nanoparticles (Cur-SLNs) for sepsis treatment. A firefly luciferase transgenic mouse was used to monitor real time interleukin 1β (IL-1β) expression in lipopolysaccharide (LPS)-induced sepsis model to examine the protective effect of Cur-SLNs, and to elucidate its underlying molecular mechanisms. Mice (female or male) were intraperitoneally administered with free Cur or Cur-SLNs (30 mg/kg) before the intraperitoneal delivery of LPS (3 mg/kg). Our results indicated that Cur-SLNs can effectively reduced levels of IL-1β expression compared to free Cur, especially at 3 h after LPS injection. Also, Cur-SLNs significantly decreased the expression of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β as compared with free Cur, but augmented anti-inflammatory cytokine IL-10 by ELISA assay. Further, marked alleviation of the sepsis-induced damage to organs, including kidney, liver, and heart was observed with Cur-SLNs treatment as determined by hematoxylin/eosin-staining. Western blot analyses revealed that Cur-SLNs can significantly lower the expression levels of TLR4, TLR2, and TNF-α in lymph node tissues. Meanwhile, it showed suppressions of NF-κB activation and IκBα degradation levels. In conclusion, we suggested that Cur-SLNs may be used as an effective and safe therapeutic agent in treating sepsis in high-risk patient groups.

Topics: Animals; Anti-Inflammatory Agents; Curcumin; Cytokines; Drug Carriers; Inflammation Mediators; Interleukin-1beta; Lipids; Lipopolysaccharides; Mice; Mice, Transgenic; Nanoparticles; Promoter Regions, Genetic; Sepsis; Signal Transduction

The objective of this study is to develop a nanostructured parenteral delivery system, laden with curcumin (CUR), for the therapeutic intervention of sepsis and associated pathologies.. Nanoemulsions were fabricated using sonication and speed homogenization. Size and zeta potential were evaluated by dynamic light scattering and transmission electron microscopy analysis. Pharmacodynamic and pharmacokinetic studies were performed on a rat model of lipopolysaccharide (LPS)-induced sepsis.. The drug content of optimized nanoemulsion (F5) formulation (particle size 246 ± 08 nm, polydispersity index (PDI) of 0.120, zeta potential of -41.1 ± 1.2 mV) was found to be 1.25 mg/ml. In vitro release studies demonstrated that F5 was able to sustain the release of CUR for up to 24 h. Minimal hemolysis and cellular toxicity demonstrated its suitability for intravenous administration. Significant reduction of inflammatory mediator levels was mediated through enhanced uptake by in RAW 264.7 and THP-1 in absence/presence of LPS. Nanoemulsion resulted in an improvement of plasma concentration (AUCF5/AUC CUR = 8.80) and tissue distribution of CUR in rats leading to a reduction in LPS-induced lung and liver injury due to less neutrophil migration, reduced TNF-α levels and oxidative stress (demonstrated by levels of lipid peroxides as well as carbonylated proteins) as confirmed by histopathological studies.. The findings suggest that the therapeutic performance (i.e., reduction in oxidative damage in tissues) of CUR can be enhanced by employing tocol acetate nanoemulsions (via improving pharmacokinetics and tissue distribution) as a platform for drug delivery in sepsis-induced organ injury.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Curcumin; Cytokines; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Emulsions; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Flow Cytometry; Infusions, Parenteral; Lipid Peroxides; Lipopolysaccharides; Liver Diseases; Male; Nanoparticles; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Sepsis; Tissue Distribution; Vitamins

To study the effects of mitochondrial permeability transition (MPT) on hepatocyte apoptosis and mitochondrial damage, and investigate the effects of curcumin on MPT and the related mechanisms in septic rat.. Fifteen healthy male Sprague-Dawley (SD) rats were randomly divided into three groups: sham group, sepsis group and curcumin group, with 5 rats in each group. Septic rat model was reproduced by cecal ligation and puncture (CLP). The rats in sham group were flipped the cecum without perforation and ligation. The rats in the curcumin group were treated with curcumin 100 mg × kg⁻¹ × d⁻¹ (dissolved in saline to 10 mL/kg) by oral gavage for 7 days, while the other groups were treated with normal saline. Tissue samples were harvested in each group at 12 hours after operation. Pathological changes in hepatic mitochondria were observed under electron microscopy, concentration of free calcium was examined with confocal laser scanning microscope. After Fluo-3/AM staining, protein and mRNA expression of active caspase-3, Bcl-2 and Bax were examined by Western Blot and reverse transcription-polymerase chain reaction (RT-PCR).. Under the transmission electron microscope, intact cell membrane, adqulis cytoplasm, and normal and clear mitochondrion was found in the sham group. Mitochondria in sepsis group swelled obviously with mitochondrial cristae broken or disappearance, unclear bilateral membrane structure, while the curcumin group showed much less pathological changes, with few mitochondria swell, and smear bilateral membrane structure. The fluorescence intensity index of sham group, sepsis group and curcumin group was raised successively (417.33 ± 15.88, 772.95 ± 42.37, 1 560.84 ± 160.78, respectively, F=184.149, P=0.000). The protein and mRNA expression of active caspase-3 and Bax had the highest level in sepsis group, followed by the curcumin group, and that in the sham group was the lowest [active caspase-3 protein (gray scale): 1.698 ± 0.061, 0.694 ± 0.045, 0.246 ± 0.027, F=1 289.667, P=0.000; active caspase-3 mRNA (2(-ΔΔCt)): 1.031 ± 0.135, 0.578 ± 0.144, 0.183 ± 0.036, F=66.958, P=0.000; Bax protein (gray scale): 1.826 ± 0.126, 1.254 ± 0.140, 0.623 ± 0.901, F=94.536, P=0.000; Bax mRNA (2(-ΔΔCt)): 2.774 ± 0.338, 1.661 ± 0.226, 0.656 ± 0.114, F=124.710, P=0.000], all of these values had statistical significance among the three groups (all P<0.01). While Bcl-2 protein and mRNA had the highest level in curcumin group and lowest level in the sham group [Bcl-2 protein (gray scale): 0.716 ± 0.091, 1.328 ± 0.147, 1.656 ± 0.104, F=84.918, P=0.000; Bcl-2 mRNA (2(-ΔΔCt)): 0.617 ± 0.118, 1.393 ± 0.096, 1.650 ± 0.167, F=83.846, P=0.000]. The protein and mRNA expressions of Bcl-2/Bax ratio were lowest in sepsis group, then sham group, and highest in curcumin group [Bcl-2/Bax protein (gray scale): 0.726 ± 0.055, 1.150 ± 0.043, 1.333 ± 0.163, F=46.265, P=0.000; Bcl-2/Bax mRNA (2(-ΔΔCt)): 0.505 ± 0.041, 0.944 ± 0.097, 1.006 ± 0.168, F=12.211, P=0.001].. MPT can lead to mitochondrial dysfunction and further cause hepatocyte apoptosis. Mechanism of effect of curcumin on MPT may be related to reduction of intracellular calcium concentration, promotion of anti-apoptotic Bcl-2 gene expression, inhibition of caspase-3 activation and Bax gene.

Topics: Aniline Compounds; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Curcumin; Hepatocytes; Male; Mitochondria; Permeability; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Xanthenes

Curcumin has the potential to treat inflammatory diseases. This study investigated its effect on sepsis-induced acute lung injury (ALI) in a rat model. 125 healthy rats were randomly divided into five groups, including normal group, sham-operated group, sepsis group, dimethyl sulfoxide group, and curcumin-treated group (25 rats in each subgroup). Sepsis-induced acute lung injury was affected by cecal ligation and puncture surgery. At 0, 6, 12, 24, and 48 h after treatment, the lungs were harvested for histological and protein expression examinations. 24h after the initial treatment, real-time PCR and Western blot analysis showed that the expression of TGF-β1 and SMAD3-dependent signaling pathway was significantly decreased in the curcumin-treated group than other control groups (P<0.05). Therefore, curcumin played a protective role in sepsis-induced ALI, possibly through the inhibition of the expression of TGF-β1/SMAD3 pathway which may provide a new strategy for the treatment of sepsis-induced ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Curcumin; Disease Models, Animal; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Smad3 Protein; Transforming Growth Factor beta1

We previously reported the design and discovery of three series of 5-carbon linker-containing mono-carbonyl analogs of curcumin (MCACs) as excellent anti-inflammatory agents. In continuation of our ongoing research, we designed and synthesized the fourth series of MCACs, whose central linker is a piperid-4-one. Their inhibitory effects against IL-6 production were evaluated in lipopolysaccharide (LPS)-stimulated macrophages. Among them, compounds F8, F29, F33, F35, and F36 exhibited the IC50 values under 5 μM. The structure-activity relationship was discussed. Mechanistically, F35 and F36 dose-dependently prevented LPS-induced NF-κB and ERK activation. Finally, pretreatment with F35 and F36 significantly protected the C57B/L6 mice from LPS-induced septic death. Together, these data present a series of new analogs of curcumin as promising anti-inflammatory agents.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Curcumin; Dose-Response Relationship, Drug; Drug Discovery; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Inflammation; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidones; Sepsis; Signal Transduction; Structure-Activity Relationship; Survival Analysis

To investigate the effects of curcumin, an antioxidant and anti-inflammatory agent, on free oxygen radicals and lipid peroxidation in an experimental sepsis model, as well as to determine the role of curcumin in preventing hepatorenal tissue damage caused by sepsis.. The rats were randomly divided into three groups (n=8) as follows: control group (group 1); sepsis group (group 2); and sepsis + curcumin group (group 3). Sepsis was created using the cecal ligation and perforation (CLP) method. Curcumin was administered intraperitoneally (200 mg/kg) in two equal doses just after the perforation and at twelve hours post-perforation.. Serum TNF-a and IL-1ß, and tissue MDA and MPO values were higher, whereas tissue GSH and Na+/K+-ATPase values were lower, in group 2 as compared to group 1. These values in group 3 were the inverse of those in group 2. As compared to group 1, histopathological evaluation of group 2 showed damaged hepatocytes, glomeruli, and tubules, whereas the damage was significantly reduced in group 3 as compared to group 2.. The strong antioxidant and anti-inflammatory effects of curcumin against potential hepatorenal damage were shown using an experimental sepsis model in rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cecum; Curcumin; Disease Models, Animal; Free Radicals; Hepatorenal Syndrome; Injections, Intraperitoneal; Ligation; Lipid Peroxidation; Male; Random Allocation; Rats; Rats, Wistar; Sepsis; Tumor Necrosis Factor-alpha

The heart is one of the target organs susceptible to attack by sepsis, and protection of the cardiac function in sepsis or alleviation dysfunction caused by sepsis appears a serious and urgent problem.. This study was designed to explore the effect of curcumin on myocardial injury induced by sepsis and to explore the therapeutic effect of curcumin in managing sepsis induced cardiac dysfunction.. Cecal ligation and puncture surgery were used to establish the sepsis model. Curcumin was administered by peritoneal injection (200 mg/kg/d, 3 days). The effects of curcumin on the cardiac functions [Ejection Fraction (EF), Fractional Shortening (FS), Cardiac Output (CO), Heart Rate (HR)], body temperature, cTn I and superoxide dismutase levels, malondialdehyde content (an index of lipid peroxidation), and myocardial histopathological and ultrastructural studies were carried out.. We demonstrated that treatment of rats with curcumin significantly decreased elevated levels of cTn I and MDA (p < 0.05) in plasma, and increase the levels of SOD (p < 0.05) after CLP. Moreover, curcumin markedly enhanced the myocardial contractility by increasing the decreased EF and FS in rats with sepsis induced by CLP (p < 0.05). In addition, curcumin could alleviate the myocardial inflammation and structure damage of myocardial cells in sepsis induced by CLP.. In conclusion, the results from the present study demonstrate that curcumin has the protective effects on cardiac function in rats with sepsis and curcumin could be considered as an effective and safe therapeutic agent for the management of sepsis induced cardiac dysfunction.

Topics: Animals; Body Temperature Regulation; Cardiac Output; Cardiotonic Agents; Cecum; Curcumin; Disease Models, Animal; Heart Rate; Ligation; Lipid Peroxidation; Male; Malondialdehyde; Myocardial Contraction; Myocardium; Punctures; Rats; Rats, Sprague-Dawley; Sepsis; Stroke Volume; Superoxide Dismutase; Troponin I; Ventricular Dysfunction; Ventricular Function

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Male; Sepsis

The present study aimed to investigate the effect of curcumin on sepsis-induced acute lung injury (ALI) in rats, and explore its possible mechanisms. Male Sprague-Dawley rats were randomly divided into the following five experimental groups (n = 20 per group): animals undergoing a sham cecal ligature puncture (CLP) (sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with vehicle (vehicle group), curcumin at 50 mg/kg (low-dose curcumin [L-Cur] group), or curcumin at 200 mg/kg (high-dose curcumin [H-Cur] group).At 6, 12, 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level, and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathologic changes in lungs. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, as well as superoxidase dismutase (SOD) activity were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interluekin-8 (IL-8), and macrophage migration inhibitory factor (MIF) were determined in the BALF. Survival rates were recorded at 72 h in the five groups in another experiment. Treatment with curcumin significantly attenuated the CLP-induced pulmonary edema and inflammation, as it significantly decreased lung W/D ratio, protein concentration, and the accumulation of the inflammatory cells in the BALF, as well as pulmonary MPO activity. This was supported by the histopathologic examination, which revealed marked attenuation of CLP-induced ALI in curcumin treated rats. In addition, curcumin significantly increased SOD activity with significant decrease in MDA content in the lung. Also, curcumin caused down-regulation of the inflammatory cytokines TNF-α, IL-8, and MIF levels in the lung. Importantly, curcumin improved the survival rate of rats by 40%-50% with CLP-induced ALI. Taken together, these results demonstrate the protective effects of curcumin against the CLP-induced ALI. This effect can be attributed to curcumin ability to counteract the inflammatory cells infiltration and, hence, ROS generation and regulate cytokine effects.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchoalveolar Lavage Fluid; Curcumin; Dose-Response Relationship, Drug; Interleukin-8; Lung; Macrophage Migration-Inhibitory Factors; Male; Malondialdehyde; Models, Animal; Oxidative Stress; Peroxidase; Rats; Rats, Sprague-Dawley; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Triggering receptor expressed on myeloid cells 1 (TREM-1) is a member of the immunoglobulin superfamily expressed on macrophage and neutrophils and is emerging as a potent amplifier of TLR initiated inflammatory responses. Blockade of TREM-1 improves survival in animal models of sepsis. In this study, we show that curcumin or diferuloylmethane, a yellow pigment present in turmeric, a major ingredient of curry spice inhibited the expression of TREM-1 in vitro in primary bone marrow derived macrophages and in vivo in lungs of mice with sepsis. Chromatin immunoprecipitation assay confirmed that curcumin inhibits the binding of p65 to TREM-1 promoter in response to LPS. Further we show that curcumin inhibited p300 activity in the TREM-1 promoter region leading to hypoacetylation of histone 3 and 4 in the lysine residues. Inhibition of TREM-1 by curcumin is oxidant independent. These studies are the first report to define a detailed molecular mechanism by which curcumin exerts anti-inflammatory effects through regulation of TREM-1 gene activity and provide additional mechanistic insights into the anti-inflammatory effect of curcumin.

Topics: Acetylation; Animals; Curcumin; Epigenesis, Genetic; Histones; Lipopolysaccharides; Lung; Macrophages; Male; Membrane Glycoproteins; Methylation; Mice; Mice, Inbred C57BL; p300-CBP Transcription Factors; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins; Reactive Oxygen Species; Receptors, Immunologic; Sepsis; Survival Analysis; Trans-Activators; Transcription Factor RelA; Triggering Receptor Expressed on Myeloid Cells-1

We previously showed that 2,6-bis-(4-hydroxyl-3-methoxybenzylidine)cyclohexanone (BHMC), suppressed the synthesis of various proinflammatory mediators. In this study we explain the mechanism of action of BHMC in lipopolysaccharide (LPS)-induced U937 monocytes and further show that BHMC prevents lethality of CLP-induced sepsis. BHMC showed dose-dependent inhibitory effects on p38, JNK and ERK 1/2 activity as determined by inhibition of phosphorylation of downstream transcription factors ATF-2, c-Jun and Elk-1 respectively. Inhibition of these transcription factors subsequently caused total abolishment of AP-1-DNA binding. BHMC inhibited p65 NF-κB nuclear translocation and DNA binding of p65 NF-κB only at the highest concentration used (12.5μM) but failed to alter phosphorylation of JNK, ERK1/2 and STAT-1. Since the inhibition of p38 activity was more pronounced we evaluated the possibility that BHMC may bind to p38. Molecular docking experiments confirmed that BHMC fits well in the highly conserved hydrophobic pocket of p38 MAP kinase. We also show that BHMC was able to improve survival from lethal sepsis in a murine caecal-ligation and puncture (CLP) model.

Topics: Animals; Binding Sites; Blotting, Western; Curcumin; Cyclohexanones; DNA; Electrophoretic Mobility Shift Assay; Immunoprecipitation; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Mitogen-Activated Protein Kinases; Monocytes; NF-kappa B; Phosphorylation; Sepsis; Signal Transduction; Transcription Factor AP-1

Circulating cell-endothelial cell interaction in sepsis is a rate-determining factor in organ dysfunction, and interventions targeting this process have a potential therapeutic value. In this project, we examined whether curcumin, an active ingredient of turmeric and an anti-inflammatory agent, could disrupt interactions between circulating blood cells and endothelium and improve survival in a murine model of sepsis.. Mice were subjected to cecal ligation and puncture (CLP) to induce sepsis vs. sham surgery. We studied leukocyte and platelet adhesion in cerebral microcirculation using intravital fluorescent video microscopy technique, blood-brain barrier (BBB) dysfunction using Evans Blue (EB) leakage method, P-selectin expression using dual radiolabeling technique, and survival in mice subjected to Sham, CLP, and CLP with curcumin pre-treatment (CLP + curcumin).. Curcumin significantly attenuated leukocyte and platelet adhesion in cerebral microcirculation, EB leakage in the brain tissue, and improved survival in mice with CLP. P-selectin expression in mice with CLP + curcumin was significantly attenuated compared with CLP in various microcirculatory beds, including brain. Reduction in platelet adhesion was predominantly via modulation of endothelium by curcumin.. Curcumin pre-treatment modulates leukocyte and platelet adhesion and BBB dysfunction in mice with CLP via P-selectin expression and improves survival in mice with CLP.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood-Brain Barrier; Cell Adhesion; Curcumin; Disease Models, Animal; Leukocyte Rolling; Leukocytes; Male; Mice; Mice, Inbred C57BL; Microcirculation; Microscopy, Video; P-Selectin; Platelet Adhesiveness; Sepsis

The effect of erythropoietin (Epo) and granulocyte colony-stimulating factor (G-CSF) alone or in combination with the hepatoprotective antioxidant curcumin (Cur) was evaluated in a model of delayed liver regeneration.. Sprague Dawley rats underwent 70% liver resection with simultaneous cecal ligation and puncture and were randomised to five groups: no treatment, G-CSF (100 microg/kg), Epo (1,000 IU/kg), each alone or in combination with Cur (100mg/kg). Twenty-four hours after surgery, blood and tissue samples were collected. Markers of liver regeneration (liver weight, mitotic index, Ki-67 index), function (bilirubin, bile flow) and hepatocellular damage (liver enzymes, histomorphology) were determined. In addition, cytokine expression and hepatic glutathione concentrations were measured.. Liver regeneration was not improved by G-CSF or Epo monotherapy. Epo more effectively increased liver weight and regeneration markers, but the difference was not significant. Whereas liver regeneration was slightly inhibited in the G-CSF plus Cur group, Epo plus Cur significantly improved liver regeneration. This was accompanied by reduced oxidative stress. Liver function and the expression of pro-inflammatory cytokines were comparable in all treatment groups.. In the present model, Epo, at a relatively low dosage, did not improve liver regeneration. However, the combination of Epo and Cur showed a synergistic effect with highly significant stimulation of liver regeneration.

Topics: Administration, Oral; Animals; Antioxidants; Cell Division; Curcumin; Drug Administration Schedule; Drug Synergism; Erythropoietin; Granulocyte Colony-Stimulating Factor; Injections, Intraperitoneal; Intestinal Perforation; Liver Function Tests; Liver Regeneration; Organ Size; Peritonitis; Premedication; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sepsis

Although phytochemical curcumin has been shown to possess anti-inflammatory properties, it remains unknown whether this agent has any beneficial effects in sepsis. The purpose of this study was to demonstrate whether curcumin protects septic animals and, if so, whether activation of peroxisome proliferator-activated receptor (PPAR)-gamma, an anti-inflammatory nuclear receptor, plays any role.. Prospective, controlled, and randomized animal study.. A research institute laboratory.. Male Sprague-Dawley rats.. A bolus injection of 0.2 micromol of curcumin was given intravenously to male adult rats, followed by continuous infusion of curcumin (0.24 micromol/day) for 3 days via a primed 2-mL mini-pump. The rats were then subjected to sepsis by cecal ligation and puncture (CLP).. Serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase), lactate, albumin, and tumor necrosis factor (TNF)-alpha were measured at 20 hrs after CLP (i.e., late stage of sepsis). In addition, a 10-day survival curve was conducted following CLP and cecal excision with or without curcumin treatment. Furthermore, macrophages cell line RAW 264.7 cells were treated with curcumin followed by stimulation with endotoxin. TNF-alpha and PPAR-gamma expression were then measured. The results indicate that intravenous administration of curcumin before the onset of sepsis attenuated tissue injury, reduced mortality, and decreased the expression of TNF-alpha in septic animals. Similar results were also found when curcumin was administered after the onset of sepsis. Moreover, the down-regulated PPAR-gamma in the liver at 20 hrs after CLP was significantly improved by curcumin treatment. Concurrent administration of curcumin and GW9662, a specific PPAR-gamma antagonist, completely abolished the beneficial effects of curcumin under such conditions. In cultured RAW 264.7 cells, curcumin inhibited endotoxin-induced increases in TNF-alpha expression and markedly up-regulated PPAR-gamma expression without affecting cell viability. Curcumin also prevented morphologic alterations in macrophages induced by endotoxin.. The protective effect of curcumin makes it or its analogues strong candidates as a novel therapy for sepsis. The beneficial effect of curcumin appears to be mediated by up-regulation of nuclear receptor PPAR-gamma.

Topics: Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Survival; Curcumin; Down-Regulation; Endotoxins; Lactates; Liver; Macrophages; Male; PPAR gamma; Prospective Studies; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Serum Albumin; Transaminases; Tumor Necrosis Factor-alpha; Up-Regulation

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Curcumin; Mice; PPAR gamma; Sepsis; Up-Regulation

The hepatic cytochrome P-450 (CYP) enzyme system provides a major aspect of liver function, yet alterations of CYP in sepsis remain largely unknown. Although we have recently shown that CYP1A2, one of the major isoforms of CYP in rats, is downregulated in sepsis, the underlying mechanism and possible therapeutic approaches warrant further investigation. The aim of this study was to determine whether Kupffer cells (KCs) play any role in suppressing CYP1A2 in the hepatocytes (HCs) and if so, how to modulate CYP1A2 expression in sepsis. To study this, primary KCs and HCs were cultured separately or together with or without transwells. Cells and supernatant samples were collected after various stimulations. Additionally, polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP) with or without curcumin pretreatment. Liver samples were harvested 20 h post-CLP. The results show that lipopolysaccharide (LPS) did not suppress CYP1A2 in HC or HC/KC coculture with transwells. However, LPS downregulated CYP1A2, aryl hydrocarbon receptor (AhR, a nuclear receptor) and AhR nuclear translocator (Arnt) in coculture without transwells. Anti-TNF-alpha and anti-IL-1beta antibodies attenuated this downregulation. Moreover, elevated hepatic levels of TNF-alpha and IL-1beta post-CLP were decreased by curcumin pre-treatment. This reduction was associated with increased expression of AhR and CYP1A2. These results indicate that KCs-derived proinflammatory cytokines may play an important role in downregulating CYP1A2 in sepsis. The reduction of AhR/Arnt may be the underlying mechanism for such downregulation. Inhibition of proinflammatory cytokines by curcumin may provide a novel approach to modulate the hepatic CYP function in sepsis.

Topics: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator; Cells, Cultured; Curcumin; Cytochrome P-450 CYP1A2; Cytochromes; Enzyme Inhibitors; Hepatocytes; Humans; Interleukin-1beta; Isoenzymes; Kupffer Cells; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon; Sepsis; Signal Transduction; Tumor Necrosis Factor-alpha

Despite advances in the management of sepsis and acute respiratory distress syndrome, the mortality rate remains high. Delayed apoptosis of neutrophils is associated with multiple organ failure under those conditions. Thus, development of nontoxic neutrophil apoptosis regulating molecules may provide a novel therapeutic strategy. Curcumin is a promising dietary supplement for cancer prevention. However, the effect of curcumin on human neutrophil apoptosis remains unknown. We therefore hypothesized that curcumin would produce a proapoptotic effect on neutrophils.. Prospective, controlled, and randomized in vitro study.. Research institute laboratory.. Human peripheral neutrophils obtained from normal subjects.. None.. In the presence or absence of curcumin, both spontaneous neutrophil apoptosis and apoptosis of neutrophils following transmigration across a human lung endothelium-epithelium bilayer were studied by morphology and terminal dUTP nucleotide end labeling analyses, respectively. Myeloperoxidase activity and migration assays were performed to determine the impact of curcumin on neutrophil function. To elucidate the potential mechanism, the p38 mitogen-activated protein kinase pathway and caspase-3 activity were examined by Western blotting and enzymatic analyses. The data demonstrate that curcumin increased constitutive neutrophil apoptosis and abrogated the transbilayer migration-induced delay in neutrophil apoptosis. Neutrophil activation was reduced by curcumin treatment as evidenced by a decrease in migration and myeloperoxidase release. A marked increase in p38 phosphorylation and caspase-3 activity was observed following curcumin exposure. In addition, inhibition of p38 mitogen-activated protein kinase with SB203580 suppressed apoptosis and caspase-3 activation induced by curcumin. Thus, activation of p38 mitogen-activated protein kinase or an increase in caspase-3 activity appears to contribute to the proapoptotic effect of human neutrophil apoptosis by curcumin.. The characteristics of curcumin, including its proapoptotic effect and antidegranulation effect, make it a potential candidate for the therapy of neutrophil-induced lung injury and sepsis.

Topics: Antineoplastic Agents; Apoptosis; Curcumin; Humans; In Situ Nick-End Labeling; In Vitro Techniques; Neutrophils; p38 Mitogen-Activated Protein Kinases; Sepsis

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Curcumin; Enzyme Activation; Humans; Neutrophils; p38 Mitogen-Activated Protein Kinases; Respiratory Distress Syndrome; Sepsis