curcumin and Endotoxemia

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

Topics: Albumins; Animals; Anti-Inflammatory Agents; Curcumin; Dextrans; Endothelium; Endotoxemia; Lipopolysaccharides; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley

Type 2 diabetes mellitus (T2DM) is known as a complex genetic disease characterized by genetic and environmental factors. The imbalanced intestinal flora and intestinal mucosal barrier are considered to be related to T2DM. Curcumin has been proved to affect the progression of T2DM. T2DM animal was established by low-dose streptozotocin intraperitoneal injection combined with high-fat diet (HFD) feeding. Hematoxylin and eosin (HE) staining and transfer electron microscopy (TEM) were used to observe morphological changes of intestinal tissues of T2DM rats. Insulin and glucose tolerance tests were performed to investigate the influence of curcumin on blood glucose. Curcumin significantly improved the intestinal integrity, hyperglycemia and insulin resistance in diabetic rats. The metabolic endotoxemia induced by HFD in diabetic rats was inhibited remarkably. Curcumin reversed gut microbiota dysbiosis in diabetic rats caused by HFD. We demonstrated that curcumin could protect intestinal mucosal barrier, improve insulin resistance and reduce blood glucose in diabetic rats. This study might provide experimental evidence for the prevention and treatment in T2DM.

Topics: Animals; Bacteroidetes; Bifidobacterium; Curcumin; Diabetes Mellitus, Type 2; Diet, High-Fat; Endotoxemia; Firmicutes; Gastrointestinal Microbiome; Gene Ontology; Hyperglycemia; Insulin Resistance; Intestines; Lipopolysaccharides; Metabolomics; Mice; NF-kappa B; Rats; Signal Transduction; Tight Junction Proteins; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Curcumin (diferuloylmethane), a major component of turmeric is well known for its anti-inflammatory potential. Present study investigates sequential release of inflammatory mediators post LPS challenge (10 mg/kg,i.p.) causing lung inflammation and its modulation by curcumin through different routes (20 mg/kg, i.p and 10 mg/kg, i.n.) in murine model. Dexamethasone (1 mg/kg, i.p) was used as standard drug.. Lung Inflammation was evaluated by histopathological analysis, myeloperoxidase (MPO) activity followed by inflammatory cell count and total protein content measurements in bronchoalveolar fluid (BALF). Reactive oxygen species (ROS), nitrite and TNF-α levels were measured as markers of endotoxin shock at different time points (1-72 h). The mRNA expression of transforming growth factors-β1 (TGF-β1), iNOS and Toll-like receptor-4 (TLR-4) were measured followed by Masson's trichrome staining and hydroxyproline levels as collagen deposition marker leading to fibrotic changes in lungs.. We found that LPS-induced lung inflammation and injury was maximum 24-h post LPS challenge shown by MPO and histological analysis which was further supported by elevated nitrite and ROS levels whereas TNF-α level was highest after 1 h. Endotoxin-induced mortality was significantly reduced in curcumin (i.p) pretreatment groups up to 72-h post LPS challenge. Significant inhibition in mRNA expression of iNOS, TGF-β1 and TNF-α level was noted after curcumin treatment along with lowered MPO activity, inflammatory cell count, ROS, nitrite levels and collagen deposition in lungs.. Our results suggest that higher endotoxin dose causes inflammatory mediator release in chronological order which tend to increase with time and reached maximum after 24-h post-endotoxin (LPS) exposure. Intraperitoneal route of curcumin administration was better in modulating inflammatory mediator release in early phase as compared to intranasal route of administration. It can be used as supplementary therapeutic intervention at early stage of endotoxemia, having fewer side effects.

Topics: Animals; Bronchoalveolar Lavage Fluid; Curcumin; Disease Models, Animal; Endotoxemia; Inflammation Mediators; Lipopolysaccharides; Lung; Mice; Nitric Oxide Synthase Type II; Peroxidase; Pneumonia; Reactive Oxygen Species; RNA, Messenger; Toll-Like Receptor 4; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Oxidative stress is implicated in various pathological conditions, including septic shock, and other diseases associated with local or systemic inflammation. Curcumin, a major component from turmeric (Curcuma longa), possesses diverse anti-inflammatory, anti-tumour and antioxidant properties. The aim of this study was to investigate the effect of curcumin on modulation of vascular dysfunction and oxidative stress induced by lipopolysaccharide (LPS) in mice. Male ICR mice were treated with curcumin (50 or 100 mg/kg), administered intragastrically, either before or after intraperitoneal injection of LPS (10 mg/kg). Fifteen hours after LPS administration, arterial blood pressure was measured and vascular response to vasoactive agents were assessed. Aortic tissues and blood samples were taken for assays of antioxidant and oxidative stress markers. LPS caused marked hypotension, tachycardia and vascular hyporeactivity. The mean arterial pressures in responses to phenylephrine, acetylcholine, and sodium nitroprusside of LPS-treated mice were significantly decreased when compared with the untreated controls. Curcumin modulated heart rate and restored arterial blood pressure in a dose-dependent manner in both protectively- and therapeutically-treated regimens. Furthermore, the vascular responsiveness of LPS-treated mice was improved by curcumin. Interestingly, the improvements of haemodynamics and vascular response during endotoxaemia were related to alleviation of oxidative stress by reducing aortic-derived superoxide production, suppression of lipid peroxidation and protein oxidation, and decrease in urinary nitric oxide metabolites with preservation of the ratio of glutathione/glutathione disulfide. This study provides the first evidence for the potential role of curcumin in prevention and treatment of vascular dysfunction in mice with endotoxaemia elicited by LPS.

Topics: Animals; Antioxidants; Blood Vessels; Curcumin; Endotoxemia; Hemodynamics; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Oxidants; Oxidative Stress

Disseminated intravascular coagulation (DIC) is a lethal situation in severe infections, characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. Current clinical trials are not promising. In this study, we investigated the protective effect of curcumin in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by sustained infusion of LPS (10 mg/kg body weight) for 4 h through the tail vein. Curcumin (60 mg/kg body weight) was given intraperitoneally 3 h before LPS infusion. Results showed that, in vivo, curcumin reduced the mortality rate of LPS-infused rats by decreasing the circulating TNF-alpha levels and the consumption of peripheral platelets and plasma fibrinogen. Furthermore, in vivo curcumin also has the effect of preventing the formation of fibrin deposition in the glomeruli of kidney. These results reveal the therapeutic potential of curcumin in infection-related coagulopathy of DIC.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Curcumin; Disease Models, Animal; Disseminated Intravascular Coagulation; Endotoxemia; Escherichia coli; Fibrin; Fibrinogen; Injections, Intraperitoneal; Kidney Glomerulus; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Survival Rate; Tumor Necrosis Factor-alpha

Intercellular adhesion molecule-1 (ICAM-1) is involved in neutrophil transmigration across endothelium during sepsis-induced acute lung injury and anti-ICAM-1 interventions may represent new strategy of pulmonary protection. Haem oxygenase-1 (HO-1) has been demonstrated to exert anti-inflammatory actions via decrease of expression of adhesion molecules. We investigated the role of HO-1 in the action of curcumin, a naturally occurring yellow pigment isolated from plant Curcuma longa L., on ICAM-1 expression in tumour necrosis factor-alpha-stimulated EA.hy926 cells and lungs of lipopolysaccharide-treated mice. Both, in vitro and in vivo curcumin induced HO-1 and curcumin-elicited induction of HO-1 was associated with inhibition ICAM-1 expression. Moreover, curcumin significantly inhibited pulmonary sequestration of leucocytes in response to lipopolysaccharide as evidenced by decrease of myeloperoxidase activity in lung tissue. Both in vitro and in vivo effects of curcumin were reversed by an inhibitor of HO activity, chromium (III) mesoporphyrin IX chloride. We conclude that induction of HO-1, via decrease of endothelial ICAM-1, plays a pivotal role in curcumin-dependent prevention of pulmonary sequestration of neutrophils in a mouse model of endotoxaemia.

Topics: Animals; Cells, Cultured; Curcuma; Curcumin; Disease Models, Animal; Endothelium, Vascular; Endotoxemia; Female; Heme Oxygenase-1; Humans; In Vitro Techniques; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Lung; Mice; Mice, Inbred C57BL; Neutrophils; Peroxidase; Random Allocation; Tumor Necrosis Factor-alpha; Up-Regulation

Curcuminoids, derived from the plant Curcuma domestica Val., have been shown to be free radical scavengers that suppress the production of superoxide by macrophages and potent anti-inflammatory agents that inhibit the lipopolysacharide (LPS)-induced production of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta, and the activation of nuclear factor (NF)-kappaB in human monocytic derived cells. The present study was undertaken to determine the efficacy of curcuminoids in inhibiting the hepatic microvascular inflammatory response elicited by LPS. BALB/C mice were gavaged intragastricly with curcuminoids [40 mg/kg body weight (bw) or 80 mg/kg bw] 1 h before intravenous injection of LPS (Escherichia coli, O111:B4, 100 microg/kg bw). The liver was examined 2 h after LPS injection using in vivo microscopic methods. LPS-treated mice showed significantly increased phagocytic activity of centrilobular Kupffer cells. The numbers of leukocytes adhering to the sinusoidal wall and swollen endothelial cells increased significantly in both the periportal and centrilobular regions, concomitant with a reduction in the numbers of sinusoids containing flow. Pretreatment with curcuminoids at the doses of 40 mg/kg bw or 80 mg/kg bw to endotoxemic mice significantly reduced the phagocytic activity of Kupffer cells, the numbers of adhering leukocytes and swollen endothelial cells. As a result, the number of sinusoids containing flow was increased in animals treated with 40 mg/kg curcuminoids and restored to control levels with 80 mg/kg curcuminoids. Neutrophil sequestration was reduced when measured in sections stained with naphtol AS-D chloroacetate esterase technique. These results demonstrate that curcuminoids are effective in suppressing the hepatic microvascular inflammatory response to LPS and may be a natural alternative anti-inflammatory substance.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcuma; Curcumin; Endothelium; Endotoxemia; Endotoxins; Hepatitis; Kupffer Cells; Leukocytes; Liver; Male; Mice; Mice, Inbred BALB C; Microcirculation; Phagocytosis