Anti-inflammatory effect of cinnamaldehyde and linalool from the leaf essential oil of Cinnamomum osmophloeum Kanehira in endotoxin-induced mice.

Cinnamomum osmophloeum Kanehira is a Taiwan native plant that belongs to genus Cinnamomum and is also known as pseudocinnamomum or indigenous cinnamon. Its leaf is traditionally used by local people in cooking and as folk therapy. We previously demonstrated the chemical composition and anti-inflammatory effect of leaf essential oil of Cinnamomum osmophloeum Kanehira of linalool chemotype in streptozotocin-induced diabetic rats and on endotoxin-injected mice. The aim of the present study is to evaluate whether cinnamaldehyde and linalool the active anti-inflammatory compounds in leaf essential oil of Cinnamomum osmophloeum Kanehira. Before the injection of endotoxin, C57BL/6 mice of the experimental groups were administered cinnamaldehyde (0.45 or 0.9 mg/kg body weight) or linalool (2.6 or 5.2 mg/kg body weight), mice of the positive control group were administered the leaf essential oil (13 mg/kg body weight), and mice of the negative group were administered vehicle (corn oil, 4 mL/kg body weight) by gavage every other day for two weeks. All mice received endotoxin (i.p. 10 mg/mL/kg body weight) the next day after the final administration and were killed 12 h after the injection. Normal control mice were pretreated with vehicle followed by the injection with saline. None of the treatment found to affect body weight or food or water intake of mice before the injection of endotoxin. Cinnamaldehyde and linalool were found significantly reversed endotoxin-induced body weight loss and lymphoid organ enlargement compared with vehicle (P < 0.05). Both compounds also significantly lowered endotoxin-induced levels of peripheral nitrate/nitrite, interleukin (IL)-1ß, IL-18, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and High-mobility group box 1 protein (HMGB-1), and levels of nitrate/nitrite, IL-1ß, TNF-α, and IFN-γ in spleen and mesenteric lymph nodes (MLNs) (P < 0.05). Endotoxin-induced expression of toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), myeloid differentiation protein 2 (MD2), Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and caspase-1 in spleen and mesenteric lymph nodes (MLNs) were inhibited by all tested doses of cinnamaldehyde and linalool (P < 0.05). Subsequently, the activation of nuclear factor (NF)-κB and the activity of caspase-1 in spleen and MLNs were also suppressed by these two compounds (P < 0.05). In addition, cinnamaldehyde and linalool at the dose equivalent to their corresponding content in the tested dose of the leaf essential oil, which was 0.9 mg/kg and 5.2 mg/kg, respectively, showed similar or slightly less inhibitory activity for most of these inflammatory parameters compared with that of the leaf essential oil. Our data confirmed the potential use of leaf essential oil of Cinnamomum osmophloeum Kanehira as an anti-inflammatory natural product and provide evidence for cinnamaldehyde and linalool as two potent agents for prophylactic use in health problems associated with inflammations that being attributed to over-activated TLR4 and/or NLRP3 signaling pathways.

Noni (Morinda citrifolia L.) Fruit Extracts Improve Colon Microflora and Exert Anti-Inflammatory Activities in Caco-2 Cells.

Intestinal microflora and inflammation are associated with the risk of inflammatory bowel diseases. Noni (Morinda citrifolia L.) has various bioactivities, but its effect on colon health remains unknown. This study focused on the effects of fermented noni fruit extracts on colon microflora and inflammation of colon epithelial cells. The anti-inflammatory activities of ethanol and ethyl acetate extracts on Caco-2 cells were evaluated including interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2). The growth of Lactobacillus and Bifidobacterium species was promoted by ethanol extract. Ethyl acetate extract decreased intracellular reactive oxygen species and significantly suppressed COX-2, IL-8, and prostaglandin E2 production and neutrophil chemotaxis by suppressing the translocation of the p65 subunit. Quercetin was the main contributor to the anti-inflammatory activity. The fermented noni fruit promoted probiotic growths and downregulated the intracellular oxidation and inflammation in Caco-2 cells. These results suggest that fermented noni fruit might protect against inflammatory diseases of the colon.

A Comparison of Food-grade Folium mori ( Sang Yè) Extract and 1-Deoxynojirimycin for Glycemic Control and Renal Function in Streptozotocin-induced Diabetic Rats.

Folium mori ( Sang Yè, leaf of Morus alba L.; FM) is known to possess hypoglycemic effects, and 1-deoxynojirimycin (1-DNJ) has been proposed as an important functional compound in FM. However, the hypoglycemic activity of purified 1-DNJ has been rarely studied. It is also not known how FM and 1-DNJ affect the development of DM nephropathy. This study compared the antidiabetic effect of a commercial FM product with that of purified 1-DNJ in streptozotocin-induced diabetic rats. Seven days after induction, the diabetic rats were gavaged with FM (1, 3, 10, and 30 mg/kg/day), 1-DNJ (30 mg/kg/day), or vehicle (distilled deionized water; 2 ml/kg/day) for 7 days. All doses of FM ameliorated fasting and post-prandial blood glucose concomitantly with an increase in peripheral and pancreatic levels of insulin and improved homeostasis model assessment (HOMA-IR) in diabetic rats in a dose-dependent manner. Increased thiobarbituric acid reactive substances (TBARS) and nitrate/nitrite levels in the kidney, liver, and muscle of diabetic rats were reversed by all doses of FM. The renal function of the diabetic rats was normalized by all doses of FM, while blood pressure changes were reversed by FM at doses of 3 mg/kg and above. Moreover, most of the above-mentioned parameters were improved by FM at doses of 3 mg/kg and above to a similar extent as that of 1-DNJ. The results showed superior antidiabetic potential of the commercial FM product for glycemic control and protection against the development of diabetic nephropathy.

Andrographis paniculata Extract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats.

Andrographolide is the most abundant terpenoid of A. paniculata which is used in the treatment of diabetes. In this study, we investigated the effects of A. paniculata extract (APE) and andrographolide on the expression of drug-metabolizing enzymes in rat liver and determined whether modulation of these enzymes changed the pharmacokinetics of tolbutamide. Rats were intragastrically dosed with 2 g/kg/day APE or 50 mg/kg/day andrographolide for 5 days before a dose of 20 mg/kg tolbutamide was given. APE and andrographolide reduced the AUC0-12 h of tolbutamide by 37% and 18%, respectively, compared with that in controls. The protein and mRNA levels and enzyme activities of CYP2C6/11, CYP1A1/2, and CYP3A1/2 were increased by APE and andrographolide. To evaluate whether APE or andrographolide affected the hypoglycemic action of tolbutamide, high-fat diet-induced obese mice were used and treated in the same manner as the rats. APE and andrographolide increased CYP2C6/11 expression and decreased plasma tolbutamide levels. In a glucose tolerance test, however, the hypoglycemic effect of tolbutamide was not changed by APE or andrographolide. These results suggest that APE and andrographolide accelerate the metabolism rate of tolbutamide through increased expression and activity of drug-metabolizing enzymes. APE and andrographolide, however, do not impair the hypoglycemic effect of tolbutamide.

The Antidiabetic Effect of Garlic Oil is Associated with Ameliorated Oxidative Stress but Not Ameliorated Level of Pro-inflammatory Cytokines in Skeletal Muscle of Streptozotocin-induced Diabetic Rats.

Oxidative stress and inflammatory condition has been broadly accepted being associated with the progression of diabetes. On the other hand, garlic ( dà suàn, bulb of Allium sativum) has been shown to possess both antioxidant and anti-inflammatory action in several clinical conditions. Our previous study demonstrated that treatment with garlic oil improves oral glucose tolerance and insulin tolerance and improves the insulin-stimulated utilization of glucose to synthesize glycogen in skeletal muscle in streptozotocin (STZ)-induced diabetes, in vivo and ex vivo, respectively. The aim of the present study is to investigate the antioxidant and anti-inflammatory effects of garlic oil (GO) in the skeletal muscle of diabetic rats. Rats with STZ-induced diabetes received GO (10, 50, or 100 mg/kg body weight) or corn oil by gavage every other day for 3 weeks. Control rats received corn oil only. GO dose-dependently improved insulin sensitivity, as assessed by the insulin tolerance test, and oral glucose tolerance. GO significantly elevated total glutathione and glutathione peroxidase activity and lowered the nitrate/nitrite content in skeletal muscle at 50 and 100 mg/kg and significantly elevated glutathione reductase activity and lowered lipid peroxidation at 100 mg/kg. By contrast, GO did not reverse diabetes-induced elevation of IL-1ß and TNF-α in skeletal muscle at any tested dose. On the other hand, GO elevated the expression of GLUT4 in skeletal muscle along with glycogen content as observed with PAS staining. In conclusion, the antidiabetic effect of garlic oil is associated with ameliorated oxidative stress in skeletal muscle.

Effect of garlic sulfur compounds on neutrophil infiltration and damage to the intestinal mucosa by endotoxin in rats.

We investigated the protective effects of garlic sulfur compounds (GSCs), specifically, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), on endotoxin-induced intestinal damage. Wistar rats received by gavage 0.125 or 0.025 mmol/kg body wt of each GSC or the vehicle (corn oil; 2 mL/kg body wt) every other day for 2 weeks before being injected with endotoxin (ip, 5 mg/kg body wt). Control rats were administered corn oil and were injected with sterile saline. Rats were killed at 18 h after injection. Both doses of DAS suppressed endotoxin-induced neutrophilia, serum levels of sICAM-1 and CINC-1, cellular CD11b on neutrophils, and intestinal contents of ICAM-1, CINC-1, TNF-alpha, and IL-1beta (p<0.05). DADS suppressed endotoxin-induced intestinal contents of ICAM-1, TNF-alpha, and IL-1beta at both doses, but only suppressed the serum sICAM-1 level and cellular CD11b on neutrophils at the low dose (p<0.05). DATS did not ameliorate the endotoxin-induced serum level of sICAM-1 or CINC-1 but suppressed intestinal IL-1beta at both doses. The low but not the high dose of DATS also ameliorated the intestinal contents of ICAM-1 and TNF-alpha (p<0.05). All GSCs reversed endotoxin-induced neutrophil infiltration and damage in the intestine, and the order of the effects of these GSCs to normalize intestinal morphology was DAS>DADS>DATS.

Effect of garlic oil on neutrophil infiltration in the small intestine of endotoxin-injected rats and its association with levels of soluble and cellular adhesion molecules.

Garlic ( Allium sativum ) possesses anti-inflammatory effects. This study investigated the effects of garlic oil on endotoxin-induced neutrophil infiltration in the small intestine. Wistar rats received by gavage 10, 50, or 100 mg/kg body wt garlic oil (GO) or the vehicle (corn oil; 2 mL/kg body wt) every other day for 2 weeks before being injected with endotoxin (ip, 5 mg/kg body wt). Control rats were administered corn oil and injected with sterile saline. Blood samples for the measurement of soluble adhesion molecules were collected at various time points after injection, and all other samples were collected 18 h after injection. The 10 and 50 mg/kg doses suppressed endotoxin-induced neutrophilia, serum levels of sL-selectin and sICAM-1, cellular CD11b on neutrophils, intestinal ICAM-1 content, and neutrophil infiltration (P < 0.05). The 100 mg/kg dose significantly lowered local ICAM-1 and cellular CD11b on neutrophils (P < 0.05) but did not have a beneficial effect on neutrophil infiltration. In addition, 100 mg/kg of GO worsened the elevation of the local TNF-α level and neutrophilia. Appropriate doses of garlic oil have a preventive effect on endotoxin-induced neutrophil infiltration and damage to the small intestine.

Cardiac contractile dysfunction and apoptosis in streptozotocin-induced diabetic rats are ameliorated by garlic oil supplementation.

Previous studies have suggested that garlic oil could protect the cardiovascular system. However, the mechanism by which garlic oil protects diabetes-induced cardiomyopathy is unclear. In this study, streptozotocin (STZ)-induced diabetic rats received garlic oil (0, 10, 50, or 100 mg/kg of body weight) by gastric gavage every 2 days for 16 days. Normal rats without diabetes were used as control. Cardiac contractile dysfunction examined by echocardiography and apoptosis evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay were observed in diabetic rat hearts. Additionally, a shift in cardiac myosin heavy chain (MHC) gene expression from α- to ß-MHC isoform, decreased levels of superoxide dismutase-1 (SOD-1) and cardiac α-actin, and elevated cardiac thiobarbituric acid reactive substances (TBARS) and caspase- and p38-NFκB-leading apoptosis signaling activities were demonstrated in diabetic hearts. However, these diabetes-related cardiac dysfunctions were almost dose-dependently ameliorated by garlic oil administration. In conclusion, garlic oil possesses significant potential for protecting hearts from diabetes-induced cardiomyopathy.

Diallyl disulfide and diallyl trisulfide protect endothelial nitric oxide synthase against damage by oxidized low-density lipoprotein.

Garlic is viewed as an effective health food against atherosclerosis. In this study, we examined whether diallyl disulfide (DADS) and diallyl trisulfide (DATS) protect endothelial nitric oxide synthase (eNOS) activation against oxidized LDL (ox-LDL) insult and through what mechanism. We found that DADS and DATS reversed the suppression of eNOS Ser1177 phosphorylation by ox-LDL, and wortmannin abolished the reversal by DADS and DATS. Similarly, the inhibition of cellular cGMP and nitric oxide production by ox-LDL was reversed by DADS and DATS (p<0.05). This increase in nitric oxide bioavailability by the allyl sulfides was attenuated by wortmannin. Immunoprecipitation assay revealed that DADS and DATS preserved the interaction of eNOS with caveolin-1 in the membrane. In addition, DADS and DATS suppressed the reduction of the cellular eNOS protein content by ox-LDL. When cycloheximide was added to block protein synthesis, DADS and DATS suppressed eNOS protein degradation similarly to that noted by MG132. Ox-LDL increased chymotrypsin-like proteasome activity, and this increase was inhibited by the allyl sulfides and MG132 (p<0.05). These results suggest that DADS and DATS protect eNOS activity against ox-LDL insult. This protection can be attributed partly to their mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and prevention of eNOS degradation.

Effect of supplementation with garlic oil on activity of Th1 and Th2 lymphocytes from rats.

Garlic and garlic products are known to induce anti-inflammatory effects, but much of the research to date has focused on the inhibitory effect of garlic on the activity of mononuclear cells/macrophages. The effect of garlic on the balance of the two mutually inhibitory T helper cell subtypes, Th1 and Th2 cells, has hitherto received little attention. We thus studied the effect of supplementation with garlic oil on the activity of Th1 and Th2 cells. Rats were administered by gavage with garlic oil (10 - 200 mg/kg) or corn oil every other day for 2 weeks. Cervical lymph nodes were collected to assay the lymphocyte proliferation rate and the production of Th1 interleukin 2 (IL-2) and interferon gamma (IFN-gamma) and the Th2 cytokines IL-4 and IL-10 upon stimulation with concanavalin A. Garlic oil enhanced the lymphocyte proliferation rate accompanied by an elevated production of all four cytokines when given at a dose of 100 mg/kg. At 200 mg/kg, the production of IL-4 and IL-10 was further enhanced but IFN-gamma production was suppressed. The ratio of IFN-gamma to IL-4 was enhanced by 50 mg/kg garlic oil but suppressed by 200 mg/kg garlic oil. In conclusion, supplemental garlic oil has a dual effect on Th1-Th2 cell balance: an enhanced T cell response towards the Th1 type at low doses and towards the Th2 type at high doses.

Does garlic have a role as an antidiabetic agent?

Diabetes affects a large segment of the population worldwide, and the prevalence of this disease is rapidly increasing. Despite the availability of medication for diabetes, traditional remedies are desirable and are currently being investigated. Garlic (Allium sativum), which is a common cooking spice and has a long history as a folk remedy, has been reported to have antidiabetic activity. However, there is no general agreement on the use of garlic for antidiabetic purposes, primarily because of a lack of scientific evidence from human studies and inconsistent data from animal studies. The validity of data from previous studies of the hypoglycemic effect of garlic in diabetic animals and the preventive effects of garlic on diabetes complications are discussed in this review. The role of garlic as both an insulin secretagogue and as an insulin sensitizer is reviewed. Evidence suggests that garlic's antioxidative, antiinflammatory, and antiglycative properties are responsible for garlic's role in preventing diabetes progression and the development of diabetes-related complications. Large-scale clinical studies with diabetic patients are warranted to confirm the usefulness of garlic in the treatment and prevention of diabetes.

Effects of garlic oil and two of its major organosulfur compounds, diallyl disulfide and diallyl trisulfide, on intestinal damage in rats injected with endotoxin.

Garlic and its active components are known to possess antioxidant and antiinflammatory effects. The present study investigated the effects of garlic oil and its organosulfur compounds on endotoxin-induced intestinal mucosal damage. Wistar rats received by gavage 50 or 200 mg/kg body weight garlic oil (GO), 0.5 mmol/kg body weight diallyl disulfide or diallyl trisulfide, or the vehicle (corn oil; 2 ml/kg body weight) every other day for 2 weeks before being injected with endotoxin (i.p., 5 mg/kg body weight). Control rats were administered with corn oil and were injected with sterile saline. Samples for the measurement of proinflammatory cytokines were collected 3 h after injection, and all other samples were collected 18 h after injection. The low dose of GO suppressed endotoxin-induced inducible nitric oxide synthase (iNOS) activity, ulceration, and apoptosis in the intestinal mucosa (P < 0.05). The high dose of GO significantly lowered the peripheral level of nitrate/nitrite and endotoxin-induced iNOS activity in the intestinal mucosa (P < 0.05) but worsened intestinal mucosal damage accompanied by elevated peripheral proinflammatory cytokines. Diallyl trisulfide but not diallyl disulfide showed similar toxic effect as that of high-dose GO. These results suggest the preventive effect and possible toxicity of garlic oil and its organosulfur compounds in endotoxin-induced systemic inflammation and intestinal damage.

Effects of garlic oil and diallyl trisulfide on glycemic control in diabetic rats.

We investigated the effects of garlic oil and diallyl trisulfide on glycemic control in rats with streptozotocin-induced diabetes. Diabetic rats received by gavage garlic oil (100 mg/kg body weight), diallyl trisulfide (40 mg/kg body weight), or corn oil every other day for 3 weeks. Control rats received corn oil only. Both garlic compounds significantly raised the basal insulin concentration. The insulin resistance index as assessed by homeostasis model assessment and the first-order rate constant for glucose disappearance were significantly improved by both garlic compounds (P<0.05). Oral glucose tolerance was also improved by both garlic compounds and was accompanied by a significantly increased rate of insulin secretion (P<0.05). Glycogen formation (but not that of lactate or carbon dioxide) from glucose by the soleus muscle in the presence of 10 or 100 microU/ml of insulin was significantly better after treatment with both garlic compounds. Both garlic oil and diallyl trisulfide improve glycemic control in diabetic rats through increased insulin secretion and increased insulin sensitivity.

Effect of supplemental L-arginine on the function of T lymphocytes and the formation of advanced glycosylated end products in rats with streptozotocin-induced diabetes.

OBJECTIVE: We investigated the effect of supplemental L-arginine on lymphocyte function in diabetes and its association with suppressed formation of advanced glycosylated end products (AGEs). METHODS: For the in vivo study, rats with streptozotocin-induced (65 mg/kg of body weight, intravenously) diabetes were treated with or without 2% L-arginine or glycine (as a positive control) in drinking water for 8 wk. We then measured serum fructosamine concentrations and concanavalin A-induced proliferative ability of lymphocytes from these animals. For the in vitro study, AGEs derived from albumin were prepared by incubating D-glucose (200 mmol/L) and bovine serum albumin (100 mg/mL) at 37 degrees C for 2 wk in the presence or absence of L-arginine (0.1-10 mmol/L). These preparations were quantified for their bovine serum albumin--derived AGE content, and their effect on concanavalin A-induced proliferative activity of T lymphocyte from normal rats was measured. RESULTS: Serum fructosamine concentrations were significantly higher in the diabetic rats than in the control rats (P<0.05) but were significantly lowered with L-arginine supplementation (P<0.05). The lower lymphocyte proliferation rate found in the diabetic rats was reversed by supplemental L-arginine (P<0.05). During the course of incubation of bovine serum albumin with D-glucose, the presence of L-arginine prevented the formation of bovine serum albumin-derived AGEs and attenuated their inhibitory effect on the rate of lymphocyte proliferation in a dose-dependent manner. CONCLUSION: Supplemental L-arginine improved the function of T lymphocytes in diabetic rats in association with decreased formation of AGEs.