Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

Azithromycin Mitigates Cisplatin-Induced Lung Oxidative Stress, Inflammation and Necroptosis by Upregulating SIRT1, PPARγ, and Nrf2/HO-1 Signaling.

Acute lung injury (ALI) is one of the adverse effects of the antineoplastic agent cisplatin (CIS). Oxidative stress, inflammation, and necroptosis are linked to the emergence of lung injury in various disorders. This study evaluated the effect of the macrolide antibiotic azithromycin (AZM) on oxidative stress, inflammatory response, and necroptosis in the lungs of CIS-administered rats, pinpointing the involvement of PPARγ, SIRT1, and Nrf2/HO-1 signaling. The rats received AZM for 10 days and a single dose of CIS on the 7th day. CIS provoked bronchial and alveolar injury along with increased levels of ROS, MDA, NO, MPO, NF-κB p65, TNF-α, and IL-1ß, and decreased levels of GSH, SOD, GST, and IL-10, denoting oxidative and inflammatory responses. The necroptosis-related proteins RIP1, RIP3, MLKL, and caspase-8 were upregulated in CIS-treated rats. AZM effectively prevented lung tissue injury, ameliorated oxidative stress and NF-κB p65 and pro-inflammatory markers levels, boosted antioxidants and IL-10, and downregulated necroptosis-related proteins in CIS-administered rats. AZM decreased the concentration of Ang II and increased those of Ang (1-7), cytoglobin, PPARγ, SIRT1, Nrf2, and HO-1 in the lungs of CIS-treated rats. In conclusion, AZM attenuated the lung injury provoked by CIS in rats through the suppression of inflammation, oxidative stress, and necroptosis. The protective effect of AZM was associated with the upregulation of Nrf2/HO-1 signaling, cytoglobin, PPARγ, and SIRT1.

The time course of cytokine expressions plays a determining role in faster healing of intestinal and colonic anastomatic wounds.

OBJECTIVES: Inflammation is critical in the early phases of wound healing. It has been reported previously that small intestinal and colonic wounds display a more rapid healing than those of other organs. However, the underlying mechanism has not yet been elucidated. Here we examined whether differences in the time course of specified cytokine expression, in colonic and small intestinal anastomotic lesions, might play a major role in this observation in comparison to lesions effecting skin and muscle tissue. MATERIALS AND METHODS: Tissue lesions were applied to 36 male Sprague-Dawley rats. Tissue samples were harvested at 1, 3, 5, 7, and 14 days postoperatively with the levels of TNF-α, IL-6, and IFN-α determined by ELISA-derived methods. RESULTS: The characteristics of TNF-α, IL-6, and IFN-α expression during the healing process for intestinal and colonic lesions were comparable. However, data differed significantly with that observed during healing of skin and muscle lesions. Intestinal and colonic lesions exhibited a significant and sustained increase in specified cytokine levels on day 5 to day 14 as compared with day 1 and 3. Skin and muscle lesions had random or unaltered cytokine levels throughout the study period. CONCLUSION: Differences in expression of cytokines TNF-α, IL-6, and IFN-α indicate that these play an important role underlying the more rapid healing processes observed in small intestinal and colonic lesions.

Temporal expression of IL-1ß and IL-10 in rat skin, muscle, small bowel, and colon wounds: a correlative study.

BACKGROUND: Cytokines play a major role in coordinated wound healing events. We hypothesized that rapid intestinal healing is due to an early upregulation of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), followed by increases in the expression of the anti-inflammatory cytokine IL-10. METHODS: We characterized the time course of IL-1ß and IL-10 release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague-Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7, and 14 days postoperatively (n=6-8 per group) and analyzed by enzyme-linked immunosorbent assay kits for IL-1ß and IL-10. RESULTS: IL-1ß expression peaked at days 5 and 7 in small bowel and colonic wounds when compared to skin or muscle. Similarly, IL-10 showed high expression in these time points in small bowel and colonic wounds. However, IL-10 showed the same expression in all time points in muscle and skin tissues except at day 1. CONCLUSIONS: The high expression in IL-1ß and IL-10 levels in small bowel and colon might explain the accelerated healing process in these wounds in comparison to skin and muscle tissues. Additional studies are required to determine whether IL-1ß and IL-10 expression is the major factor defining site-specific differences in healing rates in different tissues. Understanding cytokine action in the wound healing process could lead to novel and effective therapeutic strategies.

Antioxidant activities for superoxide dismutase in patients with Crohn's disease.

BACKGROUND: In this study, we aimed to determine the levels of antioxidant activity for superoxide dismutase (SOD) enzymes in patients with Crohn's disease (CD) to investigate their contribution to tissue injury in CD. METHODS: Forty-two patients with CD and 38 matched healthy subjects (control group) were recruited. SOD enzymatic activity was measured by purely chemical system based on NAD(P)H oxidation. RESULTS: Plasma antioxidant activities for SOD in CD patients were significantly lower than that in the control group. CONCLUSIONS: Low antioxidant activity for SOD in CD is an important indication of oxidative stress. CD patients are more susceptible to oxidative stress. This study supports the hypothesis that increased oxidative stress and decreased antioxidant defense in CD.

Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing--does it matter?

BACKGROUND: The proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-ß). METHODS: We characterized the time course of CINC-1, MCP-1 and TGF-ß release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6-8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-ß. RESULTS: CINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP-1 was shown in colonic wounds. TGF-ß levels were unchanged in all wound sites. CONCLUSION: An earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-ß levels was observed. These findings support the early healing process in intestinal anastomotic wounds.

Concepts of oxidative stress and antioxidant defense in Crohn's disease.

Oxygen free radical and lipid peroxides (oxidative stress) are highly reactive and represent very damaging compounds. Oxidative stress could be a major contributing factor to the tissue injury and fibrosis that characterize Crohn's disease. An imbalance between increased reactive oxygen species levels and decreased antioxidant defenses occurs in Crohn's patients. Decreased blood levels of vitamins C and E and decreased intestinal mucosal levels of CuZn superoxide dismutase, glutathione, vitamin A, C, E, and ß-carotene have been reported for Crohn's patients. Increased levels of proinflammatory cytokines, such as interleukin-1 and -8 and tumor necrosis factor, have been detected in inflammatory bowel disease. Oxidative stress significantly increased the production of neutrophils, chemokines, and interleukin-8. These effects were inhibited by antioxidant vitamins and arachidonic acid metabolite inhibitors in human intestinal smooth muscle cells isolated from the bowels of Crohn's disease patients. The main pathological feature of Crohn's disease is an infiltration of polymorphonuclear neutrophils and mononuclear cells into the affected part of the intestine. Activated neutrophils produce noxious substances that cause inflammation and tissue injury. Due to the physiological and biochemical actions of reactive oxygen species and lipid peroxides, many of the clinical and pathophysiological features of Crohn's disease might be explained by an imbalance of increased reactive oxygen species and a net decrease of antioxidant molecules. This review describes the general concepts of free radical, lipid peroxide and antioxidant activities and eventually illustrates their interferences in the development of Crohn's strictures.

The effect of one night of continuous positive airway pressure therapy on oxidative stress and antioxidant defense in hypertensive patients with severe obstructive sleep apnea.

PURPOSE: The purpose of this study was to examine the effects of one night of continuous positive airway pressure (CPAP) therapy on oxidative stress (lipid peroxidation) levels and the antioxidant activities of superoxide dismutase (SOD) in hypertensive patients with severe obstructive sleep apnea (OSA). METHODS: The study group consisted of 34 hypertensive, non-smoking patients with a mean age of 45.09 ± 11.77 years, body mass index of 37.4 ± 8.4 kg/m(2), apnea hypopnea index of 79.17 ± 31.35/h, and desaturation index of 55.07 ± 27.06/h. Patients included in the study were not on medications that may affect antioxidant activity. Patients spent four nights in the sleep disorder center as follows: night 1, an adaptation night; night 2, a diagnostic night; night 3, CPAP titration night; and night 4, a therapeutic night for CPAP treatment. Blood samples were collected in the morning upon awakening on nights 2 and 4 and were immediately transferred to the laboratory for SOD and lipid peroxidation measurements. Oxidative stress levels were quantified by measuring thiobarbituric acid reactive substances. SOD enzymatic activity was measured using a purely chemical system based on NAD(P)H oxidation. RESULTS: Mean SOD concentrations were not significantly different in pre-and post-CPAP treatment (0.22 ± 0.09 vs. 0.22 ± 0. U/ml, respectively). However, CPAP treatment significantly inhibited lipid peroxidation levels (2.81 ± 0.27 vs. 2.47 ± 0.35 mmol/ml, respectively, p < 0.005). CONCLUSION: The present study supports the theory that CPAP therapy decreases the levels of oxidative stress in OSA patients but may not affect antioxidant defense.

Neutrophil chemokines GCP-2 and GRO-alpha in patients with inflammatory bowel disease.

OBJECTIVE: To measure the serum levels of neutrophils chemokine granulocyte chemotactic protein-2 (GCP-2) and interleukin-8 (IL-8) in Crohn's disease (CD) and ulcerative colitis (UC) patients and compare them with serum levels of growth-related oncogene (GRO-alpha). METHODS: Forty-two patients with inflammatory bowel disease (24 CD and 18 UC) and 38 matched healthy subjects were recruited. Their serum GCP-2, IL-8 and GRO-alpha were measured by a specific enzyme immunoassay kit. RESULTS: The serum levels of GCP-2 were significantly higher in the CD than the UC patients but lower than in the healthy subjects. The GCP-2 in the UC patients were significantly lower than in the healthy subjects. The GRO-alpha levels were significantly higher in the IBD patients than in the healthy subjects. The IL-8 levels were under the detectable limit in both the IBD and the healthy subjects. CONCLUSION: In this group of patients, GCP-2 did not participate in the inflammatory response in IBD. GRO-alpha could be an important factor that enhances the inflammatory state in IBD.

Circulatory neutrophil chemokines in statin-treated diabetic patients.

OBJECTIVE: To assess the effect of statins on the circulatory levels of neutrophil chemokines, namely, granulocyte chemotactic protein-2 GCP-2, growth regulated oncogene-alpha GRO-alpha and epithelial-cell-derived neutrophil-activating peptide-78 ENA-78 in patients with diabetes. METHODS: We studied 91 diabetic patients 46 were statin-treated and 45 were not and 28 healthy subjects. We measured the levels of GCP-2, GRO-alpha, and ENA-78 in the serum for the 3 groups using an enzyme linked immunosorbent assay. This cross-sectional study was conducted at King Khalid University Hospital KKUH, Riyadh, Kingdom of Saudi Arabia, from January 2006 to July 2007. RESULTS: Circulating levels of GCP-2, ENA-78, and not GRO-alpha, were significantly higher in diabetic patients as compared to healthy subjects p<0.05. Statins dropped the levels of both GCP-2 and GRO-a. The ENA-78 levels were not affected by statin therapy. There was no correlation between the levels of these chemokines with the body mass index and glycemia in the population studied. CONCLUSION: Diabetes is associated with an elevation of GCP-2 and ENA-78, and not GRO-alpha. Statins have a significant role in reducing the level of GCP-2.

Lipid peroxides, superoxide dismutase and circulating IL-8 and GCP-2 in patients with severe obstructive sleep apnea: a pilot study.

Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality and many other physiological and immunological disorders. An increase in hypoxia due to OSA may cause generation of reactive oxygen species (ROS). ROS are toxic to biomembranes and may lead to peroxidation of lipids. An increase in systemic biomarkers of inflammation and oxidative stress has been found in patients with OSA. The first aim of this study was to test the hypothesis that OSA is linked to increased oxidative stress (lipid peroxidation) and decreased antioxidant defense [superoxide dismutase (SOD)]. The second aim was to measure the serum levels of neutrophil chemokines [interleukin-8 (IL-8)], and granulocyte chemotactic protein-2 (GCP-2) in OSA patients. Twenty five patients with severe OSA and 17 healthy subjects were recruited. IL-8 and GCP-2 were measured in the serum by a specific enzyme immunoassay kit. Oxidative stress level was quantitated by measurement of thiobarbituric acid reactive substances. SOD enzymatic activity was measured by purely chemical system based on NAD(P)H oxidation. Mean SOD and lipid peroxidation concentrations of patients were not significantly different from those of control subjects (0.29+/-0.015 vs 0.31+/-0.01 U/ml and 4.64+/-0.57 vs 4.62+/-0.54 mmol/ml, respectively). Higher concentrations of IL-8 and GCP-2 were found in OSA patients (198.8+/-4.76 vs 180.83+/-3.38 and 383.34+/-46.19 vs 218+/-13.16 pg/ml, respectively, p<0.005). The present study does not support the hypothesis that OSA is linked to increased oxidative stress and decreased antioxidant defense. On the other hand, it suggests that systemic inflammation characterizes OSA patients.