Influence of ß-D-mannuronic Acid, as a New Member of Non-steroidal Anti- Inflammatory Drugs Family, on the Expression Pattern of Chemokines and their Receptors in Rheumatoid Arthritis.

BACKGROUND: Based on the encouraging results of phase III clinical trial of ß-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. METHODS: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 µg/mL) of M2000 and optimum dose (1 µg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. RESULTS: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac. CONCLUSION: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

Febuxostat mitigates concanavalin A-induced acute liver injury via modulation of MCP-1, IL-1ß, TNF-α, neutrophil infiltration, and apoptosis in mice.

AIM: Liver plays a crucial role in innate immunity reactions. This role predisposes the liver to innate-mediated liver injury when uncontrolled inflammation occurs. In this study, the effect of febuxostat administration on acute liver injury induced by concanavalin A (Con A) injection into mouse eye orbital sinus was studied. MATERIALS AND METHODS: Two doses of febuxostat (10 and 20 mg/kg, orally) were administered either 1 h before or 30 min after the administration of Con A. Febuxostat at a low dose (10 mg/kg) before and after Con A modulated the elevation of serum ALT, liver uric acid, liver myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) induced by Con A. The same dose of febuxostat before Con A also decreased serum total bilirubin and neutrophil infiltration, as evidenced by flow cytometry and histopathological analysis. KEY FINDINGS: Febuxostat at a high dose (20 mg/kg) significantly improved serum ALT, AST, albumin, total bilirubin, liver uric acid, MPO, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-4 (IL-4), IL-1ß, and neutrophil infiltration induced by Con A administration. The results of histopathological examination of liver cells paralleled the observed biochemical improvements. Hepatocyte apoptosis as evidenced by immunohistochemical examination of cleaved caspase-3 was markedly decreased in the febuxostat protection and treatment groups, in a dose-dependent manner SIGNIFICANCE: These results indicate that febuxostat, especially at the higher dose, may be an effective inhibitor of immune reactions evoked by Con A administration.

Effectual components of Polygonum ciliinerve protects against Staphylococcus aureus infection with immunomodulatory functions in C57BL/6 mice1.

PURPOSE: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. METHODS: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. RESULTS: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. CONCLUSION: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.

Effectual components of Polygonum ciliinerve protects against Staphylococcus aureus infection with immunomodulatory functions in C57BL/6 mice

Abstract Purpose: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. Methods: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. Results: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. Conclusion: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions.

Heparin-derived oligosaccharide inhibits vascular intimal hyperplasia in balloon-injured carotid artery.

The aims of the present study were to determine the effects of heparin-derived oligosaccharides (HDOs) on vascular intimal hyperplasia (IH) in balloon-injured carotid artery and to elucidate the underlying mechanisms of action. An animal model was established by rubbing the endothelia within the common carotid artery (CCA) in male rabbits. The rabbits were fed a high-cholesterol diet. Arterial IH was determined by histopathological changes to the CCA. Serum lipids were detected using an automated biochemical analysis. Expressions of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), scavenger receptor class B type I (SR-BI), and ATP-binding cassette transporter A1 (ABCA-1) were analyzed using reverse transcription polymerase chain reaction assays. Expressions of VEGF, VCAM-1, MCP-1, SR-BI and ABCA-1 proteins were analyzed by Western blotting. Enzyme-linked immunosorbent assays were used to quantify expression levels of VEGF and bFGF. Our results showed that administration of HDO significantly inhibited CCA histopathology and restenosis induced by balloon injury. The treatment with HDOs significantly decreased the mRNA and protein expression levels of VEGF, bFGF, VCAM-1, MCP-1, and SR-BI in the arterial wall; however, ABCA-1 expression level was elevated. HDO treatment led to a reduction in serum lipids (total cholesterol, triglycerides, high-density and low-density lipoproteins). Our results from the rabbit model indicated that HDOs could ameliorate IH and underlying mechanism might involve VEGF, bFGF, VCAM-1, MCP-1, SR-BI, and ABCA-1.

Monocyte Chemoattractant Protein-1 (MCP-1) as a Potential Therapeutic Target and a Noninvasive Biomarker of Liver Fibrosis Associated With Transient Myeloproliferative Disorder in Down Syndrome.

Liver fibrosis is one of the common complications of transient myeloproliferative disorder (TMD) in Down syndrome (DS), but the exact molecular pathogenesis is largely unknown. We herein report a neonate of DS with liver fibrosis associated with TMD, in which we performed the serial profibrogenic cytokines analyses. We found the active monocyte chemoattractant protein-1 expression in the affected liver tissue and also found that both serum and urinary monocyte chemoattractant protein-1 concentrations are noninvasive biomarkers of liver fibrosis. We also showed a prospective of the future anticytokine therapy with herbal medicine for the liver fibrosis associated with TMD in DS.

Hyperbaric oxygen therapy increases insulin sensitivity in overweight men with and without type 2 diabetes.

AIMS: The onset of insulin resistance is an important metabolic event in the development of type 2 diabetes. For patients with type 2 diabetes, we recently showed that peripheral insulin sensitivity was increased during hyperbaric oxygen treatment (HBOT). This study aims to investigate whether this occurs in a non-patient population with and without type 2 diabetes, along with the mechanism of this effect. METHODS: Overweight and obese male participants were recruited from the community, 11 without and eight with type 2 diabetes. Insulin sensitivity was measured by the glucose infusion rate (GIR) during a hyperinsulinaemic euglycaemic clamp (80 mU·m⁻²·min⁻¹) at baseline and during the third HBOT session. Monocyte chemo-attractant protein-1 (MCP-1), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured in fasting serum and adipose tissue samples taken for their gene expression at baseline and immediately following four HBOT sessions. Additional fasting serum samples were collected during the first HBOT at 0, 60 and 120 minutes, and 24-hours after the last HBOT. RESULTS: In response to HBOT, GIR was increased by 29±32% in those without (n=10, P=0.01), and by 57±66% in those with type 2 diabetes (n=7, P=0.04). This increase was maintained for 30 minutes post HBOT. Reduced MCP-1 and TNF-α were observed after HBOT, whereas IL-6 was increased only in individuals without diabetes and this correlated with the increase in insulin sensitivity (r²=0.72, P=0.004). CONCLUSIONS: Peripheral insulin sensitivity was increased following HBOT in overweight or obese males with and without type 2 diabetes; this increase was maintained for at least 30 minutes post HBOT. Changes in inflammatory cytokines may partly explain this effect.

Effects of Schisandra chinensis Turcz. fruit on contact dermatitis induced by dinitrofluorobenzene in mice.

Schisandra chinensis Turcz. fruit is widely used to treat skin diseases. The aim of this study was to determine the anti-inflammatory effects of the methanol extract of S. chinensis (MESC) on 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) in mice. The effects of MESC on ear thickness and weight, histopathological changes, immune cell filtration and cytokine production were investigated in DNFB-induced CD mice. Topical application of MESC effectively inhibited ear swelling (30 or 300 µg on the left ear, P<0.001; 30 µg on the right ear, P<0.001). MESC also inhibited hyperplasia, spongiosis (100 µg/ear, P<0.05 and 300 µg/ear, P<0.001, respectively) and immune cell infiltration (100 µg/ear, P<0.05; 300 µg/ear, P<0.001) induced by DNFB. In addition, MESC suppressed increases in tumor necrosis factor (TNF)-α levels (100 or 300 µg/ear, P<0.05), interferon (INF)-γ (30 µg/ear, P<0.05; 100 µg/ear, P<0.01; 300 µg/ear, P<0.001), interleukin (IL)-6 (300 µg/ear, P<0.05) and monocyte chemoattractant protein (MCP)-1 (30 µg/ear, P<0.05; 100 µg/ear, P<0.01; 300 µg/ear, P<0.001). These results suggest that the anti-inflammatory effects of MESC are mediated by the reduced production of TNF-α, IFN-γ, IL-6 and MCP-1, and that MESC has potential use for the treatment of inflammatory skin diseases.

Anti-diabetic nephropathy compounds from Cinnamomum cassia.

ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Cinnamomum cassia, called 'Rou-Gui', a traditional spice and medicine in China, is used to treat diseases resulted from kidney yang deficiency, including diabetic nephropathy. The aim of this study is to investigate the anti-diabetic nephropathy activity of Rou-Gui and the active compounds in it. MATERIALS AND METHODS: The air-dried bark of C. cassia was extracted with 90% EtOH, the obtained residue was successively partitioned by petroleum ether, EtOAc, and n-BuOH followed by concentrating to give petroleum ether (RG-1), EtOAc (RG-2), n-BuOH (RG-3), and water fraction (RG-4), respectively. The anti-diabetic nephropathy activity of fraction (RG-1-4) was evaluated in vitro by inhibiting the expression of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 in high-glucose-induced mesangial cells. By bioassay screenings, repeated column chromatography on fractions of RG-1, 2, and 3, led to the isolation of 23 compounds, whose structures were determined by extensive spectroscopic analyses, and the anti-diabetic nephropathy activity of the isolated compounds was also evaluated. RESULTS: Four new sesquiterpenoids, cinnamoids A-D (1-4), a new natural product (5), and 18 known compounds (6-23) were isolated from the EtOH extract of the bark of C. cassia under the bioassay-guided screenings. The anti-diabetic nephropathy activity assay showed that fractions of RG-1, 2, and 3 could significantly inhibit the production of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 in high-glucose-stimulated mesangial cells at the concentration of 50 µg/ml; and sesquiterpenoids 5, 6, 14 and compound 20 could significantly inhibit the expression of fibronectin, monocyte chemoattractant protein-1 and interleukin-6 at the concentration of 50 µM. CONCLUSIONS: The results revealed that sesquiterpenoids may be the active compounds in C. cassia bark on diabetic nephropathy which provided new evidences for the traditional use of this herb to treat diabetic nephropathy and associated kidney diseases.

Irradiation by gallium-aluminum-arsenate diode laser enhances the induction of nitric oxide by Porphyromonas gingivalis in RAW 264.7 cells.

BACKGROUND: Low-level laser irradiation promotes cell viability and wound healing in periodontal tissue. However, its effect on periodontal pathogenic bacteria is unknown. The purpose of this study is to investigate the biologic effect of low-level laser irradiation on Porphyromonas gingivalis. METHODS: A murine macrophage cell line (RAW 264.7) was cultured and treated with gallium-aluminum-arsenate (GaAlAs) laser-irradiated P. gingivalis with varying levels of energy fluency. Gene expression of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interferon-ß (IFN-ß), and inducible nitric oxide synthase (iNOS) was examined by reverse transcription-polymerase chain reaction. Production of iNOS was determined by Western blot analysis, and nitric oxide (NO) release was assessed using Griess reagent. Flow cytometric analysis was performed to determine the activation of Toll-like receptors (TLRs) in response to P. gingivalis. RESULTS: The laser-irradiated P. gingivalis significantly enhanced messenger RNA and protein levels of iNOS in RAW 264.7. Although the laser irradiation on P. gingivalis did not alter the expression level of MCP-1, IL-6, and IFN-ß, it showed a noticeable effect on NO production in RAW 264.7. Furthermore, the laser-irradiated P. gingivalis accelerated TLR2 activation, but not TLR4 activation. CONCLUSIONS: This study reveals that GaAlAs laser irradiation on P. gingivalis induced iNOS expression at the transcriptional and translation levels and increased NO release in macrophages. Moreover, it is confirmed that this process was mediated specifically by TLR2 activation. These findings suggest that low-level laser irradiation to periodontal pathogenic bacteria could be detrimental to periodontal treatments.

The standardized herbal formula, PM014, ameliorated cigarette smoke-induced lung inflammation in a murine model of chronic obstructive pulmonary disease.

BACKGROUND: In this study, we evaluated the anti-inflammatory effect of PM014 on cigarette smoke induced lung disease in the murine animal model of chronic obstructive pulmonary disease (COPD). METHODS: Mice were exposed to cigarette smoke (CS) for 2 weeks to induce COPD-like lung inflammation. Two hours prior to cigarette smoke exposure, the treatment group was administered PM014 via an oral injection. To investigate the effects of PM014, we assessed PM014 functions in vivo, including immune cell infiltration, cytokine profiles in bronchoalveolar lavage (BAL) fluid and histopathological changes in the lung. The efficacy of PM014 was compared with that of the recently developed anti-COPD drug, roflumilast. RESULTS: PM014 substantially inhibited immune cell infiltration (neutrophils, macrophages, and lymphocytes) into the airway. In addition, IL-6, TNF-α and MCP-1 were decreased in the BAL fluid of PM014-treated mice compared to cigarette smoke stimulated mice. These changes were more prominent than roflumilast treated mice. The expression of PAS-positive cells in the bronchial layer was also significantly reduced in both PM014 and roflumilast treated mice. CONCLUSIONS: These data suggest that PM014 exerts strong therapeutic effects against CS induced, COPD-like lung inflammation. Therefore, this herbal medicine may represent a novel therapeutic agent for lung inflammation in general, as well as a specific agent for COPD treatment.

Effects of Wenxiao II decoction on the expression of MCP-1 and VCAM-1 in atherosclerotic rabbits.

OBJECTIVE: To observe the effects of different doses of wenxiao II decoction on the expression of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in an experimental model of atherosclerosis in rabbits and to explore the mechanism by which it alleviates atherosclerosis. METHODS: Sixty 3-4 month-old New Zealand rabbits of both sexes were randomly divided into six groups: simvastain; model; blank; and high-dose, mid-dose, and low-dose wenxiao II decoction groups. Except for those in the blank group, all rabbits were fed a high-cholesterol diet. Carotid atherosclerosis was established by balloon-induced injury to the endothelium of the carotid artery in conjunction with consumption of a high-cholesterol diet. After 8 weeks, all rabbits were killed to evaluate the expression of MCP-1 and VCAM-1 by immunohistochemical staining. RESULTS: Expressions of MCP-1 and VCAM-1 were significantly decreased in all groups except the blank group compared with the model group (P < 0.05). When compared with the simvastain group only variation of MCP-1 expression in low-dose group was not appreciable, and the differences were indistinct (P < 0.05). When comparing among wenxiao II decoction groups, MCP-1 expression in the mid- and high-dose groups was significantly lower than that seen in the low-dose group (P< 0.01), but there were no differences among three dosage groups with respect to VCAM-1 expression (P > 0.05). CONCLUSION: These data suggested that high, mid, and low doses of Wenxiao II Decoction can inhibit the expression of MCP-1 and VCAM-1, which may prevent the formation of or stabilize atherosclerotic plaques. There may be a direct relationship between the dosage of wenxiao II decoction and its therapeutic efficacy.

Anti-inflammatory and immunomodulatory effects of iridoid glycosides from Paederia scandens (LOUR.) MERRILL (Rubiaceae) on uric acid nephropathy rats.

AIMS: Uric acid nephropathy (UAN) is due to excessive uric acid, which leads to hyperuricemia and kidney damage via the deposition of urate microcrystals in the kidneys. Iridoid glycosides of Paederia scandens (IGPS) is a major active component isolated from the traditional Chinese herb P. scandens (LOUR.) MERRILL (Rubiaceae). This study aimed to evaluate the anti-inflammatory and immunomodulatory effects of IGPS and its mechanism on UAN rats. MAIN METHODS: The experimental model of UAN rats was induced by using uricopoiesis promoter adenine and uricase inhibitor potassium oxonate (PO). Treatment groups received three different doses of IGPS, allopurinol (AP) and benzbromarone (BEN) daily for 24days respectively. The histopathology of renal tissues in UAN rats were assessed for conventional morphological evaluation. The nuclear factor-κBp65 (NF-κBp65), monocyte chemoattractant protein-1 (MCP-1) and α-smooth muscle actin (α-SMA) protein expression of renal tissues in UAN rats were investigated by immunohistochemistry. MCP-1 and α-SMA mRNA levels were monitored by method of reverse transcription polymerase chain reaction (RT-PCR). KEY FINDINGS: Treatment with IGPS significantly ameliorated UAN induced renal tissue injury, inhibited the biological activity of NF-κBp65, MCP-1 and α-SMA, and suppressed the mRNA expressions of MCP-1 and α-SMA. SIGNIFICANCE: IGPS exerts a protective effect against renal injury in UAN rats, possesses anti-inflammatory and immunomodulatory effects by inactivating NF-κBp65 pathway transmembrane signal transduction, down regulating the expression of MCP-1 and α-SMA to modulate pro-inflammatory mediator production in nephropathy tissue to improve renal fibrosis in UAN rats.

Anti-inflammatory effects of pomegranate (Punica granatum L.) husk ellagitannins in Caco-2 cells, an in vitro model of human intestine.

This study aimed at evaluating the anti-inflammatory properties of a pomegranate fruit husk (PomH) polyphenolic extract, rich in punicalagin, using Caco-2 cells, an in vitro model of human intestinal epithelium. Differentiated cells in bicameral inserts were pretreated or not with a PomH extract or punicalagin, as reference, at the apical side, representing the intestinal lumen. Inflammation was then induced with a cocktail of cytokines (Il-1ß, TNFα and IFNγ) and LPS. After 24 h incubation, 3 pro-inflammatory markers, i.e., interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, were assayed both at their gene transcription (qRT-PCR) and secretion (ELISA) levels. As previously described, the pro-inflammatory cocktail significantly stimulated these 3 markers, at the gene transcript and secretion levels. In inflamed cells, a significant down-regulation of the transcription of the genes encoding IL-6 and MCP-1 was observed in the presence of the PomH extract or punicalagin, while IL-8 transcription was unaffected. Both treatments also decreased the amounts of the 3 proteins with dose-response effects, but only in the apical compartment. A lowered ELISA response was also observed when either IL-6, IL-8 or MCP-1 were mixed with punicalagin in a cell-free culture medium, indicating a direct molecular interaction. In conclusion, the punicalagin-rich PomH extract tested showed anti-inflammatory properties in the Caco-2 in vitro intestinal model. It acted both on the pro-inflammatory gene transcription and protein levels, the later phenomenon being possibly due to a direct molecular trapping. These data suggest that pomegranate husk could be an interesting natural source contributing to prevent intestinal chronic inflammation.

The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats.

SCOPE: We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury. METHODS AND RESULTS: Three groups of Sprague-Dawley rats (n=16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n=4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-ß expression, apoptosis, and tissue levels of arachidonic acid, MIP-1α, IL-1ß, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue. CONCLUSIONS: Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury.

A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.

OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Treatment of db/db diabetic mice with triptolide: a novel therapy for diabetic nephropathy.

BACKGROUND: Current research on the progression of diabetic nephropathy (DN) suggests many important factors; metabolic disturbance, haemodynamic abnormity, chronic inflammation, oxidative stress, innate immune system activation and podocyte lesion. Triptolide, which is active diterpene purified from the traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF), has anti-inflammatory, anti-oxidative, immunosuppressive and podocyte-protective effects. Herein, we investigated the therapeutic effects of triptolide on DN in db/db diabetic mice and studied the potential mechanisms. METHODS: db/db mice with DN were administrated with triptolide or valsartan. After 4, 8 and 12 weeks of treatment, 24-h urine albumin level, blood biochemical parameters and body weight were measured. Glomerulus area, glomerulus volume to Bowman's capsule volume ratio, podocyte changes and inflammatory and oxidative stress markers were quantitatively determined to evaluate renal lesions. RESULTS: The albuminuria in db/db diabetic mice was markedly attenuated after triptolide treatment, accompanied with alleviated glomerular hypertrophy and podocyte injury. In addition, the inflammation and oxidative stress in the kidneys were also attenuated, accompanied with improved hyperlipidaemia and obesity. The efficacy increased with the prolonging of triptolide treatment, and the efficacy in high-dose triptolide group was superior to that in the low-dose group. The effect of triptolide on glomerular hypertrophy was similar to valsartan, but the effects of triptolide on renal inflammation and oxidative stress were more profound than those of valsartan. CONCLUSIONS: Triptolide can dramatically attenuate albuminuria and renal lesion accompanied with dyslipidaemia and obesity in db/db diabetic mice. It is a new drug that exerts comprehensive protective effects on preventing DN progression.

In vitro fatty acid enrichment of macrophages alters inflammatory response and net cholesterol accumulation.

Dietary long-chain PUFA, both n-3 and n-6, have unique benefits with respect to CVD risk. The aim of the present study was to determine the mechanisms by which n-3 PUFA (EPA, DHA) and n-6 PUFA (linoleic acid (LA), arachidonic acid (AA)) relative to SFA (myristic acid (MA), palmitic acid (PA)) alter markers of inflammation and cholesterol accumulation in macrophages (MPhi). Cells treated with AA and EPA elicited significantly less inflammatory response than control cells or those treated with MA, PA and LA, with intermediate effects for DHA, as indicated by lower levels of mRNA and secretion of TNFalpha, IL-6 and monocyte chemoattractant protein-1. Differences in cholesterol accumulation after exposure to minimally modified LDL were modest. AA and EPA resulted in significantly lower MPhi scavenger receptor 1 mRNA levels relative to control or MA-, PA-, LA- and DHA-treated cells, and ATP-binding cassette A1 mRNA levels relative to control or MA-, PA- and LA-treated cells. These data suggest changes in the rate of bidirectional cellular cholesterol flux. In summary, individual long-chain PUFA have differential effects on inflammatory response and markers of cholesterol flux in MPhi which are not related to the n position of the first double bond, chain length or degree of saturation.

Intravenous iron sucrose changes the intraperitoneal homeostasis.

BACKGROUND/AIMS: Intravenous iron infusion is the accepted way of supplementation of that compound in uremic patients. The aim of the study was to evaluate whether this treatment affects intraperitoneal homeostasis in patients on peritoneal dialysis. METHODS: Blood and peritoneal dialysate samples were collected from 10 patients treated with continuous ambulatory peritoneal dialysis who were given 100 mg iron sucrose (IS) intravenously. Systemic and peritoneal permeability as well as transperitoneal transport were studied. The effect of spent dialysate was tested in vitro on human peritoneal mesothelial cells (MCs). RESULTS: Dialysate total iron was increased (+19%, p < 0.01) during intravenous infusion of IS. Immediately after infusion the concentration of 8-OHdG was increased in plasma (+10%, p < 0.01) and in dialysate (+5%, p < 0.05). IS infusion caused a transient decrease in peritoneal permeability to protein (-42%, p < 0.05) and glucose (-30%, p < 0.01) and a reduction in dialysate cell count (-58%, p < 0.05). During the exchange dialysate hyaluronan was increased by 27% (p < 0.01). Spent dialysate, tested ex vivo on cultured MC, induced oxidative stress (+39%, p < 0.01), slowed their proliferation (-20%, p < 0.01), and stimulated MCP-1 synthesis (+46%, p < 0.01). Iron content in MCs exposed to dialysate obtained after IS infusion was increased by 32% (p < 0.01). CONCLUSION: Intravenous infusion of IS causes oxidative stress and inflammation within peritoneal MCs which may impair viability of the peritoneum.

Effects of parenteral glutamine supplementation on modulating the immune response in rats undergoing a total gastrectomy.

The present study investigated the effect of parenteral glutamine (Gln) supplementation on cellular adhesion molecule expression and release of chemokines responsible for inflammatory cell recruitment in rats undergoing a total gastrectomy. Normal rats with internal jugular catheters were assigned to one control group and two experimental groups and received total parenteral nutrition (TPN). A total gastrectomy was performed in the experimental groups, whereas the control group received a sham operation (Sham). The TPN solutions were isonitrogenous and identical in nutrient composition except that the Sham group and one of the experimental group received conventional (Conv) TPN solution, whereas the other experimental group received 25% of the amino acid nitrogen as Gln. Half of the rats in each group were killed 1 or 3 d after surgery or the Sham to examine their immune response. The results showed that the surgery produced higher polymorphonuclear leucocyte CD11b/CD18 expressions, and Gln supplementation lowered CD11b/CD18 expressions compared with the Conv group post-operatively. The levels of monocyte chemotactic protein-1 and macrophage inflammatory protein-2 in peritoneal lavage fluid were higher in the Gln group than those in the Conv group 1 d post-operatively; these chemotactic proteins had returned to the levels comparable with those in the Sham group on post-operative day 3. These results suggest that Gln supplementation attenuated polymorphonuclear leucocyte integrin expression. In addition, Gln-enriched parenteral nutrition induced an earlier more intensive and rapid immune response to injury than the Conv parenteral nutrition after a total gastrectomy.