Amelioration Of Inflammation Research Articles

Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-\u03baB and p38 MAPK

BackgroundEpidemiological and experimental studies have extensively indicated that chronic subclinical systemic inflammation (CSSI) and oxidative stress are risk factors for several chronic diseases, including cancer, arthritis, type 2 diabetes, and cardiovascular and neurodegenerative diseases. This study examined the protective effect of stingless bee honey (SBH) supplementation against lipopolysaccharide (LPS)-induced CSSI, pointing to the possible involvement of NF-κB, p38 MAPK and Nrf2 signaling.MethodsCSSI was induced in male Sprague Dawley rats by intraperitoneal injection of LPS three times per week for 28 days, and SBH (4.6 and 9.3 g/kg/day) was supplemented for 30 days.ResultsLPS-induced rats showed significant leukocytosis, and elevated serum levels of CRP, TNF-α, IL-1β, IL-6, IL-8, MCP-1, malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), accompanied with diminished antioxidants. Treatment with SBH significantly ameliorated inflammatory markers, MDA and 8-OHdG, and enhanced antioxidants in LPS-induced rats. In addition, SBH decreased NF-κB p65 and p38 MAPK, and increased Nrf2 expression in the liver, kidney, heart and lung of LPS-induced rats. Furthermore, SBH prevented LPS-induced histological and functional alterations in the liver, kidney, heart and lung of rats.ConclusionSBH has a substantial protective role against LPS-induced CSSI in rats mediated via amelioration of inflammation, oxidative stress and NF-κB, p38 MAPK and Nrf2 signaling.

Shexiang Baoxin Pill, Derived From the Traditional Chinese Medicine, Provides Protective Roles Against Cardiovascular Diseases.

Shexiang Baoxin Pill (SBP), derived from the traditional Chinese medicine, has been broadly applied for the treatment of cardiovascular diseases including coronary heart disease, heart failure, and hypertension in East Asia for decades. Emerging pharmacological studies have revealed that SBP displays pleiotropic roles in protecting the cardiovascular system, as seen by the promotion of angiogenesis, amelioration of inflammation, improvement of endothelium dysfunction, mitigation of dyslipidemia, repression of vascular smooth muscle cell proliferation, and migration and restraint of cardiac remodeling. In terms of clinical practice, the clinical trials and meta-analyses have proved the efficacy and safety of SBP. In this review, we, for the first time, systematically summarize the cardioprotective effects and underlying mechanisms of SBP and provide novel insights into future research directions of SBP based on the experimental and clinical perspectives.

Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter.

Dyslipidemia, or altered blood lipid content, is a risk factor for developing cardiovascular disease. Furthermore, several autoimmune diseases, including systemic lupus erythematosus, psoriasis, diabetes, and rheumatoid arthritis, are correlated highly with dyslipidemia. One common thread between both autoimmune diseases and altered lipid levels is the presence of inflammation, suggesting that the immune system might act as the link between these related pathologies. Deciphering the role of innate and adaptive immune responses in autoimmune diseases and, more recently, obesity-related inflammation, have been active areas of research. The broad picture suggests that antigen-presenting molecules, which present self-peptides to autoreactive T cells, can result in either aggravation or amelioration of inflammation. However, very little is known about the role of self-lipid reactive T cells in dyslipidemia-associated autoimmune events. Given that a range of autoimmune diseases are linked to aberrant lipid profiles and a majority of lipid-specific T cells are reactive to self-antigens, it is important to examine the role of these T cells in dyslipidemia-related autoimmune ailments and determine if dysregulation of these T cells can be drivers of autoimmune conditions. CD1 molecules present lipids to T cells and are divided into two groups based on sequence homology. To date, most of the information available on lipid-reactive T cells comes from the study of group 2 CD1d-restricted natural killer T (NKT) cells while T cells reactive to group 1 CD1 molecules remain understudied, despite their higher abundance in humans compared to NKT cells. This review evaluates the mechanisms by which CD1-reactive, self-lipid specific T cells contribute to dyslipidemia-associated autoimmune disease progression or amelioration by examining available literature on NKT cells and highlighting recent progress made on the study of group 1 CD1-restricted T cells.

Rapid inhibition of atherosclerotic plaque progression by sonodynamic therapy.

Currently, efficient regimens to reverse atherosclerotic plaques are not available in the clinic. Herein, we present sonodynamic therapy (SDT) as a novel methodology to rapidly inhibit progression of atherosclerotic plaques. In atherosclerotic rabbit and apoE-deficient mouse models, SDT efficiently decreased the atherosclerotic burden within 1 week, revealing a decrease in the size of the atherosclerotic plaque and enlarged lumen. The shrunken atherosclerotic plaques displayed compositional alterations, with a reduction in lesional macrophages and lipids. The rapid efficacy of SDT may be due to its induction of macrophage apoptosis, enhancement of efferocytosis, and amelioration of inflammation in the atherosclerotic plaque. Compared with atorvastatin, the standard of care for atherosclerosis, SDT showed more significant plaque shrinkage and lumen enlargement during 1 week treatment. Furthermore, SDT displayed good safety without obvious side effects. In a pilot clinical trial recruiting the patients suffering atherosclerotic peripheral artery disease, combination therapy of SDT with atorvastatin efficiently reduced progression of atherosclerotic plaque within 4 weeks, and its efficacy was able to last for at least 40 weeks. SDT is a non-invasive and efficacious regimen to inhibit atherosclerotic plaque progression.

RP105 ameliorates hypoxia̸reoxygenation injury in cardiac microvascular endothelial cells by suppressing TLR4̸MAPKs̸NF-κB signaling.

The radioprotective 105kDa protein (RP105) has been implicated in the pathological process of multiple cardiovascular diseases through its functional and physical interactions with Toll‑like receptor4 (TLR4). However, the effects of RP105 on cardiac microvascular endothelial cells (CMECs) in response to hypoxia̸reoxygenation(H̸R) injury have not been extensively investigated. The aim of the present study was to elucidate the potential roles of RP105 in the protection of CMECs against H̸R injury, and investigate the underlying mechanisms. CMECs isolated from Sprague‑Dawley rats were transduced with adenoviral vectors encoding RP105 or green fluorescent protein (GFP). At 48h post‑transfection, CMECs were subjected to hypoxia for 4h and reoxygenation for 2h (H̸R) to simulate the invivo ischemia̸reperfusion model. The mRNA and protein levels of RP105 were detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis, respectively. The effects of RP105 on CMEC proliferation, migration and apoptosis were measured by GFP‑8, Transwell chamber and flow cytometry assays, respectively. The secretion of interleukin (IL)‑6 and tumor necrosis factor (TNF)‑α in the culture medium was measured by ELISA. Moreover, the expression level of TLR4, p38mitogen‑activated protein kinase (MAPK), extracellular-signal-regulated kinase1̸2, c-Jun N-terminal kinase, nuclear factor (NF)‑κB̸p65, IL‑6, TNF‑α and intercellular adhesion melecule‑1 was evaluated by western blot analysis. The results demonstrated that RP105 was minimally expressed in CMECs subjected to H̸R injury. Overexpression of RP105 via adenoviral vectors was able to significantly protect CMECs against H̸R injury, as evidenced by the promotion of cell proliferation and migration, as well as the amelioration of inflammation and apoptosis. These beneficial effects were at least partly mediated through inhibition of TLR4̸MAPKs̸NF‑κB signaling. Therefore, RP105 may be a promising candidate for prevention against CMECs‑associated H̸R injury.

Effects of Xin-Ji-Er-Kang on heart failure induced by myocardial infarction: Role of inflammation, oxidative stress and endothelial dysfunction

BackgroundXin-Ji-Er-Kang (XJEK) is a Chinese herbal formula, which has been reported to exert effective protection on cardiovascular diseases like hypertension and myocarditis. PurposeTo elucidate the protective effects of XJEK on heart failure (HF) induced by myocardial infarction (MI) through the amelioration of inflammation, oxidative stress (OS) and endothelial dysfunction(ED). Materials and methodsFifty-seven male KM mice were randomized into the following six groups (n = 9–10 for each): control group, model group, MI+XJEK low dose group(XJEKL) group, MI+XJEK middle dose group(XJEKM), MI+XJEK high dose group(XJEKH), and MI+fosinopril group (positive control group). After treatment for four weeks, electrocardiography (ECG) and haemodynamics were recorded. Serum and tissues were collected for further analysis. Endothelium-dependent relaxation induced by acetylcholine was assessed in isolated thoracic aorta ring experiment. Hematoxylin and eosin (HE) and Van Gieson (VG) staining were used to detect the pathological changes of heart and thoracic aorta. Colorimetric analysis was employed to determine serum nitric oxide level (NO), malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity. ELISA was used to detect serum B-type natriuretic peptide (BNP) and serum inflammatory cytokines, as well as endothelial NO synthetase (eNOS), angiotensinII (Ang II) and endothelin-1(ET-1) concentration in both serum and cardiac tissues. Immunohistochemistry and Western blotting (WB) were employed to detect eNOS and inflammatory cytokine expressions in cardiac tissues. ResultsXJEK administration markedly ameliorated cardiac dysfunction and abnormal ECG manifested by decreased weight/body weight (HW/BW) ratio, BNP and remedied hypertrophy of cardiomyocytes and deposition of collagen, which might be in part attributed to the increased SOD and decreased MDA in serum. Furthermore, XJEK administration improved ED with boosted eNOS activities in serum and cardiac tissues, as well as up-regulated NO levels in serum, down-regulated Ang II and ET-1 content in serum and cardiac tissues. Lastly, protein expression of pro-inflammation cytokines significantly decreased, and anti-inflammatory cytokine was significantly enhanced in serum and cardiac tissues compared to model group. ConclusionXJEK may exert beneficial effects on HF induced by MI in mice, and the underlying mechanism may be attributable to the amelioration of ED, anti-OS and anti-inflammation effects.

Administration of Protein Kinase D1 Induces a Protective Effect on Lipopolysaccharide-Induced Intestinal Inflammation in a Co-Culture Model of Intestinal Epithelial Caco-2 Cells and RAW264.7 Macrophage Cells.

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases involving all or part of the gastrointestinal tract. The stress-activated serine-threonine protein kinase D1 (PKD1) protein has previously been implicated in intestinal immune regulation. The objective of this study was to evaluate the effects of human PKD1 in relation to intestinal inflammation, using a co-culture model of intestinal epithelial Caco-2 cells and RAW264.7 macrophages. An inflammatory response was induced in the macrophages by lipopolysaccharide (LPS), upregulating the expression of tumour necrosis factor alpha (TNF-α), interleukin- (IL-) 1β, and IL-6 besides increasing the secretion of TNF-α protein. The effect of administering PKD1 to Caco-2 was evaluated in relation to both amelioration of inflammation and the ability to suppress inflammation initiation. Administration of PKD1 (10–100 ng/ml) following induction of inflammation induced downregulation of TNF-α expression in RAW264.7 cells. In addition, PKD1 administered for 3 h prior to LPS stimulation reduced the subsequent inflammatory response through downregulation of TNF-α, IL-1β, and IL-6 in RAW264.7 cells. These results demonstrate a potential role of PKD1 in the intercellular communication between intestinal epithelial and immune cells, proposing a protective effect of PKD1 on the induction of an inflammatory response in macrophages, an important aspect during the pathogenesis of IBD.

The inhibitor of semicarbazide-sensitive amine oxidase, PXS-4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model.

Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death, often induced by cigarette smoking (CS). It is characterized by pulmonary inflammation and fibrosis that impairs lung function. Existing treatments aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A new potential target is the ectoenzyme, semicarbazide-sensitive mono-amine oxidase (SSAO; also known as vascular adhesion protein-1). SSAO is elevated in smokers' serum and is a pro-inflammatory enzyme facilitating adhesion and transmigration of leukocytes from the vasculature to sites of inflammation. PXS-4728A was developed as a low MW inhibitor of SSAO. A model of COPD induced by CS in mice reproduces key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. This model was used to assess suppression of SSAO activity and amelioration of inflammation and other characteristic features of COPD. Treatment with PXS-4728A completely inhibited lung and systemic SSAO activity induced by acute and chronic CS-exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS-exposure. Therapeutic treatment during chronic CS-exposure, when the key features of experimental COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function. Treatment with a low MW inhibitor of SSAO, PXS-4728A, suppressed airway inflammation and fibrosis and improved lung function in experimental COPD, demonstrating the therapeutic potential of PXS-4728A for this debilitating disease.

ANALYSIS OF THREE-DIMENSIONAL CHOROIDAL VOLUME WITH ENHANCED DEPTH IMAGING FINDINGS IN PATIENTS WITH BIRDSHOT RETINOCHOROIDOPATHY.

To describe changes in three-dimensional choroidal volume and thickness with full raster scans of enhanced depth imaging optical coherence tomography in patients with birdshot retinochoroidopathy. This prospective case series collected spectral domain optical coherence tomography images with the enhanced depth imaging technique from eight eyes of eight patients with birdshot retinochoroidopathy including four active patients (four eyes) and four quiet patients (four eyes). Fifty scans of each patient were manually segmented before automated built-in calibration software was used. Of all active patients, there were no statistically significant differences in the total choroidal volume and mean central choroidal thickness between the active and inactive phase over 6 months of follow-up. Alterations in choroidal parameters were evident and consistent after amelioration of inflammation, whereas the retinal volume and thickness remained stable. Regarding the eight inactive eyes at 6 months, the mean total choroidal volume and mean central choroidal thickness were significantly less than historical controls (P = 0.03 and P < 0.001, respectively). Persistent suprachoroidal hyporeflective space in two patients was noted despite the fact that clinical inflammation completely subsided at 6 months. Choroidal volume and thickness changes were consistent with inflammation in patients with birdshot retinochoroidopathy. Patients with inactive birdshot retinochoroidopathy have significant reduction in choroidal volume and thickness than do normal patients.

Rutin protects against aging-related metabolic dysfunction.

Aging is a complex process which is accompanied by multiple related chronic diseases. Among them, metabolic dysfunction is one of the most important aging-related disorders. In the present study, we aimed to investigate the effect of rutin on aging-related metabolic dysfunction. We found that the increase of fasting blood glucose, insulin levels, blood pressure and HOMA-IR in aged rats was significantly inhibited by rutin. In addition, rutin improved glucose and insulin tolerance in aged rats, as reflected by decreased glucose level in IPGTT and IPITT test. Rutin treatment notably increased Akt and IRS-1 phosphorylation in the livers of old rats. The increase of inflammatory markers, such as IL-1β and TNFα, was prevented by the rutin administration. Moreover, in circulation and livers of old rats, rutin treatment significantly decreased the content of TG. Rutin also inhibited the increase of serum AST and ALT levels. Furthermore, rutin treatment markedly inhibited aging-related mitochondrial dysfunction, ER stress, and oxidative stress, as evidenced by increased oxygen consumption rate and activities of Na(+)/K(+)-ATPase and Ca2(+)-ATPase, decreased expression of ATF3 and GRP78, decreased level of MDA, increased content of GSH and enhanced activity of SOD in aged rats. We show that the administration of rutin could effectively improve aging-related metabolic dysfunction. The amelioration of inflammation, lipid accumulation, mitochondrial dysfunction, ER stress, and oxidative stress may be involved in the effect of rutin on aging-related metabolic dysfunction. These findings provide novel insights into the potential use of rutin in the intervention of aging and its related metabolic diseases.

Similarities and differences between alpha-tocopherol and gamma-tocopherol in amelioration of inflammation, oxidative stress and pre-fibrosis in hyperglycemia induced acute kidney inflammation.

BACKGROUND/OBJECTIVESDiabetes mellitus (DM) is a major chronic disease which increases global health problems. Diabetes-induced renal damage is associated with inflammation and fibrosis. Alpha (AT) and gamma-tocopherols (GT) have shown antioxidant and anti-inflammatory effects in inflammation-mediated injuries. The primary aim of this study was to investigate effects of AT and GT supplementations on hyperglycemia induced acute kidney inflammation in alloxan induced diabetic mice with different levels of fasting blood glucose (FBG).MATERIALS/METHODSDiabetes was induced by injection of alloxan monohydrate (150 mg/kg, i.p) in ICR mice (5.5-week-old, male) and mice were subdivided according to their FBG levels and treated with different diets for 2 weeks; CON: non-diabetic mice, m-DMC: diabetic control mice with mild FBG levels (250 mg/dl ≤ FBG ≤ 450 mg/dl), m-AT: m-DM mice fed AT supplementation (35 mg/kg diet), m-GT: m-DM mice with GT supplementation (35 mg/kg diet), s-DMC: diabetic control mice with severe FBG levels (450 mg/dl < FBG), s-AT: s-DM mice with AT supplementation, s-GT: s-DM mice with GT supplementation.RESULTSBoth AT and GT supplementations showed similar beneficial effects on NFκB associated inflammatory response (phosphorylated inhibitory kappa B-α, interleukin-1β, C-reactive protein, monocyte chemotactic protein-1) and pre-fibrosis (tumor growth factor β-1 and protein kinase C-II) as well as an antioxidant emzyme, heme oxygenase-1 (HO-1) in diabetic mice. On the other hands, AT and GT showed different beneficial effects on kidney weight, FBG, and oxidative stress associated makers (malondialdehyde, glutathione peroxidase, and catalase) except HO-1. In particular, GT significantly preserved kidney weight in m-DM and improved FBG levels in s-DM and malondialdehyde and catalase in m- and s-DM, while AT significantly attenuated FBG levels in m-DM and improved glutathione peroxidase in m- and s-DM.CONCLUSIONSThe results suggest that AT and GT with similarities and differences would be considered as beneficial nutrients to modulate hyperglycemia induced acute renal inflammation. Further research with careful approach is needed to confirm beneficial effects of tocopherols in diabetes with different FBG levels for clinical applications.

Interleukin 17 inhibits progenitor cells in rheumatoid arthritis cartilage

Mesenchymal stem cells are known to exert immunomodulatory effects in inflammatory diseases. Immuneregulatory cells lead to progressive joint destruction in rheumatoid arthritis (RA). Proinflammatory cytokines, such as tumour necrosis factor α (TNF‐α) and interleukins (ILs) are the main players. Here, we studied progenitor cells from RA cartilage (RA‐CPCs) that are positive for IL‐17 receptors to determinate the effects of inflammation on their chondrogenic potenial. IL‐17A/F reduced the chondrogenic potential of these cells via the upregulation of RUNX2 protein and enhanced IL‐6 protein and MMP3 mRNA levels. Blocking antibodies against IL‐17 positively influenced their repair potential. Furthermore, treating the RA‐CPCs with the anti‐human IL‐17 antibody secukinumab or the anti‐TNF‐α antibody adalimumab reduced the proinflammatory IL‐6 protein level and positively influenced the secretion of anti‐inflammatory IL‐10 protein. Additionally, adalimumab and secukinumab in particular reduced RUNX2 protein to promote chondrogenesis. The amelioration of inflammation, particularly via IL‐17 antagonism, might be a new therapeutic approach for enhancing intrinsic cartilage repair mechanisms in RA patients.

Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy.

Ghrelin is a stomach-derived growth hormone secretagogue that promotes various physiological effects, including energy metabolism and amelioration of inflammation. The purpose of this study was to investigate the protective mechanism of ghrelin against liver fibrosis. Liver fibrosis was induced in C57BL/6 mice by intraperitoneal injection of CCl4 (2.0 mL/kg of 10% CCl4 v/v solution in peanut oil) two times per week for eight weeks. Ghrelin (10 μg/kg) was intraperitoneally injected two times per week for eight weeks. A second murine liver fibrosis model was induced by bile duct ligation (BDL) and concurrent ghrelin administration for four weeks. Hematoxylin eosin (H&E), and Masson’s trichrome were used to detect pathological changes to liver tissue. Western blotting was used to detect protein levels of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), I-collage, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1, phosphorylated NF-κB (p-NF-κB), and microtubule-associated protein light chain 3 (LC3). In addition, qRT-PCR was used to detect mRNA levels of TGF-β1, I-collage, α-SMA, MMP2, TIMP1 and LC3, while levels of TGF-β1, p-Smad3, I-collage, α-SMA, and LC3 were detected immunohistochemically. Levels of aspartate aminotransferase and alanine aminotransferase were significantly decreased by ghrelin treatment. Ghrelin administration also significantly reduced the extent of pathological changes in both murine liver fibrosis models. Expression levels of I-collage and α-SMA in both models were clearly reduced by ghrelin administration. Furthermore, ghrelin treatment decreased protein expression of TGF-β1 and p-Smad3. The protein levels of NF-κB and LC3 were increased in the CCl4- and BDL-treatment groups but were significantly reduced following ghrelin treatment. In addition, ghrelin inhibited extracellular matrix formation by decreasing NF-κB expression and maintaining the balance between MMP2 and TIMP1. Our results demonstrated that ghrelin attenuates liver fibrosis via inhibition of the TGF-β1/Smad3 and NF-κB signaling pathways, as well as autophagy suppression.

The Effects of Leucine, Zinc, and Chromium Supplements on Inflammatory Events of the Respiratory System in Type 2 Diabetic Rats.

Diabetes mellitus is a major cause of serious micro- and macrovascular diseases that affect nearly every system in the body, including the respiratory system. Non-enzymatic protein glycation due to hyperglycaemic stress has fundamental implications due to the large capillary network and amount of connective tissue in the lung. The current study was designed to determine whether leucine, zinc, and chromium supplementations influence the function and histological structure of the respiratory tract in a rat model of type 2 diabetes. Seventy-seven rats were divided into eleven groups, consisting of 7 animals each. One group served as negative control and insulin and glibenclamide were used as positive control drugs. Thus, eight groups received the nutritional supplements alone or in combination with each other. Nutritional supplements and glibenclamide were added to the drinking water and neutral protamine Hagedorn insulin was subcutaneously injected during the 4 weeks of treatment period. The induction of type 2 diabetes in the rats caused an infiltration of mononuclear cells and edema in the submucosa of the trachea and lung, severe fibrosis around the vessels and airways, and perivascular and peribronchial infiltration of inflammatory cells and fibrin. In the diabetic group, the total inflammation score and Reid index significantly increased. Diabetes induction significantly reduced the total antioxidant status and elevated the lipid peroxidation products in the serum, lung lavage and lung tissue of the diabetic animals. Treatment with nutritional supplements significantly decreased the histopathological changes and inflammatory indices in the diabetic animals. Supplementation of diabetic rats with leucine, zinc, and chromium, alone and in combination, significantly increased the total antioxidant status and lipid peroxidation level in the diabetic animals. The nutritional supplements improved the enzymatic antioxidant activity of catalase, glutathione peroxidase, myeloperoxidase, and superoxide dismutase in the diabetic rats. The present results demonstrate beneficial effects and amelioration of inflammation in the respiratory system of type 2 diabetic rats by leucine, zinc, and chromium supplements, probably due to their hypoglycaemic and antioxidant properties. Using safe and effective nutritional supplements, such as leucine, chromium and zinc, to replace proven conventional medical treatments may help to control diabetes and/or its complications.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

BackgroundCardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia.MethodsRats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared.ResultsAt baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P < 0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P < 0.05).ConclusionsFenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats.

Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia.

BackgroundInflammation and endothelial dysfunction is implicated in the atherosclerosis initiation and progression in the setting of hyperlipidemia. Colchicine is a potent anti-inflammatory agent and whether colchicine combined with atorvastatin has synergistic effects on inflammation amelioration and endothelial function improvement is unknown.MethodsHyperlipidemic rat model was produced by high-fat and high-cholesterol diet for 6 weeks. Rats with normal diet were served as shame group. In hyperlipidemic group, normal saline, atorvastatin (10 mg/kg body weight/day), colchicines (0.5 mg/kg body weight/day), or atorvastatin combined with colchicines (same dosages) were prescribed for 2 weeks. Serum levels of lipid profile, C-reactive protein (CRP), liver enzyme, lipoprotein associated phospholipase A2 (Lp-PLA2) and nitric oxide (NO) production were serially assessed.ResultsBefore the beginning of the study, all laboratory variables were comparable among each group. After 6 weeks of hyperlipidemic model production, serum levels of cholesterols, CRP and Lp-PLA2 were significantly increased when compared to sham group, whereas NO production was reduced. With 2 weeks of colchicine therapy, serum levels of CRP and Lp-PLA2 were decreased and NO production was enhanced in the colchicine group in a lipid-lowering independent manner. Added colchicine into atorvastatin therapy further improved NO production and decreased CRP and Lp-PLA2 levels, indicating a potential synergism of colchicine and atorvastatin.ConclusionColchicine combined with atorvastatin may have stronger protective effects on improving endothelial function and ameliorating inflammation in rats with hyperlipidemia.

Effects of Honey and Its Mechanisms of Action on the Development and Progression of Cancer

Honey is a natural product known for its varied biological or pharmacological activities—ranging from anti-inflammatory, antioxidant, antibacterial, antihypertensive to hypoglycemic effects. This review article focuses on the role of honey in modulating the development and progression of tumors or cancers. It reviews available evidence (some of which is very recent) with regards to the antimetastatic, antiproliferative and anticancer effects of honey in various forms of cancer. These effects of honey have been thoroughly investigated in certain cancers such as breast, liver and colorectal cancer cell lines. In contrast, limited but promising data are available for other forms of cancers including prostate, bladder, endometrial, kidney, skin, cervical, oral and bone cancer cells. The article also underscores the various possible mechanisms by which honey may inhibit growth and proliferation of tumors or cancers. These include regulation of cell cycle, activation of mitochondrial pathway, induction of mitochondrial outer membrane permeabilization, induction of apoptosis, modulation of oxidative stress, amelioration of inflammation, modulation of insulin signaling and inhibition of angiogenesis. Honey is highly cytotoxic against tumor or cancer cells while it is non-cytotoxic to normal cells. The data indicate that honey can inhibit carcinogenesis by modulating the molecular processes of initiation, promotion, and progression stages. Thus, it may serve as a potential and promising anticancer agent which warrants further experimental and clinical studies.

Effect of Angiotensin II Type 2 Receptor-Interacting Protein on Adipose Tissue Function via Modulation of Macrophage Polarization

We demonstrated that angiotensin II type 2 (AT2) receptor-interacting protein (ATIP) 1 ameliorates inflammation-mediated vascular remodeling independent of the AT2 receptor, leading us to explore the possibility of whether ATIP1 could exert anti-inflammatory effects and play a role in other pathophysiological conditions. We examined the possible anti-inflammatory effects of ATIP1 in adipose tissue associated with amelioration of insulin resistance. In mice fed a high-cholesterol diet, adipose tissue macrophage (ATM) infiltration and M1-to-M2 ratio were decreased in ATIP1 transgenic mice (ATIP1-Tg) compared with wild-type mice (WT), with decreased expression of inflammatory cytokines such as tumor necrosis factor-α and monocyte chemoattractant protein-1 in white adipose tissue (WAT), but an increase in interleukin-10, an anti-inflammatory cytokine. Moreover, 2-[3H]deoxy-d-glucose (2-[3H]DG) uptake was significantly increased in ATIP1-Tg compared with WT. Next, we examined the roles of ATIP1 in BM-derived hematopoietic cells, employing chimeric mice produced by BM transplantation into irradiated type 2 diabetic mice with obesity, KKAy, as recipients. ATM infiltration and M1-to-M2 ratio were decreased in ATIP1 chimera (ATIP1-tg as BM donor), with improvement of insulin-mediated 2-[3H]DG uptake and amelioration of inflammation in WAT. Moreover, serum adiponectin concentration in ATIP1 chimera was significantly higher than that in WT chimera (WT as BM donor) and KKAy chimera (KKAy as BM donor). These results indicate that ATIP1 could exert anti-inflammatory effects in adipose tissue via macrophage polarization associated with improvement of insulin resistance, and ATIP1 in hematopoietic cells may contribute to these beneficial effects on adipose tissue functions in type 2 diabetes.