Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Pparg^flox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Pparg^flox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.     

Acetyl-11-keto-β-boswellic acid triggers premature senescence via induction of DNA damage accompanied by impairment of DNA repair genes in hepatocellular carcinoma cells in vitro and in vivo

Cellular senescence, a state of irreversible growth arrest, occurs in all somatic cells and causes the cells to exhaust replicative capacity. Recently, cellular senescence has been emerging as one of the principal mechanisms of tumor suppression, which can be induced by low doses of therapeutic drugs in cancer cells. Acetyl-11-keto-β-boswellic acid (AKBA), an active ingredient isolated from the plant Boswellia serrata, has been identified to induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we found that low concentrations of AKBA treatment triggered cell growth arrest at G0/G1 phase with features of premature cellular senescence phenotype in both HCC cell lines HepG2 and SMMC7721, as observed by enlarged and flattened morphology, significant increase in cells with senescence-associated β-galactosidase staining, and decrease in cell proliferation and DNA synthesis. Furthermore, cellular senescence induced by AKBA occurred via activation of DNA damage response and impairment of DNA repair, as evidenced by strong induction of γH2AX and p53, and downregulated expressions of multiple DNA repair associated genes. Induction of p53 by AKBA caused a significant increase in p21^CIP1, which had a critical involvement in the induction of cellular senescence. Additionally, in vivo study demonstrated that induction of senescence contributed to the anticancer efficacy of AKBA. Therefore, our findings suggested that induction of premature senescence by AKBA through DNA damage response accompanied by impairment of DNA repair genes defines a novel mechanism contributing to its growth suppression in HCC cells.     

The link between IFN-γ and allograft arteriopathy: is the answer NO?

Vascularized organ transplants often fail because of smooth muscle cell migration and proliferation in the intima of graft arteries, leading to progressive lumenal narrowing and resultant ischemic damage. Graft arterial disease is caused by IFN-gamma secreted by alloreactive T cells. New evidence indicates that IFN-gamma dysregulates expression of the enzymes eNOS and iNOS in graft-infiltrating leukocytes. Dysregulated NO synthase expression occurs prior to and is causally linked to intimal smooth muscle cell accumulation.     

Administration of PPAR��/�� agonist reduces copper-induced liver damage in mice: possible implications in clinical practice

In this study we investigated if peroxisome proliferator-activated receptor β/δ activation protects from copper-induced acute liver damage. Mice treated with copper had significant body weight loss, serum alanine aminotransferase increase, modest changes in liver histology, increase of tumor necrosis factor α and macrophage inflammatory protein 2 mRNA and 8-hydroxy-2''-deoxyguanosine. Mice treated with copper and peroxisome proliferator-activated receptor β/δ agonist GW0742 had significantly less body weight loss, less serum alanine aminotransferase increase, less tumor necrosis factor α, macrophage inflammatory protein-2 and 8-hydroxy-2''-deoxyguanosine upregulation than copper treated mice. The opposite effect was observed in mice treated with copper and peroxisome proliferator-activated receptor β/δ antagonist GSK0660. In vitro, copper induced reactive oxygen species, which was lower in cells treated with GW0742 or transfected with peroxisome proliferator-activated receptor β/δ expression vector; together, transfection and GW0742 had an additive reactive oxygen species-reducing effect. Copper also upregulated Fas ligand and Caspase 3/7 activity, effects that were significantly lower in cells also treated with GW0742. In conclusion, peroxisome proliferator-activated receptor β/δ activation reduced copper-induced reactive oxygen species, pro-inflammatory and acute phase reaction cytokines in mice liver. Peroxisome proliferator-activated receptor β/δ agonists could become useful in the management of copper-induced liver damage.     

Relapsing polychondritis with p-ANCA associated vasculitis: Which triggers the other?

Relapsing polychondritis (RP) is a rare autoimmune disease with chronic inflammatory/destructive lesions of the cartilaginous tissues. In one third of the cases it is associated with other autoimmune disorders, mostly with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). We report three cases of RP with p-ANCA positive AAV. In the first patient RP developed 1.5 years after the onset of AAV. In the others the signs of RP were present before the onset of severe crescent glomerulonephritis. Patients responded well on steroid and cyclophosphamide. In dialysis dependent cases plasmapheresis was also used successfully. During the 2 and 1.5 years of follow up, they were symptom-free, and had stable glomerular filtration rate. The first patient died after four years of follow-up due to the complications of sudden unset pancytopenia, which raises the possibility of associated hemophagocytic syndrome. In the setting of RP or AAV physicians should always be aware of the possibility of sudden or insidious appearance of the other disease.     

Changes of PPARγ protein expression and activity in peripheral blood lymphocytes of patients with sepsis

Objective To investigate the changes of PPARγ protein expression and activity of peripheral blood lymphocytes in patients with sepsis and its association with severity and prognosis of sepsis. Method Ac-cording to the guidelines to sepsis set by ACCP/SCCM consensus conference in 2003, 48 patients with sepsis ad-mitted in Emergency and Surgical ICU from December 2007 to March 2008 were enrolled in this perspective study. Sixteen healthy individuals were selected as controls. Patients with metastatic tumors, autoimmune disease, AIDS or under immunosuppressive therapy were excluded. This study was approved by the ethical committee of Zhong-shan Hospital, Fudan University. All patients were divided into mild and severe sepsis groups. Patients were also divided into survivor and non-survivor groups as per 28-day mortality. Peripheral blood lymphocytes were isolated by using Ficoll density gradient centrifugation. PPART protein expression was determined by using Westem Blot-ting. The activity of PPARγ was analyzed by using EMSA. Differences among groups were analyzed by using one-way ANOVA. Results The protein expression and activity of PPARγ were significantly increased in mild sepsis patients (0.56±0.12 and 4.13±0.22, respectively) compared with both healthy controls (0.39±0.07 and 2.42±0.17, respectively) and severe sepsis patients (0.30±0.07 and 1.63±0.12, respectively) (P < 0.05). However, the protein expression and activity of PPARγ were obviously decreased in severe sepsis patients compared with healthy individuals and mild spsis patients (P < 0.05). Survivors from sepsis had significantly higher protein expression and activity (0.54±0.11 and 3.59±0.34, respectively) than non-survivors (0.21±0.08 and 1.94 ±0.25, respectively) (P < 0.05). Conclusions These data suggest that the protein expression and activity of PPARγ in peripheral blood lymphocytes might be valuable biomarkers in assessing the severity and outcome of pa-tients with sepsis.     

Thymosin β4: multiple functions in protection,repair and regeneration of the mammalian heart

Introduction: Despite recent improvements in interventional medicine, cardiovascular disease still represents the major cause of morbidity worldwide, with myocardial infarction being the most common cardiac injury. This has sustained the development of several regenerative strategies based on the use of stem cells and tissue engineering approaches in order to achieve cardiac repair and regeneration by enhancing coronary neovascularization, modulating acute inflammation and supporting myocardial regeneration to provide new functional muscle.

Areas covered: The actin monomer binding peptide, Thymosin β4 (Tβ4), has recently been described as a powerful regenerative agent with angiogenic, anti-inflammatory and cardioprotective effects on the heart and which specifically acts on its resident cardiac progenitor cells. In this review we will discuss the state of the art regarding the many roles of Tβ4 in preserving and regenerating the mammalian heart, with specific attention to its ability to activate the quiescent adult epicardium and specific subsets of epicardial progenitor cells for repair.

Expert opinion: The therapeutic potential of Tβ4 for the treatment of cardiac failure is herein evaluated alongside existing, emerging and prospective novel treatments.     

Gastrointestinal motility and glycemic control in diabetes: the chicken and the egg revisited?

Upper gastrointestinal dysfunction occurs frequently in diabetes and potentially contributes to both abdominal symptoms and impaired glycemic control; conversely, variations in blood glucose concentration reversibly affect gut motility in humans. In this issue of the JCI, Anitha et al. report apoptosis of rodent enteric neurons under hyperglycemic conditions, both in vitro and in vivo, associated with impaired PI3K activity and preventable by glial cell line-derived neurotrophic factor. These observations add to recent insights gained from animal models regarding the etiology of diabetic gastrointestinal dysfunction, but investigators must strive to translate animal data to human diabetes.     

Pain and the Placebo in Physiotherapy: A benevolent lie?

The aim of this paper is to discuss the mechanisms and magnitude of the placebo effect of treatment and to consider the ethical and moral implications of using placebo physiotherapy. Placebo or non-specific treatment effects were long considered to contribute a fixed fraction (one-third) to any treatment effect. Recent evidence has revealed this commonly held clinical belief to be erroneous. The placebo effect of any treatment is a highly variable and complex phenomenon that is influenced by a myriad factors. The outcome may be positive (eg analgesia) or negative (eg increased dependency on healthcare practitioners). Although the mechanisms of effect are not fully understood, evidence supports the influence of classical conditioning, anxiety reduction, and the expectations of both patients and practitioners. The relationship between patients and practitioners influences the magnitude of placebo effects as does the method of treatment presentation. A charismatic or caring practitioner can evoke analgesia with or without further treatment. And treatment presented with an air of ‘mystery‘, apparent sophistication, or positive expectation can evoke analgesia simply through the method of its presentation.

Questions regarding the ethical use of treatments that are primarily placebo need to be addressed. When and under what conditions are placebo treatments acceptable in the short or long term? Is it a benevolent lie, or a regular lie, to use treatments that have only placebo effects? And, perhaps more importantly, do we know what those treatments are?     

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders?

BACKGROUND: Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are risk factors for several disorders with inflammatory components, including coronary heart disease (CHD) and diabetes, though the mechanisms involved are unclear. Aim: To examine the hypothesis that vitamin D status modulates the matrix metalloproteinase (MMP) system in a population with a high prevalence of vitamin D deficiency, a situation affecting susceptibility to CHD and diabetes. DESIGN: Prospective cross-sectional, interventional and embedded studies. METHODS: Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were measured during studies of vitamin-D deficiency as a risk factor for type 2 diabetes and CHD in 171 healthy British Bangladeshi adults, free of known diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1, folate and homocysteine were measured. Vitamin-D-deficient subjects were re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were measured in 41 subjects halfway through 5-year follow-up. Independent determinants of circulating concentrations of MMP9, TIMP-1 and CRP were assessed by multiple regression analysis. RESULTS: Vitamin D status was the sole determinant of circulating MMP9 (inversely) and an independent determinant of CRP (inversely). Determinants of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype (TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%) concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D insufficiency is associated with increased circulating MMP2,9 and CRP, correctable by supplementation. This finding provides a possible mechanism for tissue damage in chronic inflammatory conditions, including CHD and diabetes.     

Brain damage and cardiopulmonary bypass: is there really any association?

Brain damage, in the form of stroke and cognitive deficit associated with heart surgery, has long been attributed unquestioningly to cardiopulmonary bypass (CPB). The aim of this paper is to review the randomised control trials (RCT), systematic reviews and meta-analyses of studies, comparing patients who have undergone on- or off-pump coronary artery bypass grafting (CABG) surgeries that have used stroke or cognition as an outcome to determine whether CPB is associated with brain damage. Although not definitive, the evidence base to date strongly suggests that the incidence of stroke and the effect on cognition, if any, are no different whether CABG surgery is undertaken on- or off-pump. In addition and contrary to long-held beliefs, this review leads to the conclusion that CPB may well not be the cause of the brain damage associated with heart surgery.