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At least 217 records · Page 12Linked to original sources

PubMed1997

ExGen 500 is an efficient vector for gene delivery to lung epithelial cells in vitro and in vivo.

Nonviral vectors might represent a safe alternative to adenovirus for gene therapy of lung disorders, in particular cystic fibrosis (CF). Cationic lipids have been shown to correct the CF defect both in vitro and in vivo, but more efficient vectors are needed to improve the low gene transfer efficiency. Here, we show that the cationic polymer ExGen 500, a linear polyethylenimine derivative, is more efficient than cationic lipids in transferring reporter genes to lung epithelial cells in vitro. In vivo ExGen 500 was able to mediate gene transfer into both newborn and adult rabbit lungs with comparable efficiencies. The best levels of transfection were obtained using neutral complexes. Under such conditions, luciferase activities corresponding to about 10(3) RLU/10 s/mg of protein were reproducibly obtained 2 days after transfection throughout the four lung lobes of newborn and adult rabbits. A nlslacZ reporter gene showed transfected cells around the lumen of large and small bronchi. No signs of acute toxicity (inflammation, cellular infiltration etc) were detected by direct histopathological analysis. Within 1 week after instillation, transgene expression decreased by two orders of magnitude.

Animals↗

PubMed1996

Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades.

The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasma-membrane receptors to initiate nuclear transcriptional events. This cascade has recently been subdivided into two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In concurrent experiments utilizing rat glomerular mesangial cells (MCs), we demonstrate that growth factors or sphingosine activate ERK but not SAPK. In contrast, inflammatory cytokines or cell-permeable ceramide analogues activate SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor- or sphingosine-induced ERK activation as well as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.

Animals↗

PubMed2000

[Recruitment of immunocompetent cells in a transplanted lung is not impaired despite incompletel reinnervation].

BACKGROUND: It is not clear whether surgical intervention during lung transplantation which includes cutting vegetative nerves, lymphatic vessels and bronchial arteries, leads to alterations in immune responses. Thus, it was studied in an animal model whether an induced pulmonary immune reaction after syngenic lung transplantation was impaired without the influence of immunosuppression and rejection. The recruitment of leukocytes and the status of reinnervation was examined. METHODS: Syngenic transplantation of the left lung was performed in Lewis rats without rejection and therefore without immunosuppressive therapy. In a subgroup of animals host and donor leukocytes were distinguished. An ovalbumin (OVA)-specific pulmonary immune response was induced four months after transplantation. Bronchoalveolar lavage (BAL) and interstitial leukocytes were examined using flow cytometry and immunocytology, comparing the right lung and the grafted left lung. Immunohistology was performed to detect nerve fibers on cryostat sections. RESULTS: An induced cellular inflammation was observed in the right host lung as well as in the grafted left lung. However, the CD4 T cell numbers in the BAL were increased in the left lung. Single donor-type leukocytes could still be observed four months after transplantation. A partial reinnervation was found. CONCLUSIONS: The recruitment of immune cells into the lung interstitium and bronchoalveolar space of grafted lungs is not impaired. The incomplete reinnervation has no influence on leukocyte recruitment.

Animals↗

PubMed2003

[Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)].

Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) designates interstitial lung changes in smokers, characterized histologically by bronchiolocentric accumulation of pigmented alveolar macrophages and fibrotic or cellular inflammatory changes of pulmonary interstitium. The definition is nearly identical to that of condensate pneumopathy, smoker's pneumopathy or smoker's lung, defined by accumulation of pigmented alveolar macrophages with bland alveoloseptal or peribronchial fibrosis and cellular inflammation of the bronchial wall. In addition to respiratory bronchiolitis, which is found in nearly all smokers, RB-ILD comprises a broad spectrum of varying degrees of the interstitial reaction to the exogenous injury of inhalation smoking with gradual transition to desquamative interstitial pneumonia (DIP). In most cases RB-ILD manifestations are subclinical and detected coincidentally. Radiographic features are reticulonodular and ground glass opacities of the lung. The high resolution computed tomography reveals centrilobular nodules, ground glass opacities, thickening of bronchial walls, and in some cases a reticular pattern. Mild emphysema is frequent. Lung function analysis reveals only minor restrictive or obstructive defects in most cases, often combined with hyperinflation. CO diffusing capacity is slightly to moderately impaired. Pronounced interstitial lung diseases with serious restrictive defects and arterial hypoxemia have been reported infrequently. In differential diagnosis smoking related interstitial lung diseases (DIP, Langerhans cell histiocytosis, idiopathic pulmonary fibrosis) and other interstitial lung diseases have to be excluded. In most cases diagnosis can be achieved by bronchoalveolar lavage and transbronchial lung biopsy. In cases of pronounced interstitial lung disease or assumption of an additional interstitial lung disease besides RB-ILD a thoracoscopic or open lung biopsy can be necessary. RB-ILD has a favourable prognosis. After smoking cessation lung changes are reversible. Corticosteroid therapy is not necessary. A fatal outcome of RB-ILD has not been reported. Follow-up examinations are advisable in order to preclude other interstitial lung diseases. RB-ILD seems to be more frequent than it is assumed at present. The clinical picture is masked in most cases by the concomitant smoking induced chronic bronchitis. Thus only pronounced cases with structural changes and resulting differential diagnostic problems are diagnosed.

Bronchiolitis↗

PubMed2005

The relationship between apoptosis and non-alcoholic fatty liver disease: an evolutionary cornerstone turned pathogenic.

The data currently available favor a model for the pathogenesis of non-alcoholic fatty liver disease that is based on an apparent sequential relationship of intrahepatic apoptosis, inflammation and fibrogenesis. Based on both hepatic and peripheral insulin resistance, the hepatocellular accumulation of triglycerides, termed steatosis, initially leads to an altered metabolism of glucose and free fatty acids in the liver. In response, increased expression of death receptors in simple steatosis enhances the hepatocytes' susceptibility for pro-apoptotic stimuli, thus eliciting excessive hepatocyte apoptosis and inflammation. Evidence indicates that these processes, if prolonged, activate both hepatic stellate and Kupffer cells, thus leading to a vicious circle in which apoptosis, inflammation, cellular activation, and collagen deposition are upregulated even further.

Animals↗

PubMed2002

Expression and function of histamine receptors 1 and 2 on human monocyte-derived dendritic cells.

BACKGROUND: Histamine is a well-known mediator of inflammatory and allergic reactions and has immunomodulatory capacities. There is increasing evidence that dendritic cells as professional antigen-presenting cells play a major role in the development of allergic reactions. However, a possible link between histamine and dendritic cells has not been investigated thus far. OBJECTIVE: We investigated the effect of histamine on human monocyte-derived dendritic cells (MoDCs). METHODS: Expression of histamine H1 and H2 receptors (H1R and H2R) on MoDCs was assessed by means of RT-PCR and flow cytometry. Functional exploration of these receptors was performed by monitoring the increase of intracellular calcium levels (H1R), cyclic adenosine monophosphate formation (H2R), F-actin polymerization, and IL-12p70 production. RESULTS: MoDCs express both H1R and H2R. Stimulation of dendritic cells with histamine resulted in F-actin polymerization and cyclic adenosine monophosphate production through H2R. Influx of calcium could not be detected after stimulation of dendritic cells with histamine under conditions in which histamine induced calcium influx in monocytes. Histamine and H1R and H2R agonists downregulated IL-12p70 production of prestimulated MoDCs. CONCLUSION: MoDCs express histamine H1 and H2 receptors. Our results indicate chemotactic (F-actin polymerization) and immunomodulatory (inhibition of IL-12p70 production) effects of histamine on MoDCs. Therefore histamine might represent a link between immediate-type hypersensitivity reactions and cellular inflammation in allergic disease (eg, in atopic dermatitis).

Actins↗

PubMed2001

Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

We present genome-wide microarray expression analysis of 11,000 genes in an aging potentially mitotic tissue, the liver. This organ has a major impact on health and homeostasis during aging. The effects of life- and health-span-extending caloric restriction (CR) on gene expression among young and old mice and between long-term CR (LT-CR) and short-term CR (ST-CR) were examined. This experimental design allowed us to accurately distinguish the effects of aging from those of CR on gene expression. Aging was accompanied by changes in gene expression associated with increased inflammation, cellular stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic metabolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks of ST-CR reversed the majority of these changes. LT-CR produced in young mice a pattern of gene expression that is a subset of the changes found in old LT-CR mice. It is possible that the early changes in gene expression, which extend into old age, are key to the life- and health-span-extending effects of CR. Further, ST-CR substantially shifted the "normo-aging" genomic profile of old control mice toward the "slow-aging" profile associated with LT-CR. Therefore, many of the genomic effects of CR are established rapidly. Thus, expression profiling should prove useful in quickly identifying CR- mimetic drugs and treatments.

Aging↗

PubMed1994

Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma.

A transgenic mouse strain that expresses the hepatitis B virus (HBV) large envelope protein in the liver was used to determine the extent of oxidative DNA damage that occurs during chronic HBV infection. This mouse strain develops a chronic necroinflammatory liver disease that mimics the inflammation, cellular hyperplasia, and increased risk for cancer that is evident in human chronic active hepatitis. When perfused in situ with nitroblue tetrazolium, an indicator for superoxide formation, the liver of transgenic mice displayed intense formazan deposition in Kupffer cells, indicating oxygen radical production, and S-phase hepatocytes were commonly seen adjacent to the stained Kupffer cells. Similar changes were not observed in nontransgenic control livers. To determine whether these events were associated with oxidative DNA damage, genomic DNA from the livers of transgenic mice and nontransgenic controls was isolated and examined for 8-oxo-2'-deoxyguanosine, an oxidatively modified adduct of deoxyguanosine. Results showed a significant, sustained accumulation in steady-state 8-oxo-2'-deoxyguanosine that started early in life exclusively in the transgenic mice and increased progressively with advancing disease. The most pronounced increase occurred in livers exhibiting microscopic nodular hyperplasia, adenomas, and hepatocellular carcinoma. Thus, HBV transgenic mice with chronic active hepatitis display greatly increased hepatic oxidative DNA damage. Moreover, the DNA damage occurs in the presence of heightened hepatocellular proliferation, increasing the probability of fixation of the attendant genetic and chromosomal abnormalities and the development of hepatocellular carcinoma.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2002

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo.

The lung innate immune response to lipopolysaccharide (LPS) coordinates cellular inflammation, mediator, and protease release essential for host defense but deleterious in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In vitro, LPS signals to the transcription factors NFkappaB via TLR4, MyD88, and IL-1R-associated kinase (IRAK), to AP-1 by mitogen-activated protein (MAP) kinases, and via an alternate route in IRAK-deficient mice, but the in vivo lung signaling pathway(s) are not understood. We investigated the role of Akt and Erk1/2 as LPS intensely stimulates granulocyte/macrophage-colony-stimulating factor (GM-CSF) release, and neutralizing GM-CSF profoundly suppressed LPS-induced inflammation, suppressed expression and activity of lung proteases, significantly reduced GM-CSF and tumor necrosis factor alpha (TNFalpha) mRNA expression, and dampened nuclear localization of both NFkappaB (p50/65) and AP-1. LPS markedly activated Akt and Erk1/2, but not p38, in a GM-CSF-dependent manner in direct temporal association with NFkappaB and AP-1 activation. Pharmacological inhibition of Akt or Erk activation in LPS-treated tracheal explants ex vivo inhibited the release of GM-CSF. These data implicate GM-CSF-dependent activation of Akt in the amplification of this response and demonstrate the role of Erks rather than p38 in lung LPS inflammatory responses. Inhibition of GM-CSF may be of therapeutic benefit in inflammatory diseases in which LPS contributes to lung damage.

Administration, Intranasal↗

PubMedDate not supplied

The ultrastructure of nasal mucosa in children with asthma.

Nasal brushing has sometimes been used to characterize some affections of the respiratory tract, but seldom employed in chronic diseases such as asthma, for the possible presence of cellular inflammation in the small specimens used for electron microscopy. The present study evaluated the ultrastructure of epithelial cells obtained by nasal brushing in 11 allergic children with asthma, before and after staying in an environment free of allergens, usually implicated in the genesis of inflammatory events. The ultrastructural alterations of the nasal mucosa have been graded on the basis of their severity. Grade I lesions were characterized by well-differentiated mucous and ciliated cells. The ciliated cells appeared usually well preserved but decreased in number. In grade II lesions, most of the epithelial surface was covered by mucous cells. A further phenotype composed of poorly differentiated ciliated or mucous cells was detected. Grade III lesions showed aspects of depletion of the ciliated and mucous cells. The epithelium was largely composed of undifferentiated cells. Furthermore, the comparison of specimens at 2 different times of sampling did not differ. The data demonstrate that in allergic children with asthma, the nasal mucosa showed ultrastructural changes, which appeared to be unmodifiable during a prolonged stay in an environment free of allergens. Moreover, the nasal epithelium may provide a convenient sampling site, allowing grade of mucosal damage, with the benefit that the brush method is minimally invasive and avoids complications related to bronchoscopic examination.

Allergens↗

PubMedDate not supplied

Mucosal toxicity studies of a gel formulation of native pokeweed antiviral protein.

Pokeweed antiviral protein (PAP), a 29-kDa plant-derived protein isolated from Phytolacca americana, is a promising nonspermicidal broad-spectrum antiviral microbicide. This study evaluated the mucosal toxicity potential of native PAP in the in vivo rabbit vaginal irritation model as well as the in vitro reconstituted human vaginal epithelial tissue model. Twenty-two New Zealand white rabbits in 4 subgroups were exposed intravaginally to a gel with and without 0.01, 0.1, or 1.0% native PAP for 10 consecutive days. The dose of PAP used represented nearly 200- to 20,000 times its in vitro anti-HIV IC50 value. Animals were euthanized on day 11 and vaginal tissues were evaluated for histologic and immunohistochemical evidence of mucosal toxicity, cellular inflammation, and hyperplasia. Blood was analyzed for changes in hematology and clinical chemistry profiles. Reconstituted human vaginal epithelial tissue grown on membrane filters was exposed to 0.01, 0.1, or 1.0% native PAP in medium or topically via a gel for 24 hours and tissue damage was evaluated by histological assessment. In the in vivo rabbit vaginal irritation model, half of all PAP-treated rabbits (8/16) exhibited an acceptable range of vaginal mucosal irritation (total score <8 out of a possible 16), whereas nearly a third of PAP-treated rabbits (5/16) developed moderate to marked vaginal mucosal irritation (total score >11). However, no treatment-related adverse effects were seen in hematological or clinical chemistry measurements. Furthermore, in vitro exposure of a 3-dimensional human vaginal tissue grown on polycarbonate membrane filters to identical concentrations of PAP either added to culture medium or applied topically via gel formulation did not result in direct toxicity as determined by histologic evaluation. These findings indicate careful monitoring of vaginal irritation will be required in the clinical development of PAP as a nonspermicidal microbicide.

Administration, Intravaginal↗

PubMed1996

Cerebrospinal fluid and blood lymphocyte subpopulations following subarachnoid haemorrhage.

Lymphocyte subpopulations from 10 patients who had had a subarachnoid haemorrhage were analysed. In CSF, an increase of CD3 cells was found in two of ten, CD4 in one of ten, CD8 in three of ten, and CD19 in three of ten patients. Three patients with delayed ischaemic deficit (DID) showed a statistically significant increase of intrathecal suppressor/cytotoxic/NK-cells. The cellular inflammation had been modulated within the CNS indicating a pathogenic role in the biochemical cascades following SAH.

Adult↗

PubMed2006

Pathways leading to muscle insulin resistance--the muscle--fat connection.

Type 2 diabetes is a heterogeneous disease characterized by hyperglycemia and insulin resistance in peripheral tissues such as adipose tissue and skeletal muscle. This review focuses on obesity as one of the major environmental factors contributing to the development of diabetes. It has become evident that adipose tissue represents an active secretory organ capable of releasing a variety of cytokines such as TNFalpha, IL-6, adiponectin and other still unknown factors that might constitute the missing link between adipose tissue and insulin resistance. In fact, adipocyte-derived factors are significantly increased in obesity and represent good predictors of the development of type 2 diabetes. The negative crosstalk between adipocytes and skeletal muscle cells leads to disturbances in muscle cell insulin signalling and insulin resistance involving major pathways in inflammation, cellular stress and mitogenesis. Positive regulators of insulin sensitivity include the adipocyte hormone adiponectin and inhibitors of inflammatory pathways such as JNK-, IKK- and ERK-inhibitors. In summary, a better knowledge of intracellular and intercellular mechanisms by which adipose tissue affects skeletal muscle cell physiology may help to develop new strategies for diabetes treatment.

Adipocytes↗

PubMed1985

Inhibition of plasmacytoma development in BALB/c mice by indomethacin.

Indomethacin given continuously in the drinking water (20 micrograms/ml) to BALB/cAn pi mice during the latent period of pristane-induced plasmacytoma development dramatically reduced the plasmacytoma incidence from 34.9 to 2.2%. Additionally, indomethacin given from day 0 to 120 or begun as late as 60 d after a single injection of 1.0 ml pristane was also highly effective in reducing the development of plasmacytomas. Indomethacin treatment did not prevent the formation of a peritoneal inflammatory exudate or peritoneal oil granulomatous tissue, although it had a mild inhibitory effect on the intensity of the cellular inflammation, particularly after extensive treatment of greater than 100 d. Indomethacin treatment reduced the incidence of arthritis by 50%. A major effect of indomethacin treatment was a reduction in the appearance of microscopic plasmacytomas that appear in the oil granuloma before plasmacytomas can be detected by routine sampling of the peritoneal exudate. Between days 116 and 181, 16 of 20 mice given 0.5 ml pristane were found to have foci of plasmacytoma cells, while only 2 of 20 indomethacin-treated mice had foci-containing plasmacytoma cells. The number of mice with microscopic foci in the pristane-treated group greatly exceeded the expected incidence of plasmacytomas (22%) at this dose of pristane. The growth of primary plasmacytomas in transplant that is dependent on the pristane-conditioned peritoneal environment was not inhibited by indomethacin treatment. The role of indomethacin in inhibiting plasmacytoma development was not established; two possibilities are that it inhibits production of mutagenic and tissue destructive oxidants by inflammatory cells, and it inhibits prostaglandin synthesis and intracellular production of oxidant biproducts.

Animals↗

PubMed2002

Laparoscopic interstitial laser coagulation of renal tissue with and without hilar occlusion in the porcine model.

PURPOSE: To evaluate the safety and efficacy of interstitial laser coagulation (ILC), applied via a laparoscopic approach, with and without hilar occlusion in the porcine model. MATERIALS AND METHODS: In nine female farm pigs, bilateral renal mobilization was performed via a transperitoneal laparoscopic approach. Using a 600- micro m bare-tip silicon diode laser fiber inserted 0.5 cm into the lower pole of each kidney, diode laser energy (wavelength 805 nm) was applied for 15 minutes at 6 W. In each pig, the left renal hilum was clamped during ILC. Animals were sacrificed immediately (N = 3) or at 2 weeks (N = 3) or 4 weeks (N = 3). The kidneys were inspected grossly, and the lesions were evaluated microscopically. Nicotinamide adenine dinucleotide (NADH) histochemical staining was performed to assess viability. RESULTS: Grossly, parenchymal lesions appeared firm and white with a central zone of carbonization, cavitation, or both. Histopathology examination revealed cellular inflammation in acute lesions; chronic lesions demonstrated coagulative necrosis with progressive fibrosis. The NADH staining showed residual viable cells within the treatment zone of survival animals but not in acute animals. The mean size of the treatment zone in kidneys with unoccluded blood flow was 2.4 x 2.1 x 2.0 cm, 4.0 x 3.3 x 2.8 cm, and 3.3 x 3.5 x 2.0 cm in the acute, 2-week, and 4-week group, respectively. Hilar occlusion resulted in a slightly, but statistically insignificantly, larger lesion. In the 2-week survival group, one animal had a left subcapsular hematoma on the hilar-occluded side. In another 2-week animal, extension of the ILC zone was noted beyond the kidney into the psoas muscle. In the 4-week survival group, two animals developed gross hematuria; one had a left perinephric urinoma and urine leak noted at necropsy. CONCLUSIONS: Renal ILC may represent an alternative minimally invasive technique for ablation of renal tumors. However, histologic evidence of viable cells within the treatment zone mandates refinement of the technique in the animal model before further application in humans. Hilar occlusion does not appear to enhance tissue ablation.

Animals↗

PubMed1995

Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies.

Guillain-Barré syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barré syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barré syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barré syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barré syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barré syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barré syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2004

Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel alpha-methylene-gamma-butyrolactone derivatives.

The transcription factor nuclear factor-kappaB (NF-kappaB) is a regulator related to cellular inflammation, immune responses and carcinogenesis. Therefore, components of the NF-kappaB-activating singnaling pathways are frequent targets for the anti-inflammatory and anticancer agents. In this study, CYL-19 s and CYL-26z, two synthetic alpha-methylene-gamma-butyrolactone derivatives, were shown to inhibit the tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human A549 alveolar epithelial cells and the adhesion of U937 cells to these cells. RT-PCR analysis also demonstrated their inhibitory effects on TNF-alpha-induced ICAM-1 mRNA expression. TNF-alpha-induced ICAM-1 and NF-kappaB-dependent promoter activities were attenuated by CYL-19 s and CYL-26z. ICAM-1 promoter activities induced by the over-expression of wild-type NF-kappaB-inducing kinase and IkappaB kinase beta (IKKbeta) were also inhibited by both compounds. Furthermore, CYL-19 s and CYL-26z inhibited the TNF-alpha-induced phosphorylation and degradation of IkappaBalpha and NF-kappaB-specific DNA-protein binding activity via targeting IKK complex directly, without any effect on the activations of other kinases such as ERK1/2 and p38. In addition to ICAM-1 expression, CYL-19 s and CYL-26z also suppressed other NF-kappaB-mediated gene expressions such as matrix metalloproteinase-9 (MMP-9) mRNA and cyclooxygnease-2 (COX-2) protein. In Matrigel assays, ICAM-1 and COX-2 expressions induced by TNF-alpha elicited A549 and NCI-H292 cell invasion, respectively, and these effects were inhibited by both compounds. In summary, our data demonstrated that CYL-19 s and CYL-26z down-regulate the TNF-alpha-induced inflammatory genes expression through suppression of IKK activity and NF-kappaB activation. These agents may be effective in the anti-inflammatory and anticancer therapy.

4-Butyrolactone↗

PubMed1997

Urinary transforming growth factor-beta 1 in membranous glomerulonephritis.

BACKGROUND: Human idiopathic membranous glomerulonephritis (MGN) has a highly variable clinical course and factors determining its outcome are poorly known. Since transforming growth factor-beta 1 (TGF-beta 1) has an essential role in renal fibrogenesis, we studied the possibility to use urinary excretion of TGF-beta 1 in the assessment of progression of the disease in patients with MGN. METHODS: Urinary TGF-beta 1 was determined in 41 patients with MGN, 25 healthy subjects, six non-proteinuric renal transplant patients, 10 patients with IgA glomerulonephritis, and seven proteinuric patients (with non-progressive diseases) using a novel, double antibody enzyme immunoassay. The results were compared with renal morphology and clinical indices of activity of MGN over 12 months. RESULTS: The median urinary TGF-beta 1 excretion (pg/mg creatinine) was significantly higher (1730; range 60-16,970) in MGN patients than in the healthy controls (300; 30-1330; P < 0.0001). In renal allograft recipients the excretion was 840 (250-3440; P < 0.0001 vs healthy controls), in IgA GN it was 1130 (30-4910; P = 0.039), and in proteinuric patients it was 39 (29-165; P = NS). In MGN but not in the proteinuric controls or renal allograft recipients, urinary TGF-beta 1 correlated with urinary albumin excretion (r = 0.86, P < 0.0001) but no correlation with renal function or the duration of the disease was found. Urinary TGF-beta 1 at renal biopsy correlated with interstitial cellular inflammation and its excretion 1 year before the biopsy correlated with indices of sclerosis/fibrosis. Immunosuppressive therapy significantly decreased urinary TGF-beta 1 from 2800 (1610-16,960) to 840 (170-1600) pg/mg creatinine (P = 0.028). Patients with persistent nephrotic syndrome and/or declining renal function had a higher initial TGF-beta 1 excretion (median 3680; 1830-7420 pg/mg creatinine) than those entering partial or complete remission (1060; 60-1960; P = 0.003) within 12 months from sampling.

Adult↗