The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO3)2 NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO3)2 NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO3)2 NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ1), interleukin 6(IL-6), IL-1α and IL-1β , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO3)2 NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period.

• MeSH
• aktiny agonisté   genetika   imunologie   MeSH
• alveolární makrofágy účinky léků   imunologie   patologie   MeSH
• aplikace inhalační MeSH
• biologická dostupnost MeSH
• dusičnany farmakokinetika   toxicita   MeSH
• exprese genu MeSH
• inhalační expozice analýza   MeSH
• interleukin-1alfa agonisté   genetika   imunologie   MeSH
• interleukin-1beta agonisté   genetika   imunologie   MeSH
• interleukin-6 agonisté   genetika   imunologie   MeSH
• játra účinky léků   imunologie   patologie   MeSH
• kovové nanočástice aplikace a dávkování   toxicita   MeSH
• látky znečišťující vzduch farmakokinetika   toxicita   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• NF-kappa B agonisté   genetika   imunologie   MeSH
• olovo farmakokinetika   toxicita   MeSH
• plíce účinky léků   imunologie   patologie   MeSH
• poločas MeSH
• spektrofotometrie atomová MeSH
• tkáňová distribuce MeSH
• TNF-alfa agonisté   genetika   imunologie   MeSH
• transformující růstový faktor beta1 agonisté   genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

TGF-β has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-β1 activity with a TGF-β1-specific, humanized, neutralizing monoclonal antibody (TGF-β1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3-3.3 mg/dl for women and 1.5-3.5 mg/dl for men (or eGFR of 20-60 ml/min per 1.73 m(2)), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-β1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-β1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-β1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

• MeSH
• diabetické nefropatie farmakoterapie   imunologie   MeSH
• dvojitá slepá metoda MeSH
• lidé středního věku MeSH
• lidé MeSH
• monoklonální protilátky aplikace a dávkování   terapeutické užití   MeSH
• transformující růstový faktor beta1 imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. AIM: The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. MATERIALS AND METHODS: Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. RESULTS: No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection. CONCLUSION: We established a large animal model of toxic liver injury that is comparable with CASH. The toxic injury that was induced without pause between administrations was probably more extensive than occurs in CASH, and there was no effect of MAB-TGFβ administration on liver regeneration. MAB-TGFβ administration did not lead to any observable side-effects, indicating that it could be a promising solution for use as an oncologic-targeted treatment.

• MeSH
• chlorid uhličitý MeSH
• ethanol MeSH
• hepatektomie MeSH
• hepatocyty fyziologie   MeSH
• játra patologie   patofyziologie   MeSH
• lékové postižení jater farmakoterapie   patofyziologie   MeSH
• monoklonální protilátky farmakologie   MeSH
• regenerace jater účinky léků   MeSH
• Sus scrofa MeSH
• transformující růstový faktor beta1 antagonisté a inhibitory   imunologie   MeSH
• velikost buňky MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Normal human B lymphocytes are sensitive to the growth-inhibitory action of TGF-beta1 whereas malignant B lymphoma cells are mostly resistant to TGF-beta1 effects. We have shown in our previous work that, TGF-beta1 treatment resulted in significant growth inhibition of the DoHH2 cell line. In the present study we showed that TGF-beta1-induced growth arrest was associated with notable downregulation of the myc-binding protein-1 (MBP-1). Moreover, our results indicated that c-Myc overexpression in TGF-beta1-arrested malignant B cells is mediated by binding of MBP-1, as a transcription repressor, to the (+118/+153) element of the promoter region of the myc gene.

• MeSH
• 2D gelová elektroforéza metody   využití   MeSH
• financování organizované využití   MeSH
• folikulární lymfom genetika   imunologie   MeSH
• polymerázová řetězová reakce metody   využití   MeSH
• promotorové oblasti (genetika) MeSH
• protoonkogenní proteiny c-myc genetika   imunologie   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice metody   využití   MeSH
• TATA box genetika   imunologie   MeSH
• transformující růstový faktor beta1 genetika   imunologie   MeSH
• western blotting metody   využití   MeSH

• MeSH
• apoptóza imunologie   účinky léků   MeSH
• arachidonát-5-lipoxygenasa metabolismus   MeSH
• buněčná diferenciace genetika   imunologie   účinky léků   MeSH
• cytokiny imunologie   metabolismus   účinky léků   MeSH
• financování organizované MeSH
• HL-60 buňky cytologie   chemie   metabolismus   MeSH
• indomethacin metabolismus   terapeutické užití   MeSH
• kyselina arachidonová antagonisté a inhibitory   metabolismus   MeSH
• lékařská onkologie metody   trendy   MeSH
• leukemie genetika   imunologie   MeSH
• lidé MeSH
• nádorové buněčné linie účinky léků   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• průtoková cytometrie metody   využití   MeSH
• TNF-alfa metabolismus   účinky léků   MeSH
• transformující růstový faktor beta1 imunologie   účinky léků   MeSH
• western blotting metody   využití   MeSH
• Check Tag
• lidé MeSH