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.

• Klíčová slova
• LA-ICP-MS imaging, clearance, inhalation, lead nanoparticles, toxicity,
• 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
• Názvy látek
• aktiny MeSH
• alpha-smooth muscle actin, mouse MeSH Prohlížeč
• dusičnany MeSH
• Il1a protein, mouse MeSH Prohlížeč
• IL1B protein, mouse MeSH Prohlížeč
• interleukin-1alfa MeSH
• interleukin-1beta MeSH
• interleukin-6, mouse MeSH Prohlížeč
• interleukin-6 MeSH
• látky znečišťující vzduch MeSH
• lead nitrate MeSH Prohlížeč
• NF-kappa B MeSH
• olovo MeSH
• Tgfb1 protein, mouse MeSH Prohlížeč
• TNF-alfa MeSH
• transformující růstový faktor beta1 MeSH

The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1-5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1-5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1-5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1-5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds.

• MeSH
• antiflogistika chemie   farmakologie   terapeutické užití   MeSH
• antitumorózní látky chemie   farmakologie   terapeutické užití   MeSH
• edém farmakoterapie   MeSH
• hepatocyty účinky léků   MeSH
• hypoxanthiny chemie   farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• zánět farmakoterapie   MeSH
• zlato chemie   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-deazahypoxanthine MeSH Prohlížeč
• antiflogistika MeSH
• antitumorózní látky MeSH
• hypoxanthiny MeSH
• zlato MeSH

A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1-9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4-6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4-6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1-30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study.

• MeSH
• antiflogistika chemie   farmakologie   toxicita   MeSH
• antitumorózní látky chemie   farmakologie   toxicita   MeSH
• buněčné linie MeSH
• hypoxanthin chemie   farmakologie   toxicita   MeSH
• lidé MeSH
• makrofágy účinky léků   metabolismus   MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• organofosforové sloučeniny chemie   farmakologie   toxicita   MeSH
• zlato chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika MeSH
• antitumorózní látky MeSH
• hypoxanthin MeSH
• organofosforové sloučeniny MeSH
• triphenylphosphine MeSH Prohlížeč
• zlato MeSH

Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(L(n))2Cl2]·Solv (1-5) and [Zn(HL(n))Cl3] · xL(n) (6-7); n=1-5, Solv=CH3OH for 1 and 2H2O for 2; x =1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (L(n)) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS)-activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 µM), apart from complex 4, with an IC50=10.9 ± 1.1 µM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1β production by a factor of 1.47-2.22 compared with the control (DMSO), but did not affect TNF-α and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes.

• MeSH
• aktivace makrofágů účinky léků   MeSH
• aminochinoliny MeSH
• antiflogistika chemická syntéza   farmakologie   MeSH
• biologický transport MeSH
• chloridy chemie   MeSH
• cystein chemie   MeSH
• exprese genu účinky léků   MeSH
• fluorescenční barviva MeSH
• glutathion chemie   MeSH
• interleukin-1beta antagonisté a inhibitory   genetika   metabolismus   MeSH
• kationty dvojmocné MeSH
• kinetin chemie   MeSH
• komplexní sloučeniny chemická syntéza   farmakologie   MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• makrofágy cytologie   účinky léků   metabolismus   MeSH
• matrixová metaloproteinasa 2 genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• TNF-alfa genetika   metabolismus   MeSH
• tosylové sloučeniny MeSH
• viabilita buněk účinky léků   MeSH
• zinek chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminochinoliny MeSH
• antiflogistika MeSH
• chloridy MeSH
• cystein MeSH
• fluorescenční barviva MeSH
• glutathion MeSH
• interleukin-1beta MeSH
• kationty dvojmocné MeSH
• kinetin MeSH
• komplexní sloučeniny MeSH
• lipopolysacharidy MeSH
• matrixová metaloproteinasa 2 MeSH
• N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide MeSH Prohlížeč
• TNF-alfa MeSH
• tosylové sloučeniny MeSH
• zinek MeSH