Alzheimer's disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

• Klíčová slova
• Alzheimer’s disease, DAMPs, SASP, astrocytes, immunosenescence, inflammasome, microglia, mitochondria, neuroinflammation,
• Publikační typ
• časopisecké články MeSH
• přehledy 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