Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.

• MeSH
• adenosin imunologie   MeSH
• adenosindeaminasa imunologie   MeSH
• apyrasa imunologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci * etiologie   imunologie   terapie   MeSH
• purinergní receptory P1 * imunologie   MeSH
• roztroušená skleróza * etiologie   imunologie   terapie   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

• MeSH
• adenosin biosyntéza   genetika   imunologie   terapeutické užití   MeSH
• cílená molekulární terapie * MeSH
• imunoterapie trendy   MeSH
• karcinogeneze účinky léků   imunologie   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   imunologie   MeSH
• nádory genetika   imunologie   terapie   MeSH
• purinergní receptory P1 imunologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Newly developed acyclic nucleoside phosphonates, derivatives of adenine and 2,6-diaminopurine bearing the 2-hydroxy-3-(phosphonomethoxy)propyl (HPMP) moiety at the N9-side chain (i.e., HPMPA and HPMPDAP, respectively) were screened for in vitro immunobiological activity, using mouse resident peritoneal macrophages and splenocytes. Both HPMPA and HPMPDAP augmented the interferon-gamma-triggered production of NO as well as expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages. HPMPDAP activated secretion of tumor necrosis factor-alpha (TNF-alpha), chemokines "regulated-upon-activation, normal T cell expressed and secreted" (RANTES) and macrophage inflammatory protein-1alpha (MIP-1alpha), and marginally also secretion of interleukin-10 (IL-10) in both macrophages and splenocytes. The HPMPA, less prominently than HPMPDAP, elevated only secretion of RANTES and TNF-alpha. The compounds also activated secretion of TNF-alpha (HPMPDAP > HPMPA) in human peripheral blood mononuclear cells (PBMC). Distinct N6-substituted derivatives, i.e., N6-dimethyl-, N6-cyclopropyl-, N6-piperidin-1-yl-, N6-(2-methoxyethyl)-, N6-(2-hydroxyethyl)-, N6-allyl- and N6-2-(dimethylamino)ethyl-HPMPA/HPMPDAP as well as 6-thio and 6-hydroxy derivatives usually showed loss of the activity compared to the parent compounds. The immunomodulatory effects were found to be at least in part dependent on P1 purinoreceptors, and mediated by transcriptional factor nuclear factor-kappaB.

• MeSH
• adenin analogy a deriváty   farmakologie   chemie   MeSH
• antagonisté purinergního receptoru P1 MeSH
• chinazoliny farmakologie   MeSH
• cytokiny sekrece   MeSH
• dihydropyridiny farmakologie   MeSH
• exprese genu genetika   MeSH
• financování organizované MeSH
• interferon gama farmakologie   MeSH
• kofein analogy a deriváty   farmakologie   MeSH
• lipopolysacharidy farmakologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• molekulární struktura MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nukleotidy farmakologie   chemie   imunologie   MeSH
• organofosfonáty farmakologie   chemie   MeSH
• organofosforové sloučeniny farmakologie   chemie   MeSH
• oxid dusnatý biosyntéza   MeSH
• peritoneální makrofágy cytologie   metabolismus   účinky léků   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• purinergní receptory P1 fyziologie   imunologie   MeSH
• synthasa oxidu dusnatého, typ II genetika   MeSH
• triazoly farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH