Role of purinergic signalling and proinflammatory cytokines in diabetes

   Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are pre­sent on the pancreatic islet cells as well as on hepato­cytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell gran­ules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracel­lular ATP concentration. Ecto-NTPDases in cooperation with 5’-nucleotidase may significantly increase ecto-adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour ne­crosis factor-a (TNF-a) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes distur­bance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflamma­tory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90–100)Extracellular purines activate P1 adenosine receptors and P2 nucleotide receptors. These receptors are pre­sent on the pancreatic islet cells as well as on hepato­cytes, adipocytes, pancreatic blood vessels and nerves. ATP is released together with insulin from b-cell gran­ules in response to a rapid decrease in blood glucose levels. The ATP-dependent P2X receptor activation on pancreatic b-cells results in a positive autocrine signal and subsequent insulin secretion. Adenosine, through activation of P1 receptors present on adipocytes and pancreatic islet cells, inhibits the release of insulin. Adenosine activates A2B receptors thereby stimulating production of IL-6 and other cytokines, which increases insulin resistance. Interleukin-6 also plays an important role in diabetes. In type 2 diabetes and obesity, the long-term increase of IL-6 concentration in blood above 5 pg/mL leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in insulin resistance in cells of the skeletal muscles, liver and adipose tissue. In diabetes there is an increased synthesis and release of pro-inflammatory cytokines, which cause the damage of the pancreatic islet cells, and in type 2 diabetes cause the development of insulin resistance. Ecto-enzymes metabolizing nucleotides are involved in the termination of the nucleotide signalling pathway and play the key role in regulation of extracel­lular ATP concentration. Ecto-NTPDases in cooperation with 5’-nucleotidase may significantly increase ecto-adenosine concentration. NTPDase3 activity has only been demonstrated on Langerhans cells. NTPDase3 may influence the secretion of insulin by hydrolysing adenine nucleotides. In diabetes the pro-inflammatory cytokines such as interleukin 1b (IL-1b), tumour ne­crosis factor-a (TNF-a) and interferon-g (IFN-g), as well as pancreatic derived factor PANDER are involved in the apoptosis of pancreatic b-cells. This causes distur­bance of the balance between pro-inflammatory and protective cytokines. We believe that neutralization of pro-inflammatory cytokines, especially interleukin 1b, with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1b antibodies might cause the reduction of the inflamma­tory process in pancreas islets, normalize concentration of glucose in blood and decrease the insulin resistance. (Clin Diabetol 2017; 6, 3: 90–100

Rola puryn i cytokin prozapalnych w cukrzycy

   Receptory purynergiczne P1 i P2 są obecne na komórkach wysp trzustki, wątroby, tkanki tłuszczowej, w układzie krążenia i nerwach trzustki. W następstwie hipoglikemi ATP jest uwalniany z ziarnistości komórek b łącznie z insuliną. Aktywacja przez ATP receptora P2X3 obecne­go na komórkach b powoduje powstanie pozytywnego, autokrynnego sygnału, wpływającego na wydzielanie insuliny. Istotną rolę w patogenezie cukrzycy odgrywa adenozyna i receptory P1, zwłaszcza A1 i A2B obecne na komórkach wysp trzustki i tkanki tłuszczowej. Ade­nozyna oraz agoniści receptora A1 hamują wydzielanie insuliny, a ponadto adenozyna stymuluje wydzielanie glukagonu. Związki te obniżają stężenie wolnych kwasów tłuszczowych i triglicerydów oraz obniżają insulinooporność. Adenozyna, aktywując receptory A2B, powoduje wzrost uwalniania IL-6 i innych cytokin, a przez to insulinooporności. W cukrzycy typu 2 i otyłości szkodliwe jest długotrwałe wysokie stężenie IL-6, która powoduje wzrost ekspresji SOCS3. Na komórkach wysp trzustki i naczyń krwionośnych wykazano aktywność enzymów uczestniczących w przemianie nukleotydów. Wśród NTPDaz istotną rolę w cukrzycy przypisuje się NTPDazie3, której aktywność wykazano wyłącznie na komórkach Langerhansa. NTPDaza3 wpływa na wydzie­lanie insuliny, uczestnicząc w hydrolizie nukleotydów adeninowych, dlatego inhibitory ektonukleotydaz mogą powodować wzrost wydzielania insuliny. W cuk­rzycy dochodzi do wzrostu wytwarzania i uwalniania cytokin prozapalnych, takich jak interleukina 1b (IL-1b), czynnik martwicy nowotworów-a (TNF-a) i interferon-g (IFN-g) oraz czynnik pochodzenia trzustkowego PANDER które uszkadzają komórki wysp trzustki, a w cukrzycy typu 2 powodują wzrost insulinooporności. W cukrzycy dochodzi do zachwiania równowagi między ilością cytokin prozapalnych a protekcyjnych. Przypuszcza się, że neutralizacja działania cytokin prozapalnych, zwłaszcza interleukiny 1b przez antagonistów recep­tora IL-1 i/lub przeciwciał przeciw IL-1b może powo­dować wygaszenie procesu zapalnego wysp trzustki, a przez to prowadzić do normoglikemii i zmniejszenia insulinooporności

Rola ektopuryn w procesie od zapalenia do demielinizacji – perspektywy powstania nowych metod leczenia stwardnienia rozsianego

Nucleotides released from activated and/or injured cells activate P2 receptors. Extracellular nucleotides serve as danger signals or damage-associated molecular patterns (DAMPs) that trigger various immune responses. Indeed, P2 receptors are highly expressed in the astrocytes, microglia and other immune cells such as T and B lymphocytes that migrate to the central nervous system. The activation of P2 receptors triggers the secretion of proinflammatory cytokines and chemokines as well as immune cell migration and proliferation that contribute to demyelination and axonal damage. The activation of P2 receptors is controlled by the ectonucleotidases which hydrolyze extracellular nucleotides. Ecto-NTPDases and ecto-5′-nucleotidase are expressed in the astrocytes, oligodendrocytes, microglia, endothelial cells and activated T cells. The hydrolysis of extracellular ATP and ADP by enzymes results in the generation of extracellular adenosine. This nucleoside interacts with P1 receptors and activates anti-inflammatory and immuno-suppressive responses in the cells involved in MS.Autorzy przedstawili rolę sygnalizacji purynergicznej w indukcji procesów zapalnych w ośrodkowym układzie nerwowym (OUN) prowadzących do powstania stwardnienia rozsianego. Biorą w nich udział nukleotydy uwalniane z aktywowanych bądź uszkodzonych komórek. Pozakomórkowe nukleotydy rozpoznawane są w OUN jako ostrzegawcze sygnały i poprzez aktywację receptorów P2 (jonotropowe P2X i metabotropowe P2Y) aktywują procesy zapalne. Receptory P2 są obecne na komórkach OUN (komórki astrogleju i mikrogleju) oraz na komórkach układu immunologicznego, tj. limfocytach T i B, migrujących do OUN. Aktywacja obecnych na tych komórkach receptorów P2 aktywuje egzocytozę prozapalnych cytokin i chemokin oraz migrację i proliferację komórek immunologicznych, co prowadzi do demielinizacji i uszkodzenia aksonów. Aktywacja receptorów P2 jest kontrolowana przez enzymy – ektonukleotydazy, hydrolizujące pozakomórkowe nukleotydy, które są obecne na astrocytach, oligodendrocytach, komórkach mikrogleju oraz komórkach śródbłonka i limfocytach T. Hydroliza pozakomórkowego ATP i ADP przez NTPD-azy i ekto-5′-nukleotydazę powoduje powstanie ektoadenozyny, która poprzez pobudzenie receptorów P1 indukuje procesy hamujące zapalenie i immunosupresję

The role of MR cholangiography in the detection of biliary complications after orthotopic liver transplantation

Background: To assess the usefulness of magnetic resonance cholangiography (MRC) in the diagnostics of biliary complications after liver transplantation. Material/Methods: In 40 patients (17 men, 23 women) 51 MRC examinations were performed, from 1 to 58 months (mean-12) after liver transplantation. Studies were performed with 1.5 T unit. The imaging protocol consisted of tree hydrographic TSE sequences: 2D, 3D and single-slice technique. The results were compared with ERCP (n=10), percutaneous cholangiography (n=4), T-tube cholangiography (n=1), T-tube cholangiography and percutaneous cholangiography (n=1), T-tube cholangiography and ERCP (n=1), fistulography (n=2) and histopathology (n=3). In remaining patients other imaging studies (US, CT), laboratory liver functions tests and clinical status were evaluated. Results: In 46 cases (90%) abnormalities of biliary tract were depicted. Following biliary complications were diagnosed: dilatation of biliary tree (n=29), biliary strictures located beside anastomosis site (n=19), anastomotic biliary strictures (n=17), intrahepatic strictures (n=7), biliary obstruction (n=2), biliary stones/sludge (n=14), bile leak (n=12). In 5 cases (10%) MRC was normal. In 50 cases (98%) there was concordance between MRC results and the standard of reference, 1 remaining case (2%) of bile duct ischemia was not confirmed by other studies. Conclusions: MRC is a noninvasive modality, providing accurate assessment of biliary complications in patients after liver transplantation

The role of MR cholangiography in the detection of biliary complications after orthotopic liver transplantation

Background: To assess the usefulness of magnetic resonance cholangiography (MRC) in the diagnostics of biliary complications after liver transplantation. Material/Methods: In 40 patients (17 men, 23 women) 51 MRC examinations were performed, from 1 to 58 months (mean-12) after liver transplantation. Studies were performed with 1.5 T unit. The imaging protocol consisted of tree hydrographic TSE sequences: 2D, 3D and single-slice technique. The results were compared with ERCP (n=10), percutaneous cholangiography (n=4), T-tube cholangiography (n=1), T-tube cholangiography and percutaneous cholangiography (n=1), T-tube cholangiography and ERCP (n=1), fistulography (n=2) and histopathology (n=3). In remaining patients other imaging studies (US, CT), laboratory liver functions tests and clinical status were evaluated. Results: In 46 cases (90%) abnormalities of biliary tract were depicted. Following biliary complications were diagnosed: dilatation of biliary tree (n=29), biliary strictures located beside anastomosis site (n=19), anastomotic biliary strictures (n=17), intrahepatic strictures (n=7), biliary obstruction (n=2), biliary stones/sludge (n=14), bile leak (n=12). In 5 cases (10%) MRC was normal. In 50 cases (98%) there was concordance between MRC results and the standard of reference, 1 remaining case (2%) of bile duct ischemia was not confirmed by other studies. Conclusions: MRC is a noninvasive modality, providing accurate assessment of biliary complications in patients after liver transplantation

Adenosine A2A receptors in Parkinson’s disease treatment

Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug

Role of purinergic signalling and cytokines in the ischaemic stroke

Inflammation plays an important role in the aetiology of various diseases of the central nervous system including the stroke. Accumulating evidence indicates that inflammation in the central nervous system is controlled by purinergic signalling. The mediators of purinergic signalling are extracellular nucleotides (e.g. ATP, ADP, UTP and UDP) and adenosine that act via activation of P2 and P1 purinergic receptors, respectively. The activation of P2 and P1 receptors is regulated by the enzymes ectonucleotidases that hydrolyse either extracellular nucleotides or adenosine. This review focuses on the role of purinergic signalling in the ischaemic stroke. We and others have demonstrated the presence of nucleotides and adenosine in the cerebrospinal fluid. We have also shown that the concentration of ATP and other nucleotides is increased in cerebrospinal fluid of patients with ischaemic stroke. Evidence suggests that the activation of P2 and P1 recep-tors have an opposite role in the ischaemic stroke, i.e. while the nucleoside adenosine exert neuroprotective effects, nucleotides generally promote the proinflammatory and apoptotic responses. P2X7, P2Y2, P2Y6, P2Y11 and P2Y12 are proposed to be involved in the central nervous system inflammation as they are expressed in the brain and their activation is known to control the key inflammatory processes such as release of inflammatory mediators (e.g. cytokines, NO), migration of leukocytes, phagocytosis, apoptosis and thrombosis. The activation of P2 receptors can also increase the release of excitatory neurotransmitters that further exacerbate the inflammatory response. Three cytokines whose release is controlled by P2 receptors have a major role in the ischaemic stroke, namely tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1) and interleukin 6 (IL-6). By promoting inflammation and thrombosis, these proinflammatory cytokines contribute to the increase in lesion size and thus functional impairment of the affected tissue. Cytokines as well as extracellular nucleotides are involved in leukocyte migration to lesions. By their adherence to endothelium, leukocytes impair cerebral blood circulation and thus exacerbate damage to the brain. The hydrolysis of nucleotides to adenosine by the ectonucleotidases leads to deactivation of proinflammatory responses. Similar effect can also be obtained with P2X7 and IL-1 receptor antagonists that are presently under clinical development and investigation.Wyniki badań opublikowanych w ostatnich latach wskazują, że indukcja stanów zapalnych w ośrodkowym układzie nerwowym może stanowić podstawę patofizjologiczną wielu chorób, w tym udaru niedokrwiennego mózgu. Istotną rolę w tych procesach przypisuje się sygnalizacji purynergicznej i cytokinom. Receptory purynergiczne P1 i P2 oraz enzymy uczestniczące w degradacji nukleotydów są szeroko rozpowszechnione na komórkach ośrodkowego układu nerwowego. Puryny i pirymidyny wykazują dwojakie działanie w udarze niedokrwiennym mózgu: pozytywne (neuroprotekcyjne) nukleozydów oraz negatywne (prozapalne i proapoptotyczne) nukleotydów. W przebiegu udaru niedokrwiennego mózgu udowodniono udział w indukcji procesów zapalnych trzech cytokin: czynnika martwicy nowotworów α (TNF-α), interleukiny 1 (IL-1) i interleukiny 6 (IL-6). Cytokiny prozapalne wywołują procesy zapalne i prozakrzepowe, przez co zwiększają obszar zawału, a w konsekwencji stopień deficytu neurologicznego. Cytokiny i ATP sprzyjają migracji leukocytów do miejsca niedokrwienia mózgu, natomiast adenozyna działa przeciwstawnie. Leukocyty, przylegając do śródbłonka, upośledzają przepływ mózgowy krwi, w wyniku czego nasilają uszkodzenie tkanki nerwowej. Na uwalnianie cytokin prozapalnych, głównie interleukiny 1β, wpływa aktywacja receptora P2X7. Przypuszcza się, że w procesach zapalnych ośrodkowego układu nerwowego mogą uczestniczyć także receptory: P2Y2, P2Y6, P2Y11, P2Y12. Wydaje się, że degradacja nukleotydów z powstaniem adenozyny może być skutecznym sposobem obniżenia stężenia w przestrzeni pozakomórkowej nukleotydów, jak również cytokin prozapalnych i wygaszania procesów zapalnych. Inną metodą osłabienia intensywności procesów zapalnych jest zastosowanie antagonistów receptora P2X7 oraz inhibitora receptora IL-1 (IL-1Ra). Obecnie prowadzone są badania zarówno nad potencjalnymi antagonistami receptora P2X7, jak i inhibitorem receptora IL-1 (IL-1Ra)

Relationship between the induction of inflammatory processes and infectious diseases in patients with ischemic stroke

Pro-inflammatory cytokines participate in the induction of ischemic stroke. So far, their participation in the cerebral ischemia was proven for the tumor necrosis factor TNF-α, interleukin-1 (IL-1), and interleukin-6 (IL-6). The release of the pro-inflammatory cytokines into the extracellular space causes the enlargement of the brain damage region, and consequently increases the neurological deficit and negatively affects the survival rate prognoses. That is confirmed by the increased concentration of pro-inflammatory cytokines in blood and the cerebrospinal fluid of patients with brain stroke, as well as by the research on the induced/experimental cerebral ischemia in animals. The pro-inflammatory cytokines participate in the migration of the reactive T lymphocytes to the regions of brain ischemia where they enhance the nerve tissue damage by down-regulation of microcirculation, induce the pro-thrombotic processes and release other neurotoxic cytokines. Also, in the early stage of cerebral ischemia, cytokines activate the axis hypothalamus-pituitary gland-adrenal cortex and increase the cortisol concentration in blood, what results in the decreased resistance to infectious diseases. Administration of the inhibitor of the interleukin-1 receptor (IL-1Ra) inhibits the inflammatory processes in the region of brain ischemia, and subsequently improves the prognosis for the size of the neurological deficit and the survival rate, as well as resistance to infectious diseases

Role of pro-inflammatory cytokines of pancreatic islets and prospects of elaboration of new methods for the diabetes treatment

Several relations between cytokines and pathogenesis of diabetes are reviewed. In type 1 and type 2 diabetes an increased synthesis is observed and as well as the release of pro-inflammatory cytokines, which cause the damage of pancreatic islet cells and, in type 2 diabetes, the development of the insulin resistance. That process results in the disturbed balance between pro-inflammatory and protective cytokines. Pro-inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), as well as recently discovered pancreatic derived factor PANDER are involved in the apoptosis of pancreatic β-cells. Inside β-cells, cytokines activate different metabolic pathways leading to the cell death. IL-1β activates the mitogen-activated protein kinases (MAPK), affects the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activates the inducible nitric oxide synthase (iNOS). TNF-α and IFN-γ in a synergic way activate calcium channels, what leads to the mitochondrial dysfunction and activation of caspases. Neutralization of pro-inflammatory cytokines, especially interleukin 1β with the IL-1 receptor antagonist (IL-1Ra) and/or IL-1β antibodies might cause the extinction of the inflammatory process of pancreatic islets, and consequently normalize concentration of glucose in blood and decrease the insulin resistance. In type 1 diabetes interleukin-6 participates in regulation of balance between Th17 and regulatory T cells. In type 2 diabetes and obesity, the long-duration increase of IL-6 concentration in blood above 5 pg/ml leads to the chronic and permanent increase in expression of SOCS3, contributing to the increase in the insulin resistance in cells of the skeletal muscles, liver and adipose tissue