26 research outputs found
A bronchiolitis obliterans szindrĂłma pathomechanizmusa = Pathomechanism of bronchiolitis obliterans syndrome
TĂĽdĹ‘transzplantált betegek lĂ©gĂşti infekciĂłja során a kilĂ©gzett nitrogĂ©n monoxid (NO) szint megemelkedik. A teszt specificitása magas, szenzitivitása alacsony. A bronchiolitis obliterans szindrĂłmában (BOS) szenvedĹ‘ transzplantált betegekben az NO szint emelkedik, de csak elĹ‘rehaladott stádiumban. A kilĂ©gzett szĂ©n-monoxid (CO) szintek Ă©s a transzplantáltakban elĹ‘fordulĂł pulmonális szövĹ‘dmĂ©nyek (rejekciĂł, infekciĂł, BOS) között összefĂĽggĂ©st nem találtunk. Protein microarray technikát használva a BOS-ban szenvedĹ‘ betegek kondenzátumának citokin mintázata eltĂ©r a BOS-mentes betegekĂ©hez viszonyĂtva. Stabil tĂĽdĹ‘transzplantált betegek kilĂ©gzett levegĹ‘ kondenzátumának pH-ja Ă©s ennek variabilitása megegyezik az egĂ©szsĂ©ges nem-transzplantált emberekĂ©vel. A renin-angiotenzin rendszer (RAS) gátlása ACE-inhibitorokkal Ă©s az endothelin rendszer gátlása receptor antagonistákkal hasonlĂł mĂ©rtĂ©kben csökkentik az obliteratĂv lĂ©gĂşti betegsĂ©g kialakulását az experimentalis BO-ban patkányokban. A kĂ©t farmakon egyĂĽttes adása során az obliteratĂv folyamat mĂ©g jobban visszaszorul. A kedvezĹ‘ hatásokat a transforming growth factor (TGF)-beta1 Ă©s platelet-derived growth factor (PDGF)-A Ă©s -B növekedĂ©si faktorok alacsonyabb mRNS expressziĂłja kĂsĂ©ri. A donor Ă©s a recipiens neme vagy az ischaemiás idĹ‘ nem befolyásolta az obliteratĂv lĂ©gĂşti betegsĂ©g kialakulását ebben az állatmodellben. | Pulmonary infections increase exhaled nitric oxide (NO) in lung transplant recipients. The test has high specificity and low sensitivity. With regard to bronchiolitis obliterans syndrome (BOS), we demonstrated increased NO levels; however, only in the advanced status. Exhaled carbon-monoxide (CO) levels were not associated with pulmonary complications (infection, rejection and BOS) in lung transplant recipients. Using the protein microarray method BOS patients have distinct exhaled breath condensate (EBC) cytokine pattern compared to BOS-free recipients. EBC pH and its variability are similar in stable lung transplant recipients compared to healthy non-transplant subjects. Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors prevents the development of experimental BO to a similar extent as the blockade of endothelin system with receptor antagonists in rats. Interruption of both pathways provides superior graft protection. Beneficial effects of these drugs are associated with decreased intragraft transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF)-A and -B mRNA expressions. Donor or recipient gender and the ischemic time did not influence the development of obliterate airways disease in this animal model
Monitoring oxidative stress during chronic obstructive pulmonary disease exacerbations using malondialdehyde
Sejt-sejt Ă©s sejt-mátrix interakciĂłk szerepe a progresszĂv vesefibrĂłzis patomechanizmusában = The role of cell-cell and cell-matrix interactions in the pathomechanism of progressive renal fibrosis
A transforming growth factor-beta (TGF) által indukált epithelialis-mesenchymalis transzformáciĂł (EMT) szabályozásában az ERK, a p38-beta MAP kináz, a Smad2 Ă©s a Smad3 fehĂ©rje is rĂ©szt vesz. A TGF konfluens sejtrĂ©tegben nem idĂ©zett elĹ‘ EMT-t, a sejtkapcsolatok szĂ©tkapcsolása visszaállĂtotta a TGF EMT-t indukálĂł hatását. A TGF hatására bekövetkezĹ‘ simaizomsejt aktin (SMA) fehĂ©rje termelĹ‘dĂ©s beta-catenin dependens. ModellĂĽnk szerint az EMT kialakulásához epithel sĂ©rĂĽlĂ©s Ă©s TGF hatás egyĂĽttesen szĂĽksĂ©ges. Az adherens junctiok szĂ©tkapcsolása aktiválta a p21 Rho GTP-ázt, a Rho kinázt (ROK) Ă©s ezen keresztĂĽl a myosin könnyű lánc (MLC) kinázt. A sejtkapcsolatok dezintegráciĂłja Ă©s a SMA transzkripciĂł közötti kapcsolatban szerepe van a serum response factor (SRF) Ă©s a myocardin-related transcription factor (MRTF) Rho dependens nukleáris transzlokáciĂłjának. A RhoA mellett a p21 Rac1 Ă©s a CDC42 is hozzájárulnak az EMT kiváltásához, mĂg a p21 Ras GTP-áz gátolta azt. Tubulus sejtekben az angiotenzin II tirozin kinázok közreműködĂ©sĂ©vel fokozta a Plasminogen Activator Inhibitor-1 promĂłter aktivitását. A proximális renin promĂłter e sejtekben angiotenzin II hatására paradox mĂłdon aktiválĂłdik, s e hatásban a tirozin kinázok mellett a c-Jun-N-terminal Kinase is rĂ©szt vesz. VĂ©gĂĽl igazoltuk, hogy a tubulus sejtekben az I. tĂpusĂş discoidin domain receptor expresszálĂłdik, s e receptort az I. tĂpusĂş kollagĂ©n aktiválja. | ERK, p38-beta MAP kinase, Smad2 and Smad3 proteins contribute to the epithelial-mesenchymal transformation (EMT) induced by transforming growth factor-beta (TGF) in renal tubular cells. TGF did not induce EMT in confluent cultures but TGF readily transformed tubular cells after disruption of cell contacts. Smooth muscle cell actin (SMA) expression was beta-catenin dependent. We suggest a ?two hit? model where both epithelial injury and TGF effect are necessary to induce EMT. Disruption of adherent junctions activated p21 Rho GTP-ase, Rho kinase (ROK) and myosin light chain (MLC) phosphorylation. Rho dependent nuclear translocation of serum response factor (SRF) and myocardin-related transcription factor (MRTF) contributed to SMA transcription induced by disruption of cell contacts. In addition to Rho A both p21 Rac and CDC42 contribute to induction of EMT whereas p21 Ras GTP-ase inhibited this process. Angiotensin II stimulated the activity of the Plasminogen Activator Inhibitor-1 promoter through tyrosine kinases in tubular cells. Interestingly, angiotensin II induced a paradoxical activation of the proximal renin promoter in these cells. Both tyrosine kinases and the c-Jun-N-terminal Kinase contributed to this effect. Finally, we have demonstrated the expression of type I discoidin domain receptor in proximal tubular cells. We have shown that tyrosine phosphorylation of these receptors is induced by fibrillary type I collagen
Flavonoid diosmetin increases ATP levels in kidney cells and relieves ATP depleting effect of ochratoxin A
Diosmetin (DIOS) is a flavone aglycone commonly occurring in citrus species and olive leaves, in addition it is one of the active ingredients of some medications. Based on both in vitro and in vivo studies several beneficial effects are attributed to DIOS but the biochemical background of its action seems to be complex and it has not been completely explored yet. Previous investigations suggest that most of the flavonoid aglycones have negative effect on ATP synthesis in a dose dependent manner. In our study 17 flavonoids were tested and interestingly DIOS caused a significant elevation of intracellular ATP levels after 6- and 12-h incubation in MDCK kidney cells. In order to understand the mechanism of action, intracellular ATP and protein levels, ATP/ADP ratio, cell viability and ROS levels were determined after DIOS treatment. In addition, impacts of different enzyme inhibitors and effect of DIOS on isolated rat liver mitochondria were also tested. Finally, the influence of DIOS on the ATP depleting effect of the mycotoxin, ochratoxin A was also investigated. Our major conclusions are the followings: DIOS increases intracellular ATP levels both in kidney and in liver cells. Inhibition of glycolysis or citric acid cycle does not decrease the observed effect. DIOS-induced elevation of ATP levels is completely abolished by the inhibition of ATP synthase. DIOS is able to completely reverse the ATP-depleting effect of the mycotoxin, ochratoxin A. Most probably the DIOS-induced impact on ATP system does not originate from the antioxidant property of DIOS. Based on our findings DIOS may be promising agent to positively influence ATP depletion caused by some metabolic poisons
Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction
Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction of a 4-aryl-2-phenyl-1,4-benzoxazepine derivative obtained from flavanone. The relative configuration of products were determined by the correlation of 3JH,H coupling data with the geometry of major conformers accessed by DFT conformational analysis. Separated enantiomers of the products were characterized by HPLC-ECD data, which allowed their configurational assignment on the basis of TDDFT-ECD calculation of the solution conformers. Two compounds showed neuroprotective activities against hydrogen peroxide (H2O2) or β-amyloid25–35 (Aβ25–35)-induced cellular injuries in human neuroblastoma SH-SY5Y cells in the range of those of positive controls
A COVID–19-járvány hatása a leggyakoribb légzőszervi megbetegedések lefolyására
Bevezetés: A SARS-CoV-2 által okozott fertőzés az elmúlt három évben meghatározta mindennapi életünket, és nem
várt terhet rótt az egészségügyi ellátórendszerre, többek között azáltal, hogy komoly kockázati tényezőt jelenthet a
már meglévő, különböző légzőszervi megbetegedésekkel küzdő betegek számára is.
Célkitűzés: A COVID–19 és a fertőzéskor már fennálló légzőszervi megbetegedések, elsősorban a krónikus obstruk-
tĂv tĂĽdĹ‘betegsĂ©g (COPD), valamint az asztma összefĂĽggĂ©seinek feltárása.
MĂłdszer: Hazai vizsgálatunkban közel 29 000 beteg adatait dolgoztuk fel retrospektĂven.
EredmĂ©nyek: EredmĂ©nyeink alapján elmondhatĂł, hogy a COPD mint társbetegsĂ©g meglĂ©te a nemzetközi megállapĂ-
tással egybehangzĂłan összefĂĽggĂ©st mutat a COVID–19-fertĹ‘zĂ©s sĂşlyosságával, illetve enyhĂ©n növeli az intenzĂv osz-
tályos kezelés és a gépi lélegeztetés szükségességének kockázatát a SARS-CoV-2 okozta megbetegedés során. Asztma
esetĂ©ben mindezt nem sikerĂĽlt kimutatnunk, vagyis sem a SARS-CoV-2-fertĹ‘zĂ©s sĂşlyosságát, sem az intenzĂv osztá-
lyos kezelés és a gépi lélegeztetés szükségességét nem befolyásolta jelentősen az asztma mint társbetegség megléte.
MegbeszĂ©lĂ©s: Ahogy nemzetközi tanulmányokban is olvashatĂł, a COPD mint társbetegsĂ©g meglĂ©te nem növeli jelentĹ‘s mĂ©rtĂ©kben a SARS-CoV-2-fertĹ‘zĂ©s kockázatát. Ugyanakkor kijelenthetĹ‘, hogy a COPD növeli a COVID–19-pozitĂv betegek kĂłrházba kerĂĽlĂ©sĂ©nek esĂ©lyĂ©t, Ă©s emeli a megbetegedĂ©s sĂşlyosabb lefolyásának valĂłszĂnűsĂ©gĂ©t. Tekintettel a COPD-betegekben a tĂĽdĹ‘ károsodása során vĂ©gbemenĹ‘ szerkezeti átĂ©pĂĽlĂ©sre Ă©s rendellenes regenerálĂłdási folyamatokra, e betegek a vĂrusfertĹ‘zĂ©s lezajlása után fokozott odafigyelĂ©st, valamint szemĂ©lyre szabott rehabilitáciĂłt igĂ©nyelnek.
KövetkeztetĂ©s: Ă–sszessĂ©gĂ©ben elmondhatĂł, hogy a jövĹ‘ben a szemĂ©lyre szabott terápiás megközelĂtĂ©s bevezetĂ©sĂ©hez
elengedhetetlen a kĂĽlönbözĹ‘ COPD-s fenotĂpusok (valamint egyĂ©b krĂłnikus tĂĽdĹ‘betegsĂ©gek) Ă©s a SARS-CoV-2-fer-
tőzés klinikai megnyilvánulásainak mélyreható vizsgálata
[1,5]-Hydride Shift-Cyclization versus C(sp2)-H Functionalization in the Knoevenagel-Cyclization Domino Reactions of 1,4- and 1,5-Benzoxazepines
Domino cyclization reactions of N-aryl-1,4- and 1,5-benzoxazepine derivatives involving [1,5]-hydride shift or C(sp2)-H functionalization were investigated. Neuroprotective and acetylcholinesterase activities of the products were studied. Domino Knoevenagel-[1,5]-hydride shift-cyclization reaction of N-aryl-1,4-benzoxazepine derivatives with 1,3-dicarbonyl reagents having active methylene group afforded the 1,2,8,9-tetrahydro-7bH-quinolino [1,2-d][1,4]benzoxazepine scaffold with different substitution pattern. The C(sp3)-H activation step of the tertiary amine moiety occurred with complete regioselectivity and the 6-endo cyclization took place in a complete diastereoselective manner. In two cases, the enantiomers of the chiral condensed new 1,4-benzoxazepine systems were separated by chiral HPLC, HPLC-ECD spectra were recorded, and absolute configurations were determined by time-dependent density functional theory- electronic circular dichroism (TDDFT-ECD) calculations. In contrast, the analogue reaction of the regioisomeric N-aryl-1,5-benzoxazepine derivative did not follow the above mechanism but instead the Knoevenagel intermediate reacted in an SEAr reaction [C(sp2)-H functionalization] resulting in a condensed acridane derivative. The AChE inhibitory assays of the new derivatives revealed that the acridane derivative
had a 6.98 uM IC50 value
Cyclophilin D-dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia
Microorganisms or LPS (lipopolysaccharide), an outer membrane component of Gram-negative bacteria, can induce a systemic inflammatory response that leads to sepsis, multiple organ dysfunction, and mortality. Here, we investigated the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of LPS-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, we used liver RNA sequencing (RNAseq) data, Ingenuity® Pathway Analysis (IPA ® ) to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2844 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptor (TNFR)-mediated processes in wild-type mice. The disruption of CypD reduced LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases