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001-es BibID:	BIBFORM077036
035-os BibID:	(WoS)000458934000210 (Scopus)85061291471
Első szerző:	Bombicz Mariann (gyógyszerész)
Cím:	The Drug Candidate BGP-15 Delays the Onset of Diastolic Dysfunction in the Goto-Kakizaki Rat Model of Diabetic Cardiomyopathy / Bombicz Mariann, Priksz Daniel, Gesztelyi Rudolf, Kiss Rita, Hollos Nora, Varga Balazs, Nemeth Jozsef, Toth Attila, Papp Zoltan, Szilvassy Zoltan, Juhasz Bela
Dátum:	2019
ISSN:	1420-3049
Megjegyzések:	Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. Methods: Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. Results: BGP-15 restored diastolic parameters (e·/a·, E/e·, LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. Conclusions: Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM.
Tárgyszavak:	Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk BGP-15 diastolic dysfunction type 2 diabetes Goto-Kakizaki echocardiography
Megjelenés:	Molecules. - 24 : 3 (2019), p. 1-18. -
További szerzők:	Priksz Dániel (1989-) (farmakológus) Gesztelyi Rudolf (1969-) (kísérletes farmakológus) Kiss Rita (1974-) (laboratóriumi diagnosztika szakorvos) Hollós Nóra (1995-) (hallgató) Varga Balázs (1984-) (kísérletes farmakológus) Németh József (1954-) (vegyész, analitikus) Tóth Attila (1971-) (biológus) Papp Zoltán (1965-) (kardiológus, élettanász) Szilvássy Zoltán (1957-) (belgyógyász, farmakológus, klinikai farmakológus) Juhász Béla (1978-) (kísérletes farmakológus)
Pályázati támogatás:	GINOP-2.3.4-15-2016-00002 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM099194
035-os BibID:	(WOS)000751415800001 (Scopus)85124483518
Első szerző:	Priksz Dániel (farmakológus)
Cím:	Nicotinic-acid derivative BGP-15 improves diastolic function in a rabbit model of atherosclerotic cardiomyopathy / Priksz Daniel, Lampe Nora, Kovacs Arpad, Herwig Melissa, Bombicz Mariann, Varga Balazs, Wilisicz Tician, Szilvassy Judit, Posa Aniko, Kiss Rita, Gesztelyi Rudolf, Raduly Arnold, Szekeres Reka, Sieme Marcel, Papp Zoltan, Toth Attila, Hamdani Nazha, Szilvassy Zoltan, Juhasz Bela
Dátum:	2022
ISSN:	0007-1188
Megjegyzések:	Background and purpose: Small molecule BGP-15 has been reported to alleviate signs of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. Experimental approach: Rabbits were maintained on standard chow (Control) or atherogenic diet (HC) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed, and key molecules of the protein kinase G (PKG) axis were examined by ELISA and Western blot. Passive force generation was investigated in skinned cardiomyocytes. Key results: Both acute and chronic BGP-15 treatment improved the diastolic performance of the diseased heart, however, vasorelaxation and serum lipid markers were unaffected. Myocardial cGMP levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group, and the substance inhibited PDE1 enzyme. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased, and PKG-dependent N2B-titin phosphorylation elevated in the BGP-15-treated group. Conclusions and implications: Here we report that BGP-15-treatment improves diastolic function, reduces cardiomyocyte stiffness, and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG axis. As BGP-15 is proven to be safe, it may have clinical value in the treatment of diastolic dysfunction.
Tárgyszavak:	Orvostudományok Gyógyszerészeti tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk BGP-15 diastolic dysfunction hypercholesterolemia protein kinase G titin
Megjelenés:	British Journal Of Pharmacology. - 179 : 10 (2022), p. 2240-2258. -
További szerzők:	Lampé Nóra Kovács Árpád (1986-) (kardiológus) Herwig, Melissa Bombicz Mariann (1987-) (gyógyszerész) Varga Balázs (1984-) (kísérletes farmakológus) Wilisicz, Tician Szilvássy Judit (1960-2022) (fül- orr- gégész) Pósa Anikó Kiss Rita (1974-) (laboratóriumi diagnosztika szakorvos) Gesztelyi Rudolf (1969-) (kísérletes farmakológus) Ráduly Arnold Péter (1993-) Szekeres Réka (1995-) (orvos) Sieme, Marcel Papp Zoltán (1965-) (kardiológus, élettanász) Tóth Attila (1971-) (biológus) Hamdani, Nazha Szilvássy Zoltán (1957-) (belgyógyász, farmakológus, klinikai farmakológus) Juhász Béla (1978-) (kísérletes farmakológus)
Pályázati támogatás:	GINOP-2.3.2-15-2016-00043 GINOP TKP2020-IKA-04 Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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