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001-es BibID:	BIBFORM099926
035-os BibID:	(WOS)000522703800001 (Scopus)85083217977
Első szerző:	Kiss Tamás (vegyész)
Cím:	Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain / Kiss Tamas, Nyúl-Tóth Ádám, Balasubramanian Priya, Tarantini Stefano, Ahire Chetan, DelFavero Jordan, Yabluchanskiy Andriy, Csipo Tamas, Farkas Eszter, Wiley Graham, Garman Lori, Csiszar Anna, Ungvari Zoltan
Dátum:	2020
ISSN:	2509-2715 2509-2723
Megjegyzések:	Age-related phenotypic changes of cerebromicrovascular endothelial cells lead to dysregulation of cerebral blood flow and blood-brain barrier disruption, promoting the pathogenesis of vascular cognitive impairment (VCI). In recent years, endothelial cell senescence has emerged as a potential mechanism contributing to microvascular pathologies opening the avenue to the therapeutic exploitation of senolytic drugs in preclinical studies. However, difficulties with the detection of senescent endothelial cells in wild type mouse models of aging hinder the assessment of the efficiency of senolytic treatments. To detect senescent endothelial cells in the aging mouse brain, we analyzed 4233 cells in fractions enriched for cerebromicrovascular endothelial cells and other cells associated with the neurovascular unit obtained from young (3-month-old) and aged (28-month-old) C57BL/6 mice. We define 13 transcriptomic cell types by deep, single-cell RNA sequencing. We match transcriptomic signatures of cellular senescence to endothelial cells identified on the basis of their gene expression profile. Our study demonstrates that with advanced aging, there is an increased ratio of senescent endothelial cells (~ 10%) in the mouse cerebral microcirculation. We propose that our single-cell RNA sequencing-based method can be adapted to study the effect of aging on senescence in various brain cell types as well as to evaluate the efficiency of various senolytic regimens in multiple tissues.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Aging Blood-brain barrier Geroscience Senescence Vascular cognitive impairment
Megjelenés:	GeroScience. - 42 : 2 (2020), p. 429-444. -
További szerzők:	Nyúl-Tóth Ádám Balasubramanian, Priya Tarantini, Stefano Ahire, Chetan DelFavero, Jordan Yabluchanskiy, Andriy Csípő Tamás (1990-) Farkas Eszter Wiley, Graham Garman, Lori Csiszár Anna Ungvári Zoltán
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM082129
035-os BibID:	(WOS)000493693900001 (Scopus)85074812973
Első szerző:	Tarantini, Stefano
Cím:	Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging / Tarantini Stefano, Yabluchanskiy Andriy, Csipo Tamas, Fulop Gabor, Kiss Tamas, Balasubramanian Priya, DelFavero Jordan, Ahire Chetan, Ungvari Anna, Nyúl-Tóth Ádám, Farkas Eszter, Benyo Zoltan, Tóth Attila, Csiszar Anna, Ungvari Zoltan
Dátum:	2019
ISSN:	2509-2715 2509-2723
Megjegyzések:	Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) plays an important role in the maintenance of healthy cognitive function. Strong evidence demonstrates that age-related cerebromicrovascular endothelial dysfunction and consequential impairment of NVC responses contribute importantly to cognitive decline. Recent studies demonstrate that NAD(+) availability decreases with age in the vasculature and that supplemental NAD(+) precursors can ameliorate cerebrovascular dysfunction, rescuing NVC responses and improving cognitive performance in aged mice. The mechanisms underlying the age-related decline in [NAD(+)] in cells of the neurovascular unit are likely multifaceted and may include increased utilization of NAD(+) by activated poly (ADP-ribose) polymerase (PARP-1). The present study was designed to test the hypothesis that inhibition of PARP-1 activity may confer protective effects on neurovascular function in aging, similar to the recently demonstrated protective effects of treatment with the NAD+ precursor nicotinamide mononucleotide (NMN). To test this hypothesis, 24-month-old C57BL/6 mice were treated with PJ-34, a potent PARP inhibitor, for 2 weeks. NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with PJ-34 improved NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory. PJ-34 treatment also improved endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, PARP-1 activation, likely by decreasing NAD(+) availability, contributes to age-related endothelial dysfunction and neurovascular uncoupling, exacerbating cognitive decline. The cerebromicrovascular protective effects of pharmacological inhibition of PARP-1 highlight the preventive and therapeutic potential of treatments that restore NAD+ homeostasis as effective interventions in patients at risk for vascular cognitive impairment (VCI).
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Cellular energetics Oxidative stress ROS Endothelial dysfunction Functional hyperemia Microcirculation Senescence
Megjelenés:	GeroScience. - 41 : 5 (2019), p. 533-542. -
További szerzők:	Yabluchanskiy, Andriy Csípő Tamás (1990-) Fülöp Gábor Áron (1988-) (általános orvos) Kiss Tamás Balasubramanian, Priya DelFavero, Jordan Ahire, Chetan Ungvári Anna Nyúl-Tóth Ádám Farkas Eszter Benyó Zoltán Tóth Attila (1971-) (biológus) Csiszár Anna Ungvári Zoltán
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001-es BibID:	BIBFORM099928
035-os BibID:	(WOS)000516499100001 (Scopus)85078289607
Első szerző:	Yabluchanskiy, Andriy
Cím:	Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice / Yabluchanskiy Andriy, Tarantini Stefano, Balasubramanian Priya, Kiss Tamas, Csipo Tamas, Fülöp Gábor A., Lipecz Agnes, Ahire Chetan, DelFavero Jordan, Nyul-Toth Adam, Sonntag William E., Schwartzman Michal L., Campisi Judith, Csiszar Anna, Ungvari Zoltan
Dátum:	2020
ISSN:	2509-2715 2509-2723
Megjegyzések:	Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Aging Dementia Functional hyperemia Radiation Senescence Vascular cognitive impairment WBI WBRT Whole brain radiation therapy
Megjelenés:	GeroScience. - 42 : 2 (2020), p. 409-428. -
További szerzők:	Tarantini, Stefano Balasubramanian, Priya Kiss Tamás (1950-) (vegyész) Csípő Tamás (1990-) Fülöp Gábor Áron (1988-) (általános orvos) Lipécz Ágnes Ahire, Chetan DelFavero, Jordan Nyúl-Tóth Ádám Sonntag, William E. Schwartzman, Michal L. Campisi, Judith Csiszár Anna Ungvári Zoltán
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