Cyclic nucleotide phosphodiesterase inhibitors: possible therapeutic drugs for female fertility regulation

Gupta, Akhil; Pandey, Ashutosh; Sharma, Alka; Tiwari, Meenakshi; Yadav, Pramod K.; Yadav, Anil Kumar; Pandey, Ajai Kumar; Shrivastav, Tulsidas G.; Chaube, Shail K.

doi:10.1016/j.ejphar.2020.173293

Cited by 12 publications

(8 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results are consistent with those of previous studies in which sheep oocytes supplemented with milrinone showed improved developmental competence (Wang et al, 2016). The mechanism of milrinone, as a specific PDE3 inhibitor, is as follows: it downregulates PDE3, which affects the hydrolysis of cyclic nucleotides, cAMP and cGMP, in the cytoplasm of the oocytes (Gupta et al, 2020). Thus, the maturation promoting factors that trigger the meiotic exit of the oocyte are destabilized.…”

Section: Discussionsupporting

confidence: 92%

Enhancing Oocyte Competence With Milrinone as a Phosphodiesterase 3A Inhibitor to Improve the Development of Porcine Cloned Embryos

Roy

Qamar

Tanga

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The objective of this study was to investigate the effect of milrinone supplementation as a phosphodiesterase 3A inhibitor during in vitro maturation (IVM) to coordinate the cytoplasmic and nuclear maturation of porcine oocytes and subsequent development of porcine cloned embryos. Brilliant cresyl blue (BCB)-stained (BCB +) oocytes, classified as well-developed, and BCB− oocytes were used in parthenogenesis (PA) and cloning, and their preimplantation development was compared. In PA embryos, BCB + oocytes had significantly higher rates of development than BCB− oocytes in terms of maturation (87.5 vs. 71.3%), cleavage (88.6 vs. 76.3%), and blastocyst development (34.3 vs. 25.3%) and also had higher cell numbers (46.9 vs. 38.9%), respectively (p < 0.05). In cloned embryos, the BCB + group also had a significantly higher blastocyst formation rate than the BCB− group (30.6 vs. 20.1%; p < 0.05). Supplementation with 75 μM milrinone during IVM of BCB− oocytes showed improvement in maturation and blastocyst development rates, which may be due to the coordinated maturation of the cytoplasm with the nucleus as an effect of milrinone. Moreover, the analysis of nuclear reprogramming via the examination of the expression levels of the reprogramming-related genes POU5F1, DPPA2, and NDP52IL in milrinone-supplemented BCB− oocytes showed higher expression levels than that in non-treated BCB− oocytes. These findings demonstrate that milrinone is useful in improving developmental competence in less competent oocytes during IVM and for proper nuclear reprogramming in the production of porcine cloned embryos by coordinating cytoplasmic and nucleus maturation.

show abstract

Section: Discussionsupporting

confidence: 92%

Enhancing Oocyte Competence With Milrinone as a Phosphodiesterase 3A Inhibitor to Improve the Development of Porcine Cloned Embryos

Roy

Qamar

Tanga

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…We also found that the accessible chromatin in oocytes and embryos both involved PDE activity, which degraded cAMP, and high levels of cAMP are related to the inhibition of meiosis [38,39]. The PA and SCNT embryos had recently completed meiosis, and this chromatin open site may be inherited from the M2 oocyte.…”

Section: Discussionmentioning

confidence: 70%

Identification of Chromatin Accessibility During The Early Stage of Pig SCNT Embryo Reprogramming by ATAC-Seq

Zhang¹,

Li²,

Tao³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Somatic cell nuclear transplantation (SCNT) can transform highly differentiated donor nuclei into pluripotent nuclei through the large-scale reprogramming of chromatin. The reprogramming of chromatin has been documented to take place in the first few hours after SCNT embryo activation. Thus, studies that characterize dynamic changes in chromatin during the first few hours after embryo activation could provide insight into the mechanism and significance of genome-wide reprogramming. However, few studies have examined the epigenetic remodeling of reconstructed embryos during the early stage of reprogramming.Results: We conducted ATAC-seq on 50 porcine SCNT-HMC embryos and 50 parthenogenetic activation (PA) embryos 10 h after activation. Along with pig embryonic fibroblast (PEF) ATAC-seq data, we found low levels of chromatin accessibility and gene transcription in SCNT and PA embryos. Moreover, PEF genes and the X chromosome became inaccessible during embryo reprogramming. GO enrichment analysis revealed that the molecular functions related to accessible chromatin in embryos primarily included transcriptional regulatory activity and SMAD binding. The differentially accessible chromatin sites between SCNT and PEF were primarily related to transcriptional activity and histone modification.Conclusions: Despite the tight chromatin structure during the early stage of embryo reprogramming, some accessible chromatin sites, which were primarily distributed in the intergenic region, were still detected. Dynamic changes in chromatin accessibility during reprogramming were primarily related to transcriptional activity and histone modification. Generally, this study provided new insight into the dynamics and importance of chromatin accessibility during the early stages of embryo reprogramming.

show abstract

“…Cuando los niveles de AMPc dentro del oocito descienden, se induce la continuación de la meiosis, caracterizada por el rompimiento de la vesícula germinal generando la maduración del oocito (Ferré et al, 2020). A su vez, los niveles de AMPc son regulados por las enzimas fosfodiesterasas (PDE) que hidrolizan el AMPc en AMP, con una expresión especifica de compartimiento en la unidad folicular, donde la PDE tipo 3 (PDE-3) se expresa en el oocito y la PDE tipo 4 en las células del cúmulo (López et al, 2008;Gupta et al, 2020). Así entonces, la utilización del YM976 debería prevenir la degradación de AMPc en oocitos bovinos, resultando en su acumulación en cúmulos y oocitos, manteniendo estables las uniones gap, retardando la reanudación de la meiosis (Santana et al, 2019).…”

Section: Discussionunclassified

“…Por otro lado, la degradación de AMPc se produce como resultado de la activación de la fosfodiesterasa de nucleótidos cíclicos (PDE) dentro de los complejos cúmulo-oocito ( Lo anterior ha conducido a la búsqueda de modificaciones en los protocolos de producción in vitro de embriones, encaminados a la prevención de la maduración nuclear espontánea a través de mediadores químicos. Una alternativa sería el uso de inhibidores de las enzimas fosfodiesterasas del AMPc (Thomas et al, 2004;Botigelli et al, 2017;Gupta et al, 2020). Debido a la expresión específica de PDE en la unidad folicular, se han evaluado medicamentos que permitan una inhibición selectiva, aumentando la concentración intracelular de AMPc, ya sea en las células de la granulosa o en el oocito (López et al, 2008).…”

Section: Introductionunclassified

Evaluación del YM976 como alternativo a las hormonas gonadotrópicas en la maduración in vitro de oocitos bovinos y su competencia para el desarrollo embrionario

Carrillo-González

Hernández-Herrera

Araque

2021

Rev. investig. vet. Perú

View full text Add to dashboard Cite

El objetivo del estudio fue evaluar el efecto del YM976 como inhibidor específico de la fosfodiesterasa tipo 4 (PDE-4) sobre la maduración in vitro de oocitos bovinos y su capacidad de desarrollo embrionario. Para ello, complejos cúmulo-oocito se obtuvieron por aspiración folicular de ovarios obtenidos en planta de sacrificio. Se maduraron in vitro por 24 horas en medio TCM-199 suplementado con cuatro concentraciones de YM976 (1, 10, 100 y 1000 nM) o con gonadotropinas (LH y FSH). Se evaluó la expansión del cúmulo por observación visual y la reanudación de la metafase II por tinción con colorante Hoechst. Los oocitos fueron fertilizados y cultivados en medio KSOM Evolve por ocho días. El porcentaje de expansión grado 3 de las células de cúmulo en oocitos cultivados con gonadotropinas fue diferente (p= 0.00016) respecto de los cultivado en presencia del YM976. La reanudación de la metafase II fue similar entre oocitos madurados a 10 nM de YM976 y los madurados con gonadotropinas. Los oocitos madurados en concentraciones de 1 y 10 nM de YM976 presentaron un desarrollo embrionario temprano similar al encontrado en los madurados con gonadotropinas. Por el contrario, altas concentraciones de YM976 tuvieron efectos deletéreos. En conclusión, concentraciones 1 y 10 nM del inhibidor de PDE-4 YM976 durante la maduración in vitro de oocitos retrasa la expansión de las células de la granulosa, pero permite una maduración nuclear y competencia para el desarrollo embrionario, similar a los oocitos madurados con gonadotropinas, sugiriendo que, el uso de YM976 puede ser aplicado en procesos de maduración in vitro de oocitos bovinos.

show abstract

Cyclic nucleotide phosphodiesterase inhibitors: possible therapeutic drugs for female fertility regulation

Cited by 12 publications

References 101 publications

Enhancing Oocyte Competence With Milrinone as a Phosphodiesterase 3A Inhibitor to Improve the Development of Porcine Cloned Embryos

Enhancing Oocyte Competence With Milrinone as a Phosphodiesterase 3A Inhibitor to Improve the Development of Porcine Cloned Embryos

Identification of Chromatin Accessibility During The Early Stage of Pig SCNT Embryo Reprogramming by ATAC-Seq

Evaluación del YM976 como alternativo a las hormonas gonadotrópicas en la maduración in vitro de oocitos bovinos y su competencia para el desarrollo embrionario

Contact Info

Product

Resources

About