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Metabolic disorders caused by impairments of the Gsα/cAMP/PKA pathway affecting the signaling of PTH/PTHrP lead to features caused by non-responsiveness of target organs, in turn leading to manifestations similar to the deficiency of the hormone itself. Pseudohypoparathyroidism (PHP) and related disorders derive from a defect of the α subunit of the stimulatory G protein (Gsα) or of downstream effectors of the same pathway, such as the PKA regulatory subunit 1A and the phosphodiesterase type 4D. The increasing knowledge on these diseases made the actual classification of PHP outdated as it does not include related conditions such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), so that a new nomenclature and classification has been recently proposed grouping these disorders under the term "inactivating PTH/PTHrP signaling disorder" (iPPSD). This review will focus on the pathophysiology, clinical and molecular aspects of these rare, heterogeneous but closely related diseases. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In this study, we aimed to investigate the mechanism of PDE3A downregulation in chemoresistant non-small cell lung cancer (NSCLC) cells, its functional role in chemotherapy response and association with survival outcomes. MATERIALS AND METHODS: The raw data of GDS5247 was downloaded from GEO datasets and reanalyzed. The expression of PDE3A in patients with NSCLC and its DNA methylation status were analyzed in NSCLC cohort in TCGA database. Cisplatin resistant A549/Cis cells and the parental A549 cells were used as the in vitro cell model. The association between PDE3A expression and overall survival (OS) and progression- free survival (PFS) in NSCLC patients with adenocarcinoma or squamous cell carcinoma, as well as the median OS and PFS, were assessed by Kaplan-Meier curves using Kaplan- Meier plotter. RESULTS: PDE3A was significantly downregulated in chemoresistant NSCLC cells. Heat map of PDE3A expression and methylation in NSCLC patient cohort in TCGA database indicated a negative association between PDE3A expression and DNA methylation in lung adenocarcinoma. A549/Cis cells treated with 5-AZA-dC, a demethylation reagent, had significantly restored PDE3A expression. High PDE3A expression was associated with favorable OS (HR: 0.53, 95% CI: 0.41-0.68, p<0.0001) and PFS (HR: 0.54, 95% CI: 0.39-0.75, p<0.001) in patients with adenocarcinoma. However, in patients with squamous cell carcinoma, high PDE3A expression was associated with unfavorable OS (HR: 1.56, 95% CI: 1.08- 2.24, p=0.017) and PFS (HR: 1.83, 95% CI: 1.02- 3.29, p=0.04). CONCLUSIONS: PDE3A is downregulated in chemoresistant NSCLC cells due to DNA hypermethylation. Enforced PDE3A expression can sensitize A549/Cis cells to cisplatin. High PDE3A expression is associated with better OS and PFS in patients with adenocarcinoma, but not in patients with squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

It is known that Di (2-ethylhexyl) phthalate (DEHP) may impact mammalian reproduction and that in females one target of the drug's action is follicle assembly. Here we revisited the phthalate's action on the ovary and from bioinformatics analyses of the transcriptome performed on newborn mouse ovaries exposed in vitro to DEHP, up-regulation of PDE3A, as one of the most important alterations caused by DEHP on early folliculogenesis, was identified. We obtained some evidence suggesting that the decrease of cAMP level in oocytes and the parallel decrease of PKA expression, consequent on the PDE3A increase, were a major cause of the reduction of follicle assembly in the DEHP-exposed ovaries. In fact, Pde3a RNAi on cultured ovaries reducing cAMP and PKA decrease counteracted the primordial follicle assembly impairment caused by the compound. Moreover, RNAi normalized the level of Kit, Nobox , Figla mRNA and GDF9, BMP15, CX37, γH2AX proteins in oocytes, and KitL transcripts in granulosa cells as well as their proliferation rate altered by DEHP exposure. Taken together, these results identify PDE3A as a new critical target of the deleterious effects of DEHP on early oogenesis in mammals and highlight cAMP-dependent pathways as major regulators of oocyte and granulosa cell activities crucial for follicle assembly. Moreover, we suggest that the level of intracellular cAMP in the oocytes may be an important determinant for their capability to repair DNA lesions caused by DNA damaging compounds including DEHP. Image 1 • DEHP exposure impairs the primordial follicle assembly of newborn mouse ovaries. • DEHP exposure promotes PDE3A expression in the early stage of folliculogenesis. • Pde3a RNAi counteracted the influence of DEHP on ovaries by reducing cAMP and PKA. PDE3A is one of the most important regulators caused by DEHP exposure on impairment of early folliculogenesis. [ABSTRACT FROM AUTHOR]