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Cellular Signalling Aug 2023Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyse the intracellular second messengers cAMP and cGMP to their inactive forms 5'AMP... (Review)
Review
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyse the intracellular second messengers cAMP and cGMP to their inactive forms 5'AMP and 5'GMP. Some members of the PDE family display specificity towards a single cyclic nucleotide messenger, and PDE4, PDE7, and PDE8 specifically hydrolyse cAMP. While the role of PDE4 and its use as a therapeutic target have been well studied, less is known about PDE7 and PDE8. This review aims to collate the present knowledge on human PDE7 and outline its potential use as a therapeutic target. Human PDE7 exists as two isoforms PDE7A and PDE7B that display different expression patterns but are predominantly found in the central nervous system, immune cells, and lymphoid tissue. As a result, PDE7 is thought to play a role in T cell activation and proliferation, inflammation, and regulate several physiological processes in the central nervous system, such as neurogenesis, synaptogenesis, and long-term memory formation. Increased expression and activity of PDE7 has been detected in several disease states, including neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's disease, autoimmune diseases such as multiple sclerosis and COPD, and several types of cancer. Early studies have shown that administration of PDE7 inhibitors may ameliorate the clinical state of these diseases. Targeting PDE7 may therefore provide a novel therapeutic strategy for targeting a broad range of disease and possibly provide a complementary alternative to inhibitors of other cAMP-selective PDEs, such as PDE4, which are severely limited by their side-effects.
Topics: Humans; Cyclic Nucleotide Phosphodiesterases, Type 7; Phosphodiesterase Inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases; Nucleotides, Cyclic
PubMed: 37120115
DOI: 10.1016/j.cellsig.2023.110689 -
International Journal of Molecular... Apr 2023Phosphodiesterases are key regulators that fine tune the intracellular levels of cyclic nucleotides, given their ability to hydrolyze cAMP and cGMP. They are critical... (Review)
Review
Phosphodiesterases are key regulators that fine tune the intracellular levels of cyclic nucleotides, given their ability to hydrolyze cAMP and cGMP. They are critical regulators of cAMP/cGMP-mediated signaling pathways, modulating their downstream biological effects such as gene expression, cell proliferation, cell-cycle regulation but also inflammation and metabolic function. Recently, mutations in PDE genes have been identified and linked to human genetic diseases and PDEs have been demonstrated to play a potential role in predisposition to several tumors, especially in cAMP-sensitive tissues. This review summarizes the current knowledge and most relevant findings regarding the expression and regulation of PDE families in the testis focusing on PDEs role in testicular cancer development.
Topics: Male; Humans; Testicular Neoplasms; Cyclic AMP; Phosphoric Diester Hydrolases; Cyclic GMP
PubMed: 37108780
DOI: 10.3390/ijms24087617 -
Frontiers in Endocrinology 2023Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females....
INTRODUCTION
Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats.
DESIGN
Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12μg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48μg/kg.d; KTZ 3-12-48mg/kg.d).
RESULTS
Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted "Creb signaling in Neurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood.
CONCLUSION
nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.
Topics: Pregnancy; Rats; Animals; Female; Fungicides, Industrial; Ketoconazole; Sexual Maturation; Hypothalamus; Gonadotropin-Releasing Hormone
PubMed: 37077353
DOI: 10.3389/fendo.2023.1140886 -
PloS One 2023A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process...
A synthetic estrogen, diethylstilbestrol (DES), is known to cause adult vaginal carcinoma by neonatal administration of DES to mice. However, the carcinogenic process remains unclear. By Cap Analysis of Gene Expression method, we found that neonatal DES exposure up-regulated inflammatory Cxcl chemokines 2, 3, 5, and 7 located in the 5qE1 region in the vaginal epithelium of mice 70 days after birth. When we examined the gene expressions of these genes much earlier stages, we found that neonatal DES exposure increased these Cxcl chemokine genes expression even after 17 days after birth. It implies the DES-mediated persistent activation of inflammatory genes. Intriguingly, we also detected DES-induced non-coding RNAs from a region approximately 100 kb far from the Cxcl5 gene. The non-coding RNA up-regulation by DES exposure was confirmed on the 17-day vagina and continued throughout life, which may responsible for the activation of Cxcl chemokines located in the same region, 5qE1. This study shows that neonatal administration of DES to mice causes long-lasting up-regulation of inflammatory Cxcl chemokines in the vaginal epithelium. DES-mediated inflammation may be associated with the carcinogenic process.
Topics: Animals; Female; Mice; Animals, Newborn; Carcinogens; Diethylstilbestrol; Epithelium; Estradiol Congeners; Vagina; Vaginal Neoplasms; Chemokines, CXC
PubMed: 36928065
DOI: 10.1371/journal.pone.0280421 -
Circulation Research Mar 2023Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has...
BACKGROUND
Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing.
METHODS
Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans.
RESULTS
We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth.
CONCLUSIONS
We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors.
Topics: Humans; Myocytes, Cardiac; Cyclic AMP; Proteomics; Phosphoric Diester Hydrolases; Hypertrophy; Adrenergic Agents
PubMed: 36883446
DOI: 10.1161/CIRCRESAHA.122.321448 -
Redox Biology May 2023Identifying direct substrates of enzymes has been a long-term challenge. Here, we present a strategy using live cell chemical cross-linking and mass spectrometry to...
Identifying direct substrates of enzymes has been a long-term challenge. Here, we present a strategy using live cell chemical cross-linking and mass spectrometry to identify the putative substrates of enzymes for further biochemical validation. Compared with other methods, our strategy is based on the identification of cross-linked peptides supported by high-quality MS/MS spectra, which eliminates false-positive discoveries of indirect binders. Additionally, cross-linking sites allow the analysis of interaction interfaces, providing further information for substrate validation. We demonstrated this strategy by identifying direct substrates of thioredoxin in both E. coli and HEK293T cells using two bis-vinyl sulfone chemical cross-linkers BVSB and PDES. We confirmed that BVSB and PDES have high specificity in cross-linking the active site of thioredoxin with its substrates both in vitro and in live cells. Applying live cell cross-linking, we identified 212 putative substrates of thioredoxin in E. coli and 299 putative S-nitrosylation (SNO) substrates of thioredoxin in HEK293T cells. In addition to thioredoxin, we have shown that this strategy can be applied to other proteins in the thioredoxin superfamily. Based on these results, we believe future development of cross-linking techniques will further advance cross-linking mass spectrometry in identifying substrates of other classes of enzymes.
Topics: Humans; Escherichia coli; HEK293 Cells; Oxidoreductases; Tandem Mass Spectrometry; Thioredoxins; Protein Interaction Mapping
PubMed: 36863169
DOI: 10.1016/j.redox.2023.102642 -
Toxics Feb 2023With the widespread use of diethylstilbestrol (DES), it has become a common contaminant in the aquatic environment. It is toxic to a wide range of aquatic organisms,...
With the widespread use of diethylstilbestrol (DES), it has become a common contaminant in the aquatic environment. It is toxic to a wide range of aquatic organisms, disrupting the water flea growth and further interfering with several ecosystem services. Nevertheless, the molecular mechanism of DES in water fleas is still unexplicit. In this study, the 21-day chronic test showed that a negative effect of growth and reproduction can be observed with DES exposure. Subsequently applied transcriptomic analysis illustrated the molecular mechanism in mode freshwater invertebrate () exposed to 2, 200, and 1000 μg·L of DES for 9 days. Meanwhile, exposure to DES at 200 and 1000 μg·L significantly restrains the growth (body length) and reproduction (first spawning time) of . Identified differentially expressed genes (DEGs) are majorly enriched relative to energy metabolism, lipid metabolism, the digestive system, transport and catabolism pathways which were remarkably changed. These repressed and up-regulated pathways, in relation to energy synthesis and metabolism, may be the reasons for the reduced body length and delayed first spawning time. Taken together, this study revealed that DES is a threat to in the aquatic environment and clarifies the molecular mechanism of the toxicity.
PubMed: 36851071
DOI: 10.3390/toxics11020197 -
International Journal of Environmental... Jan 2023Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause... (Observational Study)
Observational Study
OBJECTIVE
Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause permanent adverse health effects in the exposed mothers, their children (exposed in utero), and also their grandchildren through germline contribution to the zygote. This study evaluated pregnancy duration and birthweight (BW) variations in the children and grandchildren born before, during, and after maternal DES treatment in the same informative families, to rule out genetic, endocrine, and environmental factors.
DESIGN AND SETTING
Nationwide retrospective observational study on 529 families of DES-treated women registered at the HHORAGES-France Association. The inclusion criteria were: (i) women with at least three pregnancies and three viable children among whom the first was not exposed in utero to DES, followed by one or more children with fetal exposure to DES, and then by one or more children born after DES treatment; (ii) women with at least one pre-DES or post-DES grandchild and one DES grandchild; (iii) confirmed data on total DES dose. Women with severe pathologies or whose illness status, habitat, lifestyle habits, profession, treatment changed between pregnancies, and all mothers who reported pregnancy-related problems, were excluded.
RESULTS
In all, 74 women met all criteria. The preterm birth (PTB) rate was 2.7% in pre-DES, 14.9% in DES, and 10.8% in post-DES children (Cochran-Armitage test for trend, = 0.0095). The mean BW was higher in DES than pre-DES full-term neonates (≥37 weeks of gestation) ( = 0.007). In grandchildren, BW was not different, whereas the PTB and low BW rates were slightly increased in children of DES women.
CONCLUSIONS
These data within the same informative families show the DES impact on BW and PTB in DES and post-DES children and grandchildren. In particular, mean BW was higher in DES than pre-DES full-term neonates. This result may be in opposition to previous data from American cohorts, which reported lower BW in DES children, but is consistent with animal study. Our retrospective observational study highlights a multigenerational and likely transgenerational effect of this EDC in humans.
Topics: Animals; Humans; Pregnancy; Infant, Newborn; Female; Child; Diethylstilbestrol; Cohort Studies; Prenatal Exposure Delayed Effects; Premature Birth; Estrogens, Non-Steroidal
PubMed: 36767903
DOI: 10.3390/ijerph20032542 -
Gynecologic Oncology Reports Feb 2023Vaginoscopy has been mainly used diagnostically due to the lack of adequate equipment for performing complicated surgeries (Johary et al., 2015). However, herein, we...
Vaginoscopy has been mainly used diagnostically due to the lack of adequate equipment for performing complicated surgeries (Johary et al., 2015). However, herein, we report therapeutic vaginal endoscopic surgery (pneumovaginoscopy) for secondary malignant vaginal tumors using the vNOTES technique and devices (Kita et al., 2021, Yokoe et al., 2022). To our knowledge, this report and surgical video demonstrate the first case of successful fertility-sparing R0 tumor resection of a rare primary cervical clear cell adenocarcinoma using pneumovaginoscopy. A 12-year-old girl was referred to our outpatient clinic with a chief complaint of a genital tumor and possible clear cell carcinoma on biopsy. There was no history of diethylstilbestrol exposure. MRI and CT images suggested a polypoid cervical tumor without metastatic lesions. Therefore, we performed therapeutic pneumovaginoscopic surgery with diagnostic laparoscopy and hysteroscopy. The cervical tumor was resected completely, and hysteroscopy and laparoscopy revealed no abnormalities. The total surgical time was 123 min, and the blood loss volume was minimal. R0 resection was achieved microscopically. Postoperatively, we performed a partial cervical resection around the first surgical scar to confirm no residual tumor. There were no postoperative complications, and a 2-year follow-up revealed no recurrence. The standard treatment for early-stage cervical cancer (IA2-IB1) remains radical hysterectomy with pelvic lymphadenectomy. However, fertility-sparing minimally invasive surgery has recently been introduced for clear cell adenocarcinoma of the cervix (Su et al., 2020). Our report supports the possibility of this minimally invasive surgery under exceptional conditions. This study was approved by the ethics committee of Kansai Medical University. Written and signed informed consent was obtained from the patient's legal guardian.
PubMed: 36714371
DOI: 10.1016/j.gore.2023.101135 -
Mathematical Biosciences and... Sep 2022This paper shows how biological population dynamic models in the form of coupled reaction-diffusion equations with nonlinear reaction terms can be applied to...
This paper shows how biological population dynamic models in the form of coupled reaction-diffusion equations with nonlinear reaction terms can be applied to heterogeneous landscapes. The presented systems of coupled partial differential equations (PDEs) combine the dispersal of disease-vector mosquitoes and the spread of the disease in a human population. Realistic biological dispersal behavior is taken into account by applying chemotaxis terms for the attraction to the human host and the attraction of suitable breeding sites. These terms are capable of generating the complex active movement patterns of mosquitoes along the gradients of the attractants. The nonlinear initial boundary value problems are solved numerically for geometries of heterogeneous landscapes, which have been imported from geographic information system data to construct a general-purpose finite-element solver for systems of coupled PDEs. The method is applied to the dispersal of the dengue disease vector for Aedes aegypti in a small-scale rural setting consisting of small houses and different breeding sites, and to a large-scale section of the suburban zone of a metropolitan area in Vietnam. Numerical simulations illustrate how the setup of model equations and geographic information can be used for the assessment of control measures, including the spraying patterns of pesticides and biological control by inducing male sterility.
Topics: Animals; Humans; Male; Aedes; Mosquito Vectors; Disease Vectors; Breeding; Dengue
PubMed: 36654028
DOI: 10.3934/mbe.2022603