Osteoblast-activating peptide exhibits a specific distribution pattern in mouse ovary and may regulate ovarian steroids and local calcium levels.
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ABSTRACT:
SUBMITTER: Noreldin AE
PROVIDER: S-EPMC8290782 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels.We quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta.All genes encoding tachykinins (Tac1, Tac2 and Tac4) and tachykinin receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2.These results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.
| S-EPMC2724541 | biostudies-literature
Project description:With extended life spans in modern humans, menopause has become a significant risk factor for depression, anxiety, loss of cognitive functions, weight gain, metabolic disease, osteoporosis, cardiovascular disease, and neurodegenerative diseases. Clinical studies have found beneficial neural effects of ovarian steroid hormone therapy (HT) during the menopausal transition and data are emerging that it can be continued long term. To further understand molecular underpinnings of the clinical studies, we used quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to examine gene expression in the serotonergic dorsal raphe of old (>18 years) rhesus macaques, focusing on genes related to depression, cellular resilience, and neurodegenerative diseases. The animals were ovariectomized (Ovx, surgically menopausal) and subjected to either estradiol or estradiol plus progesterone HT, or to placebo, starting 2 months after Ovx and continuing for ? 4 years. Significant changes were observed in 36 of 48 genes examined that encode proteins supporting serotonin neurotransmission, synapse assembly, glutamate neurotransmission, DNA repair, chaperones, ubiquinases and transport motors, as well as genes encoding proteins that have potential to delay the onset of neuropathologies. The data reveal important gene targets for chronic HT that contribute to neural health. Alternatively, the loss of ovarian steroids may lead to loss of functions at the gene level that contribute to many of the observable neural deficits after menopause.
| S-EPMC4699313 | biostudies-literature
Project description:BACKGROUND: Investigation of the mechanisms of guided cell migration can contribute to our understanding of many crucial biological processes, such as development and regeneration. Endogenous and exogenous direct current electric fields (dcEF) are known to induce directional cell migration, however the initial cellular responses to electrical stimulation are poorly understood. Ion fluxes, besides regulating intracellular homeostasis, have been implicated in many biological events, including regeneration. Therefore understanding intracellular ion kinetics during EF-directed cell migration can provide useful information for development and regeneration. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the initial events during migration of two osteogenic cell types, rat calvarial and human SaOS-2 cells, exposed to strong (10-15 V/cm) and weak (< or = 5 V/cm) dcEFs. Cell elongation and perpendicular orientation to the EF vector occurred in a time- and voltage-dependent manner. Calvarial osteoblasts migrated to the cathode as they formed new filopodia or lamellipodia and reorganized their cytoskeleton on the cathodal side. SaOS-2 cells showed similar responses except towards the anode. Strong dcEFs triggered a rapid increase in intracellular calcium levels, whereas a steady state level of intracellular calcium was observed in weaker fields. Interestingly, we found that dcEF-induced intracellular calcium elevation was initiated with a local rise on opposite sides in calvarial and SaOS-2 cells, which may explain their preferred directionality. In calcium-free conditions, dcEFs induced neither intracellular calcium elevation nor directed migration, indicating an important role for calcium ions. Blocking studies using cadmium chloride revealed that voltage-gated calcium channels (VGCCs) are involved in dcEF-induced intracellular calcium elevation. CONCLUSION/SIGNIFICANCE: Taken together, these data form a time scale of the morphological and physiological rearrangements underlying EF-guided migration of osteoblast-like cell types and reveal a requirement for calcium in these reactions. We show for the first time here that dcEFs trigger different patterns of intracellular calcium elevation and positional shifting in osteogenic cell types that migrate in opposite directions.
| S-EPMC2702840 | biostudies-literature
Project description:Depression often accompanies the perimenopausal transition and it often precedes overt symptomology in common neurodegenerative diseases (NDDs, such as Alzheimer's, Parkinson's, Huntington, amyotrophic lateral sclerosis). Serotonin dysfunction is frequently found in the different etiologies of depression. We have shown that ovariectomized (Ovx) monkeys treated with estradiol (E) for 28 days supplemented with placebo or progesterone (P) on days 14-28 had reduced DNA fragmentation in serotonin neurons of the dorsal raphe nucleus, and long-term Ovx monkeys had fewer serotonin neurons than intact controls. We questioned the effect of E alone or E+P (estradiol supplemented with progesterone) on gene expression related to DNA repair, protein folding (chaperones), the ubiquitin-proteosome, axon transport and NDD-specific genes in serotonin neurons. Ovx macaques were treated with placebo, E or E+P (n=3 per group) for 1 month. Serotonin neurons were laser captured and subjected to microarray analysis and quantitative real-time PCR (qRT-PCR). Increases were confirmed with qRT-PCR in five genes that code for proteins involved in repair of strand breaks and nucleotide excision. NBN1, PCNA (proliferating nuclear antigen), GADD45A (DNA damage-inducible), RAD23A (DNA damage recognition) and GTF2H5 (gene transcription factor 2H5) significantly increased with E or E+P treatment (all analysis of variance (ANOVA), P<0.01). Chaperone genes HSP70 (heat-shock protein 70), HSP60 and HSP27 significantly increased with E or E+P treatment (all ANOVA, P<0.05). HSP90 showed a similar trend. Ubiquinase coding genes UBEA5, UBE2D3 and UBE3A (Parkin) increased with E or E+P (all ANOVA, P<0.003). Transport-related genes coding kinesin, dynein and dynactin increased with E or E+P treatment (all ANOVA, P<0.03). SCNA (α-synuclein) and ADAM10 (α-secretase) increased (both ANOVA, P<0.02) but PSEN1 (presenilin1) decreased (ANOVA, P<0.02) with treatment. APP decreased 10-fold with E or E+P administration. Newman-Keuls post hoc comparisons indicated variation in the response to E alone versus E+P across the different genes. In summary, E or E+P increased gene expression for DNA repair mechanisms in serotonin neurons, thereby rendering them less vulnerable to stress-induced DNA fragmentation. In addition, E or E+P regulated four genes encoding proteins that are often misfolded or malfunctioning in neuronal populations subserving overt NDD symptomology. The expression and regulation of these genes in serotonergic neurons invites speculation that they may mediate an underlying disease process in NDDs, which in turn may be ameliorated or delayed with timely hormone therapy in women.
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Project description:Polycystin-2 (PC2, TRPP2) is a Ca(2+)-permeable, nonselective cation channel implicated in Ca(2+) transport and epithelial cell signaling. Although PC2 may contribute to Ca(2+) transport in human term placenta, the regulatory mechanisms associated with Ca(2+) handling in this tissue are largely unknown. In this work we assessed the regulation by Ca(2+) of PC2 channel function from a preparation of apical membranes of human syncytiotrophoblast (PC2hst) reconstituted in a lipid bilayer system. Addition of either EGTA or BAPTA to the cis hemi-chamber, representing the cytoplasmic domain of the channel, and lowering Ca(2+) to ∼0.6-0.8 nM, inhibited spontaneous PC2hst channel activity, with a time response dependent on the chelator tested. EGTA reduced PC2hst channel currents by 86%, with a t1/2 = 3.6 min, whereas BAPTA rapidly and completely (100%) eliminated channel activity with a t1/2 = 0.8 min. Subsequent titration with Ca(2+) reversed the inhibition, which followed a Hill-type function with apparent dissociation constants of 1-5 nM, and 4 Ca(2+) binding sites. The degree of inhibition by the cis Ca(2+) chelator largely depended on increasing trans Ca(2+). This was consistent with measurable Ca(2+) transport through the channel, feeding the regulatory sites in the cytoplasmic domain. Interestingly, the reconstituted in vitro translated PC2 (PC2iv) was completely insensitive to Ca(2+) regulation, suggesting that the regulatory sites are not intrinsic to the channel protein. Our findings demonstrate the presence of a Ca(2+) microdomain largely accessible through the channel that controls PC2 function in human syncytiotrophoblast of term placenta.
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Project description:miRNAs are endogenously expressed 18- to 25-nucleotide RNAs that regulate gene expression through translational repression by binding to a target mRNA. Recently, it has been indicated that miRNAs are closely related to osteogenesis. Our previous data suggested that miR-30 family members might be important regulators during the biomineralization process. However, whether and how they modulate osteogenic differentiation have not been explored. In this study, we demonstrated that miR-30 family members negatively regulate BMP-2-induced osteoblast differentiation by targeting Smad1 and Runx2. Evidentially, overexpression of miR-30 family members led to a decrease of alkaline phosphatase activity, whereas knockdown of them increased the activity. Then bioinformatic analysis identified potential target sites of the miR-30 family located in the 3' untranslated regions of Smad1 and Runx2. Western blot analysis and quantitative RT-PCR assays demonstrated that miR-30 family members inhibit Smad1 gene expression on the basis of repressing its translation. Furthermore, dual-luciferase reporter assays confirmed that Smad1 is a direct target of miR-30 family members. Rescue experiments that overexpress Smad1 and Runx2 significantly eliminated the inhibitory effect of miR-30 on osteogenic differentiation and provided strong evidence that miR-30 mediates the inhibition of osteogenesis by targeting Smad1 and Runx2. Also, the inhibitory effects of the miR-30 family were validated in mouse bone marrow mesenchymal stem cells. Therefore, our study uncovered that miR-30 family members are key negative regulators of BMP-2-mediated osteogenic differentiation.
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Project description:The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17?-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.
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Project description:The objective of the study was to uncover the developmental dynamics in the artificially induced somatic embryogenesis of Vitis vinifera on the transcriptome level.
2024-07-23 | GSE234231 | GEO
Project description:Myosin 1A (Myo1a) is a mechanoenzyme previously thought to be located exclusively in the intestinal epithelium. It is the principle calmodulin-binding protein of the brush border. Based on earlier studies in chickens, we hypothesized that Myo1a facilitates calcium transport across the brush border membrane of the intestinal epithelium, perhaps in association with the calcium channel Trpv6. Working with C2Bbe1 cells, a human intestinal epithelial cell line, we observed that overexpression of Myo1a increased, whereas the antisense construct blocked calcium transport. To further test this hypothesis, we examined mice in which either or both Myo1a and Trpv6 had been deleted. Although the Trpv6-null mice had decreased intestinal calcium transport, the Myo1a-null mouse did not, disproving our original hypothesis, at least in mice. Expecting that a reduction in intestinal calcium transport would result in decreased bone, we examined the skeletons of these mice. To our surprise, we found no decrease in bone in the Trpv6-null mouse, but a substantial decrease in the Myo1a-null mouse. Double deletions were comparable to the Myo1a null. Moreover, Myo1a but not Trpv6 was expressed in osteoblasts. In vitro, the bone marrow stromal cells from the Myo1a-null mice showed normal numbers of colony-forming units but marked decrements in the formation of alkaline phosphatase-positive colonies and mineralized nodules. We conclude that Myo1a regulates osteoblast differentiation independent of its role, if any, in intestinal calcium transport, whereas Trpv6 functions primarily to promote intestinal calcium transport with little influence in osteoblast function.
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