Progesterone-induced calcium ion (Ca2+) signals in the neck region of sperm play a pivotal role in promoting sperm motility. Here, we show that a long-lasting Ca2+ signal required for sperm motility in response to progesterone depends on their pH-dependent fusion with prostasomes, which are small vesicles secreted by the prostate. We found that prostasome fusion led to the transfer of progesterone receptors, cyclic adenosine diphosphoribose (cADPR)-synthesizing enzymes, ryanodine receptors (RyRs), and other Ca2+ signaling tools from prostasomes to the sperm neck. Progesterone-induced sperm motility relied on cADPR-mediated Ca2+ mobilization through RyR located on acidic Ca2+ stores, followed by Ca2+ entry through store-operated channels. Treatment of prostasome-fused sperm with a cADPR antagonist or fusion with prostasomes in which type 2 RyR was depleted resulted in low fertilization rates, reduced sperm motility, or both. Thus, we conclude that sperm motility depends on the acquisition of Ca2+ signaling tools from prostasomes.
ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca(2+)-mobilizing second messenger, cADP-ribose (cADPR), from NAD(+). In this study, we investigated the molecular basis of ADPR-cyclase activation in the ANG II signaling pathway and cellular responses in adult rat cardiomyocytes. The results showed that ANG II generated biphasic intracellular Ca(2+) concentration increases that include a rapid transient Ca(2+) elevation via inositol trisphosphate (IP(3)) receptor and sustained Ca(2+) rise via the activation of L-type Ca(2+) channel and opening of ryanodine receptor. ANG II-induced sustained Ca(2+) rise was blocked by a cADPR antagonistic analog, 8-bromo-cADPR, indicating that sustained Ca(2+) rise is mediated by cADPR. Supporting the notion, ADPR-cyclase activity and cADPR production by ANG II were increased in a time-dependent manner. Application of pharmacological inhibitors and immunological analyses revealed that cADPR formation was activated by sequential activation of Src, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), phospholipase C (PLC)-gamma1, and IP(3)-mediated Ca(2+) signal. Inhibitors of these signaling molecules not only completely abolished the ANG II-induced Ca(2+) signals but also inhibited cADPR formation. Application of the cADPR antagonist and inhibitors of upstream signaling molecules of ADPR-cyclase inhibited ANG II-stimulated hypertrophic responses, which include nuclear translocation of Ca(2+)/calcineurin-dependent nuclear factor of activated T cells 3, protein expression of transforming growth factor-beta1, and incorporation of [(3)H]leucine in cardiomyocytes. Taken together, these findings suggest that activation of ADPR-cyclase by ANG II entails a novel signaling pathway involving sequential activation of Src, PI 3-kinase/Akt, and PLC-gamma1/IP(3) and that the activation of ADPR-cyclase can lead to cardiac hypertrophy.
Background: Although several mechanisms underlying the asthma-obesity connection have been proposed, debates still remain. This study was to determine whether overweight is associated with a higher prevalence of atopy, asthma symptoms, airway obstruction, bronchial hyperresponsiveness (BHR) or biomarkers of inflammation in a sample of Korean adolescents. Methods: We conducted a cross-sectional survey involving questionnaires, skin tests, spirometry and methacholine challenge tests among 717 adolescents from Seoul (South Korea). Overweight status was defined as a BMI greater than the local age- and gender-specific 85th percentile. Results: Overweight subjects more frequently reported ever having wheezing (24.6 vs. 14.0%, p = 0.001) and wheezing in the previous 12 months (11.5 vs. 6.3%, p = 0.02) than normal-weight subjects, especially in boys. Atopy was more common among overweight adolescents than among those of normal weight (61.5 vs. 49.2%, p = 0.002), especially in boys (65.0 vs. 52.8%, p = 0.005). Overweight subjects had higher total WBC counts and eosinophil counts, especially boys. The presence of BHR was more common only among overweight girls (32.8 vs. 18.0%, p = 0.028). Overweight status was a significant risk factor for the presence of atopy (odds ratio = 1.49; 95% CI 1.06–2.10), after adjusting for various confounders by logistic regression analysis. Conclusions: An association was found between overweight status and both atopy and an increased prevalence of wheezing in adolescent Korean boys. These findings suggest that being overweight in puberty may be one of several risk factors responsible for atopy, BHR, and asthma symptoms.
A successful pregnancy depends on a complex process that establishes fetomaternal tolerance. Seminal plasma is known to induce maternal immune tolerance to paternal alloantigens, but the seminal factors that regulate maternal immunity have yet to be characterized. Here, we show that a soluble form of CD38 (sCD38) released from seminal vesicles to the seminal plasma plays a crucial role in inducing tolerogenic dendritic cells and CD4+ forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs), thereby enhancing maternal immune tolerance and protecting the semiallogeneic fetus from resorption. The abortion rate in BALB/c females mated with C57BL/6 Cd38 −/− males was high compared with that in females mated with Cd38 +/+ males, and this was associated with a reduced proportion of Tregs within the CD4 + T-cell pool. Direct intravaginal injection of sCD38 to CBA/J pregnant mice at preimplantation increased Tregs and pregnancy rates in mice under abortive sonic stress from 48 h after mating until euthanasia. Thus, sCD38 released from seminal vesicles to the seminal plasma acts as an immunoregulatory factor to protect semiallogeneic fetuses from maternal immune responses.eventy-five percent of pregnancies that are lost represent failure of implantation and are therefore not clinically recognized as pregnancies (1). Recurrent miscarriage (the spontaneous loss of three or more consecutive pregnancies) is a significant health issue for 1-2% of women, with no identifiable biological cause and no effective treatment. During early stages of pregnancy, complex processes help to create a uterine environment that is conducive to a successful pregnancy. These include immunological adaptation to the semiallogeneic fetus. Tolerance to paternal alloantigens is critical for successful reproduction in placental mammals (2, 3). Many studies have proposed that regulatory T cells (Tregs) play an essential role in the development of fetomaternal tolerance in mice and humans (4-7). Seminal plasma contains potent immunoregulatory molecules that contribute to the induction of tolerogenic DCs (tDCs) and ultimately Treg expansion, which is necessary to establish maternal tolerance against paternal antigens (8-10). However, the specific molecules in semen that are responsible for expansion of Tregs and establishment of maternal tolerance remain undefined.CD38, a mammalian prototype of ADP ribosyl cyclases (ADPRCs), is a type II transmembrane (TM) glycoprotein expressed in many cell types and seminal fluid (11-16). CD38 produces calcium-mobilizing second messengers, cyclic ADP ribose, and nicotinic acid adenine dinucleotide phosphate (11, 12). We previously showed that intact CD38 in prostasomes assists progesterone-induced sperm Ca 2+ signaling (13). In addition to its enzymatic role for Ca 2+ signaling, CD38 may also have a nonenzymatic role through its interaction with CD31 (17, 18). CD31, a type I TM homophilic or heterophilic receptor, is expressed in endothelial cells and a variety of immune cells (19) and is involved in attenuating the infl...
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