Suppression of bioactive luteinizing hormone and testosterone by a progesterone antagonist ZK 98.734 in adult male common marmosets, Callithrix jacchus

The effects of a progesterone antagonist ZK 98.734 on release of bioactive luteinizing hormone (LH) and testosterone were studied in adult male common marmosets by using the following experimental protocols: (1) the blocking of the nocturnal rise in testosterone levels by ZK 98.734, (2) the pharmacodynamic effects of ZK 98.734 on testosterone and LH levels, (3) the reversal of ZK 98.734-induced decrease in testosterone by treatment with human chorionic gonadotropin (hCG), and (4) the blocking of estradiol-induced positive feedback release of LH by ZK 98.734. Sixteen adult male common marmosets were used for different experiments after resting them for at least 4 wk between experiments. Testosterone and bioactive LH levels were measured by specific radioimmunoassay and in vitro bioassay methods, respectively. Treatment (i.m.) of male common marmosets (n = 6/group) with ZK 98.734 (1 mg or 5 mg/day) at 1700 h for 3 consecutive days significantly (p less than 0.05) suppressed the nocturnal (2200 h) rise in testosterone levels. The effects of the two doses were not dose-related; however, the decrease on the first day of treatment was more pronounced with the 5-mg dose than with the 1-mg dose. Diurnal rhythms were restored during the post-treatment period. Similarly, treatment with ZK 98.734 (5 mg, n = 8/group) at 1000 h caused a decrease in testosterone and LH levels. The levels were significantly (p less than 0.05) lower at 3 and 6 h after treatment compared to pretreatment levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum hormone levels in women undergoing abortion with intra-amniotic,extra-amniotic or intra-muscular administration of 15(S)15-methyl-prostaglandin F2α

The serum levels of estradiol-17β, progesterone and HPL have been estimated by specific radioimmunoassay in thirty women undergoing abortion with 15-methyl-PGF_2α given by intra-amniotic, extra-amniotic or intra-muscular route. A significant decline in the levels of these hormones was observed in 27 cases in which the pregnancy was terminated. However, in the remaining three cases, 15-methyl-PGF_2α was found to be unsuccesful, and no significant change in the hormone levels was evident. The decline in these hormones was more marked by intra-muscular route, than that observed by the other routes. The pattern of estradiol-17β decline was more consistent when compared with progesterone and HPL. The levels of progesterone and HPL, in a few cases, rather showed an increase in the initial hours of 15-methyl-PGF_2α administration before the decline began and this pattern was more prominent on extra-amniotic administration. In general, the decline in the hormone levels was slower in cases which took longer time for abortion than cases with shorter induction-abortion time (IAT).The decline in estradiol-17β levels was about 65 percent at six hour of intra-muscular administration of 15-methyl-PGF_2α, whereas the corresponding fall with intra-amniotic and extra-amniotic routes was 29 and 22 percent, respectively. However, the net drop in its levels during IAT was not significantly different (range 70 to 80 percent) by the three routes. About 38 percent fall in progesterone levels was observed at six hour of intra-muscular administration whereas, by intra-amniotic the fall was 19 percent. The net decline in progesterone levels, during IAT, was in the range of 46 to 60 percent by the three routes. Similarly, intra-muscular 15-methyl-PGF_2α evoked a sharper decline in HPL levels as compared with other routes. The total decline during IAT was 58 to 66 percent. The results, thus indicated that the abortion with 15-methyl-PGF_2α was associated with a fall in the serum hormone levels, which could be resultant effect of alterations in the hormone production by the foeto-placental unit. This along with the uterine contractions may play a significant role in the abortifacient action of 15-methyl-PGF_2α.     

Biology and comparative predation efficacy of three heteropteran species recorded as predators ofBemisia tabaci in Maharashtra

Two mirids,Deraeocoris sp. andCampylomma nicolasi Reuter and one lygaeid,Geocoris ochropterus Fieber were found preying onB. tabaci (Gennadius) for the first time in Maharashtra State of India during 1987–88. Their biology and predation capacity onB. tabaci were studied in detail under laboratory conditions. The nymphal stage ofDeraeocoris sp. passed through 6 instars, whereas 5 instars in case of the remaining species.G. ochropterus, Deraeocoris sp. andC. nicolasi consumed on an average 482.5, 275.3 and 128.8 nymphs of 57.3, 25.5 and 20.6 days, respectively. On the basis of consumption rate per day,Deraeocoris sp. proved to be a superior predator. Part of Ph. D. Thesis submitted to Marathwada Agricultural University, Parbhani 431402, India.     

Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway

Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals.     

Wnt signaling establishes the microtubule polarity in neurons through regulation of Kinesin-13

Neuronal polarization is facilitated by the formation of axons with parallel arrays of plus-end-out and dendrites with the nonuniform orientation of microtubules. In C. elegans, the posterior lateral microtubule (PLM) neuron is bipolar with its two processes growing along the anterior–posterior axis under the guidance of Wnt signaling. Here we found that loss of the Kinesin-13 family microtubule-depolymerizing enzyme KLP-7 led to the ectopic extension of axon-like processes from the PLM cell body. Live imaging of the microtubules and axonal transport revealed mixed polarity of the microtubules in the short posterior process, which is dependent on both KLP-7 and the minus-end binding protein PTRN-1. KLP-7 is positively regulated in the posterior process by planar cell polarity components of Wnt involving rho-1/rock to induce mixed polarity of microtubules, whereas it is negatively regulated in the anterior process by the unc-73/ced-10 cascade to establish a uniform microtubule polarity. Our work elucidates how evolutionarily conserved Wnt signaling establishes the microtubule polarity in neurons through Kinesin-13.     

Association between Gender,Process of Care Measures,and Outcomes in ACS in India: Results from the Detection and Management of Coronary Heart Disease (DEMAT) Registry

Background

Studies from high-income countries have shown that women receive less aggressive diagnostics and treatment than men in acute coronary syndromes (ACS), though their short-term mortality does not appear to differ from men. Data on gender differences in ACS presentation, management, and outcomes are sparse in India.

Methods and Results

The Detection and Management of Coronary Heart Disease (DEMAT) Registry collected data from 1,565 suspected ACS patients (334 women; 1,231 men) from ten tertiary care centers throughout India between 2007–2008. We evaluated gender differences in presentation, in-hospital and discharge management, and 30-day death and major adverse cardiovascular event (MACE; death, re-hospitalization, and cardiac arrest) rates. Women were less likely to present with STEMI than men (38% vs. 55%, p<0.001). Overall inpatient diagnostics and treatment patterns were similar between men and women after adjustment for potential confounders. Optimal discharge management with aspirin, clopidogrel, beta-blockers, and statin therapy was lower for women than men, (58% vs. 65%, p = 0.03), but these differences were attenuated after adjustment (OR = 0.86 (0.62, 1.19)). Neither the outcome of 30-day mortality (OR = 1.40 (0.62, 3.16)) nor MACE (OR = 1.00 (0.67, 1.48)) differed significantly between men and women after adjustment.

Conclusions

ACS in-hospital management, discharge management, and 30-day outcomes did not significantly differ between genders in the DEMAT registry, though consistently higher treatment rates and lower event rates in men compared to women were seen. These findings underscore the importance of further investigation of gender differences in cardiovascular care in India.     

Cyclooxygenase-2 dependent metabolism of 20-HETE increases adiposity and adipocyte enlargement in mesenchymal stem cell-derived adipocytes

20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a product of the cytochrome P450 (CYP)-catalyzed ω-hydroxylation of arachidonic acid, induces oxidative stress and, in clinical studies, is associated with increased body mass index (BMI) and the metabolic syndrome. This study was designed to examine the effects of exogenous 20-HETE on mesenchymal stem cell (MSC)-derived adipocytes. The expression levels of CYP4A11 and CYP4F2 (major 20-HETE synthases in humans) in MSCs decreased during adipocyte differentiation; however, exogenous administration of 20-HETE (0.1–1 μM) increased adipogenesis in a dose-dependent manner in these cells (P < 0.05). The inability of a 20-HETE analog to reproduce these effects suggested the involvement of a metabolic product of 20-HETE in mediating its pro-adipogenic effects. A cyclooxygenase (COX)-1 selective inhibitor enhanced, whereas a COX-2 selective or a dual COX-1/2 inhibitor attenuated adipogenesis induced by 20-HETE. The COX-derived metabolite of 20-HETE, 20-OH-PGE₂, enhanced adipogenesis and lipid accumulation in MSCs. The pro-adipogenic effects of 20-HETE and 20-OH-PGE₂ resulted in the increased expression of the adipogenic regulators PPARγ and β-catenin in MSC-derived adipocytes. Taken together we show for the first time that 20-HETE-derived COX-2-dependent 20-OH-PGE₂ enhances mature inflamed adipocyte hypertrophy in MSC undergoing adipogenic differentiation.     

PrPC regulates epidermal growth factor receptor function and cell shape dynamics in Neuro2a cells

The prion protein (PrP) plays a key role in prion disease pathogenesis. Although the misfolded and pathologic variant of this protein (PrP^SC) has been studied in depth, the physiological role of PrP^C remains elusive and controversial. PrP^C is a cell‐surface glycoprotein involved in multiple cellular functions at the plasma membrane, where it interacts with a myriad of partners and regulates several intracellular signal transduction cascades. However, little is known about the gene expression changes modulated by PrP^C in animals and in cellular models. In this article, we present PrP^C‐dependent gene expression signature in N2a cells and its implication in the most overrepresented functions: cell cycle, cell growth and proliferation, and maintenance of cell shape. PrP^C over‐expression enhances cell proliferation and cell cycle re‐entrance after serum stimulation, while PrP^C silencing slows down cell cycle progression. In addition, MAP kinase and protein kinase B (AKT) pathway activation are under the regulation of PrP^C in asynchronous cells and following mitogenic stimulation. These effects are due in part to the modulation of epidermal growth factor receptor (EGFR) by PrP^C in the plasma membrane, where the two proteins interact in a multimeric complex. We also describe how PrP^C over‐expression modulates filopodia formation by Rho GTPase regulation mainly in an AKT‐Cdc42‐N‐WASP‐dependent pathway.