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Prostaglandins have stimulative influence on the human uterus and therefore were introduced to medical treatment in reproductive healthcare as labor inductors or abortifacients. The UHPLC-ESI-QqQ-MS/MS method was developed for six prostaglandins: carboprost, cloprostenol, dinoprost (PGF2α), dinoprostone (PGE2), misoprostol and sulprostone (substances for pregnancy termination) in pharmaceutical samples and was applied for the toxicological examination of pills containing misoprostol (collected during gynecological examination). There were used two internal standards: misoprostol-d5 and PGF2α-d4. The quantification of analytes was performed in the MRM mode. The linearity of method was in the range from 0.1 to 10 µg/mL, with a coefficient of determination above 0.997 (R2) for each compound. The precision and accuracy values did not exceed ±5.0%. Analysis of the pills revealed the presence of two substances: misoprostol and diclofenac. Misoprostol and diclofenac dose per sample were as follows: 608.8 ng (sample 1), 708.4 ng (sample 2), 618.8 ng (sample 3) and 67.7 mg (sample 1), 65.3 mg (sample 2) 67.3 mg (sample 3), respectively. A simple, precise and reliable method can be applied for routine examinations in terms of clinical and forensic toxicology examinations as well as in quality control of drugs for pharmaceutical purposes (original drugs and counterfeit medications).
Prostaglandin F2α (PGF2α) may differentially affect viability of luteal cells by inducing either proliferation or cell death (via apoptosis or necroptosis). The diverse effects of PGF2α may depend on its local vs. systemic actions. In our study, we determined changes in expression of genes related to: (i) apoptosis: caspase (CASP) 3, CASP8, BCL2 associated X (BAX), B-cell lymphoma 2 (BCL2) and (ii) necroptosis: receptor-interacting protein kinase (RIPK) 1, RIPK3, cylindromatosis (CYLD), and mixed lineage kinase domain-like (MLKL) in the early and mid-stage corpus luteum (CL) that accompany local (intra-CL) vs. systemic (i.m.) analogue of PGF2α (aPGF2α) actions. Cows at day 4 (n = 24) or day 10 (n = 24) of the estrous cycle were treated by injections as follows: (1) systemic saline, (2) systemic aPGF2α (25 mg; Dinoprost), (3) local saline, (4) local aPGF2α (2.5 mg; Dinoprost). After 4 h, CLs were collected by ovariectomy. Expression levels of mRNA and protein were investigated by RT-q PCR, Western blotting and immunohistochemistry, respectively.
1. In this study we characterized the CGRP-receptor subtype by Schild-plot analysis using the C-terminal fragment, human-alphaCGRP(8-37), a putative competitive CGRP1-receptor selective antagonist. In addition, the effect of rat-alphaCGRP was compared with that of homologous peptides rat-betaCGRP, rat-amylin, rat-adrenomedullin and [Cys(Acm)2,7]-human-alphaCGRP, a putative selective CGRP2-receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats. 2. Isolated rings from the distal, intramural part of the left anterior descending (LAD) coronary artery in both groups of rats were mounted on a double wire-myograph. The arteries were then stretched to their optimal lumen diameter for active tension development and precontracted with 10(-5) M prostaglandin F2alpha (PGF2alpha), after which agonists were added to the organ bath in a cumulative manner. 3. Rat-alphaCGRP induced endothelium-independent relaxations in male and female Sprague-Dawley rats. Rat-betaCGRP concentration-response relations (10[-11]-10[-7] M) were similar to those of rat-alphaCGRP in either sex. The maximal relaxations induced by rat-amylin and rat-adrenomedullin, both at 10(-6) M, were significantly (P<0.05) lower than those induced by rat-alpha- and rat-betaCGRP. In contrast, the selective CGRP2-receptor agonist [Cys(Acm)2,7]-human-alphaCGRP failed to induce significant relaxations at the highest concentration used (10[-7] M) in the coronary arteries of male and female rats. 4. The C-terminal fragment, human-alphaCGRP(8-37) blocked concentration-dependently (10[-7]-10[-6] M) the rat-alphaCGRP-induced relaxation in 10(-5) M PGF2alpha-precontracted coronary arteries. The slopes of the regression lines of the Schild-plots for both male and female rats were not significantly (P>0.05) different from unity and the pA2 values for human-alphaCGRP(8-37) were 6.93 and 6.98 in arteries from male and female rats, respectively. There was no significant (P>0.05) difference in estimated pKB values for human-alphaCGRP(8-37) between male (6.99+/-0.10, n=13) and female (6.95+/-0.08, n=13) rats. 5. The concentration-response relationships for rat-alpha- and rat-betaCGRP were similar in male and female Sprague Dawley rats. The predominant CGRP receptor subtype in small intramural coronary arteries appeared to belong to the CGRP1-receptor subtype in both sexes.
The present study aimed to evaluate hormonal responses and their association with the TAK-683 blood concentrations in goats administered TAK-683 at a low dose, which had been previously determined as the minimally effective dose for luteinizing hormone (LH) stimulation in ovariectomized goats. In Experiment 1, 5 µg of TAK-683 treatment had no significant stimulatory effect on LH secretion in ovariectomized Shiba goats (n = 4). In Experiment 2, cycling goats received the treatment of prostaglandin F2α and progesterone-releasing controlled internal drug releasing (CIDR) to induce the follicular phase, then they were treated with 5 µg of TAK-683 (hour 0) intravenously (n = 4, IV) or subcutaneously (n = 3, SC) or with vehicle intravenously (n = 4, control) at 12 h after CIDR removal. Blood samples were collected at 10-min (-2-6 h), 2-h (6-24 h), or 6-h (24-48 h) intervals. Ovarian ultrasonographic images were assessed daily to confirm ovulation after the treatment. A surge-like release of LH was immediately observed after injection in all animals in the IV (peak time: 4.2 ± 0.6 h, peak concentration: 73.3 ± 27.5 ng/ml) and SC (peak time: 4.6 ± 0.4 h, peak concentration: 62.6 ± 23.2 ng/ml) groups, but not in the control group. Ovulation was detected within 3 days after TAK-683 injection in all animals in the IV and SC groups, and the interval period from TAK-683 administration to ovulation in the IV group was significantly (P < 0.05) shorter than that of the control group. No significant changes were observed between the IV and SC groups in terms of luteal diameter and blood progesterone levels after ovulation. The present findings suggest that the involvement of one or more ovarian factor(s) is indispensable for a TAK-683-induced LH surge leading to ovulation in goats.
Subarachnoid hemorrhage (SAH) is associated with increased cerebral artery sensitivity to vasoconstrictors and release of the perivascular sensory vasodilator CGRP. In the current study the constrictive phenotype and the vasodilatory effects of exogenous and endogenous perivascular CGRP were characterized in detail applying myograph technology to cerebral artery segments isolated from experimental SAH and sham-operated rats. Following experimental SAH, cerebral arteries exhibited increased vasoconstriction to endothelin-1, 5-hydroxytryptamine and U46419. In addition, depolarization-induced vasoconstriction (60 mM potassium) was significantly increased, supporting a general SAH-associated vasoconstrictive phenotype. Using exogenous CGRP, we demonstrated that sensitivity of the arteries to CGRP-induced vasodilation was unchanged after SAH. However, vasodilation in response to capsaicin (100 nM), a sensory nerve activator used to release perivascular CGRP, was significantly reduced by SAH (P = 0.0079). Because CGRP-mediated dilation is an important counterbalance to increased arterial contractility, a reduction in CGRP release after SAH would exacerbate the vasospasms that occur after SAH. A similar finding was obtained with artery culture (24 h), an in vitro model of SAH-induced vascular dysfunction. The arterial segments maintained sensitivity to exogenous CGRP but showed reduced capsaicin-induced vasodilation. To test whether a metabolically stable CGRP analogue could be used to supplement the loss of perivascular CGRP release in SAH, SAX was systemically administered in our in vivo SAH model. SAX treatment, however, induced CGRP-desensitization and did not prevent the development of vasoconstriction in cerebral arteries after SAH.
Frequent mutation in the ATM/P53 signaling pathway has been documented in many human cancers. Reportedly, cancer cells with deficient P53/ATM pathways depend on functional Ataxia-telangiectasia and Rad3-related (ATR) protein for survival. This has prompted research in developing ATR inhibitors for the selective sensitization of cancer cells that are P53/ATM-deficient, but no clinical success has been attained thus far. This study explores the therapeutic potential of SPK98, an analogue of Torin2 in P53- and ATM-deficient cancer cells. Furthermore, the prospect of improving the therapeutic outcome of the genotoxic agent was also explored. SPK98 was shown to inhibit full-length human ATR protein purified from HEK293T cells. Cellular investigation using SPK98 demonstrated that it selectively sensitizes P53- and ATM-deficient cells at low concentrations compared to P53-/ATM-proficient cells. Furthermore, SPK98 drives the cancer cells toward cell death by promoting the formation of DNA double-strand breaks. Taken together, our findings suggest that SPK98 is a promising therapeutic molecule for P53- or ATM-deficient malignancy that merits additional preclinical investigation.
Proteostasis deficiency in mutated ion channels leads to a variety of ion channel diseases that are caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking. We investigated proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors, the primary mediators of neuronal inhibition in the mammalian central nervous system. We screened a structurally diverse, Food and Drug Administration-approved drug library and identified dinoprost (DNP) and dihydroergocristine (DHEC) as highly efficacious enhancers of surface expression of four epilepsy-causing trafficking-deficient mutant receptors. Furthermore, DNP and DHEC restore whole-cell and synaptic currents by incorporating mutated subunits into functional receptors. Mechanistic studies revealed that both drugs reduce subunit degradation by attenuating the Grp94/Hrd1/Sel1L/VCP-mediated ERAD pathway and enhance the subunit folding by promoting subunit interactions with major GABAA receptors-interacting chaperones, BiP and calnexin. In summary, we report that DNP and DHEC remodel the endoplasmic reticulum proteostasis network to restore the functional surface expression of mutant GABAA receptors.
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5-7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.
The aim of this study was to investigate the effects of PGF2α and oxytocin in vitro on myometrial contractility in puerperal uteri. Thirteen puerperal uteri were removed and perfused after euthanasia of cows with (n=7) and without metritis (n=6). Measurement of uterine contractility was done using four piezoelectric crystals, which were implanted into the myometrium along the greater curvature of the uterine horn where fetal implantation occurred during the previous pregnancy. After 30min of equilibration, oxytocin (5 IU) or PGF2α (2.5mg Dinoprost) was administered randomly into both uterine arteries, and 30min later, the second administration of either oxytocin or PGF2α occurred. Treatment with oxytocin induced contractions in uteri with metritis and uteri without metritis (P<0.05). In uteri with metritis, greater uterine contractions occurred after stimulation with oxytocin than in uteri without metritis (P<0.05). Treatment with PGF2α did not (P>0.05) result in increased contractions in the uteri without metrtitis, however, induced an initial decrease in contractions followed by an increase (P<0.05) in contractions in uteri with metritis. Myometrial and endometrial gene expression of PGF2α (FPR) and oxytocin receptor (OTR) was greater (P<0.05) in uteri with metritis than in uteri without metritis. The results suggest that oxytocin, but not PGF2α, is an effective uterotonic drug in puerperal cows. Uteri in which metritis was diagnosed contracted more strongly after treatment with oxytocin than uteri in which metritis was not diagnosed. This effect was paralleled by greater gene expression of OTR as well as FPR in uteri with metritis compared with uteri in which metritis was not diagnosed.
The sudden outbreak of novel coronavirus has caused a global concern due to its infection rate and mortality. Despite extensive research, there are still no specific drugs or vaccines to combat SARS-CoV-2 infection. Hence, this study was designed to evaluate some plant-based active compounds for drug candidacy against SARS-CoV-2 by using virtual screening methods and various computational analyses. A total of 27 plant metabolites were screened against SARS-CoV-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain, spike ecto-domain and HR2 domain using a molecular docking approach. Four metabolites, i.e., asiatic acid, avicularin, guajaverin, and withaferin showed maximum binding affinity with all key proteins in terms of lowest global binding energy. The crucial binding sites and drug surface hotspots were unravelled for each viral protein. The top candidates were further employed for ADME (absorption, distribution, metabolism, and excretion) analysis to investigate their drug profiles. Results suggest that none of the compounds render any undesirable consequences that could reduce their drug likeness properties. The analysis of toxicity pattern revealed no significant tumorigenic, mutagenic, irritating, or reproductive effects by the compounds. However, withaferin was comparatively toxic among the top four candidates with considerable cytotoxicity and immunotoxicity. Most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases hydrolases, phosphatases). Moreover, results of drug similarity prediction revealed two approved structural analogs of Asiatic acid i.e. Hydrocortisone (DB00741) (previously used for SARS-CoV-1 and MERS) and Dinoprost-tromethamine (DB01160) from DrugBank. In addition, two other biologically active compounds, Mupirocin (DB00410) and Simvastatin (DB00641) could be an option for the treatment of viral infections. The study may pave the way to develop effective medications and preventive measure against SARS-CoV-2. Due to the encouraging results, we highly recommend further in vivo trials for the experimental validation of our findings.
We aimed to determine gene expression patterns in the anterior pituitary (AP) of heifers before and after ovulation via deep sequencing of the transcriptome (RNA-seq) to identify new genes and clarify important pathways. Heifers were slaughtered on the estrus day (pre-ovulation; n=5) or 3 days after ovulation (post-ovulation; n=5) for AP collection. We randomly selected 4 pre-ovulation and 4 post-ovulation APs, and the ribosomal RNA-depleted poly (A)+RNA were prepared to assemble next-generation sequencing libraries. The bovine APs expressed 12,769 annotated genes at pre- or post-ovulation. The sum of the reads per kilobase of exon model per million mapped reads (RPKM) values of all transcriptomes were 599,676 ± 38,913 and 668,209 ± 23,690, and 32.2 ± 2.6% and 44.0 ± 4.4% of these corresponded to the AP hormones in the APs of pre- and post-ovulation heifers, respectively. The bovine AP showed differential expression of 396 genes (P<0.05) in the pre- and post-ovulation APs. The 396 genes included two G-protein-coupled receptor (GPCR) genes (GPR61 and GPR153) and those encoding 13 binding proteins. The AP also expressed 259 receptor and other 364 binding proteins. Moreover, ingenuity pathway analysis for the 396 genes revealed (P=2.4 × 10-3) a canonical pathway linking GPCR to cytoskeleton reorganization, actin polymerization, microtubule growth, and gene expression. Thus, the present study clarified the novel genes found to be differentially expressed before and after ovulation and clarified an important pathway in the AP.
This experiment was designed to evaluate the effects of increasing doses of estradiol cypionate (ECP) on reproductive function of lactating dairy cows during the summer. In Exp. 1, 643 lactating Holstein cows were blocked by parity and assigned to receive 1) an intravaginal P4 device (1.9 g of P4) and 2.0 mg of estradiol benzoate on day -11, 25 mg (i.m.) of dinoprost tromethamine on day -4, 1.0 mg (i.m.) of estradiol cypionate and CIDR withdrawal on day -2, followed by TAI on day 0 (n = 326; ECP-1) or 2) the same synchronization protocol with 2.0 mg of ECP on day -2 (n = 317; ECP-2). In both treatments, cows were TAI on day 0 of the protocol, and cow rectal temperature was measured on days -2, 0, and 7. In Exp. 2, 608 lactating crossbred Holstein × Gir dairy cows were blocked by parity and enrolled to the same treatments as in Exp. 1, but on day 7, cows received one viable embryo into the uterine horn. In Exp. 1, a greater percentage of ECP-2 cows were detected on estrus (81.3 vs. 91.1%, respectively). A treatment × body condition score (BCS) interaction was observed on day 60 pregnancy per AI (P/AI), as ECP-2 cows with a BCS <2.75 had a greater P/AI vs. ECP-1, but an opposite result was observed in cows with a BCS ≥2.75. Regardless of treatment, there were effects of mean rectal temperature and heat stress events on P/AI. Treatment affected the diameter of the ovulatory follicle at TAI (ECP-1 = 15.3 mm vs. ECP-2 = 14.8 mm) and a greater percentage of ECP-1 cows had larger follicles (≥16.5 mm), but ECP-2 resulted in a greater incidence of early ovulatory cows (ovulating before day 0). Therefore, follicle diameter at TAI affected P/AI on day 60 in cows receiving ECP-2 and tended to affect ECP-1 cows. A treatment effect was observed on time to estrus following ECP treatments and a reduced proportion of ECP-2 cows showed estrus at TAI. Regardless of treatment, cows detected on estrus 48 h after ECP administration had a greater P/AI on day 60 vs. cows detected on estrus 24 h. In Exp. 2, a greater percentage of ECP-2 cows were detected on estrus (68.3 vs. 81.4%, respectively). In summary, a greater dose of ECP increased the percentage of animals expressing estrus, but it did not benefit the reproductive function of lactating dairy cows during the summer, regardless if animals were assigned to a TAI or timed-embryo transfer (TET) protocol.
This study was conducted to identify factors affecting PGF(2alpha) efficacy to synchronize estrus in water buffalo cows. After detection of a corpus luteum (CL) by rectal palpation, cows were treated (im) with dinoprost (12.5, 25 or 50mg) or D(+) cloprostenol (75, 150 or 300 microg) in a total of 66 treatments. Blood samples were collected 0, 24 and 48 h after treatment and ultrasound examinations and observations for estrus were performed daily to the day of ovulation or to 6 days after treatment. No PGF(2alpha) dose-response pattern was observed and overall rates of luteal regression (progesterone <1.0 ng/ml at 48 h), estrus, no detected behavioral estrus with ovulation occurring, and ovulation were 71.2, 36.4, 19.7 and 54.5%, respectively. To analyze plasma progesterone concentrations and ovarian dynamics, cows were divided in three groups according to their response to treatment. Cows that failed to have ovulations from a follicle after treatment (Group A, n = 30) had (P < 0.05) a lower plasma progesterone concentration (2.98 ng/ml) and smaller CL area (CLA; 187.3 mm(2)) before treatment as compared with cows that had an ovulation from a follicle (4.43 ng/ml and 223.7 mm(2), respectively; Groups B and C, n = 36). In cows that failed to ovulate, plasma progesterone concentration decreased in the first 24 h, but did not decline further and was >1.0 ng/ml 48 h after treatment. Moreover, no significant change in CLA after treatment was detected, indicating that treatment induced only partial luteolysis. In cows that ovulated, plasma progesterone concentration and CLA decreased continuously from treatment to ovulation (consistent with complete luteolysis). Threshold values of 2.8 ng/ml for plasma progesterone concentration and 189 mm(2) for CLA were identified as the best predictors of ovulation before treatment (83.3 and 80.6% sensitivity and 58.6 and 65.5% specificity, respectively, with positive and negative predictive values around 71%). When the origin of the ovulatory follicle was investigated, the interval from treatment to ovulation was shorter (91.9 versus 113.3 h; P < 0.05), and the ovulatory follicle had a slower growth rate (1.02 versus 1.55 mm per day; P < 0.005), a lesser increase in diameter from treatment to ovulation (4.7 versus 8.0 mm; P < 0.001), and a greater maximum diameter (13.2 versus 12.1 mm; P < 0.05) in cows that ovulated from the largest follicle present in the ovary before treatment (Group B, n = 27) compared with cows that ovulated from the second largest follicle present in the ovary before treatment (Group C, n = 9). In summary, the efficacy of PGF(2alpha) for causing luteolysis and synchronizing estrus and ovulation in buffalo cows was dependent upon plasma progesterone concentration, CL size and ovarian follicular status before treatment.
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