Synchronization of estrus and ovulation are of paramount importance in modern livestock improvement programs. These methods are critical for assisted reproduction technologies, including artificial insemination and embryo transfer, that can increase productivity. In the current study, subcutaneous implants containing norgestomet were placed for long (14 days), medium (9 days), and short (5 days) periods of time in 70 crossbred ewes undergoing fixed-time artificial insemination. The resulting effects on estrus synchronization and conception rates were subsequently evaluated. Among the synchronized ewes, 85.7% (60/70) underwent estrus over a period of 72 h after progestagen treatment ceased. The shortest mean interval between withdrawal of the device and onset of estrus (34.2 +/- 8.9 h) was observed in the G14 days of P4 group (p < 0.05). The conception rate of the G14 days of P4 group was statistically higher than that of the other groups (83.3% vs. 60.9% vs. 47.8%; p < 0.05). In conclusion, 14 days of norgestomet treatment produced higher conception rates and a greater number of pregnancies at the beginning of the breeding season.
Animals ; Drug Implants/therapeutic use ; Estrus Synchronization/drug effects/*methods ; Female ; Fertilization/drug effects ; Insemination, Artificial/methods/*veterinary ; Pregnenediones/administration & dosage/*pharmacology ; Sheep

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily. It is highly related to the formation of metabolic syndrome and the glucose homeostasis, and therefore represents an important drug target against metabolic diseases and diabetes. In recent years, great progress has been made in the agonists, antagonists, and crystal structures of FXR. The diverse FXR ligands and their structure-activity relationship are reviewed in this article. The advances in the crystal structures of FXR in complex with different ligands are also introduced.
Animals ; Anticholesteremic Agents ; chemical synthesis ; chemistry ; pharmacology ; Azepines ; chemical synthesis ; chemistry ; pharmacology ; Benzene Derivatives ; chemical synthesis ; chemistry ; pharmacology ; Chenodeoxycholic Acid ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Crystallization ; Humans ; Indoles ; chemical synthesis ; chemistry ; pharmacology ; Isoxazoles ; chemical synthesis ; chemistry ; pharmacology ; Ligands ; Molecular Structure ; Multienzyme Complexes ; chemical synthesis ; chemistry ; pharmacology ; Pregnenediones ; chemical synthesis ; chemistry ; pharmacology ; Receptors, Cytoplasmic and Nuclear ; agonists ; antagonists & inhibitors ; metabolism ; Structure-Activity Relationship

Information on precise effects of deflazacort on bone cell function, especially osteoclasts, is quite limited. Therefore, the present study was undertaken to test effects of deflazacort on osteoclast-like cell formation in mouse bone marrow cultures and on the regulation of osteoprotegerin (OPG) and its ligand (RANKL) mRNA expressions by RT-PCR in the ST2 marrow stromal cells. TRAP-positive mononuclear cells increased after the treatment of deflazacort at 10(-9) to 10(-7) M alone for 6 days in a dose-dependent manner. Number of TRAP-positive multi-nucleated cells (MNCs) increased significantly with combined treatment of deflazacort at 10(-7) M and 1,25-(OH)2D3 at 10(-9) M compared to that of cultures treated with 1,25-(OH)2D3 alone (p<0.05). Exposure to deflazacort at 10(-7) M in the presence of 1,25-(OH)2D3 at 10(-9) M in the last 3-day culture had greater stimulatory effect on osteoclast-like cell formation than that of the first 3-day culture did. Deflazacort at 10(-10) -10(-6) M downregulated OPG and upregulated RANKL in mRNA levels in a dose-dependent manner. These observations suggest that deflazacort stimulate osteoclast precursor in the absence of 1,25-(OH)2D3 and enhance differentiation of osteoclasts in the presence of 1,25-(OH)2D3. These effects are, in part, thought to be mediated by the regulation of the expression of OPG and RANKL mRNA in marrow stromal cells.
Animal ; Bone Marrow Cells/*cytology ; Calcitriol/pharmacology ; Calcium Channel Agonists/pharmacology ; Carrier Proteins/*genetics ; Cell Differentiation/drug effects ; Cells, Cultured ; Dexamethasone/pharmacology ; Gene Expression/drug effects ; Glucocorticoids, Synthetic/pharmacology ; Glycoproteins/*genetics ; Immunosuppressive Agents/*pharmacology ; Male ; Membrane Glycoproteins/*genetics ; Mice ; Mice, Inbred ICR ; Osteoclasts/*cytology ; Pregnenediones/*pharmacology ; RNA, Messenger/analysis ; Receptors, Cytoplasmic and Nuclear/*genetics ; Stromal Cells/cytology

The present study is to investigate the protective actions of guggulsterone against the cytotoxicity produced by exposure to hydrogen peroxide (H2O2) in PC12 cells. It was evaluated by MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] reduction assay, lactate dehydrogenase (LDH) release assay, and the release of nitric oxide (NO). ROS and Ca2+ in cells were evaluated by DCFH and Fura 2-AM, respectively. Mitochondrial membrane potential (MMP) was assessed by the retention of rhodamine 123 (Rh 123). Apoptosis and morphological alteration in PC12 cells were monitored with flow cytometry and electric microscope. Vitamin E, a potent antioxidant, was employed as a comparative agent. The results showed that preincubation of PC12 cells with guggulsterone (0.1 - 10 micromol x L(-1)) prevented cytotoxicity induced by H2O2. Extracellular accumulation of LDH, NO and intracellular accumulation of ROS, Ca2+ resulting from H2O2 were significantly reduced by guggulsterone. Incubation of cells with H2O2 caused a marked decrease in MMP, which was significantly inhibited by guggulsterone. The percentage of H2O2-induced apoptosis in PC12 cells was 24.3%, and decreased in the presence of guggulsterone (0.1 - 10 micromol x L(-1)) by 18.4%, 15.9%, 11.8%, respectively. Guggulsterone exhibited comparable potency against oxidative stress induced by H2O2 in PC12 cells as that of vitamin E. The present findings showed that guggulsterone attenuated H2O2-induced cytotoxicity, extracellular accumulation of LDH and NO, intracellular accumulation of ROS and Ca2+, loss of MMP, and apoptosis, which may represent the cellular mechanisms for its neuroprotective action.
Animals ; Antioxidants ; pharmacology ; Apoptosis ; drug effects ; Calcium ; metabolism ; Commiphora ; chemistry ; Cytoprotection ; drug effects ; Hydrogen Peroxide ; toxicity ; L-Lactate Dehydrogenase ; metabolism ; Membrane Potentials ; drug effects ; Mitochondria ; physiology ; Nitric Oxide ; metabolism ; PC12 Cells ; Plants, Medicinal ; chemistry ; Pregnenediones ; pharmacology ; Rats ; Reactive Oxygen Species ; metabolism

OBJECTIVETo investigate the effect of farnesoid-X-receptor (FXR) antagonist Z-guggulsterone in an in vivo high-fat fed apolipoprotein E knockout (ApoE(-/-)) mice model of myocardial ischemia/reperfusion (I/R).

METHODSMale ApoE(-/-) mice were randomly divided into three groups: standard ApoE(-/-) group (fed with standard mouse diet for 12 weeks before myocardial I/R procedure, n = 18), high-fat ApoE(-/-) group (fed with high-fat mouse diet for 12 weeks before myocardial I/R procedure, n = 22), and high-fat ApoE(-/-) + FXR antagonist group(fed with high-fat mouse diet for 12 weeks and received FXR antagonist Z-Guggulsterone 30 minutes before myocardial I/R procedure, n = 17). The expression of FXR was detected by real-time quantitative-PCR. Myocardial infarct size was determined by Evans blue/TTC double staining methods. Myocardial apoptosis was determined by in situ TUNEL technique. Markers of the mitochondrial-mediated apoptotic pathway (cytochrome c release, caspase-9 activity, and BAX and BCL-2 levels), endoplasmic reticulum stress apoptotic pathway (caspase-12 activity and CHOP level), and death receptor apoptotic pathway (caspase-8 activity, and Fas and FasL levels) were also measured.

RESULTFXR expression (3.7-fold higher, P < 0.01), myocardial infarct size [(62.1 ± 7.0)% vs. (33.8 ± 5.8)%, P < 0.01] and myocardial apoptosis index[ (36.8 ± 5.7)% vs. (17.2 ± 3.8)%, P < 0.01]were all significantly higher in high-fat ApoE(-/-) group than those in standard ApoE(-/-) group. Compared with high-fat ApoE(-/-) group, myocardial infarct size [(24.4 ± 4.7)% vs. (62.1 ± 7.0)%, P < 0.01] and myocardial apoptosis index [(13.8 ± 2.7)% vs. (36.8 ± 5.7)%, P < 0.01] were significantly reduced in high-fat ApoE(-/-) + FXR antagonist group. Moreover, levels of mitochondrial-mediated apoptotic pathway markers (cytochrome c release, caspase-9 activity, and BAX/BCL-2 levels) and endoplasmic reticulum stress apoptotic pathway markers (caspase-12 activity and CHOP level) were significantly lower in high-fat ApoE(-/-) + FXR antagonist group than those in high-fat ApoE(-/-) group (all P < 0.01). Levels of death receptor apoptotic pathway markers (caspase-8 activity, and Fas and FasL levels) were similar between high-fat ApoE(-/-) group and high-fat ApoE(-/-) + FXR antagonist group.

CONCLUSIONFXR antagonist alleviates myocardial reperfusion injury in cholesterol-fed ApoE(-/-) mice via inhibition of the mitochondrial-mediated and endoplasmic-reticulum stress pathway.

Animals ; Apolipoproteins E ; genetics ; Apoptosis ; drug effects ; Caspase 9 ; metabolism ; Cholesterol, Dietary ; administration & dosage ; Cytochromes c ; metabolism ; Disease Models, Animal ; Endoplasmic Reticulum Stress ; Male ; Mice ; Mice, Knockout ; Myocardial Reperfusion Injury ; metabolism ; pathology ; prevention & control ; Pregnenediones ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Receptors, Cytoplasmic and Nuclear ; antagonists & inhibitors ; metabolism ; bcl-2-Associated X Protein ; metabolism