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3.
Oncogene ; 36(41): 5768-5769, 2017 Oct 12.
Article in English | MEDLINE | ID: mdl-28714962

ABSTRACT

This corrects the article DOI: 10.1038/onc.2014.445.

4.
Lett Appl Microbiol ; 65(1): 98-104, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28434202

ABSTRACT

To determine the distribution of Norovirus (NoV) genotypes in natural river water in Thailand, we conducted a genome analysis using a next-generation sequencer. Twenty-five river water samples were collected at five different sites of the Khlong Klon River in the suburbs of Bangkok between August 2013 and December 2014. The partial genome of NoV was detected in 15 of the 25 samples (60·0%). Seven of these 15 samples (46·7%) contained multiple NoV GII genotypes: GII.4, GII.6, and GII.17. Our data showed that GII.17 had already emerged in August 2013 as a minor population, and it became a major genotype in December 2014. Our findings indicate that the virus was likely to have been circulating in the community before it appeared in the river water. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study was to investigate the frequencies of multiple genogroups and genotypes of norovirus in the river water near Bangkok, Thailand, by ultra-deep sequencing-based analysis. This study revealed that the epidemic strain was likely to have been circulating in the community before it appeared in the river water. Monitoring of the Norovirus (NoV) genomes in the natural environment may contribute to an understanding of the emergence of new epidemic NoV strains in human populations.


Subject(s)
Caliciviridae Infections/epidemiology , Gastroenteritis/epidemiology , Norovirus/genetics , Rivers/virology , Base Sequence , Caliciviridae Infections/virology , Gastroenteritis/virology , Genome, Viral/genetics , Genotype , High-Throughput Nucleotide Sequencing , Humans , Norovirus/classification , Phylogeny , Thailand/epidemiology
6.
Oncogene ; 35(37): 4891-902, 2016 09 15.
Article in English | MEDLINE | ID: mdl-26876205

ABSTRACT

The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N(4)-(3-ethynylphenyl)-6,7-dimethoxy-N(2)-(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Histone Chaperones/genetics , Liver Neoplasms/drug therapy , Prognosis , Quinazolines/administration & dosage , Transcription Factors/genetics , Animals , Apoptosis/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA-Binding Proteins , Female , Gene Expression Regulation, Neoplastic/drug effects , Histone Chaperones/antagonists & inhibitors , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Mice , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Quinazolines/chemical synthesis , Sorafenib , Transcription Factors/antagonists & inhibitors , Xenograft Model Antitumor Assays
7.
Oncogene ; 34(41): 5252-63, 2015 Oct 08.
Article in English | MEDLINE | ID: mdl-25619838

ABSTRACT

Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3(Tyr705) oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly downregulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3(Tyr705) and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-ß1 (TGF-ß1)-induced p-STAT3(Tyr705) and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-ß1-induced p-STAT3(Tyr-705) and EMT characteristics, further supporting the mechanism that suppression of TGF-ß1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-ß1-induced p-STAT3(Tyr705) and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3(Tyr705). Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43-SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3(Tyr705) and thereby prevented HCC EMT and metastasis.


Subject(s)
Carcinoma, Hepatocellular/enzymology , Epithelial-Mesenchymal Transition , Liver Neoplasms/enzymology , Lung Neoplasms/enzymology , Protein Tyrosine Phosphatase, Non-Receptor Type 6/physiology , Animals , Carcinoma, Hepatocellular/secondary , Cell Line, Tumor , Humans , Liver Neoplasms/pathology , Lung Neoplasms/secondary , Mice, Nude , Neoplasm Transplantation , STAT3 Transcription Factor/metabolism
8.
Cell Death Dis ; 5: e1359, 2014 Jul 31.
Article in English | MEDLINE | ID: mdl-25077545

ABSTRACT

Protein phosphatase 2A (PP2A) is a tumor suppressor, which is functionally defective in various cancers. Previously, we found that PP2A activity determined the anticancer effect of bortezomib and erlotinib in hepatocellular carcinoma (HCC) cells. Here, we tested a novel erlotinib derivative, TD52, in four HCC cell lines, PLC5, Huh-7, Hep3B and Sk-Hep1. Using MTT and flow cytometry, we showed that TD52 had more potent apoptotic effects than erlotinib in HCC cells. TD52-induced apoptosis was associated with dose- and time- dependent reactivation of PP2A and downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) and p-Akt. Inhibition of PP2A or ectopic expression of CIP2A or Akt in PLC5 cells abolished the effects of TD52. Furthermore, we demonstrated that TD52 affected the binding of Elk-1 to the proximal promoter of the CIP2A gene, thus downregulating transcription of CIP2A. Importantly, TD52-induced tumor inhibition was associated with reactivation of PP2A and downregulation of CIP2A and p-Akt in vivo. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A determines the apoptotic effect induced by TD52. Our findings disclose the therapeutic mechanism of this novel targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.


Subject(s)
Antineoplastic Agents/pharmacology , Autoantigens/metabolism , Carcinoma, Hepatocellular/enzymology , Liver Neoplasms/enzymology , Membrane Proteins/metabolism , Protein Phosphatase 2/metabolism , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Autoantigens/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/physiopathology , Cell Line, Tumor , Erlotinib Hydrochloride , Gene Expression Regulation, Neoplastic/drug effects , Humans , Intracellular Signaling Peptides and Proteins , Liver Neoplasms/genetics , Liver Neoplasms/physiopathology , Male , Membrane Proteins/genetics , Mice , Mice, Nude , Protein Phosphatase 2/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Quinazolines/chemistry , Xenograft Model Antitumor Assays
9.
Hum Exp Toxicol ; 31(4): 397-404, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22076497

ABSTRACT

Acute pancreatitis is a potentially fatal disease with no known cure. The initial events in acute pancreatitis may occur within the acinar cells. We examined the effect of sesamol on (i) a cerulein-induced pancreatic acinar cancer cell line, AR42J, and (ii) cerulein-induced experimental acute pancreatitis in rats. Sesamol inhibited amylase activity and increased cell survival. It also inhibited medium lipid peroxidation and 8-hydroxydeoxyguanosine in AR42J cells compared with the cerulein-alone groups. In addition, in cerulein-treated rats, sesamol inhibited serum amylase and lipase levels, pancreatic edema, and lipid peroxidation, but it increased pancreatic glutathione and nitric oxide levels. Thus, we hypothesize that sesamol attenuates cerulein-induced experimental acute pancreatitis by inhibiting the pancreatic acinar cell death associated with oxidative stress in rats.


Subject(s)
Antioxidants/therapeutic use , Benzodioxoles/therapeutic use , Oxidative Stress/drug effects , Pancreatitis/prevention & control , Phenols/therapeutic use , Acute Disease , Amylases/metabolism , Animals , Antioxidants/administration & dosage , Benzodioxoles/administration & dosage , Cell Line, Tumor , Cell Survival/drug effects , Ceruletide/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Lipid Peroxidation/drug effects , Male , Mice , Pancreatitis/chemically induced , Pancreatitis/enzymology , Pancreatitis/pathology , Phenols/administration & dosage , Rats , Rats, Wistar
10.
Appl Radiat Isot ; 69(12): 1803-6, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21478023

ABSTRACT

To introduce our preliminary experience of treating locally and regionally recurrent Head and Neck cancer patients at Tsing Hua Open-Pool Reactor in Taiwan, four patients (M/F=3/1, median age 68 Y/O) were enrolled. BNCT with BPA (400 mg/kg) injected in 2 phases and prescription dose of 12-35 Gy (Eq.)/fraction for 2 fractions at 30 day interval can be given with sustained blood boron concentration and tolerable early toxicities for recurrent H & N cancer.


Subject(s)
Boron Neutron Capture Therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/radiotherapy , Aged , Boron Neutron Capture Therapy/adverse effects , Female , Humans , Male , Multimodal Imaging , Neoplasm Recurrence, Local , Positron-Emission Tomography , Taiwan , Tomography, X-Ray Computed
11.
Oncogene ; 30(33): 3570-84, 2011 Aug 18.
Article in English | MEDLINE | ID: mdl-21399663

ABSTRACT

Existence of humoral immunity has been previously demonstrated in malignant ascitic fluids. However, only a limited number of immunogenic tumor-associated antigens (TAAs) were identified, and few of which are associated with ovarian cancer. Here, we identified salt-inducible kinase 3 (SIK3) as a TAA through screening of a random peptide library in the phage display system. Overexpression of SIK3 markedly promoted cell proliferation, attenuated p21(Waf/Cip1) and p27(Kip) expressions in low-grade OVCAR3 cells, and permitted the cells to grow in mice. Decrease in SIK3 expression in high-grade SK-OV3 cells consistently demonstrated its tumorigenic potency by modulating the protein levels of cell cycle regulators. When the expressions of SIK3 and CA125 were compared in cancer tissues, immunohistochemical (IHC) studies indicated that cytoplasm-localized SIK3 was highly expressed in 55% of the ovarian cancer samples. In contrast, it was rarely detected in adenomyosis, leiomyoma and normal ovary tissues, showing its higher specificity (97%) to CA125 (65%) in ovarian cancer. Moreover, experiments using pharmacological inhibitors to block SIK3-induced p21(Waf/Cip1) expression revealed that activation of c-Src and phosphoinositide-3-kinase were critically required for its biological activity, suggesting that they are the downstream signaling mediators of SIK3. These data were further supported by IHC studies, showing coexpression of c-Src with SIK3 in 85% of the ovarian tumor samples stained positive for SIK3. Collectively, our findings indicate that SIK3 is a novel ovarian TAA. Overexpression of SIK3 promotes G1/S cell cycle progression, bestows survival advantages to cancer cells for growth and correlates the clinicopathological conditions of patients with ovarian cancer.


Subject(s)
Antigens, Neoplasm/physiology , Ovarian Neoplasms/etiology , Protein Kinases/physiology , AMP-Activated Protein Kinases/physiology , Animals , Antigens, Neoplasm/analysis , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p21/genetics , Female , Genes, src , Humans , Male , Mice , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Protein Kinases/analysis
12.
Cancer Gene Ther ; 16(1): 83-90, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18802451

ABSTRACT

Non-invasive gene monitoring is important for most gene therapy applications to ensure selective gene transfer to specific cells or tissues. We developed a non-invasive imaging system to assess the location and persistence of gene expression by anchoring an anti-dansyl (DNS) single-chain antibody (DNS receptor) on the cell surface to trap DNS-derivatized imaging probes. DNS hapten was covalently attached to cross-linked iron oxide (CLIO) to form a 39+/-0.5 nm DNS-CLIO nanoparticle imaging probe. DNS-CLIO specifically bound to DNS receptors but not to a control single-chain antibody receptor. DNS-CLIO (100 microM Fe) was non-toxic to both B16/DNS (DNS receptor positive) and B16/phOx (control receptor positive) cells. Magnetic resonance (MR) imaging could detect as few as 10% B16/DNS cells in a mixture in vitro. Importantly, DNS-CLIO specifically bound to a B16/DNS tumor, which markedly reduced signal intensity. Similar results were also shown with DNS quantum dots, which specifically targeted CT26/DNS cells but not control CT26/phOx cells both in vitro and in vivo. These results demonstrate that DNS nanoparticles can systemically monitor the expression of DNS receptor in vivo by feasible imaging systems. This targeting strategy may provide a valuable tool to estimate the efficacy and specificity of different gene delivery systems and optimize gene therapy protocols in the clinic.


Subject(s)
Contrast Media/pharmacology , Dansyl Compounds/pharmacology , Ferric Compounds/pharmacology , Fluorescent Dyes/pharmacology , Haptens/pharmacology , Magnetic Resonance Imaging/methods , Nanoparticles , Neoplasms, Experimental/pathology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Cell Line, Tumor , Contrast Media/chemistry , Dansyl Compounds/chemistry , Ferric Compounds/chemistry , Fluorescent Dyes/chemistry , Genetic Therapy , Haptens/chemistry , Mice , Mice, Inbred BALB C , Microscopy, Fluorescence/methods , Nanoparticles/chemistry , Neoplasms, Experimental/therapy , Sensitivity and Specificity
13.
J Membr Biol ; 204(3): 109-16, 2005 Apr.
Article in English | MEDLINE | ID: mdl-16245033

ABSTRACT

The mammalian renal collecting duct increases its water permeability in response to antidiuretic hormone (ADH). ADH causes cytoplasmic endosomes containing the water channel, aquaporin 2 (AQP 2), to fuse with the apical membrane so that the water permeability of the tubule increases many times above baseline. SNARE proteins are involved in the docking and fusion of vesicles with the cell membrane in neuron synapses. Whether these proteins are involved in the fusion of vesicles to the cell membrane in other tissues is not entirely clear. In the present study, we examined the role of SNARE proteins in the insertion of water channels in the collecting-duct response to ADH by using botulinum toxins A, B and C. Toxins isolated from clostridium botulinum are specific proteases that cleave different SNARE proteins and inactivate them. Tubules were perfused in vitro with botulinum toxin in the perfusate (50 nM for A and B and 15 nM for C). ADH (200 pM) was then added to the bath after baseline measurements of osmotic water permeability (P(f)) and the change in P(f) was followed for one hour. Botulinum toxins significantly inhibited the maximum P(f) by approximately 50%. Botulinum toxins A and C also decreased the rate of rise of P(f). Thus, SNARE proteins are involved in the insertion of the water channels in the collecting duct.


Subject(s)
Aquaporins/metabolism , Botulinum Toxins/administration & dosage , Cell Membrane Permeability/physiology , Kidney Tubules, Collecting/metabolism , Vasopressins/administration & dosage , Vesicular Transport Proteins/metabolism , Water/metabolism , Animals , Aquaporin 2 , Cell Membrane Permeability/drug effects , Drug Interactions , In Vitro Techniques , Kidney Tubules, Collecting/drug effects , Rabbits , SNARE Proteins
15.
J Med Virol ; 64(3): 269-74, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11424114

ABSTRACT

Epidemics of acute hemorrhagic conjunctivitis (AHC) caused by a variant of coxsackievirus A24 (CA24v) reappeared in Taiwan in 1990 and 1994, following the first two epidemics of 1985--86 and 1988--89. To analyze the genetic diversity of recent CA24v in Taiwan, 7 Taiwanese strains isolated during the 1990--94 period were studied together with one Japanese and two Thai strains isolated in 1993. A fragment of 674 nucleotides between the carboxy terminal 3A and the amino terminal 3D polymerase, including the entire 3C protease (3C(pro)), was amplified by a reverse transcription-polymerase chain reaction (RT-PCR) and the nucleotide sequences were determined. In the 549 nucleotides (183 amino acids) of the entire 3C(pro), we found nucleotide differences at 80 positions between 10 strains and the prototype strain, EH24/70, one of the earliest strains of CA24v. Most of the nucleotide changes were synonymous substitutions and only nine amino acid changes were found. The nucleotide sequence homologies among 71 strains worldwide were 88-100%. These 71 nucleotide sequences were then analyzed by Neighbor-joining method and phylogenetically separated into three distinct genotypes. Genotype I consisted of early strains isolated in 1970--71 from Singapore and Hong Kong. Genotype II included isolates from Singapore and Thailand obtained in 1975. Genotype III comprised strains from the eastern hemisphere isolated in 1985--94 from Japan, Taiwan, China, Hong Kong, Thailand, Singapore, Pakistan and Ghana. They were further divided chronologically into six clusters. The recent isolates from Taiwan obtained in 1985/1986, 1988/1989 and 1990--94 were classified into genotype III Clusters 1, 5, and 6 respectively. The evolutionary rate was re-estimated to be 3 x 10(- 3) 30 years after the emergence of the virus.


Subject(s)
Coxsackievirus Infections/genetics , Coxsackievirus Infections/virology , Enterovirus/genetics , RNA, Viral/chemistry , Amino Acid Sequence , Amino Acid Substitution , Base Pairing , Base Sequence , Codon , Conjunctivitis, Acute Hemorrhagic/epidemiology , Conjunctivitis, Acute Hemorrhagic/genetics , Conjunctivitis, Acute Hemorrhagic/virology , Coxsackievirus Infections/epidemiology , Cytopathogenic Effect, Viral , Enterovirus/isolation & purification , Evolution, Molecular , Genotype , Humans , Phylogeny , Point Mutation , Reverse Transcriptase Polymerase Chain Reaction , Sequence Alignment , Sequence Homology, Amino Acid , Taiwan , Time Factors
17.
Arch Virol ; 146(3): 589-600, 2001.
Article in English | MEDLINE | ID: mdl-11338392

ABSTRACT

Taiwan suffered a severe and widespread outbreak of enterovirus infection in 1998. More than 400 children were hospitalized, with seventy-eight fatalities due to central nerve system (CNS) involvement and cardiopulmonary collapse. Enterovirus 71 (EV71) was incriminated as the causative agent for the fatal cases. To understand the viral molecular epidemiology in this outbreak, fragments of 207-bp length of the VP4 region in 23 Taiwanese EV 71 isolates were sequenced. Pair-wise comparison revealed a 17.5-24.4% difference between the isolates and the prototype BrCr. However, all the changes in the VP4 region of the isolated strains were synonymous substitutions. Phylogenetic analysis was performed on these 23 isolates and 21 others deposited in GenBank. In this study, forty-four EV71 isolates from the world were separated into three distinct genotypes: A, B and C. The EV71 prototype strain, BrCr/70, is the only strain of genotype A. Group B included strains from the United States, Japan and Taiwan. Most strains in genotype B were isolated prior to 1990. Group C consisted of strains from Japan and Taiwan. Most strains of genotype C were isolated after 1990, they were further divided into 3 clusters: i.e. C-1, C-2 and C-3. In Taiwan, two genotypes, B and C-3, were co-circulating during the outbreak in 1998, although a minor group of genotype B may have appeared in Taiwan before 1986. The majority of the isolates clustered in genotype C-3. Genotype C showed a higher evolutionary rate than genotype B (3.9 x 10(-3) vs. 1.4 x 10(-3)) in the VP4 region. There seems to be a worldwide trend with strains of genotype B appearing earlier than strains of genotype C which took over later in the dominance.


Subject(s)
Disease Outbreaks , Enterovirus Infections/epidemiology , Enterovirus/genetics , Base Sequence , Genotype , Humans , Molecular Epidemiology , Molecular Sequence Data , Phylogeny , RNA, Viral/genetics , Sequence Alignment , Taiwan/epidemiology
19.
J Reprod Fertil Suppl ; 57: 35-43, 2001.
Article in English | MEDLINE | ID: mdl-11787174

ABSTRACT

The relationship between changes in plasma progesterone concentrations and endometrial degeneration in bitches was determined. Mature bitches (n = 14) were ovariectomized and treated with oestradiol benzoate for 11-12 days, followed by progestagen (2 mg megestrol acetate kg-1 body weight per day) for 35-37 days. Two bitches were necropsied at this stage (progestagen group). The other bitches were treated once a day for a further 3 weeks with 0.5 mg megestrol acetate kg-1 (decreased dose group; n = 3), 2 mg megestrol acetate kg-1 (standard dose group; n = 3), or 3 (1 week), 4 (1 week) and 5 (1 week) mg megestrol acetate kg-1 (increased dose group; n = 3), or received no treatment (withdrawal dose group; n = 3). A further five bitches with intact ovaries were examined during dioestrus (n = 4) and anoestrus (n = 1; 3 weeks after plasma progesterone concentration < 0.3 nmol l-1). Marked degeneration (> 80% cells) of the luminal epithelium was observed in the withdrawal dose and decreased dose groups, and in the intact bitches with plasma progesterone concentrations of 21, 36 and 39 nmol l-1. Medium (40-60% cells) degeneration was detected in the standard dose group and in the anoestrous bitch. However, a very small proportion (< 10%) of degenerated cells was found in the increased dose and progestagen groups, and no degeneration was detected in the dioestrous bitch with a plasma progesterone concentration of 90 nmol l-1. The numbers of endometrial leucocytes were low in all groups except for the withdrawal dose group and the anoestrous bitch. These results indicate that endometrial degeneration and exfoliation in bitches reflects a reduction or insufficiency of plasma progesterone concentrations. The mechanisms involved are unclear.


Subject(s)
Endometrium/pathology , Estrus/blood , Megestrol Acetate/pharmacology , Progesterone Congeners/pharmacology , Progesterone/blood , Anestrus/blood , Animals , Diestrus/blood , Dogs , Dose-Response Relationship, Drug , Endometrium/drug effects , Endometrium/immunology , Epithelium/drug effects , Epithelium/immunology , Epithelium/pathology , Estradiol/pharmacology , Female , Leukocyte Count , Ovariectomy
20.
J Reprod Fertil Suppl ; 57: 45-54, 2001.
Article in English | MEDLINE | ID: mdl-11787189

ABSTRACT

The aim of this study was to validate a model in ovariectomized bitches for the study of uterine function. Mature bitches (n = 21) were ovariectomized and treated with oestradiol benzoate (0.6-4.8 micrograms kg-1, i.m. twice each day) and then with progestagen (megestrol acetate, 2 mg kg-1, p.o. once a day) and were necropsied at stages simulating pro-oestrus (n = 2), oestrus (n = 2) and dioestrus (n = 2). Other bitches received oestradiol benzoate and then megestrol acetate and were necropsied 3 weeks (midanoestrous group, n = 2) and 9 weeks (late anoestrous group, n = 2) after treatment. Untreated bitches (n = 1 per group) served as controls. The treatments induced oestrous behaviour, vulvar swelling, vulval discharge, vaginal smears, plasma oestradiol concentrations and uterine histology similar to that reported in intact bitches at each stage of the oestrous cycle. Marked endometrial degeneration and increased numbers of endometrial leucocytes were observed in the mid-anoestrous group. The endometrium was repaired in the late anoestrous group. A suture was placed in the lumen of the uterus of another six bitches at ovariectomy. Four of these bitches were treated with oestradiol benzoate and then megestrol acetate. Two bitches with a suture but not treated with hormones served as controls. In the hormone-treated bitches the suture resulted in cystic endometrial hyperplasia in two bitches and in cystic endometrial hyperplasia with pyometra in two bitches. The control bitches showed no cystic endometrial hyperplasia or pyometra. We have established in the ovariectomized bitch a model simulating the normal oestrous cycle that will facilitate studies of uterine function. This model will be used to study further the mechanisms of the endometrial degeneration and the pathogenesis of cystic endometrial hyperplasia.


Subject(s)
Dogs/physiology , Estradiol/pharmacology , Estrus/physiology , Megestrol Acetate/pharmacology , Ovariectomy , Progesterone Congeners/pharmacology , Uterus/physiology , Animals , Endometrium/cytology , Endometrium/immunology , Endometrium/physiology , Female , Leukocyte Count , Models, Animal , Random Allocation , Sutures , Uterus/anatomy & histology
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