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Celastrol Attenuates Intrahepatic Cholestasis of Pregnancy by Inhibiting Matrix Metalloproteinases-2 and 9
Junjun Guo, Yong Wang, Na Wang, Yulai Bai, Dandan Shi
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shidandan000@aliyun.com

Correspondence and reprint request:
Cangzhou Central Hospital, No. 16, Xinhuazhong Road, Cangzhou City, Hebei Province, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Introduction</span><p id="p0010" class="elsevierStylePara elsevierViewall">Intrahepatic cholestasis of pregnancy &#40;ICP&#41;&#44; otherwise clinically referred to as obstetric hepatosis&#44; obstetric cholestasis or jaundice during pregnancy&#44; is a serious liver abnormality only observed in pregnant women&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> The primary characteristic of ICP is pruritus that begins at the second or third trimester of pregnancy&#44; but the symptom disappears following delivery&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">2</span></a> About one in ten patients in documented cases exhibited moderate jaundice no later than 4 weeks after beginning of itching&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">3&#44;4</span></a> Additional atypical symptoms that have been reported include abdominal pain&#44; subclinical steatorrhea possibly due to vitamin K deficiency<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">5&#44;6</span></a> and encephalopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">7</span></a> It has also been indicated that geographical location and ethnic origin greatly influence the prevalence of ICP&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">1&#44;8&#44;9</span></a> The incidence rates in Chile&#44; Scandinavia and Bolivia are among the highest&#44; up to 15&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">2&#44;10</span></a> Environmental elements and diets in those areas have been identified as major risk factors that may cause the high ICP prevalence&#44; which in fact has shown a steady decline over the past years&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">10&#44;11</span></a> At the same time&#44; ICP incidence in Asia has gradually climbed up in recent years&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">12&#44;13</span></a> Unfortunately&#44; despite the high risk of preterm labor and unexpected intrauterine fetal death&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">8</span></a> in clinics ICP is still mostly considered a minor disorder&#44; and the treatment for ICP mainly aims to improve fetal outcome as well as ameliorate maternal symptoms&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">Currently&#44; the precise etiology for ICP remains unclear&#46; As a result&#44; accurate diagnosis of ICP and the development of pharmacological treatments have been greatly hindered&#46; A number of studies investigating ICP reported that ICP patients exhibited increased flux of total bile acids &#40;TBA&#41; to the fetus from the expecting mother&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">14-16</span></a> High level of maternal TBA greatly affects the production of placental hormones&#44; placental transport and chorionic vessel constriction&#46; Continued elevation of serum TBA is believed to be the most sensitive symptom of ICP in the laboratory&#46; However&#44; it is further noted by several reports that the basal serum level of TBA appears to be variable depending on the population studied&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">17&#44;18</span></a> This finding argues that serum level of TBA alone is not sufficient to serve as a reliable clinical biomarker for diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">19</span></a> During tissue remodeling&#44; matrix metalloproteinases &#40;MMPs&#41;&#44; enzymes responsible for the degradation of the extracellular matrix&#44; are produced by and secreted from the placental cells&#46; MMPs&#44; in particular MMP-2 and -9&#44; are often implicated in various diseases during pregnancy&#44; including fetal inflammatory response&#44; peripartum cardio-myopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">20</span></a> preterm labor&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a> pre-eclampsia&#44;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">22&#44;23</span></a> as well as ICP&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">24</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">Celastrol is a natural triterpenoid extracted from the Chinese herb <span class="elsevierStyleItalic">Tripterygium wilfordii Hook&#46;f&#46;&#44;</span> which is known to exert various biological effects&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">25</span></a> A growing number of reports have highlighted its potent property in inhibiting MMPs&#46; For instance&#44; it was able to inhibit the migration and invasion of both breast cancer cells and rheumatoid fibroblast-like synoviocytes&#44; through suppressing MMP-9 expression&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">26-29</span></a> Celastrol was also reported to function as an inhibitor of heat shock protein 90P&#44; and suppress the expressions of several MMPs including MMP-9 in primary human osteoarthritic chondrocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">30</span></a> In addition&#44; nanomicelles loaded with celastrol could attenuate cytokine secretion in macrophages and inhibit macrophage-induced corneal neovascularization&#44; likely by inhibiting MMP-9 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">31</span></a></p><p id="p0025" class="elsevierStylePara elsevierViewall">Given the widely reported functions of celastrol in inhibiting MMPs&#44; we aimed in the present study to investigate whether celastrol exerts similar inhibitory effects on MMP-2 and -9 in a rat model of 17 a-ethinylestradiol &#40;EE&#41;-induced ICP&#46; Furthermore&#44; we assessed the potential protective role of celastrol against symptoms of ICP in rats&#46;</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Materials and Methods</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Animals</span><p id="p0030" class="elsevierStylePara elsevierViewall">Experiments in the present study were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health&#46; The animal protocols were approved by the Ethical Committee of Cangzhou Central Hospital&#46; Special attention and efforts were paid to ensure minimum suffering of the animals&#46;</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Rat model of 17 -ethinylestradiol &#40;EE&#41;-induced ICP</span><p id="p0035" class="elsevierStylePara elsevierViewall">Adult female Sprague-Dawley rats&#44; obtained from the animal facility of Cangzhou Central Hospital&#44; were housed under 40&#37;-60&#37; humidity with a 12&#58;12 light&#47;dark cycle at 22 &#177; 2&#175;C&#46; Before experiments&#44; rats were acclimatized for two weeks on regular laboratory chow&#46; Female rats &#40;~ 8 weeks&#41; were mated with males of similar age&#46; After 12 h&#44; females were inspected for solid ivory pessaries&#44; followed by examinations under the microscope to identify the presence of sperms in the vagina&#46; Once pregnancy is determined&#44; female rats &#40;n &#61; 48&#41; were randomly assigned into three groups including sham&#44; ICP and ICP &#43; celastrol group &#40;n &#61; 16 each&#41;&#46; At 10 days into pregnancy&#44; rats in the sham group were given 1&#37; methylcellulose &#40;as vehicle&#41; through oral gavage daily for 5 consecutive days&#46; To induce ICP&#44; rats in the ICP group received a daily oral administration of EE &#40;E4876&#44; purity &#177;98&#37;&#59; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; dissolved in 1&#37; methylcellulose at the dose of 5 mg per kilogram of body weight &#40;bw&#41; for 5 consecutive days&#44; as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">32</span></a> Rats in the ICP &#43; celastrol group were also treated with EE to establish ICP&#44; followed by an oral administration of celastrol &#40;Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41; at the dose of 5 mg per kg bw daily for 5 consecutive days&#44; as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">33</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Bile flow rate analysis</span><p id="p0040" class="elsevierStylePara elsevierViewall">After various treatments&#44; bile samples were collected while animals were under deep anesthetization&#46; To minimize circadian fluctuations&#44; all procedures were conducted between 9-11 am&#46; An incision near the middle abdomen was made&#44; then the common bile duct was cannulated with a PE-10 polyethylene tubing&#46; Rats were kept warm at 37 &#175;C using heating equipment&#44; in order to avoid variations in bile flow caused by hypothermia&#46; Rate of bile flow was calculated by gravimetrical methods as <span class="elsevierStyleItalic">fiL</span> per min per kg bw&#44; and subsequently standardized using the gravity of bile at 1&#46;0 g&#47;mL&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Blood sample analysis</span><p id="p0045" class="elsevierStylePara elsevierViewall">Blood samples were drawn via heart puncture before animals were sacrificed&#44; then immediately centrifuged to obtain the serum&#44; which was subsequently stored at -80 &#175;C for analysis of the biochemical parameters&#46; Measurements of enzymatic activities&#44; including alanine aminotransferase &#40;ALT&#41;&#44; aspartate aminotransferase &#40;AST&#41;&#44; alkaline phosphatase &#40;ALP&#41; and y-glutamyltranspeptidase &#40;GGT&#41;&#44; were performed according to established protocols&#46; After using Sep-Pak to extract the solid-phase&#44; TBA was quantified as previously described with an enzymatic-fluorimetric method&#46;<a class="elsevierStyleCrossRef" href="#bib0175">34</a> Finally&#44; serum levels of MMP-2 and -9 were determined by enzyme-linked immunosorbent assay &#40;ELISA&#41; kits specific for rat MMP-2 and -9 &#40;USCN Life Science&#44; Wuhan&#44; China&#41;&#46;</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Quantitative real time polymerase chain reaction &#40;RT-PCR&#41;</span><p id="p0050" class="elsevierStylePara elsevierViewall">Animals were euthanized with cervical dislocation&#44; then liver tissues were collected and quickly transferred into liquid nitrogen&#46; Extraction of total ribonucleic acid &#40;RNA&#41; from the liver homogenate was carried out using the RNeasy MiniPrep Kit &#40;Qiagen&#44; Valencia&#44; CA&#44; USA&#41;&#44; followed by reverse-transcription using Superscript II First-Strand Synthesis kit &#40;Life Technologies&#44; Pleasanton&#44; CA&#44; USA&#41; according to the manufacturer&#39;s instructions&#46; Relative levels of gene expression were quantified as 2-Ct with GAPDH as the internal control&#46; Primer sequences used are as follows&#58; MMP-2&#58; forward 5&#39;-CCC ATA CTT TAC TCG GAC CA-3&#39;&#44; reverse 5&#39;-TGA CCT TGA CCA GAA CAC CA-3&#39;&#59; MMP-9&#58; forward 5&#39;-CCA CCG AGC TAT CCA CTC AT-3&#39;&#44; reverse 5&#39;-GTC CGG TTT CAG CAT GTT TT-3&#39;&#59; GAPDH&#58; forward 5&#39;-CAG TGC CAG CCT CGT CTC AT-3&#39;&#44; reverse 5&#39;-AGG GGC CAT CCA CAG TCT TC-3&#39;&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Western blot</span><p id="p0055" class="elsevierStylePara elsevierViewall">Purification of the proteins from the liver tissues was performed with the radioimmunoprecipitation assay lysis buffer&#44; then added with 15 <span class="elsevierStyleItalic">fiL</span> of 2X sample buffer &#40;BioRad&#44; Hercules&#44; CA&#44; USA&#41; that had been boiled for 10 min before electrophoresis&#46; Proteins were separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis&#44; then transferred to nitrocellulose membrane &#40;BioRad&#44; Hercules&#44; CA&#44; USA&#41;&#44; followed by incubation with antibodies specific for MMP-2&#44; MMP-9 and GAPDH &#40;Ab-cam&#44; Cambridge&#44; MA&#44; USA&#41;&#46; Blots were finally visualized using the ECL kit &#40;Millipore&#44; Billerica&#44; MA&#44; USA&#41;&#46;</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Statistics</span><p id="p0060" class="elsevierStylePara elsevierViewall">Values are presented as mean &#177; standard deviation &#40;SD&#41;&#46; Differences between groups were determined by two-tailed Student&#8217;s t test&#46; Pearson&#39;s correlation coefficient test was conducted to determine the correlation between parameters for ICP symptoms and levels of MMPs&#46; A p value less than 0&#46;05 is considered statistically significant&#46;</p></span></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Results</span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Establishing ICP rat model by 17a-ethinylestradiol &#40;EE&#41; induction</span><p id="p0065" class="elsevierStylePara elsevierViewall">It has been previously reported that EE could induce cholestasis in rats&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">35&#44;36</span></a> which provided a suitable rat model of ICP for the current study&#46; Female rats that have been pregnant for 10 days were given EE at a dose of 5 mg per kg bw daily through oral gavage for 5 consecutive days &#40;ICP group&#44; n &#61; 16&#41;&#46; Meanwhile&#44; rats in the sham group &#40;n &#61; 16&#41; with comparable pregnancy stage received 1&#37; methylcellulose &#40;as vehicle&#41; for 5 consecutive days through oral gavage&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall">Following the treatment with EE or vehicle&#44; the rates of bile flow in each group were measured to reveal the first signs of ICP&#46; For rats of the ICP group&#44; the bile flow rate was significantly lower than that of the sham rats &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 1A</a>&#41;&#46; Furthermore&#44; since the elevation of serum TBA concentration is a most sensitive diagnostic trait of ICP clinically&#44; it was important to compare the levels of serum TBA from both treatment groups&#46; Indeed&#44; treatment with EE caused a marked increase of serum TBA levels in the ICP group in comparison to the sham group &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 1B</a>&#41;&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0075" class="elsevierStylePara elsevierViewall">Besides serum TBA&#44; elevated activities of ALT&#44; GGT&#44; AST and ALP were characteristics of ICP as well&#46; Therefore&#44; we also examined these parameters to confirm that ICP rats exhibit similar clinical symptoms&#46; As expected&#44; the serum activities of AST&#44; GGT&#44; ALT and ALP were all significantly and consistently upregulated in ICP rats &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 1C</a>&#41;&#46; These results demonstrated that EE elicited ICP in rats with symptoms closely resembling those described in human ICP patients&#46;</p></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Both MMP-2 and -9 were elevated in rats with ICP</span><p id="p0080" class="elsevierStylePara elsevierViewall">MMP-2 and -9 are both implicated in pregnancy-related disorders&#44; however&#44; there is no evidence for a direct connection between MMPs and ICP yet&#46; In our current study&#44; we began with assessing these two MMP levels in the ICP rats&#46; Not surprisingly&#44; there were dramatic elevations of the serum levels of both MMPs in the ICP group but not the sham group &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2A</a>&#41;&#46; To confirm the results&#44; liver tissues of both sham and ICP rats were harvested and prepared for Western blot analysis and RT-PCR to determine the expressions of MMPs at both protein and messenger RNA &#40;mRNA&#41; levels&#46; Agreeing with our findings from the serum levels&#44; we observed significantly higher mRNA levels of both MMP-2 and -9 in the livers of ICP rats than the sham rats &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2B</a>&#41;&#46; A similar trend was found in the protein levels of both MMPs &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2C</a>&#41;&#46; These results provided direct evidences that both MMP-2 and -9 were involved in ICP&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Celastrol reduced levels of MMP-2 and -9 in rats with ICP</span><p id="p0085" class="elsevierStylePara elsevierViewall">Various studies have demonstrated that celastrol functions to repress MMP-9 activity&#44; we therefore speculated that celastrol might exert similar functions in the EE-induced ICP rat model&#46; After the treatment with EE&#44; rats in the ICP &#43; celastrol group &#40;n &#61; 16&#41; received additional administration of celastrol at 5 mg per kg bw&#44; and rats in the ICP group &#40;n &#61; 16&#41; served as control&#46; At the end of the celastrol treatment&#44; the levels of MMP-2 and -9 in the serum and liver tissues from both groups were measured&#46; As expected&#44; activities of both MMPs in the serum were greatly lowered after celastrol treatment&#44; as compared to the ICP group &#40;<a class="elsevierStyleCrossRef" href="#f0020">Figure 3A</a>&#41;&#46; Also&#44; both mRNA and protein levels of MMP-2 and -9 in the liver were significantly lower in the ICP &#43; celastrol rats than the ICP group &#40;<a class="elsevierStyleCrossRef" href="#f0020">Figure 3B</a><a class="elsevierStyleCrossRef" href="#f0020">Figure 3C</a>&#41;&#46; These findings suggested that celastrol treatment in ICP rats reduced serum activities and liver expressions of both MMPs&#46;</p><elsevierMultimedia ident="f0020"></elsevierMultimedia></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">Celastrol ameliorated symptoms in ICP rats</span><p id="p0090" class="elsevierStylePara elsevierViewall">Since both MMPs were up-regulated in ICP rats and inhibited by celastrol treatment &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2</a> and <a class="elsevierStyleCrossRef" href="#f0020">Figure 3</a>&#41;&#44; we next evaluated the effect of celastrol in alleviating ICP symptoms&#44; including serum TBA levels&#44; rate of bile flow and activities of GGT&#44; ALT&#44; ALP and AST&#46; First&#44; celastrol treatment effectively reversed bile flow rates of ICP &#43; celastrol rats compared to the ICP group&#44; as shown in <a class="elsevierStyleCrossRef" href="#f0025">Figure 4A</a>&#46; Second&#44; celastrol treatment dramatically reduced serum levels of TBA in the ICP &#43; celastrol group compared with the ICP rats &#40;<a class="elsevierStyleCrossRef" href="#f0025">Figure 4B</a>&#41;&#46; Furthermore&#44; liver enzyme activities of GGT&#44; ALT&#44; ALP and AST were all markedly down-regulated in ICP &#43; celastrol group compared to the ICP group &#40;<a class="elsevierStyleCrossRef" href="#f0025">Figure 4C</a>&#41;&#46; Our data clearly presented evidences for the potential role of celastrol as a novel therapeutic tool for the treatment of ICP&#46;</p><elsevierMultimedia ident="f0025"></elsevierMultimedia><p id="p0095" class="elsevierStylePara elsevierViewall">Finally&#44; we speculated that the above observed amelioration in ICP symptoms was attributed to the actions of celastrol in repressing MMP-2 and -9&#46; To evaluate this possibility&#44; we performed Pearson&#39;s correlation coefficient test between serum levels of both MMPs with parameters for ICP symptoms in the rats of the ICP &#43; celastrol group&#46; Indeed&#44; strong linear correlations were found between serum TBA levels and levels of both MMP-2 and MMP-9 &#40;<a class="elsevierStyleCrossRef" href="#f0030">Figure 5A</a> and <a class="elsevierStyleCrossRef" href="#f0030">Figure 5B</a>&#44; respectively&#41;&#44; which suggested that the inhibitory effect of celastrol on MMPs contributed to the amelioration of ICP symptoms in the ICP rat model&#46;</p><elsevierMultimedia ident="f0030"></elsevierMultimedia></span></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0110">Discussion</span><p id="p0100" class="elsevierStylePara elsevierViewall">ICP has posed prominent clinical challenge around the globe given its high risk of preterm labor and unexpected intrauterine fetal death&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">8</span></a> There has been substantial progress in ICP diagnosis&#44; with up-regulated serum concentration of TBA being the most sensitive factor&#46; However&#44; serum TBA level alone is not sufficient to diagnose ICP&#44; for it shows variations depending on the population examined&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">17&#44;18</span></a> Besides the lack of a definite factor for ICP diagnosis&#44; limited knowledge on the pathogenesis of the disease further hinders the development effective treatments&#44; worsened by the lack of appropriate animal models&#46; EE is an agent commonly used to induce cholestasis in rats&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">35&#44;36</span></a> but this model displays limited resemblance to symptoms observed in human patients&#44; therefore making conclusions generated from studies using such models unreliable&#46; We speculate that the reason for this discrepancy is the pregnancy stage at the time of EE administration&#46; In human patients&#44; ICP often manifests near the late second or at the beginning of the third trimester&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">2</span></a> Therefore in our current study&#44; we treated rats at a comparable pregnancy stage&#44; where EE was given at 10 days into pregnancy&#44; corresponding to the beginning of the third trimester of pregnancy in human&#46; The consistency for the time of EE administration elicited symptoms that highly resembled human ICP patients&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">37</span></a> as evidenced by the reduction in bile flow rate&#44; elevated activities of liver enzymes such as GGT&#44; AST&#44; ALP&#44; and ALT&#44; as well as serum levels of TBA&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">Our results indicated that MMP-2 and -9&#44; both involved in several pregnancy-related disorders&#44; were greatly up-regulated in the serum as well as liver of rats with ICP&#46; It has been previously shown that reduced maternal MMP-2 levels in the serum is linked to fetal inflammation and preterm labor<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a>&#44; while increased MMP-2 serum levels are commonly observed in peripartum cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">20</span></a> Furthermore&#44; changes in synthesis of MMP-2 and - 9 were associated with pre-eclampsia&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">22&#44;23</span></a> It was also reported that during defective placental development&#44; the secretions of MMP-2 and -9 were markedly suppressed&#44; causing intrauterine growth restriction&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">38</span></a> Moreover&#44; the abnormal increase in activities of MMP-2 and -9 on the amnion of fetal membrane was shown to contribute to premature membrane rupture&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">39</span></a>During pregnancy&#44; levels of MMP-2 and -9 in the serum are tightly regulated&#44; perturbations of which often leads to various maternal and fetal disorders&#46; In the present study&#44; MMP-2 and -9 were found to be up-regulated&#44; suggesting that both MMPs are indeed involved in ICP&#44; which necessitates further investigations into their functions in the disease&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">Besides ICP&#44; cholestasis is reportedly the major syndrome of hepatotoxicity&#44; in particular those induced by ingestion of harmful herbal products&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">40&#44;41</span></a> MMPs are also thought to contribute to hepatotoxicity&#44; supported by reports demonstrating the protective effects against hepato-toxicity exerted through down-regulation of MMP-9&#46;<a class="elsevierStyleCrossRef" href="#bib0215">42</a> On a related note&#44; celastrol has been shown to inhibit MMP-9 activity by several independent reports&#46; For instance&#44; celastrol was shown to inhibit MMP-9 expression in both breast cancer cells and rheumatoid fibroblast-like synoviocytes to suppress their migration and invasion&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">26-29</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Given these accumulating evidences supporting the effect of celastrol to inhibit MMPs&#44; we aimed to examine whether celastrol functioned in a similar fashion in our rat ICP model&#44; to suppress both MMPs and thereby ameliorate ICP symptoms&#46; Indeed&#44; treatment with celastrol significantly down-regulated MMP-2 and -9 in the liver as well as in the serum of the ICP rats&#46; It is worth noting that MMP-2 and -9 were markedly reduced at both mRNA and protein levels by celastrol treatment&#44; suggesting that the suppression of MMPs by celastrol could occur as early as the transcriptional stage&#46; Future investigations are needed to reveal the transcriptional mechanisms underlying the inhibitory effects of celastrol on MMP-2 and MMP-9&#44; as well as to identify potential targets of celastrol other than these two MMPs&#46; Furthermore&#44; our findings strongly support that the protective functions of celastrol against ICP symptoms are likely mediated through its inhibition on MMP-2 and -9&#44; because we found strong correlations between the serum TBA levels and the levels of both MMPs&#46; However&#44; cautions should be taken when applying discoveries in our animal study to clinical settings&#44; since ICP symptoms in patients bare differences with those of animal model&#46;</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0115">Conclusions</span><p id="p0120" class="elsevierStylePara elsevierViewall">In summary&#44; we first established a rat model of ICP induced by EE&#44; with symptoms highly resembling those observed clinically in pregnant women with ICP&#46; Next&#44; using this rat model&#44; we showed that activities and expressions of MMP-2 and -9 were markedly up-regulated in ICP rats&#46; Furthermore&#44; we discovered that the symptoms in the pregnant rats with ICP were significantly ameliorated by celastrol&#44; likely through the inhibition of MMP-2 and -9&#46; Altogether&#44; our findings in the present study have demonstrated for the first time the protective roles of celastrol in alleviating ICP symptoms&#44; providing supports for celastrol as a potential therapeutic tool in treating ICP&#46; Nevertheless&#44; to translate the effects of celastrol from animal models to clinical settings&#44; further investigations are required to confirm the efficacy as well as safety of celastrol&#46;</p></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0120">Abbreviations</span><p id="p0125" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ICP</span>&#58; Intrahepatic cholestasis of pregnancy&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">MMP</span>&#58; Matrix metalloproteinase&#46;</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TBA</span>&#58; Total bile acids&#46;</p></li></ul></p></span><span id="s0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0125">Funding</span><p id="p0145" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="s0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0130">Authors&#8217; Contributions</span><p id="p0150" class="elsevierStylePara elsevierViewall">Junjun Guo&#44; Yong Wang&#44; Na Wang&#44; Yulai Bai&#58; data collection and analysis&#59; Dandan Shi&#58; study design and manuscript writing&#46; All authors read and approved the final submission&#46;</p></span><span id="s0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0135">Acknowledgments</span><p id="p0155" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="s0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0140">Conflict of Interests</span><p id="p0160" class="elsevierStylePara elsevierViewall">The authors declares that there is no conflict of interest regarding the publication of this article&#46;</p></span></span>"
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          "identificador" => "xpalclavsec1138847"
          "titulo" => "Key words"
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        2 => array:2 [
          "identificador" => "s0010"
          "titulo" => "Introduction"
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        3 => array:3 [
          "identificador" => "s0015"
          "titulo" => "Materials and Methods"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "s0020"
              "titulo" => "Animals"
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            1 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Rat model of 17 -ethinylestradiol &#40;EE&#41;-induced ICP"
            ]
            2 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Bile flow rate analysis"
            ]
            3 => array:2 [
              "identificador" => "s0035"
              "titulo" => "Blood sample analysis"
            ]
            4 => array:2 [
              "identificador" => "s0040"
              "titulo" => "Quantitative real time polymerase chain reaction &#40;RT-PCR&#41;"
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            5 => array:2 [
              "identificador" => "s0045"
              "titulo" => "Western blot"
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              "titulo" => "Statistics"
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          "titulo" => "Results"
          "secciones" => array:4 [
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              "identificador" => "s0060"
              "titulo" => "Establishing ICP rat model by 17a-ethinylestradiol &#40;EE&#41; induction"
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            1 => array:2 [
              "identificador" => "s0065"
              "titulo" => "Both MMP-2 and -9 were elevated in rats with ICP"
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            2 => array:2 [
              "identificador" => "s0070"
              "titulo" => "Celastrol reduced levels of MMP-2 and -9 in rats with ICP"
            ]
            3 => array:2 [
              "identificador" => "s0075"
              "titulo" => "Celastrol ameliorated symptoms in ICP rats"
            ]
          ]
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          "titulo" => "Discussion"
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          "titulo" => "Conclusions"
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          "titulo" => "Abbreviations"
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          "identificador" => "s0095"
          "titulo" => "Funding"
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          "titulo" => "Conflict of Interests"
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          "titulo" => "References"
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    "fechaRecibido" => "2017-09-06"
    "fechaAceptado" => "2017-11-16"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Intrahepatic cholestasis of pregnancy"
            1 => "Celastrol"
            2 => "Matrix metalloproteinase"
            3 => "Ethinylestradiol"
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    "resumen" => array:1 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Introduction and aim</span>&#46; Matrix metalloproteinase &#40;MMP&#41;-2 and MMP-9 are reported to participate in several pregnancy-related diseases&#44; including intrahepatic cholestasis of pregnancy &#40;ICP&#41;&#44; which is a severe liver disorder in pregnant women&#46; Meanwhile&#44; ample evidences have demonstrated that celastrol inhibits the activity and expression of MMPs&#46; The present study aims to examine the effect of celastrol to alleviate symptoms of ICP in rat model&#46;</p><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Material and methods</span>&#46; By inducing ICP with 17 - ethinylestradiol in pregnant female rats&#44; we assessed the impact of celastrol administration on symptoms of ICP&#44; such as the rate of bile flow&#44; the level of total bile acids &#40;TBA&#41;&#44; and the activities of MMP-2 and -9&#46; Furthermore&#44; the correlations between the levels of MMPs with the examined ICP symptoms were investigated&#46;</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results</span>&#46; In rats with ICP&#44; both MMP-2 and -9 exhibited significantly elevated activities&#44; which were inhibited by the administration of celastrol&#46; Furthermore&#44; ICP symptoms such as bile flow rate and total TBA were restored by celastrol&#46; Lastly&#44; there were strong correlations between levels of the two MMPs and TBA&#46;</p><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclusion</span>&#46; Our findings described for the first time the effects of celastrol to attenuate ICP symptoms through an inhibition of both MMP-2 and -9&#44; providing evidence for a potential role of celastrol as a new drug for the treatment of ICP&#46;</p></span>"
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          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Celastrol ameliorated symptoms in ICP rats&#44; &#40;A and B&#41; Relative levels of bile flow rate &#40;A&#41; and total bile acids &#40;B&#41; in ICP and ICP &#43; celastrol groups of rats &#40;n &#61; 20 each&#41;&#44; &#40;C&#41; Enzymatic activities of alanine aminotransferase &#40;ALT&#41;&#44; aspartate aminotransferase &#40;AST&#41;&#44; alkaline phosphatase &#40;ALP&#41; and y-glutamyltranspeptidase &#40;GGT&#41; in ICP and ICP &#43; celastrol groups of rats &#40;n &#61; 16 each&#41;&#46; Values were mean &#177; SD&#44; &#42;&#42;p &#60; 0&#46;01&#44; &#42; p &#60;0&#46;05&#44; between ICP and ICP &#43; celastrol&#46;</p>"
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          "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Levels of TBA were strongly correlated with serum levels of MMP-2 and MMP-9 in ICP rats receiving celastrol treatment&#46; Pearson&#8217;s correlation coefficient test was performed between TBA and serum levels of MMP-2 &#40;A&#41; and MMP-9 &#40;B&#41;&#44; respectively&#44; in ICP &#43; celastrol group of rats &#40;n &#61; 16&#41;&#46; Values were in arbitrary units &#40;AU&#41;&#46;</p>"
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Article information
ISSN: 16652681
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos