Pregnancy is associated with uteroplacental and vascular remodeling in order to adapt for the growing fetus and the hemodynamic changes in the maternal circulation. We have previously shown upregulation of uterine matrix metalloproteinases (MMPs) during pregnancy. Whether pregnancy-associated changes in MMPs are localized to the uterus or are generalized in feto-placental and maternal circulation is unclear. Also, the mechanisms causing the changes in uteroplacental and vascular MMPs during pregnancy are unclear. MMPs expression, activity and tissue distribution were measured in uterus, placenta and aorta of virgin, mid-pregnant (mid-Preg) and late pregnant (late-Preg) rats. Western blots and gelatin zymography revealed increases in MMP-2 and -9 in uterus and aorta of late-Preg compared with virgin and mid-Preg rats. In contrast, MMP-2 and -9 were decreased in placenta of late-Preg versus mid-Preg rats. Extracellular MMP inducer (EMMPRIN) was increased in uterus and aorta of pregnant rats, but was less in placenta of late-Preg than mid-Preg rats. Prolonged treatment of uterus or aorta of virgin rats with 17β-estradiol and progesterone increased the amount of EMMPRIN, MMP-2 and -9, and the sex hormone-induced increases in MMPs were prevented by EMMPRIN neutralizing antibody. Immunohistochemistry revealed that MMP-2 and -9 and EMMPRIN increased in uterus and aorta of pregnant rats, but decreased in placenta of late-Preg versus mid-Preg rats. Thus pregnancy-associated upregulation of uterine MMPs is paralleled by increased vascular MMPs, and both are mediated by EMMPRIN and induced by estrogen and progesterone, suggesting similar role of MMPs in uterine and vascular tissue remodeling and function during pregnancy. The decreased MMPs and EMMPRIN in placenta of late-Preg rats suggests reduced role of MMPs in feto-placental circulation during late pregnancy.

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BACKGROUND AND PURPOSENormal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin-1 (ET-1) causes vasoconstriction via endothelin receptor type A (ETAR), but could activate ETBR in the endothelium and release vasodilator substances. However, the roles of ETBR in the regulation of vascular function during pregnancy and the vascular mediators involved are unclear. EXPERIMENTAL APPROACHPressurized mesenteric microvessels from pregnant and virgin Sprague-Dawley rats were loaded with fura-2/AM for simultaneous measurement of diameter and [Ca 2+ ]i. KEY RESULTSHigh KCl (51 mM) and phenylephrine (PHE) caused increases in vasoconstriction and [Ca 2+ ]i that were similar in pregnant and virgin rats. ET-1 caused vasoconstriction that was less in pregnant than virgin rats, with small increases in [Ca 2+ ]i. Pretreatment with the ETBR antagonist BQ-788 caused greater enhancement of ET-1-induced vasoconstriction in pregnant rats. ACh caused endothelium-dependent relaxation and decreased [Ca 2+ ]i, and was more potent in pregnant than in virgin rats. ET-1 + ETAR antagonist BQ-123, and the ETBR agonists sarafotoxin 6c (S6c) and IRL-1620 caused greater vasodilation in pregnant than in virgin rats with no changes in [Ca 2+ ]i, suggesting up-regulated ETBR-mediated relaxation pathways. ACh-, S6c-and IRL-1620-induced relaxation was reduced by the NO synthase inhibitor Nω-nitro-L-arginine methyl ester, and abolished by tetraethylammonium or endothelium removal. Western blots revealed greater amount of ETBR in intact microvessels of pregnant than virgin rats, but reduced levels in endothelium-denuded microvessels, supporting a role of endothelial ETBR. CONCLUSIONS AND IMPLICATIONSThe enhanced ETBR-mediated microvascular relaxation may contribute to the decreased vasoconstriction and vascular resistance during pregnancy. ]i, intracellular free Ca 2+ concentration; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial NOS; ET-1, endothelin-1; ETAR, endothelin receptor type A; ETBR, endothelin receptor type B; INDO, indomethacin; IRL-1620, Suc-Asp-Glu-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-AspIle-Ile-Trp; L-NAME, Nω-nitro-L-arginine methyl ester; pD2 (−log EC50), concentration of drug required to evoke a half-maximal response; PGI2, prostacyclin; PHE, phenylephrine; S6c, sarafotoxin 6c; SNP, sodium nitroprusside; TEA, tetraethylammonium chloride; VSM, vascular smooth muscle BJP British Journal of Pharmacology

The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-β was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-β compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.

Normal pregnancy is associated with systemic vasodilation and decreased vascular contraction, partly due to increased release of endothelium-derived vasodilator substances. Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor acting via endothelin receptor type A (ETAR) and possibly type B (ETBR) in vascular smooth muscle cells (VSMCs), with additional vasodilator effects via endothelial ETBR. However, the role of ET-1 receptor subtypes in the regulation of vascular function during pregnancy is unclear. We investigated whether the decreased vascular contraction during pregnancy reflects changes in the expression/activity of ETAR and ETBR. Contraction was measured in single aortic VSMCs isolated from virgin, mid-pregnant (mid-Preg, day 12) and late-Preg (day 19) Sprague-Dawley rats, and the mRNA expression, protein amount, tissue and cellular distribution of ETAR and ETBR were examined using RT-PCR, Western blots, immunohistochemistry and immunofluorescence. Phenylephrine (Phe, 10−5 M), KCl (51 mM) and ET-1 (10−6 M) caused VSMC contraction that was in late-Preg < mid-Preg and virgin rats. In VSMCs treated with ETBR antagonist BQ788, ET-1 caused significant contraction that was still in late-Preg < mid-Preg and virgin rats. In VSMCs treated with the ETAR antagonist BQ123, ET-1 caused a small contraction; and the ETBR agonists IRL-1620 and sarafotoxin 6c (S6c) caused similar contraction that was in late-Preg < mid-Preg and virgin rats. RT-PCR revealed similar ETAR, but greater ETBR mRNA expression in pregnant vs. virgin rats. Western blots revealed similar ETAR, and greater protein amount of ETBR in endothelium-intact vessels, but reduced ETBR in endothelium-denuded vessels of pregnant vs. virgin rats. Immunohistochemistry revealed prominent ETBR staining in the intima, but reduced ETAR and ETBR in the aortic media of pregnant rats. Immunofluorescence signal for ETAR and ETBR was less in VSMCs of pregnant vs. virgin rats. The pregnancy-associated decrease in ETAR- and ETBR-mediated VSMC contraction appears to involve downregulation of ETAR and ETBR expression/activity in VSM, and may play a role in the adaptive vasodilation during pregnancy.

We investigated if corilagin can ameliorate or reverse atherosclerotic development via the toll-like receptor 4 (TLR4) signaling pathway in vitro and in vivo. Ana-1 cells or mouse peritoneal macrophages (MPMs) were stimulated with oxidized low-density lipoprotein followed by corilagin treatment. TLR4 expression in Ana-1 cells was upregulated by lentiviral transduction and downregulated by small interfering RNA. Peripheral blood mononuclear cells (PBMCs), plasma samples, and femoral arteries were collected from rats exhibiting peripheral artery disease (PAD). mRNA and protein expression of TLR4 and downstream molecules were decreased significantly by corilagin treatment in Ana-1 cells, MPMs, and rat PBMCs, and the reduction remained irrespective of downregulation or upregulation of TLR4 expression in Ana-1 cells. Corilagin also exerted a prominent effect on changes in plasma levels of cytokines and the pathologic manifestation of atherosclerosis in femoral arteries. Corilagin could ameliorate the development of atherosclerotic plaques by inhibiting the TLR4 signaling pathway in monocyte/macrophages and reduce the release of proinflammatory cytokines. This study provides a new therapeutic target and new niche targeting drug to oppose atherosclerosis and reveals the enormous potential of corilagin for control of PAD in humans.

The general characteristics, outcomes and risk factors of the patients with aortic dissection (AD) were evaluated in a single medical center. From January 2002 to December 2008, 284 patients with AD were treated and followed-up at our institution, including 105 cases of type A AD and 179 cases of type B AD. The patients in each type were divided into three groups according to management: medical treatment group (A or B), open surgery group (A or B), and stent-graft group (A or B). The characteristics and follow-up outcomes were compared between the groups or subgroups. The results showed that there was significant difference in the prognosis for type A AD between medical treatment group and open surgery group, but there was no significant difference in the prognosis for type B AD between medical treatment group and stent-graft group. Independent risk factors of follow-up mortality for patients with type A AD included a history of atherosclerosis (HR, 3.807; 95% confidence interval [CI], 1.489 to 7.611; P=0.003), in-hospital hypotension/shock (HR, 4.687; 95% CI, 1.846 to 11.900; P=0.001), in-hospital myocardial ischemia or infarction (HR, 3.734; 95% CI, 1.613 to 8.643; P=0.002), pleural effusion (HR, 2.210; 95% CI, 1.080 to 4.521; P=0.030), branch vessel involvement (HR, 2.747; 95% CI, 1.202 to 6.278; P=0.016) and surgical treatment (HR, 0.177; 95% CI, 0.063 to 0.502; P=0.001). And there were insignificant independent predictors for mortality of the patients with type B AD. It was concluded that there were significant differences in characteristics and one year mortality between type A AD and type B AD, but after one year, there was no significant difference in the mortality and complications of them. There were several discordant risk factors of AD, such as female gender, age, thrombus, abrupt onset of pain that were considered as the risk factors in some papers. And there was no definite risk factor of mortality in this study in the patients with type B AD.

Deep Vein Thrombosis (DVT) has been known as a common medical problem all over the world. Thrombus traveling in blood vessels may lead to pulmonary embolism (PE), associated with high rates of mortality. Anticoagulant therapy is the mainstay treatment of DVT. Common anticoagulants, Vitamin K antagonists (VKAs), unfractionated heparin (UFH) and Low-molecular-weight heparin (LMWH) have been used in clinical application over decades, but can increase the risk of hemorrhage. Thereby, several new oral anticoagulants (NOACs) have been developed, which includes direct thrombin inhibitors (DTI) and direct factor Xa inhibitors. To be contrast with VKAs and UFH, NOACs have many advantages such as rapid offset action, few drug/food interactions and no need for routine coagulation monitoring, etc. Many NOACs are still being evaluated in Phase III clinical trials such as Betrixaban and Darexaban (YM150). However, NOACs still have problems to be solved such as lack of antidotes and laboratory monitoring, high drug costs, etc. Besides, several agents have already shown the potential to be new anticoagulants. Factor Xa play an important role in thrombin generation and coagulation pathway. Thus, the new compounds directly targeting on factor Xa for prevention DVT are highly anticipated. DPC423, a new series of 6-substituted coumarin derivatives and Phenyltriazolinones as potent factor Xa inhibitors have been recently reported. Recent studies revealed that agents extracted from botanicals not only have anti-coagulant effects but also possess other pharmacological activities such as anti-inflammation to alleviate the post-thrombotic syndromes. All the evidence above suggests that many new compounds might have great potential to be more effective and safe oral anticoagulants.