Yongxiang Yin

The increased maternal serum levels of IL-6 are associated with the severity and onset of preeclampsia.

Preeclampsia is a complex disease of pregnancy with both feto-placental and maternal factors contributing to its pathogenesis. Although the cause of this disease is uncertain, imbalance between pro-and anti-inflammatory cytokines has been implicated in the pathogenesis of preeclampsia. Increased levels of the inflammatory cytokine IL-6 has been postulated to be involved in some ways in the pathogenesis of preeclampsia. However studies investigating whether levels of IL-6 in the maternal circulation differ between the disease severities or between times of onset of preeclampsia, or between preeclamptic pregnancies that are or are not complicated by fetal growth restriction (FGR) are limited. 104 women with preeclampsia and 75 health pregnant women were included into this study. The levels of IL-6 in maternal circulation were measured by enzyme-linked immunosorbent assay (ELISA). The levels of IL-6 in serum were significantly increased in women with preeclampsia in early onset and late onset preeclampsia compared to gestation matched health pregnant women. In addition, the levels of IL-6 were significantly increased in women with severe preeclampsia, but not with mild preeclampsia compared to gestation matched health pregnant women. Furthermore there was no correlation in IL-6 levels between preeclamptic with or without FGR. Our data shows increased level of circulating IL-6 levels in both women with early onset or late onset preeclampsia and in women with severe preeclampsia. These results suggest the excessive maternal inflammatory response in preeclampsia.

Increased expression of Rab25 in breast cancer correlates with lymphatic metastasis.

Breast cancer is the most common cancer in women worldwide. Studies have suggested that Ras-related protein 25 (Rab25), a member of Rab small GTPase family, is involved in the pathogenesis of breast cancer. In this study, we investigated whether the expression of Rab25 correlated with lymphatic metastasis in breast cancer and whether the expression of Rab25 was positively correlated with oestrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 42 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of Rab25 mRNA and protein measured by quantitative real-time PCR and immunohistochemistry, respectively. The mRNA level of Rab25 was significantly increased in invasive ductal breast cancer with lymphatic metastasis compared to that in invasive ductal breast cancer without lymphatic metastasis. Immunohistochemical analysis demonstrated that Rab25 and vascular endothelial growth factor (VEGF) were highly expressed in invasive ductal breast cancer with lymphatic metastasis regardless of whether the cancer is ER and PR positive or negative. Higher expression of Rab25 positively correlated with VEGF expression. However, the expressions of Rab25 in ER and PR-positive cancers were much higher than ER and PR-negative cancers regardless of whether lymphatic metastasis occurred. These data suggest that higher level of Rab25 was associated with lymphatic metastasis, specifically in ER and PR-positive breast cancer. The better understanding of the mechanism of Rab25 may provide a basis for the development of a novel therapeutic target in breast cancer.

Increased expression of high mobility group box 1 (HMGB1) in the cytoplasm of placental syncytiotrophoblast from preeclamptic placentae.

BACKGROUND Preeclampsia is a pregnancy-specific disorder characterised by an inappropriate maternal inflammatory response during pregnancy. High mobility group box 1 (HMGB1) was originally characterised as a nuclear protein but when released into the extracellular environment following necrotic cell death, it is proinflammatory. HMGB1 is expressed in the syncytiotrophoblast of human placenta. Higher levels of uric acid are reported in preeclampsia. The aim of this study was to investigate whether the expression of HMGB1differed between early onset and late onset preeclampsia or severe and mild preeclampsia and whether its expression correlated with the levels of uric acid. METHODS 74 preeclamptic placentae and 110 normotensive placentae were included in this study. The levels of uric acid in women with preeclampsia were measured. The expression of HMGB1 in preeclamptic placentae or in first trimester and term placentae that had been treated with uric acid was measured. RESULTS HMGB1 was expressed predominantly in the syncytiotrophoblast of the placenta and the expression of HMGB1 in the cytoplasm of the syncytiotrophoblast was significantly increased in both severe preeclampsia and early onset preeclampsia compared to normotensive pregnancies. The circulating levels of uric acid were significantly increased in preeclampsia and correlated with the expression of HMGB1. Increased levels of HMGB1 were significantly correlated with the severity and the time of onset of preeclampsia, but pathologic levels of uric acid did not increase the expression of HMGB1. CONCLUSION Our data provides a better understanding of the function of HMGB1, a danger molecule in the pathogenesis of preeclampsia.

Heat shock protein 27: a potential biomarker of peritoneal metastasis in epithelial ovarian cancer?

Ovarian cancer is the major gynaecologic malignancy and the leading cause of death in gynaecological cancer. Heat shock proteins (HSPs) are highly expressed in many malignant cancers and involved in metastasis including ovarian cancer. The early detection of peritoneal metastases in epithelial ovarian cancer may be more important in clinical care. HSP27, a small heat shock protein, is correlated with peritoneal metastases in epithelial ovarian cancer tissues. In this study, we investigated whether the levels of total HSP27 were detectable in serum and whether it could be a predictive biomarker for peritoneal metastases in epithelial ovarian cancer. Serum samples from 48 patients with epithelial ovarian cancer, 35 patients with benign ovarian tumours and 24 healthy women were included in this study. The serum levels of total HSP27 were measured by enzyme-linked immunosorbent assay (ELISA). There was no difference in the serum levels of total HSP27 between women with benign ovarian tumours and healthy women. However, the serum levels of total HSP27 were significantly increased in patients with epithelial ovarian cancer. The increased serum levels of total HSP27 were only seen in patients with peritoneal metastases. Furthermore, increased serum levels of total HSP27 were significantly reduced after the combination chemotherapies in patients with peritoneal metastases. These data suggest that circulating HSP27 levels were increased in epithelial ovarian cancer and correlated with peritoneal metastases. The measurement of serum HSP27 levels may be used as a potential additional indicator for peritoneal metastases in epithelial ovarian cancer and response to treatment.

The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer.

The involvement of hormonal factors in developing endometrial cancer is well documented. In particular, excess or unopposed estrogen is a major risk factor. Endometrial cancer is divided into estrogen-dependent and estrogen-independent types. Studies suggested that the subtypes of endometrial cancer share many common risk factors. Whether the levels of sex hormones differ between types 1 and 2 endometrial cancer has not been investigated. In this study, levels of estrogen, progesterone, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were investigated between type 1 and type 2 endometrial cancer taking into account menopausal status and parity. The sex hormones levels and estrogen and progesterone receptors were measured in 187 women with endometrial cancer. The levels of estradiol (E2), progesterone, testosterone, FSH and LH were not different between the subtypes of endometrial cancer regardless of menopausal status. In addition, the sex hormones were not different between patients of different party regardless of the menopausal status. The majority of type 1 (96%) and type 2 (82%) endometrial cancers were estrogen and progesterone receptor positive. Our data suggest that type 2 endometrial cancer is not completely estrogen independent, and type 1 and type 2 endometrial cancers may have a similar pathogenesis.

Placental expression of VEGF is increased in pregnancies with hydatidiform mole: possible association with developing very early onset preeclampsia.

BACKGROUND Hydatidiform mole is an abnormal pregnancy with over-proliferation of the placenta, which causes the dysfunction of placenta. Although more than 80% of hydatidiform moles are benign with good outcome, hydatidiform moles are associated with developing very early onset preeclampsia. However the association between hydatidiform mole and very early onset preeclampsia is unclear. Preeclampsia is associated with altered levels of angiogenic factors, like vascular endothelial growth factor (VEGF) and soluble endoglin. AIM The aim of this study is to investigate the levels of VEGF and endoglin in hydatidiform molar placenta. STUDY DESIGN 21 placentas from complete hydatidiform mole, 9 placentas from partial hydatidiform mole and 18 placentas from gestation matched placenta were collected in this study. SUBJECTS The subjects of this study are human placentas. OUTCOME MEASURES The protein levels and mRNA levels of VEGF and endoglin were measured using immunohistochemistry, western blotting and real time PCR. RESULTS The protein levels of VEGF measured by immunohistochemistry and western blotting were significant increased, as well as mRNA levels of VEGF quantified by real time PCR in hydatidiform molar placenta in comparison to normal controls. There was no difference in the protein levels of VEGF between complete and partial hydatidiform moles. In contrast, the levels of protein and mRNA in endoglin were no difference between hydatidiform molar placenta and normal controls. CONCLUSION In this study our data show that hydatidiform moles produce more VEGF than normal early pregnant placenta. The increased levels of angiogenic factors VEGF in hydatidiform moles may link to the mechanism of developing very early onset preeclampsia.

HtrA3 is negatively correlated with lymph node metastasis in invasive ductal breast cancer

Breast cancer is the most common cancer in women worldwide. Studies have shown that the high temperature requirement factor A3 (HtrA3) is involved in important physiological processes including maintenance of mitochondrial homeostasis, cell death, and cell signaling. HtrA3 is reported to be downregulated in several cancers and has been correlated with advancing cancer stage. We performed a retrospective study using our breast cancer tissue bank to investigate whether the expression of HtrA3 correlated with lymphatic metastasis in breast cancer and whether the expression of HtrA3 was correlated with estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 156 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of HtrA3 were measured by immunohistochemistry and western blotting. The expression of HtrA3 was lower in breast cancer. In particular, HtrA3 expression in breast cancer with lymphatic metastasis was lower than that in breast cancer without lymphatic metastasis. In breast cancers with no lymphatic metastasis, the expression of HtrA3 was lower in patients with ER- and PR-positive tumors, but when breast cancers with lymphatic metastasis were analyzed, there was no difference in HtrA3 expression between ER- and PR-positive or ER- and PR-negative tumors. These data suggest that the expression of HtrA3 was negatively correlated with lymphatic metastasis in breast cancer but not correlated with ER and PR positivity or negativity. A better understanding of the mechanism of HtrA3 may provide the basis for future development of a novel therapeutic target in breast cancer.

The reduction in circulating levels of estrogen and progesterone in women with preeclampsia

Abnormalities in the development of placental vasculature in early pregnancy and the failure of transformation of the spiral arteries are associated with the pathogenesis of preeclampsia. Sex hormones influence neovascularisation during pregnancy. However the profiling of estrogen and progesterone in preeclampsia is controversial. In this study we investigated the serum levels of estrogen and progesterone in women with preeclampsia. Blood samples were collected from 86 preeclamptic and 97 gestation-matched normotensive pregnancies. The levels of 17β-estradiol (E2), progesterone and 2-methoxyestradiol (2-ME) in serum were measured. In addition, the levels of E2 and progesterone in conditioned media from preeclamptic or normotensive term placental explant cultures or placental explants that had been treated with hydrogen peroxide (H2O2) were measured. The expression of estrogen receptors (ER) and progesterone receptors (PR) in preeclamptic and control placentae were measured by immunohistochemistry. The serum levels of E2, progesterone and 2-ME were significantly reduced in women with preeclampsia compared to controls. There was no difference in the serum levels of E2 and progesterone between severe and mild or between early-onset and late-onset preeclampsia as well as between preeclampsia with and without fetal growth restriction (FGR). The levels of E2 and progesterone in preeclamptic placental explants cultures were significantly lower than in normotensive term placental explant cultures. Treatment with H2O2 was found to be associated with a reduction in E2 production by the placenta. We demonstrated lower levels of estrogen in preeclampsia and speculate that this reduction may be due to the impairment of placental function in preeclampsia.

The reduction of circulating levels of IL-6 in pregnant women with preeclampsia by magnesium sulphate and nifedipine: In vitro evidence for potential mechanisms

INTRODUCTION Women with preeclampsia have elevated levels of inflammatory cytokines including IL-6. IL-6, which is known to activate endothelial cells and induce the production of necrotic trophoblastic debris from the placenta, may be important in the pathogenesis of preeclampsia. MgSO4 is a major therapy for the prevention of seizures in preeclampsia but it has been suggested to also have anti-inflammatory and vasodilatory properties. METHODS 22 pregnant women with preeclampsia and 68 normotensive controls were recruited and circulating IL-6 levels in these women were measured before MgSO4 and nifedipine treatment and after delivery. In addition, endothelial cells were treated with IL-6 or necrotic trophoblastic debris, generated from first trimester placental explants in the presence or absence of MgSO4in vitro, and cell-surface ICAM-1 was measured by ELISA. The levels of IL-6 in the culture medium were also measured. Furthermore nitric oxide synthetase activity in endothelial cells that had been treated with IL-6 was measured using l-NAME. RESULTS Circulating levels of IL-6 in preeclampsia were reduced significantly following administration of MgSO4. In vitro, MgSO4 reversed the activation of endothelial cells induced by IL-6 but not by necrotic trophoblastic debris. The effect of MgSO4 in reversing the IL-6 induced activation of endothelial cells was not dependent upon nitric oxide synthetase. Treating placental explants with MgSO4 prevented the production of necrotic trophoblastic debris induced by IL-6. DISCUSSION we demonstrated that IL-6 levels drop following treatment with MgSO4 and nifedipine in vivo, and have identified several mechanisms by which this positive effect on IL-6 may occur in vitro.

Interleukin‐6 contributes to chemoresistance in MDA‐MB‐231 cells via targeting HIF‐1α

Chemoresistance is a critical challenge in the clinical treatment of triple‐negative breast cancer (TNBC). It has been well documented that inflammatory mediators from tumor microenvironment are involved in the pathogenesis of TNBC and might be related to chemoresistance of cancer cells. In this study, the contribution of interleukin‐6 (IL‐6), one of the principal oncogenic molecules, in chemoresistance of a TNBC cell line MDA‐MB‐231 was first investigated. The results showed that IL‐6 treatment could induce upregulation of HIF‐1α via the activation of STAT3 in MDA‐MB‐231 cells, which consequently contributed to its effect against chemotherapeutic drug‐induced cytotoxicity and cell apoptosis. However, knockdown of HIF‐1α attenuated such effect via affecting the expressions of apoptosis‐related molecules as Bax and Bcl‐2 and drug transporters as P‐gp and MRP1. This study indicated that targeting at IL‐6/HIF‐1α signaling pathway might be an effective strategy to overcome chemoresistance in TNBC therapy.