Background Early and late-onset preeclampsia is thought to be different disease entities. This study aimed to determine the effects of early-onset preeclampsia-like symptoms on feto-placental outcomes and the adverse ...Background Early and late-onset preeclampsia is thought to be different disease entities. This study aimed to determine the effects of early-onset preeclampsia-like symptoms on feto-placental outcomes and the adverse impacts of various factors on placental and fetal growth and development at different gestational stages in a mouse model. Methods Pregnant C57BL/6J mice were divided into control and preeclampsia （PE） groups, and injected subcutaneously with the nitric oxide synthase inhibitor L-arginine methyl ester （L-NAME） 50 mg·kg^-1·d^-1. The PE group was divided into early-, mid- and late-PE groups with L-NAME injections starting on days 7, 11 and 16 of pregnancy, respectively. Corresponding control groups were injected with saline at the same time points. Blood pressure was measured until days 14 and 18, when the fetuses and placentas were removed under anesthesia. Blood pressure, urinary protein, and fetal and placental conditions were analyzed. Results Blood pressure and urinary protein increased following L-NAME injection. The fetal survival rate and fetal weight were reduced and the fetal absorption rate was increased in the early-PE group on days 14 and 18 of pregnancy, compared with the control group. There were no significant differences in these parameters between the late-PE group and the respective control group. Placental weights in the early- and mid-PE groups were significantly reduced at days 14 and 18 of pregnancy compared with the control groups, but there was no significant difference in placental weight between the late-PE group and the respective control group. Morphologic examination of placentas from the early- and mid-PE groups showed varying degrees of fibrinoid necrosis and villous interstitial edema, but no significant pathologic changes were found in the placentas from the late-PE or control groups. Conclusion Preeclampsia-like symptoms occurring during the early stage of pregnancy are more likely to affect placental and fetal development, whereas late onset preeclampsia-li展开更多
Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus （HBV） infection. In this study, we report a mouse model with sust...Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus （HBV） infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus （AAV） carrying a replicable HBV genome （AAV/ HBV）. Similar to the clinical HBV carriers, the mice infected with AAV/H BV were sero-negative for antibodies against HBV surface antigen （HBsAg）. Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/H BV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism（s） of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.展开更多
Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen se...Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.展开更多
目的建立小鼠脓毒症模型并进行评价,为研究脓毒症致病机制和开发抗炎药物提供模型动物。方法采用盲肠结扎穿孔法(cecal ligation and puncture,CLP)诱导小鼠脓毒症,通过动物生存、术后小鼠载菌量、血常规和血生化指标、细胞因子水平、...目的建立小鼠脓毒症模型并进行评价,为研究脓毒症致病机制和开发抗炎药物提供模型动物。方法采用盲肠结扎穿孔法(cecal ligation and puncture,CLP)诱导小鼠脓毒症,通过动物生存、术后小鼠载菌量、血常规和血生化指标、细胞因子水平、组织病理变化等方面对模型进行评价。结果小鼠的死亡率与盲肠结扎部位密切相关,盲肠结扎50%小鼠12 d存活率在40%左右,结扎75%小鼠4 d全部死亡(P<0.01)。与假手术组相比,50%结扎CLP小鼠血液和腹腔中载菌量增加,白细胞下降,差异有显著性(P<0.001)。CLP小鼠肝转氨酶ALT、AST和血清尿素氮BUN水平升高,差异具有显著性(P<0.01),炎症因子IL1α、IL6、IL10、MIP1α、MIP1β、TNFα水平升高。手术后48 h小鼠的肝和肺出现明显组织病理损伤。结论小鼠CLP模型具有典型的脓毒症病理特征,为后期研究抗炎药物的筛选提供了较好的动物模型。展开更多
基金This work was supported by a grant from the National Natural Science Foundation of China （No. 30840088）.
文摘Background Early and late-onset preeclampsia is thought to be different disease entities. This study aimed to determine the effects of early-onset preeclampsia-like symptoms on feto-placental outcomes and the adverse impacts of various factors on placental and fetal growth and development at different gestational stages in a mouse model. Methods Pregnant C57BL/6J mice were divided into control and preeclampsia （PE） groups, and injected subcutaneously with the nitric oxide synthase inhibitor L-arginine methyl ester （L-NAME） 50 mg·kg^-1·d^-1. The PE group was divided into early-, mid- and late-PE groups with L-NAME injections starting on days 7, 11 and 16 of pregnancy, respectively. Corresponding control groups were injected with saline at the same time points. Blood pressure was measured until days 14 and 18, when the fetuses and placentas were removed under anesthesia. Blood pressure, urinary protein, and fetal and placental conditions were analyzed. Results Blood pressure and urinary protein increased following L-NAME injection. The fetal survival rate and fetal weight were reduced and the fetal absorption rate was increased in the early-PE group on days 14 and 18 of pregnancy, compared with the control group. There were no significant differences in these parameters between the late-PE group and the respective control group. Placental weights in the early- and mid-PE groups were significantly reduced at days 14 and 18 of pregnancy compared with the control groups, but there was no significant difference in placental weight between the late-PE group and the respective control group. Morphologic examination of placentas from the early- and mid-PE groups showed varying degrees of fibrinoid necrosis and villous interstitial edema, but no significant pathologic changes were found in the placentas from the late-PE or control groups. Conclusion Preeclampsia-like symptoms occurring during the early stage of pregnancy are more likely to affect placental and fetal development, whereas late onset preeclampsia-li
文摘Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus （HBV） infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus （AAV） carrying a replicable HBV genome （AAV/ HBV）. Similar to the clinical HBV carriers, the mice infected with AAV/H BV were sero-negative for antibodies against HBV surface antigen （HBsAg）. Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/H BV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism（s） of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.
基金supported by funding from Cancer Prevention & Research Institute of Texas (CPRIT, RR140012)V Foundation (V2015-2022)+1 种基金Sabin Family Foundation Fellowship at MD Anderson (2016-00052285)generous support from the McNair Foundation
文摘Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.
