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Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

null

《医学前沿（英文）》 2017年 第11卷 第3期   页码 403-409 doi: 10.1007/s11684-017-0522-y

摘要：

Tissue factor pathway inhibitor (TFPI) is the main inhibitor of tissue factor-mediated coagulation. TFPI is expressed by endothelial and smooth muscle cells in the vasculature. Endothelium-derived TFPI has been reported to play a regulatory role in arterial thrombosis. However, the role of endogenous TFPI in vascular smooth muscle cells (VSMCs) in thrombosis and vascular disease development has yet to be elucidated. In this TFPIFlox mice crossbred with Sma–Cre mice were utilized to establish TFPI conditional knockout mice and to examine the effects of VSMC-directed TFPI deletion on development, hemostasis, and thrombosis. The mice with deleted TFPI in VSMCs (TFPISma) reproduced viable offspring. Plasma TFPI concentration was reduced 7.2% in the TFPISma mice compared with TFPIFlox littermate controls. Plasma TFPI concentration was also detected in the TFPITie2 (mice deleted TFPI in endothelial cells and cells of hematopoietic origin) mice. Plasma TFPI concentration of the TFPITie2 mice was 80.4% lower (P<0.001) than that of the TFPIFlox mice. No difference in hemostatic measures (PT, APTT, and tail bleeding) was observed between TFPISma and TFPIFlox mice. However, TFPISma mice had increased ferric chloride–induced arterial thrombosis compared with TFPIFlox littermate controls. Taken together, these data indicated that endogenous TFPI from VSMCs inhibited ferric chloride–induced arterial thrombosis without causing hemostatic effects.

关键词： arterial thrombosis     conditional knockout mice     tissue factor pathway inhibitor     vascular smooth muscle cells    

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Adenovirus-mediated tissue inhibitor of metalloproteinase-3 gene transfection inhibits rabbit intervertebral

Xudong YU MM, Zengwu SHAO MD, Liming XIONG MD, Weiwei XU MM, Hezhong WANG MM, Huifa XU MM,

《医学前沿（英文）》 2009年 第3卷 第4期   页码 415-420 doi: 10.1007/s11684-009-0072-z

摘要： The aim of this study was to investigate the inhibitory effects of recombinant adenovirus vector carrying tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) against degeneration of rabbit intervertebral disc. Thirty Japanese white rabbits of 4 months old were randomly divided into 5 groups. Mild or moderate rabbit lumbar disc degeneration model was constructed with the controllable axial loading device by imposing 98N pressure at the discs for 2 weeks. Various doses of virus were injected into the degenerated discs as follows: 20μL of normal saline in group 1; 20μL of RAd66 (an empty adenovirus vector, 1.0×10OPU/mL) in group 2; and 20, 10, and 5μL of RAdTIMP-3 (1.0×10OPU/mL) in groups 3, 4, and 5, respectively. Two weeks after the injection, the discs were collected for investigations, including assessment of degeneration degrees according to the Thompson’s grading system, reverse-transcription polymerase chain reaction (RT-PCR) assay for TIMP-3 gene, Safranin O-Fast green staining, and immunohistochemical staining for TIMP-3 and type II collagen. According to Thompson’s criteria, the degeneration of groups 3, 4, and 5, especially group 3, was alleviated as compared with groups 1 and 2. RT-PCR revealed that the expression of TIMP-3 in groups 3, 4, and 5, especially in group 3, was significantly enhanced as compared with group 1 (<0.01). Both Safranin O-Fast green staining and type II collagen staining demonstrated better reserved integrity of disc matrix in groups 3, 4, and 5 than in groups 1 and 2. TIMP-3 staining exhibited an obvious increase of positive-staining rate in groups 3, 4, and 5 as compared with group 1. The positive-staining rate in group 3 (79.42%±1.35%) was about 3times that of group 1 (25.47%±5.46%, <0.01). RAdTIMP-3 can effectively protect the matrix of rabbit intervertebral disc against overloading-induced degeneration in a dose-dependent manner, resulting in the alleviation of disc degeneration.

关键词： tissue inhibitor of metalloproteinase-3     intervertebral disc     rabbit     gene therapy    

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Expression of integrin in hepatic fibrosis and intervention of resveratrol

Jianye WU, Chuanyong GUO, Jun LIU, Xuanfu XUAN

《医学前沿（英文）》 2009年 第3卷 第1期   页码 100-107 doi: 10.1007/s11684-009-0013-x

摘要： The aim of this study was to explore the expression of integrin-β1 in different stages of hepatic fibrosis and intervention of resveratrol as well as the way by which integrin-β1 promoted hepatic fibrosis. Hepatic fibrosis models of male Sprague Dawley (SD) rats were created and intragastric administration of resveratrol was given in low (40 mg/kg), middle (120 mg/kg) and high (200 mg/kg) dose groups. The expression of integrin-β1, tumor growth factor-β (TGF-β) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in different stages of hepatic fibrosis was detected by using RT-PCR. The expression of hexadecenoic acid (HA) and precollagen III (pc III) was assayed by radioimmunoassay. The expression of integrin-β1, TGF-β and TIMP-1 was determined in each group. Liver function and pathological sections of each group in different stages of hepatic fibrosis was tested to judge the therapeutic efficacy of resveratrol at different doses. The expression of integrin-β1 in normal control group was low and steady and was not increased as the development of hepatic fibrosis, but it is increased in other groups. The expression levels of integrin-β1 in the model control group (0.878±0.03, <0.01) and low dose group (0.855±0.04, <0.01) were higher than other groups, but there was no difference between model control group and low dose group ( >0.05). The expression levels of integrin-β1 and TGF-β in middle dose group and high dose group were higher than other groups ( <0.01). The expression levels of integrin-β1 and TGF-β in model control group and low dose group were lower than the normal control group ( <0.01). The expression levels of TIMP-1 in the model control and low dose groups were higher than the other groups ( <0.01). The expression levels of TIMP-1 in the middle dose group and the high dose group were lower than the normal control group ( <0.01). The expression of integrin-β1 existed in all stages of hepatic fibrosis of SD rats, and it was increased as the development of hepatic fibrosis. The expression of TGF-β and TIMP-1 was consistent with that of integrin-β1 in different stages of hepatic fibrosis. Resveratrol could improve the degree of hepatic fibrosis of SD rats and decrease the expression of integrin-β1 markedly at a dose of 120 mg/kg.

关键词： liver fibrosis     integrin-β1     resveratrol     tumor growth factor-β     tissue inhibitor of metalloproteinase-1    

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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

《医学前沿（英文）》 2023年 第17卷 第2期   页码 275-289 doi: 10.1007/s11684-022-0945-y

摘要： The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor     ErbB receptors     HM781-36B     nasopharyngeal carcinoma     molecular targeted therapy     cisplatin    

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Current advances for bone regeneration based on tissue engineering strategies

Rui Shi, Yuelong Huang, Chi Ma, Chengai Wu, Wei Tian

《医学前沿（英文）》 2019年 第13卷 第2期   页码 160-188 doi: 10.1007/s11684-018-0629-9

摘要： Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.

关键词： bone tissue engineering     stem cell     bone scaffold     growth factor     bone regeneration    

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Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

《医学前沿（英文）》 2020年 第14卷 第1期   页码 60-67 doi: 10.1007/s11684-019-0694-8

摘要： Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

关键词： BPTF     small molecule     epigenetics     non-small-cell lung cancer    

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Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?

Xu WANG MS, Xiao-Wei GONG MD, PhD, Yong JIANG MD, PhD, Yu-Hua LI PhD,

《医学前沿（英文）》 2010年 第4卷 第1期   页码 46-53 doi: 10.1007/s11684-010-0010-0

摘要： Mitogen-activated protein kinase (MAPK) signaling pathway, one of the most important signaling pathways in eukaryotic organism, is involved in multiple cellular events such as cell growth, differentiation, and apoptosis. MAPK is of great importance to the normal function of organisms, while its dysfunction results in various diseases. So far, inhibitors specifically against each subfamilies of MAP kinase have been developed, while more endeavors are needed to discover the compounds selectively targeting a particular subfamily member. Most of the kinase inhibitors exert their functions in an ATP-competitive way or a non-ATP-competitive way. Further studies on the effective mechanism of the MAPK inhibitors and their therapeutic roles in the treatment of diseases are helpful for the illumination of MAP kinase function, the development of novel inhibitors, and the therapy of diseases caused by the dysfunction of the MAPK pathway.

关键词： mitogen-activated protein kinase     drug target     inhibitor     signal transduction     disease    

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Atypical pituitary hormone–target tissue axis

《医学前沿（英文）》 2023年 第17卷 第1期   页码 1-17 doi: 10.1007/s11684-022-0973-7

摘要： A long-held belief is that pituitary hormones bind to their cognate receptors in classical target glands to actuate their manifold functions. However, a number of studies have shown that multiple types of pituitary hormone receptors are widely expressed in non-classical target organs. Each pituitary gland-derived hormone exhibits a wide range of nonconventional biological effects in these non-classical target organs. Herein, the extra biological functions of pituitary hormones, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, adrenocorticotrophic hormone, and prolactin when they act on non-classical organs were summarized, defined by the novel concept of an “atypical pituitary hormone–target tissue axis.” This novel proposal explains the pathomechanisms of abnormal glucose and lipid metabolism, obesity, hypertension, fatty liver, and atherosclerosis while offering a more comprehensive and systematic insights into the coordinated regulation of environmental factors, genetic factors, and neuroendocrine hormones on human biological functions. The continued exploration of the physiology of the “atypical pituitary hormone–target tissue axis” could enable the identification of novel therapeutic targets for metabolic diseases.

关键词： thyroid-stimulating hormone     follicle-stimulating hormone     luteinizing hormone     adrenocorticotrophic hormone     prolactin    

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Low-temperature caproate production, microbial diversity, and metabolic pathway in xylose anaerobic fermentation

《环境科学与工程前沿（英文）》 2023年 第17卷 第3期 doi: 10.1007/s11783-023-1637-9

摘要：

● Converting xylose to caproate under a low temperature of 20 °C by MCF was verified.

关键词： Xylose fermentation     Caproate     Low temperature     Bifidobacterium     FAB pathway     RBO pathway    

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Progress and perspectives of neural tissue engineering

null

《医学前沿（英文）》 2015年 第9卷 第4期   页码 401-411 doi: 10.1007/s11684-015-0415-x

摘要：

Traumatic injuries to the nervous system lead to a common clinical problem with a quite high incidence and affect the patient’s quality of life. Based on a major challenge not yet addressed by current therapeutic interventions for these diseases, a novel promising field of neural tissue engineering has emerged, grown, and attracted increasing interest. This review provides a brief summary of the recent progress in the field, especially in combination with the research experience of the author’s group. Several important aspects related to tissue engineered nerves, including the theory on their construction, translation into the clinic, improvements in fabrication technologies, and the formation of a regenerative environment, are delineated and discussed. Furthermore, potential research directions for the future development of neural tissue engineering are suggested.

关键词： nerve injury     tissue engineering     nerve grafts    

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The stem cell and tissue engineering research in Chinese ophthalmology

GE Jian, LIU Jingbo

《医学前沿（英文）》 2007年 第1卷 第1期   页码 6-10 doi: 10.1007/s11684-007-0002-x

摘要： Much has been considerably developed recently in the ophthalmic research of stem cell (SC) and tissue engineering (TE). They have become closer to the clinical practice, standardized and observable. Leading edge research of SC and TE on the ocular surface reconstruction, neuroregeneration and protection, and natural animal model has become increasingly available. However, challenges remain on the way, especially on the aspects of function reconstruction and specific differentiation. This paper reviews the new developments in this area with an intention of identifying research priorities for the future.

关键词： available     observable     neuroregeneration     protection     function reconstruction    

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Decellularized extracellular matrix mediates tissue construction and regeneration

《医学前沿（英文）》 2022年 第16卷 第1期   页码 56-82 doi: 10.1007/s11684-021-0900-3

摘要： Contributing to organ formation and tissue regeneration, extracellular matrix (ECM) constituents provide tissue with three-dimensional (3D) structural integrity and cellular-function regulation. Containing the crucial traits of the cellular microenvironment, ECM substitutes mediate cell–matrix interactions to prompt stem-cell proliferation and differentiation for 3D organoid construction in vitro or tissue regeneration in vivo. However, these ECMs are often applied generically and have yet to be extensively developed for specific cell types in 3D cultures. Cultured cells also produce rich ECM, particularly stromal cells. Cellular ECM improves 3D culture development in vitro and tissue remodeling during wound healing after implantation into the host as well. Gaining better insight into ECM derived from either tissue or cells that regulate 3D tissue reconstruction or organ regeneration helps us to select, produce, and implant the most suitable ECM and thus promote 3D organoid culture and tissue remodeling for in vivo regeneration. Overall, the decellularization methodologies and tissue/cell-derived ECM as scaffolds or cellular-growth supplements used in cell propagation and differentiation for 3D tissue culture in vitro are discussed. Moreover, current preclinical applications by which ECM components modulate the wound-healing process are reviewed.

关键词： decellularized extracellular matrix     3D culture     organoids     tissue repair    

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Non-closure of the peritoneum and subcutaneous tissue at radical hysterectomy: A randomized controlled

Zhou-Fang XIONG MD, Wei-Hong DONG MD, Ze-Hua WANG MD,

《医学前沿（英文）》 2010年 第4卷 第1期   页码 112-116 doi: 10.1007/s11684-010-0016-7

摘要： We conducted a trial to assess the influence of closure or nonclosure of the peritoneum and subcutaneous tissue on the clinical outcomes of cervical cancer patients who underwent radical hysterectomy with lower abdominal cross incision. This randomized controlled trial was performed on 158 cervical cancer patients in our hospital between January 2002 and June 2004. Eighty-two patients were allocated to the “closure” group and 76 patients to the “nonclosure” group. Results showed that non-closure of the peritoneum and subcutaneous tissue could shorten operation time and febrile duration, reduce antibiotics requirement, increase the volume of drainage and decrease the incidence of liquefaction of subcutaneous fat (<0.05). There was no difference in blood loss, postoperative complications, bowel function restoration and post-operative stay between the two groups (>0.05). Our study revealed that closure of the peritoneum and subcutaneous tissue provides no immediate postoperative benefits while unnecessarily lengthening surgical time and anesthesia exposure. The practice of closure of the peritoneum and subcutaneous tissue at radical hysterectomy should be questioned.

关键词： cervical cancer     radical surgery     peritoneum     subcutaneous tissue    

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Primary cilia in hard tissue development and diseases

《医学前沿（英文）》 2021年 第15卷 第5期   页码 657-678 doi: 10.1007/s11684-021-0829-6

摘要： Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.

关键词： primary cilia     bone     mechanical sensing     hard tissue     cilium-related bone disease     tooth    

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FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression

《医学前沿（英文）》 2023年 第17卷 第4期   页码 714-728 doi: 10.1007/s11684-022-0959-5

摘要： FRMD6, a member of the 4.1 ezrin–radixin–moesin domain-containing protein family, has been reported to inhibit tumor progression in multiple cancers. Here, we demonstrate the involvement of FRMD6 in lung cancer progression. We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues. In addition, the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma (n = 75, P = 0.0054) and lung adenocarcinoma (n = 94, P = 0.0330). Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6. Mechanistically, FRMD6 interacts and colocalizes with mTOR and S6K, which are the key molecules of the mTOR signaling pathway. FRMD6 markedly enhances the interaction between mTOR and S6K, subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells. Furthermore, knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6−/− gene KO MEFs and mice. Altogether, our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.

关键词： FRMD6     lung cancer     mTOR pathway    

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标题 作者 时间 类型 操作

Endogenous tissue factor pathway inhibitor in vascular smooth muscle cells inhibits arterial thrombosis

null

期刊论文

Adenovirus-mediated tissue inhibitor of metalloproteinase-3 gene transfection inhibits rabbit intervertebral

Xudong YU MM, Zengwu SHAO MD, Liming XIONG MD, Weiwei XU MM, Hezhong WANG MM, Huifa XU MM,

期刊论文

Expression of integrin in hepatic fibrosis and intervention of resveratrol

Jianye WU, Chuanyong GUO, Jun LIU, Xuanfu XUAN

期刊论文

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal

期刊论文

Current advances for bone regeneration based on tissue engineering strategies

Rui Shi, Yuelong Huang, Chi Ma, Chengai Wu, Wei Tian

期刊论文

Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell

Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu

期刊论文

Mitogen-activated protein kinase pathway inhibitors: inhibitors for diseases?

Xu WANG MS, Xiao-Wei GONG MD, PhD, Yong JIANG MD, PhD, Yu-Hua LI PhD,

期刊论文

Atypical pituitary hormone–target tissue axis

期刊论文

Low-temperature caproate production, microbial diversity, and metabolic pathway in xylose anaerobic fermentation

期刊论文

Progress and perspectives of neural tissue engineering

null

期刊论文

The stem cell and tissue engineering research in Chinese ophthalmology

GE Jian, LIU Jingbo

期刊论文

Decellularized extracellular matrix mediates tissue construction and regeneration

期刊论文

Non-closure of the peritoneum and subcutaneous tissue at radical hysterectomy: A randomized controlled

Zhou-Fang XIONG MD, Wei-Hong DONG MD, Ze-Hua WANG MD,

期刊论文

Primary cilia in hard tissue development and diseases

期刊论文

FERM domain-containing protein FRMD6 activates the mTOR signaling pathway and promotes lung cancer progression

期刊论文