Most defective and unwanted cells die by apoptosis, cells without damaging the surrounding tissue. Once a an exquisitely controlled genetic programme for removing such cell has committed to apoptosis, the process is r...Most defective and unwanted cells die by apoptosis, cells without damaging the surrounding tissue. Once a an exquisitely controlled genetic programme for removing such cell has committed to apoptosis, the process is remarkably efficient, and is completed within a few minutes of initiation. This point of no retum for an apoptotic cell is commonly held to be the point at which the outer mitochondrial membrane is permeabilised, a process regulated by the Bcl-2 family of proteins. How these proteins regulate this decision point is central to diseases such as cancer where apoptotic control is lost. In this review, we will discuss apoptotic signalling and how a cell makes the irreversible decision to die. We will focus on one set of survival signals, those derived by cell adhesion to the extracellular matrix (ECM), and use these to highlight the complexities of apoptotic signalling. In particular, we will illustrate how multiple signalling pathways converge to determine critical cell fate decisions.展开更多
A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signa...A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signaling plays a very important role in progression, invasion and metastasis of bladder cancer cells. In this study, we investigated whether IGF-1R was involved in the growth stimulating activity and drug resistance of bladder cancer cells. The results showed: The mRNAs of IGF-1, IGF-2 and IGF-1R were strongly expressed in serum-free cultured T24 cell line, whereas normal urothelial cells did not express these factors/receptors or only in trace levels; T24 cell responded far better to growth stimulation by IGF-1 than did normal urothelial cells; blockage of IGF1R by antisense oligodeoxynucleotide (ODN) significantly inhibited the growth of T24 cell and enhanced sensitivity and apoptosis of T24 cells to mitomycin (MMC). These results suggested that blockage of IGF-IR signaling might potentially contribute to the treatment of bladder cancer cells which are insensitive to chemotherapy.展开更多
Fibroblast growth factor (FGF) receptor substrate 2a (FRS2α) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine an...Fibroblast growth factor (FGF) receptor substrate 2a (FRS2α) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PS/T of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.展开更多
Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor (VEGF-ATF) on the VEGF signaling pathway in diabetes mellitus. Methods Totally, 20 C57BL/6 mice fed with high f...Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor (VEGF-ATF) on the VEGF signaling pathway in diabetes mellitus. Methods Totally, 20 C57BL/6 mice fed with high fat diet was induced into diabetes mellitus. Ten diabetes mellitus mice received a lower limb muscle injection with VEGF-ATF plasmid, and another ten were as control. VEGF-ATF is an engineered transcription factor designed to increase VEGF expression. Three days later, mice were sacrificed and the injected gastrocnemius was used for analysis. VEGF mRNA and protein expressions were examined by real-time PCR and ELISA respectively. VEGF receptor 2 mRNA expression was tested with RT-PCR. Phosphorylated Akt, Akt, endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS were assessed by western blot. Results At 3 days post-injection, in mice with diabetes mellitus, VEGF gene transfer increased VEGF mRNA copies and VEGF protein expression in injected muscles compared with control; and reinstated the impaired VEGF signaling pathway with increasing the ratios of phosphorylated Akt/Akt and phosphorylated eNOS/eNOS. However, it did not affect the expression of VEGF receptor 2 mRNA. Conclusion Gene transfer with VEGF-ATF is able to reinstate the impaired VEGF downstream pathway, and potentially promote therapeutic angiogenesis in mice with diabetes mellitus.展开更多
Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation ...Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor, use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.展开更多
The purpose of the work is to identify the acoustic emission (AE) signal in the melt and from the interphase during the crystal growth and to establish the connection between issue parameters: the number of signal ...The purpose of the work is to identify the acoustic emission (AE) signal in the melt and from the interphase during the crystal growth and to establish the connection between issue parameters: the number of signal events of frequency and the signal power with the growth conditions of temperature gradient and crystallization rate. Experiments on single crystal growth were carried out using hardware and software system which allows to perform spectral Fourier analysis of AE signals and to simultaneously remove the cooling curve for the entire period of crystallization. On the basis of spectral analysis of AE signals, a theoretical model of clusters in the aluminum melt was designed. The experimental results indicate an uneven abrupt advancement of the interface according to the configuration of each individual cluster.展开更多
The epidermal growth factor receptor (EGFR) is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphoryl...The epidermal growth factor receptor (EGFR) is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphorylation and activation of important downstream signaling pathways in normal and neoplastic cells, mainly the Ras GTPase/MAP kinase (MAPK), STAT3, and phosphatidylinositide 3 kinase-AKT pathways. EGFR deregulation is common in malignant glioma, especially primary glioblastoma, and exists in three forms: gene overexpression (amplification), autocrine effects of EGFR activation, and activating receptor mutation (EGFRvlII). However, some EGFR abnormalities have also been found in low-grade gliomas, including the nuclear localization of EGFR, expression in the microfoci of anaplastic transformation, and association with neovascularization in the mesenchyma of the glioma, which suggests that some unknown EGFR-related mechanisms are possibly responsible for its central role in the initiation and progression of malignant glioma. Uncovering these mechanisms will have potential value in the development of radio- therapy, chemotherapy, and EGFR-targeted therapy for glioma.展开更多
Growth is a polygenic trait that is under the influence of multiple physiological pathways regulating energy metabolism and muscle growth.Among the possible growth-regulating pathways in vertebrates,components of the ...Growth is a polygenic trait that is under the influence of multiple physiological pathways regulating energy metabolism and muscle growth.Among the possible growth-regulating pathways in vertebrates,components of the somatotropic axis are thought to have the greatest influence.There is growing body of literature focusing on the somatotropic axis and its role regulating growth in fish.This includes research into growth hormone,upstream hypothalamic hormones,insulin-like growth factors,and downstream signaling molecules.Many of these signals have both somatic effects stimulating the growth of tissues and metabolic effects that play a role in nutrient metabolism.Signals of other endocrine axes exhibit profound effects on the function of the somatotropic axis in vivo.In this review we highlight recent advances in our understanding of the teleost fish endocrine somatotropic axis,including emerging research using genetic modified models.These studies have revealed new aspects and challenges associated with regulation of the important steps of somatic growth.展开更多
Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1...Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis(DOP).Serum from patients with or without DOP was collected to measure the IGF-1 R level using enzyme-linked immunosorbent assay(ELISA).Rats were given streptozotocin following a four-week high-fat diet induction(DOP group),or received vehicle after the same period of a normal diet(control group).Dual energy X-ray absorption,a biomechanics test,and hematoxylin-eosin(HE)staining were performed to evaluate bone mass,bone strength,and histomorphology,respectively,in vertebrae.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were performed to measure the total and phosphorylation levels of IGF-1 R,glycogen synthase kinase-3β(GSK-3β),andβ-catenin.The serum IGF-1 R level was much higher in patients with DOP than in controls.DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group.HE staining showed that the histomorphology of DOP vertebrae was seriously impaired,which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae.PCR analysis demonstrated that IGF-1 R mRNA expression was significantly up-regulated,and western blotting detection showed that phosphorylation levels of IGF-1 R,GSK-3β,andβ-catenin were enhanced in DOP rat vertebrae.Our results suggest that the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of DOP.This may contribute to development of the underlying therapeutic target for DOP.展开更多
Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PD...Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PDGF-BB)- or transforming growth factor β1 (TGF-β1)-induced fibrosis in cultured human skin fibroblasts, and to further examine the molecular mechanisms involved. Human dermal flbroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) and serum-starved for 48 h before treatment. Cells were grouped as follows: "PDGF-BB", "PDGF-BB+ endostatin", "TGF-β1", "TGF-β1+endostatin", "endostatin", and "blank control". The fibroblasts were stimulated with either TGF-β1 or PDGF-BB for 72 h in order to set up the fibrosis model in vitro. The cells were co-cultured with either TGF-β1 or PDGF-BB and endostatin and were used to check the inhibiting effect of endostatin. A blank control group and an endostatin group were used as negative control groups. The biomarkers of fibrosis, including the expression of collagen I, hydrroxyproline, and α-smooth muscle actin (a-SMA), were evaluated using an enzyme-linked immune- sorbent assay (ELISA) and Western blot. The expression of phosphorylated PDGF receptor β (p-PDGFRβ), PDGFRβ, phosphorylated extracellular signal-regulated kinase (p-ERK), and ERK was detected using Western blot and im- munofiuorescent staining was used to explore the mechanisms. Both PDGF-BB and TGF-β1 significantly up-regulated the expression of collagen I, hydroxyproline, and a-SMA. Endostatin significantly attenuated both the PDGF-BB- and TGF-β1-induced over-expression of collagen I, hydroxyproline, and a-SMA. PDGF-BB and TGF-β1 both promoted the expression of PDGFR, ERK, and p-ERK. Endostatin inhibited the expression of PDGFR and p-ERK but did not affect the expression of total ERK. Endostatin inhibited hypertrophic scar by modulating the PDGFRI3/ERK pathway. En- dostatin could be a promising multi-target drug in future fibrosis therapy.展开更多
Aggressive mimicry occurs when an organism resembles some aspect of another organism (the model) in order to obtain prey through its deceptive resemblance. This may function either through the overt response of the ...Aggressive mimicry occurs when an organism resembles some aspect of another organism (the model) in order to obtain prey through its deceptive resemblance. This may function either through the overt response of the receiver or through the lack of response of the receiver. Reviewing selected examples, I discuss some of the difficulties in ascribing a model for the mimic. I also discuss how a single animal can have multiple ploys in its armoury of deceptive signals, thus belonging within two or more categories of deceptive signalling. In addition to aggressive mimicry, these may include crypsis or camouflage, mas- querade (mimicry of inanimate objects), and Batesian or protective mimicry. Each of these examples of deception has multiple evolutionary pathways, and some deceptive signals may be more costly to receivers than others, but no single organism is subject to a single selection pressure, leading to the reality that many evolutionary pathways contribute to the diversity we see around us. New technologies are opening new channels of investigation into deceptive signaling in many different sensory modalities, and this is reflected in the recent increase in studies investigating the structure and function of deceptive signals. In turn, these studies are beginning to expose the fascinating complexity of deceptive signaling systems, allowing us to discover the myriad, non-mutually exclusive, solutions that can be selected for to obtain prey展开更多
Since the discovery of leptin as an adipokine in 1994, much progress has been made in the research about leptin. Circulating leptin binds to leptin receptor, activates STAT3-dependent and STAT3-independent signaling p...Since the discovery of leptin as an adipokine in 1994, much progress has been made in the research about leptin. Circulating leptin binds to leptin receptor, activates STAT3-dependent and STAT3-independent signaling pathways, and plays an effective role in energy home- ostasis, neuroendocrine function and metabolism mainly through acting on the central nervous system, especially the hypothalamus. Leptin resistance is considered as a key risk factor for obesity. Various mechanisms have been formu- lated in order to explain leptin resistance, including impairment in leptin transport, attenuation in leptin sig- naling, ER stress, inflammation and deficiency in autop- hagy. Here, we review our current knowledge about leptin action, leptin signaling and leptin resistance, hoping to provide new ideas for the battle against obesity.展开更多
The COP9 signalosome(CSN) is a highly conserved multiprotein complex in all eukaryotes and involved in regulation of organism development. In filamentous fungi, several lines of evidence indicate that fungal developme...The COP9 signalosome(CSN) is a highly conserved multiprotein complex in all eukaryotes and involved in regulation of organism development. In filamentous fungi, several lines of evidence indicate that fungal development and secondary metabolism(SM) are mediated by the fifth subunit of CSN, called CsnE. Here we uncover a connection with CsnE and conidial formation as well as SM regulation in the plant endophytic fungus Pestalotiopsis fici. A homology search of the P. fici genome with CsnE, involved in sexual development and SM in Aspergillus nidulans, identified PfCsnE. Deletion of PfcsnE resulted in a mutant that stopped conidial production, but the conidia are recovered in a PfcsnE complemented strain. This indicates that PfCsnE is required for the formation of conidia. Secondary metabolite analysis demonstrated that the ΔPfcsnE strain produced more chloroisosulochrin, less ficiolide A production in comparison to wild type(WT). Transcriptome analysis of WT andΔPfcsnE strains indicated that PfcsnE impacts the expression levels of 8.37% of 14,797 annotated genes. Specifically, nine biosynthetic gene clusters(BGCs) were up-regulated and three BGCs were down-regulated by PfCsnE. Our results suggest that PfCsnE plays major roles in SM regulation and conidial development in P. fici.展开更多
Objective: To observe the effects of moxibustion pretreatment on the protein expressions of epidermal growth factor receptor (EGFR), phosphorylation extracellular signal-regulated kinase I/2 (p-ERKI/2) and activa...Objective: To observe the effects of moxibustion pretreatment on the protein expressions of epidermal growth factor receptor (EGFR), phosphorylation extracellular signal-regulated kinase I/2 (p-ERKI/2) and activated protein-1 (AP-2), the key factors of extracellular signal-regulated kinase signaling transduction pathway in gastric tissue of rats with stress-induced gastric mucosal damage, and to discuss the mechanisms of moxibustion therapy in promoting the restoration of damaged gastric mucosa. Methods: Thirty Sprague-Dawley (SD) rats were randomly divided into a normal group, a model group, and a moxibustion group using the random digits table, 10 in each group. Except the rats in the normal group, rats in the other two groups were used to make stress-induced gastric mucosal damage model using restraint and cold stress. Before modeling, rats in the moxibustion group were alternately treated with moxibustion a/t Zusanli (ST 36) and Zhongwan (CV 12), or Pishu (BL 20) and Weishu (BL 22), once a day, for a total of 8 d. Histolo^cal changes of gastric mucosa were observed under the light microscopy, the expression of gastric tissue p-ERKI/2 was detected by immunohistochemistry assay, and the protein levels of EGFR and AP-I were measured by Western blots. Results: Compared with rats in the normal group, gastric mucosal damage was more serious, and protein expressions of gastric tissue EGFR, p-ERK1/2 and AP-1 increased in the model group (P〈0.01, P〈O.05, P〈0.05). Compared with rats in the model group, gastric mucosal damage was milder, and protein expressions of gastric tissue EGFR, p-ERK1/2 and AP-1 increased in the moxibustion group (all P〈0.01). Conclusion: Moxibustion at Zusanli (ST 36), Zhongwan (CV 12), Pishu (BL 20) and Weishu (BL 21) could increase EGFR, p-ERK1/2 and AP-1 expression levels in gastric tissue of stress-induced gastric mucosal damage rats, maintain the information transfer function of ERK signaling transduction pathway, and promote restoration of gastric mucosal damage.展开更多
Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets...Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-l,3,4,9-tetrahydro-^-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation ofmicrovascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.展开更多
文摘Most defective and unwanted cells die by apoptosis, cells without damaging the surrounding tissue. Once a an exquisitely controlled genetic programme for removing such cell has committed to apoptosis, the process is remarkably efficient, and is completed within a few minutes of initiation. This point of no retum for an apoptotic cell is commonly held to be the point at which the outer mitochondrial membrane is permeabilised, a process regulated by the Bcl-2 family of proteins. How these proteins regulate this decision point is central to diseases such as cancer where apoptotic control is lost. In this review, we will discuss apoptotic signalling and how a cell makes the irreversible decision to die. We will focus on one set of survival signals, those derived by cell adhesion to the extracellular matrix (ECM), and use these to highlight the complexities of apoptotic signalling. In particular, we will illustrate how multiple signalling pathways converge to determine critical cell fate decisions.
文摘A major problem which is poorly understood in the management of bladder cancer is low sensitivity to chemotherapy and high recurrence after transurethral resection. Insulin-like growth factor 1 receptor (IGF-1R) signaling plays a very important role in progression, invasion and metastasis of bladder cancer cells. In this study, we investigated whether IGF-1R was involved in the growth stimulating activity and drug resistance of bladder cancer cells. The results showed: The mRNAs of IGF-1, IGF-2 and IGF-1R were strongly expressed in serum-free cultured T24 cell line, whereas normal urothelial cells did not express these factors/receptors or only in trace levels; T24 cell responded far better to growth stimulation by IGF-1 than did normal urothelial cells; blockage of IGF1R by antisense oligodeoxynucleotide (ODN) significantly inhibited the growth of T24 cell and enhanced sensitivity and apoptosis of T24 cells to mitomycin (MMC). These results suggested that blockage of IGF-IR signaling might potentially contribute to the treatment of bladder cancer cells which are insensitive to chemotherapy.
文摘Fibroblast growth factor (FGF) receptor substrate 2a (FRS2α) is the main mediator of signaling in the FGF pathway. Recent studies have shown that mitogen-activated protein kinase (MAPK) phosphorylates serine and threonine residues in FRS2, negatively affecting FGF-induced tyrosine phosphorylation (PY) of FRS2. Several kinds of stimuli can induce serine/threonine phosphorylation (PS/T) of FRS2, indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways. Here, we report that FGF-induced PY of FRS2 can be attenuated by EGF co-stimulation in PC12cells; this inhibitory effect could be completely reversed by U0126, an inhibitor of MEK. We further identified the ERK1/2-binding motif in FRS2 and generated FRS2-3KL, a mutant lacking MAPK binding and PT upon FGF and/or EGF stimulation. Unlike wild-type (WT) FRS2, FGF-induced PY of FRS2-3KL could not be inhibited by EGF co-stimulation, and FRS2-3KL-expressing PC12 cells exhibited more differentiating potential than FRS2-WT-expressing cells in response to FGF treatment. These results suggest that PS/T of FRS2 mediated by the FRS2-MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR-generated signal transduction.
基金supported by National Nature Science Foundation of China (30772114)Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry
文摘Objective To investigate the role of vascular endothelial growth factor-activating transcriptional factor (VEGF-ATF) on the VEGF signaling pathway in diabetes mellitus. Methods Totally, 20 C57BL/6 mice fed with high fat diet was induced into diabetes mellitus. Ten diabetes mellitus mice received a lower limb muscle injection with VEGF-ATF plasmid, and another ten were as control. VEGF-ATF is an engineered transcription factor designed to increase VEGF expression. Three days later, mice were sacrificed and the injected gastrocnemius was used for analysis. VEGF mRNA and protein expressions were examined by real-time PCR and ELISA respectively. VEGF receptor 2 mRNA expression was tested with RT-PCR. Phosphorylated Akt, Akt, endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS were assessed by western blot. Results At 3 days post-injection, in mice with diabetes mellitus, VEGF gene transfer increased VEGF mRNA copies and VEGF protein expression in injected muscles compared with control; and reinstated the impaired VEGF signaling pathway with increasing the ratios of phosphorylated Akt/Akt and phosphorylated eNOS/eNOS. However, it did not affect the expression of VEGF receptor 2 mRNA. Conclusion Gene transfer with VEGF-ATF is able to reinstate the impaired VEGF downstream pathway, and potentially promote therapeutic angiogenesis in mice with diabetes mellitus.
基金Supported in part by the funds from Central Arkansas Veterans Healthcare System
文摘Erythropoietin (Epo) is the regulator of red blood cell formation. Its receptor (EpoR) is now found in many cells and tissues of the body. EpoR is also shown to occur in tumor cells and Epo enhances the proliferation of these cells through cell signaling. EpoR antagonist can reduce the growth of the tumor in vivo. In view of our current knowledge of Epo, its recombinant forms and receptor, use of Epo in cancer patients to enhance the recovery of hematocrit after chemotherapy treatment has to be carefully evaluated.
文摘The purpose of the work is to identify the acoustic emission (AE) signal in the melt and from the interphase during the crystal growth and to establish the connection between issue parameters: the number of signal events of frequency and the signal power with the growth conditions of temperature gradient and crystallization rate. Experiments on single crystal growth were carried out using hardware and software system which allows to perform spectral Fourier analysis of AE signals and to simultaneously remove the cooling curve for the entire period of crystallization. On the basis of spectral analysis of AE signals, a theoretical model of clusters in the aluminum melt was designed. The experimental results indicate an uneven abrupt advancement of the interface according to the configuration of each individual cluster.
文摘The epidermal growth factor receptor (EGFR) is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphorylation and activation of important downstream signaling pathways in normal and neoplastic cells, mainly the Ras GTPase/MAP kinase (MAPK), STAT3, and phosphatidylinositide 3 kinase-AKT pathways. EGFR deregulation is common in malignant glioma, especially primary glioblastoma, and exists in three forms: gene overexpression (amplification), autocrine effects of EGFR activation, and activating receptor mutation (EGFRvlII). However, some EGFR abnormalities have also been found in low-grade gliomas, including the nuclear localization of EGFR, expression in the microfoci of anaplastic transformation, and association with neovascularization in the mesenchyma of the glioma, which suggests that some unknown EGFR-related mechanisms are possibly responsible for its central role in the initiation and progression of malignant glioma. Uncovering these mechanisms will have potential value in the development of radio- therapy, chemotherapy, and EGFR-targeted therapy for glioma.
基金supported by the National Basic Research Program of China(2010CB126302 and 2014CB138602)to Yin Zhan
文摘Growth is a polygenic trait that is under the influence of multiple physiological pathways regulating energy metabolism and muscle growth.Among the possible growth-regulating pathways in vertebrates,components of the somatotropic axis are thought to have the greatest influence.There is growing body of literature focusing on the somatotropic axis and its role regulating growth in fish.This includes research into growth hormone,upstream hypothalamic hormones,insulin-like growth factors,and downstream signaling molecules.Many of these signals have both somatic effects stimulating the growth of tissues and metabolic effects that play a role in nutrient metabolism.Signals of other endocrine axes exhibit profound effects on the function of the somatotropic axis in vivo.In this review we highlight recent advances in our understanding of the teleost fish endocrine somatotropic axis,including emerging research using genetic modified models.These studies have revealed new aspects and challenges associated with regulation of the important steps of somatic growth.
基金Project supported by the National Natural Science Foundation of China(Nos.81774338 and 81674000)the Natural Science Foundation of Guangdong Province(No.2016A030313645)+1 种基金the Science and Technology Projects of Guangdong Province(No.2016A020226006)the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2018),China
文摘Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis(DOP).Serum from patients with or without DOP was collected to measure the IGF-1 R level using enzyme-linked immunosorbent assay(ELISA).Rats were given streptozotocin following a four-week high-fat diet induction(DOP group),or received vehicle after the same period of a normal diet(control group).Dual energy X-ray absorption,a biomechanics test,and hematoxylin-eosin(HE)staining were performed to evaluate bone mass,bone strength,and histomorphology,respectively,in vertebrae.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were performed to measure the total and phosphorylation levels of IGF-1 R,glycogen synthase kinase-3β(GSK-3β),andβ-catenin.The serum IGF-1 R level was much higher in patients with DOP than in controls.DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group.HE staining showed that the histomorphology of DOP vertebrae was seriously impaired,which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae.PCR analysis demonstrated that IGF-1 R mRNA expression was significantly up-regulated,and western blotting detection showed that phosphorylation levels of IGF-1 R,GSK-3β,andβ-catenin were enhanced in DOP rat vertebrae.Our results suggest that the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of DOP.This may contribute to development of the underlying therapeutic target for DOP.
基金Project supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY15H150004)the Teaching Department of the Zhejiang Province(No.Y201330073),China
文摘Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PDGF-BB)- or transforming growth factor β1 (TGF-β1)-induced fibrosis in cultured human skin fibroblasts, and to further examine the molecular mechanisms involved. Human dermal flbroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) and serum-starved for 48 h before treatment. Cells were grouped as follows: "PDGF-BB", "PDGF-BB+ endostatin", "TGF-β1", "TGF-β1+endostatin", "endostatin", and "blank control". The fibroblasts were stimulated with either TGF-β1 or PDGF-BB for 72 h in order to set up the fibrosis model in vitro. The cells were co-cultured with either TGF-β1 or PDGF-BB and endostatin and were used to check the inhibiting effect of endostatin. A blank control group and an endostatin group were used as negative control groups. The biomarkers of fibrosis, including the expression of collagen I, hydrroxyproline, and α-smooth muscle actin (a-SMA), were evaluated using an enzyme-linked immune- sorbent assay (ELISA) and Western blot. The expression of phosphorylated PDGF receptor β (p-PDGFRβ), PDGFRβ, phosphorylated extracellular signal-regulated kinase (p-ERK), and ERK was detected using Western blot and im- munofiuorescent staining was used to explore the mechanisms. Both PDGF-BB and TGF-β1 significantly up-regulated the expression of collagen I, hydroxyproline, and a-SMA. Endostatin significantly attenuated both the PDGF-BB- and TGF-β1-induced over-expression of collagen I, hydroxyproline, and a-SMA. PDGF-BB and TGF-β1 both promoted the expression of PDGFR, ERK, and p-ERK. Endostatin inhibited the expression of PDGFR and p-ERK but did not affect the expression of total ERK. Endostatin inhibited hypertrophic scar by modulating the PDGFRI3/ERK pathway. En- dostatin could be a promising multi-target drug in future fibrosis therapy.
文摘Aggressive mimicry occurs when an organism resembles some aspect of another organism (the model) in order to obtain prey through its deceptive resemblance. This may function either through the overt response of the receiver or through the lack of response of the receiver. Reviewing selected examples, I discuss some of the difficulties in ascribing a model for the mimic. I also discuss how a single animal can have multiple ploys in its armoury of deceptive signals, thus belonging within two or more categories of deceptive signalling. In addition to aggressive mimicry, these may include crypsis or camouflage, mas- querade (mimicry of inanimate objects), and Batesian or protective mimicry. Each of these examples of deception has multiple evolutionary pathways, and some deceptive signals may be more costly to receivers than others, but no single organism is subject to a single selection pressure, leading to the reality that many evolutionary pathways contribute to the diversity we see around us. New technologies are opening new channels of investigation into deceptive signaling in many different sensory modalities, and this is reflected in the recent increase in studies investigating the structure and function of deceptive signals. In turn, these studies are beginning to expose the fascinating complexity of deceptive signaling systems, allowing us to discover the myriad, non-mutually exclusive, solutions that can be selected for to obtain prey
基金Acknowledgments This work was supported by the National Basic Research Program of China (2013CB530601, 2011CB910201), the National Natural Science Foundation of China (31571401, 81270954, 31030048, 81390350), the Shanghai Rising Star Program (13QH1400800). The Department of Biochemistry and Molecular Biology at Fudan University Shanghai Medical College is supported by the Shanghai Leading Academic Discipline Projects B 110 and by "985" Project 985III-YFX0302.
文摘Since the discovery of leptin as an adipokine in 1994, much progress has been made in the research about leptin. Circulating leptin binds to leptin receptor, activates STAT3-dependent and STAT3-independent signaling pathways, and plays an effective role in energy home- ostasis, neuroendocrine function and metabolism mainly through acting on the central nervous system, especially the hypothalamus. Leptin resistance is considered as a key risk factor for obesity. Various mechanisms have been formu- lated in order to explain leptin resistance, including impairment in leptin transport, attenuation in leptin sig- naling, ER stress, inflammation and deficiency in autop- hagy. Here, we review our current knowledge about leptin action, leptin signaling and leptin resistance, hoping to provide new ideas for the battle against obesity.
基金Wenbing Yin is a scholar of "the 100 Talents Project" of Chinese Academy of Sciencessupported by the National Key Research and Development Program (2016YFD0400105)+1 种基金National Natural Science Foundation of China (31670402 and 31400334)Sate Key Laboratory of Mycology Open Project (SKLMKF 2015-1)
文摘The COP9 signalosome(CSN) is a highly conserved multiprotein complex in all eukaryotes and involved in regulation of organism development. In filamentous fungi, several lines of evidence indicate that fungal development and secondary metabolism(SM) are mediated by the fifth subunit of CSN, called CsnE. Here we uncover a connection with CsnE and conidial formation as well as SM regulation in the plant endophytic fungus Pestalotiopsis fici. A homology search of the P. fici genome with CsnE, involved in sexual development and SM in Aspergillus nidulans, identified PfCsnE. Deletion of PfcsnE resulted in a mutant that stopped conidial production, but the conidia are recovered in a PfcsnE complemented strain. This indicates that PfCsnE is required for the formation of conidia. Secondary metabolite analysis demonstrated that the ΔPfcsnE strain produced more chloroisosulochrin, less ficiolide A production in comparison to wild type(WT). Transcriptome analysis of WT andΔPfcsnE strains indicated that PfcsnE impacts the expression levels of 8.37% of 14,797 annotated genes. Specifically, nine biosynthetic gene clusters(BGCs) were up-regulated and three BGCs were down-regulated by PfCsnE. Our results suggest that PfCsnE plays major roles in SM regulation and conidial development in P. fici.
基金supported by National Basic Research Program of China(973 Program,No.2015CB554502)National Natural Science Foundation of China(No.81202770,No.81574082)+5 种基金Special Research Fund for the Doctoral Program of Higher Education of China for New Teachers(No.20124323120002)Hunan Provincial Natural Science Foundation of China(No.13JJ6060)Foundation for the Author of Excellent Doctoral Dissertation of Hunan Province(No.YB2013B037)Fund Project of Hunan Province Education Office(No.14B129)2013 Project of Scientific and Technological Innovation and Entrepreneurship Platform for Huxiang Youth2013 Training Project of 225 for High-level Medical Personnel of Hunan Province~~
文摘Objective: To observe the effects of moxibustion pretreatment on the protein expressions of epidermal growth factor receptor (EGFR), phosphorylation extracellular signal-regulated kinase I/2 (p-ERKI/2) and activated protein-1 (AP-2), the key factors of extracellular signal-regulated kinase signaling transduction pathway in gastric tissue of rats with stress-induced gastric mucosal damage, and to discuss the mechanisms of moxibustion therapy in promoting the restoration of damaged gastric mucosa. Methods: Thirty Sprague-Dawley (SD) rats were randomly divided into a normal group, a model group, and a moxibustion group using the random digits table, 10 in each group. Except the rats in the normal group, rats in the other two groups were used to make stress-induced gastric mucosal damage model using restraint and cold stress. Before modeling, rats in the moxibustion group were alternately treated with moxibustion a/t Zusanli (ST 36) and Zhongwan (CV 12), or Pishu (BL 20) and Weishu (BL 22), once a day, for a total of 8 d. Histolo^cal changes of gastric mucosa were observed under the light microscopy, the expression of gastric tissue p-ERKI/2 was detected by immunohistochemistry assay, and the protein levels of EGFR and AP-I were measured by Western blots. Results: Compared with rats in the normal group, gastric mucosal damage was more serious, and protein expressions of gastric tissue EGFR, p-ERK1/2 and AP-1 increased in the model group (P〈0.01, P〈O.05, P〈0.05). Compared with rats in the model group, gastric mucosal damage was milder, and protein expressions of gastric tissue EGFR, p-ERK1/2 and AP-1 increased in the moxibustion group (all P〈0.01). Conclusion: Moxibustion at Zusanli (ST 36), Zhongwan (CV 12), Pishu (BL 20) and Weishu (BL 21) could increase EGFR, p-ERK1/2 and AP-1 expression levels in gastric tissue of stress-induced gastric mucosal damage rats, maintain the information transfer function of ERK signaling transduction pathway, and promote restoration of gastric mucosal damage.
基金supported by Major State Basic Research Development Program of China(2015CB910400)National Natural Science Foundation of China(81272463,81472788,81330049,81673304)The Science and Technology Commission of Shanghai Municipality(15431902200)
文摘Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-l,3,4,9-tetrahydro-^-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation ofmicrovascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.