Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) ...Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.展开更多
AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled int...AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled into this study.SHP-2 expression was carried out in 305 gastric cancer specimens,of which 83 were paired adjacent normal gastric mucus samples,using a tissue microarray immunohistochemical method.Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes.Serum anti-Helicobacter pylori(H.pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay.Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients.RESULTS:SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells.Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively(P < 0.001).Though SHP-2 staining intensities were stronger in the H.pylori(+) group than in the H.pylori(-) group,no statistically significant difference was found in the expression levels of SHP-2 between H.pylori(+) and H.pylori(-) gastric cancer(P = 0.40).The SHP-2 expression in gastric cancer was not significantly associated with cancer stages,lymph node metastases,and distant metastasis of the tumors(P = 0.34,P = 0.17,P = 0.52).Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival(P = 0.86).CONCLUSION:Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant upregulation of SHP-2 protein might play an important role in the gastric carcinogenesis.展开更多
Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic...Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.展开更多
Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PT...Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.展开更多
PCP-2 is a member of receptor-like protein tyrosine phosphatase of the MAM do- main family. To investigate which part of PCP-2 was involved in its interaction with β-catenin, we constructed various deletion mutants o...PCP-2 is a member of receptor-like protein tyrosine phosphatase of the MAM do- main family. To investigate which part of PCP-2 was involved in its interaction with β-catenin, we constructed various deletion mutants of PCP-2. These PCP-2 mutants and wild-type PCP-2 were co-transfected into BHK-21 cells with β-catenin individually. An in vivo binding assay revealed that the expression of wild-type PCP-2, PCP-2 ?C1C2 (deleted PCP-2 without both PTP domains) and PCP-2 ?C2 (deleted PCP-2 without the second PTP domain) could be immunoprecipitated by anti-catenin antibody in every co-transfection, but PCP-2 EXT (deleted PCP-2 without the juxtamembrane region and both PTP domains) was missing, which implied that PCP-2 and β-catenin could associate directly and the juxtamembrane region in PCP-2 was sufficient for the process.展开更多
In mammals,the growth and maturation of oocytes within growing follicles largely depends on ovarian granulosa cells(GCs)in response to gonadotropin stimulation.Many signals have been shown to regulate GC proliferation...In mammals,the growth and maturation of oocytes within growing follicles largely depends on ovarian granulosa cells(GCs)in response to gonadotropin stimulation.Many signals have been shown to regulate GC proliferation and apoptosis.However,whether the tyrosine phosphatase SHP2 is involved remains unclear.In this study,we identified the crucial roles of SHP2 in modulating GC proliferation and apoptosis.The production of both mature oocytes and pups was increased in mice with Shp2 specifically deleted in ovarian GCs via Fshr-Cre.Shp2 deletion simultaneously promoted GC proliferation and inhibited GC apoptosis.Furthermore,Shp2 deficiency promoted,while Shp2 overexpression inhibited,the proliferation of cultured primary mouse ovarian GCs and the human ovarian granulosa-like tumor cell line KGN in vitro.Shp2 deficiency promoted follicule-stimulating hormone(FSH)-activated phosphorylation of AKT in vivo.SHP2 deficiency reversed the inhibitory effect of hydrogen peroxide(H_(2)O_(2))on AKT activation in KGN cells.H_(2)O_(2) treatment promoted the interaction between SHP2 and the p85 subunit of PI3K in KGN cells.Therefore,SHP2 in GCs may act as a negative modulator to balance follicular development by suppressing PI3K/AKT signaling.The novel function of SHP2 in modulating proliferation and apoptosis of GCs provides a potential therapeutic target for the clinical treatment of follicle developmental dysfunction.展开更多
Background：Src homology 2 domain-containing protein tyrosine phosphatase-2 （SHP-2） is a kind of intracellular protein tyrosine phosphatase.Studies have revealed its roles in various disease,however,whether SHP-2 in...Background：Src homology 2 domain-containing protein tyrosine phosphatase-2 （SHP-2） is a kind of intracellular protein tyrosine phosphatase.Studies have revealed its roles in various disease,however,whether SHP-2 involves in renal fibrosis remains unclear.The aim of this study was to explore the roles of myeloid cells SHP-2 in renal interstitial fibrosis.Methods：Myeloid cells SHP-2 gene was conditionally knocked-out （CKO） in mice using loxP-Cre system,and renal interstitial fibrosis was induced by unilateral ureter obstruction （UUO）.The total collagen deposition in the renal interstitium was assessed using picrosirius red stain.F4/80 immunostaing was used to evaluate macrophage infiltration in renal tubular interstitium.Quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to analyze the production of cytokines in the kidney.Transferase-mediated dUTP nick-end labeling stain was used to assess the apoptotic renal tubular epithelial cells.Results：Src homology 2 domain-containing protein tyrosine phosphatase-2 gene CKO in myeloid cells significantly reduced collagen deposition in the renal interstitium after UUO.Macrophage infiltration was evidently decreased in renal tubular interstitium of SHP-2 CKO mice.Meanwhile,the production of pro-inflammatory cytokines was significantly suppressed in SHP-2 CKO mice.However,no significant difference was observed in the number of apoptotic renal tubular epithelial cells between wild-type and SHP-2 CKO mice.Conclusions：Our observations suggested that SHP-2 in myeloid cells plays a pivotal role in the pathogenesis of renal fibrosis,and that silencing of SHP-2 gene in myeloid cells may protect renal from inflammatory damage and prevent renal fibrosis after renal injury.展开更多
基金Supported by Grants from the Swiss National Science Foundation(SNF)to MSGrant No.314730-146204 and No.CRSII3_154488/1(to Rogler G)+2 种基金Grant No.310030-120312the Swiss IBD CohortGrant No.3347CO-108792
文摘Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.
基金Supported by National Natural Science Foundation of China,No. 81072369Natural Science Foundation of Jilin Province,China,No. 200905131
文摘AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled into this study.SHP-2 expression was carried out in 305 gastric cancer specimens,of which 83 were paired adjacent normal gastric mucus samples,using a tissue microarray immunohistochemical method.Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes.Serum anti-Helicobacter pylori(H.pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay.Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients.RESULTS:SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells.Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively(P < 0.001).Though SHP-2 staining intensities were stronger in the H.pylori(+) group than in the H.pylori(-) group,no statistically significant difference was found in the expression levels of SHP-2 between H.pylori(+) and H.pylori(-) gastric cancer(P = 0.40).The SHP-2 expression in gastric cancer was not significantly associated with cancer stages,lymph node metastases,and distant metastasis of the tumors(P = 0.34,P = 0.17,P = 0.52).Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival(P = 0.86).CONCLUSION:Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant upregulation of SHP-2 protein might play an important role in the gastric carcinogenesis.
基金Supported by the Natural Science Foundation of Guangxi Province(Nos.2013GXNSFAA019019 and 2013GXNSFAA019041)
文摘Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.
基金supported by the Natural Science Research Project of Anhui Province University, No.2023AH040394 (to TY)Hefei Comprehensive National Science Center Leading Medicine and Frontier Technology Research Institute Project, No.2023IHM01073 (to TY)the Natural Science Foundation of Anhui Province, Nos.2308085QH258 (to JW), 2008085MH246 (to TY)。
文摘Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.30270686 and 30370740)the Key Research Project(30110811 and 03DJ14007).
文摘PCP-2 is a member of receptor-like protein tyrosine phosphatase of the MAM do- main family. To investigate which part of PCP-2 was involved in its interaction with β-catenin, we constructed various deletion mutants of PCP-2. These PCP-2 mutants and wild-type PCP-2 were co-transfected into BHK-21 cells with β-catenin individually. An in vivo binding assay revealed that the expression of wild-type PCP-2, PCP-2 ?C1C2 (deleted PCP-2 without both PTP domains) and PCP-2 ?C2 (deleted PCP-2 without the second PTP domain) could be immunoprecipitated by anti-catenin antibody in every co-transfection, but PCP-2 EXT (deleted PCP-2 without the juxtamembrane region and both PTP domains) was missing, which implied that PCP-2 and β-catenin could associate directly and the juxtamembrane region in PCP-2 was sufficient for the process.
基金National Key Research and Development Program of China(2018YFC1003701 and 2017YFC1001402)National Natural Science Foundation of China(31970797 and 31671564).
文摘In mammals,the growth and maturation of oocytes within growing follicles largely depends on ovarian granulosa cells(GCs)in response to gonadotropin stimulation.Many signals have been shown to regulate GC proliferation and apoptosis.However,whether the tyrosine phosphatase SHP2 is involved remains unclear.In this study,we identified the crucial roles of SHP2 in modulating GC proliferation and apoptosis.The production of both mature oocytes and pups was increased in mice with Shp2 specifically deleted in ovarian GCs via Fshr-Cre.Shp2 deletion simultaneously promoted GC proliferation and inhibited GC apoptosis.Furthermore,Shp2 deficiency promoted,while Shp2 overexpression inhibited,the proliferation of cultured primary mouse ovarian GCs and the human ovarian granulosa-like tumor cell line KGN in vitro.Shp2 deficiency promoted follicule-stimulating hormone(FSH)-activated phosphorylation of AKT in vivo.SHP2 deficiency reversed the inhibitory effect of hydrogen peroxide(H_(2)O_(2))on AKT activation in KGN cells.H_(2)O_(2) treatment promoted the interaction between SHP2 and the p85 subunit of PI3K in KGN cells.Therefore,SHP2 in GCs may act as a negative modulator to balance follicular development by suppressing PI3K/AKT signaling.The novel function of SHP2 in modulating proliferation and apoptosis of GCs provides a potential therapeutic target for the clinical treatment of follicle developmental dysfunction.
基金grants from National Natural Science Foundation of China，National Natural Science Foundation of China for Youths，Shanghai Committee of Science and Technology General Program for Medicine，Key Project of Science and Innovation Foundation of Shanghai Ministry of Education，Military Fund for Health Care （No.13BJZ29）.Conflict of Interest：None declared
文摘Background：Src homology 2 domain-containing protein tyrosine phosphatase-2 （SHP-2） is a kind of intracellular protein tyrosine phosphatase.Studies have revealed its roles in various disease,however,whether SHP-2 involves in renal fibrosis remains unclear.The aim of this study was to explore the roles of myeloid cells SHP-2 in renal interstitial fibrosis.Methods：Myeloid cells SHP-2 gene was conditionally knocked-out （CKO） in mice using loxP-Cre system,and renal interstitial fibrosis was induced by unilateral ureter obstruction （UUO）.The total collagen deposition in the renal interstitium was assessed using picrosirius red stain.F4/80 immunostaing was used to evaluate macrophage infiltration in renal tubular interstitium.Quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to analyze the production of cytokines in the kidney.Transferase-mediated dUTP nick-end labeling stain was used to assess the apoptotic renal tubular epithelial cells.Results：Src homology 2 domain-containing protein tyrosine phosphatase-2 gene CKO in myeloid cells significantly reduced collagen deposition in the renal interstitium after UUO.Macrophage infiltration was evidently decreased in renal tubular interstitium of SHP-2 CKO mice.Meanwhile,the production of pro-inflammatory cytokines was significantly suppressed in SHP-2 CKO mice.However,no significant difference was observed in the number of apoptotic renal tubular epithelial cells between wild-type and SHP-2 CKO mice.Conclusions：Our observations suggested that SHP-2 in myeloid cells plays a pivotal role in the pathogenesis of renal fibrosis,and that silencing of SHP-2 gene in myeloid cells may protect renal from inflammatory damage and prevent renal fibrosis after renal injury.
