Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to ...Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide (LPS). Methods Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin (5 and 20 mg/kg) for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases (MAPK) p38 in lung were detected by real-time polymerase chain reaction (PCR), immunohistochemistry or Western blotting. Tumor necrosis factor (TNF)-α and IL-8 in bronchoalveolar lavage fluid (BALF) were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay (ELISA). Results Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung (P 〈0.05). Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-α and IL-8 in BALF follows LPS stimulation (P 〈0.05). The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung (P 〈0.05). Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation (P 〈0.05). However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration. Conclusions Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.展开更多
Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearanc...Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearance, abnormal bacterial plantation, mucus plug in the airway, and dysfunction of gas exchange.5 To block this vicious cycle, chronic inflammation in the airway must be controlled and mucus hypersecretion must be reduced.展开更多
Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte ch...Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte chemotactic protein-inducing protein 1(MCPIP1)was a key negative regulator of inflammation.Recent studies showed that inflammation was largely suppressed by enhanced MCPIP1 expression in many inflammatory diseases.However,the role and potential mechanism of MCPIP1 in airway inflammation and mucus hypersecretion in asthma were still not well studied.This study was to explore the role of MCPIP1 in asthmatic airway inflammation and mucus hypersecretion in both mice and BEAS-2B cells,and its potential mechanism.Methods:In vivo,mice were sensitized and challenged by ovalbumin(OVA)to induce asthma.Airway inflammation and mucus secretion were analyzed.In vitro,BEAS-2B cells were chosen.Interleukin(IL)-13 was used to stimulate inflammation and mucus hypersecretion in cells.MCPIP1 Lentiviral vector(LA-MCPIP1)and plasmid-MCPIP1 were used to up-regulate MCPIP1 in lung and cells,respectively.MCP-1,thymic stromal lymphopoietin(TSLP),mucin 5AC(MUC5AC),MCPIP1,and GABAARβ2 expressions were measured in both lung and BEAS-2B cells.Immunofluorescence staining was performed to observe the expression of GABAARβ2 in cells.Results:MCPIP1 was up-regulated by LA-MCPIP1(P<0.001)and plasmid-MCPIP1(P<0.001)in lung and cells,respectively.OVA-induced airway inflammation and mucus hypersecretion,OVA-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and OVA-reduced MCPIP1 were significantly blunted by LA-MCPIP1 in mice(all P<0.001).IL-13-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and IL-13-reduced MCPIP1 were markedly abrogated by plasmid-MCPIP1 in BEAS-2B cells(all P<0.001).Conclusion:The results of this study suggested that OVA and IL-13-induced airway inflammation and mucus hypersecretion were negatively regulated by MCPIP1 in both lung and BEAS-2B cells,involving GABAAR signaling pathway.展开更多
Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway ...Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway from the cell surface to the nucleus through which cigarette smoke causes upregulation of mucin gene expression is not well known. This study was designed to investigate the role of extracellular signal-regulated Kinase 1/2 (ERK 1/2) in airway mucus hypersecretion induced by cigarette smoke in rats. Methods A rat model of airway mucus hypersecretion was induced by exposure to cigarette smoke for 4 weeks. Rats exposed to inhalation of cigarette smoke or normal saline were given an intraperitoneal injection of U0126, a specific MEK1 kinase inhibitor, at doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg for 14 days. Expression of MUC5AC mRNA and protein, ERK 1/2 and phosphorylated-ERK 1/2 (p-ERK 1/2) were detected by RT-PCR, immunohistochemistry and Western blotting. Results Cigarette smoke significantly increased airway goblet cells metaplasia, induced the overexpression of MUC5AC mRNA and protein in bronchial epithelia, and increased the ratio of p-ERK 1/2 and ERK 1/2. U0126 significantly attentuated the expression of MUC5AC mRNA and protein induced by cigarette smoke (P 〈0.05). Moreover, there was a significant positive correlation between the ratio of p-ERK1/2 to ERK1/2 and the expression of MUC5AC mRNA and protein (P 〈0.05). Conclusions Inhibition of ERK 1/2 by U0126 decreased the ratio of p-ERK 1/2 to ERK 1/2 and expression of MUC5AC mRNA and protein. ERK 1/2 may play an essential role in cigarette smoke-induced mucus hypersecretion in vivo.展开更多
Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critica...Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected.Immunohistochemistry and enzyme-linked immunosorbent assay were performed.NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected.Results:Compared to the healthy control group,the asthma group had significantly higher sputum MUC5A(20.12±5.07 versus 36.21±6.13)and NLRP3(72.31±15.13 versus 119.21±31.21)levels(P<0.05)but lower MUC5B levels(1.35±0.12 versus 0.53±0.11,P<0.05).Immunohistochemistry showed that NLRP3,MUC5AC,and MUC5B expressions were consistent with the sputum results.Conclusion:NLRP3 and MUC5AC levels are significantly increased in asthmatic patients,whereas MUC5B levels are reduced in these patients.They can be used as targets for the diagnosis and treatment of asthma.展开更多
Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patie...Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patients with acute exacerbation of COPD,and to observe its effect on lung function(FEV1,FEV1/FVC),so as to provide new ideas and theoretical basis for the prevention and treatment of COPD.Methods:160 patients with acute exacerbation of COPD were randomly divided into observation group and control group with 80 cases each according to the numerical table method.The observation group was treated with aerosol inhalation of Elephantopus scaber Linn on the basis of conventional treatment.Both groups were treated for 2 weeks.During the same period,80 healthy patients were selected as the healthy control group.The expression of NE and MUC5AC in serum of observation group,control group and healthy control group before and after treatment was detected by enzymelinked immunosorbent assay(ELISA).The changes of lung function(FEV1,FEV1/FVC)after treatment in the observation group and the control group were compared and analyzed,and the efficacy of Elephantopus scaber Linn in patients with acute exacerbation of copd was observed.Results:Compared with the control group,the total effective rate of the observation group was significantly better than that of the control group,with statistical significance(P<0.05).Compared with the healthy control group,there were significant differences in serum NE and MUC5AC between the observation group and the control group(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Compared with the control group after treatment,there were significant differences in serum NE and MUC5AC in the observation group after treatment(P<0.05),and the increase of FEV1/FVC and FEV1 was significantly better than that of the control group after treatment(P<0.05).Conclusion:Elephantopus scaber Linn can significantly improve the clinical treatment effect of patients with acute exacerbation of COPD,improve lung function and airway mucus hypersecretion.It can effectively inhibit the expression of NE and MUC5AC in the blood.There were significant differences in serum NE and MUC5AC between the observation group and the control group after treatment(P<0.05),showing a positive correlation,suggesting that inhibition of MUC5AC secretion by Elephantopus scaber Linn in patients with COPD may be related to NE-mediated pathways.展开更多
Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined....Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.展开更多
Background Chronic obstructive pulmonary disease (COPD) is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha (TNF-α...Background Chronic obstructive pulmonary disease (COPD) is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha (TNF-α) is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-α converting enzyme (TACE) is involved in the activation of both TNF-α and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-α and ErbB3 and to explore the correlations among TACE,TNF-α and ErbB3 respectively. Methods Thirty Wistar male rats were randomly divided into COPD group (group C, n=10), saline solution parallel group (group P, n=-8), and normal control group (group N, n=-8). Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-α and ErbB3 in lungs of all rats were determined histochemically. Results The expressions of TACE, TNF-α and ErbB3 were significantly higher in group C than in group N (P〈0.01). The contents of TNF-α in serum (P〈0.01) and bronchoalveolar lavage fluid (BALF) (P〈0.01) were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-α (r=0.784, P〈0.01) and between TACE and ErbB3 (r=0.526, P〈0.01) respectively. Conclusions TNF-α and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-α and ErbB3.展开更多
基金This study was supported by grants from National Natural Science Foundation of China to Dr. WEN Fu-qing (No. 30425007, 30370627, 30670921) and from China Medical Board of New York to Dr. WEN Fu-qiang (No. 0-722).
文摘Background Mucus hypersecretion in the respiratory tract and goblet cell metaplasia in the airway epithelium contribute to the morbidity and mortality associated with airway inflammatory diseases. This study aimed to examine the effect and mechanisms of simvastatin on airway mucus hypersecretion in rats treated with lipopolysaccharide (LPS). Methods Mucus hypersecretion in rat airways was induced by intra-tracheal instillation of LPS. Rats treated with or without LPS were administered intra-peritoneally simvastatin (5 and 20 mg/kg) for 4 days. Expression of Muc5ac, RhoA and mitogen-activated protein kinases (MAPK) p38 in lung were detected by real-time polymerase chain reaction (PCR), immunohistochemistry or Western blotting. Tumor necrosis factor (TNF)-α and IL-8 in bronchoalveolar lavage fluid (BALF) were assayed by an enzyme-linked lectin assay and enzyme linked immunosorbent assay (ELISA). Results Simvastatin attenuated LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5ac hypersecretion at both the gene and protein levels in lung (P 〈0.05). Moreover, simvastatin inhibited neutrophil accumulation and the increased concentration of TNF-α and IL-8 in BALF follows LPS stimulation (P 〈0.05). The higher dose of simvastatin was associated with a more significant reduction in Muc5ac mRNA expression, neutrophil accumulation and inflammatory cytokine release. Simultaneously, the increased expression of RhoA and p38 MAPK were observed in LPS-treated lung (P 〈0.05). Simvastatin inhibited the expression of RhoA and p38 phosphorylation in lung following LPS stimulation (P 〈0.05). However, the increased expression of p38 protein in LPS-treated lung was not affected by simvastatin administration. Conclusions Simvastatin attenuates airway mucus hypersecretion and pulmonary inflammatory damage induced by LPS. The inhibitory effect of simvastatin on airway mucus hypersecretion may be through, at least in part, the suppression of neutrophil accumulation and inflammatory cytokine release via inactivation of RhoA and p38 signaling pathway.
基金This study was supported by the grants from National Natural Science Foundation of China and China Medical Board of New York to Dr. Wen (No. 30425007, 30370627, 00-722, 00-384).
文摘Mucus hypersecretion is a distinguishing feature of chronic inflammation diseases, such as asthma,chronic bronchitis, bronchiectasis and cystic fibrosis Mucus hypersecretion leads to impairment of mucociliary clearance, abnormal bacterial plantation, mucus plug in the airway, and dysfunction of gas exchange.5 To block this vicious cycle, chronic inflammation in the airway must be controlled and mucus hypersecretion must be reduced.
基金supported by grants from the National Natural Science Foundation of China for Young Scholar(No.81801484)China Postdoctoral Science Foundation(No.2014M552369)+1 种基金Natural Science Foundation of Guangdong Province(No.2017A030310286)Scientific Research Project of Guangzhou(No.201707010282)。
文摘Background:Mounting evidence,consistent with our previous study,showed thatγ-aminobutyric acid type A receptor(GABAAR)played an indispensable role in airway inflammation and mucus hypersecretion in asthma.Monocyte chemotactic protein-inducing protein 1(MCPIP1)was a key negative regulator of inflammation.Recent studies showed that inflammation was largely suppressed by enhanced MCPIP1 expression in many inflammatory diseases.However,the role and potential mechanism of MCPIP1 in airway inflammation and mucus hypersecretion in asthma were still not well studied.This study was to explore the role of MCPIP1 in asthmatic airway inflammation and mucus hypersecretion in both mice and BEAS-2B cells,and its potential mechanism.Methods:In vivo,mice were sensitized and challenged by ovalbumin(OVA)to induce asthma.Airway inflammation and mucus secretion were analyzed.In vitro,BEAS-2B cells were chosen.Interleukin(IL)-13 was used to stimulate inflammation and mucus hypersecretion in cells.MCPIP1 Lentiviral vector(LA-MCPIP1)and plasmid-MCPIP1 were used to up-regulate MCPIP1 in lung and cells,respectively.MCP-1,thymic stromal lymphopoietin(TSLP),mucin 5AC(MUC5AC),MCPIP1,and GABAARβ2 expressions were measured in both lung and BEAS-2B cells.Immunofluorescence staining was performed to observe the expression of GABAARβ2 in cells.Results:MCPIP1 was up-regulated by LA-MCPIP1(P<0.001)and plasmid-MCPIP1(P<0.001)in lung and cells,respectively.OVA-induced airway inflammation and mucus hypersecretion,OVA-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and OVA-reduced MCPIP1 were significantly blunted by LA-MCPIP1 in mice(all P<0.001).IL-13-enhanced MCP-1,TSLP,MUC5AC,and GABAARβ2 expressions,and IL-13-reduced MCPIP1 were markedly abrogated by plasmid-MCPIP1 in BEAS-2B cells(all P<0.001).Conclusion:The results of this study suggested that OVA and IL-13-induced airway inflammation and mucus hypersecretion were negatively regulated by MCPIP1 in both lung and BEAS-2B cells,involving GABAAR signaling pathway.
基金This study was supported by a grant from China Postdoctoral Science Foundation (No. 37508).
文摘Background Airway mucus hypersecretion is an important pathophysiological feature of chronic obstructive pulmonary disease, which is closely associated with cigarette smoking. However, the signal transduction pathway from the cell surface to the nucleus through which cigarette smoke causes upregulation of mucin gene expression is not well known. This study was designed to investigate the role of extracellular signal-regulated Kinase 1/2 (ERK 1/2) in airway mucus hypersecretion induced by cigarette smoke in rats. Methods A rat model of airway mucus hypersecretion was induced by exposure to cigarette smoke for 4 weeks. Rats exposed to inhalation of cigarette smoke or normal saline were given an intraperitoneal injection of U0126, a specific MEK1 kinase inhibitor, at doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg for 14 days. Expression of MUC5AC mRNA and protein, ERK 1/2 and phosphorylated-ERK 1/2 (p-ERK 1/2) were detected by RT-PCR, immunohistochemistry and Western blotting. Results Cigarette smoke significantly increased airway goblet cells metaplasia, induced the overexpression of MUC5AC mRNA and protein in bronchial epithelia, and increased the ratio of p-ERK 1/2 and ERK 1/2. U0126 significantly attentuated the expression of MUC5AC mRNA and protein induced by cigarette smoke (P 〈0.05). Moreover, there was a significant positive correlation between the ratio of p-ERK1/2 to ERK1/2 and the expression of MUC5AC mRNA and protein (P 〈0.05). Conclusions Inhibition of ERK 1/2 by U0126 decreased the ratio of p-ERK 1/2 to ERK 1/2 and expression of MUC5AC mRNA and protein. ERK 1/2 may play an essential role in cigarette smoke-induced mucus hypersecretion in vivo.
基金This work was supported by Xi’an Science and Technology Plan Project(22YXYJ0136).
文摘Objective:To explore the role of NLRP3 in mucus hypersecretion in asthmatic patients.Methods:From January 2020 to June 2022,90 patients with asthma and 60 healthy patients under the Department of Pulmonary and Critical Care Medicine of the First Affiliated Hospital of Xi’an Medical University were selected.Immunohistochemistry and enzyme-linked immunosorbent assay were performed.NLRP3 inflammasome and mucins MUC5AC and MUC5B levels in lung tissue and sputum were detected.Results:Compared to the healthy control group,the asthma group had significantly higher sputum MUC5A(20.12±5.07 versus 36.21±6.13)and NLRP3(72.31±15.13 versus 119.21±31.21)levels(P<0.05)but lower MUC5B levels(1.35±0.12 versus 0.53±0.11,P<0.05).Immunohistochemistry showed that NLRP3,MUC5AC,and MUC5B expressions were consistent with the sputum results.Conclusion:NLRP3 and MUC5AC levels are significantly increased in asthmatic patients,whereas MUC5B levels are reduced in these patients.They can be used as targets for the diagnosis and treatment of asthma.
基金National Natural Science Foundation of China(No.81660010,31660329,8191101552)。
文摘Objective:To observe the effect of Elephantopus scaber Linn on chronic obstructive pulmonary disease(COPD),to investigate its effect on the MUC5AC hypersecretion of airway mucus mediated by neutrophil elastin in patients with acute exacerbation of COPD,and to observe its effect on lung function(FEV1,FEV1/FVC),so as to provide new ideas and theoretical basis for the prevention and treatment of COPD.Methods:160 patients with acute exacerbation of COPD were randomly divided into observation group and control group with 80 cases each according to the numerical table method.The observation group was treated with aerosol inhalation of Elephantopus scaber Linn on the basis of conventional treatment.Both groups were treated for 2 weeks.During the same period,80 healthy patients were selected as the healthy control group.The expression of NE and MUC5AC in serum of observation group,control group and healthy control group before and after treatment was detected by enzymelinked immunosorbent assay(ELISA).The changes of lung function(FEV1,FEV1/FVC)after treatment in the observation group and the control group were compared and analyzed,and the efficacy of Elephantopus scaber Linn in patients with acute exacerbation of copd was observed.Results:Compared with the control group,the total effective rate of the observation group was significantly better than that of the control group,with statistical significance(P<0.05).Compared with the healthy control group,there were significant differences in serum NE and MUC5AC between the observation group and the control group(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Serum NE,MUC5AC,FEV1 and FEV1/FVC were significantly different in the observation group before and after treatment(P<0.05).Compared with the control group after treatment,there were significant differences in serum NE and MUC5AC in the observation group after treatment(P<0.05),and the increase of FEV1/FVC and FEV1 was significantly better than that of the control group after treatment(P<0.05).Conclusion:Elephantopus scaber Linn can significantly improve the clinical treatment effect of patients with acute exacerbation of COPD,improve lung function and airway mucus hypersecretion.It can effectively inhibit the expression of NE and MUC5AC in the blood.There were significant differences in serum NE and MUC5AC between the observation group and the control group after treatment(P<0.05),showing a positive correlation,suggesting that inhibition of MUC5AC secretion by Elephantopus scaber Linn in patients with COPD may be related to NE-mediated pathways.
基金supported by research grants from the National Natural Science Foundation of China(81420108007 and 81830024 to X.H.,82270844,82070843,and 81870531 to Y.Zhu).
文摘Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
文摘Background Chronic obstructive pulmonary disease (COPD) is associated not only with airway inflammation characterized by mucin hypersecretion but also with systemic inflammation. Tumor necrosis factor alpha (TNF-α) is found to take part in systemic inflammation, and ErbB3 plays an important role in mucin hypersecretion of COPD. Since TNF-α converting enzyme (TACE) is involved in the activation of both TNF-α and ErbB3, we established rat models of COPD to investigate the expressions of TACE, TNF-α and ErbB3 and to explore the correlations among TACE,TNF-α and ErbB3 respectively. Methods Thirty Wistar male rats were randomly divided into COPD group (group C, n=10), saline solution parallel group (group P, n=-8), and normal control group (group N, n=-8). Group C was challenged with passive cigarette smoking and intratracheal instillation of lipopolysaccharide. Six weeks later pulmonary functions were tested, bronchoalveolar fluid and arterial blood gases were assayed, and histopathological evaluations were performed in turn. The expressions of TACE, TNF-α and ErbB3 in lungs of all rats were determined histochemically. Results The expressions of TACE, TNF-α and ErbB3 were significantly higher in group C than in group N (P〈0.01). The contents of TNF-α in serum (P〈0.01) and bronchoalveolar lavage fluid (BALF) (P〈0.01) were elevated more significantly in group C than in group N. A positive correlation existed between TACE and TNF-α (r=0.784, P〈0.01) and between TACE and ErbB3 (r=0.526, P〈0.01) respectively. Conclusions TNF-α and ErbB3 are involved in the pathogenesis of COPD. TACE contributes to the progress of COPD indirectly through the function of TNF-α and ErbB3.