BACKGROUND IL-22 plays a pivotal role in the processes of inflammation and tissue healing.,but its role in cholangiocarcinoma(CCA)remains unclear.our study explored the IL-22/IL-22R1 pathway and its impact on CCA prog...BACKGROUND IL-22 plays a pivotal role in the processes of inflammation and tissue healing.,but its role in cholangiocarcinoma(CCA)remains unclear.our study explored the IL-22/IL-22R1 pathway and its impact on CCA progression through the ERK1/2 signaling cascade.AIM To determine the mechanism of the IL-22/IL-22R1 pathway in CCA and provide new directions for its clinical treatment.METHODS IL-22R1 expression was assessed in human and rat CCA tissues utilizing immunohistochemical techniques,Western blot analysis,and quantitative reverse transcription PCR.The impact of IL-22 on CCA cells was assessed in vitro via tests for proliferation,migration,invasion,and apoptosis assays.The rat models of thioacetamide-induced CCA and subcutaneous xenografts in nude mice were used to assess the in vivo effects.ERK1/2 inhibitors were applied to elucidate the mechanistic role of the pathway.RESULTS IL-22R1 was overexpressed in CCA cell lines and tissues.IL-22 treatment increased the phosphorylation of ERK1/2,promoting tumor cell proliferation,migration,invasion,and resistance to apoptosis.ERK1/2 inhibition considerably reversed these effects both in vitro and in vivo.CONCLUSION The IL-22/IL-22R1 axis promotes CCA progression by activating ERK1/2 signaling.Targeting this pathway with ERK1/2 inhibitors offers potential therapeutic strategies for CCA.展开更多
Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substanti...Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.展开更多
基金National Natural Science Foundation of China,No.82372194.
文摘BACKGROUND IL-22 plays a pivotal role in the processes of inflammation and tissue healing.,but its role in cholangiocarcinoma(CCA)remains unclear.our study explored the IL-22/IL-22R1 pathway and its impact on CCA progression through the ERK1/2 signaling cascade.AIM To determine the mechanism of the IL-22/IL-22R1 pathway in CCA and provide new directions for its clinical treatment.METHODS IL-22R1 expression was assessed in human and rat CCA tissues utilizing immunohistochemical techniques,Western blot analysis,and quantitative reverse transcription PCR.The impact of IL-22 on CCA cells was assessed in vitro via tests for proliferation,migration,invasion,and apoptosis assays.The rat models of thioacetamide-induced CCA and subcutaneous xenografts in nude mice were used to assess the in vivo effects.ERK1/2 inhibitors were applied to elucidate the mechanistic role of the pathway.RESULTS IL-22R1 was overexpressed in CCA cell lines and tissues.IL-22 treatment increased the phosphorylation of ERK1/2,promoting tumor cell proliferation,migration,invasion,and resistance to apoptosis.ERK1/2 inhibition considerably reversed these effects both in vitro and in vivo.CONCLUSION The IL-22/IL-22R1 axis promotes CCA progression by activating ERK1/2 signaling.Targeting this pathway with ERK1/2 inhibitors offers potential therapeutic strategies for CCA.
基金the Major Special Project of Jiangsu Administration of Traditional Chinese Medicine(Project No.ZT202116)the Key R&D Project of Jiangsu Province(Project No.BE2020727)+2 种基金the Yangzhou Science and Technology Program(Project No.YZ2021062,YZ2024143 and YZ2024194)the Third Batch of Academic Mentorship Program for Senior TCM Experts in Jiangsu Province(Project No.2019028)the 2023 Jiangsu Pharmaceutical Association–Aosaikang Hospital Pharmacy Research Project(Project No.A202333).
文摘Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.
