Excess water production has become an important issue in the oil and gas extraction process.Preformed particle gels(PPGs),show the capability to control the conformance and reduce excess water cut.However,conventional...Excess water production has become an important issue in the oil and gas extraction process.Preformed particle gels(PPGs),show the capability to control the conformance and reduce excess water cut.However,conventional PPGs have poor mechanical properties and their swollen particles are easily damaged by shearing force when passing through the fractures in formations,meanwhile PPGs can be also degraded into various byproducts,leading to permanent damage to the reservoir permeability after temporary plugging.Herein,a novel type of dual cross-linked PPGs(dPPGs)was designed and synthesized using sodium alginate(SA)and acrylamide(AAm),cross-linked with N,N’-methylenebisacrylamide(MBA)and Fe^(3+).Results show that dPPGs have excellent mechanical properties with a storage modulus up to 86,445 Pa,which is almost 20 times higher than other reported PPGs.Meanwhile,dPPGs can be completely degraded into liquid without any solid residues or byproducts and the viscosity of dPPGs degraded liquid was found to be lower than 5 mPa·s.A laboratory coreflooding test showed that the plugging efficiency of dPPGs was up to 99.83%on open fractures.The obtained results demonstrated that dPPGs could be used as economical and environment-friendly temporary plugging agent with high-strength,self-degradation,thermal stability,and salt stability,thus making it applicable to a wide range of conformance control to enhance oil recovery.展开更多
Tailored lipid nanoparticles(LNPs)-mediated small interfering RNA(siRNA)nanomedicines show promise in treating liver disease,such as acute liver injury(ALI)and non-alcoholic steatohepatitis(NASH).However,constructing ...Tailored lipid nanoparticles(LNPs)-mediated small interfering RNA(siRNA)nanomedicines show promise in treating liver disease,such as acute liver injury(ALI)and non-alcoholic steatohepatitis(NASH).However,constructing LNPs that address biosafety concerns,ensure efficient delivery,and target specific hepatic subcellular fractions has been challenging.To evade above obstacles,we develop three novel self-degradable“gemini-like”ionizable lipids(SS-MA,SS-DC,SS-MH)by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head.Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release,improving both biosafety and siRNA delivery efficiency.Furthermore,the distance of ester bond and tertiary amino head significantly influences the LNPs’pKa,thereby affecting endosomal escape,hemolytic efficiency,absorption capacity of ApoE,uptake efficiency of hepatocytes and liver accumulation.We also develop the modified-mannose LNPs(M-LNP)to target liver macrophages specifically.The optimized M-MH_LNP@TNFa exhibits potential in preventing ALI by decreasing tumor necrosis factor a(TNFa)levels in the macrophages,while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2(DGAT2)in the hepatocytes.Our findings provide new insights into developing novel highly effective and low-toxic“gemini-like”ionizable lipids for constructing LNPs,potentially achieving more effective treatment for hepatic diseases.展开更多
Autophagy is a physiological mechanism in which cells degrade themselves and quickly recover the degraded cell components.Recent studies have shown that autophagy plays an important role in the occurrence,development,...Autophagy is a physiological mechanism in which cells degrade themselves and quickly recover the degraded cell components.Recent studies have shown that autophagy plays an important role in the occurrence,development,treatment,and prognosis of colorectal cancer.In the early stages of colorectal cancer,autophagy can inhibit the production and development of tumors through multiple mechanisms such as maintaining DNA stability,inducing tumor death,and enhancing immune surveillance.However,as colorectal cancer progresses,autophagy may mediate tumor resistance,enhance tumor metabolism,and other pathways to promote tumor development.Therefore,intervening in autophagy at the appropriate time has broad clinical application prospects.This article summarizes the recent research progress of autophagy and colorectal cancer and is expected to provide new theoretical basis and reference for clinical treatment of colorectal cancer.展开更多
The dose-related adverse effects of MDM2-P5 3 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective ...The dose-related adverse effects of MDM2-P5 3 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2-P53 interaction.The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53.The new homo-PROTACs are designed to induce self-degradation of MDM2.The results of the investigation have shown that PROTAC 11 a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells.Furthermore,markedly,enantiomer 11 a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model,which is the first example of homo-PROTAC with in vivo therapeutic potency.This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown,which could be developed into a safe therapy for cancer treatment.展开更多
基金supported by Shanxi Provincial Key Research and Development Project(No.20201102002)the Science Foundation of China University of Petroleum,Beijing(No.2462020BJRC007,2462020YXZZ003)State Key Laboratory of Petroleum Resources and Prospecting,China University of Petroleum(No.PRP/DX-2216)
文摘Excess water production has become an important issue in the oil and gas extraction process.Preformed particle gels(PPGs),show the capability to control the conformance and reduce excess water cut.However,conventional PPGs have poor mechanical properties and their swollen particles are easily damaged by shearing force when passing through the fractures in formations,meanwhile PPGs can be also degraded into various byproducts,leading to permanent damage to the reservoir permeability after temporary plugging.Herein,a novel type of dual cross-linked PPGs(dPPGs)was designed and synthesized using sodium alginate(SA)and acrylamide(AAm),cross-linked with N,N’-methylenebisacrylamide(MBA)and Fe^(3+).Results show that dPPGs have excellent mechanical properties with a storage modulus up to 86,445 Pa,which is almost 20 times higher than other reported PPGs.Meanwhile,dPPGs can be completely degraded into liquid without any solid residues or byproducts and the viscosity of dPPGs degraded liquid was found to be lower than 5 mPa·s.A laboratory coreflooding test showed that the plugging efficiency of dPPGs was up to 99.83%on open fractures.The obtained results demonstrated that dPPGs could be used as economical and environment-friendly temporary plugging agent with high-strength,self-degradation,thermal stability,and salt stability,thus making it applicable to a wide range of conformance control to enhance oil recovery.
基金supported by National Key R&D Program of China(2021YFA0909900)Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education(TMIT2024Y01,China)+4 种基金Liaoning Province Applied Basic Research Program(2022JH2/101300097,China)Liaoning Province Department of Education Project(LJKMZ20221365,China)National Postdoctoral Foundation of China(2023M730375)Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20240050,China)Outstanding youth fund of Shenyang Pharmaceutical University(YQ202208,China).
文摘Tailored lipid nanoparticles(LNPs)-mediated small interfering RNA(siRNA)nanomedicines show promise in treating liver disease,such as acute liver injury(ALI)and non-alcoholic steatohepatitis(NASH).However,constructing LNPs that address biosafety concerns,ensure efficient delivery,and target specific hepatic subcellular fractions has been challenging.To evade above obstacles,we develop three novel self-degradable“gemini-like”ionizable lipids(SS-MA,SS-DC,SS-MH)by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head.Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release,improving both biosafety and siRNA delivery efficiency.Furthermore,the distance of ester bond and tertiary amino head significantly influences the LNPs’pKa,thereby affecting endosomal escape,hemolytic efficiency,absorption capacity of ApoE,uptake efficiency of hepatocytes and liver accumulation.We also develop the modified-mannose LNPs(M-LNP)to target liver macrophages specifically.The optimized M-MH_LNP@TNFa exhibits potential in preventing ALI by decreasing tumor necrosis factor a(TNFa)levels in the macrophages,while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2(DGAT2)in the hepatocytes.Our findings provide new insights into developing novel highly effective and low-toxic“gemini-like”ionizable lipids for constructing LNPs,potentially achieving more effective treatment for hepatic diseases.
文摘Autophagy is a physiological mechanism in which cells degrade themselves and quickly recover the degraded cell components.Recent studies have shown that autophagy plays an important role in the occurrence,development,treatment,and prognosis of colorectal cancer.In the early stages of colorectal cancer,autophagy can inhibit the production and development of tumors through multiple mechanisms such as maintaining DNA stability,inducing tumor death,and enhancing immune surveillance.However,as colorectal cancer progresses,autophagy may mediate tumor resistance,enhance tumor metabolism,and other pathways to promote tumor development.Therefore,intervening in autophagy at the appropriate time has broad clinical application prospects.This article summarizes the recent research progress of autophagy and colorectal cancer and is expected to provide new theoretical basis and reference for clinical treatment of colorectal cancer.
基金supported by National Natural Science Foundation of China (Grant Nos. 82030105, 21738002 and 21807113)the National Key R&D Program of China (Grant No. 2020YFA0509100)the Innovation Program of Shanghai Municipal Education Commission (Grant No. 2019-01-07-00-07E00073, China)。
文摘The dose-related adverse effects of MDM2-P5 3 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2-P53 interaction.The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53.The new homo-PROTACs are designed to induce self-degradation of MDM2.The results of the investigation have shown that PROTAC 11 a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells.Furthermore,markedly,enantiomer 11 a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model,which is the first example of homo-PROTAC with in vivo therapeutic potency.This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown,which could be developed into a safe therapy for cancer treatment.
