The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains chall...The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.展开更多
The therapeutic outcomes of conventional oral medications against ulcerative colitis(UC)are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment...The therapeutic outcomes of conventional oral medications against ulcerative colitis(UC)are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment.Herein,a fluorinated pluronic(FP127)was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles(MLNs)loading with resveratrol nanocrystals(RNs).The obtained FP127@RN-MLNs possessed exosome-like morphologies,desirable particle sizes(around 171.4 nm),and negatively charged surfaces(−14.8 mV).The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect.展开更多
CONSPECTUS:Interventional fluorescence imaging has gradually developed into a promising imaging strategy for the diagnosis of diseases in clinic.This strategy could benefit interventional targeted treatment because of...CONSPECTUS:Interventional fluorescence imaging has gradually developed into a promising imaging strategy for the diagnosis of diseases in clinic.This strategy could benefit interventional targeted treatment because of the clear display of microstructures at the margins and boundaries.There are some stranded crucial issues in clinical application:(i)fast clearance of fluorescence probes;(ii)light instability and photobleaching;and(iii)residual and microsatellite lesions.The development of superstable homoge-neous intermixed formulation technology(SHIFT)can solve the aforementioned clinical problems for precision hepatectomy.Interventional fluorescence imaging based on SHIFT-prepared product has some advantages such as(i)strong stability,(ii)greatly extending imageable time window,and(iii)precisely visualizing microsatellite lesions.In this Account,we overview our current progress in interventional fluorescence imaging based on SHIFT method for surgical resection following long-lasting embolization conversion.To greatly realize interventional fluorescence imaging,we summarize clinical and preclinical application of interventional fluorescence imaging in a transarterial delivery system.Indeed,compared with conventional fluorescence imaging,interventional fluorescence imaging possesses non-negligible strengths on improved intensity in target location and step-down systemic toxicity.Unfortunately,a challenging issue is that immobile fluorescence performance is difficult to maintain after long-time embolization,resulting in a failed hepatectomy.On this basis,associated with our previous research,SHIFT was proposed and developed.Thus,we detailedly introduce and account the development and preponderance of SHIFT on interventional fluorescence imaging.Predictably,after lengthy embolization,its lightful fluorescence was still observable in tumor targets of a clinical trial.To regulate the fluorescence rendering of microsatellite lesion,SHIFT combining with pure nanoprobes(nanoICG)occurs,namely SHIFT nanoICG,and we dwell on its performance in transarterial invasive surgical navigation and its clinical application under interventional fluorescence imaging compared with conventional indocyanine green(ICG)formulations.Amazingly,the SHIFT nanoICG brings us an extraordinary imaging consequence for deep-seated tumor tissues and imperceptible microsatellite lesions.Finally,we offer perspectives on the future tendency of interventional imaging-guided SHIFT products in clinical translation such as chemoembolization,radioembolization,and immunotherapy.Actually,these directions have been underway for some time,and even relative products are already applied for clinical trials,exhibiting effective therapeutic outcomes.Our green high-performance SHIFT products are concentrated on meeting clinical needs and solving clinical problems,breaking through the cure limitations of patients with advanced diseases.Thus,the discovery offers insight into the development and superiority of SHIFT products under interventional fluorescence imaging and simultaneously provides a new view on the development of clinically pragmatic products.展开更多
As one of the vital tectonic units of the Wulian Metamorphic Core Complex(MCC), the Wulian detachment fault zone(WDFZ), which developed in the Jiaodong peninsula, separates the lower plate of the ultrahigh pressure(UH...As one of the vital tectonic units of the Wulian Metamorphic Core Complex(MCC), the Wulian detachment fault zone(WDFZ), which developed in the Jiaodong peninsula, separates the lower plate of the ultrahigh pressure(UHP) metamorphic rocks in the Sulu orogenic belt from the upper plate of the early Cretaceous Zhucheng basin and the basin basement. The fault zone generally strikes NNE with a dip in the west along the southern portion of the MCC and strikes NE with a dip in the WNWalong the northern portion. The fault zone displays a wavy-tile-shaped extension on the plane, principally composed of the fault breccias and mylonite and transits downward to the mylonitic gneiss. As a whole, the detachment fault zone shows a top-towest or a WNW extension. By calculating the harmonic mean, we obtain a Flynn index K of 0.98–2.0, and the mean value is approximately 1.35 in the fault zone. According to the polar Mohr construction, the extensional crenulation cleavage, the RS/θ,and the quartz C-axial fabric methods, we acquire mean kinematic vorticity values of 0.64–0.97, 0.76–0.93, 0.6–0.92, and 0.63–0.98 with mean values of 0.83, 0.80, 0.78 and 0.86, respectively, for mylonite and promylonite. The strain measurement results and the kinematic vorticity values indicate that the WDFZ is a normal ductile shear zone developed in the extensional setting.The kinematic track shows that the kinematic vorticity value decreases gradually from the NW to the SE as a whole. A simple shear dominates in the middle and upper parts of the shear zone, which is reflected by a higher vorticity value(>0.75, up to 0.98),a low thinning rate and a lower K value. In contrast, toward the footwall, the pure shear is increased significantly, showing a lower vorticity value(<0.70, low to 0.64), a relatively high thinning rate and a higher K value. Combined with the geotectonic background, the development and evolution of the WDFZ should respond to lithospheric thinning and the destruction of the North China Craton(NCC). As a result, the WDFZ can be defined as a thinning normal shear zone developed in the extension tectonic setting and the combined result of the simple shear caused by the crust extension and pure shear led by the rapid uplift of the footwall and magmatic upwelling.展开更多
The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death(ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumo...The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death(ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment(ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin(DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels(DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful antitumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.展开更多
基金supported by the National Natural Science Foundation of China(82072060,82360110,and 22008201)the Fundamental Research Funds for the Central Universities(SWU-XDPY22006,China)+2 种基金the Venture&Innovation Support Program for Chongqing Overseas Returnees(2205012980212766,China)the Distinguished Young Scholars of Chongqing(2022NSCQ-JQX5279,China)the Science and Technology Department of Jiangxi Province(20212BDH81019 and 20224BAB206073,China).
文摘The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.
基金the National Natural Science Foundation of China(82072060 and 22008201)the Fundamental Research Funds for the Central Universities(SWU-XDPY22006)+2 种基金the Venture&Innovation Support Program for Chongqing Overseas Returnees(2205012980212766)the Natural Science Foundation Project of Chongqing(cstc2020jcyj-msxmX0292)the Natural Science Foundation Project of Chongqing for Distinguished Young Scholar.
文摘The therapeutic outcomes of conventional oral medications against ulcerative colitis(UC)are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment.Herein,a fluorinated pluronic(FP127)was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles(MLNs)loading with resveratrol nanocrystals(RNs).The obtained FP127@RN-MLNs possessed exosome-like morphologies,desirable particle sizes(around 171.4 nm),and negatively charged surfaces(−14.8 mV).The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect.
基金supported by the Major State Basic Research Development Program of China(2017YFA0205201)the National Natural Science Foundation of China(81925019,81422023,and U1705281)+1 种基金the Fundamental Research Funds for the Central Universities(20720190088,20720200019,and 2020Y4003)the Program for New Century Excellent Talents in University,China(NCET-13-0502).
文摘CONSPECTUS:Interventional fluorescence imaging has gradually developed into a promising imaging strategy for the diagnosis of diseases in clinic.This strategy could benefit interventional targeted treatment because of the clear display of microstructures at the margins and boundaries.There are some stranded crucial issues in clinical application:(i)fast clearance of fluorescence probes;(ii)light instability and photobleaching;and(iii)residual and microsatellite lesions.The development of superstable homoge-neous intermixed formulation technology(SHIFT)can solve the aforementioned clinical problems for precision hepatectomy.Interventional fluorescence imaging based on SHIFT-prepared product has some advantages such as(i)strong stability,(ii)greatly extending imageable time window,and(iii)precisely visualizing microsatellite lesions.In this Account,we overview our current progress in interventional fluorescence imaging based on SHIFT method for surgical resection following long-lasting embolization conversion.To greatly realize interventional fluorescence imaging,we summarize clinical and preclinical application of interventional fluorescence imaging in a transarterial delivery system.Indeed,compared with conventional fluorescence imaging,interventional fluorescence imaging possesses non-negligible strengths on improved intensity in target location and step-down systemic toxicity.Unfortunately,a challenging issue is that immobile fluorescence performance is difficult to maintain after long-time embolization,resulting in a failed hepatectomy.On this basis,associated with our previous research,SHIFT was proposed and developed.Thus,we detailedly introduce and account the development and preponderance of SHIFT on interventional fluorescence imaging.Predictably,after lengthy embolization,its lightful fluorescence was still observable in tumor targets of a clinical trial.To regulate the fluorescence rendering of microsatellite lesion,SHIFT combining with pure nanoprobes(nanoICG)occurs,namely SHIFT nanoICG,and we dwell on its performance in transarterial invasive surgical navigation and its clinical application under interventional fluorescence imaging compared with conventional indocyanine green(ICG)formulations.Amazingly,the SHIFT nanoICG brings us an extraordinary imaging consequence for deep-seated tumor tissues and imperceptible microsatellite lesions.Finally,we offer perspectives on the future tendency of interventional imaging-guided SHIFT products in clinical translation such as chemoembolization,radioembolization,and immunotherapy.Actually,these directions have been underway for some time,and even relative products are already applied for clinical trials,exhibiting effective therapeutic outcomes.Our green high-performance SHIFT products are concentrated on meeting clinical needs and solving clinical problems,breaking through the cure limitations of patients with advanced diseases.Thus,the discovery offers insight into the development and superiority of SHIFT products under interventional fluorescence imaging and simultaneously provides a new view on the development of clinically pragmatic products.
基金supported by the National Natural Science Foundation of China (Grant No. 41172089)the Natural Science Foundation of Shandong Province (Grant Nos. ZR2018MD010, ZR2017PD001)Key R & D Plan of Shandong Province (Grant No. 2017CXGC1602)
文摘As one of the vital tectonic units of the Wulian Metamorphic Core Complex(MCC), the Wulian detachment fault zone(WDFZ), which developed in the Jiaodong peninsula, separates the lower plate of the ultrahigh pressure(UHP) metamorphic rocks in the Sulu orogenic belt from the upper plate of the early Cretaceous Zhucheng basin and the basin basement. The fault zone generally strikes NNE with a dip in the west along the southern portion of the MCC and strikes NE with a dip in the WNWalong the northern portion. The fault zone displays a wavy-tile-shaped extension on the plane, principally composed of the fault breccias and mylonite and transits downward to the mylonitic gneiss. As a whole, the detachment fault zone shows a top-towest or a WNW extension. By calculating the harmonic mean, we obtain a Flynn index K of 0.98–2.0, and the mean value is approximately 1.35 in the fault zone. According to the polar Mohr construction, the extensional crenulation cleavage, the RS/θ,and the quartz C-axial fabric methods, we acquire mean kinematic vorticity values of 0.64–0.97, 0.76–0.93, 0.6–0.92, and 0.63–0.98 with mean values of 0.83, 0.80, 0.78 and 0.86, respectively, for mylonite and promylonite. The strain measurement results and the kinematic vorticity values indicate that the WDFZ is a normal ductile shear zone developed in the extensional setting.The kinematic track shows that the kinematic vorticity value decreases gradually from the NW to the SE as a whole. A simple shear dominates in the middle and upper parts of the shear zone, which is reflected by a higher vorticity value(>0.75, up to 0.98),a low thinning rate and a lower K value. In contrast, toward the footwall, the pure shear is increased significantly, showing a lower vorticity value(<0.70, low to 0.64), a relatively high thinning rate and a higher K value. Combined with the geotectonic background, the development and evolution of the WDFZ should respond to lithospheric thinning and the destruction of the North China Craton(NCC). As a result, the WDFZ can be defined as a thinning normal shear zone developed in the extension tectonic setting and the combined result of the simple shear caused by the crust extension and pure shear led by the rapid uplift of the footwall and magmatic upwelling.
基金financially supported by National Natural Science Foundation of China(51703187,81874131,and 81672668)the Chongqing Talent Plan for Young Top Notch Talents(CQYC202005029,China)+2 种基金Major State Basic Research Development Program of China(2017YFA0205201 and 2018YFA0107301)National Key Research and Development Program(2017YFSF090107,China)the Hubei Province Natural Science Funds for Distinguished Young Scholar 2017CFA062。
文摘The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death(ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment(ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin(DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels(DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful antitumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.