A rotary sealing device that automatically compensates for wear is designed to address the issues of easy wear and the short service life of the rotary sealing device with automatic wear compensation in mining machine...A rotary sealing device that automatically compensates for wear is designed to address the issues of easy wear and the short service life of the rotary sealing device with automatic wear compensation in mining machinery.After the end face of the guide sleeve wears out,it still tightly adheres to the sealing valve seat under the pressure difference,achieving automatic wear compensation.Based on fluid-solid coupling technology,the structural strength of the rotary sealing device was checked.The influence of factors on the sealing performance of rotary sealing devices was studied using the control variable method.The results show that as the pressure of water increases,the leakage rate of the sealing device decreases,and after 30 MPa,the leakage rate is almost 0 mL/h.The temperature of the rotating sealing device increases with the increase of rotation speed or pressure,and the temperature is more affected by the rotation speed factor.The frictional torque increases with increasing pressure and is independent of rotational speed.Comprehensive analysis shows that the wear resistance and reliability level of the sealing guide sleeve material is PVDF>PEEK>PE>PA.This study designs a high-pressure automatic compensation wear rotary sealing device and selects the optimal sealing material,providing technical support for the application of high-pressure water jet in mining machinery.展开更多
Since conventional photocatalytic technology fails to achieve complete elimination of chlorophenol contaminants from aqueous environments,this study presents a synergistic photocatalysis-capacitive deionization(PC-CDI...Since conventional photocatalytic technology fails to achieve complete elimination of chlorophenol contaminants from aqueous environments,this study presents a synergistic photocatalysis-capacitive deionization(PC-CDI)system as an advanced solution for industrial chlorophenol wastewater remediation.The PC-CDI system,employing boron nitride/carbon nitride(BN/CN)heterojunction electrodes,demonstrates exceptional degradation performance toward chlorophenols.The high-surface-area porous BN/CN heterojunction facilitates electro-adsorption and charge carrier separation,thereby synergistically optimizing both photocatalytic(PC)and capacitive deionization(CDI)functionalities.Remarkably,the integrated system achieves a 2,4-DCP degradation efficiency of 97.15%and a 2,4,6-TCP degradation efficiency of 100%in 2 h.The CDI component enables spatial separation through the electro-adsorption of Cl^(-)ions at the anode,effectively mitigating their interference and suppressing chlorinated byproduct formation.Concurrently,the electro-adsorption of positively charged chlorophenol pollutants accelerates their diffusion to catalytic sites,promoting the reactive oxygen species(ROS)-driven degradation of chlorophenol pollutants.The PC-CDI system exhibits robust stability(>95%efficiency retention over five cycles)and broad applicability across various chlorophenol derivatives.By circumventing Cl^(-)-induced side reactions and inhibiting chlorine radical generation during photocatalysis,this strategy minimizes the environmental risks associated with chlorinated byproducts during chlorophenol wastewater treatment.These findings establish the PC-CDI system as a sustainable and eco-friendly technology for industrial wastewater treatment.展开更多
Elastic cartilage in the rabbit external ear is an important animal model with attractive potential value for researching the physiological and pathological states of cartilages especially during wound healing.In this...Elastic cartilage in the rabbit external ear is an important animal model with attractive potential value for researching the physiological and pathological states of cartilages especially during wound healing.In this work,nonlinear optical microscopy based on two-photon excited fluor-escence and second harmonic generation were employed for imaging and quantifying the intact elastic cartilage.The morphology and distribution of main components in elastic carti lage incuding cartilage cells,collagen and elastic fibers were clearly observed from the high-resolution two-di mensional nonlinear optical images.The areas of cell nuclei,a parameter related to the pathological changes of nornal or abnormal elastic cartilage,can be easily quantifed.Moreover,the three-dimensional structure of chondrocytes and matrix were displayed by constructing threedimensional image of cartilage tissue.At last,the enmission spectra from cartilage were obtained and analyzed.We found that the different ratio of collagen over elastic fibens can be used to locate the observed position in the elastic cartilage.The redox ratio based on the ratio of nicotinamide adenine dimucleotide(NADH)over flavin adenine dinucleotide(FAD)fuorescence can also be calculated to analyze the metabolic state of chondrocytes in different regions.Our results demonstrated that this technique has the potential to provide more accurate and comprehensive information for the physiological states of elastic cartilage.展开更多
In the cold regions of northern China, incidents of municipal underground gas pipeline rupture and leakage occur quite fi-equently, aaost often in winter. To prevent harm to citizen safety and property, analysis of th...In the cold regions of northern China, incidents of municipal underground gas pipeline rupture and leakage occur quite fi-equently, aaost often in winter. To prevent harm to citizen safety and property, analysis of the causes of such cracking and leakage is therefore valuable. Two incident analyses are discussed here and the reasons why most of these types of cases occur dttring winter are clarified. Fhe effects of vehicle loadings above buried pipelines are calculated and compared with the effects and calculations of frost heaving forces. We demonstrate thtit when the soil layer above a pipeline freezes rapidly, the soil generates repeated frost heaving, which exerts heaving forces on the pipeline that can result in fatigue crack propagation and ultimate pipeline failure. Therefore, the incident induced 9y frost heaving is one of the primary reasons of gas pipeline failure. Based on these analyses, we present some recommendations pertaining to the proper design, construction, and management of gas pipelines.展开更多
In this study,araucarene diterpenes,characterized by a pimarene skeleton with a variably oxidized side chain at C-13,were investigated.A total of 16 araucarene diterpenoids and their derivatives were isolated from the...In this study,araucarene diterpenes,characterized by a pimarene skeleton with a variably oxidized side chain at C-13,were investigated.A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara,including 11 previously unreported compounds:dammaradione(1),dammarones D-G(2,5,14,15),dammaric acids B-F(8-12),and dammarol(16).The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy(HR-ESI-MS)and one-dimensional/two-dimensional(1D/2D)nuclear magnetic resonance(NMR),while their absolute configurations were determined through the electronic circular dichroism(ECD)exciton chirality method and Snatzke's method.The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model,and a structure-activity relationship(SAR)analysis was conducted.Araucarone(3)and dammaric acid C(9),serving as representative compounds,demonstrated significant hypoglycemic effects on zebrafish.The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake.Specifically,these compounds enhance the differentiation of pancreatic endocrine precursor cells(PEP cells)intoβcells in zebrafish.展开更多
Multiphoton microscopy(MPM),based on two-photon excited fuorescence and second harmonic generation,enables direct noninvasive visualization of tissue architecture and cell morphology in live tissues without the admini...Multiphoton microscopy(MPM),based on two-photon excited fuorescence and second harmonic generation,enables direct noninvasive visualization of tissue architecture and cell morphology in live tissues without the administration of exogenous contrast agents.In this paper,we used MPM to image the microstructures of the mucosa in fresh,unfixed,and unstained intestinal tissue of mouse.The morphology and distribution of the main components in mucosa layer such as columnar cells,goblet cells,intestinal glands,and a little collagen fibers were clearly observed in MPM images,and then compared with standard H&:E images from paired specimens.Our results indicate that MPM combined with endoscopy and miniaturization probes has the potential application in the clinical diagnosis and in vivo monitoring of early intestinal cancer.展开更多
Precisely distinguishing between hyperplastic and adenomatous polyps and normal human colonic mucosa at the cellular level is of great medical significance.In this work,multiphoton laserscarming microscopy(MPLSM)was u...Precisely distinguishing between hyperplastic and adenomatous polyps and normal human colonic mucosa at the cellular level is of great medical significance.In this work,multiphoton laserscarming microscopy(MPLSM)was used to obtain the high.-contrast images and the morpho-logical characteristics from normal colonic mucosa,hyperplastic polyps and tubular adenoma.Byintegrating the length and area measurement tools and computing tool,we quantified thedifference of crypt morphology and the alteration of nuclei in normal and diseased human colonicmucosa.Our results demonstrated that the morphology of crypts had an obvious tendency tocystic dilatation or elongated in hyperplastic polyps and tubular adenoma.The cont ent andnumber of mucin droplets of the scattered goblet cells had a piecemeal reduction in hyperplastic polyps and a large decrease in tubular adenoma The nuclei of epithelial cells might be elongated and pseudostratified,but overt dysplasia was absent in hyperplastic polyps.Nevertheless,thenuclei showed enlarged,crowded,stratified and a rod-like structure,with loss of polarity intubular adenoma.These results suggest that MPLSM has the capacity to distinguish betweenhyperplastic and adenomat ous polyps and normal human colonic mucosa at the celular level.展开更多
Background:Concurrent chemoradiotherapy(CCRT)is the standard treatment for locally advanced esophageal squamous cell carcinoma(ESCC).However,the optimal radiotherapy regimen,particularly in terms of total dose and pla...Background:Concurrent chemoradiotherapy(CCRT)is the standard treatment for locally advanced esophageal squamous cell carcinoma(ESCC).However,the optimal radiotherapy regimen,particularly in terms of total dose and planned range of irradiation field,remains unclear.This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.Methods:This trial compared two aspects of radiation treatment,total dose and field,using a two-by-two factorial design.The high-dose(HD)group received 59.4 Gy radiation,and the standard-dose(SD)group received 50.4 Gy.The involved field irradiation(IFI)group and elective nodal irradiation(ENI)group adopted different irradiation ranges.The participants were assigned to one of the four groups(HD+ENI,HD+IFI,SD+ENI and SD+IFI).The primary endpoint was overall survival(OS),and the secondary endpoints included progressionfree survival(PFS).The synergy indexwas used to measure the interaction effect between dose and field.Results:The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field.In comparison to the target field,patients in IFI or ENI showed similar OS(hazard ratio[HR]=0.99,95%CI:0.80-1.23,p=0.930)and PFS(HR=1.02,95%CI:0.82–1.25).TheHDtreatment did not show significantly prolonged OS compared with SD(HR=0.90,95%CI:0.72–1.11,p=0.318),but it suggested improved PFS(25.2 months to 18.0 months).Among the four groups,the HD+IFI group presented the best survival,while the SD+IFI group had the worst prognosis.No significant difference in the occurrence of severe adverse events was found in dose or field comparisons.Conclusions:IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC.The HD demonstrated improved PFS,but did not significantly improve OS.The dose escalation based on IFI(HD+IFI)showed better therapeutic efficacy than the current recommendation(SD+ENI)and is worth further validation.展开更多
The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy,and activating Nur77’s non-genotypic anticancer function has demonstrated strong therapeutic potential.However,few Nur77 site B...The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy,and activating Nur77’s non-genotypic anticancer function has demonstrated strong therapeutic potential.However,few Nur77 site B ligands have been identified as excellent anticancer compounds.There are no co-crystal structures of effective anticancer agents at Nur77 site B,which greatly limits the development of novel Nur77 site B ligands.Moreover,the lack of pharmaceutical ligands restricts Nur77’s therapeutic proof of concept.Herein,we developed a first-in-class Nur77 site B ligand(NB1)that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria.The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode.Importantly,NB1 showed favorable pharmacokinetic profiles and safety,as evidenced by its good oral bioavailability in rats and lack of mortality,bodyweight loss,and pathological damage at the 512.0 mg/kg dose in mice.Furthermore,oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model.Together,our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.展开更多
Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance...Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance.However,the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic.This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo.TAMs have been found to suppress cervical cancer cells ferroptosis.Mechanistically,macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells.In cancer cells,miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis.Moreover,the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway.Importantly,in clinical cervical cancer cases,ALOX15 is negatively associated with macrophages infiltration,which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer.Moreover,both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer.Altogether,this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.展开更多
基金Supported by Jiangsu Provincial Natural Science Foundation(Grant No.BK20231497)Jiangsu Provincial Post graduate Research&Practice Innovation Program(Grant No.KYCX25_2982)+3 种基金China University of Mining and Technology Graduate Innovation Program(Grant No.2025WLKXJ094)National Natural Science Foundation of China(Grant No.51975573)National Key R&D Program of China(Grant No.2022YFC2905600)Priority Academic Program Development of Jiangsu Higher Education Institute of China.
文摘A rotary sealing device that automatically compensates for wear is designed to address the issues of easy wear and the short service life of the rotary sealing device with automatic wear compensation in mining machinery.After the end face of the guide sleeve wears out,it still tightly adheres to the sealing valve seat under the pressure difference,achieving automatic wear compensation.Based on fluid-solid coupling technology,the structural strength of the rotary sealing device was checked.The influence of factors on the sealing performance of rotary sealing devices was studied using the control variable method.The results show that as the pressure of water increases,the leakage rate of the sealing device decreases,and after 30 MPa,the leakage rate is almost 0 mL/h.The temperature of the rotating sealing device increases with the increase of rotation speed or pressure,and the temperature is more affected by the rotation speed factor.The frictional torque increases with increasing pressure and is independent of rotational speed.Comprehensive analysis shows that the wear resistance and reliability level of the sealing guide sleeve material is PVDF>PEEK>PE>PA.This study designs a high-pressure automatic compensation wear rotary sealing device and selects the optimal sealing material,providing technical support for the application of high-pressure water jet in mining machinery.
文摘Since conventional photocatalytic technology fails to achieve complete elimination of chlorophenol contaminants from aqueous environments,this study presents a synergistic photocatalysis-capacitive deionization(PC-CDI)system as an advanced solution for industrial chlorophenol wastewater remediation.The PC-CDI system,employing boron nitride/carbon nitride(BN/CN)heterojunction electrodes,demonstrates exceptional degradation performance toward chlorophenols.The high-surface-area porous BN/CN heterojunction facilitates electro-adsorption and charge carrier separation,thereby synergistically optimizing both photocatalytic(PC)and capacitive deionization(CDI)functionalities.Remarkably,the integrated system achieves a 2,4-DCP degradation efficiency of 97.15%and a 2,4,6-TCP degradation efficiency of 100%in 2 h.The CDI component enables spatial separation through the electro-adsorption of Cl^(-)ions at the anode,effectively mitigating their interference and suppressing chlorinated byproduct formation.Concurrently,the electro-adsorption of positively charged chlorophenol pollutants accelerates their diffusion to catalytic sites,promoting the reactive oxygen species(ROS)-driven degradation of chlorophenol pollutants.The PC-CDI system exhibits robust stability(>95%efficiency retention over five cycles)and broad applicability across various chlorophenol derivatives.By circumventing Cl^(-)-induced side reactions and inhibiting chlorine radical generation during photocatalysis,this strategy minimizes the environmental risks associated with chlorinated byproducts during chlorophenol wastewater treatment.These findings establish the PC-CDI system as a sustainable and eco-friendly technology for industrial wastewater treatment.
基金supported by the Program for Changjiang Scholars and Innovative Research Team in University(Grant No.IRT1115)the National Natural Science Foundation of China(Grant Nos.81101209,61275006,81271620).
文摘Elastic cartilage in the rabbit external ear is an important animal model with attractive potential value for researching the physiological and pathological states of cartilages especially during wound healing.In this work,nonlinear optical microscopy based on two-photon excited fluor-escence and second harmonic generation were employed for imaging and quantifying the intact elastic cartilage.The morphology and distribution of main components in elastic carti lage incuding cartilage cells,collagen and elastic fibers were clearly observed from the high-resolution two-di mensional nonlinear optical images.The areas of cell nuclei,a parameter related to the pathological changes of nornal or abnormal elastic cartilage,can be easily quantifed.Moreover,the three-dimensional structure of chondrocytes and matrix were displayed by constructing threedimensional image of cartilage tissue.At last,the enmission spectra from cartilage were obtained and analyzed.We found that the different ratio of collagen over elastic fibens can be used to locate the observed position in the elastic cartilage.The redox ratio based on the ratio of nicotinamide adenine dimucleotide(NADH)over flavin adenine dinucleotide(FAD)fuorescence can also be calculated to analyze the metabolic state of chondrocytes in different regions.Our results demonstrated that this technique has the potential to provide more accurate and comprehensive information for the physiological states of elastic cartilage.
基金supported by the National Natural Science Foundation of China (NNSF) (No. 10472020)the Special Foundation of Dalian University of Technology (DUT) (DUTTX2009-103)
文摘In the cold regions of northern China, incidents of municipal underground gas pipeline rupture and leakage occur quite fi-equently, aaost often in winter. To prevent harm to citizen safety and property, analysis of the causes of such cracking and leakage is therefore valuable. Two incident analyses are discussed here and the reasons why most of these types of cases occur dttring winter are clarified. Fhe effects of vehicle loadings above buried pipelines are calculated and compared with the effects and calculations of frost heaving forces. We demonstrate thtit when the soil layer above a pipeline freezes rapidly, the soil generates repeated frost heaving, which exerts heaving forces on the pipeline that can result in fatigue crack propagation and ultimate pipeline failure. Therefore, the incident induced 9y frost heaving is one of the primary reasons of gas pipeline failure. Based on these analyses, we present some recommendations pertaining to the proper design, construction, and management of gas pipelines.
基金supported by the Traditional Chinese Medicine Foundation of Xiamen City,China(No.XWZY-2023-0303)the Natural Science Foundation of Xiamen City,China(No.3502Z20227162)。
文摘In this study,araucarene diterpenes,characterized by a pimarene skeleton with a variably oxidized side chain at C-13,were investigated.A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara,including 11 previously unreported compounds:dammaradione(1),dammarones D-G(2,5,14,15),dammaric acids B-F(8-12),and dammarol(16).The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy(HR-ESI-MS)and one-dimensional/two-dimensional(1D/2D)nuclear magnetic resonance(NMR),while their absolute configurations were determined through the electronic circular dichroism(ECD)exciton chirality method and Snatzke's method.The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model,and a structure-activity relationship(SAR)analysis was conducted.Araucarone(3)and dammaric acid C(9),serving as representative compounds,demonstrated significant hypoglycemic effects on zebrafish.The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake.Specifically,these compounds enhance the differentiation of pancreatic endocrine precursor cells(PEP cells)intoβcells in zebrafish.
基金supported by the Program for Changjiang Scholars and Innovative Research Team in University(Grant No.IRT1115)the National Natural Science Foundation of China(Grant Nos.81271620,61275006,81101209,30970783).
文摘Multiphoton microscopy(MPM),based on two-photon excited fuorescence and second harmonic generation,enables direct noninvasive visualization of tissue architecture and cell morphology in live tissues without the administration of exogenous contrast agents.In this paper,we used MPM to image the microstructures of the mucosa in fresh,unfixed,and unstained intestinal tissue of mouse.The morphology and distribution of the main components in mucosa layer such as columnar cells,goblet cells,intestinal glands,and a little collagen fibers were clearly observed in MPM images,and then compared with standard H&:E images from paired specimens.Our results indicate that MPM combined with endoscopy and miniaturization probes has the potential application in the clinical diagnosis and in vivo monitoring of early intestinal cancer.
基金National Natural Science Foundation of ChinaContract grant numbers:81271620,61275006,81101209+1 种基金Program for Changjiang Scholars and Innovative Research Teamin UniversityContract grant number:IRT1115.
文摘Precisely distinguishing between hyperplastic and adenomatous polyps and normal human colonic mucosa at the cellular level is of great medical significance.In this work,multiphoton laserscarming microscopy(MPLSM)was used to obtain the high.-contrast images and the morpho-logical characteristics from normal colonic mucosa,hyperplastic polyps and tubular adenoma.Byintegrating the length and area measurement tools and computing tool,we quantified thedifference of crypt morphology and the alteration of nuclei in normal and diseased human colonicmucosa.Our results demonstrated that the morphology of crypts had an obvious tendency tocystic dilatation or elongated in hyperplastic polyps and tubular adenoma.The cont ent andnumber of mucin droplets of the scattered goblet cells had a piecemeal reduction in hyperplastic polyps and a large decrease in tubular adenoma The nuclei of epithelial cells might be elongated and pseudostratified,but overt dysplasia was absent in hyperplastic polyps.Nevertheless,thenuclei showed enlarged,crowded,stratified and a rod-like structure,with loss of polarity intubular adenoma.These results suggest that MPLSM has the capacity to distinguish betweenhyperplastic and adenomat ous polyps and normal human colonic mucosa at the celular level.
基金Key Research and Development Program of Shandong Province of China,Grant/Award Number:2017CXZC1206National Natural Science Foundation of China,Grant/Award Number:81874224+1 种基金Academic promotion program of Shandong First Medical University,China,Grant/Award Number:2019LJ004Key Research and Development Program of Shandong Province,Grant/Award Numbers:2021LCZX04,2021SFGC0501。
文摘Background:Concurrent chemoradiotherapy(CCRT)is the standard treatment for locally advanced esophageal squamous cell carcinoma(ESCC).However,the optimal radiotherapy regimen,particularly in terms of total dose and planned range of irradiation field,remains unclear.This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields.Methods:This trial compared two aspects of radiation treatment,total dose and field,using a two-by-two factorial design.The high-dose(HD)group received 59.4 Gy radiation,and the standard-dose(SD)group received 50.4 Gy.The involved field irradiation(IFI)group and elective nodal irradiation(ENI)group adopted different irradiation ranges.The participants were assigned to one of the four groups(HD+ENI,HD+IFI,SD+ENI and SD+IFI).The primary endpoint was overall survival(OS),and the secondary endpoints included progressionfree survival(PFS).The synergy indexwas used to measure the interaction effect between dose and field.Results:The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field.In comparison to the target field,patients in IFI or ENI showed similar OS(hazard ratio[HR]=0.99,95%CI:0.80-1.23,p=0.930)and PFS(HR=1.02,95%CI:0.82–1.25).TheHDtreatment did not show significantly prolonged OS compared with SD(HR=0.90,95%CI:0.72–1.11,p=0.318),but it suggested improved PFS(25.2 months to 18.0 months).Among the four groups,the HD+IFI group presented the best survival,while the SD+IFI group had the worst prognosis.No significant difference in the occurrence of severe adverse events was found in dose or field comparisons.Conclusions:IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC.The HD demonstrated improved PFS,but did not significantly improve OS.The dose escalation based on IFI(HD+IFI)showed better therapeutic efficacy than the current recommendation(SD+ENI)and is worth further validation.
基金supported by grants from the National High Level Hospital Clinical Research Funding&Elite Medical Professionals Project of China-Japan Friendship Hospital(2023-NHLHCRF-DJMS-03&NO.ZRJY2023-GG07)the Fundamental Research Funds for the Central Universities of China(20720180051 and 3332023095)+3 种基金the National Key Research and Development Program of China(2022YFF0710803 and 2022YFF0710800)the Joint Research Project of Fujian Provincial Health Commission and Fujian Department of Education(#2019-WJ-39,China)the National Natural Science Foundation of China(82300051)Fujian Provincial Health Commission(#2021zylc29,China).
文摘The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy,and activating Nur77’s non-genotypic anticancer function has demonstrated strong therapeutic potential.However,few Nur77 site B ligands have been identified as excellent anticancer compounds.There are no co-crystal structures of effective anticancer agents at Nur77 site B,which greatly limits the development of novel Nur77 site B ligands.Moreover,the lack of pharmaceutical ligands restricts Nur77’s therapeutic proof of concept.Herein,we developed a first-in-class Nur77 site B ligand(NB1)that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria.The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode.Importantly,NB1 showed favorable pharmacokinetic profiles and safety,as evidenced by its good oral bioavailability in rats and lack of mortality,bodyweight loss,and pathological damage at the 512.0 mg/kg dose in mice.Furthermore,oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model.Together,our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.
基金supported by the National Natural Science Foundation of China(81972479,U2004118,82072899,81772643 and 81772803)Natural Science Foundation of Guangdong province(2019A1515011100 and 2021A1515012576,China)+5 种基金Henan Natural Science Foundation(202300410359,China)Henan Medical Program(SBGJ2020002081,China)Guangzhou High-Level Clinical Key Specialty Construction ProjectClinical Key Specialty Construction Project of Guangzhou Medical University(202005,China)the Innovation Project of Universities in Guangdong Province(NO.2021KTSCX026,China)Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University(QNCXTD2023019,China)。
文摘Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance.However,the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic.This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo.TAMs have been found to suppress cervical cancer cells ferroptosis.Mechanistically,macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells.In cancer cells,miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis.Moreover,the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway.Importantly,in clinical cervical cancer cases,ALOX15 is negatively associated with macrophages infiltration,which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer.Moreover,both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer.Altogether,this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.
