Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to ...Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.展开更多
Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly l...Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.展开更多
BACKGROUND Esophageal cancer surgery is associated with a high risk of postoperative pulmonary complications,particularly pneumonia.Although conventional respiratory rehabilitation strategies–such as preoperative ins...BACKGROUND Esophageal cancer surgery is associated with a high risk of postoperative pulmonary complications,particularly pneumonia.Although conventional respiratory rehabilitation strategies–such as preoperative inspiratory muscle training–have demonstrated limited efficacy,the low-intensity traditional Chinese Qigong practice"Liuzijue"(Six-Character Formula)shows promise.However,robust clinical evidence supporting its use in patients undergoing esophagectomy remains lacking.AIM To evaluate the effects of early postoperative"Liuzijue"training on pulmonary function and pneumonia incidence following radical esophagectomy.METHODS This retrospective study included 306 patients who underwent esophagectomy.The control group(n=163)received standard care,consisting of abdominal breathing,incentive spirometry,and early ambulation.The intervention group(n=143)received the same standard care plus twice-daily"Liuzijue"training for 14 days.Primary outcomes were the incidence of pneumonia(defined by Centers for Disease Control and Prevention criteria)and changes(Δ)in forced vital capacity(FVC),forced expiratory volume in 1 second(FEV_(1)),and maximum voluntary ventilation(MVV)from baseline to postoperative day 14.RESULTS The"Liuzijue"intervention was associated with a significantly lower incidence of pneumonia(11.9%vs 24.5%,P=0.005;relative risk=0.48).Significant improvements were observed inΔFVC(+502.1 mL vs+326.5 mL,P<0.001),ΔFEV_(1)(+701.7 mL vs+434.4 mL,P<0.001),andΔMVV(+19.4 L/minute vs+14.4 L/minute,P<0.001).Absolute FEV_(1) values on postoperative day 14 were higher in the intervention group(2270.8 mL vs 2066.1 mL,P=0.021),along with significantly lower Borg dyspnea/fatigue scores(P=0.045).No significant differences were observed in changes in diffusing capacity of the lung for carbon monoxide,total lung capacity,or 6-minute walk distance.CONCLUSION Early initiation of"Liuzijue"training after esophagectomy is associated with reduced pneumonia incidence and accelerated recovery of key pulmonary function parameters.These findings support the integration of"Liuzijue"into enhanced recovery after surgery protocols for esophageal cancer patients.展开更多
Mg/MgH_(2) has garnered significant attention primarily due to its abundant availability and high gravimetric density.Nevertheless,its practical implementation hindered by its high thermodynamic stability and sluggish...Mg/MgH_(2) has garnered significant attention primarily due to its abundant availability and high gravimetric density.Nevertheless,its practical implementation hindered by its high thermodynamic stability and sluggish kinetics.Fortunately,the introduction of transition metal single atom(TM SA)catalysts has emerged as an effective method to enhance the hydrogen storage properties of Mg/MgH_(2).Among these catalysts,the synergistic effect of nanoconfinement and TM SAs plays a pivotal role in the hydriding/dehydriding kinetics of Mg/MgH_(2).However,the effects of varying TM SAs interacting with N modified confined materials on H_(2) adsorption and desorption and underlying mechanisms remain enigmatic.Leveraging DFT calculations,we investigated the potential of combining TM SA catalysts with N-modified Carbon nanomaterials(CNT)to enhance the hydrogenation/dehydrogenation of Mg/MgH_(2).TM SA N-CNTs-Mg/MgH_(2) heterojunction systems encompassing ten 3d/4d transition metals were designed and constructed.We systematically investigated the impact of TM SA N-CNTs on the hydrogen absorption and desorption properties of Mg/MgH_(2) by examining parameters such as the electronic localization function(ELF),distorted charge density distributions,adsorption energies,dissociation energies,electronegativity,and the D-band center.Notably,the energy barriers for Mg/MgH_(2) hydrogenation and dehydrogenation were significantly reduced by 0.2-0.7 eV and 1.6-2.2 eV,respectively,through the catalytic promotion of TM SA N-CNTs.Herein,a novel“electronic-ropeway”effect was proposed to elucidate the underlying mechanism responsible for enhancing the hydrogen absorption and desorption kinetics in Mg/MgH_(2).Specifically,the contribution degree of TM SA N-CNTs and system electronegativity emerged as effective descriptors for predicting the reduced hydrogenation/dehydrogenation energy barriers.It is anticipated that elucidating the role of TM SA-N-CNTs will pave the way for developing innovative strategies to enhance the hydrogen absorption and desorption kinetics of Mg/MgH_(2) systems,thereby providing valuable design principles for the construction of novel Mg/MgH_(2) hydrogen storage materials.展开更多
ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine （N6-mA）, a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the...ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine （N6-mA）, a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells （MSCs） was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBHl-depleted MSCs also exhibited a restricted capacity for bone formation in vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region of ATF4, which subsequently silenced ATF4 transcription. In addition, restoring the expression of ATP by adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.展开更多
Osteoarthritis （OA） is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor （EGFR） signaling as an important regulat...Osteoarthritis （OA） is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor （EGFR） signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus （DMM） to induce OA in two mouse models with reduced EGFR activity, one with genetic modification （, was/＋ mice） and the other one with pharmacological inhibition （gefitinib treatment）. Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 （MMP13）, the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α （HIF2α）, a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.展开更多
Copper （Cu） is an essential trace mineral element for all forms of life, and is an important structural component and co-factor for a variety of metalloenzymes （Pefia et al., 1999; Bertinato and L＇Abbe, 2004）. In...Copper （Cu） is an essential trace mineral element for all forms of life, and is an important structural component and co-factor for a variety of metalloenzymes （Pefia et al., 1999; Bertinato and L＇Abbe, 2004）. In humans, Cu deficiency is not common because of the ubiquitous occurrence of Cu and ease of gastrointestinal absorption （Zidar et al., 1977; Uauy et al., 1998）.展开更多
Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common ...Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.展开更多
Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR si...Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.展开更多
Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and （-）-gossypol are two kinds of chemical...Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and （-）-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years.展开更多
Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This ...Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This study aims to explore the biologic effects and the molecular mechanisms of deregulated TRAF7 signaling in hepatocellular carcinoma(HCC)progression.展开更多
Johnson et al. (1993) showed that coexposure to UV-A between 300-400 nm enhanced the toxicity of nitrotoluenes to Phoiobacterium phosphoreum, a marine bioluminescent bacteria used in the Microtox test (Microbics Inc.)...Johnson et al. (1993) showed that coexposure to UV-A between 300-400 nm enhanced the toxicity of nitrotoluenes to Phoiobacterium phosphoreum, a marine bioluminescent bacteria used in the Microtox test (Microbics Inc.). This paper reports that UV-A photoenhanced the toxicity of polynuclear aromatic hydrocarbons, other types of organic compounds, and some transition metals to P. phosphoreum. Coexposure to 400 μw/cm2 for 15 min increased the toxicity of psoralen, α-terthienyl, anthracene, acridine, fluoranthene,TNT, Cu2+, As3+, Ni2, and Cd2+. Phenanthrene was photoenhanced after 30 min coexposure at 400 μw/cm2+, and Mn2+ at 800 μw/cm2 aftef 15 min. Naphthalene was not enhanced at 800 μw/cm2 for 30 min展开更多
Sigma-1 receptors are unique receptors that are postulated to act as intracellular amplifiers for signal transduction within cells of the nervous system.The present paper studied the effect and mechanism of sigma-1 re...Sigma-1 receptors are unique receptors that are postulated to act as intracellular amplifiers for signal transduction within cells of the nervous system.The present paper studied the effect and mechanism of sigma-1 receptor agonists on intracellular Ca2+concentration at presynaptic sites using synaptosomes from the medial prefrontal cortex by fluorometric and biochemical methods combined with a pharmacological approach.The results showed that sigma-1 receptor agonist PRE-084 and SKF10047 could increase intrasynaptosomal Ca2+concentration in a dose-dependent manner.展开更多
BACKGROUND： Interstitial stem cell is charactenzed by multiple differentiations, and retinoic acid （RA） can induce differentiation of stromal cells into nerve tissue cells in fetal liver of mice, so, its signal tra...BACKGROUND： Interstitial stem cell is charactenzed by multiple differentiations, and retinoic acid （RA） can induce differentiation of stromal cells into nerve tissue cells in fetal liver of mice, so, its signal transduction pathway should be discussed to trigger differentiation. OBJECTIVE ： To study the effect of RA on expression of neural specific gene and its signal transduction in fetal liver of mice.DESIGN ： Paired controlled study on the basis of cell.SETTING ： Institute of Hematology, Medical College of Jinan University.MATERIALS： The experiment was completed in the Institute of Hematology, Medical College of Jinan University from April to December 2005. C57BL/6 mice, of clean grade, aged 8-10 weeks, weighting 20-35 g, 10 females and 4 males, were selected in this study.METHODS： Sca-1^＋ cells in fetal liver were prepared with MACS kit and cultured with DMEM ＋ 10% fetal bovine serum （FBS）. On the fourth day, it was added with or without protein kinase C （PKC） inhibitor chelerythrine chloride （3μmol/L） and 5×10^-7 mol/L RA for 24 hours, and then incubated in serum-free medium for 5 days. Expressions of genes were assayed by Westem blotting and semi-quantitative RT-PCR.MAIN OUTCOME MEASURES ： Expression of neural specific gene NF-L, NF-H, BF-1 and TH.RESULTS： Expression of neural specific gene NF-L, NF-H, BF-1 and TH was significantly increased after treatment with RA and they were increased 5.06, 5.15, 4.63 and 3.33 times, respectively. However, chelerythrine chloride could inhibit expression of neural specific gene NF-L, NF-H, BF-1 and TH induced by RA.CONCLUSION ： RA can promote the expression of neural specific genes in Sca-1^＋ cells of fetal liver, and its pathway may be related to PKC.展开更多
Multiple links between miRNA activity and cancer have been established. Several miRNAs have been describedas oncogenes while others act as tumour suppressors[1]. MiR-449a is a member of miR-34 family which locates onh...Multiple links between miRNA activity and cancer have been established. Several miRNAs have been describedas oncogenes while others act as tumour suppressors[1]. MiR-449a is a member of miR-34 family which locates onhuman chromosome 5q11.2, a region identified as a susceptibility locus in a variety of malignancies, includingprostate cancer[2]. In line with the tumor-suppressive role of miR-34, miR-449a was shown to be significantly downregulatedin prostate cancer cell lines and tissue relative to normal tissues and plays a critical role in growth ofprostate cancer cells [3;4].展开更多
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor regulating the expression ofantioxidant genes. Under oxidative stress conditions or other stimulus, Nrf2 translocating from the cyto...Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor regulating the expression ofantioxidant genes. Under oxidative stress conditions or other stimulus, Nrf2 translocating from the cytoplasminto the nucleus, binds to antioxidant response elements, and increases the expression of antioxidant enzymes[1;2].Constitutive Nrf2 activation in many tumors enhances cell survival and resistance. For instance, high level of Nrf2 isobserved in non-small cell lung cancer A549 cells[3;4]. The gain of Nrf2 function has been implicated in the resistanceof cancer cells to radiation therapy.展开更多
c-Myc was one of the first oncogenes to be identified and its overexpression at the RNA and protein levels has subsequently been linked to a wide variety of human cancers[1]. Overexpression of the c-Myc protein or c-M...c-Myc was one of the first oncogenes to be identified and its overexpression at the RNA and protein levels has subsequently been linked to a wide variety of human cancers[1]. Overexpression of the c-Myc protein or c-Myc gene has been shown in 80% of breast cancers, 70% of colon cancers, 90% of gynecological cancers, 50% of hepatocellular carcinomas and a variety of hematological tumors.展开更多
Transient receptor potential vanilloid 1(TRPVl) that is known as capsaicin receptor is a non-selective cationion channel[1]. TRPV1 can regulate Ca2+ influx, participate in a variety of physiological and pathological p...Transient receptor potential vanilloid 1(TRPVl) that is known as capsaicin receptor is a non-selective cationion channel[1]. TRPV1 can regulate Ca2+ influx, participate in a variety of physiological and pathological processof tumor[2]. One such agent is Capsazepine (CPZ) that is now widely used as a selective vanilloid type 1 receptor(TRPV1) antagonist. CPZ can be directly actived on the capsaicin receptor, blocked its biological effects, and abolishedosteosarcoma-induced hyperalgesia when administered subcutaneously at doses ranging from 3 to 10 mg/kg,blocked calcium channels[3]. However, the mechanisms underlying the anticancer effects of CPZ have not fully beenunderstood. Whether CPZ can induce apoptosis of human hepatocellular carcinoma cell line HepG2 is not known.Therefore, the objective of the study reported here was to determine whether CPZ can enhance radiation sensitivityin HepG2 cell, and impact on cell proliferation.展开更多
From October 10 to 17,the Festival of China 2009 was held in Kathmandu,capital of Nepal.This one-week biennial celebration,initiated in 2003,aims to"promote
文摘Objectives:The eukaryotic initiation factor 4F(eIF4F)translation initiation complex inhibitors(eIF4Fi)were recently found to hyperactivate extracellular signal-regulated kinases 1/2(ERK1/2)signals,which contribute to acquired resistance to BRAF(B-Raf proto-oncogene,serine/threonine kinase)inhibitors in melanoma.This present study aims to elucidate how to overcome the resistance of the eIF4Fi in BRAFV600E mutant melanoma cells and explore the underlying mechanisms.Methods:Melanoma A375(vemurafenib[VEM]-sensitive)and A375R(VEM-resistant)cells were exposed to eIF4Fi RocA at varying doses and durations in vitro.We investigated the impact of RocA on the activity of ERK1/2,AKT serine/threonine kinase 1(AKT1),eIF4E,and enhancer of zeste homolog 2(EZH2).We then examined the impact of RocA on pro-apoptotic BH3-only proteins and proliferative proteins.We subsequently determined the effect of combined eIF4Fi,AKT1 inhibitor,EZH2 inhibitor or VEM on tumor growth in vitro and in vivo.Results:RocA inhibited proliferation and induced apoptosis in A375 cells,but inhibited proliferation in A375R cells.RocA rapidly reactivated ERK1/2 at 3 h and returned to baseline levels at 48 h.However,eIF4E and AKT1 activation began at 12 h and peaked at 48 h.ERK1/2 positively regulated EZH2 and EZH2-dependent expression of c-Fos and EGR1,while AKT1 negatively regulated c-Myc,c-Jun,and BMF,but positively regulated eIF4E.RocA downregulated ERK1/2(or EZH2,AKT1,and eIF4E)independent bcl-2 and Mcl-1 expression.AKT1i enhanced RocA-induced cell apoptosis,while EZH2i reduced RocA-induced cell proliferation.Combined CR-1-31-B,EZH2i,and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo.Conclusion:The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways,resulting in resistance to both eIF4Fi and VEM.Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.
基金supported by the National Natural Science Foundation of China(Nos.T2293753,52203194)the National Key R&D Program of China(No.2021YFA1201200)+1 种基金the Natural Science Foundation of Zhejiang Province(No.LR18E030002)2023 Hangzhou West Lake Pearl Project Leading Innovative Youth Team Project.
文摘Chemodynamic therapy(CDT),using Fenton agents to generate highly cytotoxic•OH from H_(2)O_(2)has been demonstrated as a powerful anticancer method.However,the insufficient endogenous H_(2)O_(2)in tumor cells greatly limited its therapeutic effect.Herein,we prepared a pH-responsiveβ-lapachone-loaded ironpolyphenol nanocomplex(LIPN)through a one-pot method.β-Lapachone in LIPN selectively enhanced H_(2)O_(2)concentration in tumor cells,and ferrous ions cascadely generated abundant cytotoxic•OH.Therefore,LIPN with cascade amplification of reactive oxygen species(ROS)showed high chemodynamic cytotoxicity in tumor cells,efficiently improving the expression of damage-associated molecular patterns(DAMPs),and exerting strong immunogenic cell death(ICD).As a result,LIPN exhibited efficient tumor inhibition ability in 4T1 subcutaneous tumor model in vivo with great biocompatibility.Additionally,the infiltration of cytotoxic CD8^(+)T lymphocytes and inhibition of regulatory CD4^(+)FoxP3^(+)T lymphocytes in tumors demonstrated the activation of immunosuppressive tumor microenvironment by LIPN-induced ICD.Therefore,this work provided a new approach to enhance ICD of chemodynamic therapy through selective cascade amplification of ROS in cancer cells.
基金Supported by Xuhui District Health Commission,No.SHXH202214.
文摘BACKGROUND Esophageal cancer surgery is associated with a high risk of postoperative pulmonary complications,particularly pneumonia.Although conventional respiratory rehabilitation strategies–such as preoperative inspiratory muscle training–have demonstrated limited efficacy,the low-intensity traditional Chinese Qigong practice"Liuzijue"(Six-Character Formula)shows promise.However,robust clinical evidence supporting its use in patients undergoing esophagectomy remains lacking.AIM To evaluate the effects of early postoperative"Liuzijue"training on pulmonary function and pneumonia incidence following radical esophagectomy.METHODS This retrospective study included 306 patients who underwent esophagectomy.The control group(n=163)received standard care,consisting of abdominal breathing,incentive spirometry,and early ambulation.The intervention group(n=143)received the same standard care plus twice-daily"Liuzijue"training for 14 days.Primary outcomes were the incidence of pneumonia(defined by Centers for Disease Control and Prevention criteria)and changes(Δ)in forced vital capacity(FVC),forced expiratory volume in 1 second(FEV_(1)),and maximum voluntary ventilation(MVV)from baseline to postoperative day 14.RESULTS The"Liuzijue"intervention was associated with a significantly lower incidence of pneumonia(11.9%vs 24.5%,P=0.005;relative risk=0.48).Significant improvements were observed inΔFVC(+502.1 mL vs+326.5 mL,P<0.001),ΔFEV_(1)(+701.7 mL vs+434.4 mL,P<0.001),andΔMVV(+19.4 L/minute vs+14.4 L/minute,P<0.001).Absolute FEV_(1) values on postoperative day 14 were higher in the intervention group(2270.8 mL vs 2066.1 mL,P=0.021),along with significantly lower Borg dyspnea/fatigue scores(P=0.045).No significant differences were observed in changes in diffusing capacity of the lung for carbon monoxide,total lung capacity,or 6-minute walk distance.CONCLUSION Early initiation of"Liuzijue"training after esophagectomy is associated with reduced pneumonia incidence and accelerated recovery of key pulmonary function parameters.These findings support the integration of"Liuzijue"into enhanced recovery after surgery protocols for esophageal cancer patients.
基金financed by the National Key Research and Development Program of China [grants number 2023YFB3809101]the National Natural Science Foundation of China [grants number 52471225, 52271212, 52201250]+1 种基金the Natural Science Foundation of Hebei Province [grants number E2018502054]the Fundamental Research Funds for the Central Universities [grants number 2023MS148]
文摘Mg/MgH_(2) has garnered significant attention primarily due to its abundant availability and high gravimetric density.Nevertheless,its practical implementation hindered by its high thermodynamic stability and sluggish kinetics.Fortunately,the introduction of transition metal single atom(TM SA)catalysts has emerged as an effective method to enhance the hydrogen storage properties of Mg/MgH_(2).Among these catalysts,the synergistic effect of nanoconfinement and TM SAs plays a pivotal role in the hydriding/dehydriding kinetics of Mg/MgH_(2).However,the effects of varying TM SAs interacting with N modified confined materials on H_(2) adsorption and desorption and underlying mechanisms remain enigmatic.Leveraging DFT calculations,we investigated the potential of combining TM SA catalysts with N-modified Carbon nanomaterials(CNT)to enhance the hydrogenation/dehydrogenation of Mg/MgH_(2).TM SA N-CNTs-Mg/MgH_(2) heterojunction systems encompassing ten 3d/4d transition metals were designed and constructed.We systematically investigated the impact of TM SA N-CNTs on the hydrogen absorption and desorption properties of Mg/MgH_(2) by examining parameters such as the electronic localization function(ELF),distorted charge density distributions,adsorption energies,dissociation energies,electronegativity,and the D-band center.Notably,the energy barriers for Mg/MgH_(2) hydrogenation and dehydrogenation were significantly reduced by 0.2-0.7 eV and 1.6-2.2 eV,respectively,through the catalytic promotion of TM SA N-CNTs.Herein,a novel“electronic-ropeway”effect was proposed to elucidate the underlying mechanism responsible for enhancing the hydrogen absorption and desorption kinetics in Mg/MgH_(2).Specifically,the contribution degree of TM SA N-CNTs and system electronegativity emerged as effective descriptors for predicting the reduced hydrogenation/dehydrogenation energy barriers.It is anticipated that elucidating the role of TM SA-N-CNTs will pave the way for developing innovative strategies to enhance the hydrogen absorption and desorption kinetics of Mg/MgH_(2) systems,thereby providing valuable design principles for the construction of novel Mg/MgH_(2) hydrogen storage materials.
基金supported by grants from the National Natural Science Foundation of China (No.81271178 and 81470777)
文摘ALKBH1 was recently discovered as a demethylase for DNA N6-methyladenine （N6-mA）, a new epigenetic modification, and interacts with the core transcriptional pluripotency network of embryonic stem cells. However, the role of ALKBH1 and DNA N6-mA in regulating osteogenic differentiation is largely unknown. In this study, we demonstrated that the expression of ALKBH1 in human mesenchymal stem cells （MSCs） was upregulated during osteogenic induction. Knockdown of ALKBH1 increased the genomic DNA N6-mA levels and significantly reduced the expression of osteogenic-related genes, alkaline phosphatase activity, and mineralization. ALKBHl-depleted MSCs also exhibited a restricted capacity for bone formation in vivo. By contrast, the ectopic overexpression of ALKBH1 enhanced osteoblastic differentiation. Mechanically, we found that the depletion of ALKBH1 resulted in the accumulation of N6-mA on the promoter region of ATF4, which subsequently silenced ATF4 transcription. In addition, restoring the expression of ATP by adenovirus-mediated transduction successfully rescued osteogenic differentiation. Taken together, our results demonstrate that ALKBH1 is indispensable for the osteogenic differentiation of MSCs and indicate that DNA N6-mA modifications area new mechanism for the epigenetic regulation of stem cell differentiation.
基金supported by ASBMR Research Career Enhancement Award (to LQ)NIH grants AR060991 (to LQ)AR062908 (to ME-I)
文摘Osteoarthritis （OA） is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor （EGFR） signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus （DMM） to induce OA in two mouse models with reduced EGFR activity, one with genetic modification （, was/＋ mice） and the other one with pharmacological inhibition （gefitinib treatment）. Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 （MMP13）, the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α （HIF2α）, a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.
基金jointly supported by the National Key Technology Support Program(No.2015BAD05B02)the National Natural Science Foundation of China(Nos.31270426,31470443 and 31371596)
文摘Copper （Cu） is an essential trace mineral element for all forms of life, and is an important structural component and co-factor for a variety of metalloenzymes （Pefia et al., 1999; Bertinato and L＇Abbe, 2004）. In humans, Cu deficiency is not common because of the ubiquitous occurrence of Cu and ease of gastrointestinal absorption （Zidar et al., 1977; Uauy et al., 1998）.
基金funded by Ministry of Education,University and Research(MIUR)ex-60% research fund University of Brescia,Italy
文摘Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.
基金supported by Elam M. and Georgina E.Hack Memorial Research Funds,Department of Periodontics,University of Washington,Seattle,WA,USAsupported by WVCTSI funds,West Virginia University,Morgantown,WV,USA
文摘Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.
基金supported by the National Natural Science Foundation of China(81170467 and 81270569)Major Project of PLA Medical S&T foundation(AWS11C004)Medical Science Research Foundation of Chongqing Health and Family Planning Committee(2015MSXM224)
文摘Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and （-）-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years.
文摘Objective:The tumor necrosis factor receptor-associated factor 7(TRAF7)is one of the components of the tumor necrosis factor alpha(TNF-α)/nuclear factor kappa B(NF-κB)pathway and a putative E3-ubiquitin ligase.This study aims to explore the biologic effects and the molecular mechanisms of deregulated TRAF7 signaling in hepatocellular carcinoma(HCC)progression.
文摘Johnson et al. (1993) showed that coexposure to UV-A between 300-400 nm enhanced the toxicity of nitrotoluenes to Phoiobacterium phosphoreum, a marine bioluminescent bacteria used in the Microtox test (Microbics Inc.). This paper reports that UV-A photoenhanced the toxicity of polynuclear aromatic hydrocarbons, other types of organic compounds, and some transition metals to P. phosphoreum. Coexposure to 400 μw/cm2 for 15 min increased the toxicity of psoralen, α-terthienyl, anthracene, acridine, fluoranthene,TNT, Cu2+, As3+, Ni2, and Cd2+. Phenanthrene was photoenhanced after 30 min coexposure at 400 μw/cm2+, and Mn2+ at 800 μw/cm2 aftef 15 min. Naphthalene was not enhanced at 800 μw/cm2 for 30 min
文摘Sigma-1 receptors are unique receptors that are postulated to act as intracellular amplifiers for signal transduction within cells of the nervous system.The present paper studied the effect and mechanism of sigma-1 receptor agonists on intracellular Ca2+concentration at presynaptic sites using synaptosomes from the medial prefrontal cortex by fluorometric and biochemical methods combined with a pharmacological approach.The results showed that sigma-1 receptor agonist PRE-084 and SKF10047 could increase intrasynaptosomal Ca2+concentration in a dose-dependent manner.
文摘BACKGROUND： Interstitial stem cell is charactenzed by multiple differentiations, and retinoic acid （RA） can induce differentiation of stromal cells into nerve tissue cells in fetal liver of mice, so, its signal transduction pathway should be discussed to trigger differentiation. OBJECTIVE ： To study the effect of RA on expression of neural specific gene and its signal transduction in fetal liver of mice.DESIGN ： Paired controlled study on the basis of cell.SETTING ： Institute of Hematology, Medical College of Jinan University.MATERIALS： The experiment was completed in the Institute of Hematology, Medical College of Jinan University from April to December 2005. C57BL/6 mice, of clean grade, aged 8-10 weeks, weighting 20-35 g, 10 females and 4 males, were selected in this study.METHODS： Sca-1^＋ cells in fetal liver were prepared with MACS kit and cultured with DMEM ＋ 10% fetal bovine serum （FBS）. On the fourth day, it was added with or without protein kinase C （PKC） inhibitor chelerythrine chloride （3μmol/L） and 5×10^-7 mol/L RA for 24 hours, and then incubated in serum-free medium for 5 days. Expressions of genes were assayed by Westem blotting and semi-quantitative RT-PCR.MAIN OUTCOME MEASURES ： Expression of neural specific gene NF-L, NF-H, BF-1 and TH.RESULTS： Expression of neural specific gene NF-L, NF-H, BF-1 and TH was significantly increased after treatment with RA and they were increased 5.06, 5.15, 4.63 and 3.33 times, respectively. However, chelerythrine chloride could inhibit expression of neural specific gene NF-L, NF-H, BF-1 and TH induced by RA.CONCLUSION ： RA can promote the expression of neural specific genes in Sca-1^＋ cells of fetal liver, and its pathway may be related to PKC.
基金Key Program of National Natural Science Foundation of China (U1432248), National Natural Science Foundationof China (10835011, 11205219), Western Talent Program of Chinese Academy of Sciences(Y260230XB0).
文摘Multiple links between miRNA activity and cancer have been established. Several miRNAs have been describedas oncogenes while others act as tumour suppressors[1]. MiR-449a is a member of miR-34 family which locates onhuman chromosome 5q11.2, a region identified as a susceptibility locus in a variety of malignancies, includingprostate cancer[2]. In line with the tumor-suppressive role of miR-34, miR-449a was shown to be significantly downregulatedin prostate cancer cell lines and tissue relative to normal tissues and plays a critical role in growth ofprostate cancer cells [3;4].
基金Key Program of National Natural Science Foundation of China (U1432248), National Natural Science Foundationof China (11205219), Western Talent Program of Chinese Academy of Sciences(Y260230XB0).
文摘Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor regulating the expression ofantioxidant genes. Under oxidative stress conditions or other stimulus, Nrf2 translocating from the cytoplasminto the nucleus, binds to antioxidant response elements, and increases the expression of antioxidant enzymes[1;2].Constitutive Nrf2 activation in many tumors enhances cell survival and resistance. For instance, high level of Nrf2 isobserved in non-small cell lung cancer A549 cells[3;4]. The gain of Nrf2 function has been implicated in the resistanceof cancer cells to radiation therapy.
基金Key Program of National Natural Science Foundation of China (U1432248), National Natural Science Foundation of China (11305226)
文摘c-Myc was one of the first oncogenes to be identified and its overexpression at the RNA and protein levels has subsequently been linked to a wide variety of human cancers[1]. Overexpression of the c-Myc protein or c-Myc gene has been shown in 80% of breast cancers, 70% of colon cancers, 90% of gynecological cancers, 50% of hepatocellular carcinomas and a variety of hematological tumors.
基金Key Program of National Natural Science Foundation of China (U1432248), National Natural Science Foundationof China (11175222, 11205219) , Western Talent Program of Chinese Academy of Sciences (Y260230XB0).
文摘Transient receptor potential vanilloid 1(TRPVl) that is known as capsaicin receptor is a non-selective cationion channel[1]. TRPV1 can regulate Ca2+ influx, participate in a variety of physiological and pathological processof tumor[2]. One such agent is Capsazepine (CPZ) that is now widely used as a selective vanilloid type 1 receptor(TRPV1) antagonist. CPZ can be directly actived on the capsaicin receptor, blocked its biological effects, and abolishedosteosarcoma-induced hyperalgesia when administered subcutaneously at doses ranging from 3 to 10 mg/kg,blocked calcium channels[3]. However, the mechanisms underlying the anticancer effects of CPZ have not fully beenunderstood. Whether CPZ can induce apoptosis of human hepatocellular carcinoma cell line HepG2 is not known.Therefore, the objective of the study reported here was to determine whether CPZ can enhance radiation sensitivityin HepG2 cell, and impact on cell proliferation.
文摘From October 10 to 17,the Festival of China 2009 was held in Kathmandu,capital of Nepal.This one-week biennial celebration,initiated in 2003,aims to"promote
