OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential med...OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential mediator IL-27.We investigated whether andrographolide,apreviously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata,could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR viaits anti-oxidative property.METHODS Mouse macrophage cell line Raw264.7,mouse primary pulmonary monocyte/macrophage,and BALB/c mouse were treated with LPS/IFN-γ,in the presence and absence of increasing doses of dexamethasone and/or andrographolide.mRNA and protein levels of IL-27 in vitro and in vivo were examined,and mouse AHR was assessed.RESULTS Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in mice.Andrographolide significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage,mouse bronchoalveolar lavage fluid and lung tissue,and furthermore on the incurring AHR.LPS/IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory action.Andrographolide at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)restored nuclear HDAC2 protein levels both in cells and in mouse lungs,possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor Nrf-2level.CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.展开更多
Biodegradable zinc(Zn)and its alloys have rapidly emerged as a promising alternative for implants with medium to high loadbearing requirements due to their superior strength and ductility compared to Mg alloys in the ...Biodegradable zinc(Zn)and its alloys have rapidly emerged as a promising alternative for implants with medium to high loadbearing requirements due to their superior strength and ductility compared to Mg alloys in the past decade[1].Furthermore,the in vivo degradation rates of Zn-based devices more closely match the tissue healing periods(3-6 months for vascular healing[2],2-3 months for bone healing[3]).Recent studies have demonstrated the ability of Zn alloys to promote osteogenesis and modulate immune responses[3,4].These exciting findings have accelerated the translational research of Zn alloys,with clinical studies initiated to evaluate the safety and efficacy of biodegradable Zn alloy devices such as a maxillofacial internal fixation system,interference screws,and a resorbable Zn alloy drugeluting coronary artery stent.展开更多
Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neu...Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons.Unfortunately,within weeks after implantation,neural recording quality from microelectrodes degrades,owing largely to a neuroinflammatory response.Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress.We developed a mechanically-adaptive,resveratrol-eluting(MARE)neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity.In this work,we demonstrate that compared to rigid silicon controls,highly-flexible MARE probes exhibit improved recording performance,more stable impedance,and a healing tissue response.With further optimization,MARE probes can serve as long-term,robust neural probes for brain-machine interface applications.展开更多
Prostate cancer(PCa)is the second leading cause of cancer-related death in the US.Androgen receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use therap...Prostate cancer(PCa)is the second leading cause of cancer-related death in the US.Androgen receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use therapies.However,despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting,resistance mechanisms inevitably occur.Thus,novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival.Among the key cellular processes that are regulated by androgens,metabolic reprogramming stands out because of its intricate links with cancer cell biology.In this review,we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy.We describe the interplay between genetic alterations,metabolic vulnerabilities and castration resistance.Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression,we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies.We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression.We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies.Finally,we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers,and non-invasive approaches to monitor therapy response.展开更多
基金The project supported by National Medical Research Council of Singapore(NMRC/CBRG/0027/2012)
文摘OBJECTIVE Steroid-resistant airway hyper-responsiveness(AHR)has been proposed to be related to the activation of innate host defense pathways such as those induced by LPS,IFN-γ,and LPS/IFN-γ-stimulated essential mediator IL-27.We investigated whether andrographolide,apreviously demonstrated anti-inflammatory bioactive molecule extracted from the plant Andrographis paniculata,could restore steroid sensitivity to block LPS/IFN-γ-induced IL-27 production and AHR viaits anti-oxidative property.METHODS Mouse macrophage cell line Raw264.7,mouse primary pulmonary monocyte/macrophage,and BALB/c mouse were treated with LPS/IFN-γ,in the presence and absence of increasing doses of dexamethasone and/or andrographolide.mRNA and protein levels of IL-27 in vitro and in vivo were examined,and mouse AHR was assessed.RESULTS Dexamethasone alone failed to inhibit LPS/IFN-γ-induced IL-27 and AHR in mice.Andrographolide significantly facilitated the suppressive effect of dexamethasone on LPS/IFN-γ-induced IL-27 level in macrophage cell line and primary monocyte/macrophage,mouse bronchoalveolar lavage fluid and lung tissue,and furthermore on the incurring AHR.LPS/IFN-γdid not impede nuclear translocation of glucocorticoid receptors but diminishthe protein level of histone deacetylase-2(HDAC2),an essential epigenetic enzymeresponsible for steroid anti-inflammatory action.Andrographolide at low doses(5μmol·L-1 in vitro;1mg·kg-1,ip in vivo)restored nuclear HDAC2 protein levels both in cells and in mouse lungs,possibly via suppression of PI3K/Akt signaling pathway and up-regulation of the anti-oxidative transcription factor Nrf-2level.CONCLUSION Our data suggest that andrographolide may resensitize steroid action on blocking LPS/IFN-γ-induced IL-27 and resultant AHR by restoring HDAC2 level.
文摘Biodegradable zinc(Zn)and its alloys have rapidly emerged as a promising alternative for implants with medium to high loadbearing requirements due to their superior strength and ductility compared to Mg alloys in the past decade[1].Furthermore,the in vivo degradation rates of Zn-based devices more closely match the tissue healing periods(3-6 months for vascular healing[2],2-3 months for bone healing[3]).Recent studies have demonstrated the ability of Zn alloys to promote osteogenesis and modulate immune responses[3,4].These exciting findings have accelerated the translational research of Zn alloys,with clinical studies initiated to evaluate the safety and efficacy of biodegradable Zn alloy devices such as a maxillofacial internal fixation system,interference screws,and a resorbable Zn alloy drugeluting coronary artery stent.
基金funded by Merit Review Award#I01RX003083(A.H.-D./J.R.C.)and a Research Career Scientist Award Grant#12635707(J.R.C.)from the United States Department of Veterans Affairs Rehabilitation Research and Development Servicesupport was provided in a pre-doctoral fellowship to N.N.M.from the Department of Defense National Defense Science and Engineering Fellowship Program。
文摘Intracortical microelectrodes are used for recording activity from individual neurons,providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities.Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons.Unfortunately,within weeks after implantation,neural recording quality from microelectrodes degrades,owing largely to a neuroinflammatory response.Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress.We developed a mechanically-adaptive,resveratrol-eluting(MARE)neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity.In this work,we demonstrate that compared to rigid silicon controls,highly-flexible MARE probes exhibit improved recording performance,more stable impedance,and a healing tissue response.With further optimization,MARE probes can serve as long-term,robust neural probes for brain-machine interface applications.
基金supported by the Barr Award from the Dana-Farber Cancer Institute to Zadra G.
文摘Prostate cancer(PCa)is the second leading cause of cancer-related death in the US.Androgen receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use therapies.However,despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting,resistance mechanisms inevitably occur.Thus,novel strategies are required to circumvent resistance occurrence and thereby to improve PCa survival.Among the key cellular processes that are regulated by androgens,metabolic reprogramming stands out because of its intricate links with cancer cell biology.In this review,we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine therapy.We describe the interplay between genetic alterations,metabolic vulnerabilities and castration resistance.Since PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression,we review our current knowledge on the association between diet/obesity and resistance to anti-androgen therapies.We briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa progression.We discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine therapies.Finally,we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers,and non-invasive approaches to monitor therapy response.
