OBJECTIVE To establish a small compound library via a versatile synthetic route for the investigation of natural-inspiring compounds containing N-hydroxypyridones motif as potential anti-plasmodial,anti-bacterial and ...OBJECTIVE To establish a small compound library via a versatile synthetic route for the investigation of natural-inspiring compounds containing N-hydroxypyridones motif as potential anti-plasmodial,anti-bacterial and iron(Ⅱ)-chelating agents.METHODS An amidation/cyclization approach was adopted to synthesize a library of N-hydroxyquinolinones.The anti-plasmodial susceptibility of lab clone 3D7 P.falciparum was measured using aprotocol modified from the WHO microtest.The minimum bactericidal concentration(MBC)values were determined against Escherichia coli and Staphylococcus arueus.Nine compounds were selected to test their iron(Ⅱ)-chelating abilities.The iron(Ⅱ)-chelating ability was determined by measuring the absorbance of ferrozine-iron complex at 562 nm.RESULTS A new route for the facile synthesis of a library of N-hydroxyquinolinones based on one-pot palladium catalyzed C-N amidation/dehydrocyclizationsequence was implemented.Four compounds show anti-plasmodial activities with the range of 1.1-1.4μmol·L-1,50% chelation abilities of the nine selected compounds were shown to be 0.24-0.29mmol·L-1.CONCLUSION Alibrary of N-hydroxyquinolinones was synthesized via a novel synthetic route.The anti-plasmodial and anti-bacterial activities of these compounds were evaluated.Four compounds show potent anti-plasmodial activities Nine compounds were examined for their propensities to undergo iron chelation and these compounds were shown to be promising iron(Ⅱ)chelators as compared to EDTA.展开更多
The Convergence of Hematology and Immunology(CHI),which was sponsored by State Key Laboratory of Experimental Hematology,Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences(CAMS),wa...The Convergence of Hematology and Immunology(CHI),which was sponsored by State Key Laboratory of Experimental Hematology,Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences(CAMS),was held in Tianjin,China.Co-chaired by Tao Cheng of Institute of Hematology and Blood Diseases Hospital at CAMS(Tianjin,China),Lai Guan NG,and Florent Ginhoux of Singapore Immunology Network(Singapore),the two-day meeting invited 34 scientists from China,the United States,Singapore,Israel,Sweden,Switzerland,Japan,Italy,and Australia to present and share their latest views on the topics in hematology and immunology.展开更多
Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor...Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.展开更多
Nucleotide-binding oligomerization domain(NOD)-containing protein-like receptors(NLRs)are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response followi...Nucleotide-binding oligomerization domain(NOD)-containing protein-like receptors(NLRs)are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition.Some NLRs form the framework for cytosolic platforms called inflammasomes,which orchestrate the early inflammatory process via IL-1b activation.Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases.Moreover,the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis.In this review,we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.展开更多
There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been sho...There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition,origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes.展开更多
Neutrophils are essential immune cells that defend the host against pathogenic microbial agents.Neutrophils are produced in the bone marrow and are retained there through CXCR4–CXCL12 signaling.However,patients with ...Neutrophils are essential immune cells that defend the host against pathogenic microbial agents.Neutrophils are produced in the bone marrow and are retained there through CXCR4–CXCL12 signaling.However,patients with the Warts,Hypogammaglobulinemia,Infections,and Myelokathexis(WHIM)syndrome are prone to infections due to increased accumulation of neutrophils in the bone marrow leading to low numbers of circulating neutrophils.How neutrophils accumulate in the bone marrow in this condition is poorly understood.To better understand factors involved in neutrophil accumulation in the bone marrow,neutrophils from wildtype and WHIM mouse models were characterized in their response to CXCL12 stimulation.WHIM neutrophils were found to exert stronger traction forces,formed significantly more lamellipodia-type protrusions and migrated with increased speed and displacement upon CXCL12 stimulation as compared to wildtype cells.Migration speed of WHIM neutrophils showed a larger initial increase upon CXCL12 stimulation,which decayed over a longer time period as compared to wildtype cells.We proposed a computational model based on the chemotactic behavior of neutrophils that indicated increased CXCL12 sensitivity and prolonged CXCR4 internalization adaptation time in WHIM neutrophils as being responsible for increased accumulation in the bone marrow.These findings provide a mechanistic understanding of bone marrow neutrophil accumulation in WHIM condition and novel insights into restoring neutrophil regulation in WHIM patients.展开更多
基金The project supported by the Agency for Science Technology and Research(A*STAR)(JCO-10/03/FG/06/02)
文摘OBJECTIVE To establish a small compound library via a versatile synthetic route for the investigation of natural-inspiring compounds containing N-hydroxypyridones motif as potential anti-plasmodial,anti-bacterial and iron(Ⅱ)-chelating agents.METHODS An amidation/cyclization approach was adopted to synthesize a library of N-hydroxyquinolinones.The anti-plasmodial susceptibility of lab clone 3D7 P.falciparum was measured using aprotocol modified from the WHO microtest.The minimum bactericidal concentration(MBC)values were determined against Escherichia coli and Staphylococcus arueus.Nine compounds were selected to test their iron(Ⅱ)-chelating abilities.The iron(Ⅱ)-chelating ability was determined by measuring the absorbance of ferrozine-iron complex at 562 nm.RESULTS A new route for the facile synthesis of a library of N-hydroxyquinolinones based on one-pot palladium catalyzed C-N amidation/dehydrocyclizationsequence was implemented.Four compounds show anti-plasmodial activities with the range of 1.1-1.4μmol·L-1,50% chelation abilities of the nine selected compounds were shown to be 0.24-0.29mmol·L-1.CONCLUSION Alibrary of N-hydroxyquinolinones was synthesized via a novel synthetic route.The anti-plasmodial and anti-bacterial activities of these compounds were evaluated.Four compounds show potent anti-plasmodial activities Nine compounds were examined for their propensities to undergo iron chelation and these compounds were shown to be promising iron(Ⅱ)chelators as compared to EDTA.
文摘The Convergence of Hematology and Immunology(CHI),which was sponsored by State Key Laboratory of Experimental Hematology,Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Sciences(CAMS),was held in Tianjin,China.Co-chaired by Tao Cheng of Institute of Hematology and Blood Diseases Hospital at CAMS(Tianjin,China),Lai Guan NG,and Florent Ginhoux of Singapore Immunology Network(Singapore),the two-day meeting invited 34 scientists from China,the United States,Singapore,Israel,Sweden,Switzerland,Japan,Italy,and Australia to present and share their latest views on the topics in hematology and immunology.
文摘Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.
基金This work was supported by Agency for Science,Technology and Research(A*STAR)of Singapore.
文摘Nucleotide-binding oligomerization domain(NOD)-containing protein-like receptors(NLRs)are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition.Some NLRs form the framework for cytosolic platforms called inflammasomes,which orchestrate the early inflammatory process via IL-1b activation.Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases.Moreover,the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis.In this review,we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.
基金This work was supported by Singapore Immunology Network(SigN)core funding,A*STAR,Singapore to L.G.N.
文摘There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition,origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target "tumorreprogrammed" neutrophils while sparing normal neutrophils to improve patient outcomes.
文摘Neutrophils are essential immune cells that defend the host against pathogenic microbial agents.Neutrophils are produced in the bone marrow and are retained there through CXCR4–CXCL12 signaling.However,patients with the Warts,Hypogammaglobulinemia,Infections,and Myelokathexis(WHIM)syndrome are prone to infections due to increased accumulation of neutrophils in the bone marrow leading to low numbers of circulating neutrophils.How neutrophils accumulate in the bone marrow in this condition is poorly understood.To better understand factors involved in neutrophil accumulation in the bone marrow,neutrophils from wildtype and WHIM mouse models were characterized in their response to CXCL12 stimulation.WHIM neutrophils were found to exert stronger traction forces,formed significantly more lamellipodia-type protrusions and migrated with increased speed and displacement upon CXCL12 stimulation as compared to wildtype cells.Migration speed of WHIM neutrophils showed a larger initial increase upon CXCL12 stimulation,which decayed over a longer time period as compared to wildtype cells.We proposed a computational model based on the chemotactic behavior of neutrophils that indicated increased CXCL12 sensitivity and prolonged CXCR4 internalization adaptation time in WHIM neutrophils as being responsible for increased accumulation in the bone marrow.These findings provide a mechanistic understanding of bone marrow neutrophil accumulation in WHIM condition and novel insights into restoring neutrophil regulation in WHIM patients.
