DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA sequences.These structures have been found to play a crucial role in highly transcribed genes,especi...DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA sequences.These structures have been found to play a crucial role in highly transcribed genes,especially in cancer-related oncogenes,making them attractive targets for cancer therapeutics.Significantly,targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins,such as MYC,BCL2,KRAS,and EGFR.Natural products have long been an important source of drug discovery,particularly in the fields of cancer and infectious diseases.Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs.Numerous DNA G4s,such as MYC-G4,BCL2-G4,KRAS-G4,PDGFR-b-G4,VEGF-G4,and telomeric-G4,have been identified as potential targets of natural products,including berberine,telomestatin,quindoline,sanguinarine,isaindigotone,and many others.Herein,we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders,focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature.We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.展开更多
Due to uncontrolled cell proliferation and disrupted vascularization,many cancer cells in solid tumors have limited oxygen supply.The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells...Due to uncontrolled cell proliferation and disrupted vascularization,many cancer cells in solid tumors have limited oxygen supply.The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells,contributing to therapy resistance and metastasis.To identify better targets for the effective removal of hypoxia-adaptive cancer cells,it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions.Here,we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering(CRS)microscopy.We discovered the accumulation of lipid droplets(LDs)in the endoplasmic reticulum(ER)in hypoxia.Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure.Additionally,we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation,while glucose was essential to alleviate lipotoxicity.Hyperspectralstimulated Raman scattering(SRS)microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells.This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation.This study unveils important lipid metabolic changes in hypoxic cancer cells,providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.展开更多
The epidermal growth factor receptor(EGFR)is one of the most well-studied signaling pathways in cancer progression.As a result,numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have b...The epidermal growth factor receptor(EGFR)is one of the most well-studied signaling pathways in cancer progression.As a result,numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver.Several of these EGFR inhibitors(EGFRi)have been evaluated in metastatic breast cancer,as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis.Surprisingly,these trials have been unanimously unsuccessful at improving patient outcomes.Numerous factors,such as lack of proper patient selection may have contributed to the failure of these trials.However,recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion,dissemination and ultimate metastasis of breast cancer cells.Herein,we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting.Overall,we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors,a process we term the‘EGFR paradox,’contribute to the clinically observed inherent resistance to EGFRi.Furthermore,this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.展开更多
Diabetes mellitus,with sustained high-sugar levels in the blood,has been steadily rising in prevalence worldwide.Around 12–14%of the US population has been diagnosed with diabetes in recent years.1 One major reason f...Diabetes mellitus,with sustained high-sugar levels in the blood,has been steadily rising in prevalence worldwide.Around 12–14%of the US population has been diagnosed with diabetes in recent years.1 One major reason for the rise of diabetes is dietary changes.Increased consumption of processed carbohydrates with inadequate consumption of dietary fiber(DF)has been recognized as a major risk factor for diabetes,as hypothesized several decades ago by Trowell.展开更多
Dear Editor,Hepatic stellate cells(HSCs)play a key role in the fibrotic response,thus inactivating activated HSC could be a potential therapy for fibrosis.^(1,2) CCL20 expressed by HSCs and macrophages,may serve as a ...Dear Editor,Hepatic stellate cells(HSCs)play a key role in the fibrotic response,thus inactivating activated HSC could be a potential therapy for fibrosis.^(1,2) CCL20 expressed by HSCs and macrophages,may serve as a mediator of in flammation and fibrosis.^(3) LIX1L is a putative RNA-binding protein(RBP)that may play an important role in post-transcriptional gene regulation.^(4) However,the biological function of LIX1L in liver fibrosis remains unclear,we therefore aimed to characterize its functions in HSC activation and liver fibrosis.展开更多
Since the discovery of protein phosphorylation as an important modulator of many cellular processes, the involvement of protein kinases in diseases, such as cancer, diabetes, cardiovascular diseases, and central nervo...Since the discovery of protein phosphorylation as an important modulator of many cellular processes, the involvement of protein kinases in diseases, such as cancer, diabetes, cardiovascular diseases, and central nervous system pathologies, has been extensively documented. Our understanding of many disease pathologies at the molecular level, therefore, requires the comprehensive identification of substrates targeted by protein kinases. In this review, we focus on recent techniques for kinase substrate identification in high throughput, in particular on genetic and proteomic approaches. Each method with its inherent advantages and limitations is discussed.展开更多
Chronic infection of the liver by the hepatitis B virus(HBV)is associated with increased risk for developing hepatocellular carcinoma(HCC).A multitude of studies have investigated the mechanism of liver cancer pathoge...Chronic infection of the liver by the hepatitis B virus(HBV)is associated with increased risk for developing hepatocellular carcinoma(HCC).A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection.Chronic inflammation,expression of specific viral proteins such as HBx,the integration site of the viral genome into the host genome,and the viral genotype,are key players contributing to HCC pathogenesis.In addition,the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis.Despite the plethora of studies,the molecular mechanism of HCC pathogenesis remains incompletely understood.In this review,the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC.Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA,acting by modifying the host chromatin structure via covalent post-translational histone modifications,changing the DNA methylation status,expression of non-coding RNAs such as microRNAs and long noncoding RNAs,and altering the spatial,3-D organization of the chromatin of the virus-infected cell.Herein,studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation.In contrast to genetic mutations which are permanent,epigenetic alterations are dynamic and reversible.Accordingly,the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.展开更多
Tcells are one of the most migratory cells in the body. The development and function of T cells depend on their interaction with other cells, which is, in turn, dependent on optimal cell migra- tion. T cells migrate l...Tcells are one of the most migratory cells in the body. The development and function of T cells depend on their interaction with other cells, which is, in turn, dependent on optimal cell migra- tion. T cells migrate largely in three dif- ferent ways： rapid distribution via blood vessels through hemodynamic move- ment, transendothelial migration and interstitial movement. Transendothelial migration involves sequential activation of selectins, chemokine receptors and integrin molecules expressed by migrat- ing T cells, leading to extravasation from blood vessel into local tissue environ- ments.展开更多
基金supported by the National Institutes of Health(R01CA177585,U01CA240346,and R01CA153821)(DY)the Purdue Center for Cancer Research(P30CA023168)+2 种基金the National Natural Science Foundation of China(82173707 and 82322065)the Program for Jiangsu Province Innovative Research Scholar(JSSCRC2021512)the“Double First-Class”University Project(CPUQNJC22_08).
文摘DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA sequences.These structures have been found to play a crucial role in highly transcribed genes,especially in cancer-related oncogenes,making them attractive targets for cancer therapeutics.Significantly,targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins,such as MYC,BCL2,KRAS,and EGFR.Natural products have long been an important source of drug discovery,particularly in the fields of cancer and infectious diseases.Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs.Numerous DNA G4s,such as MYC-G4,BCL2-G4,KRAS-G4,PDGFR-b-G4,VEGF-G4,and telomeric-G4,have been identified as potential targets of natural products,including berberine,telomestatin,quindoline,sanguinarine,isaindigotone,and many others.Herein,we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders,focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature.We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.
基金supported by a pioneer grant from Purdue Center for Cancer Research and NIH R35GM147092.
文摘Due to uncontrolled cell proliferation and disrupted vascularization,many cancer cells in solid tumors have limited oxygen supply.The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells,contributing to therapy resistance and metastasis.To identify better targets for the effective removal of hypoxia-adaptive cancer cells,it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions.Here,we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering(CRS)microscopy.We discovered the accumulation of lipid droplets(LDs)in the endoplasmic reticulum(ER)in hypoxia.Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure.Additionally,we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation,while glucose was essential to alleviate lipotoxicity.Hyperspectralstimulated Raman scattering(SRS)microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells.This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation.This study unveils important lipid metabolic changes in hypoxic cancer cells,providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.
基金This work was supported in part by the National Institutes of Health(R00CA166140)and the METavivor Foundation.
文摘The epidermal growth factor receptor(EGFR)is one of the most well-studied signaling pathways in cancer progression.As a result,numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver.Several of these EGFR inhibitors(EGFRi)have been evaluated in metastatic breast cancer,as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis.Surprisingly,these trials have been unanimously unsuccessful at improving patient outcomes.Numerous factors,such as lack of proper patient selection may have contributed to the failure of these trials.However,recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion,dissemination and ultimate metastasis of breast cancer cells.Herein,we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting.Overall,we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors,a process we term the‘EGFR paradox,’contribute to the clinically observed inherent resistance to EGFRi.Furthermore,this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer.
基金This study was supported partly from NIH grants(R01AI074745,R01DK076616,R01AI080769 and R01AI121302).
文摘Diabetes mellitus,with sustained high-sugar levels in the blood,has been steadily rising in prevalence worldwide.Around 12–14%of the US population has been diagnosed with diabetes in recent years.1 One major reason for the rise of diabetes is dietary changes.Increased consumption of processed carbohydrates with inadequate consumption of dietary fiber(DF)has been recognized as a major risk factor for diabetes,as hypothesized several decades ago by Trowell.
基金supported by National Natural Science Foundation of China(No.82074068,81872889)Natural Science Foundation of Jiangsu Province(BK20181332)to HZ NIH grant DKO44533 to OA and NIH grant P30CA023168 to the Purdue Center for Cancer Research.The 111 project(Bl8056)+1 种基金the"Double First-Class"University Project(CPU2018GF03)the Drug Innovation Major Project(2018ZX09711-001-007,2018ZX09735002-003)to L.Y.K.
文摘Dear Editor,Hepatic stellate cells(HSCs)play a key role in the fibrotic response,thus inactivating activated HSC could be a potential therapy for fibrosis.^(1,2) CCL20 expressed by HSCs and macrophages,may serve as a mediator of in flammation and fibrosis.^(3) LIX1L is a putative RNA-binding protein(RBP)that may play an important role in post-transcriptional gene regulation.^(4) However,the biological function of LIX1L in liver fibrosis remains unclear,we therefore aimed to characterize its functions in HSC activation and liver fibrosis.
文摘Since the discovery of protein phosphorylation as an important modulator of many cellular processes, the involvement of protein kinases in diseases, such as cancer, diabetes, cardiovascular diseases, and central nervous system pathologies, has been extensively documented. Our understanding of many disease pathologies at the molecular level, therefore, requires the comprehensive identification of substrates targeted by protein kinases. In this review, we focus on recent techniques for kinase substrate identification in high throughput, in particular on genetic and proteomic approaches. Each method with its inherent advantages and limitations is discussed.
基金supported by NIH grant(DK044533)to OA and NIH grant(P30CA023168)to Purdue Center for Cancer Research.
文摘Chronic infection of the liver by the hepatitis B virus(HBV)is associated with increased risk for developing hepatocellular carcinoma(HCC).A multitude of studies have investigated the mechanism of liver cancer pathogenesis due to chronic HBV infection.Chronic inflammation,expression of specific viral proteins such as HBx,the integration site of the viral genome into the host genome,and the viral genotype,are key players contributing to HCC pathogenesis.In addition,the genetic background of the host and exposure to environmental carcinogens are also predisposing parameters in hepatocarcinogenesis.Despite the plethora of studies,the molecular mechanism of HCC pathogenesis remains incompletely understood.In this review,the focus is on epigenetic mechanisms involved in the pathogenesis of HBV-associated HCC.Epigenetic mechanisms are dynamic molecular processes that regulate gene expression without altering the host DNA,acting by modifying the host chromatin structure via covalent post-translational histone modifications,changing the DNA methylation status,expression of non-coding RNAs such as microRNAs and long noncoding RNAs,and altering the spatial,3-D organization of the chromatin of the virus-infected cell.Herein,studies are described that provide evidence in support of deregulation of epigenetic mechanisms in the HBV-infected/-replicating hepatocyte and their contribution to hepatocyte transformation.In contrast to genetic mutations which are permanent,epigenetic alterations are dynamic and reversible.Accordingly,the identification of essential molecular epigenetic targets involved in HBV-mediated HCC pathogenesis offers the opportunity for the design and development of novel epigenetic therapeutic approaches.
文摘Tcells are one of the most migratory cells in the body. The development and function of T cells depend on their interaction with other cells, which is, in turn, dependent on optimal cell migra- tion. T cells migrate largely in three dif- ferent ways： rapid distribution via blood vessels through hemodynamic move- ment, transendothelial migration and interstitial movement. Transendothelial migration involves sequential activation of selectins, chemokine receptors and integrin molecules expressed by migrat- ing T cells, leading to extravasation from blood vessel into local tissue environ- ments.
