Despite that some approved drugs and genetically engineered vaccines against hepatitis B virus(HBV)are available for HBV patients,HBV infection is still a severe public health problem in the world.All the approved the...Despite that some approved drugs and genetically engineered vaccines against hepatitis B virus(HBV)are available for HBV patients,HBV infection is still a severe public health problem in the world.All the approved therapeutic drugs(including interferonalpha and nucleoside analogues)have their limitations.No drugs or therapeutic methods can cure hepatitis B so far.Therefore,it is urgently needed to discover and develop new anti-HBV drugs,especially nonnucleoside agents.Naturally originated compounds with enormous molecular complexity and diversity offer a great opportunity to find novel anti-HBV lead compounds with specific antiviral mechanisms.In this review,the natural products against HBV are discussed according to their chemical classes such as terpenes,lignans,phenolic acids,polyphenols,lactones,alkaloids and flavonoids.Furthermore,novel mode of action or new targets of some representative anti-HBV natural products are also discussed.The aim of this review is to report new discoveries and updates pertaining to anti-HBV natural products in the last 20years,especially novel skeletons and mode of action.Although many natural products with various skeletons have been reported to exhibit potent anti-HBV effects to date,scarcely any of them are found in the list of conventional anti-HBV drugs worldwide.Additionly,in anti-HBV mechanism of action,only a few references reported new targets or novel mode of action of antiHBV natural products.展开更多
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form...Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging;a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.展开更多
Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inh...Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC_(50)) of 2.8 and0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.展开更多
Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves isc...Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.展开更多
The cotton sesquiterpene cyclase, (+)-δ-cadinene synthase.is encoded by a gene family, which can be divided into two subfamilies: CAD1-A and CAD1-C. The gene CAD1-A was isolated from G. arboreum. In situ hybridizatio...The cotton sesquiterpene cyclase, (+)-δ-cadinene synthase.is encoded by a gene family, which can be divided into two subfamilies: CAD1-A and CAD1-C. The gene CAD1-A was isolated from G. arboreum. In situ hybridization performed on seven-day-old cotton seedlings localized transcripts of both the CAD1-A and CAD1-C mainly in lateral root primordium and apical ground meristem, vascular tissues of emerging lateral roots, and also in procambium and some subepidermal cells of the hypocotyl. The CAD1-A promoter showed a similar tissue-specificity in transgenic tobacco plants. Histochemistry showed occurrence of sesquiterpene aldehydes in outer cells of the lateral root tips, as well as in pigment glands. The CAD1 gene expression in G. arboreum seedlings and the spatial pattern of sesquiterpene biosynthesis constitute a chemical defense machinery in cotton seedlings.展开更多
Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a ...Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.展开更多
Recent genome-wide association studies(GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms(SNPs), especially rs2736100 locat...Recent genome-wide association studies(GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms(SNPs), especially rs2736100 located in the telomerase reverse transcriptase(TERT) gene show unique and significant association with non-small cell lung cancer(NSCLC) in a few subpopulations including women,nonsmokers, East Asians and those with adenocarcinoma. Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental(e.g., less-smoking) and physiological factors(gender and age) that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor(EGFR) mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity. By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.展开更多
The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level i...The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.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
基金Supported by Zhejiang Provincial Natural Science Foundation of China,No.LY14H310010Public Welfare Technology Applied Research Project of Zhejiang Province?Experimental Animal Science and Technology Project,No.2013C37020Key Project of Chinese Ministry of Education,No.212073
文摘Despite that some approved drugs and genetically engineered vaccines against hepatitis B virus(HBV)are available for HBV patients,HBV infection is still a severe public health problem in the world.All the approved therapeutic drugs(including interferonalpha and nucleoside analogues)have their limitations.No drugs or therapeutic methods can cure hepatitis B so far.Therefore,it is urgently needed to discover and develop new anti-HBV drugs,especially nonnucleoside agents.Naturally originated compounds with enormous molecular complexity and diversity offer a great opportunity to find novel anti-HBV lead compounds with specific antiviral mechanisms.In this review,the natural products against HBV are discussed according to their chemical classes such as terpenes,lignans,phenolic acids,polyphenols,lactones,alkaloids and flavonoids.Furthermore,novel mode of action or new targets of some representative anti-HBV natural products are also discussed.The aim of this review is to report new discoveries and updates pertaining to anti-HBV natural products in the last 20years,especially novel skeletons and mode of action.Although many natural products with various skeletons have been reported to exhibit potent anti-HBV effects to date,scarcely any of them are found in the list of conventional anti-HBV drugs worldwide.Additionly,in anti-HBV mechanism of action,only a few references reported new targets or novel mode of action of antiHBV natural products.
基金Indiana University Collaborative Research GrantIndiana Clinical and Translational Sciences Institute,No.NIH UL1TR001108,No.NIH R01 AR069657,No.NIH R01AR060863 and No.NIH R01AG060621
文摘Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging;a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
基金support from National Institute of Health(NIH)grants R01GM117275(RH)P30 CA023168(Purdue University Center for Cancer Research,West Lafayette,IN,USA)
文摘Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC_(50)) of 2.8 and0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.
基金supported by research grants from the National Natural Science Foundation of China(81573410)the National Science and Technology Major Project(2018ZX09711001-004006,China)the Natural Sciences Foundation of Shandong Province(ZR2015QL008,China)awarded to Kewei Wang
文摘Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.
文摘The cotton sesquiterpene cyclase, (+)-δ-cadinene synthase.is encoded by a gene family, which can be divided into two subfamilies: CAD1-A and CAD1-C. The gene CAD1-A was isolated from G. arboreum. In situ hybridization performed on seven-day-old cotton seedlings localized transcripts of both the CAD1-A and CAD1-C mainly in lateral root primordium and apical ground meristem, vascular tissues of emerging lateral roots, and also in procambium and some subepidermal cells of the hypocotyl. The CAD1-A promoter showed a similar tissue-specificity in transgenic tobacco plants. Histochemistry showed occurrence of sesquiterpene aldehydes in outer cells of the lateral root tips, as well as in pigment glands. The CAD1 gene expression in G. arboreum seedlings and the spatial pattern of sesquiterpene biosynthesis constitute a chemical defense machinery in cotton seedlings.
基金support from NIH P30 CA023168(Purdue University Center for Cancer Research)the NSERC grant(RGPIN-2021-02728(Jinrong Min)).
文摘Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.
基金supported in part by American Cancer SocietyIL Division (Grant No. 189273) (to W. Liu)Start-Up Fund of the College of Pharmacy, Purdue University (Grant No. 003055) (to W. Liu)
文摘Recent genome-wide association studies(GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms(SNPs), especially rs2736100 located in the telomerase reverse transcriptase(TERT) gene show unique and significant association with non-small cell lung cancer(NSCLC) in a few subpopulations including women,nonsmokers, East Asians and those with adenocarcinoma. Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental(e.g., less-smoking) and physiological factors(gender and age) that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor(EGFR) mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity. By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.
基金supported in part by a NIH grant,No.R01 DK106540(to WL).
文摘The genetic basis underlying liver fibrosis remains largely unknown.We conducted a study to identify genetic alleles and underlying pathways associated with hepatic fibrogenesis and fibrosis at the genome-wide level in 121 human livers.By accepting a liberal significance level of P<1e-4,we identified 73 and 71 candidate loci respectively affecting the variability in alpha-smooth muscle actin(a-SMA)levels(fibrogenesis)and total collagen content(fibrosis).The top genetic loci associated with the two markers were BAZA1 and NOL10 for a-SMA expression and FAM46A for total collagen content(P<1e-6).We further investigated the relationship between the candidate loci and the nearby gene transcription levels(cis-expression quantitative trait loci)in the same liver samples.We found that 44 candidate loci for a-SMA expression and 44 for total collagen content were also associated with the transcription of the nearby genes(P<0.05).Pathway analyses of these genes indicated that macrophage migration inhibitory factor(MIF)related pathway is significantly associated with fibrogenesis and fibrosis,though different genes were enriched for each marker.The association between the single nucleotide polymorphisms,MIF and a-SMA showed that decreased MIF expression is correlated with increased a-SMA expression,suggesting that variations in MIF locus might affect the susceptibility of fibrogenesis through controlling MIF gene expression.In summary,our study identified candidate alleles and pathways underlying both fibrogenesis and fibrosis in human livers.Our bioinformatics analyses suggested MIF pathway as a strong candidate involved in liver fibrosis,thus further investigation for the role of the MIF pathway in liver fibrosis is warranted.The study was reviewed and approved by the Institutional Review Board(IRB)of Wayne State University(approval No.201842)on May 17,2018.
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.
