Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this s...Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.展开更多
Lassa hemorrhagic fever,caused by Lassa mammarenavirus(LASV)infection,accumulates up to 5000 deaths every year.Currently,there is no vaccine available to combat this disease.In this study,a library of 200 bioactive co...Lassa hemorrhagic fever,caused by Lassa mammarenavirus(LASV)infection,accumulates up to 5000 deaths every year.Currently,there is no vaccine available to combat this disease.In this study,a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block theα-dystroglycan(α-DG)receptor and prevent LASV influx.Following rigorous absorption,distribution,metabolism,and excretion(ADME)and quantitative structure-activity relationship(QSAR)profiling,molecular docking was conducted with the top ligands against theα-DG receptor.The compounds chrysin,reticuline,and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity.Post-docking analysis revealed that interactions with Arg76,Asn224,Ser259,and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands.Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes.In-depth assessment of root-mean-square deviation(RMSD),root mean square fluctuation(RMSF),polar surface area(PSA),B-Factor,radius of gyration(Rg),solvent accessible surface area(SASA),and molecular surface area(MolSA)values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes.To authenticate the potentialities of the ligands as target-specific drugs,an in vivo study is underway in real time as the continuation of the research.展开更多
Magnetic albumin microspheres bearing adriamycin (ADM MAM) is a novel chemotherapeutic compound with site specific drug delivery characteristics. The acute and subacute toxic tests of the compound, local irritating ...Magnetic albumin microspheres bearing adriamycin (ADM MAM) is a novel chemotherapeutic compound with site specific drug delivery characteristics. The acute and subacute toxic tests of the compound, local irritating test and anaphylactic test were performed on mice and guinea pigs. The results showed there was no macroscopically and microscopically direct cytotoxic injuries of the compound to the animal organs or to the cells. The LD 50 value of the compound was higher than that of the single used adriamycin, indicating that the compound was less toxic than the single adriamycin and quite safe in its therapeutic dosage. Furthermore, there was also no side effects or toxic reactions to be observed on clinical patients with advanced carcinoma or gastric cancer.展开更多
Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved t...Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.展开更多
Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as a...Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins(ACDMPV).To correct endothelial dysfunction,there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision.While several nanoparticle delivery systems targeting endothelial cells have been recently developed,none of them are specific to lung endothelial cells without targeting other organs in the body.In the present study,we successfully solved this problem by developing non-toxic poly(β-amino)ester(PBAE)nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells.After intravenous administration,the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types.IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs.Fluorination of PBAE was required for lung endothelial cell-specific targeting.Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice.Thus,fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.展开更多
Flavonoid biosynthetic genes are often coordinately regulated in a temporal manner during flower or fruit development, resulting in specific accumulation profiles of flavonoid compounds. R2R3-MYB-type transcription fa...Flavonoid biosynthetic genes are often coordinately regulated in a temporal manner during flower or fruit development, resulting in specific accumulation profiles of flavonoid compounds. R2R3-MYB-type transcription factors （TFs） ＂recruit＂ a set of biosynthetic genes to produce flavonoids, and, therefore, R2R3-MYBs are responsible for the coordinated expression of structural genes. Although a wealth of information regarding the identified and functionally characterized R2R3-MYBs that are involved in flavonoid accumulation is available to date, this is the first review on the global regulation of MYB factors in the flavonoid pathway. The data presented in this review demonstrate that anthocyanin, flavone/flavonol/3-deoxyflavonoid （FFD）, proanthocyanidin （PA）, and isoflavonoid are independently regulated by different subgroups of R2R3-MYBs. Furthermore, FFD-specific R2R3-MYBs have a preference for early biosynthetic genes （EBGs） as their target genes; anthocyanin-specific R2R3-MYBs from dicot species essentially regulate late biosynthetic genes （LBGs）; the remaining R2R3-MYBs have a wider range of target gene specificity. To elucidate the nature of the differential target gene specificity between R2R3-MYBs, we analyzed the DNA binding domain （also termed the MYB-domain） of R2R3-MYBs and the distribution of the recognition cis-elements. We identified four conserved amino acid residues located in or just before helix-3 of dicot anthocyanin R2R3-MYBs that might account for the different recognition DNA sequence and subsequently the different target gene specificity to the remaining R2R3-MYB TFs.展开更多
A fluorescent turn-on probe for specifically targeting γ-glutamyltranspeptidase （GGT） was designed and synthe- sized by integrating boron-dipyrromethene （BODIPY） as a chromophore and glutathione （GSH） as the GG...A fluorescent turn-on probe for specifically targeting γ-glutamyltranspeptidase （GGT） was designed and synthe- sized by integrating boron-dipyrromethene （BODIPY） as a chromophore and glutathione （GSH） as the GGT sub- strate. GGT-catalyzed the cleavage of the γ-glutamyl bond and generated the aromatic hydrocarbon transfer between the sulfur and the nitrogen atom in BODIPY, leading to distinct optical changes. Such specific responsiveness pro- vides an easily distinguishable fluorescence signal to visualize the GGT activity in living cells and differentiate GGT-positive cancer cells from GGT-negative cells.展开更多
Herein,we first discuss advancements in our understanding of the mechanisms involved in the induction of anesthesia.This includes the fundamentals of anesthesia as shaped by three influential theories:The non-specific...Herein,we first discuss advancements in our understanding of the mechanisms involved in the induction of anesthesia.This includes the fundamentals of anesthesia as shaped by three influential theories:The non-specific lipid theory,the specific protein target theory,and the neural circuit theory.We then discuss the traditional identification of purely passive recovery from anesthesia due to the elimination of anesthetics from the body and brain.This is followed by a recent study that has revealed a common mechanism based on the brain’s intrinsic ability to actively reboot consciousness from anesthesia.Finally,a novel theory of how the brain emerges from anesthesia and regains consciousness is presented.展开更多
In recent years, macromolecules such as antibodies, peptides,and nucleic acids have captured a significant share of the pharmaceutical market. Compared to small-molecule drugs, macromolecules exhibit superior target s...In recent years, macromolecules such as antibodies, peptides,and nucleic acids have captured a significant share of the pharmaceutical market. Compared to small-molecule drugs, macromolecules exhibit superior target specificity due to their structural complexity and precise biological mechanisms, including antigen-antibody recognition, ligand-receptor interactions,and complementary base pairing [1,2]. These properties enhance their safety profile and reduce toxicity. However, the oral absorption of macromolecules is particularly challenging due to their large molecular weight and complex spatial conformation [3].展开更多
Transcription factors(TFs)regulate gene expression by binding to cis-regulatory sequences in the promoters of target genes.Recent research is helping to decipher in part the cis-regulatory code in eukaryotes,including...Transcription factors(TFs)regulate gene expression by binding to cis-regulatory sequences in the promoters of target genes.Recent research is helping to decipher in part the cis-regulatory code in eukaryotes,including plants,but it is not yet fully understood how paralogous TFs select their targets.Here we addressed this question by studying several proteins of the basic helix-loop-helix(bHLH)family of plant TFs,all of which recognize the same DNA motif.We focused on the MYC-related group of bHLHs,that redundantly regulate the jasmonate(JA)signaling pathway,and we observed a high correspondence between DNA-binding profiles in vitro and MYC function in vivo.We demonstrated that A/T-rich modules flanking the MYC-binding motif,conserved from bryophytes to higher plants,are essential for TF recognition.We observed particular DNA-shape features associated with A/T modules,indicating that the DNA shape may contribute to MYC DNA binding.We extended this analysis to 20 additional bHLHs and observed correspondence between in vitro binding and protein function,but it could not be attributed to A/T modules as in MYCs.We conclude that different bHLHs may have their own codes for DNA binding and specific selection of targets that,at least in the case of MYCs,depend on the TF-DNA interplay.展开更多
基金support from the Open Access Publication Fund of the University of Duisburg-Essensupported by the Deutsche Forschungsgemeinschaft(DFG/JA-2461/7-1)+1 种基金CRC TRR332 project A05 to JJthe Stiftung Tumorforschung Kopf-Hals to CK.
文摘Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.
文摘Lassa hemorrhagic fever,caused by Lassa mammarenavirus(LASV)infection,accumulates up to 5000 deaths every year.Currently,there is no vaccine available to combat this disease.In this study,a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block theα-dystroglycan(α-DG)receptor and prevent LASV influx.Following rigorous absorption,distribution,metabolism,and excretion(ADME)and quantitative structure-activity relationship(QSAR)profiling,molecular docking was conducted with the top ligands against theα-DG receptor.The compounds chrysin,reticuline,and 3-caffeoylshikimic acid emerged as the top three ligands in terms of binding affinity.Post-docking analysis revealed that interactions with Arg76,Asn224,Ser259,and Lys302 amino acid residues of the receptor protein were important for the optimum binding affinity of ligands.Molecular dynamics simulation was performed comprehensively to study the stability of the protein-ligand complexes.In-depth assessment of root-mean-square deviation(RMSD),root mean square fluctuation(RMSF),polar surface area(PSA),B-Factor,radius of gyration(Rg),solvent accessible surface area(SASA),and molecular surface area(MolSA)values of the protein-ligand complexes affirmed that the candidates with the best binding affinity formed the most stable protein-ligand complexes.To authenticate the potentialities of the ligands as target-specific drugs,an in vivo study is underway in real time as the continuation of the research.
基金This project was supported by a grant from the National Key Tasks'foundation(No.96 90 6 0 116 )
文摘Magnetic albumin microspheres bearing adriamycin (ADM MAM) is a novel chemotherapeutic compound with site specific drug delivery characteristics. The acute and subacute toxic tests of the compound, local irritating test and anaphylactic test were performed on mice and guinea pigs. The results showed there was no macroscopically and microscopically direct cytotoxic injuries of the compound to the animal organs or to the cells. The LD 50 value of the compound was higher than that of the single used adriamycin, indicating that the compound was less toxic than the single adriamycin and quite safe in its therapeutic dosage. Furthermore, there was also no side effects or toxic reactions to be observed on clinical patients with advanced carcinoma or gastric cancer.
文摘Pegylated interferon α (IFNα) in combination with ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. This combination therapy has drastically improved the rate of sustained virological response, specifically in difficult-to-treat patients. Recently, individualized treatment, such as response-guided therapy, is being developed based on host-, HCV- and treatment-related factors. Furthermore, modified regimens with currently available medications, novel modified IFNα and ribavirin or combinations with specifically targeted antiviral therapy for HCV agents, are currently being investigated. The purpose of this review is to address some issues and epoch-making topics in the treatment of chronic HCV infection, and to discuss more optimal and highly individualized therapeutic strategies for HCV-infected patients.
文摘Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension,viral and bacterial pneumonia,bronchopulmonary dysplasia,and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins(ACDMPV).To correct endothelial dysfunction,there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision.While several nanoparticle delivery systems targeting endothelial cells have been recently developed,none of them are specific to lung endothelial cells without targeting other organs in the body.In the present study,we successfully solved this problem by developing non-toxic poly(β-amino)ester(PBAE)nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells.After intravenous administration,the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types.IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs.Fluorination of PBAE was required for lung endothelial cell-specific targeting.Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice.Thus,fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.
文摘Flavonoid biosynthetic genes are often coordinately regulated in a temporal manner during flower or fruit development, resulting in specific accumulation profiles of flavonoid compounds. R2R3-MYB-type transcription factors （TFs） ＂recruit＂ a set of biosynthetic genes to produce flavonoids, and, therefore, R2R3-MYBs are responsible for the coordinated expression of structural genes. Although a wealth of information regarding the identified and functionally characterized R2R3-MYBs that are involved in flavonoid accumulation is available to date, this is the first review on the global regulation of MYB factors in the flavonoid pathway. The data presented in this review demonstrate that anthocyanin, flavone/flavonol/3-deoxyflavonoid （FFD）, proanthocyanidin （PA）, and isoflavonoid are independently regulated by different subgroups of R2R3-MYBs. Furthermore, FFD-specific R2R3-MYBs have a preference for early biosynthetic genes （EBGs） as their target genes; anthocyanin-specific R2R3-MYBs from dicot species essentially regulate late biosynthetic genes （LBGs）; the remaining R2R3-MYBs have a wider range of target gene specificity. To elucidate the nature of the differential target gene specificity between R2R3-MYBs, we analyzed the DNA binding domain （also termed the MYB-domain） of R2R3-MYBs and the distribution of the recognition cis-elements. We identified four conserved amino acid residues located in or just before helix-3 of dicot anthocyanin R2R3-MYBs that might account for the different recognition DNA sequence and subsequently the different target gene specificity to the remaining R2R3-MYB TFs.
基金We gratefully acknowledge the financial support by the National Natural Science Foundation of China （Nos. 21372083. 21672062）.
文摘A fluorescent turn-on probe for specifically targeting γ-glutamyltranspeptidase （GGT） was designed and synthe- sized by integrating boron-dipyrromethene （BODIPY） as a chromophore and glutathione （GSH） as the GGT sub- strate. GGT-catalyzed the cleavage of the γ-glutamyl bond and generated the aromatic hydrocarbon transfer between the sulfur and the nitrogen atom in BODIPY, leading to distinct optical changes. Such specific responsiveness pro- vides an easily distinguishable fluorescence signal to visualize the GGT activity in living cells and differentiate GGT-positive cancer cells from GGT-negative cells.
基金National Natural Science Foundation of China(No.82350710225)
文摘Herein,we first discuss advancements in our understanding of the mechanisms involved in the induction of anesthesia.This includes the fundamentals of anesthesia as shaped by three influential theories:The non-specific lipid theory,the specific protein target theory,and the neural circuit theory.We then discuss the traditional identification of purely passive recovery from anesthesia due to the elimination of anesthetics from the body and brain.This is followed by a recent study that has revealed a common mechanism based on the brain’s intrinsic ability to actively reboot consciousness from anesthesia.Finally,a novel theory of how the brain emerges from anesthesia and regains consciousness is presented.
基金supported by the National Key Research and Development Program of China (2020YFA0908200)the National Natural Science Foundation of China (32271383)。
文摘In recent years, macromolecules such as antibodies, peptides,and nucleic acids have captured a significant share of the pharmaceutical market. Compared to small-molecule drugs, macromolecules exhibit superior target specificity due to their structural complexity and precise biological mechanisms, including antigen-antibody recognition, ligand-receptor interactions,and complementary base pairing [1,2]. These properties enhance their safety profile and reduce toxicity. However, the oral absorption of macromolecules is particularly challenging due to their large molecular weight and complex spatial conformation [3].
文摘Transcription factors(TFs)regulate gene expression by binding to cis-regulatory sequences in the promoters of target genes.Recent research is helping to decipher in part the cis-regulatory code in eukaryotes,including plants,but it is not yet fully understood how paralogous TFs select their targets.Here we addressed this question by studying several proteins of the basic helix-loop-helix(bHLH)family of plant TFs,all of which recognize the same DNA motif.We focused on the MYC-related group of bHLHs,that redundantly regulate the jasmonate(JA)signaling pathway,and we observed a high correspondence between DNA-binding profiles in vitro and MYC function in vivo.We demonstrated that A/T-rich modules flanking the MYC-binding motif,conserved from bryophytes to higher plants,are essential for TF recognition.We observed particular DNA-shape features associated with A/T modules,indicating that the DNA shape may contribute to MYC DNA binding.We extended this analysis to 20 additional bHLHs and observed correspondence between in vitro binding and protein function,but it could not be attributed to A/T modules as in MYCs.We conclude that different bHLHs may have their own codes for DNA binding and specific selection of targets that,at least in the case of MYCs,depend on the TF-DNA interplay.
