Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer（CRC）.The long-term use of non-steroidal anti-inflammatory drugs（NSAIDs） has been shown to reduce the...The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer（CRC）.The long-term use of non-steroidal anti-inflammatory drugs（NSAIDs） has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies.The NSA1 D sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC.The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity.Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMβ-dependent protein kinase,PKG,through the elevation of the second messenger cyclic guanosine monophosphote,cGMP.PKG activation has been shown to inhibit the nuclear translocation of β-catenin,reduce β-catenin mRNA and protein levels,and suppress the transcriptional activity of β-catenin.This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.展开更多
Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests tha...Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests that impaired cholesterol metabolism,increased lipid uptake or synthesis,increased fatty acid oxidation,lipid droplet accumulation and an imbalance in biologically active sphingolipids(such as ceramide,ceramide-1-phosphate and sphingosine-1-phosphate)contribute to the development of diabetic kidney disease(DKD).Currently,the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production,oxidative stress,inflammation,or cell death.Therefore,control of renal lipid dysmetabolism is a very important therapeutic goal,which needs to be archived.This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.展开更多
Glioblastoma multiforme(GBM) is an essentially incurable brain tumor, which has been explored for approximately a century. Nowadays, surgical resection, chemotherapy, and radiation therapy are still the standardized t...Glioblastoma multiforme(GBM) is an essentially incurable brain tumor, which has been explored for approximately a century. Nowadays, surgical resection, chemotherapy, and radiation therapy are still the standardized therapeutic options. However, due to the intrinsic invasion and metastasis features and the resistance to chemotherapy, the survival rate of glioblastoma patients remains unsatisfactory. To improve the current situation, much more research is needed to provide comprehensive knowledge of GBM. In this review, we summarize the latest updates on GBM treatment and invasion. Firstly, we review the traditional and emerging therapies that have been used for GBM treatment. Given the limited efficiency of these therapies, we further discuss the role of invasion in GBM recurrence and progression, and present current research progress on the mode and mechanisms of GBM invasion.展开更多
Nicotiflorin is a flavonoid extracted from Carthamus tinctorius.Previous studies have shown its cerebral protective effect,but the mechanism is undefined.In this study,we aimed to determine whether nicotiflorin protec...Nicotiflorin is a flavonoid extracted from Carthamus tinctorius.Previous studies have shown its cerebral protective effect,but the mechanism is undefined.In this study,we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway.The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion.Nicotiflorin（10 mg/kg） was administered by tail vein injection.Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase d UTP nick end labeling assay.Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining.Additionally,p-JAK2,p-STAT3,Bcl-2,Bax,and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay.Nicotiflorin altered the shape and structure of injured neurons,decreased the number of apoptotic cells,down-regulates expression of p-JAK2,p-STAT3,caspase-3,and Bax,decreased Bax immunoredactivity,and increased Bcl-2 protein expression and immunoreactivity.These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.展开更多
Aim To identify heterogeneity of Candida albicans （C. albicans） isolated from the population with cancer in China by using identification medium, subculture molecular typing, and antifungal susceptibility test. Meth...Aim To identify heterogeneity of Candida albicans （C. albicans） isolated from the population with cancer in China by using identification medium, subculture molecular typing, and antifungal susceptibility test. Methodology Oral cheek mucosal specimens from 52 cancer patients receiving chemotherapy were cultured on CHROMagar CandidaTM plates for Candida identification. All the C. albicans colonies on the plates were subcultured and reconfirmed by API20C, then submitted to the antifimgal drug susceptibility test with fluconazole and molecular typing using randomly amplified polymorphic DNA-PCR （RAPD） with primers RSD6 and RSD12.Results 54% （28/52） patients were oral yeast carriage in which C. albicans predominated. More than 7 C. albicans colonies were isolated from each of 12 patients （Group A）, while less than 5 colonies were isolated from each of 16 patients （Group B）. RSD6 and RSD12 were successful in eliciting 17 （A1-A17） and 2 （B1-B2） genotypes, respectively from among the 205 isolates. The two primers were combined to generate 21 genotypes. The C. albicans isolates obtained from the same patient and episode showed a diversity for fluconazole revealed by MIC50 and MIC90. Conclusion The heterogeneity of the C. albicans colonies isolated from the same patients can be detected. C. albicans with varied fluconazole susceptibility and genotypic characteristics may coexist in the same oral Candida population.展开更多
Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. L...Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. Lycorine, an alkaloid from Amaryllidaceae plants, has antiviral activity against a number of viruses such as coronavirus, flavivirus and enterovirus. In this study, we found that lycorine could inhibit CHIKV in cell culture at a concentration of 10 lmol/L without apparent cytotoxicity. In addition, it exhibited broad-spectrum anti-alphavirus activity, including Sindbis virus(SINV),Semliki Forest virus(SFV), and Venezuelan equine encephalomyelitis virus(VEEV). The time of addition studies indicated that lycorine functions at an early post-entry stage of CHIKV life cycle. The results based on two different CHIKV replicons provided further evidence that lycorine exerts its antiviral activity mainly by inhibiting CHIKV translation.Overall, our study extends the antiviral spectrum of lycorine.展开更多
Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino ...Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert hornologation, the optically pure precursor R-amino acid is difficult to prepare. We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in 〉99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure. This protocol requires only cheap starting materials and friendly reaction condition. The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare α-amino acid and the subsequent β-amino acid.展开更多
[ Objective ] This study aimed to investigate the optimal method for extracting RNA from roots of medicinal plant herba violae by comparing the effects of liquid nitrogen grinding method and low-temperature sectioning...[ Objective ] This study aimed to investigate the optimal method for extracting RNA from roots of medicinal plant herba violae by comparing the effects of liquid nitrogen grinding method and low-temperature sectioning method on RNA extraction. [ Method] Roots of herba violae were respectively crushed by using liquid nitrogen grinding method and low-temperature sectioning method to extract RNA. The extraction effects of these two methods were compared based on detec- tion of RNA concentration, purity and integrity and amplification of GAPDH gene by RT-PCR. [Result] The concentration of RNA extracted by liquid nitrogen grinding method and low-temperature sectioning method was 1.21 and 3.57 p^g/~, respectively. Both RNA extracted by these two methods showed two distinct bands after agarose gel electrophoresis. The ratio of brightness of the 28S rRNA to the 18S rRNA bands was greater than 1. PCR amplification showed that the length of GAPDH gene was about 230 bp, which was consistent with the expected result. [ Conclusion ] The experimental results indicated that using low-tempera ture sectioning method to crush the roots of herba violae can meet the needs of most molecular biological experiments including gene cloning and expression analysis, which is an effective and simple method for extracting RNA from plant roots.展开更多
ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonstero...ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.展开更多
Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely r...Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely related to their physicochemical properties,and establishment of a structure-activity relationship for nanomaterials at the nano-bio interface is of great significance for deep understanding antibacterial toxicity mechanisms of nanomaterials and designing safer antibacterial nanomaterials.In this study,the antibacterial behaviors of well-defined crystallographic facets of a series of Au nanocrystals,including{100}-facet cubes,{110}-facet rhombic dodecahedra,{111}-facet octahedra,{221}-facet trisoctahedra and{720}-facet concave cubes,was investigated,using the model bacteria Staphylococcus aureus.We find that Au nanocrystals display substantial facet-dependent antibacterial activities.The low-index facets of cubes,octahedra,and rhombic dodecahedra show considerable antibacterial activity,whereas the high-index facets of trisoctahedra and concave cubes remained inert under biological conditions.This result is in stark contrast to the previous paradigm that the high-index facets were considered to have higher bioactivity as compared with low-index facets.The antibacterial mechanism studies have shown that the facet-dependent antibacterial behaviors of Au nanocrystals are mainly caused by differential bacterial membrane damage as well as inhibition of cellular enzymatic activity and energy metabolism.The faceted Au nanocrystals are unique in that they do not induce generation of reactive oxygen species,as validated for most antibiotics and antimicrobial nanostructures.Our findings may provide a deeper understanding of facet-dependent toxicological responses and suggest the complexities of the na no material-cell interactions,shedding some light on the development of high performance Au nanomaterials-based antibacterial therapeutics.展开更多
Given the important roles of miRNAs in post-transcriptional gene regulation, identification of differentially expressed miRNAs will facilitate the elucidation of molecular mechanisms underlying kernel development. In ...Given the important roles of miRNAs in post-transcriptional gene regulation, identification of differentially expressed miRNAs will facilitate the elucidation of molecular mechanisms underlying kernel development. In this study, we constructed a small RNA library to comprehensively represent the full complement of individual small RNAs and to characterize miRNA expression profiles in pooled ears of maize(Zea mays L.) at 10, 15,20, 22, 25 and 30 days after pollination(DAP). At least 21 miRNAs were differentially expressed. The differential expression of three of these miRNAs, i.e., miR528a, miR167a and miR160b, at each stage was verified by qRT-PCR. The results indicated that these miRNAs might be involved in kernel development. In addition, the predicted functions of target genes indicated that most of the target genes are involved in signal transduction and cell communication pathways, particularly the auxin signaling pathway. The expression of candidate germination-associated miRNAs was analyzed by hybridization to a maize genome microarray, and revealed differential expression of genes involved in plant hormone signaling pathways. This finding suggests that phytohormones play a critical role in the development of maize kernels. We found that in combination with other miRNAs, miR528a regulated a putative laccase, a Ring-H2 zinc finger protein and a MADS box-like protein, whereas miR167a and miR160b regulated multiple target genes,including ARF(auxin response factor), a member of the B3 transcription factor family. All three miRNAs are important for ear germination, development and physiology. The small RNA transcriptomes and mRNA obtained in this study will help us gain a betterunderstanding of the expression and function of small RNAs in the development of maize kernel.展开更多
Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generati...Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,respectively.The total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.展开更多
Plasminogen activator inhibitor-1(PAI-1)is the primary inhibitor of urinary-type and tissue-type plasmino-gen activators and a key regulator of fibrinolysis.PAI-1 also regulates the function of vascular cells,includin...Plasminogen activator inhibitor-1(PAI-1)is the primary inhibitor of urinary-type and tissue-type plasmino-gen activators and a key regulator of fibrinolysis.PAI-1 also regulates the function of vascular cells,includingvascular smooth muscle cells(VSMCs).展开更多
Plasminogen activator inhibitor-1(PAI-1)is a member of the evolutionarily conserved serine pro⁃tease inhibitor family.The increased expression of PAI-1 leads to pathological diseases such as vascular diseases,obesity,...Plasminogen activator inhibitor-1(PAI-1)is a member of the evolutionarily conserved serine pro⁃tease inhibitor family.The increased expression of PAI-1 leads to pathological diseases such as vascular diseases,obesity,and metabolic syndrome.Senescence-associated secretory phenotype(SASP)mediates tissue damage and plays a role in adipose tissue dysfunction.Chronic inflammation in adipose tissue is associated with the development of metabolic diseases,including obesity,insulin resistance,and type 2 diabetes.PAI-1 plays a vital role in adipose tissue physiology,glucose metabolism,insulin secretion and sensitivity,inflammation,and macrophage chemotaxis.This article reviews the possible role of PAI-1,as one of the SASP markers,and speculates the potential role of PAI-1 in adipose tissue senescence and inflammatory macrophage infiltration in obesity.展开更多
A recent study published in Nature by Scott et al.1 uses in vivo isotope tracing in patients and orthotopic mouse models to show that whereas the cortex channels glucose into oxidative/tricarboxylic acid(TCA)and neuro...A recent study published in Nature by Scott et al.1 uses in vivo isotope tracing in patients and orthotopic mouse models to show that whereas the cortex channels glucose into oxidative/tricarboxylic acid(TCA)and neurotransmitter metabolism,glioblastoma(GBM)repartitions glucose carbon toward nucleotide and NAD(H)biosynthesis.Leveraging the preference of GBM for imported serine,dietary serine/glycine restriction reroutes carbon,depresses nucleotide production,and sensitizes tumors to chemoradiation(Fig.1).展开更多
Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of ...Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration.Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view.Here we report the discovery and characterization of a novel VEGFR2 inhibitor(CHMFLVEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L)and VEGFR2 autophosphorylation in cells(EC50s^100 nmol/L)as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=150 nmol/L).In addition,CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK(pharmacokinetics)profile with bioavailability over 49%and antiangiogenesis efficacy in both zebrafish and mouse models without apparent toxicity.These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.展开更多
Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been ident...Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been identified as a major pathogenic factor in several B-cell non-Hodgkin lymphoma(B-NHL)subtypes,including diffuse large Bcell lymphoma(DLBCL),mantle cell lymphoma(MCL),follicular lymphoma(FL),and chronic lymphocytic leukemia(CLL).1 Therefore,BTK has been recognized as a validated therapeutic target for B-cell malignancies.Ibrutinib,the first approved BTK inhibitor that binds irreversibly to cysteine residue 481,has shown potent clinical activity in the majority of CD20 positive B-cell malignancies.2 However,due to the inhibition of off-target kinases such as EGFR,ITK,and TXK,which have a cysteine residue at the identical position of Cys481 of BTK,Ibrutinib also results in some adverse events,such as the antagonizing Rituximab-dependent NK-cell-mediated antibody-dependent cell-mediated cytotoxicity(ADCC)due to its irreversible binding to ITK,which is required for FcR-stimulated NK cell function.3 Although several secondary generation inhibitors have shown improved selectivity,4,5 more pharmacologically diverse novel inhibitors are still highly demanded in the clinic.展开更多
AlphaFold3(AF3),as the latest generation of artificial intelligence model jointly developed by Google DeepMind and Isomorphic Labs,has been widely heralded in the scientific research community since its launch.With un...AlphaFold3(AF3),as the latest generation of artificial intelligence model jointly developed by Google DeepMind and Isomorphic Labs,has been widely heralded in the scientific research community since its launch.With unprecedented accuracy,the AF3 model may successfully predict the structure and interactions of virtually all biomolecules,including proteins,ligands,nucleic acids,ions,etc.By accurately simulating the structural information and interactions of biomacromolecules,it has shown great potential in many aspects of structural prediction,mechanism research,drug design,protein engineering,vaccine development,and precision therapy.In order to further understand the characteristics of AF3 and accelerate its promotion,this article sets out to address the development process,working principle,and application in drugs and biomedicine,especially focusing on the intricate differences and some potential pitfalls compared to other deep learning models.We explain how a structure-prediction tool can impact many research fields,and in particular revolutionize the strategies for designing of effective next generation vaccines and chemical and biological drugs.展开更多
Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the em...Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the emergence of treatment-resistant and metastatic tumors.In response,we synthesized a novel bioactive compound,ethyl 6-chlorocoumarin-3-carboxylyl L-theanine(TClC),which significantly inhibited NSCLC growth,epithelial mesenchymal transition(EMT),migration,and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity.TClC disrupts autocrine loops that promote tumor progression,particularly in stem-like CD133-positive NSCLC(CD133+LC)cells,which are pivotal in tumor metastasis.Through targeted molecular assays,we identified direct binding targets of TClC,including Akt,NF-κB,β-catenin,EZH2,and PD-L1.This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter,underscoring the compound’s poly-pharmacological potential.These results position TClC as a promising candidate for NSCLC treatment,signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.展开更多
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
文摘The activation of the Wnt/β-catenin signaling cascade has been well studied and documented in colorectal cancer（CRC）.The long-term use of non-steroidal anti-inflammatory drugs（NSAIDs） has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies.The NSA1 D sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC.The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity.Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMβ-dependent protein kinase,PKG,through the elevation of the second messenger cyclic guanosine monophosphote,cGMP.PKG activation has been shown to inhibit the nuclear translocation of β-catenin,reduce β-catenin mRNA and protein levels,and suppress the transcriptional activity of β-catenin.This review describes the relationship between the Wnt/β-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels.
基金the National Institute of Health(Research in Dr.Alessia Fornoni’s laboratory),No.R01DK117599,No.R01DK104753,No.R01CA227493,No.U54DK083912,No.UM1DK100846,and No.U01DK116101the Miami Clinical Translational Science Institute,No.UL1TR000460and the Chernowitz Medical Research Foundation(Mitrofanova A and Burke G),No.GR016291.
文摘Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests that impaired cholesterol metabolism,increased lipid uptake or synthesis,increased fatty acid oxidation,lipid droplet accumulation and an imbalance in biologically active sphingolipids(such as ceramide,ceramide-1-phosphate and sphingosine-1-phosphate)contribute to the development of diabetic kidney disease(DKD).Currently,the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production,oxidative stress,inflammation,or cell death.Therefore,control of renal lipid dysmetabolism is a very important therapeutic goal,which needs to be archived.This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.
基金supported by National Natural Science Foundation of China (Grant No. 82003764 to L.F.)Universities Natural Science Research Project of Jiangsu Province (Grant No. 19KJB350001to L.F.)。
文摘Glioblastoma multiforme(GBM) is an essentially incurable brain tumor, which has been explored for approximately a century. Nowadays, surgical resection, chemotherapy, and radiation therapy are still the standardized therapeutic options. However, due to the intrinsic invasion and metastasis features and the resistance to chemotherapy, the survival rate of glioblastoma patients remains unsatisfactory. To improve the current situation, much more research is needed to provide comprehensive knowledge of GBM. In this review, we summarize the latest updates on GBM treatment and invasion. Firstly, we review the traditional and emerging therapies that have been used for GBM treatment. Given the limited efficiency of these therapies, we further discuss the role of invasion in GBM recurrence and progression, and present current research progress on the mode and mechanisms of GBM invasion.
基金financially supported by the Natural Science Foundation of Education Department of Sichuan Province of China,No.14ZB0152the Joint Research Program of Luzhou and Southwest Medical University,in China,No.14JC0120
文摘Nicotiflorin is a flavonoid extracted from Carthamus tinctorius.Previous studies have shown its cerebral protective effect,but the mechanism is undefined.In this study,we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway.The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion.Nicotiflorin（10 mg/kg） was administered by tail vein injection.Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase d UTP nick end labeling assay.Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining.Additionally,p-JAK2,p-STAT3,Bcl-2,Bax,and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay.Nicotiflorin altered the shape and structure of injured neurons,decreased the number of apoptotic cells,down-regulates expression of p-JAK2,p-STAT3,caspase-3,and Bax,decreased Bax immunoredactivity,and increased Bcl-2 protein expression and immunoreactivity.These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.
基金supported by grants from the National Nature Science Foundation of China (No. 30400498)
文摘Aim To identify heterogeneity of Candida albicans （C. albicans） isolated from the population with cancer in China by using identification medium, subculture molecular typing, and antifungal susceptibility test. Methodology Oral cheek mucosal specimens from 52 cancer patients receiving chemotherapy were cultured on CHROMagar CandidaTM plates for Candida identification. All the C. albicans colonies on the plates were subcultured and reconfirmed by API20C, then submitted to the antifimgal drug susceptibility test with fluconazole and molecular typing using randomly amplified polymorphic DNA-PCR （RAPD） with primers RSD6 and RSD12.Results 54% （28/52） patients were oral yeast carriage in which C. albicans predominated. More than 7 C. albicans colonies were isolated from each of 12 patients （Group A）, while less than 5 colonies were isolated from each of 16 patients （Group B）. RSD6 and RSD12 were successful in eliciting 17 （A1-A17） and 2 （B1-B2） genotypes, respectively from among the 205 isolates. The two primers were combined to generate 21 genotypes. The C. albicans isolates obtained from the same patient and episode showed a diversity for fluconazole revealed by MIC50 and MIC90. Conclusion The heterogeneity of the C. albicans colonies isolated from the same patients can be detected. C. albicans with varied fluconazole susceptibility and genotypic characteristics may coexist in the same oral Candida population.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0507201)。
文摘Chikungunya virus(CHIKV) is a mosquito-borne alphavirus. As an emerging virus, CHIKV imposes a threat to public health. Currently, there are no vaccines or antivirals available for the prevention of CHIKV infection. Lycorine, an alkaloid from Amaryllidaceae plants, has antiviral activity against a number of viruses such as coronavirus, flavivirus and enterovirus. In this study, we found that lycorine could inhibit CHIKV in cell culture at a concentration of 10 lmol/L without apparent cytotoxicity. In addition, it exhibited broad-spectrum anti-alphavirus activity, including Sindbis virus(SINV),Semliki Forest virus(SFV), and Venezuelan equine encephalomyelitis virus(VEEV). The time of addition studies indicated that lycorine functions at an early post-entry stage of CHIKV life cycle. The results based on two different CHIKV replicons provided further evidence that lycorine exerts its antiviral activity mainly by inhibiting CHIKV translation.Overall, our study extends the antiviral spectrum of lycorine.
基金supported in part by grant from Science and Technology Program of Guangdong Province(No. 2007B031503005).
文摘Sitagliptin is the first new anti-diabetic drug in DPP-Ⅳ inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert hornologation, the optically pure precursor R-amino acid is difficult to prepare. We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in 〉99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure. This protocol requires only cheap starting materials and friendly reaction condition. The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare α-amino acid and the subsequent β-amino acid.
基金Supported by National Natural Science Foundation of China(81001700)Project of Sichuan Provincial Education Department(11ZB227,11ZB124)Research Project for the Application Foundation of Sichuan Provincial Science and Technology Department(2012JY0081)
文摘[ Objective ] This study aimed to investigate the optimal method for extracting RNA from roots of medicinal plant herba violae by comparing the effects of liquid nitrogen grinding method and low-temperature sectioning method on RNA extraction. [ Method] Roots of herba violae were respectively crushed by using liquid nitrogen grinding method and low-temperature sectioning method to extract RNA. The extraction effects of these two methods were compared based on detec- tion of RNA concentration, purity and integrity and amplification of GAPDH gene by RT-PCR. [Result] The concentration of RNA extracted by liquid nitrogen grinding method and low-temperature sectioning method was 1.21 and 3.57 p^g/~, respectively. Both RNA extracted by these two methods showed two distinct bands after agarose gel electrophoresis. The ratio of brightness of the 28S rRNA to the 18S rRNA bands was greater than 1. PCR amplification showed that the length of GAPDH gene was about 230 bp, which was consistent with the expected result. [ Conclusion ] The experimental results indicated that using low-tempera ture sectioning method to crush the roots of herba violae can meet the needs of most molecular biological experiments including gene cloning and expression analysis, which is an effective and simple method for extracting RNA from plant roots.
文摘ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy failure.The primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug efflux.Cytotoxicity assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic drugs.NSAIDs were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell lines.Other experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact cells.Selective reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or ABCG2.Sulindac sulfide also inhibited transport of leukotriene C_4 into membrane vesicles.Sulindac sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced cytotoxicity.Sulindac sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable concentrations.ABCC1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.
基金the National Key Research and Development Program of China(No.2017YFA0205300)the National Natural Science Foundation of China(Nos.21675023 and 91753106)the Scientific Research Foundation of Southwest Medical University(No.19120200037)。
文摘Engineered nanomaterials have attracted significantly attention as one of the most promising antimicrobial agents for against multidrug resistant infections.The toxicological responses of nano mate rials are closely related to their physicochemical properties,and establishment of a structure-activity relationship for nanomaterials at the nano-bio interface is of great significance for deep understanding antibacterial toxicity mechanisms of nanomaterials and designing safer antibacterial nanomaterials.In this study,the antibacterial behaviors of well-defined crystallographic facets of a series of Au nanocrystals,including{100}-facet cubes,{110}-facet rhombic dodecahedra,{111}-facet octahedra,{221}-facet trisoctahedra and{720}-facet concave cubes,was investigated,using the model bacteria Staphylococcus aureus.We find that Au nanocrystals display substantial facet-dependent antibacterial activities.The low-index facets of cubes,octahedra,and rhombic dodecahedra show considerable antibacterial activity,whereas the high-index facets of trisoctahedra and concave cubes remained inert under biological conditions.This result is in stark contrast to the previous paradigm that the high-index facets were considered to have higher bioactivity as compared with low-index facets.The antibacterial mechanism studies have shown that the facet-dependent antibacterial behaviors of Au nanocrystals are mainly caused by differential bacterial membrane damage as well as inhibition of cellular enzymatic activity and energy metabolism.The faceted Au nanocrystals are unique in that they do not induce generation of reactive oxygen species,as validated for most antibiotics and antimicrobial nanostructures.Our findings may provide a deeper understanding of facet-dependent toxicological responses and suggest the complexities of the na no material-cell interactions,shedding some light on the development of high performance Au nanomaterials-based antibacterial therapeutics.
基金supported by grants from the Educational Commission of Sichuan Province (No. 2006J13-039)the Doctoral Program Foundation of Institutions of Higher Education of China (No. 20095103120002)the National Natural Science Foundation of China (No. 30900901)
文摘Given the important roles of miRNAs in post-transcriptional gene regulation, identification of differentially expressed miRNAs will facilitate the elucidation of molecular mechanisms underlying kernel development. In this study, we constructed a small RNA library to comprehensively represent the full complement of individual small RNAs and to characterize miRNA expression profiles in pooled ears of maize(Zea mays L.) at 10, 15,20, 22, 25 and 30 days after pollination(DAP). At least 21 miRNAs were differentially expressed. The differential expression of three of these miRNAs, i.e., miR528a, miR167a and miR160b, at each stage was verified by qRT-PCR. The results indicated that these miRNAs might be involved in kernel development. In addition, the predicted functions of target genes indicated that most of the target genes are involved in signal transduction and cell communication pathways, particularly the auxin signaling pathway. The expression of candidate germination-associated miRNAs was analyzed by hybridization to a maize genome microarray, and revealed differential expression of genes involved in plant hormone signaling pathways. This finding suggests that phytohormones play a critical role in the development of maize kernels. We found that in combination with other miRNAs, miR528a regulated a putative laccase, a Ring-H2 zinc finger protein and a MADS box-like protein, whereas miR167a and miR160b regulated multiple target genes,including ARF(auxin response factor), a member of the B3 transcription factor family. All three miRNAs are important for ear germination, development and physiology. The small RNA transcriptomes and mRNA obtained in this study will help us gain a betterunderstanding of the expression and function of small RNAs in the development of maize kernel.
基金supported by the China National Major Scientific and Technological Special Project for“Significant New Drugs Innovation and Development”(Grant No.:2019ZX09732002-006)the National New Drug Creation Program of China(Grant No.:2018ZX09201017-004)+5 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant Nos.:XDA12020223,XDA12020330,XDA12020360,and XDA12050305)the National Natural Science Foundation of China(Grant Nos.:81872785 and 81673347)the Science and Technology Planning Projects of Department of Science and Technology Province(Grant No.:20190202)Shanghai Municipal Commission of Science and Technology of China(Grant Nos.:17431904400,19YF1457400,and 21S11904500)Institutes for Drug Discovery and Development,the Chinese Academy of Sciences(Grant Nos.:CASIMM0120202007 and CASIMM0120202008)Major Scientific and Technological Special Project of Zhongshan City(Grant Nos.:191022172638719 and 210205143867019).
文摘Antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,respectively.The total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.
文摘Plasminogen activator inhibitor-1(PAI-1)is the primary inhibitor of urinary-type and tissue-type plasmino-gen activators and a key regulator of fibrinolysis.PAI-1 also regulates the function of vascular cells,includingvascular smooth muscle cells(VSMCs).
基金The National Natural Science Foundation of China Grant(81570263)Sichuan Province Science and Technology Agen⁃cy Grant(2020YJ0340)。
文摘Plasminogen activator inhibitor-1(PAI-1)is a member of the evolutionarily conserved serine pro⁃tease inhibitor family.The increased expression of PAI-1 leads to pathological diseases such as vascular diseases,obesity,and metabolic syndrome.Senescence-associated secretory phenotype(SASP)mediates tissue damage and plays a role in adipose tissue dysfunction.Chronic inflammation in adipose tissue is associated with the development of metabolic diseases,including obesity,insulin resistance,and type 2 diabetes.PAI-1 plays a vital role in adipose tissue physiology,glucose metabolism,insulin secretion and sensitivity,inflammation,and macrophage chemotaxis.This article reviews the possible role of PAI-1,as one of the SASP markers,and speculates the potential role of PAI-1 in adipose tissue senescence and inflammatory macrophage infiltration in obesity.
基金supported by the Summit Advancement Disciplines of Zhejiang Province(Wenzhou Medical University-Pharmaceutics),the Basal Research Fund of Wenzhou Medical University(KYYW202411)the Natural Science Foundation of Zhejiang Province(LTGY23H100001).
文摘A recent study published in Nature by Scott et al.1 uses in vivo isotope tracing in patients and orthotopic mouse models to show that whereas the cortex channels glucose into oxidative/tricarboxylic acid(TCA)and neurotransmitter metabolism,glioblastoma(GBM)repartitions glucose carbon toward nucleotide and NAD(H)biosynthesis.Leveraging the preference of GBM for imported serine,dietary serine/glycine restriction reroutes carbon,depresses nucleotide production,and sensitizes tumors to chemoradiation(Fig.1).
基金supported by the National Natural Science Foundation of China(Grant Nos.81773777,81673469,81603123,81803366)the China Postdoctoral Science Foundation(Grant Nos.2018T110634,2018M630720)+2 种基金the Anhui Province Postdoctoral Science Foundation(Grant No.2018B279)the CASHIPS Director’s Fund(Grant No.BJPY2019A03)the Key Program of 13th five-year plan,CASHIPS(Grant No.KP-2017-26).
文摘Angiogenesis is an essential process in tumor growth,invasion and metastasis.VEGF receptor 2(VEGFR2)inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment.However,most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration.Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view.Here we report the discovery and characterization of a novel VEGFR2 inhibitor(CHMFLVEGFR2-002),which exhibited high selectivity among structurally closed kinases including PDGFRs,FGFRs,CSF1 R,etc.CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay(IC50=66 nmol/L)and VEGFR2 autophosphorylation in cells(EC50s^100 nmol/L)as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells(GI50=150 nmol/L).In addition,CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK(pharmacokinetics)profile with bioavailability over 49%and antiangiogenesis efficacy in both zebrafish and mouse models without apparent toxicity.These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.
基金supported by the National Natural Science Foundation of China(Grant Nos.81773777,81872748,and 81803366)the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”of China(Grant No.2018ZX09711002)+4 种基金the Natural Science Foundation of Anhui Province(Grant No.1808085MH268)the China Postdoctoral Science Foundation(Grants Nos.2018T110634 and 2018M630720)the Frontier Science Key Research Program of CAS(Grant No.QYZDB-SSW-SLH037)the Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(Grant No.2019HSCCIP011)the CASHIPS Director’s Fund(Grant No.BJPY2019A03)the Key Program of 13th five-year plan of CASHIPS(Grant No.KP-2017-26).
文摘Dear Editor,Bruton’s tyrosine kinase(BTK)plays a crucial role in the B-cell receptor(BCR)signaling which is essential for B-cell proliferation,differentiation,and cell migration.Aberrant BCR activation has been identified as a major pathogenic factor in several B-cell non-Hodgkin lymphoma(B-NHL)subtypes,including diffuse large Bcell lymphoma(DLBCL),mantle cell lymphoma(MCL),follicular lymphoma(FL),and chronic lymphocytic leukemia(CLL).1 Therefore,BTK has been recognized as a validated therapeutic target for B-cell malignancies.Ibrutinib,the first approved BTK inhibitor that binds irreversibly to cysteine residue 481,has shown potent clinical activity in the majority of CD20 positive B-cell malignancies.2 However,due to the inhibition of off-target kinases such as EGFR,ITK,and TXK,which have a cysteine residue at the identical position of Cys481 of BTK,Ibrutinib also results in some adverse events,such as the antagonizing Rituximab-dependent NK-cell-mediated antibody-dependent cell-mediated cytotoxicity(ADCC)due to its irreversible binding to ITK,which is required for FcR-stimulated NK cell function.3 Although several secondary generation inhibitors have shown improved selectivity,4,5 more pharmacologically diverse novel inhibitors are still highly demanded in the clinic.
基金supported by funds of the Key Research and Development Grant of MOST(grant No.2023YFA095000)the Affiliated Xiangshan Hospital of Wenzhou Medical University,the National Science Foundation of China(grant No.82470005)Wenzhou Institute University of Chinese Academy of Sciences.
文摘AlphaFold3(AF3),as the latest generation of artificial intelligence model jointly developed by Google DeepMind and Isomorphic Labs,has been widely heralded in the scientific research community since its launch.With unprecedented accuracy,the AF3 model may successfully predict the structure and interactions of virtually all biomolecules,including proteins,ligands,nucleic acids,ions,etc.By accurately simulating the structural information and interactions of biomacromolecules,it has shown great potential in many aspects of structural prediction,mechanism research,drug design,protein engineering,vaccine development,and precision therapy.In order to further understand the characteristics of AF3 and accelerate its promotion,this article sets out to address the development process,working principle,and application in drugs and biomedicine,especially focusing on the intricate differences and some potential pitfalls compared to other deep learning models.We explain how a structure-prediction tool can impact many research fields,and in particular revolutionize the strategies for designing of effective next generation vaccines and chemical and biological drugs.
基金supported by the National Key Research and Development Program of China(2017YFB0702600,2017YFB0702602,2017YFB0702602-2)the Shandong Provincial Natural Science Foundation(ZR2019MH076,ZR2022MH291)+3 种基金the Ministry of Science and Technology of the People’s Republic of China(“863 grant”,2012AA020206)the Department of Science and Technology of Shan-dong Province(20092009GG10002087)the National Natural Science Foundation of China(81603024,30973553)the NIH grant R01 CA186100,Wenzhou Institute University of Chinese Academy of Sciences,and Corbett Estate Fund for the Cancer Research(62285-531021-41800,62285-531021-51800,62285-531021-61800,62285-531021-71800).
文摘Despite significant advances in targeted therapies and immunotherapies,non-small cell lung cancer(NSCLC)continues to present a global health challenge,with a modest five-year survival rate of 28%,largely due to the emergence of treatment-resistant and metastatic tumors.In response,we synthesized a novel bioactive compound,ethyl 6-chlorocoumarin-3-carboxylyl L-theanine(TClC),which significantly inhibited NSCLC growth,epithelial mesenchymal transition(EMT),migration,and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity.TClC disrupts autocrine loops that promote tumor progression,particularly in stem-like CD133-positive NSCLC(CD133+LC)cells,which are pivotal in tumor metastasis.Through targeted molecular assays,we identified direct binding targets of TClC,including Akt,NF-κB,β-catenin,EZH2,and PD-L1.This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter,underscoring the compound’s poly-pharmacological potential.These results position TClC as a promising candidate for NSCLC treatment,signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.
