Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RP...Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.展开更多
BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recu...BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection.Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps,the exact compositions and roles of bacteria in the mucosa around the lesions,rather than feces,remain unsettled.AIM To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps.METHODS Mucosal samples were collected from four patients consistently with adenomatous polyps(Ade),seven consistently with non-Ade(Pol),ten with current Pol but previous Ade,and six healthy individuals,and bacterial patterns were evaluated by 16S rDNA sequencing.Linear discriminant analysis and Student’s t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes.Pearson’s correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators.RESULTS The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals.These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps,but also existed in histologically normal tissue 10 cm distal from the lesions.Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions,Pol,and Ade.Increased abundance of Gram-negative bacteria,including Klebsiella,Plesiomonas,and Cronobacter,was observed in Pol group and Ade group,suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment.Meanwhile,age and gender were linked to bacteria changes,indicating the potential involvement of sex hormones.CONCLUSION These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps,especially adenoma.Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.展开更多
Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical trea...Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.展开更多
The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with th...The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.展开更多
Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with...Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with the Seurat,Monocle,and CellphoneDB packages in R software with standard procedures.Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides(10x Genomics)and Visium Spatial Gene Expression Slides(10x Genomics).Spatial transcriptomics analysis was performed with Space Ranger software and R software.Immunofluorescence,whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results.Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue.Several gene markers specific to postnatal epicardial tissue were identified,including Msln,C3,Efemp1,and Upk3b.Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts(from embryonic day 9.5 to postnatal day 9)could be categorized into six major cell types,which included epicardial cells.Throughout epicardial development,Wt1,Tbx18,and Upk3b were consistently expressed,whereas genes including Msln,C3,and Efemp1 exhibited increased expression during the mature stages of development.Pseudotime analysis further revealed two epicardial cell fates during maturation.Moreover,Upk3b,Msln,Efemp1,and C3 positive epicardial cells were enriched in extracellular matrix signaling.Our results suggested Upk3b,Efemp1,Msln,C3,and other genes were mature epicardium markers.Extracellular matrix signaling was found to play a critical role in the mature epicardium,thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.展开更多
After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrat...After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.展开更多
Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors...Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors.This paper proposes a heterogenous multilayer paper stacking co-culture system to establish a model of natural killer(NK)cells moving through the endothelium layer and attacking tumor spheroids.This system consists of three layers:a bottom tumor-spheroid layer,a middle invasion layer,and a top endothelium layer.NK-92 cells were placed in the supernatant on top of the three layers.After two days of co-culture,the attack of tumor spheroids by NK cells was observed.We additionally examined the infiltration of NK-92 cells within the tumor spheroids at different Z-axis depths using a confocal microscope,and the results suggested that the system successfully realizes NK cells traveling cross the endothelium layer to form tumor-infiltrating NK cells(TINKs).The potential application of multilayer paper for co-culture models involving cancer cells and immune cells holds great promise for exploring the interaction dynamics of these two cell types.展开更多
Myocardial infarction results in the loss of a massive amount of cardiomyocytes(CMs),ultimately leading to heart failure(HF).Although current medical therapeutics can alleviate the symptoms of myocardial infarction,th...Myocardial infarction results in the loss of a massive amount of cardiomyocytes(CMs),ultimately leading to heart failure(HF).Although current medical therapeutics can alleviate the symptoms of myocardial infarction,they cannot eliminate the ischemia-induced CM loss(Hume et al.,2023).In adult mammals,the reparatory response to myocardial infarction is the formation of scar tissue,which compromises heart function(Ebrahimi,2018).展开更多
The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes.In contrast,lower vertebrates such as zebrafish retain the ability to fully regenerate heart after ...The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes.In contrast,lower vertebrates such as zebrafish retain the ability to fully regenerate heart after injury.This capacity is driven not only by transcriptional and structural plasticity but also by metabolic reprogramming that supports cardiomyocyte proliferation.Adult mammalian cardiomyocytes lack both features,remaining largely refractory to regenerative cues.These limitations have prompted efforts to identify extrinsic genetic and metabolic regulators capable of reactivating proliferative competence in adult cardiomyocytes.In this review,we highlight recent advances in the molecular and metabolic control of cardiomyocyte cell-cycle reentry,focusing on strategies that modulate dedifferentiation,proliferation,and redifferentiation as well as metabolic state transitions.We also examine emerging translational approaches in swine models,which more closely recapitulate human cardiac physiology than rodents.Together,these insights provide a roadmap for unlocking endogenous regenerative pathways and identify key challenges in translating these findings into therapies for heart failure.展开更多
Recent advances in ion channel structural biology have enhanced structure-based drug design,yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules.TRPC...Recent advances in ion channel structural biology have enhanced structure-based drug design,yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules.TRPC5,a brain-enriched channel regulating depression and anxiety,is a promising therapeutic target,but current preclinical candidates suffer from moderate off-target effects.To address this,we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization,overcoming lipid-binding site challenges.Among these,JDIC-127 exhibited unprecedented potency with IC50 of 374 pmol/L—200-fold more potent than HC-070—and exceptional selectivity.Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5,minimizing activity against related TRPC channels and other ion channels.This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders.The study demonstrates how macrocycles stabilize ligand conformations,enhance affinity,and achieve selectivity in lipid-dominated binding sites.It also highlights the synergy between macrocyclic design,cryo-EM,and computational modeling to address longstanding obstacles in ion channel drug discovery.JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology,offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond,with implications for a wide range of diseases.展开更多
Amino acid metabolism is involved in cell survival and growth. However, how amino acids regulate the pancreatic adenocarcinoma (PAAD) tumor process and cellular functions is still unclear.1To ascertain the potential r...Amino acid metabolism is involved in cell survival and growth. However, how amino acids regulate the pancreatic adenocarcinoma (PAAD) tumor process and cellular functions is still unclear.1To ascertain the potential role of solute-carrier (SLC) genes in tumor progression, we aim to identify SLCs that exhibit differential expression between tumor and normal samples. Furthermore, we seek to determine those SLCs that may influence patient survival and those associated with PD-L1 expression across all SLC genes in 34 TCGA cancer types.展开更多
In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independ...In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independent of canonical tumor necrosis factor receptor 1(TNFR1)and Fas-associated death domain protein(FADD)signaling(Fig.1).These findings provide a transformative therapeutic paradigm by positioning the STINGZBP1 necroptosis axis as a pharmacologically actionable target,offering a mechanism-based strategy to treat STING-associated vasculopathy with onset in infancy(SAVI)and related interferonopathies.展开更多
A recent study published in Nature(Hou et al.,2025)described short peptides of DTLKIVWX that can disassemble tau fibrils and explain the disassembly process by a strain-relief mechanism:since the DTLKIVWX peptides are...A recent study published in Nature(Hou et al.,2025)described short peptides of DTLKIVWX that can disassemble tau fibrils and explain the disassembly process by a strain-relief mechanism:since the DTLKIVWX peptides are right-handed and the tau fibrils are left-handed,by binding of the D-peptide fibrils to the tau fibrils,both fibrils are under strain that is relieved by fragmenting the fibrils(Figure 1).This study offers a novel strain-relief mechanism by applying a peptide-based disaggregator as a therapeutic for amyloid diseases.展开更多
The liver is a common site for cancer metastasis and a key metabolic organ.Lipid metabolism irregularities are linked to liver metastasis risk,but the mechanisms are not fully understood.Herein,in colorectal cancer li...The liver is a common site for cancer metastasis and a key metabolic organ.Lipid metabolism irregularities are linked to liver metastasis risk,but the mechanisms are not fully understood.Herein,in colorectal cancer liver metastasis(CRLM)clinical samples,lipid metabolism was broadly dysregulated,and lipid metabolites accumulated,as shown by integrated transcriptome and lipidomics analyses.Functionally,lipid deposition promotes liver metastasis in vitro and in vivo.Mechanistically,lipid deposition significantly enhances YTHDF3-mediated m6A modification and degradation of PPARα,which is crucial for liver metastasis.This process reduces theβ-hydroxybutyrylation of YTHDF3,thereby promoting LLPS and increasing the stability of YTHDF3,which in turn facilitates the progression of CRC and liver metastasis.Furthermore,lipid deposition induces the interaction between STAT3 and YAP,activating YTHDF3 transcription.These two regulatory mechanisms synergize to drive YTHDF3 accumulation in lipid-rich metastatic lesions.In summary,our findings reveal that lipid deposition promotes LLPS-mediated m6A modification and decreasesβ-hydroxybutyrylation in liver metastasis,offering new strategies for the treatment of CRLM.展开更多
The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establis...The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensiveunderstanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points,thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remainsincomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hasunderscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on thedynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures andfunctions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanismsinvolved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-relateddiseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immuneresponses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines andinhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention andtreatment.展开更多
The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epitheli...The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.展开更多
Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,...Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,and viral infections have been considered“stressors”.Prolonged exposure to these stresses significantly increases the risk of tumor formation.Yet,the impact of these environmental factors on tumor metastasis remains an intriguing and open question.展开更多
N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intes...N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intestinal epithelium(Liu et al.2023).METTL3,as an important“writer”protein,has been reported to play a crucial regulatory role in the stemness and cell death of the small intestinal epithelium(Liu et al.2023).“Reader”proteins,including YTHDF1/2/3,YTHDC1/2,IGF2BP1/2/3,etc.,recognize the m6A modification sites and regulate mRNA translation,stability,splicing,and nuclear export(Zaccara et al.2019).展开更多
Genetic and microbial factors influence inflammatory bowel disease(IBD),prompting our study on non-invasive biomarkers for enhanced diagnostic precision.Using the XGBoost algorithm and variable analysis and the publis...Genetic and microbial factors influence inflammatory bowel disease(IBD),prompting our study on non-invasive biomarkers for enhanced diagnostic precision.Using the XGBoost algorithm and variable analysis and the published metadata,we developed the 10-species signature XGBoost classification model(XGB-IBD10).By using distinct species signatures and prior machine and deep learning models and employing standardization methods to ensure comparability between metagenomic and 16S sequencing data,we constructed classification models to assess the XGB-IBD10 precision and effectiveness.XGB-IBD10 achieved a notable accuracy of 0.8722 in testing samples.In addition,we generated metagenomic sequencing data from collected 181 stool samples to validate our findings,and the model reached an accuracy of 0.8066.The model's performance significantly improved when trained on high-quality data from the Chinese population.Furthermore,the microbiome-based model showed promise in predicting active IBD.Overall,this study identifies promising non-invasive biomarkers associated with IBD,which could greatly enhance diagnostic accuracy.展开更多
The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as...The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as a treatment for epilepsy,KD has been widely applied in weight loss programs and the management of metabolic diseases.Previous studies have shown that KD can potentially inhibit the growth and spread of cancer by limiting energy supply to tumor cells,thereby inhibiting tumor angiogenesis,reducing oxidative stress in normal cells,and affecting cancer cell signaling and other processes.Moreover,KD has been shown to influence T-cell-mediated immune responses and inflammation by modulating the gut microbiota,enhance the efficacy of standard cancer treatments,and mitigate the complications of chemotherapy.However,controversies and uncertainties remain regarding the specific mechanisms and clinical effects of KD as an adjunctive therapy for cancer.Therefore,this review summarizes the existing research and explores the intricate relationships between KD and cancer treatment.展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFC2804800 to W.J.)the National Natural Science Foundation of China(No.22494704.,22137002 to Y.D.,92253305 to W.J.and 31971111 to C.L.)+6 种基金the Science and Technology Commission of Shanghai Municipality(Grant 20JC1410900 to Y.D.)the University Innovation Research Group in Chongqing(No.CXQT21016 to Y.D.)the Chongqing Talent Program Project(No.CQYC20200302119 to Y.D.)High-Level Innovation Platform Cultivation Plan of Chongqing(to Y.D.)Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing(to Y.D.)Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(to W.J.)Chongqing Doctoral Express Entry Project(No.CSTB2022BSXM-JCX0044 to J.H.).
文摘Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.
基金Supported by National Science Foundation of China,No.82160546the Science Foundation of Jiangxi Province,No.20202BBG73027+1 种基金the Foundation of Jiangxi Province for Distinguished Scholars,No.jxsq2023201020the Science and Technology Project of Jiangxi Administration of Traditional Chinese Medicine,No.2022B789.
文摘BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection.Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps,the exact compositions and roles of bacteria in the mucosa around the lesions,rather than feces,remain unsettled.AIM To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps.METHODS Mucosal samples were collected from four patients consistently with adenomatous polyps(Ade),seven consistently with non-Ade(Pol),ten with current Pol but previous Ade,and six healthy individuals,and bacterial patterns were evaluated by 16S rDNA sequencing.Linear discriminant analysis and Student’s t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes.Pearson’s correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators.RESULTS The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals.These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps,but also existed in histologically normal tissue 10 cm distal from the lesions.Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions,Pol,and Ade.Increased abundance of Gram-negative bacteria,including Klebsiella,Plesiomonas,and Cronobacter,was observed in Pol group and Ade group,suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment.Meanwhile,age and gender were linked to bacteria changes,indicating the potential involvement of sex hormones.CONCLUSION These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps,especially adenoma.Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.
文摘Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.
基金supported by the National Natural Science Foundation of China(22078211)the China Postdoctoral Science Foundation(2022M721115).
文摘The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.
基金supported by grants from the National Natural Science Foundation of China(Grant No.:82270281)Chongqing Medical University Program for Youth Innovation in Future Medicine(Grant No.:W0133)+2 种基金Senior Medical Talents Program of Chongqing for Young and Middle-aged,China(Program No.:JianlinDu[2022])Postdoctoral Research Funding of the Second Affiliated Hospital of Chongqing Medical University,China(Grant No.:rsc-postdoctor114)and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University,China(Program No.:kryc-gg-2102).
文摘Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with the Seurat,Monocle,and CellphoneDB packages in R software with standard procedures.Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides(10x Genomics)and Visium Spatial Gene Expression Slides(10x Genomics).Spatial transcriptomics analysis was performed with Space Ranger software and R software.Immunofluorescence,whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results.Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue.Several gene markers specific to postnatal epicardial tissue were identified,including Msln,C3,Efemp1,and Upk3b.Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts(from embryonic day 9.5 to postnatal day 9)could be categorized into six major cell types,which included epicardial cells.Throughout epicardial development,Wt1,Tbx18,and Upk3b were consistently expressed,whereas genes including Msln,C3,and Efemp1 exhibited increased expression during the mature stages of development.Pseudotime analysis further revealed two epicardial cell fates during maturation.Moreover,Upk3b,Msln,Efemp1,and C3 positive epicardial cells were enriched in extracellular matrix signaling.Our results suggested Upk3b,Efemp1,Msln,C3,and other genes were mature epicardium markers.Extracellular matrix signaling was found to play a critical role in the mature epicardium,thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.
文摘After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.
基金supported by the National Natural Science Foundation of China(No.32171401)the Natural Science Foundation of Chongqing(Nos.CSTB2022NSCQ-MSX0808 and cstc2021jcyj-bsh0239)the Innovation Platform for Academicians of Hainan Province(No.YSPTZX202126),China。
文摘Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors.This paper proposes a heterogenous multilayer paper stacking co-culture system to establish a model of natural killer(NK)cells moving through the endothelium layer and attacking tumor spheroids.This system consists of three layers:a bottom tumor-spheroid layer,a middle invasion layer,and a top endothelium layer.NK-92 cells were placed in the supernatant on top of the three layers.After two days of co-culture,the attack of tumor spheroids by NK cells was observed.We additionally examined the infiltration of NK-92 cells within the tumor spheroids at different Z-axis depths using a confocal microscope,and the results suggested that the system successfully realizes NK cells traveling cross the endothelium layer to form tumor-infiltrating NK cells(TINKs).The potential application of multilayer paper for co-culture models involving cancer cells and immune cells holds great promise for exploring the interaction dynamics of these two cell types.
基金financially supported by the National Key R&D Program of China(2023YFA1800600 and 2018YFA0800501)the National Natural Science Foundation of China(32230032 and 82400316)。
文摘Myocardial infarction results in the loss of a massive amount of cardiomyocytes(CMs),ultimately leading to heart failure(HF).Although current medical therapeutics can alleviate the symptoms of myocardial infarction,they cannot eliminate the ischemia-induced CM loss(Hume et al.,2023).In adult mammals,the reparatory response to myocardial infarction is the formation of scar tissue,which compromises heart function(Ebrahimi,2018).
基金supported by the National Key R&D Program of China(2023YFA1800600,2018YFA0800501,and 2019YFA0801602)the National Natural Science Foundation of China(32230032,82400316,and 31730061)+1 种基金supported by GanPo Senior Investigator Award(gpyc20240020)supported by Boya postdoctoral fellowship from Peking University.
文摘The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes.In contrast,lower vertebrates such as zebrafish retain the ability to fully regenerate heart after injury.This capacity is driven not only by transcriptional and structural plasticity but also by metabolic reprogramming that supports cardiomyocyte proliferation.Adult mammalian cardiomyocytes lack both features,remaining largely refractory to regenerative cues.These limitations have prompted efforts to identify extrinsic genetic and metabolic regulators capable of reactivating proliferative competence in adult cardiomyocytes.In this review,we highlight recent advances in the molecular and metabolic control of cardiomyocyte cell-cycle reentry,focusing on strategies that modulate dedifferentiation,proliferation,and redifferentiation as well as metabolic state transitions.We also examine emerging translational approaches in swine models,which more closely recapitulate human cardiac physiology than rodents.Together,these insights provide a roadmap for unlocking endogenous regenerative pathways and identify key challenges in translating these findings into therapies for heart failure.
基金funded by National Natural Science Foundation of China(No.32271260 to Jin Zhang)Jiangxi Province Natural Science Foundation(No.20224ACB206046 to Jin Zhang,No.20242BAB20119 to Tong Che,China)+2 种基金Jiangxi Natural Science Foundation for Distinguished Young Scholars(No.20212ACB216001 to Jian Li,China)Jiangxi Key Research and Development Program(No.20203BBG73063 to Jian Li,China)Foundation of Gannan Medical University(No.QD201910 to Jian Li,China)。
文摘Recent advances in ion channel structural biology have enhanced structure-based drug design,yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules.TRPC5,a brain-enriched channel regulating depression and anxiety,is a promising therapeutic target,but current preclinical candidates suffer from moderate off-target effects.To address this,we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization,overcoming lipid-binding site challenges.Among these,JDIC-127 exhibited unprecedented potency with IC50 of 374 pmol/L—200-fold more potent than HC-070—and exceptional selectivity.Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5,minimizing activity against related TRPC channels and other ion channels.This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders.The study demonstrates how macrocycles stabilize ligand conformations,enhance affinity,and achieve selectivity in lipid-dominated binding sites.It also highlights the synergy between macrocyclic design,cryo-EM,and computational modeling to address longstanding obstacles in ion channel drug discovery.JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology,offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond,with implications for a wide range of diseases.
基金funded in part by the National Natural Science Foundation of China(No.82204269)the Chongqing Natural Science Foundation(China)(No.CSTB2022NSCQBHX0668)+1 种基金the Science and Technology Research Program of Chongqing Municipal Education Commission(China)(No.KJQN202200427)upported by the Supercomputing Center of Chongqing Medical University(China).
文摘Amino acid metabolism is involved in cell survival and growth. However, how amino acids regulate the pancreatic adenocarcinoma (PAAD) tumor process and cellular functions is still unclear.1To ascertain the potential role of solute-carrier (SLC) genes in tumor progression, we aim to identify SLCs that exhibit differential expression between tumor and normal samples. Furthermore, we seek to determine those SLCs that may influence patient survival and those associated with PD-L1 expression across all SLC genes in 34 TCGA cancer types.
基金supported by the National Natural Science Foundation of China(32525002,82573201 and 32200575).
文摘In a recent publication in Nature,Kelepouras et al.identified a novel necroptosis pathway in which activation of stimulator of interferon genes(STING)triggers Z-DNA binding protein 1(ZBP1)-mediated cell death,independent of canonical tumor necrosis factor receptor 1(TNFR1)and Fas-associated death domain protein(FADD)signaling(Fig.1).These findings provide a transformative therapeutic paradigm by positioning the STINGZBP1 necroptosis axis as a pharmacologically actionable target,offering a mechanism-based strategy to treat STING-associated vasculopathy with onset in infancy(SAVI)and related interferonopathies.
基金supported by the National Natural Science Foundation of China(32525002 and W2411011)Principal Investigator Foundation of Tianfu Jincheng Laboratory(TFJCPI20250022)the Key Research and Development Program of Zhejiang Province(2023C03044).
文摘A recent study published in Nature(Hou et al.,2025)described short peptides of DTLKIVWX that can disassemble tau fibrils and explain the disassembly process by a strain-relief mechanism:since the DTLKIVWX peptides are right-handed and the tau fibrils are left-handed,by binding of the D-peptide fibrils to the tau fibrils,both fibrils are under strain that is relieved by fragmenting the fibrils(Figure 1).This study offers a novel strain-relief mechanism by applying a peptide-based disaggregator as a therapeutic for amyloid diseases.
基金supported by the National Natural Founda tion of China(grant numbers 82130080,82273145,82372042,U24A20726)the Guangdong Basic and Applied Basic Research Foundation(grant numbers 2021A1515010224,2024A1515012816,2023A1515011339).
文摘The liver is a common site for cancer metastasis and a key metabolic organ.Lipid metabolism irregularities are linked to liver metastasis risk,but the mechanisms are not fully understood.Herein,in colorectal cancer liver metastasis(CRLM)clinical samples,lipid metabolism was broadly dysregulated,and lipid metabolites accumulated,as shown by integrated transcriptome and lipidomics analyses.Functionally,lipid deposition promotes liver metastasis in vitro and in vivo.Mechanistically,lipid deposition significantly enhances YTHDF3-mediated m6A modification and degradation of PPARα,which is crucial for liver metastasis.This process reduces theβ-hydroxybutyrylation of YTHDF3,thereby promoting LLPS and increasing the stability of YTHDF3,which in turn facilitates the progression of CRC and liver metastasis.Furthermore,lipid deposition induces the interaction between STAT3 and YAP,activating YTHDF3 transcription.These two regulatory mechanisms synergize to drive YTHDF3 accumulation in lipid-rich metastatic lesions.In summary,our findings reveal that lipid deposition promotes LLPS-mediated m6A modification and decreasesβ-hydroxybutyrylation in liver metastasis,offering new strategies for the treatment of CRLM.
基金supported by Chinese National Natural Science Funds(32125016,31925013,92169122,82473119,U20A20393 and T2321005)the National Key R&D Program of China(2021YFA1101000,2022YFA1105200,2023YFA1800200)+5 种基金“Leading Goose”R&D Program of Zhejiang Province(2024C03142)Excellent Youth Fund of Jiangsu Province(BK20240148)Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505,ZXL2022442)Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027,YXY2302017)Bo Xi Clinical Research Project of the First Affiliated Hospital of Soochow University(BXLC007)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensiveunderstanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points,thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remainsincomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hasunderscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on thedynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures andfunctions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanismsinvolved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-relateddiseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immuneresponses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines andinhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention andtreatment.
基金supported by grants from the Beijing Science and Technology Plan(Z231100007223006)the Natural Science Foundation of China(92354306,31988101)+2 种基金the National Key Research and Development Program of China(2023YFA1800603)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224 ACB209001).
文摘The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.
基金supported by the National Natural Science Foundation of China(No.31970536,32370891)the Fundamental Research Funds from Tongji University(No.2023-3-YB-06).
文摘Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,and viral infections have been considered“stressors”.Prolonged exposure to these stresses significantly increases the risk of tumor formation.Yet,the impact of these environmental factors on tumor metastasis remains an intriguing and open question.
基金supported by grants from the National Key Research and Development Program of China(2024YFA1307401,2024YFA1107701 and 2023YFA1800603)the National Natural Science Foundation of China(92354306)+1 种基金Shenzhen Medical Research Fund(B2302022)Beijing Science and Technology Plan(Z231100007223006).
文摘N6-adenosine methylation(m6A)is an important post-transcriptional modification that regulates gene expression through the“writer-reader-eraser”system(Zaccara et al.2019),which is crucial for the maintenance of intestinal epithelium(Liu et al.2023).METTL3,as an important“writer”protein,has been reported to play a crucial regulatory role in the stemness and cell death of the small intestinal epithelium(Liu et al.2023).“Reader”proteins,including YTHDF1/2/3,YTHDC1/2,IGF2BP1/2/3,etc.,recognize the m6A modification sites and regulate mRNA translation,stability,splicing,and nuclear export(Zaccara et al.2019).
基金supported by grants from the National Key Research and Development Program of China(2023YFA1800603)the Natural Science Foundation of China(31988101,92354306)+3 种基金the Beijing Science and Technology Plan(Z231100007223006)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224ACB209001)the Guangdong Postdoctoral Research Foundation(O0390302).
文摘Genetic and microbial factors influence inflammatory bowel disease(IBD),prompting our study on non-invasive biomarkers for enhanced diagnostic precision.Using the XGBoost algorithm and variable analysis and the published metadata,we developed the 10-species signature XGBoost classification model(XGB-IBD10).By using distinct species signatures and prior machine and deep learning models and employing standardization methods to ensure comparability between metagenomic and 16S sequencing data,we constructed classification models to assess the XGB-IBD10 precision and effectiveness.XGB-IBD10 achieved a notable accuracy of 0.8722 in testing samples.In addition,we generated metagenomic sequencing data from collected 181 stool samples to validate our findings,and the model reached an accuracy of 0.8066.The model's performance significantly improved when trained on high-quality data from the Chinese population.Furthermore,the microbiome-based model showed promise in predicting active IBD.Overall,this study identifies promising non-invasive biomarkers associated with IBD,which could greatly enhance diagnostic accuracy.
基金supported by a special program from the National Key Research and Development Program of China(2021YFA1101000,2022YFA1105200)the National Natural Science Fundation of China(92169122,82473119,32125016,T2321005,U20A201376,U20A20393,31925013)+3 种基金Excellent Youth Fund of Jiangsu Province(BK2024014)Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022442,ZXL2022505)Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2302017,YXY2303027)the Priority Acadamic Program Development of Jiangsu Higher Education Institutions。
文摘The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as a treatment for epilepsy,KD has been widely applied in weight loss programs and the management of metabolic diseases.Previous studies have shown that KD can potentially inhibit the growth and spread of cancer by limiting energy supply to tumor cells,thereby inhibiting tumor angiogenesis,reducing oxidative stress in normal cells,and affecting cancer cell signaling and other processes.Moreover,KD has been shown to influence T-cell-mediated immune responses and inflammation by modulating the gut microbiota,enhance the efficacy of standard cancer treatments,and mitigate the complications of chemotherapy.However,controversies and uncertainties remain regarding the specific mechanisms and clinical effects of KD as an adjunctive therapy for cancer.Therefore,this review summarizes the existing research and explores the intricate relationships between KD and cancer treatment.
