Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiolo...Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.展开更多
This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by ...This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.展开更多
Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation...Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.展开更多
Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand...Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.展开更多
[Objectives]This study was conducted to explore the curative effect of Qingfei Ditan decoction combined with targeted drug penetration therapy of traditional Chinese medicine on severe mycoplasma pneumonia in children...[Objectives]This study was conducted to explore the curative effect of Qingfei Ditan decoction combined with targeted drug penetration therapy of traditional Chinese medicine on severe mycoplasma pneumonia in children.[Methods]Based on the retrospective study method,children with severe mycoplasma pneumonia admitted to the Children s Hospital of Soochow University from April 2023 to October 2023 were selected,and divided into a treatment group including 56 cases and a control group including 145 cases.The curative effect and adverse reactions of the two groups were compared.[Results]The total effective rate of the treatment group was higher than that of the control group,and the disappearance time of cough and lung rales was shorter than that of the control group,and the incidence of adverse reactions was lower,showing statistical significance(P<0.05).However,defervescence time and bronchoscope flushing rate showed no significant difference(P>0.05).[Conclusions]Qingfei Ditan Decoction combined with targeted drug penetration therapy of traditional Chinese medicine has a significant effect on severe mycoplasma pneumonia in children,and can reduce the side effects of drugs.It is a safe and efficient combination treatment scheme of traditional Chinese medicine.展开更多
Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical r...Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.展开更多
Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains c...Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.展开更多
AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)...AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study(GWAS)summary datasets were used in this study.Causal associations between plasma proteins and POAG were identified using summary-data-based MR(SMR)analysis and the heterogeneity in dependent instruments(HEIDI)test.Colocalization analysis was then conducted to assess the genetic associations between these two factors.Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects.Finally,protein-protein interactions(PPI)were studied,and the Drug-Gene Interaction Database(DGIDb)was used to identify associations between drugs and the identified proteins.RESULTS:Four proteins(SVEP1,TMEM190,ROBO1,and ENPP5)were identified as potential drug targets in this study.Phenome-wide MR analysis showed that SVEP1,ROBO1,and ENPP5 were not associated with adverse effects,while TMEM190 was linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1.CONCLUSION:Four plasma proteins—SVEP1,TMEM190,ROBO1,and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach.Phenome-wide MR analysis reveals that SVEP1,ROBO1,and ENPP5 are not associated with adverse effects,while TMEM190 is linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1.These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.展开更多
Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculat...Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculature due to embolic presence.Clinical treatments for IS include enzymatic thrombolysis,mechanical thrombectomy,and neuroprotection.However,these approaches have obvious limitations.First,early vascular recanalization leads to secondary cascade injuries and a high risk of hemorrhagic transformation,resulting in poor clinical outcomes for patients with IS.In addition,neuroprotective agents often fail to achieve satisfactory clinical efficacy due to inadequate drug concentrations and off-target effects[1].Targeted stimuli-responsive nanoformulations for thrombolysis and neuroprotection have been developed to address these limitations in current clinical treatments.These nanoformulations are based on IS-specific thrombus-associated receptors and the pathological microenvironments,showing great promise in treating IS(Figure A).展开更多
Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search f...Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search for new and more potent drugs that target all stages of the Plasmodium falciparum life cycle from natural plant sources.This study aimed to determine the antiplasmodial effect of phytocompounds derived from A.paniculata on the stages of plasmodium falciparum.Methods:Phytocompounds from A.paniculata were identified by Gas Chromatography-Mass Spectrophotometry(GCMS)analysis.The phytocompounds were screened for their druggability using Lipinski’s rule of five and subjected to Absorption,Distribution,Metabolism,Excretion,Toxicity(ADMET)and druglikeness analysis.The phytocompounds were docked against some validated drug targets at different stages of Plasmodium falciparum(hepatic,asexual,sexual,and vector targets)using PyRx software to analyze the inhibitory potential and protein-ligand interaction.Thereafter,the stability and flexibility of the best complexes were assessed through molecular dynamics simulations at 50ns using WebGRO.Result:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl exhibited a higher binding affinity and better stability throughout the simulation period with P.falciparum dihydrofolate reductase-thymidylate synthase and Plasmodium falciparum M1 alanyl aminopeptidase for asexual blood stage and gametocyte stage of Plasmodium falciparum,respectively than the existing drugs.Meanwhile,N-Ethyl-3-methoxy-4-methylphenethylamine was also found to have a higher binding affinity and more stability throughout the simulation period with P.falciparum purine nucleoside phosphorylase and Plasmodium falciparum gametocyte surface protein for Hepatic schizonts stage of Plasmodium falciparum and gametocyte transmission blocking stage,respectively,than the existing drugs.Conclusion:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl and N-Ethyl-3-methoxy-4 methylphenethylamine from A.paniculata are predicted as an antimalarial drug candidate.Thus,it is recommended that in vitro and in vivo bioassays be conducted on these hit compounds to validate these predictions.展开更多
Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–b...Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.展开更多
Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involv...Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.展开更多
Malignant tumors have a high incidence in clinical practice,posing a significant threat to human health and severely impacting patients’quality of life.Targeted drugs represent an effective therapeutic strategy,preci...Malignant tumors have a high incidence in clinical practice,posing a significant threat to human health and severely impacting patients’quality of life.Targeted drugs represent an effective therapeutic strategy,precisely addressing tumor sites to inhibit disease progression and alleviate the adverse effects of radiotherapy and chemotherapy.Despite these benefits,the use of targeted drugs often results in various adverse reactions,necessitating enhanced clinical management and protection.This study analyzes the current state of home management of oral targeted drugs in patients with malignant tumors,identifies influencing factors,and proposes improvement measures tailored to practical conditions.These efforts aim to ensure medication safety and provide valuable references for clinical practice.展开更多
The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA t...The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA therapy,including the precise optimization of nonselective toβ2-selective agonists,im-provement from short-acting to ultra-long-acting agents,shift from targeted monotherapy to combination regimens,and alterations in drug formulation.Additionally,this review summarizes recent advances in acupuncture treatment for asthma,including the development of novel targeted therapies,application of acupuncture-based combination regimens,and optimization of the mode of administration.Taken to-gether,this article discusses key insights from research on AA that inform acupuncture approaches,with a focus on:(1)precision targeting:identifying acupuncture-specific targets to improve efficacy;(2)syn-ergistic treatment:employing multi-target combination regimens to enhance therapeutic outcomes;(3)formulation innovation:advancing acupuncture delivery methods to improve patient compliance;and(4)evidence-based development:strengthening clinical research to generate high-quality evidence to inform the discovery of novel targets and treatment strategies for asthma.展开更多
Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(R...Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(ROS),focusing on the cell cycle,and suppressing the expression of oncogenes and matrix metalloproteinases(MMPs).In this study,TQ(after reducing to thymohydroquinone)and GA are esterified to form thymohydroquinyl gallate(a prodrug).Thymohydroquinyl gallate(THQG)possesses enhanced antineoplastic efficacy and targeted delivery potential.The chemical and spectroscopic analysis confirms ester synthesis.Gold nanoparticles(AuNPs)are employed as nanocarriers due to their physicochemical and optical characteristics,biocompatibility,and low toxicity.As an efficient drug transporter,(AuNPs) shield conjugated drugs from enzymatic digestion.The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction.The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography(SPECT).131I is an antineoplastic that helps enhance the drug's efficiency.Chromatographic results reveal promising radiolabeling percentages.In vitro,drug release shows sustained release at pH~5.8.In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.展开更多
In the last century,scientists have discovered that when human epidermal growth factor receptor 2(HER2)is overexpressed or amplified-found in approximately 15%-20%of breast cancer patients-it significantly increases t...In the last century,scientists have discovered that when human epidermal growth factor receptor 2(HER2)is overexpressed or amplified-found in approximately 15%-20%of breast cancer patients-it significantly increases the risk of tumor recurrence and metastasis.This crucial discovery has made anti-HER2 therapy a central focus in breast cancer research and treatment.HER2 protein overexpression,along with gene amplification or mutation,is commonly seen in breast cancer.Techniques like immunohistochemistry and fluorescence in situ hybridization are used to detect HER2 expression and amplification,categorizing tumors as having high,low,or no HER2 expression,and highlighting their heterogeneity.Monoclonal antibodies are well-established in treating breast cancers with a high HER2 expression,while antibody-drug conjugates have shown effectiveness in cases with a lower expression.Additionally,tyrosine kinase inhibitors and monoclonal antibodies optimized for antibody-dependent cellular cytotoxicity have expanded treatment options,allowing for effective therapies in breast cancers with lower HER2 expression levels.Even for tumors with HER2 mutations or low expressions,anti-HER2 therapies can still be effective.Newer treatments,like bispecific antibodies and vaccines,are being tested in clinical trials and are expected to play a significant role in treating breast cancers with different HER2 expression profiles.These advances have revolutionized neoadjuvant therapy,guiding postoperative and intensive treatment strategies based on how well the therapies work.However,challenges such as drug resistance,drug interactions,and the mechanisms of HER2-targeted therapies are closely linked to the tumor’s immune microenvironment.As research continues,the complexity and diversity of HER2 as a target across various cancer types have become increasingly clear,presenting new challenges and driving innovation.Since the discovery of HER2 as a target,it has dramatically changed the landscape of breast cancer diagnosis,treatment,and prognosis.With more than two decades of development,the potential for further advances in HER2-targeted therapies continues to grow.This review aims to provide a comprehensive overview of current progress and future directions in HER2-targeted therapies for breast cancer and their clinical implications.展开更多
Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstr...Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstrated substantial potential in various aspects of pharmaceutical research,including drug target identification,molecular design,and clinical trial optimization(Figure 1).Industry reports suggest that AI has the potential to reduce the drug development timeline from the conventional 10–15 years to 2–3 years,while also slashing development costs by billions of dollars.This article provides a comprehensive analysis of the current applications and future trends of AI in drug development and discovery,focusing on three dimensions:current hotspots,challenges,and future directions.展开更多
Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex m...Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex multiple components.This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis(2D-DIGE)-based drug affinity responsive target stability(DARTS)with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction.The analysis identified 590 proteins,with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group.Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments,the findings indicate that protein disulfide-isomerase A3(PDIA3)may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.展开更多
Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incide...Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related contraindications.With recent advances in precision medicine,precise drug treatment provides better treatment efficacy.Data sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May 2022.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs.According to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and others.All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.Conclusions:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.展开更多
文摘Oral squamous cell carcinoma(OSCC)is the most common head and neck malignancy worldwide,accounting for more than 90%of all oral cancers,and is characterized by high invasiveness and poor long-term prognosis.Its etiology is multifactorial,involving tobacco use,alcohol consumption,and human papillomavirus(HPV)infection.Oral leukoplakia and erythroplakia are the main precancerous lesions lesions,with oral leukoplakia being the most common.Both OSCC and premalignant lesions are closely associated with aberrant activation of multiple signaling pathways.Post-translational modifications(such as ubiquitination and deubiquitination)play key roles in regulating these pathways by controlling protein stability and activity.Growing evidence indicates that dysregulated ubiquitination/deubiquitination can mediate OSCC initiation and progression via aberrant activation of signaling pathways.The ubiquitination/deubiquitination process mainly involves E3 ligases(E3s)that catalyze substrate ubiquitination,deubiquitinating enzymes(DUBs)that remove ubiquitin chains,and the 26S proteasome complex that degrades ubiquitinated substrates.Abnormal expression or mutation of E3s and DUBs can lead to altered stability of critical tumorrelated proteins,thereby driving OSCC initiation and progression.Therefore,understanding the aberrantly activated signaling pathways in OSCC and the ubiquitination/deubiquitination mechanisms within these pathways will help elucidate the molecular mechanisms and improve OSCC treatment by targeting relevant components.Here,we summarize four aberrantly activated signaling pathways in OSCC―the PI3K/AKT/mTOR pathway,Wnt/β-catenin pathway,Hippo pathway,and canonical NF-κB pathway―and systematically review the regulatory mechanisms of ubiquitination/deubiquitination within these pathways,along with potential drug targets.PI3K/AKT/mTOR pathway is aberrantly activated in approximately 70%of OSCC cases.It is modulated by E3s(e.g.,FBXW7 and NEDD4)and DUBs(e.g.,USP7 and USP10):FBXW7 and USP10 inhibit signaling,while NEDD4 and USP7 potentiate it.Aberrant activation of the Wnt/β-catenin pathway leads toβ-catenin nuclear translocation and induction of cell proliferation.This pathway is modulated by E3s(e.g.,c-Cbl and RNF43)and DUBs(e.g.,USP9X and USP20):c-Cbl and RNF43 inhibit signaling,while USP9X and USP20 potentiate it.Hippo pathway inactivation permits YAP/TAZ to enter the nucleus and promotes cancer cell metastasis.This pathway is modulated by E3s(e.g.,CRL4^(DCAF1) and SIAH2)and DUBs(e.g.,USP1 and USP21):CRL4^(DCAF1) and SIAH2 inhibit signaling,while USP1 and USP21 potentiate it.Persistent activation of the canonical NF-κB pathway is associated with an inflammatory microenvironment and chemotherapy resistance.This pathway is modulated by E3s(e.g.,TRAF6 and LUBAC)and DUBs(e.g.,A20 and CYLD):A20 and CYLD inhibit signaling,while TRAF6 and LUBAC potentiate it.Targeting these E3s and DUBs provides directions for OSCC drug research.Small-molecule inhibitors such as YCH2823(a USP7 inhibitor),GSK2643943A(a USP20 inhibitor),and HOIPIN-8(a LUBAC inhibitor)have shown promising antitumor activity in preclinical models;PROTAC molecules,by binding to surface sites of target proteins and recruiting E3s,achieve targeted ubiquitination and degradation of proteins insensitive to small-molecule inhibitors,for example,PU7-1-mediated USP7 degradation,offering new strategies to overcome traditional drug limitations.Currently,NX-1607(a Cbl-b inhibitor)has entered phase I clinical trials,with preliminary results confirming its safety and antitumor activity.Future research on aberrant E3s and DUBs in OSCC and the development of highly specific inhibitors will be of great significance for OSCC precision therapy.
文摘This article provides a comprehensive review of various approaches to targeted drug delivery for liver cancer, an area of significant need due to the limited effectiveness of current treatments. The article begins by highlighting the role of the liver in metabolism and discusses the high mortality associated with hepatocellular carcinoma (HCC). The shortcomings of traditional chemotherapy, such as multidrug resistance and off-target effects, necessitate the exploration of novel therapeutic strategies, with a focus on targeted approaches. The review details both passive and active targeting strategies. Passive targeting leverages the enhanced permeability and retention (EPR) effect and unique features of the tumor microenvironment, while active targeting employs specific ligands, such as peptides, antibodies, and proteins, to bind to overexpressed receptors on liver and tumor cells. The article further details many examples of active targeting using the asialoglycoprotein receptor (ASGPR), glycyrrhetinic acid (GA), transferrin receptor (TfR), and folate receptor (FR) on hepatocytes and tumor cells, demonstrating that there has been significant research effort put into this field. The importance of non-parenchymal cells in the liver is also discussed, and the article examines methods of targeting Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells for therapeutic benefit. The review goes on to cover the emerging field of subcellular targeting, including specific strategies to target the nucleus, mitochondria, and the endoplasmic reticulum/Golgi apparatus, noting that although there has been some progress, further research is needed in this area. The text finishes with a summary which acknowledges that while targeted therapies, including enzyme-activated prodrugs, such as Pradefovir, and other novel methods for drug delivery have shown significant promise, challenges remain in translating these therapies into clinical use due to limitations in understanding the sequential transport and the mechanisms of action. Ultimately, the article emphasizes the need for in-depth research to fully realize the potential of precision cancer therapies for liver cancer.
基金sponsored by the Fundamental Research Funds forthe Central Universities(No.2024-JYB-JBZD-047)High Level Key Discipline Construction of Traditional Chinese Medicine(zyyzdxk-2023272).
文摘Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.
文摘Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.
基金Supported by Key project of National Key R&D Program of China in 2022(2022YFC2502700).
文摘[Objectives]This study was conducted to explore the curative effect of Qingfei Ditan decoction combined with targeted drug penetration therapy of traditional Chinese medicine on severe mycoplasma pneumonia in children.[Methods]Based on the retrospective study method,children with severe mycoplasma pneumonia admitted to the Children s Hospital of Soochow University from April 2023 to October 2023 were selected,and divided into a treatment group including 56 cases and a control group including 145 cases.The curative effect and adverse reactions of the two groups were compared.[Results]The total effective rate of the treatment group was higher than that of the control group,and the disappearance time of cough and lung rales was shorter than that of the control group,and the incidence of adverse reactions was lower,showing statistical significance(P<0.05).However,defervescence time and bronchoscope flushing rate showed no significant difference(P>0.05).[Conclusions]Qingfei Ditan Decoction combined with targeted drug penetration therapy of traditional Chinese medicine has a significant effect on severe mycoplasma pneumonia in children,and can reduce the side effects of drugs.It is a safe and efficient combination treatment scheme of traditional Chinese medicine.
基金supported by grants from the National Nat-ural Science Foundation of China(82122010 and 82070659)the National High Level Hospital Clinical Research Funding(2022-PUMCH-E-003)+1 种基金the CAMS Innovation Fund for Medical Science(2022-I2M-1-004)an NIHR Senior Investigator Award。
文摘Acute pancreatitis(AP)is a common but potentially devastating disease characterized at onset patho-physiologically by premature activation of digestive enzymes within the pancreas.Despite an abundance of preclinical research and,until recently,a series of disappointing clinical trials,no specific disease mod-ifying pharmacological treatment has yet been approved for this condition.Recent novel approaches to understanding the molecular pathogenesis of AP provide us with renewed optimism for translational drug discovery.Although digestive enzyme activation is the hallmark of AP,a critical mechanism that initiates AP is intracellular calcium(Ca2+)overload in pancreatic parenchymal cells,which triggers mitochondrial dysfunction,endoplasmic reticulum(ER)stress,and impairs autophagic flux.These processes are piv-otal to the disease and present a range of drug targets,associated with the inflammatory responses that drive local and systemic inflammation in AP.Progress in translation has now been made,targeting the ORAI channel with the inhibitor zegocractin(Auxora)to reduce pancreatic injury and inflammatory re-sponses in human AP.Herein we evaluated potential drug targets for the early treatment of AP,focused on intra-acinar mechanisms of injury central to the onset and severity of AP.Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies.
基金support from the National Natural Science Foundation of China(Grant Nos.:U21A20407 and 81973467).
文摘Prodrugs need to be converted to active drugs to exert their pharmacological activities.Identifying the direct targets of active drugs is essential to elucidate the pharmacological mechanisms of prodrugs,but remains challenging,especially for active drugs with low stability.
基金Supported by the National Natural Science Foundation of China(No.81770920)Open Project of State Key Laboratory of Ophthalmology(No.303060202400383).
文摘AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study(GWAS)summary datasets were used in this study.Causal associations between plasma proteins and POAG were identified using summary-data-based MR(SMR)analysis and the heterogeneity in dependent instruments(HEIDI)test.Colocalization analysis was then conducted to assess the genetic associations between these two factors.Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects.Finally,protein-protein interactions(PPI)were studied,and the Drug-Gene Interaction Database(DGIDb)was used to identify associations between drugs and the identified proteins.RESULTS:Four proteins(SVEP1,TMEM190,ROBO1,and ENPP5)were identified as potential drug targets in this study.Phenome-wide MR analysis showed that SVEP1,ROBO1,and ENPP5 were not associated with adverse effects,while TMEM190 was linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1.CONCLUSION:Four plasma proteins—SVEP1,TMEM190,ROBO1,and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach.Phenome-wide MR analysis reveals that SVEP1,ROBO1,and ENPP5 are not associated with adverse effects,while TMEM190 is linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1.These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.
文摘Stroke is the second leading cause of death and the primary cause of permanent disability worldwide.Ischemic stroke(IS)accounts for 87%of all strokes globally and is characterized by the occlusion of cerebral vasculature due to embolic presence.Clinical treatments for IS include enzymatic thrombolysis,mechanical thrombectomy,and neuroprotection.However,these approaches have obvious limitations.First,early vascular recanalization leads to secondary cascade injuries and a high risk of hemorrhagic transformation,resulting in poor clinical outcomes for patients with IS.In addition,neuroprotective agents often fail to achieve satisfactory clinical efficacy due to inadequate drug concentrations and off-target effects[1].Targeted stimuli-responsive nanoformulations for thrombolysis and neuroprotection have been developed to address these limitations in current clinical treatments.These nanoformulations are based on IS-specific thrombus-associated receptors and the pathological microenvironments,showing great promise in treating IS(Figure A).
文摘Background:Andrographis paniculata has been widely reported as an herbal plant for malaria treatment.The increasing rate of resistance to recommended antimalarial drugs has justified the need for a continuous search for new and more potent drugs that target all stages of the Plasmodium falciparum life cycle from natural plant sources.This study aimed to determine the antiplasmodial effect of phytocompounds derived from A.paniculata on the stages of plasmodium falciparum.Methods:Phytocompounds from A.paniculata were identified by Gas Chromatography-Mass Spectrophotometry(GCMS)analysis.The phytocompounds were screened for their druggability using Lipinski’s rule of five and subjected to Absorption,Distribution,Metabolism,Excretion,Toxicity(ADMET)and druglikeness analysis.The phytocompounds were docked against some validated drug targets at different stages of Plasmodium falciparum(hepatic,asexual,sexual,and vector targets)using PyRx software to analyze the inhibitory potential and protein-ligand interaction.Thereafter,the stability and flexibility of the best complexes were assessed through molecular dynamics simulations at 50ns using WebGRO.Result:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl exhibited a higher binding affinity and better stability throughout the simulation period with P.falciparum dihydrofolate reductase-thymidylate synthase and Plasmodium falciparum M1 alanyl aminopeptidase for asexual blood stage and gametocyte stage of Plasmodium falciparum,respectively than the existing drugs.Meanwhile,N-Ethyl-3-methoxy-4-methylphenethylamine was also found to have a higher binding affinity and more stability throughout the simulation period with P.falciparum purine nucleoside phosphorylase and Plasmodium falciparum gametocyte surface protein for Hepatic schizonts stage of Plasmodium falciparum and gametocyte transmission blocking stage,respectively,than the existing drugs.Conclusion:The 7a-Isopropenyl-4,5-dimethyloctahydroinden-4-yl and N-Ethyl-3-methoxy-4 methylphenethylamine from A.paniculata are predicted as an antimalarial drug candidate.Thus,it is recommended that in vitro and in vivo bioassays be conducted on these hit compounds to validate these predictions.
基金supported by the National Natural Science Foundation of China,Nos.82171363,82371381(to PL),82171458(to XJ)Key Research and Development Project of Shaa nxi Province,Nos.2024SF-YBXM-404(to KY)。
文摘Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.
基金Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine Research Project of Tianjin Municipal Administration of Traditional Chinese Medicine(2021106)Beijing-Tianjin-Hebei Traditional Chinese Medicine Collaborative Development Specialty Alliance Construction Project(First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Qingxian County Traditional Chinese Medicine Hospital).
文摘Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.
基金Shanghai Modern Nursing Vocational Education Group-Renji Hospital Enterprise Practice Fund Project。
文摘Malignant tumors have a high incidence in clinical practice,posing a significant threat to human health and severely impacting patients’quality of life.Targeted drugs represent an effective therapeutic strategy,precisely addressing tumor sites to inhibit disease progression and alleviate the adverse effects of radiotherapy and chemotherapy.Despite these benefits,the use of targeted drugs often results in various adverse reactions,necessitating enhanced clinical management and protection.This study analyzes the current state of home management of oral targeted drugs in patients with malignant tumors,identifies influencing factors,and proposes improvement measures tailored to practical conditions.These efforts aim to ensure medication safety and provide valuable references for clinical practice.
基金Supported by National Natural Science Foundation of China:No.82374583,82274646.
文摘The development of adrenergic agonists(AAs)for asthma has provided important mechanistic insights into acupuncture-based target discovery and treatment strategies.This review describes the historical evolution of AA therapy,including the precise optimization of nonselective toβ2-selective agonists,im-provement from short-acting to ultra-long-acting agents,shift from targeted monotherapy to combination regimens,and alterations in drug formulation.Additionally,this review summarizes recent advances in acupuncture treatment for asthma,including the development of novel targeted therapies,application of acupuncture-based combination regimens,and optimization of the mode of administration.Taken to-gether,this article discusses key insights from research on AA that inform acupuncture approaches,with a focus on:(1)precision targeting:identifying acupuncture-specific targets to improve efficacy;(2)syn-ergistic treatment:employing multi-target combination regimens to enhance therapeutic outcomes;(3)formulation innovation:advancing acupuncture delivery methods to improve patient compliance;and(4)evidence-based development:strengthening clinical research to generate high-quality evidence to inform the discovery of novel targets and treatment strategies for asthma.
文摘Thymoquinone(TQ)and gallic acid(GA)are known for counter-tumorigenic characteristics.GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways,producing more reactive oxygen species(ROS),focusing on the cell cycle,and suppressing the expression of oncogenes and matrix metalloproteinases(MMPs).In this study,TQ(after reducing to thymohydroquinone)and GA are esterified to form thymohydroquinyl gallate(a prodrug).Thymohydroquinyl gallate(THQG)possesses enhanced antineoplastic efficacy and targeted delivery potential.The chemical and spectroscopic analysis confirms ester synthesis.Gold nanoparticles(AuNPs)are employed as nanocarriers due to their physicochemical and optical characteristics,biocompatibility,and low toxicity.As an efficient drug transporter,(AuNPs) shield conjugated drugs from enzymatic digestion.The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction.The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography(SPECT).131I is an antineoplastic that helps enhance the drug's efficiency.Chromatographic results reveal promising radiolabeling percentages.In vitro,drug release shows sustained release at pH~5.8.In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.
基金supported by grants from the Natural Sci-ence Foundation of China(grant numbers:92159303,81930081,82102865)Guangdong Science and Technology Department(grant numbers:2020B1212060013,2020B1212030004)+3 种基金Guangzhou Science and Technology Department(grant number:2023A04J2109)Department of Natural Resources of Guangdong Province(grant number:GDNRC[2021]51)Bureau of Science and Technology of Guangzhou(grant number:20212200003)the Program for Guangdong Introducing Innovative and Entrepreneurial Teams(grant number:2019BT02Y198).
文摘In the last century,scientists have discovered that when human epidermal growth factor receptor 2(HER2)is overexpressed or amplified-found in approximately 15%-20%of breast cancer patients-it significantly increases the risk of tumor recurrence and metastasis.This crucial discovery has made anti-HER2 therapy a central focus in breast cancer research and treatment.HER2 protein overexpression,along with gene amplification or mutation,is commonly seen in breast cancer.Techniques like immunohistochemistry and fluorescence in situ hybridization are used to detect HER2 expression and amplification,categorizing tumors as having high,low,or no HER2 expression,and highlighting their heterogeneity.Monoclonal antibodies are well-established in treating breast cancers with a high HER2 expression,while antibody-drug conjugates have shown effectiveness in cases with a lower expression.Additionally,tyrosine kinase inhibitors and monoclonal antibodies optimized for antibody-dependent cellular cytotoxicity have expanded treatment options,allowing for effective therapies in breast cancers with lower HER2 expression levels.Even for tumors with HER2 mutations or low expressions,anti-HER2 therapies can still be effective.Newer treatments,like bispecific antibodies and vaccines,are being tested in clinical trials and are expected to play a significant role in treating breast cancers with different HER2 expression profiles.These advances have revolutionized neoadjuvant therapy,guiding postoperative and intensive treatment strategies based on how well the therapies work.However,challenges such as drug resistance,drug interactions,and the mechanisms of HER2-targeted therapies are closely linked to the tumor’s immune microenvironment.As research continues,the complexity and diversity of HER2 as a target across various cancer types have become increasingly clear,presenting new challenges and driving innovation.Since the discovery of HER2 as a target,it has dramatically changed the landscape of breast cancer diagnosis,treatment,and prognosis.With more than two decades of development,the potential for further advances in HER2-targeted therapies continues to grow.This review aims to provide a comprehensive overview of current progress and future directions in HER2-targeted therapies for breast cancer and their clinical implications.
基金supported by the Centrally Guided Local Science and Technology Development Project(2024ZYD0043).
文摘Artificial intelligence(AI)is revolutionizing the traditional paradigm of drug development at an unprecedented pace.With the rapid advancement of technologies such as deep learning and machine learning,AI has demonstrated substantial potential in various aspects of pharmaceutical research,including drug target identification,molecular design,and clinical trial optimization(Figure 1).Industry reports suggest that AI has the potential to reduce the drug development timeline from the conventional 10–15 years to 2–3 years,while also slashing development costs by billions of dollars.This article provides a comprehensive analysis of the current applications and future trends of AI in drug development and discovery,focusing on three dimensions:current hotspots,challenges,and future directions.
基金supported by the National Natural Science Foundation of China(Nos.82073814,82122066,and 82104328)the"Dawn"Program of the Shanghai Education Commission(No.22SG34)+1 种基金the National Key Research and Development Program of the Ministry of China(No.2022YFC2704603)Shanghai Sailing Program(No.20YF1458900).
文摘Sini Decoction(SNT)is a traditional formula recognized for its efficacy in warming the spleen and stomach and dispersing cold.However,elucidating the mechanism of action of SNT remains challenging due to its complex multiple components.This study utilized a synergistic approach combining two-dimensional fluorescence difference in gel electrophoresis(2D-DIGE)-based drug affinity responsive target stability(DARTS)with label-free quantitative proteomics techniques to identify the direct and indirect protein targets of SNT in myocardial infarction.The analysis identified 590 proteins,with 30 proteins showing significant upregulation and 51 proteins showing downregulation when comparing the SNT group with the model group.Through the integration of 2D-DIGE DARTS with proteomics data and pharmacological assessments,the findings indicate that protein disulfide-isomerase A3(PDIA3)may serve as a potential protein target through which SNT provides protective effects on myocardial cells during myocardial infarction.
基金This work was supported by grants from the National Natural Science Foundation of China(81902484)China Postdoctoral Science Foundation(2020M670864)+2 种基金Youth Support Project of Jilin Association for Science and Technology(202028)Jilin Provincial Health Special Project(2020SCZT039)Jilin Health and Healthy Youth Science and Technology Training Plan(2020Q017).
文摘Background:Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis.Although primary prevention drugs,including non-selectiveβ-blockers,have effectively reduced the incidence of bleeding,their efficacy is limited due to side effects and related contraindications.With recent advances in precision medicine,precise drug treatment provides better treatment efficacy.Data sources:Literature search was conducted in PubMed,MEDLINE and Web of Science for relevant articles published up to May 2022.Information on clinical trials was obtained from https://clinicaltrials.gov/and http://www.chictr.org.cn/.Results:The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs.According to the site of action,these drugs could be classified into four classes:intrahepatic,extrahepatic,both intrahepatic and extrahepatic targets and others.All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.Conclusions:This review classified and summarized the promising drugs,which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension,demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.
