查看更多>>摘要：RAS mutations occur in approximately 30％of tumors worldwide and have a poor prognosis due to limited therapies.Covalent targeting of KRAS G12C has achieved significant success in recent years,but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mu-tations.A highly promising approach is to target the MAPK pathway downstream of RAS,with a partic-ular focus on RAF kinases.First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade.However,their use in RAS-mutated tumors is not recommended due to the par-adoxical ERK activation mainly caused by RAF dimerization.To address the issue of RAF dimerization,type Ⅱ RAF inhibitors have emerged as leading candidates.Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors.Promisingly,type Ⅱ RAF inhibitors in combi-nation with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors.This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treat-ment in tumors with RAS mutations,as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
查看更多>>摘要：Drug transporters are essential players in the transmembrane transport of a wide variety of clinical drugs.The broad substrate spectra and versatile distribution pattern of these membrane proteins infer their pharmacological and clinical significance.With our accumulating knowledge on the three-dimensional structure of drug transporters,their oligomerization status has become a topic of intense study due to the possible functional roles carried out by such kind of post-translational modification(PTM).In-depth studies of oligomeric complexes formed among drug transporters as well as their inter-actions with other regulatory proteins can help us better understand the regulatory mechanisms of these membrane proteins,provide clues for the development of novel drugs,and improve the therapeutic effi-cacy.In this review,we describe different oligomerization forms as well as their structural basis of major drug transporters in the ATP-binding cassette and solute carrier superfamilies,summarize our current knowledge on the influence of oligomerization for protein expression level and transport function of these membrane proteins,and discuss the regulatory mechanisms of oligomerization.Finally,we highlight the challenges associated with the current oligomerization studies and propose some thoughts on the pharma-ceutical application of this important drug transporter PTM.
查看更多>>摘要：The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has been significantly alleviated.However,long-term health effects and prevention strategy remain unresolved.Thus,it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection.Emerging research indicates a link between COVID-19 and bile acids,traditionally known for facilitating dietary fat absorption.The bile acid urso deoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X recep-tor,a bile acid nuclear receptor.The activation of G-protein-coupled bile acid receptor,another mem brane receptor for bile acids,has also been found to regulate the expression of angiotensin-converting enzyme 2,the receptor through which the virus enters human cells.Here,we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2,and reveal their complicated pathophysiological mechanisms.
查看更多>>摘要：Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal tissues.It binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and im-mune cell activation,thereby inhibiting tumor adaptive immunity.Ado downregulates major histocompat-ibility complex Ⅱ(MHCⅡ)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen presentation.It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal transduction.Ado also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor site.Furthermore,Ado dimin-ishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregu-lating immune checkpoint proteins,and enhancing immune-suppressive cell activity.Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies.Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway.Therefore,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.
查看更多>>摘要：Bispecific antibody-drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody-drug conjugates(ADCs)and bispecific antibodies(BsAbs).Posi-tioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical chal-lenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings un-derscore the imperative for ongoing refinement.This review initially delves into specific design consid-erations for BsADCs,encompassing target selection,antibody formats,and the linker-payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic"1+1"to effectively surmount the extant challenges facing the BsADC domain.
查看更多>>摘要：The N-methyl-D-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluNl/2A subtype plays a significant role in central nervous system(CNS)disorders.The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modula-tors(PAMs)and competitive antagonists.Moreover,the ligands'structure-activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable in-sights for the clinical rational design of effective drugs targeting CNS diseases.
查看更多>>摘要：Diabetes,characterized by hyperglycemia,is a major cause of death and disability world-wide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body.Compared to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred approach.However,biological barriers significantly reduce the efficacy of oral peptide therapeutics.Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide ther-apeutics and their efficacy in treating diabetes.This review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological barriers.Additionally,the review will discuss the prospects in this field.The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.
查看更多>>摘要：Growing evidences indicate that dysfunction of autophagy contributes to the disease patho-genesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenera-tive disorders.The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and FTD.According to the previous studies,GGGGCC-GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)proteins.Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains unclear.In the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced autophagy.Moreover,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,there-fore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates un-der starvation condition in cells.Importantly,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.
查看更多>>摘要：Osteosarcoma,a prevalent primary malignant bone tumor,often presents with lung metasta-ses,severely impacting patient survival rates.Extracellular vesicles,particularly exosomes,play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions.However,the commu-nication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure,with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown.This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site.This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate(MARCKS)expression.Addressing this phenomenon,in this study we employ cationic bovine serum albumin(CBSA)to form nanoparticles(CBSA-anta-194/215)via electrostatic interaction with antagomir-miR-194/215.These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles(anta-194/215@Exo)targeting osteosarcoma lung metastatic sites.Intervention with bioengineered exosome mimetics(anta-194/215@Exo)not only impedes osteosarcoma progression but also significantly pro-longs the lifespan of tumor-bearing mice.These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS,making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.
查看更多>>摘要：Parkinson's disease(PD)is a neurodegeneration disease with α-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while pa-tients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the"gut-brain"hypothesis is proposed to explain the underly-ing mechanism,where the earlier lesioned site in the brain of gastric α-synuclein and how α-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastric α-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastric α-synuclein spread to the midbrain.Our study provides valuable details for the"gut-brain"hypothesis and proposes a valuable PD model for future research on early PD intervention.
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