查看更多>>摘要：Interleukin-1 receptor-related kinase(IRAK4)is a widely expressed serine/threonine kinase involved in the regulation of innate immunity.IRAK4 plays a pivotal role as a key kinase within the downstream signaling pathway cascades of interleukin-1 receptors(IL-1R)and Toll-like receptors(TLRs).The signaling pathways orchestrated by IRAK4 are integral to inflammatory responses,and its overexpression is implicated in the pathogenesis of inflammatory diseases,autoimmune disorders,and cancer.Consequently,targeting IRAK4-mediated signaling pathways has emerged as a promising therapeutic strategy.Small molecule inhibitors and degraders designed to modulate IRAK4 have shown efficacy in mitigating related diseases.In this paper,we will provide a detailed description of the structure and function of IRAK4,the role of IRAK4 in related diseases,as well as the currently reported small molecule inhibitors and degraders of IRAK4.It is expected to provide new directions for enriching the clinical treatment of inflammation and related diseases.
查看更多>>摘要：Reactive oxygen species(ROS)-responsive drug delivery systems(DDSs)have garnered signif-icant attention in cancer research because of their potential for precise spatiotemporal drug release tailored to high ROS levels within tumors.Despite the challenges posed by ROS distribution heterogeneity and endogenous supply constraints,this review highlights the strategic alliance of ROS-responsive DDSs with photodynamic therapy(PDT),enabling selective drug delivery and leveraging PDT-induced ROS for enhanced therapeutic efficacy.This review delves into the biological importance of ROS in cancer progres-sion and treatment.We elucidate in detail the operational mechanisms of ROS-responsive linkers,including thioether,thioketal,selenide,diselencide,telluride and aryl boronic acids/esters,as well as the latest devel-opments in ROS-responsive nanomedicines that integrate with PDT strategies.These insights are intended to inspire the design of innovative ROS-responsive nanocarriers for enhanced cancer PDT.
查看更多>>摘要：The respiratory tract is susceptible to various infections and can be affected by many serious diseases.Vaccination is one of the most promising ways that prevent infectious diseases and treatment of some diseases such as malignancy.Direct delivery of vaccines to the respiratory tract could mimic the natural process of infection and shorten the delivery path,therefore unique mucosal immunity at the first line might be induced and the efficiency of delivery can be high.Despite considerable attempts at the development of respiratory vaccines,the rational formulation design still warrants attention,i.e.,how the formulation composition,particle properties,formulation type(liquid or solid),and devices would influence the immune outcome.This article reviews the recent advances in the formulation design and development of respiratory vaccines.The focus is on the state of the art of delivering antigenic com-pounds through the respiratory tract,overcoming the pulmonary bio-barriers,enhancing delivery effi-ciencies of respiratory vaccines as well as maintaining the stability of vaccines during storage and use.The choice of devices and the influence of deposition sites on vaccine efficiencies were also reviewed.
查看更多>>摘要：Microneedles(MNs)serve as a revolutionary paradigm in transdermal drug delivery,herald-ing a viable resolution to the formidable barriers presented by the cutaneous interface.This review examines MNs as an advanced approach to enhancing dermatological pathology management.It explores the complex dermis structure and highlights the limitations of traditional transdermal methods,empha-sizing MNs'advantage in bypassing the stratum corneum to deliver drugs directly to the subdermal ma-trix.The discourse outlines the diverse typologies of MNs,including solid,coated,hollow,hydrogel,and dissolvable versions.Each type is characterized by its unique applications and benefits.The treatise details the deployment of MNs in the alleviation of cutaneous cancers,the administration of inflammatory dermatoses such as psoriasis and atopic dermatitis,and their utility in wound management.Additionally,the paper contemplates the prospects of MNs within the realm of aesthetic dermatology and the burgeon-ing market traction of cosmetic MN formulations.The review summarizes the scientific and commercial challenges to the clinical adoption of MN therapeutics,including dosage calibration,pharmacodynamics,biocompatibility,patient compliance,sterilization,mass production,and regulatory oversight.It empha-sizes the need for ongoing research,innovation,and regulatory harmonization to overcome these obsta-cles and fully realize MNs'potential in treating skin diseases and improving patient welfare.
查看更多>>摘要：Reductive stress,characterized by rising level of NADH(nicotinamide adenine dinucleotide)for a status of NADH/NAD+ratio elevation,has been reported in obesity and cancer.However,the mech-anism and significance of reductive stress remain to be established in obesity.This perspective is prepared to address the issue with new insights published recently.NADH is used in production of NADPH,gluta-thione,ATP and heat in the classical biochemistry.In obesity,elevation of NADH/NAD+ratio,likely from overproduction due to substrate overloading,has been found in the liver for insulin resistance and gluconeogenesis.New evidence demonstrates that the elevation may induce lipogenesis,purine biosynthesis and gluconeogenesis through activation of transcription factors of ChREBP and NRF2.In cancer cells,NADH/NAD+elevation under the Warburg effect is primarily derived from decreased NADH consumption in the mitochondrial respiration.Alternatively,NRF2 overactivation from gene mu-tation represents another mechanism of NADH/NAD+elevation from NADH production in the cancer cells.The elevation is required for quick proliferation of cancer cells through induction of biosynthesis of the essential molecules.It appears that the causes of reductive stress are different between obesity and cancer,while its impact in anabolism is similar in the two conditions.
查看更多>>摘要：The comparison between traditional Chinese medicine Jinzhen oral liquid(JZOL)and West-ern medicine in treating children with acute bronchitis(AB)showed encouraging outcomes.This trial eval-uated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB.480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days.The primary outcome was time-to-cough resolution.The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day.This random-ized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discom-fort symptoms.Combined with clinical trials,the mechanism of JZOL against AB was uncovered by network target analysis,it was found that the pathways in TRP channels like IL-1β/IL1R/TRPV1/TRPA1,NGF/TrkA/TRPVl/TRPA1,and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles.Animal ex-periments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.
查看更多>>摘要：Uveal melanoma(UM)poses a significant lethality,with approximately 50％of those developing metastases surviving less than one year.In the progression of UM,vasculogenic mimicry(VM)induced by hypoxia plays a pivotal role,which also partially explains the resistance of UM to anti-angiogenic therapies.Nevertheless,the crucial molecular mechanisms underlying VM in the progres-sion of UM remain unclear.We identified ubiquitin conjugating enzyme E2 G2(UBE2G2)as a critical suppressor through transcriptomic sequencing and metastasis correlation screening.In UM,hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly allevi-ated by its overexpression.Mechanistically,UBE2G2 directly binds to galectin 3 binding protein(LGALS3BP)and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38(TRIM38),facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue.Further-more,UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and re-programming the tumor microenvironment.Therefore,targeting intercellular and intracellular molecular mechanisms of the hypoxia-UBE2G2-LGALS3BP axis may contribute to developing various therapeu-tic strategies for UM.
查看更多>>摘要：DNMT3A encodes a DNA methyltransferase involved in development,cell differentiation,and gene transcription,which is mutated and aberrant-expressed in cancers.Here,we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer.Based on the epigenetic inhibitor library synthetic lethal screening,we found that small-molecule HDAC6 inhibitors selectively killed DNMT3AA-defective NSCLC cells.Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells.However,sensitive cells became resistant when DNMT3A was rescued.Furthermore,the selectivity to HDAC6 inhibition was recapitulated in mice,where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells.Mechanistically,DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding.Notably,our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition.Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6.Interestingly,HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells.These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers.Together,our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.
查看更多>>摘要：Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation.In this study,we identify ubiquitin-specific protease 2(USP2)as a novel deubiquitinating enzyme of KRAS in multiple myeloma(MM).Specifically,we demonstrate that gambogic acid(GA)forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket,inhibiting its deubiquitinating activity.Inactivation or knockdown of USP2 leads to the degradation of KRAS,resulting in the suppression of MM cell proliferation in vitro and in vivo.Conversely,overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells.Furthermore,elevated USP2 levels may be associated with poorer prognoses in MM patients.These findings highlight the po-tential of the USP2/KRAS axis as a therapeutic target in MM,suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.
查看更多>>摘要：Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain,which may display sexual dimorphism.Here,we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin(IL)-17A promotes the progression of mouse bone cancer pain without sex differences.Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors.In contrast,chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity,implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain.IL-17A expression predominantly in spinal astro-cytes,whereas its receptor IL-17 receptor A(IL-17RA)was mainly detected in neurons expressing VGLUT2 and PAX2,and a few in astrocytes expressing GFAP.Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain.IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia,which could be rescued by CaMKⅡα inhibitor.Moreover,selective knockdown IL-17RA in spinal Vglut2+or Vgat+neurons,but not in astrocytes,significantly blocked the bone cancer-induced hyperalgesia.Together,our findings pro-vide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain.Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKⅡα signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.
万方数据
维普