Managing the immune microenvironment of osteosarcoma:the outlook for osteosarcoma treatment

Osteosarcoma,with poor survival after metastasis,is considered the most common primary bone cancer in adolescents.Notwithstanding the efforts of researchers,its five-year survival rate has only shown limited improvement,suggesting that existing therapeutic strategies are insufficient to meet clinical needs.Notably,immunotherapy has shown certain advantages over traditional tumor treatments in inhibiting metastasis.Therefore,managing the immune microenvironment in osteosarcoma can provide novel and valuable insight into the multifaceted mechanisms underlying the heterogeneity and progression of the disease.Additionally,given the advances in nanomedicine,there exist many advanced nanoplatforms for enhanced osteosarcoma immunotherapy with satisfactory physiochemical characteristics.Here,we review the classification,characteristics,and functions of the key components of the immune microenvironment in osteosarcoma.This review also emphasizes the application,progress,and prospects of osteosarcoma immunotherapy and discusses several nanomedicine-based options to enhance the efficiency of osteosarcoma treatment.Furthermore,we examine the disadvantages of standard treatments and present future perspectives for osteosarcoma immunotherapy.

Advances in nanotechnology-based delivery systems for EGFR tyrosine kinases inhibitors in cancer therapy

Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.

A Method for Calculating the Heats of Formation of Medium-Sized and Large-Sized Molecules

A calculation method for heats of formation (HOF, referred to as △Hf) based on the density functional theory (DFT) is presented in this work. Similar to Gaussian-3 theory, the atomic scheme is applied to calculate the heats of formation of the molecules. In this method, we have modified the formula for calculation of Gaussian-3 theory in several ways, including the correction for diffuse functions and the correction for higher polarization functions. These corrections are found to be significant. The average absolute deviation from experiment for the 164 calculated heats of formation is about 1.9 kcal·mol?1, while average absolute deviation from G3MP2 for the 149 (among the 164 molecules, 15 large-sized molecules can not be calculated at the G3MP2 level) calculated heats of formation is only about 1.9 kcal·mol?1. It indicates that the present method can be applied to predict the heats of formation of medium-sized and large-sized molecules, while the heats of formation of these molecules using Gaussian-3 theory are much difficult, even impossible, to calculate. That is, this method provides a choice in the calculation of △Hf for medium-sized and large-sized molecules.

Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping

Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.

Nucleos(t)ide analogues causes HBV S gene mutations and carcinogenesis

BACKGROUND： The long-term use of nudeos（t）ide analogues causes drug resistance and mutations in the HBV reverse tran- scriptase （RT） region of the polymerase gene. The RT region overlaps the HBV surface gene （S gene） and therefore, the mutations in the RT region simultaneously modify S gene sequence. Certain mutations in the RT region bring about truncated S proteins because the corresponding changed S gene encodes a stop codon which results in the loss of a large portion of the C-terminal hydrophobic region of HBV surface protein. The rtA181T/sW172＊, rtM204I/sW196＊ and rtV191I/sW182＊ are the most frequently reported drug-resistant mutations with C-terminal truncation, these mutations have oncogenic potential. DATA SOURCES： PubMed and Web of Science were searched using terms： ＂hepatitis B virus＂, ＂HBV drug resistance mutation＂ ＂HBV surface protein＂ ＂HBV truncation＂, ＂hepatocellular carcinoma＂, ＂rtA181T/sW172＊＂, ＂rtM204I/sW196＊＂, ＂rtV191I/sW182＊＂, and relevant articles published in English in the past decades were reviewed. RESULTS： The rtA181T/sW172＊ and rtV191I/sW182＊ mutants occurred more frequently than the rtM204I/sW196＊ mutant both in chronic hepatitis B patients and the HBV-related hepatocellular carcinoma tissues. Although these mutations occur naturally, nudeos（t）ide analogues therapy is the main driving force. These mutations may exist alone or coexist with other HBV mutations. All these three mutants impair the virion secretion and result in HBV surface protein retention and serum HBV DNA level reduction. These mutations possess potential carcinogenic properties. The three mutations are resistant to more than one nucleos（t）ide analogue and therefore, it is difficult to treat the patients with the truncated mutations.CONCLUSIONS： Nucleos（t）ide analogues induce drug resistance and HBV S gene truncated mutations. These mutations have potential carcinogenesis.

Oral squamous cell carcinomas:state of the field and emerging directions

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.

An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway

Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

The solute carrier transporters and the brain:Physiological and pharmacological implications

Solute carriers(SLCs)are the largest family of transmembrane transporters that determine the exchange of various substances,including nutrients,ions,metabolites,and drugs across biological membranes.To date,the presence of about 287 SLC genes have been identified in the brain,among which mutations or the resultant dysfunctions of 71 SLC genes have been reported to be correlated with human brain disorders.Although increasing interest in SLCs have focused on drug development,SLCs are currently still under-explored as drug targets,especially in the brain.We summarize the main substrates and functions of SLCs that are expressed in the brain,with an emphasis on selected SLCs that are important physiologically,pathologically,and pharmacologically in the blood-brain barrier,astrocytes,and neurons.Evidence suggests that a fraction of SLCs are regulated along with the occurrences of brain disorders,among which epilepsy,neurodegenerative diseases,and autism are representative.Given the review of SLCs involved in the onset and procession of brain disorders,we hope these SLCs will be screened as promising drug targets to improve drug delivery to the brain.

Ginsenoside Rg5 enhances the radiosensitivity of lung adenocarcinoma via reducing HSP90-CDC37 interaction and promoting client protein degradation

Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.

Prevalence of human papillomavirus in esophageal carcinoma in Tangshan,China

AIM:to study the prevalence of human papillomavirus(HPV) in esophageal carcinoma in tangshan,China,a high-incidence area.METHODS:Formalin-fixed,paraffin-embedded tissue specimens from 198 patients who were pathologically diagnosed with esophageal squamous cell carcinoma from 2011 to 2013 were obtained from a pathology department in Tangshan.DNA was extracted from all198 specimens to detect HPV by polymerase chain reaction(PCR).β-globin PCR was performed to check the quality of the DNA extraction procedure.PCR was performed to detect a wide range of HPV types,and type-specific PCR was performed to detect HPV types16 and 18.Negative and positive controls were used for HPV 16 and 18 detection.RESULTS:the DNA extraction method in this study appeared to be more effective than other previously reported methods.After DNA extraction,more than98%of the tissue specimens had an acceptable result in the DNA qualification test(β-globin PCR).the overall prevalence of HPV in tumor tissues by GP6+/GP5+PCR was 79.79%,and the prevalence of HPV types16 and 18 was 40.40%and 47.47%,respectively.PCR demonstrated the presence of HPV,and direct sequencing confirmed the HPV genotypes.All HPVpositive PCR products were checked by DNA sequence analysis using DNAman and compared with the known HPV sequences listed in the basic Local Alignment Search tool database to evaluate the HPV types.this analysis confirmed the presence of HPV types 16 and18.CONCLUSION:DNA of high-risk HPV types 16 and 18is present in esophageal tumors,implicating HPV as a possible etiologic factor for esophageal squamous cell carcinoma.

用于中子俘获治疗的硼携带剂

硼中子俘获治疗(boron neutron capture therapy,BNCT)是一种基于稳定同位素硼-10被中子照射产生高能α粒子时发生的核俘获和裂变反应的二元放射疗法。本综述关注了这个二元系统的一个重要组分,即具有肿瘤靶向性的硼携带剂。目前临床上正在使用的两种低分子量含硼药物是硼苯丙氨酸(boronophenylalanine,BPA)和硼卡钠(sodium borocaptate,BSH)。尽管还远未达到理想水平,但它们的治疗效果已经在高级别神经胶质瘤、头颈部复发性肿瘤以及小部分皮肤和皮肤外黑色素瘤患者中得到了证实。由于它们存在局限性,在过去的40年中,研究者们一直在为临床应用努力研发具有更高生物分布和摄取性的新型硼携带剂。这些物质包括含硼的卟啉、氨基酸、多胺、核苷、多肽、单克隆抗体、脂质体和各种类型的纳米颗粒,以及硼簇合物和共聚物。然而到目前为止,还没有一种化合物获得过有说服力的数据,能使之进入临床生物分布研究。因此,目前进一步提高BNCT临床疗效的最佳途径是优化BPA和BSH单独使用或联合使用的给药模式和递送方式,并希望未来的研究能发现更新更好的硼携带剂供临床使用。

Chemokine Ligand 13 Expression is Abundant in the Tumor Microenvironment and Indicates Poor Prognosis of Kidney Clear Cell Carcinoma

The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,we analyzed the expression profile of CXCL13 in kidney clear cell carcinoma(KIRC)and its correlation with tumor-infiltrating immune cells(TIICs).A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry(IHC).Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas(TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB.Results showed that high CXCL13 expression in TME was associated with shorter progression-free survival(PFS),disease-specific survival(DSS),and overall survival(OS).KIRC cell lines,as well as several other cancer cell lines,had negative CXCL13 expression.IHC staining from the Human Protein Atlas(HPA)and our tissue array indicated that CXCL13 might be mainly expressed by TIICs,but not KIRC tumor cells.CXCL13 expression was strongly and positively correlated withγδT cell abundance in TME.Besides,γδT cell infiltration was associated with poor survival of KIRC.Methylation 450k array data showed that CXCL13 promoter hypomethylation was common in TIICs.The methylation level of cg16361705 within the CXCL13 promoter might play an important role in modulating CXCL13 transcription.In conclusion,our study revealed that CXCL13 expression andγδT cell infiltration in TME is associated with unfavorable survival of KIRC.TIICs,most possiblyγδT cells,are the dominant source of CXCL13 in KIRC TME.

The Immune Responses Induced by Licensed Flavivirus Vaccines against Zika Virus

Zika virus(ZIKV) is a mosquito-borne virus of the Spondweni group that belongs to the Flaviviridae family and genus Flavivirus. Microcephaly(small head size, decreased brain size, and poor neurocognitive development) was linked to ZIKV infection in Brazil in 2015. Outbreaks and indications of transmission have spread quickly over the Americas, Africa, and other parts of the globe.Over 80 nations and territories have documented symptoms of Zika infection spread by mosquitoes,including microcephaly and Guillain-Barre syndrome(GBS).

Oxyresveratrol suppresses proliferation and metastasis of hepatocellular carcinoma by inhibiting autophagy in vitro and in vivo

OBJECTIVE Oxyresveratrol(OXY)has many biological activities including anti-inflammation,anti-oxida⁃tive stress,anti-cancer and immunomodulation.However,the mechanisms underlying its effects against hepatocellular carcinoma(HCC)remain poorly understood.METHODS Two HCC cell lines,HepG2 and SMMC-7721 cells,were employed.Their proliferation was determined by CCK8 assay.The migration and invasion of cells were examined by wound healing and transwell assay.Metastasis of HCC was detected by in vivo experiment.Meanwhile,transcriptome analysis was applied to explore the mechanisms of OXY.The results of transcriptome analysis were validated by in vitro experiment.Further⁃more,western blot was used to measure the expression of LC3 and p62 protein.RESULTS OXY significantly inhibited the proliferation,migration and invasion of HCC cells in vitro.OXY suppressed the metastasis of HCC in Balb/c mice with attenuated side effects compared to Doxorubicin.Transcription profiling analysis revealed that OXY may affect autophagy related signaling pathway of HepG2 cells.Western blotting showed that OXY significantly inhibite autophagy by downregulating LC3 and upregulating p62 genes expression.CONCLUSION Our study demonstrated that OXY inhibits the metastasis of HCC by inhibiting autophagy,which suggested OXY to be a candidate for HCC metastasis.

Long noncoding RNA LINC01124 activates hepatocellular carcinoma cell proliferation, migration, and invasion by absorbing microRNA-1247-5p and overexpressing FOXO3

Long intergenic non-protein coding RNA 1124(LINC01124)has been identified as an important regulator of non-small-cell lung cancer.However,the expression and detailed role of LINC01124 in hepatocellular carcinoma(HCC)remain unestablished to date.Therefore,this study aimed to elucidate the role of LINC01124 in the aggressiveness of HCC cells and identify the underlying regulatory mechanism.Quantitative reverse transcriptase-polymerase chain reaction was performed to measure the expression of LINC01124 in HCC.Cell Counting Kit-8 assay,Transwell cell migration and invasion assays,and a xenograft tumor model were used to investigate the function of LINC01124 in HCC cells,and bioinformatics analysis,RNA immunoprecipitation,luciferase reporter assay,and rescue experiments were used to elucidate the underlying mechanisms.Herein,LINC01124 overexpression was confirmed in HCC tissues as well as cell lines.Further,the downregulation of LINC01124 decreased HCC cell proliferation,migration,and invasion in vitro,whereas the upregulation of LINC01124 triggered the opposite results.Additionally,LINC01124 ablation impaired tumor growth in vivo.Mechanistic analyses revealed that LINC01124 functions as a competing endogenous RNA to sponge microRNA-1247-5p(miR-1247-5p)in HCC cells.Moreover,forkhead box O3(FOXO3)was identified as a direct target of miR-1247-5p.FOXO3 was positively regulated by LINC01124 in HCC cells through the sequestration of miR-1247-5p.Finally,rescue assays revealed that the inhibition of miR-1247-5p or overexpression of FOXO3 reversed the effects of LINC01124 silencing on the HCC cell malignant phenotype.In summary,LINC01124 plays a tumor-promoting role in HCC by regulating the miR-1247-5p-FOXO3 axis.The LINC01124-miR-1247-5p-FOXO3 pathway may provide a foundation for the identification of alternative therapies for HCC.

A folic acid-decorated nanoparticles loaded JQ1 for oral squamous cell carcinoma therapy

Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality rate.The poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC therapy.Beyond that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these drugs.Therefore,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor tissues.And then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type macrophages.In conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.

Current advance of nanotechnology in diagnosis and treatment for malignant tumors

Cancer remains a significant risk to human health.Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation.Nanomedicine shows great potential for cancer diagnosis and treatment.Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations.Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors.The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers.Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes,thus enhancing treatment outcomes while minimizing harm to healthy tissues.Simultaneously,nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors.This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors.According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites,we review the most recent developments in nanotechnology applications.Finally,we briefly discuss the prospects and challenges of nanotechnology in cancer.

Targeting autophagy-related protein kinases for potential therapeutic purpose

Autophagy,defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes,plays a significant role in the quality control of macromolecules and organelles.Since protein kinases are integral to the autophagy process,it is critically important to understand the role of kinases in autophagic regulation.At present,intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease,especially cancer.In this review,we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation.We also summarize the small-molecule kinase inhibitors/activators of these targets,highlighting the opportunities of these new therapeutic agents.

Targeting NF-κB pathway for the therapy of diseases:mechanism and clinical study

NF-κB pathway consists of canonical and non-canonical pathways.The canonical NF-κB is activated by various stimuli,transducing a quick but transient transcriptional activity,to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response.Meanwhile,the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members.Since the activation of this pathway involves protein synthesis,the kinetics of non-canonical NF-κB activation is slow but persistent,in concordance with its biological functions in the development of immune cell and lymphoid organ,immune homeostasis and immune response.The activation of the canonical and non-canonical NF-κB pathway is tightly controlled,highlighting the vital roles of ubiquitination in these pathways.Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers,and NF-κB has been long proposed as the potential target for therapy of diseases.This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation,apoptosis and M2 macrophages polarization

Glioma is a primary aggressive brain tumor with high recurrence rate.The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier(BBB) is well-known as one of the main challenges for anti-glioma therapy.Moreover,massive infiltrated tumor-associated macrophages(TAMs) in glioma further thwart the drug efficacy.Herein,a therapeutic nanosystem(SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera(PROTAC) ARV-825 into the complex micelle(SPP) composed of substance P(SP) peptide-modified poly(ethylene glycol)-poly(D,L-lactic acid)(SP-PEG-PDLL A) and methoxy poly(ethylene glycol)-poly(D,L-lac tic acid)(mPEG-PDLL A,PP),which could penetrate BBB and target brain tumor.Subsequently,released drug engenders antitumor effect via attenuating cells proliferation,inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6,STAT3 and AKT.Taken together,our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma,which may provide a novel strategy for glioma therapy in future.