查看更多>>摘要：Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma(UM).Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions.In search of genetic vulnerability for UM,we found that inhibition of euchromatic histone lysine methyltransferase 2(EHMT2)expression or activity significantly reduced the proliferation and migration capacity of cancer cells.Notably,elevated expression of EHMT2 had been validated in UM samples.Furthermore,Kaplan-Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage.Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a down-stream target of EHMT2.Its transcription was suppressed by EHMT2 in a methyltransferase-dependent pattern in GNAQ/11-mutant UM cells,leading to elevated RhoA activity.Rescuing constitu-tively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes.Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth,suggesting the driver role of these two key molecules.In summary,our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11-mutant UM.
查看更多>>摘要：The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells.The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to killer.As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics.Here,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway.In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent manner.Mechanistic studies showed XS561 potently induced the trans-location of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related apoptosis.Interest-ingly,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates.Together,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.
查看更多>>摘要：Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.
查看更多>>摘要：Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3'-Phosphoadenosine 5'-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor PAPS.The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been reported.Here,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer.Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc△gut-Het Papss2△gut)mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc△gut-Het mice.Apc△gut-Het Papss2△gut mice were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory axis.Chondroitin sulfate supplemen-tation in Apc△gut-HetPapss2△gut mice alleviated intestinal tumorigenesis.In summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling.Chondroitin sul-fate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
查看更多>>摘要：With our continuous endeavors in seeking potent anti-HIV-1 agents,we reported here the dis-covery,biological characterization,and druggability evaluation of a class of nonnucleoside reverse tran-scriptase inhibitors.To fully explore the chemical space of the NNRTI-binding pocket,novel series of dihydrothiopyrano[3,2-d]pyrimidines were developed by employing the structure-based design strategy.Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels.Among them,compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor,with EC50 values ranging from 3.43 to 21.4 nmol/L.Espe-cially,for the challenging double-mutants F227L+V106A and K103N+Y181C,23h exhibited 2.3-to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine.Besides,the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine.The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase.Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign.Furthermore,no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h.Most importantly,23h was characterized by good pharmacokinetic properties and excellent safety in vivo.Collectively,23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles.
查看更多>>摘要：The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1 R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1 R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1 R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruc-tion(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(～2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.
查看更多>>摘要：Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a novel SIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC50 value of 0.98±0.13 μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone dea-cetylases(HADC1-11 and SIRT1-3)at concentrations up to 100 μmol/L.The allosteric site and the mo-lecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor development targeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancre-atic cancer.
查看更多>>摘要：Due to low immobilized ligand density,limited binding capacity,and severe interference from serum proteins,developing ideal peptide-based biomaterials for precise recognition and in vivo anal-ysis of biopharmaceuticals remains a huge challenge.In this study,mimotope peptide modified pompon mum-like biomimetic magnetic microparticles(MMPs,3.8 μm)that mimic the specific functionalities of CD20 on malignant B cells were developed for the first time.Benefit from the numerous ligand binding sites(Ni2+)on the pompon mum-like MMPs,these novel materials achieved ≥10 times higher peptide ligand densities(＞2300 mg/g)and antibody binding capacities(1380 mg/g)compared to previous re-ported biomaterials.Leveraging the high specificity of the mimotope peptide,rituximab can be precisely recognized and enriched from cell culture media or serum samples.We also established an LC-MS/MS method using the MMPs for tracking rituximab biotransformation in patient serum.Intriguingly,deami-dation of Asn55 and Asn33,as well as oxidation of Met81 and Met34 were observed at the key complementarity determining regions of rituximab,which could potentially influence antibody function and require careful monitoring.Overall,these versatile biomimetic MMPs demonstrate superior recogni-tion and enrichment capabilities for target antibodies,offering interesting possibilities for biotransforma-tion analysis of biopharmaceuticals in patient serum.
查看更多>>摘要：Osteosarcoma is usually resistant to immunotherapy and,thus primarily relies on surgical resection and high-dosage chemotherapy.Unfortunately,less invasive or toxic therapies such as photo-thermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory out-comes.Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma.Herein,a simple nanocomposite that synergistically combines CDT,PTT,and chemo-therapy for osteosarcoma treatment was fabricated.In this composite,small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil(5-FU)with high loading capacity.The nanospheres were then adsorbed onto larger 2D Ti3C2 MXene monolayers and finally shielded by bovine serum albumin(BSA)to form 5-FU@NiFe-LDH/Ti3C2/BSA nanoplat-forms(5NiTiB).Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy,NiFe-LDH driven chemodynamic effects,and MXene-based photothermal killing collectively exhib-ited a synergistic"all-in-one"anti-tumor effect.5NiTiB improved tumor suppression rate from＜5％by 5-FU alone to～80.1％.This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose,thereby minimizing side effects.Moreover,the composite is simple to produce,enabling the fine-tuning of dosages to suit different requirements.Thus,the platform is versatile and efficient,with potential for further development.
查看更多>>摘要：A novel strategy of not only stimulating the immune cycle but also modulating the immuno-suppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy.Here,a new type of spatiotemporal biomimetic"Gemini nanoimmunoregulators"was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death(ICD),tumor-associated macrophages(TAMs)phenotype reprogramming and programmed cell death ligand 1(PD-L1)degradation.The"Gemini nanoimmunoregulators"PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine(mPDA)as nano-vectors to deliver metformin(Met)and toll-like receptor 7/8 agonist resiquimod(R848)to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane(RM)inlaid with T7 or M2 peptides.mPDA/Met@RM-T7(abbreviated as PM@RM-T7)was constructed to elicit an ampli-fied in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity.Meanwhile,PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent im-mune evasion.Subsequently,mPDA/R848@RM-M2(abbreviated as PR@RM-M2)specifically recog-nized TAMs and reset the phenotype from M2 to M1 state,thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes.This pair of sister na-noimmunoregulators cooperatively orchestrated the comprehensive anticancer activity,which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis.This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.
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