查看更多>>摘要：Nuclear receptor corepressor(NCoR1)interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids.An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development.In this study,we found that the deletion of NCoR1 in intestinal epithelial cells(IECs)mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis.The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate,whose production was significantly enhanced by PPARα activation in the fed state.Additionally,NCoR1 deletion derepressed intestinal LXR,increased cholesterol excretion,and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity,thereby reversing the possible negative effects of intestinal PPARα activation.Therefore,the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.
查看更多>>摘要：Irinotecan(CPT11)chemotherapy-induced diarrhea affects a substantial cancer population due to β-glucuronidase(Gus)converting 10-O-glucuronyl-7-ethyl-10-hydroxycamptothecin(SN38G)to toxic 7-ethyl-10-hydroxycamptothecin(SN38).Existing interventions primarily address inflammation and Gus enzyme inhibition,neglecting epithelial repair and Gus-expressing bacteria.Herein,we discov-ered that dehydrodiisoeugenol(DDIE),isolated from nutmeg,alleviates CPT11-induced intestinal muco-sitis alongside a synergistic antitumor effect with CPT11 by improving weight loss,colon shortening,epithelial barrier dysfunction,goblet cells and intestinal stem cells(ISCs)loss,and wound-healing.The anti-mucositis effect of DDIE is gut microbiota-dependent.Analysis of microbiome profiling data from clinical patients and CPT11-induced mucositis mice reveals a strong correlation between CPT11 chemotoxicity and Gus-expressing bacteria,particularly Enterococcus faecalis(E.faecalis).DDIE coun-ters CPT11-induced augmentation of E.faecalis,leading to decreased intestinal Gus and SN38 levels.The Partial Least Squares Path Model(PLS-PM)algorithm initially links E.faecalis to dysregulated epithelial renovation.This is further validated in a 3D intestinal organoid model,in which both SN38 and E.faecalis hinder the formation and differentiation of organoids.Interestingly,colonization of E.fae-calis exacerbates CPT11-induced mucositis and disturbs epithelial differentiation.Our study unveils a microbiota-driven,epithelial reconstruction-mediated action of DDIE against mucositis,proposing the'Gus bacteria-host-irinotecan axis'as a promising target for mitigating CPT11 chemotoxicity.
查看更多>>摘要：Oxaliplatin(OXA),a platinum-based chemotherapeutic agent,remains a mainstay in first-line treatments for advanced colorectal cancer(CRC).However,the eventual development of OXA resis-tance represents a significant clinical challenge.In the present study,we demonstrate that the aldo-keto reductase 1C1(AKR1C1)is overexpressed in CRC cells upon acquisition of OXA resistance,evident in OXA-resistant CRC cell lines.We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity.Mechanistically,AKR1C1 interacts with and activates the transcription factor STAT3,which upregulates the glutamate transporter EAAT3,thereby elevating intracellular glutathione levels and conferring OXA resistance.Alantolactone,a potent natural product inhibitor of AKR1C1,effectively reverses this chemoresistance,restricting the growth of OXA-resistant CRC cells both in vitro and in vivo.Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to over-come this resistance in CRC.
查看更多>>摘要：Chemoresistance to 5-fluorouracil(5-FU)is a significant challenge in treating colorectal can-cer(CRC).Novel combined regimens to thwart chemoresistance are therefore urgently needed.Herein,we demonstrated that the combination of Avenanthramide A(AVN A)and 5-FU has significant therapeu-tic advantages against CRC.Mechanistically,AVN A directly binds to the S198 site of the histone lysine demethylase KDM4C to promote its degradation,which subsequently fosters H3K9me3 occupancy on the MIR17HG promoter to block its transcription and derepress Bim expression.AVN A enhanced the therapeutic efficacy of 5-FU via impairing the KDM4C/MIR17HG/GSK-3β negative feedback loop.Importantly,the clinical correlation of the KDM4C/MIR17HG/Bim signaling axis with 5-FU response was validated in the refractory CRC patients.We provide evidence for the enhanced effectiveness of 5-FU when combined with AVN A in chemoresistant xenografts,CRC organoids,and ApcMin/+mouse model.Additionally,AVN A mitigated the systemic adverse effects of 5-FU.Overall,our findings demonstrate that combinatorial therapy with AVN A and 5-FU represents an appealing opportunity and highlights KDM4C/MIR17HG/GSK-3β negative feedback loop which confers therapeutically exploitable vulnerability to chemo-refractory CRC patients.
查看更多>>摘要：Hydrogen sulfide(H2S)is a gas signaling molecule with versatile bioactivities;however,its exploitation for disease treatment appears challenging.This study describes the design and characteriza-tion of a novel type of H2S donor-drug conjugate(DDC)based on the thio-ProTide scaffold,an evolu-tion of the ProTide strategy successfully used in drug discovery.The new H2S DDCs achieved hepatic co-delivery of H2S and an anti-fibrotic drug candidate named hydronidone,which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure.The potent hepatoprotective ef-fects were also attributed to the H2S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels.Lysosomal H2S accumulation and H2S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase,representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties.These findings provided a novel pattern for the design of optimally therapeutic H2S DDC and organelle-targeting functional molecules.
查看更多>>摘要：Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discov-ery by identifying highly potent ligands.By simulating the change from one compound structure to another,the relative binding free energy(RBFE)change can be calculated based on the theoretically rigorous free energy perturbation(FEP)method.However,existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states,which can lead to increased computational costs to obtain the converged results.To fundamentally overcome these issues and accelerate drug discovery,a new combined-structure RBFE(CS-FEP)calculation strategy was proposed,which solved the existing issues by constructing a new alchemical pathway,smoothed the alchemical transformation,increased the phase-space overlap between adjacent states,and thus signif-icantly increased the convergence and accelerated the relative binding free energy calculations.This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1(PDE1).Starting from a PDE1 inhibitor(compound 9,IC50=16.8 μmol/L),the CS-FEP guided hit-to-lead optimizations resulted in a promising lead(11b and its mesylate salt formulation 11b-Mesylate,IC50=7.0 nmol/L),with～2400-fold improved inhibitory activity.Further experimental studies re-vealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.
查看更多>>摘要：Cervical cancer,the most common gynecological malignancy,significantly and adversely af-fects women's physical health and well-being.Traditional surgical interventions and chemotherapy,while potentially effective,often entail serious side effects that have led to an urgent need for novel therapeutic methods.Photothermal therapy(PTT)has emerged as a promising approach due to its ability to minimize damage to healthy tissue.Connecting a biothiol detection group to PTT-sensitive molecules can improve tumor targeting and further minimize potential side effects.In this study,we developed a near-infrared fluorescence(NIRF)/photoacoustic(PA)dual-mode probe,S-NBD,which demonstrated robust PTT per-formance.This innovative probe is capable of activating NIRF/PA signals to enable the detection of bio-thiols with high emission wavelength(838 nm)and large Stokes shift(178 nm),allowing for in vivo monitoring of cancer cells.Additionally,the probe achieved an outstanding photothermal conversion ef-ficiency of 67.1％.The application of laser irradiation(660 nm,1.0 W/cm2,5 min)was able to achieve complete tumor ablation without recurrence.In summary,this seminal study presents a pioneering NIRF/PA dual-mode dicyanoisophorone-based probe for biothiol imaging,incorporating features from PTT for the first time.This pioneering approach achieves the dual objectives of improving tumor diagnosis and treatment.
查看更多>>摘要：The fat mass and obesity-associated protein(FTO)is an RNA demethylase required for catalytic demethylation of N6-methyladenosine(m6A);it is highly expressed and functions as an oncogene in acute myeloid leukemia(AML).Currently,the overarching objective of targeting FTO is to precisely inhibit the catalytic activity.Meanwhile,whether FTO degradation also exerts antileukemic effects remains unknown.Herein,we designed the first FTO-targeting proteolysis targeting chimera(PROTAC)degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead.Notably,QP73 significantly induced FTO degradation in a time-,dose-,and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines.Moreover,QP73 treatment significantly increased m6A modification on mRNA,promoted myeloid differentiation,and induced apoptosis of AML cells.Quantitative proteomics analysis showed that QP73 induced complete FTO degradation,upregulating RARA and ASB2 abundance and downregulating CEBPA,MYC,PFKP,and LDHB levels in AML cells.Lastly,QP73 exhibited antileukemic activity by increasing m6A modification and decreasing FTO levels in xenograft AML tumors.This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.
查看更多>>摘要：Macrophage-mediated inflammation plays a pivotal role in cardiovascular disease pathogen-esis.However,current cell-based models lack a comprehensive understanding of crosstalk between mac-rophages and cardiomyocytes,hindering the discovery of effective therapeutic interventions.Here,a microfluidic model has been developed to facilitate the coculture of macrophages and cardiomyocytes,allowing for mapping key signaling pathways and screening potential therapeutic agents against inflammation-induced dynamic myocardial injury.Through metabolic profiling and bioinformatic enrich-ment analysis,the microchip model with dynamic cell-cell crosstalk reveals robust activation of inflam-matory and oxidative stress-associated metabolic pathways,closely resembling metabolic profiles of myocardial infarction in both humans and rodents.Furthermore,an integrative screening strategy has been established to screen bioactive natural products precisely,identifying ginsenoside Rb1 and protoca-techualdehyde as promising cardioprotective candidates in vitro and in vivo.Taken together,the micro-fluidic coculture model advances mechanistic insight into macrophage-mediated cardio-immunology and may accelerate the discovery of therapeutics for myocardial injury.
查看更多>>摘要：Tumor microenvironment activatable therapeutic agents and their effective tumor accumula-tion are significant for selective tumor treatment.Herein,we provide an unadulterated nanomaterial combining the above advantages.We synthesize a perylene diimide(PDI)molecule substituted by glu-tamic acid(Glu),which can self-assemble into small spherical nanoparticles(PDI-SG)in aqueous solu-tion.PDI-SG can not only be transformed into nanofibers at low pH conditions but also be reduced to PDI radical anion(PDI·-),which exhibits strong near-infrared absorption and excellent photothermal perfor-mance.More importantly,PDI-SG can also be reduced to PDI·-in hypoxic tumors to ablate the tumors and minimize the damage to normal tissues.The morphological transformation from small nanoparticles to nanofibers makes for better tumor accumulation and retention.This work sheds light on the design of tumor microenvironment activatable therapeutics with precise structures for high-performance tumor therapy.
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