查看更多>>摘要：Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracra-nial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral dis-tribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumula-tion of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with pro-longed survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
查看更多>>摘要：The progression of ulcerative colitis(UC)is associated with immunologic derangement,in-testinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO2 nanospheres with Cu2O nanoblocks.The resulting CaO2-Cu2O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO2-Cu2O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobac-terium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO2-Cu2O offers a promising therapeutic platform for robust treatment of UC via the rectal route.
查看更多>>摘要：Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzing clinical samples,we identified circCPNEl,a dysregulated circRNA in OSCC,and its expression level was negatively correlated with the clinical stage of OSCC patients.Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1,which was then identified as a miR-330-3p sponge.MiR-330-3p was recognized as a tumor promoter in multiple studies,consistent with our finding that it could promote the proliferation,migration,and invasion of OSCC cells.These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression.Therefore,we designed cationic polylysine-cisplatin prodrugs to deliver antago-miR-330-3p(a miRNA inhibitory analog)via electrostatic interactions to form PP@miR nanoparticles(NPs).Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination(2/5),which confirmed the critical role of miR-330-3p in OSCC development.These findings provide a new perspective for the development of OSCC treatments.
查看更多>>摘要：Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes,its therapeutic potential is compromised by its short half-life and narrow therapeutic index.Current long-acting insulin analogs,such as insulin-polymer conjugates,are mainly used to improve pharmacokinetics by reducing renal clearance.However,these conjugates are synthesized without sacrificing the bioactivity of insulin,thus retaining the narrow therapeutic index of native insulin,and exceeding the efficacious dose still leads to hypoglycemia.Here,we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance.By impairing the binding affinity to the receptor and the activation of the receptor,di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly,increases its maximum tolerated dose 10-fold.The target of long-term glycemic management in vivo has been achieved through improved pharmacokinetics and a high dose.This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.
查看更多>>摘要：Although sulfonation plays crucial roles in various biological processes and is frequently uti-lized in medicinal chemistry to improve water solubility and chemical diversity of drug leads,it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides(RiPPs).Biosynthesis of RiPPs typically entails modification of hydrophilic residues,which substantially in-creases their chemical stability and bioactivity,albeit at the expense of reducing water solubility.To explore sulfonated RiPPs that may have improved solubility,we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase(ST),and discovered two distinctive biosynthetic gene clusters(BGCs)encoding both lanthipeptide synthetase(LanM)and ST.Upon expressing these BGCs,we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST.We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM.Both LanM and ST are promiscuous towards residues in the A ring,but ST displays strict regioselectivity toward Tyr5.The recognition of cyclic peptide by ST was further discussed.Bioactivity evaluation underscores the significance of the ST-catalyzed sulfona-tion.This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.
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