查看更多>>摘要：Stress and illness connection is complex and involves multiple physiological systems.Panax ginsengs,reputed for their broad-spectrum"cure-all"effect,are widely prescribed to treat stress and related illnesses.However,the identity of ginseng's"cure-all"medicinal compounds that relieve stress remains unresolved.Here,we identify ginsentides as the principal bioactives that coordinate multiple sys-tems to restore homeostasis in response to stress.Ginsentides are disulfide-rich,cell-penetrating and proteolytic-stable microproteins.Using affinity-enrichment mass spectrometry target identification together with in vitro,ex vivo and in vivo validations,we show that highly purified or synthetic ginsen-tides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway,alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta,decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation.Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation,to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice.Together,these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra-and intra-cellular proteins to reverse stress-induced damages.
查看更多>>摘要：Studies have suggested that the nucleus accumbens(NAc)is implicated in the pathophysi-ology of major depression;however,the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated.Here,we identified a specific reduction of cyclic adenosine monophosphate(cAMP)in the subset of dopamine D1 receptor medium spiny neurons(D1-MSNs)in the NAc that promoted stress susceptibility,while the stimulation of cAMP pro-duction in NAc Dl-MSNs efficiently rescued depression-like behaviors.Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons(D2-MSNs)of depressed mice,however,the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs.We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration,but not a lower dose.The fast onset property of crocin was verified through multicenter studies.Moreover,crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN.These find-ings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc,and provide a potential rapid antidepressant drug candidate,crocin.
查看更多>>摘要：Lymphatic metastasis is the main metastatic route for colorectal cancer,which increases the risk of cancer recurrence and distant metastasis.The properties of the lymph node metastatic colorectal cancer(LNM-CRC)cells are poorly understood,and effective therapies are still lacking.Here,we found that hypoxia-induced fibroblast activation protein alpha(FAPα)expression in LNM-CRC cells.Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration,invasion,epithelial-mesenchymal transition,stemness,and lymphangiogenesis via activation of the STAT3 pathway.In addition,FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells,to promote colorectal cancer lymph node metastasis(CRCLNM).Z-GP-DAVLBH,a FAPα-activated prodrug,inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells.Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
查看更多>>摘要：Glutamate-ammonia ligase(GLUL,also known as glutamine synthetase)is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation.Although GLUL plays a critical role in multiple cancers,the expression and function of GLUL in gastric cancer remain unclear.In the present study,we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues,and correlated with N stage and TNM stage,and low GLUL expression predicted poor survival for gastric cancer patients.Knockdown of GLUL promoted the growth,migration,invasion and metastasis of gastric cancer cells in vitro and in vivo,and vice versa,which was independent of its enzyme activity.Mechanistically,GLUL competed with β-Catenin to bind to N-Cadherin,increased the stability of N-Cadherin and decreased the stability ofβ-Catenin by alerting their ubiquitination.Furthermore,there were lower N-Cadherin and higher β-Ca-tenin expression levels in gastric cancer tissues compared with adjacent normal tissues.GLUL protein expression was correlated with that of N-Cadherin,and could be the independent prognostic factor in gastric cancer.Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.
查看更多>>摘要：Coronary restenosis is an important cause of poor long-term prognosis in patients with cor-onary heart disease.Here,we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum-and PDGF-BB-induced vascular smooth muscle cells(VSMCs),and in tissues of carotid artery injury-induced neointimal hyperplasia.Smyd2 overexpression in VSMCs(Smyd2-vTg)facilitates,but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown signif-icantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice.Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor(SRF)target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation.HDAC3 directly interacts with and deacetylates SRF,which enhances SRF transcriptional activity in VSMCs.Moreover,SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter.RGFP966,a specific inhibitor of HDAC3,not only coun-teracts the pro-proliferation effect of SMYD2 overexpression on VSMCs,but also inhibits carotid artery injury-induced neointima formation in mice.HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner.Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.
查看更多>>摘要：Chemotherapy-induced complications,particularly lethal cardiovascular diseases,pose sig-nificant challenges for cancer survivors.The intertwined adverse effects,brought by cancer and its complication,further complicate anticancer therapy and lead to diminished clinical outcomes.Simple supplementation of cardioprotective agents falls short in addressing these challenges.Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously.Drug repurposing was naturally endowed with co-therapeutic po-tential of two indications,implying a unique chance in the development of bi-functional agents.Herein,we further proposed a novel"trilogy of drug repurposing"strategy that comprises function-based,target-focused,and scaffold-driven repurposing approaches,aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent.Through function-based repurposing,a cardioprotective agent,carvedilol(CAR),was identified as a potential neddylation inhibitor to suppress lung cancer growth.Employing target-focused SAR studies and scaffold-driven drug design,we synthe-sized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection.Remarkably,optimal derivative 43 displayed promising bi-functional effects,especially in various self-established heart failure mice models with and without tumor-bearing.Collectively,the present study validated the practicability of the"trilogy of drug repurposing"strategy in the development of bi-functional co-therapy agents.
查看更多>>摘要：Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic ther-apy,and on-demand drug release upon radiation exposure.The optimized prodrug,DON-TK-BM3,incor-porating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell killing.Unlike the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal cells.Moreover,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in mice.This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.
查看更多>>摘要：A major challenge facing photodynamic therapy(PDT)is that the activity of the immune-induced infiltrating CD8+T cells is subject to the regulatory T lymphocytes(Tregs),leaving the tumor at risk of recurrence and metastasis after the initial ablation.To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME),a supramolecular photodynamic na-noparticle(DACss)is constructed by the host-guest interaction between demethylcantharidin-conjugatedβ-cyclodextrin(DMC-CD)and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6)to achieve intelligent delivery of photosensitizer and immunomod-ulator for breast cancer treatment.The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME,resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH,reducing photo-sensitizer toxicity and increasing photosensitizer retention in the tumor.With a significant increase in the CTL/Treg ratio,the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME,as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.
查看更多>>摘要：Small interfering RNA(siRNA)has a promising future in the treatment of ocular diseases due to its high efficiency,specificity,and low toxicity in inhibiting the expression of target genes and pro-teins.However,due to the unique anatomical structure of the eye and various barriers,delivering nucleic acids to the retina remains a significant challenge.In this study,we rationally design PACD,an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block(A),a siRNA binding block(B)and a pH-responsive block(C).PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing.By evaluating its pH-responsive activity,gene silencing efficiency in retinal cells,intraocular distribution,and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis,we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina.We are surprised to discover that,the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency,excellent gene silencing,and inhibit retinal angiogenesis.Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.
查看更多>>摘要：Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies.However,the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression.Here,we propose a self-amplifying logic-gated gene editing strategy for gene/H2O2-mediated/starvation multi-modal cancer therapy.In this approach,a hypoxia-degradable covalent-organic framework(COF)is syn-thesized to coat a-ZIF-8 in which glucose oxidase(GOx)and CRISPR system are packaged.To intensify intracellular redox dyshomeostasis,DNAzymes which can cleave catalase mRNA are loaded as well.When the nanosystem gets into the tumor,the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx,which amplifies intracellular H+and hypoxia,accelerating the nano-carrier degradation to guarantee available CRISPR plasmid and GOx release in target cells.These tandem reactions deplete glucose and oxygen,leading to logic-gated-triggered gene editing as well as synergistic gene/H2O2-mediated/starvation therapy.Overall,this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.
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