查看更多>>摘要：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,high-lighting the opportunities of these new therapeutic agents.
查看更多>>摘要：Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids.It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid,the precursor of prostaglandins and other inflammatory mediators.MAGL inhibitors have been considered as important agents in many therapeutic fields,including anti-nociceptive,anxiolytic,antiinflammatory,and even anti-cancer.Currently,ABX-1431,a first-in-class inhibitor of MAGL,is entering clinical phase 2 studies for neurological disorders and other diseases.This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors.Although a large number of MAGL inhibitors have been reported,novel inhibitors are still required,particularly reversible ones.
查看更多>>摘要：Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate.The family of P21-activated kinases (PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis.In this work,we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth.PAKl-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer.Our small molecule screening identified a relatively specific PAK1targeted inhibitor,CP734.Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity.Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways.Little toxicity of CP734 was observed in murine models.Combined with gemcitabine or 5-fluorouracil,CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells.All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.
查看更多>>摘要：Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the class I histone deacetylases (HDAC) exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein (TXNIP),causing reactive oxygen species (ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients' survival analysis further confirmed in vivo synthetic lethality between BRCA 1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif (BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCAl-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.
查看更多>>摘要：Lappaconitine (LA),a natural compound with a novel C 18-diterpenoid alkaloid skeleton,displayed extensive biological profile.Recent research on LA is focused mainly on its anti-tumor and analgesic effects,and therefore we aimed to investigate its anti-inflammatory potential.A series of novel LA derivatives with various substituents on the 20-N position was designed and synthesized.In the initial screening of LA derivatives against NO production,all the target compounds,except compound E2,exhibited excellent inhibitory ability relative to that of LA.Particularly,compound A4 exhibited the most potent inhibition with IC50 of 12.91 μmol/L.The elementary structure-activity relationships (SARs) of NO inhibitory activity indicated that replacement of the benzene ring with an electron donating group could improve the anti-inflammatory efficacy.Furthermore,compound A4 shows an anti-inflammatory mechanism by inhibiting NO,PGE2,and TNF-α generation via the suppression of NF-κB and MAPK signaling pathways.Notably,compound A4 could exert a significant therapeutic effect on LPS-induced acute lung injury (ALI) in vivo.Based on the above research,we further investigated the preliminary pharmacokinetic property of A4 in rats.Therefore,compound A4 could be a promising candidate for the development of anti-inflammatory agents in the future.
查看更多>>摘要：Drug repurposing is an efficient strategy for new drug discovery.Our latest study found that nitazoxanide (NTZ),an approved anti-parasite drug,was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD).In order to further improve the efficacy and discover new chemical entities,a series of NTZ-based derivatives were designed,synthesized,and evaluated as autophagy activator against AD.All compounds were screened by the inhibition of phosphorylation of p70S6K,which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level.Among these analogs,compound 22 exhibited excellent potency in promotingβ3-amyloid (Aβ) clearance,inhibiting tau phosphorylation,as well as stimulating autophagy both in vitro and in vivo.What's more,22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice.These results demonstrated that 22 was a potential candidate for the treatment of AD.
查看更多>>摘要：Combination therapy has shown its promise in the clinic for enhancing the efficacy of tumor treatment.However,the dose control of multiple drugs and their non-overlapping toxicity from different drugs are still great challenge.In this work,a single model drug,paclitaxel (PTX),is used to realize combination therapy and solve the problems mentioned above.Either PTX or its triphenylphosphine derivative (TPTX) is encapsulated in galactose-modified liposomes (GLips) to obtain GLips-P or GLips-TP,which are simply mixed in different ratios to finely control the proportion of PTX and TPTX.These mixed liposomes,GLips-P/TP,feature a cascade target delivery of PTX,from tissue to cell,and then to organelle.PTX plays a primary role to cause the cytotoxicity by microtubule bindings in cytoplasm,while TPTX is proved to increase the intracellular levels of caspase-3 and caspase-9 that cause apoptosis via a mitochondria-mediated pathway.Notably,GLips-P/TP 3:1 exhibited the significant drug synergy in both cytotoxicity assay of HepG2 cells and the treatment efficacy in Heps xenograft ICR mouse models.This work not only demonstrates the great promise of a cascade targeting delivery for precise tumor treatment,but also offers a novel platform to design combinatory therapy systems using a single drug.
查看更多>>摘要：Renal tubular epithelial cells (RTECs) are important target cells for the development of kidney-targeted drug delivery systems.Under physiological conditions,RTECs are under constant fluid shear stress (FSS) from original urine in the renal tubule and respond to changes of FSS by altering their morphology and receptor expression patterns,which may affect reabsorption and cellular uptake.Using a microfluidic system,controlled shear stress was applied to proximal tubule epithelial cell line HK-2.Next,2-glucosamine,bovine serum albumin,and albumin nanoparticles were selected as representative carriers to perform cell uptake studies in HK-2 cells using the microfluidic platform system with controlled FSS.FSS is proven to impact the morphology of HK-2 cells and upregulate the levels of megalin and clathrin,which then led to enhanced cellular uptake efficiencies of energy-driven carrier systems such as macromolecular and albumin nanoparticles in HK-2 cells.To further investigate the effects of FSS on endocytic behavior mediated by related receptors,a mice model of acute kidney injury with reduced fluid shear stress was established.Consistent with in vitro findings,in vivo studies have also shown reduced fluid shear stress down-regulated the levels of megalin receptors,thereby reducing the renal distribution of albumin nanoparticles.
查看更多>>摘要：Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence.The activation and proliferation of hepatic stellate cells (HSCs) is the most fundamental reason of hepatic fibrosis.There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present.We found that when hepatic fibrosis occurs,the expression of CD44 receptors on the surface of HSCs is significantly increased.Based on this finding,we designed silibinin-loaded hyaluronic acid (SLB-HA) micelles to achieve the treatment of hepatic fibrosis.Meanwhile,we constructed liver fibrosis rat model using Sprague-Dawley rats.We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages.Importantly,HA micelles showed a significant liver targeting effect in vivo,especially in fibrotic liver which highly expressed CD44 receptors.In addition,SLB-HA micelles could selectively kill activated HSCs,having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect,and also had a good biological safety and biocompatibility.Overall,HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.
查看更多>>摘要：Liquiritigenin (LG),isoliquiritigenin (Iso-LG),together with their respective glycoside derivatives liquiritin (LN) and isoliquiritin (Iso-LN),are the main active flavonoids of Glycyrrhiza uralensis,which is arguably the most widely used medicinal plant with enormous demand on the market,including Chinese medicine prescriptions,preparations,health care products and even food.Pharmacological studies have shown that these ingredients have broad medicinal value,including anti-cancer and antiinflammatory effects.Although the biosynthetic pathway of glycyrrhizin,a triterpenoid component from G.uralensis,has been fully analyzed,little attention has been paid to the biosynthesis of the flavonoids of this plant.To obtain the enzyme-coding genes responsible for the biosynthesis of LN,analysis and screening were carried out by combining genome and comparative transcriptome database searches of G.uralensis and homologous genes of known flavonoid biosynthesis pathways.The catalytic functions of candidate genes were determined by in vitro or in vivo characterization.This work characterized the complete biosynthetic pathway of LN and achieved the de novo biosynthesis of liquiritin in Saccharomyces cerevisiae using endogenous yeast metabolites as precursors and cofactors for the first time,which provides a possibility for the economical and sustainable production and application of G.uralensis flavonoids through synthetic biology.
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