CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.

SHARP BOUNDS FOR TOADER-TYPE MEANS IN TERMS OF TWO-PARAMETER MEANS

In the article,we prove that the double inequalities Gp[λ1a+(1-λ1)b,λ1 b+(1-λ1)a]A1-p(a,b)<T[A(a,b),G(a,b)]<Gp[μ1 a+(1-μ1)b,μ1b+(1-μ1)a]A1-p(a,b),Cs[λ^(2) a+(1-λ2)b,λ2 b+(1-λ2)a]A1-s(a,b)<T[A(a,b),Q(a,b)]<Cs[μ2 a+(1-μ2)b,μ2 b+(1-μ2)a]A1-p(a,b)hold for all a,b>0 with a≠b if and only ifλ1≤1/2-(1-(2/π)2/p)1/2/2,μ1≥1/2-(2p)1/2/(4 p),λ2≤1/2+(2(3/(2 s)(E(21/2/2)/π)1/s)-1)1/2/2 andμ2≥1/2+s1/2/(4 s)ifλ1,μ1∈(0,1/2),λ2,μ2∈(1/2,1),p≥1 and s≥1/2,where G(a,b)=(ab)1/2,A(a,b)=(a+b)/2,T(a,b)=∫0π/2(a2 cos2 t+b2 sin2)1/2 tdt/π,Q(a,b)=((a2+b2)/2)1/2,C(a,b)=(a2+b2)/(a+b)and E(r)=∫0π/2(1-r^(2) sin^(2))1/2 tdt.

A practical strategy to subcutaneous administered in-situ gelling co-delivery system of arsenic and retinoic acid for the treatment of acute promyelocytic leukemia

Arsenic trioxide(ATO) combined with all trans retinoic acid(ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia(APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients’ compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel(PPSG) loaded with ATO and ATRA was developed. ATO + ATRA-PPSG(AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t 1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO + ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application.

SARS-CoV-2:structure,host,virus source and pathogenesis

Cancer is a serious threat to human life and a big problem in clinical treatment.Some natural active substances extracted from Traditional Chinese Medicine can effectively inhibit the growth of cancer cells,which is a new direction for finding more effective anticancer drugs.Osthole is a natural coumarin compound extracted from Traditional Chinese Medicines such as Cnidium monnieri,Angelica pubescens and Peucedanum praeruptorum Dunn.It has significant inhibitory activity against a variety of cancers.This paper summarizes the anticancer effects and molecular mechanisms of osthole in the treatment of cancers in recent years in order to provide references for further research.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy.Isocitrate dehydrogenases(IDHs)are a class of key proteins in energy metabolism,including IDH1,IDH2,and IDH3,which are involved in the oxidative decarboxylation of isocitrate to yield a-ketoglutarate(a-KG).Mutants of IDH1 or IDH2 can produce D-2-hydroxyglutarate(D-2HG)with a-KG as the substrate,and then mediate the occurrence and development of cancer.At present,no IDH3 mutation has been reported.The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2,implying IDH1 as a promising anti-cancer target.Therefore,in this review,we summarized the regulatory mechanisms of IDH1 on cancer from four aspects:metabolic reprogramming,epigenetics,immune microenvironment,and phenotypic changes,which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies.In addition,we also reviewed available IDH1 inhibitors so far.The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Minimally invasive bioprinting for in situ liver regeneration

In situ bioprinting is promising for developing scaffolds directly on defect models in operating rooms,which provides a new strategy for in situ tissue regeneration.However,due to the limitation of existing in situ biofabrication technologies including printing depth and suitable bioinks,bioprinting scaffolds in deep dermal or extremity injuries remains a grand challenge.Here,we present an in vivo scaffold fabrication approach by minimally invasive bioprinting electroactive hydrogel scaffolds to promote in situ tissue regeneration.The minimally invasive bioprinting system consists of a ferromagnetic soft catheter robot for extrusion,a digital laparoscope for in situ monitoring,and a Veress needle for establishing a pneumoperitoneum.After 3D reconstruction of the defects with computed tomography,electroactive hydrogel scaffolds are printed within partial liver resection of live rats,and in situ tissue regeneration is achieved by promoting the proliferation,migration,and differentiation of cells and maintaining liver function in vivo.

Design,synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreaticβ-cells

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)is the most promising target for diabetes treatment by promotingβ-cell proliferation.The desmethylbellidifolin(DMB)as a DYRK1A inhibitor could facilitateβ-cell proliferation in vivo and in vitro.However,DMB has the problem of weak binding affinity to DYRK1A,which means that continuous high concentration administration of DMB is effective for the diabetes.In order to solve this problem,we designed and synthesized a series of DMBbased proteolysis targeting chimeras(PROTACs)by taking advantage of the property of PROTAC that induce protein degradation in a cycle-catalytic manner.MDM2-based PROTAC X1-4P-MDM2 was identified as the most active PROTAC molecule.Mechanism research showed that X1-4P-MDM2 formed a ternary complex with DYRK1A and murine double minute 2(MDM2),and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway.At a dose much lower than that of DMB,X1-4PMDM2 still significantly enhancedβ-cell proliferation by inhibiting transforming growth factor beta(TGF-β)and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway,which may provide a new strategy for the application of DMB in diabetes.

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths.There are currently no registered therapies for treating coronavirus infections.Because of time consuming process of new drug development,drug repositioning may be the only solution to the epidemic of sudden infectious diseases.We systematically analyzed all the proteins encoded by SARS-CoV-2 genes,compared them with proteins from other coronavirnses,predicted their structures,and built 19 structures that could be done by homology modeling.By performing target-based virtual ligand screening,a total of21 targets(including two human targets)were screened against compound libraries including ZINC drug database and our own database of natural products.Structure and screening results of important targets such as 3-chymotrypsin-like protease(3 CLpro),Spike,RNA-dependent RNA polymerase(RdRp),and papain like protease(PLpro)were discussed in detail.In addition,a database of 78 commonly used antiviral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed.Possible targets of these compounds and potential drugs acting on a certain target were predicted.This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2,new insights for those drugs currently ongoing clinical studies,and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

PROTAC technology as a novel tool to identify the target of lathyrane diterpenoids

To the Editor:Proteolysis Targeting Chimera(PROTAC)is an emerging approach to selectively degrading target proteins by utilizing endogenous proteasome.Since PROTACs can degrade target proteins without high affinity,it is natural to speculate that this technology can be used to identify the targets of natural products。Although a recent study reported the employment of PROTACs to explore the unknown non-kinase target of a multi-kinase inhibitor sorafenib,whether PROTACs can be used to find the potential targets of natural products remains unexplored.