Non-invasively differentiate non-alcoholic steatohepatitis by visualizing hepatic integrinαvβ3 expression with a targeted molecular imaging modality

BACKGROUND Non-invasive methods to diagnose non-alcoholic steatohepatitis(NASH),an inflammatory subtype of non-alcoholic fatty liver disease(NAFLD),are currently unavailable.AIM To develop an integrinαvβ3-targeted molecular imaging modality to differentiate NASH.METHODS Integrinαvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids(FFA).Hepatic integrinαvβ3 expression was analyzed in rabbits fed a high-fat diet(HFD)and in rats fed a high-fat,high-carbohydrate diet(HFCD).After synthesis,cyclic arginine-glycine-aspartic acid peptide(cRGD)was labeled with gadolinium(Gd)and used as a contrast agent in magnetic resonance imaging(MRI)performed on mice fed with HFCD.RESULTS Integrinαvβ3 was markedly expressed on FFA-cultured hepatocytes,unlike the control hepatocytes.Hepatic integrinαvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver(FL)progressed to steatohepatitis.The distribution of integrinαvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas.In comparison to mice with simple FL,the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis(P<0.05),showing a positive correlation with the NAFLD activity score(r=0.945;P<0.01).Hepatic integrinαvβ3 expression was significantly upregulated during NASH development,with hepatocytes being the primary cells expressing integrinαvβ3.CONCLUSION After using Gd-labeled cRGD as a tracer,NASH was successfully distinguished by visualizing hepatic integrinαvβ3 expression with MRI.

Effects of calculation approaches for thermal conductivity on the simulation accuracy of billet continuous casting

An unsteady, two-dimensional, explicitly solved fmite difference heat transfer model of a billet caster was presented to clarify the influence of the thermal conductivity of steel on model accuracy. Different approaches were utilized for calculating the thermal conductivity of solid, mushy and liquid steels. Model results predicted by these approaches were compared, and the advantages of advocated approaches were discussed. It is found that the approach for calculating the thermal conductivity of solid steel notably influences model predictions. Convection effects of liquid steel should be considered properly while calculating the thermal conductivity of mushy steel. Different values of the effective thermal conductivity of liquid steel adopted could partly be explained by the fact that different models adopted dissimilar ap- proaches for calculating the thermal conductivity of solid and mushy steels.

A pilot study of the differentiated landscape of peripheral blood mononuclear cells from children with incomplete versus complete Kawasaki disease

Kawasaki disease(KD)is a disorder of immune responses.The prevalence of KD among 100,000 children aged 0-4 years was 71.9-110.0 in China,170.9-194.9 in Korea,and 18.1-21.3 in the USA[1].The most severe complication of KD is coronary artery lesions(CALs),including coronary dilatation and coronary aneurysms,which may even lead to myocardial ischemia,myocardial infarction,and sudden death.

All-stage targeted therapy for the brain metastasis from triple-negative breast cancer

Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.

Engineered platelets-based drug delivery platform for targeted thrombolysis

Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life,low targeting ability,and association with serious adverse reactions,such as bleeding complications.Inspired by the natural roles of platelets during thrombus formation,we fabricated a platelet-based delivery system(NO@uPA/PLTs)comprising urokinase(uPA)and arginine(Arg)for targeted thrombolysis and inhibition of re-embolism.The anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet functions.Nitric oxide(NO)generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel,thereby inhibiting re-embolism.NO@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic efficacy.In addition,the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery injury.The coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk,providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.

Efficacy of inverso isomer of CendR peptide on tumor tissue penetration

The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule(CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1(NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides(sequence RGERPPR) as the parent L-peptide and substituted D-amino acids for the L-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumorpenetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine(Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate(TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor-penetrating peptide.

BCL9 regulates CD226 and CD96 checkpoints in CD8^(+)T cells to improve PD-1 response in cancer

To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the Wnt pathway,is highly expressed in cancers.By genetic depletion and pharmacological inhibition of BCL9 in tumors,we found that BCL9 suppression reduced tumor growth.

Preliminary investigations into surface molecularly imprinted nanoparticles for Helicobacter pylori eradication

This paper reports investigations into the preparation and characterization of surface molecularly imprinted nanoparticles(SMINs) designed to adhere to Helicobacter pylori(H.pylori).Imprinted nanoparticles were prepared by the inverse microemulsion polymerization method.A fraction of Lpp20,an outer membrane protein of H.pylori known as NQA,was chosen as template and modified with myristic acid to facilitate its localization on the surface of the nanoparticles.The interaction between these SMINs with the template NQA were evaluated using surface plasmon resonance(SPR),change in zeta potential and fluorescence polarization(FP).The results were highly consistent in demonstrating a preferential recognition of the template NQA for SMINs compared with the control nanoparticles.In vitro experiments also indicate that such SMINs are able to adhere to H.pylori and may be useful for H.pylori eradication.

A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated

AL3810,a molecular dual inhibitor of the vascular endothelial growth factor receptor(VEGFR)and fibroblast growth factor receptor(FGFR),has earned the permission of phase II clinical trial for tumor treatment by China FDA.As a reversible ATP-competitive inhibitor,AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR,whereas,AL3810 lacking interplay with extracellular region of receptors rendered deficient bloodebrain tumor barrier(BBTB)recognition,poor brain penetration and unsatisfactory anti-glioma efficacy.Integrin avb3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma.The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia,activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3 b and C5 b-9,and experienced complement-dependent opsonization.We newly proposed a pentapeptide mn with superb avb3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation,targeting ability,and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly.Stemming from attenuated immunogenicity,peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.