Platelet rich plasma-complexed hydrogel glue enhances skin wound healing in a diabetic rat model

Diabetic patients often exhibit delayed or incomplete progress in the healing of acute wounds,owing to poor blood perfusion.Platelet-rich plasma(PRP)has attracted much attention as a means to improve wound healing,because it contains high growth factor concentrations.However,the burst-like release of PRP growth factors results in a short halflife of these therapeutic proteins,thus greatly limiting the therapeutic effect.In this study,we prepared PRP from human umbilical cord blood and developed an in situ photocrosslinkable PRP hydrogel glue(HNPRP)by adding a photoresponsive hyaluronic acid(HA-NB)into PRP.The HNPRP hydrogel allowed for controlled release of plateletderived growth factor-BB(PDGF-BB)and transforming growth factor-β(TGF-β)for up to 28 days.In vitro cell culture showed that HNPRP promoted migration of fibroblasts and keratinocytes as well as PRP and did not reveal the advantages of HNPRP.However,in a diabetic rat skin wound model,HNPRP treatment promoted faster wound closure.Furthermore,the HNPRP group,compared with the control,PRP and hydrogel only groups,showed significantly greater re-epithelialization and numbers of both newly formed and mature blood vessels.The HNPRP group also displayed higher collagen formation than did the control group.In conclusion,HNPRP enhances angiogenesis and skin regeneration and consequently achieves faster wound healing,thus extending its potential for clinical applications to treat diabetic skin wounds.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Cobalt-based metal-organic framework as a dual cooperative controllable release system for accelerating diabetic wound healing

Nano Research volume 13,pages2268–2279(2020)Cite this article 131 Accesses 1 Altmetric Metrics details Abstract Insufficient angiogenesis in the chronic wound of the diabetic is one of the most important causes that making the wound unable to heal itself.In this work,a cobalt-based metal–organic framework(ZIF-67)was introduced as a carrier for loading a pro-angiogenic small molecular drug(dimethyloxalylglycine,DMOG).To achieve a long-term angiogenic therapy on the diabetic wound beds,a dual cooperative controllable release system has been designed by incorporating the drug-loaded ZIF-67 nanoparticles into the micro-patterned PLLA/Gelatin nanofibrous scaffolds.The results showed that DMOG was incorporated into ZIF-67 with a high loading ratio(359.12 mg/g),and the drug-loaded ZIF-67 nanoparticles were well embedded in the circular patterned scaffold.Notably,the DMOG as well as Co ions could continuously release from the scaffold for more than 15 days.The in vitro studies showed that the released Co ions and DMOG from the micropatterned nanofibrous scaffolds could synergistically promote the proliferation,migration and tube formation of the human umbilical vein endothelial cells(HUVECs)by inducing a hypoxia response and upregulating the expression of angiogenesis-related genes such as HIF-1α,VEGF and e-NOS.Furthermore,the in vivo results demonstrated that the composite scaffolds could significantly enhance angiogenesis,collagen deposition and eliminate inflammation in the diabetes wounds.These results indicate that the cobalt-based metal–organic framework as a dual cooperative controllable release system provides a new strategy for enhancing angiogenesis and promoting diabetic wound healing.

Highly Site-and Enantioselective N-H Functionalization of N-Monosubstituted Aniline Derivatives Affording Pyrazolones Bearing a Quaternary Stereocenter

Chiral phosphoric acid catalyzed the regio-and enantioselective N-H functionalization of N-alkylaniline with pyrazolones derived ketimines as electrophiles,providing a variety of chiral pyrazolones containing a tetrasubstituted stereocenter bearing a new N,N'-acetal motif in excellent yields and high enantioselectivities.This strategy was featured by low catalyst loading,mild conditions,and high efficiency and selectivity.

Delivery of therapeutic oligonucleotides in nanoscale

Therapeutic oligonucleotides(TOs)represent one of the most promising drug candidates in the targeted cancer treatment due to their high specificity and capability of modulating cellular pathways that are not readily druggable.However,efficiently delivering of TOs to cancer cellular targets is still the biggest challenge in promoting their clinical translations.Emerging as a significant drug delivery vector,nanoparticles(NPs)can not only protect TOs from nuclease degradation and enhance their tumor accumulation,but also can improve the cell uptake efficiency of TOs as well as the following endosomal escape to increase the therapeutic index.Furthermore,targeted and on-demand drug release of TOs can also be approached to minimize the risk of toxicity towards normal tissues using stimuli-responsive NPs.In the past decades,remarkable progresses have been made on the TOs delivery based on various NPs with specific purposes.In this review,we will first give a brief introduction on the basis of TOs as well as the action mechanisms of several typical TOs,and then describe the obstacles that prevent the clinical translation of TOs,followed by a comprehensive overview of the recent progresses on TOs delivery based on several various types of nanocarriers containing lipid-based nanoparticles,polymeric nanoparticles,gold nanoparticles,porous nanoparticles,DNA/RNA nanoassembly,extracellular vesicles,and imaging-guided drug delivery nanoparticles.

Integrating the second near-infrared fluorescence imaging with clinical techniques for multimodal cancer imaging by neodymiumdoped gadolinium tungstate nanoparticles

Second near-infrared(NIR-II)fluorescence imaging is a recently emerged technique and is highly useful for accurate diagnosis of cancer.Although a diverse array of fluorescent nanomaterials have been developed to enable NIR-II fluorescence in various situations,they normally fail to unify the clinical techniques,such as computed tomography(CT)and magnetic resonance imaging(MRI).Therefore,exploiting multimodal agents to integrate the newly emerged NIR-II fluorescence and traditional clinical techniques would be of key significance.Here,we report a rational fabrication of neodymium(Nd)-doped gadolinium tungstate nanoparticles(NPs)that are subsequentially decorated with a hydrophilic layer and demonstrate that they can achieve the harmonious integration of NIR-II fluorescence imaging,CT,and MRI.The NIR-II fluorescence emission was activated by an incident light with discrete wavelength ranging from 250 to 810 nm.NIR-II fluorescence-CT-MRI associated trimodal imaging was subsequently demonstrated for breast cancer by an 808 nm laser,along with the estimation of NIR-II fluorescence imaging for cervical cancer.The integration of newly emerged and traditional clinical imaging techniques highlights the huge potential of rare-earth-doped NPs for multimodal imaging of different types of cancer.

Long-term amelioration of an early-onset familial atrial fibrillation model with AAV-mediated in vivo gene therapy

Atrial fibrillation(AF)is a common cardiac disease with high prevalence in the general population.Despite a mild manifestation at the onset stage,it causes serious consequences,including sudden death,when the disease progresses to the late stage.Most available treatments of AF focus on symptom management or alleviation,due to a lack of fundamental knowledge and the fact that considerable variations of AF exist.With the popularisation of the next-generation sequencing technology,several causal genetic factors,including MYL4,have been discovered to contribute to AF,giving hope to developing its gene therapies.In this study,we attempted to treat a previously established rat AF model,which carried Myl4E11K/E11K loss of function mutation,via overexpression of exogenous wild-type Myl4 by AAV9 vectors.Our results showed that delivery of Myl4 expressing AAV9 to postnatal rat models rescued the symptoms of AF,indicating the therapeutic potential that early gene therapy intervention can achieve long-term effects in treating cardiac arrhythmias caused by gene mutations.