Stem cell-based ischemic stroke therapy:Novel modifications and clinical challenges

Ischemic stroke(IS)causes severe disability and high mortality worldwide.Stem cell(SC)therapy exhibits unique therapeutic potential for IS that differs from current treatments.SC’s cell homing,differentiation and paracrine abilities give hope for neuroprotection.Recent studies on SC modification have enhanced therapeutic effects for IS,including gene transfection,nanoparticle modification,biomaterial modification and pretreatment.Thesemethods improve survival rate,homing,neural differentiation,and paracrine abilities in ischemic areas.However,many problems must be resolved before SC therapy can be clinically applied.These issues include production quality and quantity,stability during transportation and storage,as well as usage regulations.Herein,we reviewed the brief pathogenesis of IS,the“multi-mechanism”advantages of SCs for treating IS,various SC modification methods,and SC therapy challenges.We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.

Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances

Neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,Huntington disease and amyotrophic lateral sclerosis throw a heavy burden on families and society. Related scientific researches make tardy progress. One reason is that the known pathogeny is just the tip of the iceberg. Another reason is that various physiological barriers,especially blood-brain barrier(BBB),hamper effective therapeutic substances from reaching site of action. Drugs in clinical treatment of neurodegenerative diseases are basically administered orally. And generally speaking,the brain targeting efficiency is pretty low. Nanodelivery technology brings hope for neurodegenerative diseases. The use of nanocarriers encapsulating molecules such as peptides and genomic medicine may enhance drug transport through the BBB in neurodegenerative disease and target relevant regions in the brain for regenerative processes. In this review,we discuss BBB composition and applications of nanocarriers-liposomes,nanoparticles,nanomicelles and new emerging exosomes in neurodegenerative diseases. Furthermore,the disadvantages and the potential neurotoxicity of nanocarriers according pharmacokinetics theory are also discussed.

Recent strategies on targeted delivery of thrombolytics

Thrombus formed in blood vessel is a progressive process, which would lead to lifethreatening thrombotic diseases such as ischemic stroke. Unlike other diseases, the recognition of thrombus is usually in the late stage where blood vessels are largely blocked. So acute thrombotic diseases have a narrow therapeutic window, and remain leading causes of morbidity and mortality, whereas current thrombolysis therapy has limited therapeutic effects and bleeding complications. Thrombolytic agents in unwanted sites would cause hemorrhage due to the activation of plasminogen. Moreover, untargeted thrombolysis therapy require large amounts of thrombolytic agents, which in return would enhance hemorrhage risk. To improve the efficiency while minimizing the adverse effects of traditional thrombolysis therapy, novel drug delivery systems have been investigated. Various targeting strategies including ultrasound and magnetic field directed targeting, and specific binding, have been designed to deliver thrombolytic drugs to the thrombotic sites. These strategies demonstrate promising results in reducing bleeding risk as well as allowing less dosage of thrombolytic drugs with lowered clot lysis time. In this review, we discuss recent progress on targeted delivery of thrombolytics, and summarize treatment advantages and shortcomings, potentially helping to further promote the development of targeted thrombolysis.

Molecular Design of Conjugated Small Molecule Nanoparticles for Synergistically Enhanced PTT/PDT

Simultaneous photothermal therapy(PTT)and photodynamic therapy(PDT)is beneficial for enhanced cancer therapy due to the synergistic effect.Conventional materials developed for synergistic PTT/PDT are generally multicomponent agents that need complicated preparation procedures and be activated by multiple laser sources.The emerging monocomponent diketopyrrolopyrrole(DPP)-based conjugated small molecular agents enable dual PTT/PDT under a single laser irradiation,but suffer from low singlet oxygen quantum yield,which severely restricts the therapeutic efficacy.Herein,we report acceptor-oriented molecular design of a donor-acceptor-donor(D-A-D)conjugated small molecule(IID-ThTPA)-based phototheranostic agent,with isoindigo(IID)as selective acceptor and triphenylamine(TPA)as donor.The strong D-A strength and narrow singlet-triplet energy gap endow IID-ThTPA nanoparticles(IID-ThTPA NPs)high mass extinction coefficient(18.2 L g^-1 cm^-1),competitive photothermal conversion efficiency(35.4%),and a dramatically enhanced singlet oxygen quantum yield(84.0%)comparing with previously reported monocomponent PTT/PDT agents.Such a high PTT/PDT performance of IID-ThTPA NPs achieved superior tumor cooperative eradicating capability in vitro and in vivo.

Biomaterials reinforced MSCs transplantation for spinal cord injury repair

Due to the complex pathophysiological mechanism, spinal cord injury (SCI) has become one of the most intractable central nervous system (CNS) diseases to therapy. Stem cell transplantation, mesenchymal stem cells (MSCs) particularly, appeals to more and more attention along with the encouraging therapeutic results for the functional regeneration of SCI. However, traditional cell transplantation strategies have some limitations, including the unsatisfying survival rate of MSCs and their random diffusion from the injection site to ambient tissues. The application of biomaterials in tissue engineering provides a new horizon. Biomaterials can not only confine MSCs in the injured lesions with higher cell viability, but also promote their therapeutic efficacy. This review summarizes the strategies and advantages of biomaterials reinforced MSCs transplantation to treat SCI in recent years,which are clarified in the light of various therapeutic effects in pathophysiological aspects of SCI.

The application of label-free imaging technologies in transdermal research for deeper mechanism revealing

The penetration behavior of topical substances in the skin not only relates to the transdermal delivery efficiency but also involves the safety and therapeutic effect of topical products,such as sunscreen and hair growth products.Researchers have tried to illustrate the transdermal process with diversified theories and technologies.Directly observing the distribution of topical substances on skin by characteristic imaging is the most convincing approach.Unfortunately,fluorescence labeling imaging,which is commonly used in biochemical research,is limited for transdermal research for most topical substances with a molecular mass less than 500 Da.Label-free imaging technologies possess the advantages of not requiring any macromolecular dyes,no tissue destruction and an extensive substance detection capability,which has enabled rapid development of such technologies in recent years and their introduction to biological tissue analysis,such as skin samples.Through the specific identification of topical substances and endogenous tissue components,label-free imaging technologies can provide abundant tissue distribution information,enrich theoretical and practical guidance for transdermal drug delivery systems.In this review,we expound the mechanisms and applications of the most popular label-free imaging technologies in transdermal research at present,compare their advantages and disadvantages,and forecast development prospects.

Rapid and effective treatment of traumatic spinal cord injury using stem cell derived exosomes

Traumatic spinal cord injury is a fatal acute event without effective clinical therapies.Following the trauma,immediate neural protection and microenvironment mitigation are vitally important for nerve tissue repair,where stem cell-based therapies could be eclipsed by the deficiency of cells due to the hostile microenvironment as well as the transport and preservation processes.Effective emergency strategies are required to be convenient,biocompatible,and stable.Herein,we assess an emergency cell-free treatment using mesenchymal stem cell-derived exosomes,which have proven capable of comprehensive mitigation of the inhibitory lesion microenvironment.The clinically validated fibrin glue is utilized to encapsulate the exosomes and in-situ gelates in transected rat spinal cords to provide a substrate for exosome delivery as well as nerve tissue growth.The emergency treatment alleviates the inflammatory and oxidative microenvironment,inducing effective nerve tissue repair and functional recovery.The therapy presents a promising strategy for effective emergency treatment of central nervous system trauma。

Hair follicle-targeting drug delivery strategies for the management of hair follicle-associated disorders

The hair follicle is not only a critical penetration route in percutaneous absorption but also has been recognized to be a target for hair follicle-associated disorders,such as androgenetic alopecia(AGA)and acne vulgaris.Hair follicle-targeting drug delivery systems allow for controlled drug release and enhance therapeutic efficacywithminimal side effects,exerting a promising method for themanagement of hair follicle-associated dysfunctions.Therefore,they have obtained much attention in several fields of research in recent years.This review gives an overviewof potential follicle-targeting drug delivery formulations currently applied based on the particularities of the hair follicles,including a comprehensive assessment of their preclinical and clinical performance.

A double-edged sword:ROS related therapies in the treatment of psoriasis

In the onset and progression of psoriasis,redox imbalance is a vital factor.It's widely accepted that too much reactive oxygen species(ROS)always make psoriasis worse.Recent research,however,has shown that the accumulation of ROS is not entirely detrimental,as it helps reduce psoriasis lesions by inhibiting epidermal proliferation and keratinocyte death.As a result,ROS appears to have two opposing effects on the treatment of psoriasis.In this review,the current ROS-related therapies for psoriasis,including basic and clinical research,are presented.Additionally,the design and therapeutic benefits of various drug delivery systems and therapeutic approaches are examined,and a potential balance between antioxidative stress and ROS accumulation is also trying to be investigated.

Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2

Renal cell carcinoma(RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that mi R-489-3 p and mi R-630 suppress OCT2 expression by directly binding to the OCT2 30-UTR. Meanwhile, via 786-O-OCT2-mi RNAs stable expression cell models, we found that mi RNAs could repress the classic substrate 1-methyl-4-phenylpyridinium(MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline(ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, mi R-489-3 p and mi R-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and q PCR validation. The increased binding of c-Myc to the promoter of pri-mi R-630, responsible for the upregulation of mi R-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that mi R-489-3 p and mi R-630 function as oncotherapy-obstructing micro RNAs by directly targeting OCT2 in RCC.

New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders:Combining with intranasal delivery

The clinical translation of stem cells and their extracellular vesicles(EVs)-based therapy for central nervous system(CNS) diseases is booming. Nevertheless, the insufficient CNS delivery and retention together with the invasiveness of current administration routes prevent stem cells or EVs from fully exerting their clinical therapeutic potential. Intranasal(IN) delivery is a possible strategy to solve problems as IN route could circumvent the brain-blood barrier non-invasively and fit repeated dosage regimens. Herein, we gave an overview of studies and clinical trials involved with IN route and discussed the possibility of employing IN delivery to solve problems in stem cells or EVs-based therapy. We reviewed relevant researches that combining stem cells or EVs-based therapy with IN administration and analyzed benefits brought by IN route. Finally, we proposed possible suggestions to facilitate the development of IN delivery of stem cells or EVs.

Volunteer rescue dispatch during the Coronavirus Disease 2019 epidemic:Using the recruitment of volunteers for pneumonia epidemic prevention and control in Chun’an County as an example

To solve the problem of volunteer dispatch during the Coronavirus Disease 2019(COVID-19)epidemic,a many-to-many two-sided matching volunteer dispatch method based on an improved predator-search algorithm is pro-posed.First,different evaluation index sets for volunteers and rescue tasks were developed,and weightings were determined using the analytic hierarchy process.Subsequently,the actual and expected values of the different indicators of the two parties were determined,and the triangular fuzzy number was used to calculate the satis-faction of the two parties.Based on this number,we used a linear weighting method to calculate the combined satisfaction and build a many-to-many two-sided matching model according to the demands of both parties.Sub-sequently,an improved predator-search algorithm was used to solve the model.Finally,taking the recruitment of volunteers for pneumonia epidemic prevention and control in Chun’an County as an example,the method proposed in our study was verified.A comparison and analysis of the results further demonstrated the feasibility and advantages of this method.