Advances in regenerative medicine applications of tetrahedral framework nucleic acid-based nanomaterials: an expert consensus recommendation

With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids(t FNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, t FNAs have been widely applied in the biomedical field as threedimensional DNA nanomaterials. Surprisingly, t FNAs exhibit positive effects on cellular biological behaviors and tissue regeneration,which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity,t FNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization,intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic t FNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic t FNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone,cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.

High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis

Drug delivery via intra-articular(IA)injection has proved to be effective in osteoarthritis(OA)therapy,limited by the drug efficiency and short retention time of the drug delivery systems(DDSs).Herein,a series of modified cross-linked dextran(Sephadex,S0)was fabricated by respectively grafting with linear alkyl chains,branched alkyl chains or aromatic chain,and acted as DDSs after ibuprofen(Ibu)loading for OA therapy.This DDSs expressed sustained drug release,excellent anti-inflammatory and chondroprotective effects both in IL-1βinduced chondrocytes and OA joints.Specifically,the introduction of a longer hydrophobic chain,particularly an aromatic chain,distinctly improved the hydrophobicity of S0,increased Ibu loading efficiency,and further led to significantly improving OA therapeutic effects.Therefore,hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.

Genome-wide identification and spatiotemporal expression profiling of zinc finger SWIM domain-containing protein family genes

The biological function of the novel zinc-finger SWIM domain-containing protein family(ZSWIM)during embryonic development remains elusive.Here,we conducted a genome-wide analysis to explore the evolutionary processes of the ZSWIM gene family members in mice,Xenopus tropicalis,zebrafish,and humans.We identified nine putative ZSWIM genes in the human and mouse genome,eight in the Xenopus genome,and five in the zebrafish genome.Based on multiple sequence alignment,three members,ZSWIM5,ZSWIM6,and ZSWIM8,demonstrated the highest homology across all four species.Using available RNA sequencing(RNAseq)data,ZSWIM genes were found to be widely expressed across different tissues,with distinct tissuespecific properties.To identify the functions of the ZSWIM protein family during embryogenesis,we examined temporal and spatial expression patterns of zswim family genes in Xenopus embryos.Quantitative real-time polymerase chain reaction(qRT-PCR)revealed that each member had a distinct expression profile.Whole-mount in situ hybridization showed that both zswim1 and zswim3 were maternally expressed genes;zswim5 and zswim6were expressed throughout embryogenesis and displayed dynamic expression in the brain,eyes,somite,and bronchial arch at the late tailbud stages;zswim7 was detected in the eye area;zswim8 showed a dynamic expression pattern during the tailbud stages,with expression detected in the brain,eyes,and somite;zswim9 was faintly expressed throughout embryonic development.This study provides a foundation for future research to delineate the functions of ZSWIM gene members.

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling

Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Total flavonoids of hawthorn leaves promote motor function recovery via inhibition of apoptosis after spinal cord injury

Flavonoids have been reported to have therapeutic potential for spinal cord injury.Hawthorn leaves have abundant content and species of total flavonoids,and studies of the effects of the total flavonoids of hawthorn leaves on spinal cord injury have not been published in or outside China.Therefore,Sprague-Dawley rats were used to establish a spinal cord injury model by Allen's method.Rats were intraperitoneally injected with 0.2 m L of different concentrations of total flavonoids of hawthorn leaves(5,10,and 20 mg/kg)after spinal cord injury.Injections were administered once every 6 hours,three times a day,for 14 days.After treatment with various concentrations of total flavonoids of hawthorn leaves,the Basso,Beattie,and Bresnahan scores and histological staining indicated decreases in the lesion cavity and number of apoptotic cells of the injured spinal cord tissue;the morphological arrangement of the myelin sheath and nerve cells tended to be regular;and the Nissl bodies in neurons increased.The Basso,Beattie,and Bresnahan scores of treated spinal cord injury rats were increased.Western blot assays showed that the expression levels of pro-apoptotic Bax and cleaved caspase-3 were decreased,but the expression level of the anti-apoptotic Bcl-2 protein was increased.The improvement of the above physiological indicators showed a dose-dependent relationship with the concentration of total flavonoids of hawthorn leaves.The above findings confirm that total flavonoids of hawthorn leaves can reduce apoptosis and exert neuroprotective effects to promote the recovery of the motor function of rats with spinal cord injury.This study was approved by the Ethics Committee of the Guangxi Medical University of China(approval No.201810042)in October 2018.

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury,surgery and infection.Excessive extracellular matrix and adhesions contract pouches,bursae and tendons,cause pain and prevent a normal range of joint motion,with devastating consequences for patient quality of life.Arthrofibrosis affects people of all ages,with published rates varying.The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers.However,current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis.The process begins when stress signals stimulate immune cells.The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts,which secrete fibrillar collagens and transforming growth factor-β(TGF-β).Positive feedback networks then dysregulate processes that normally terminate healing processes.We propose two subtypes of arthrofibrosis occur:active arthrofibrosis and residual arthrofibrosis.In the latter the fibrogenic processes have resolved but the joint remains stiff.The best therapeutic approach for each subtype may differ significantly.Treatment typically involves surgery,however,a pharmacological approach to correct dysregulated cell signalling could be more effective.Recent research shows that myofibroblasts are capable of reversing differentiation,and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments.Therapies with significant promise are currently available,with more in development,including those that inhibit TGF-βsignalling and epigenetic modifications.This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

Protein microarray analysis of cytokine expression changes in distal stumps after sciatic nerve transection

A large number of chemokines,cytokines,other trophic factors and the extracellular matrix molecules form a favorable microenvironment for peripheral nerve regeneration.This microenvironment is one of the major factors for regenerative success.Therefore,it is important to investigate the key molecules and regulators affecting nerve regeneration after peripheral nerve injury.However,the identities of specific cytokines at various time points after sciatic nerve injury have not been determined.The study was performed by transecting the sciatic nerve to establish a model of peripheral nerve injury and to analyze,by protein microarray,the expression of different cytokines in the distal nerve after injury.Results showed a large number of cytokines were up-regulated at different time points post injury and several cytokines,e.g.,ciliary neurotrophic factor,were downregulated.The construction of a protein-protein interaction network was used to screen how the proteins interacted with differentially expressed cytokines.Kyoto Encyclopedia of Genes and Genomes pathway and Gene ontology analyses indicated that the differentially expressed cytokines were significantly associated with chemokine signaling pathways,Janus kinase/signal transducers and activators of transcription,phosphoinositide 3-kinase/protein kinase B,and notch signaling pathway.The cytokines involved in inflammation,immune response and cell chemotaxis were up-regulated initially and the cytokines involved in neuronal apoptotic processes,cell-cell adhesion,and cell proliferation were up-regulated at 28 days after injury.Western blot analysis showed that the expression and changes of hepatocyte growth factor,glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were consistent with the results of protein microarray analysis.The results provide a comprehensive understanding of changes in cytokine expression and changes in these cytokines and classical signaling pathways and biological functions during Wallerian degeneration,as well as a basis for potential treatments of peripheral nerve injury.The study was approved by the Institutional Animal Care and Use Committee of the Chinese PLA General Hospital,China(approval number:2016-x9-07)in September 2016.

Bioinformatic analysis of cytokine expression in the proximal and distal nerve stumps after peripheral nerve injury

In our previous study,we investigated the dynamic expression of cytokines in the distal nerve stumps after peripheral nerve injury using microarray analysis,which can characterize the dynamic expression of proteins.In the present study,we used a rat model of right sciatic nerve transection to examine changes in the expression of cytokines at 1,7,14 and 28 days after injury using protein microarray analysis.Interleukins were increased in the distal nerve stumps at 1–14 days post nerve transection.However,growth factors and growth factor-related proteins were mainly upregulated in the proximal nerve stumps.The P-values of the inflammatory response,apoptotic response and cell-cell adhesion in the distal stumps were higher than those in the proximal nerve stumps,but the opposite was observed for angiogenesis.The number of cytokines related to axons in the distal stumps was greater than that in the proximal stumps,while the percentage of cytokines related to axons in the distal stumps was lower than that in the proximal nerve stumps.Visualization of the results revealed the specific expression patterns and differences in cytokines in and between the proximal and distal nerve stumps.Our findings offer potential therapeutic targets and should help advance the development of clinical treatments for peripheral nerve injury.Approval for animal use in this study was obtained from the Animal Ethics Committee of the Chinese PLA General Hospital on September 7,2016(approval No.2016-x9-07).

Isolated cryptococcal osteomyelitis of the ulna in an immunocompetent patient:A case report

BACKGROUND Cryptococcal osteomyelitis is a bone infection caused by cryptococcus.As an opportunistic infection,bone cryptococcosis usually occurs in patients with immunodeficiency diseases or in those undergoing immunosuppressive therapy and often displays characteristics of disseminated disease.Isolated cryptococcal osteomyelitis is extremely unusual in immunocompetent person.The pathogenic fungus often invades vertebrae,femur,tibia,rib,clavicle,pelvis,and humerus,but the ulna is a rare target.CASE SUMMARY A 79-year-old woman complaining of chronic pain,skin ulceration and a sinus on her right forearm was admitted,and soon after was diagnosed with cryptococcal osteomyelitis in the right ulna.Unexpectedly,she was also found to have apparently normal immunity.After treatment with antifungal therapy combined with surgery debridement,the patient’s osteomyelitis healed with a satisfactory outcome.CONCLUSION Although rare,cryptococcal osteomyelitis should be considered in the differential diagnosis of osteolytic lesions even in immunocompetent patients,and good outcomes can be expected if early definitive diagnosis and etiological treatment are established.

Cellular Mechanism of Mouse Atrial Development

During the development of mammalian heart, the left and right atria play an important role in cardiovascular circulation. The embryonic atrium is mainly formed by the differentiation of progenitor cells and the proliferation of cardiomyocytes, while the postnatal atrium is primarily shaped by the increase in the volume of cardiomyocytes. Cell proliferation and differentiation of atrial development is the basis for its functions such as “blood reservoir” and “supplementary pump”. Deep understanding the cellular mechanism of atrial development is imperative to explore the causes of common congenital arrhythmia heart diseases such as atrial fibrillation. We used genetically engineered mouse reproduction knowledge, lineage tracing method based on CreloxP system, molecular biology and immunofluorescence technology to track the cardiomyocyte lineage of Nppa-GFP mouse line with stereo fluorescence microscope and ultra-high-speed confocal microscope. Besides the atrium of Nppa-CreER;Rosa26 tdTomato mouse was examined during embryonic (E10.5 - E18.5) and postnatal (P0, P3, P5, P7, P14, P28, P8w) stage. Immunofluorescence results revealed that Nppa-positive cells labeled TNNI3-positive cardiomyocytes and protruded into the atrial cavity at the beginning of E11.5 - E12.0 and during subsequent development to form Nppa-positive myocardial trabeculae. Thick comb-shaped myocardium was observed after birth, and we suspect that this was particularly important for the normal contractile activity and pumping function of the atrium. Additionally, non-single origin of Nppa-positive trabecular myocardiocytes were revealed through Tamoxifen-induced lineage tracing experiment. Our findings reveal proliferation dynamics and non-comprehensive fate decisions of cardiomyocytes that produce the distinct architecture of the atrium chamber.

An aptamer-driven DNA nanodevice for improved delivery of synthetic immunostimulants

Efficient delivery of therapeutics to immune cells remains a formidable challenge for cancer immunotherapy.In this work,we demonstrate that an aptamer-driven DNA nanodevice,constructed through linkage of a synthetic immunostimulant(Toll-like receptor 9 agonist:CpG motif)to an aptamer,could significantly enhance the immunostimulatory activity by facilitating the uptake and retention of therapeutics in macrophages.Systemic administration of the DNA nanodevice results in efficient tumor growth inhibition in both breast cancer and melanoma mouse models.Our studies suggest that the DNA nanodevice leads to reeducation of tumor-associated macrophages and ultimately to reversing the tumor immune microenvironment.The strategy for aptamer-mediated and vehicle-free delivery of immunostimulatory oligonucleotides provides a potential platform for cancer immunotherapy.

Biophysical-driven piezoelectric and aligned nanofibrous scaffold promotes bone regeneration by re-establishing physiological electrical microenvironment

The initial healing stages of bone fracture is a complex physiological process involving a series of spatially and temporally overlapping events,including pathogen clearance,immunological modulation,and osteogenesis.In this study,we have developed a piezoelectric and aligned nanofibrous scaffold composed of ZnO@PCL/PVDF with multiple antibacterial,immunomodulatory,and osteogenic effects using electrospinning technology.This scaffold’s piezoelectric signal output under ultrasound(US)control can be similar to the physiological electrical signals of healthy bone tissue,creating a truly biomimetic electrical microenvironment in the bone defect.In vitro studies have shown that ZnO@PCL/PVDF scaffold significantly enhances the proliferation,migration,and osteogenic differentiation of MC3T3-E1 cells under piezoelectric drive provided by ultrasound.Furthermore,the scaffold exhibits inhibitory effects on the growth of E.coli and S.aureus,as well as the ability to induce M2 macrophage polarization,indicating potent antibacterial and immunomodulatory properties.In vivo experiments demonstrated that the ZnO@PCL/PVDF scaffold can accelerate the repair of mandibular defects in rats,effectively inhibit bacterial colonization,and reduce inflammatory responses.Altogether,this study confirms that the newly developed ZnO@PCL/PVDF scaffold effectively promotes bone repair by truly mimicking the endogenous electrical microenvironment and precisely regulating the temporospatial disorders of initial bone healing,thus providing a simple and effective solution for bone defects.

4D bioprinting of programmed dynamic tissues

Setting time as the fourth dimension,4D printing allows us to construct dynamic structures that can change their shape,property,or functionality over time under stimuli,leading to a wave of innovations in various fields.Recently,4D printing of smart biomaterials,biological components,and living cells into dynamic living 3D constructs with 4D effects has led to an exciting field of 4D bioprinting.4D bioprinting has gained increasing attention and is being applied to create programmed and dynamic cell-laden constructs such as bone,cartilage,and vasculature.This review presents an overview on 4D bioprinting for engineering dynamic tissues and organs,followed by a discussion on the approaches,bioprinting technologies,smart biomaterials and smart design,bioink requirements,and applications.While much progress has been achieved,4D bioprinting as a complex process is facing challenges that need to be addressed by transdisciplinary strategies to unleash the full potential of this advanced biofabrication technology.Finally,we present future perspectives on the rapidly evolving field of 4D bioprinting,in view of its potential,increasingly important roles in the development of advanced dynamic tissues for basic research,pharmaceutics,and regenerative medicine.

Extracellular matrix from human umbilical cordderived mesenchymal stem cells as a scaffold for peripheral nerve regeneration

The extracellular matrix,which includes collagens,laminin,or fibronectin,plays an important role in peripheral nerve regeneration.Recently,a Schwann cell-derived extracellular matrix with classical biomaterial was used to mimic the neural niche.However,extensive clinical use of Schwann cells remains limited because of the limited origin,loss of an autologous nerve,and extended in vitro culture times.In the present study,human umbilical cord-derived mesenchymal stem cells（h UCMSCs）,which are easily accessible and more proliferative than Schwann cells,were used to prepare an extracellular matrix.We identified the morphology and function of h UCMSCs and investigated their effect on peripheral nerve regeneration.Compared with a non-coated dish tissue culture,the h UCMSC-derived extracellular matrix enhanced Schwann cell proliferation,upregulated gene and protein expression levels of brain-derived neurotrophic factor,glial cell-derived neurotrophic factor,and vascular endothelial growth factor in Schwann cells,and enhanced neurite outgrowth from dorsal root ganglion neurons.These findings suggest that the h UCMSC-derived extracellular matrix promotes peripheral nerve repair and can be used as a basis for the rational design of engineered neural niches.

Single-cell RNA-seq and bulk-seq identify RAB17 as a potential regulator of angiogenesis by human dermal microvascular endothelial cells in diabetic foot ulcers

Background:Angiogenesis is crucial in diabetic wound healing and is often impaired in diabetic foot ulcers(DFUs).Human dermal microvascular endothelial cells(HDMECs)are vital components in dermal angiogenesis;however,their functional and transcriptomic characteristics in DFU patients are not well understood.This study aimed to comprehensively analyse HDMECs from DFU patients and healthy controls and find the potential regulator of angiogenesis in DFUs.Methods:HDMECs were isolated from skin specimens of DFU patients and healthy controls via magnetic-activated cell sorting.The proliferation,migration and tube-formation abilities of the cells were then compared between the experimental groups.Both bulk RNA sequencing(bulk-seq)and single-cell RNA-seq(scRNA-seq)were used to identify RAB17 as a potential marker of angiogenesis,which was further confirmed via weighted gene co-expression network analysis(WGCNA)and least absolute shrink and selection operator(LASSO)regression.The role of RAB17 in angiogenesis was examined through in vitro and in vivo experiments.Results:The isolated HDMECs displayed typical markers of endothelial cells.HDMECs isolated from DFU patients showed considerably impaired tube formation,rather than proliferation or migration,compared to those from healthy controls.Gene set enrichment analysis(GSEA),fGSEA,and gene set variation analysis(GSVA)of bulk-seq and scRNA-seq indicated that angiogenesis was downregulated in DFU-HDMECs.LASSO regression identified two genes,RAB17 and CD200,as characteristic of DFU-HDMECs;additionally,the expression of RAB17 was found to be significantly reduced in DFU-HDMECs compared to that in the HDMECs of healthy controls.Overexpression of RAB17 was found to enhance angiogenesis,the expression of hypoxia inducible factor-1α and vascular endothelial growth factor A,and diabetic wound healing,partially through the mitogen-activated protein kinase/extracellular signal-regulated kinase signalling pathway.Conclusions:Our findings suggest that the impaired angiogenic capacity in DFUs may be related to the dysregulated expression of RAB17 in HDMECs.The identification of RAB17 as a potential molecular target provides a potential avenue for the treatment of impaired angiogenesis in DFUs.

Coordination-driven self-assembly of metallo-nanodrugs for local inflammation alleviation

Developing dedicated nanomedicines to improve delivery efficacy of anti-inflammatory drugs is still a formidable challenge.In this study,we present an extremely simple yet efficient approach to obtain hybrid nanodrugs through metal-drug coordination-driven self-assembly for carrier-free drug delivery.The resulting metallo-nanodrugs exhibit well-defined morphology and high drug encapsulation capability,allowing for the combination of magnetic resonance imaging and anti-inflammatory therapy.In the case of osteoarthritis(OA),the metallo-nanodrugs remarkably alleviate synovial inflammation,preventing cartilage destruction and extracellular matrix loss.In addition,it led to significantly improved therapeutic efficacy compared with intra-articular administration of the same dose of free drugs in OA mouse model.This work provides a very simple approach for the development of anti-inflammatory nanoformulations by exploiting coordination-driven self-assembly.

Green process of biomass waste derived fluorescent carbon quantum dots for biological imaging in vitro and in vivo

In the context of the circular economy,the huge amounts of biomass waste should be converted into value-added materials and energy to diminish pollution,atmospheric CO_(2)levels and costly waste disposal.Biological imaging usually uses expensive and toxic chemicals e.g.,organic dyes,semiconductor quantum dots,calling for safer,greener,cheaper fluorescent probes for biological imaging in vitro and in vivo.In these regards,carbon quantum dots(CQDs)-based fluorescent probes using biomass waste as a precursor may have much higher potential.Here we transformed the biomass waste of peach leaves into value-added fluorescent CQDs through a low-cost and green one-step hydrothermal process.The obtained CQDs show excitation-dependent photoluminescence properties with a fluorescence lifetime of 5.96 ns and a quantum yield of 7.71%without any passivation.In addition,the CQDs have a fine size of 1.9 nm with good hydrophilicity and high fluorescent stability over pH 4.0-11.0 range.Fluorescence imaging of in vitro cell cultures and in vivo with zebrafish show that CQDs possess ultra-low toxicity and remarkable performance for biological imaging.Even when CQDs present at a concentration as high as500μg/m L,the organism can still maintain more than 90%activity both in vitro and in vivo,and present bright fluorescence.The cheaper,greener,ultra-low toxicity CQDs developed in this work is a potential candidate for biological imaging in vitro and in vivo.

Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive state.Thus developing a strategy to reshape TME is expected to achieve highly efficient radioimmunotherapy.Therefore,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer radioimmunotherapy.As expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify radiotherapy.In addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling immuno-microenvironment.As a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in vivo.Collectively,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.

Tetrahedral framework nucleic acids enhance the chondrogenic potential of human umbilical cord mesenchymal stem cells via the PI3K/AKT axis

The field of regenerative medicine faces a notable challenge in terms of the regeneration of articular cartilage.Without proper treatment,it can lead to osteoarthritis.Based on the research findings,human umbilical cord mesenchymal stem cells(hUMSCs)are considered an excellent choice for regenerating cartilage.However,there is still a lack of suitable biomaterials to control their ability to self-renew and differentiate.To address this issue,in this study using tetrahedral framework nucleic acids(tFNAs)as a new method in an in vitro culture setting to manage the behaviour of hUMSCs was proposed.Then,the influence of tFNAs on hUMSC proliferation,migration and chondrogenic differentiation was explored by combining bioinformatics methods.In addition,a variety of molecular biology techniques have been used to investigate deep molecular mechanisms.Relevant results demonstrated that tFNAs can affect the transcriptome and multiple signalling pathways of hUMSCs,among which the PI3K/Akt pathway is significantly activated.Furthermore,tFNAs can regulate the expression levels of multiple proteins(GSK3β,RhoA and mTOR)downstream of the PI3K-Akt axis to further enhance cell proliferation,migration and hUMSC chondrogenic differentiation.tFNAs provide new insight into enhancing the chondrogenic potential of hUMSCs,which exhibits promising potential for future utilization within the domains of AC regeneration and clinical treatment.

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.