KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients.V-ATPase,an ATP-driven proton pump positioned at lysosomal surfaces,is responsible for maintaining the stability of lysosome.Herein,we reported that the potassium voltage-gated channel subfamily J member 15(KCNJ15)protein,which may bind to V-ATPase,can regulate the function of lysosome.The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy.The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase,contributing to the amelioration of drug resistance.Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading,advanced stages,more metastases of lymph nodes,and shorter disease free survival of patients with breast cancer.KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy.Moreover,we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes.In conclusion,KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer,which might guide the choice of therapeutic strategies.

Molecular chaperones in stroke-induced immunosuppression

Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.

Porous hydrogel arrays for hepatoma cell spheroid formation and drug resistance investigation

Drug resistance is one of the major obstacles in the drug therapy of cancers.Efforts in this area in pre-clinical research have focused on developing novel platforms to evaluate and decrease drug resistance.In this paper,inspired by the structure of hives where swarms live and breed,we propose porous hydrogel arrays with a uniform pore structure for the generation of hepatoma cell spheroids and the investigation of drug resistance.The porous hydrogel arrays were fabricated using polyeth-ylene glycol diacrylate(PEGDA)hydrogel to negatively replicate a well-designed template.Benefiting from the elaborate processing of the template,the prepared porous hydrogel arrays possessed a uniform pore structure.Due to their anti-adhesion properties and the excellent biocompatibility of the PEGDA hydrogel,the hepatoma cells could form well-defined and uni-form hepatoma cell spheroids in the porous hydrogel arrays.We found that the resistant hepatoma cell spheroids showed more significant Lenvatinib resistance and a migratory phenotype compared with a two-dimensional(2D)cell culture,which reveals the reason for the failure of most 2D cell-selected drugs for in vivo applications.These features give such porous hydrogel arrays promising application prospects in the investigation of tumor cell spheroid culture and in vitro drug resistance.

A Novel Next-Generation Sequencing Approach without Donor-Derived Material for Acute Rejection and Infection Monitoring in Solid Organ Transplantation

Background: Donor-derived cell free DNA (ddcf DNA) has been reported as a universal noninvasive biomarker for rejection monitoring in heart, kidney, liver, and lung transplantation. Current approaches based on next-generation sequencing for quantification of ddcf DNA, although promising, may be restricted by the requirement for donor material, as donor samples may not be available. Methods: We proposed a novel next-generation sequencing approach without donor-derived material and compared the non-donor-derived approach and the donor-derived approach using simulation testing and 69 clinical specimens. We also evaluated the performance for acute rejection and infection monitoring in lung transplantation. Results: The non-donor-derived approach reached similar efficacy as the donor-derived approach with a significant linear correlation of R2 = 0.98. Subsequent validation in clinical specimens demonstrated significant difference between the acute rejection group (4.83% ± 2.11%, mean ± SD) and the non-rejection group (1.61% ± 0.63%, mean ± SD) (P ’s t test). With the cut-off value of 2.999, our approach had 90.48% sensitivity (95% CI, 69.62% - 98.83%), 100% specificity (95% CI, 91.59% - 100%), and AUC 0.9266 (95% CI, 0.8277 - 1.026). The test also had the ability to simultaneously detect infectious agents, especially cytomegalovirus, as compared with the clinical test. Conclusion: The proposed approach without donor-derived material could potentially be used to monitor acute rejection and infection in lung transplantation and may be applied to other types of solid organ transplantation.

A selective inhibitor of OMA1 and targeted delivery system for the treatment of acute myocardial infarction

The rescue of dying cardiomyocytes in penumbra within 4 hours is the best way to preserve cardiac function in acute myocardial infarction(AMI).Mitochondrial fission contributes to mitochondrial energy supply deficiency and cardiomyocytes death,and OMA1 promotes mitochondrial fission.Accurate targeting of OMA1 inhibition is important for the treatment of myocardial infarction.Here,a selective inhibitor of OMA1,UNC-R,was firstly described,which could protect the cardiomyocytes through mitochondrial fission inhibition.Moreover,the accurately targeted microsphere was designed,and loaded the UNC-R to form the POMU,which could avoid the phagocytosis of phagocytes in blood,precisely accumulated in the ischemic area,further target the dying cardiomyocytes.

Triclosan-conjugated,Lipase-responsive Polymeric Micelles for Eradication of Staphylococcal Biofilms

Bacterial biofilms present a significant challenge in treating drug-resistant infections,necessitating the development of innovative nanomedicines.In this study,we introduce triclosan-conjugated,lipase-responsive polymeric micelles designed to exploit biofilm properties and serve as a responsive drug delivery platform.The micelles were created using an amphiphilic block polymer synthesized via ring-opening polymerization ofε-caprolactone(CL)and triclosan-containing cyclic trimethylene carbonate(MTC-Tri).Poly(ethylene glycol)(PEG-OH)acted as the macro-initiator,resulting in micelles with a PEG shell that facilitated their penetration into bacterial biofilms.An important advantage of our micelles lies in their interaction with local bacterial lipases within biofilms.These lipases triggered rapid micelle degradation,releasing triclosan in a controlled manner.This liberated triclosan effectively eliminated bacteria embedded in the biofilms.Notably,the triclosan-conjugated micelles displayed minimal toxicity to murine fibroblasts,indicating their biocompatibility and safety.This finding emphasizes the potential application of these micelles in combatting drug resistance observed in bacterial biofilms.Our triclosan-conjugated,lipase-responsive polymeric micelles exhibit promising characteristics for addressing drug resistance in bacterial biofilms.By harnessing biofilm properties and implementing a responsive drug delivery system,we seek to provide an effective solution in the fight against drug-resistant bacteria.

Protein@PP-Zn nanocomplex assembled by coordination of zinc ions used for intracellular protein delivery

In recent years,intracellular delivery of protein drugs has attracted great attention,and polymer-based systems have been extensively exploited to develop efficient and safe carriers.However,efficient intracellular delivery of protein drugs remains a challenge because of the cell membrane barrier and endosome entrapment.Herein,we report a protein@PP-Zn nanocomplex,which consists of an imidazole-containing block polymer poly(ethylene glycol)-block-poly(β-amino ester)(PEG-b-PAE(Im),PP),zinc ions,and protein drugs,for efficient intracellular protein delivery.PEG-b-PAE(Im)could conjugate proteins via the bridging effect of zinc ions which simultaneously coordinate with imidazole groups on polymer and electron donor groups,such as imidazole and primary amine groups,on protein to improve the loading stability of proteins.Under a slightly acidic environment near cancer cells,the protonation of PAE(Im)backbone increases the positive charge density of the nanocomplex and promotes endocytosis.While under a more acidic environment in endosomes,further protonation of imidazole groups leads to the disintegration of the nanocomplex and the breakdown of endosomes because of the proton sponge effect.Finally,protein is released into the cytoplasm.With the assistance of the nanocomplex,proteins with different sizes and isoelectric points are effectively delivered into cells.This work provides a stable,efficient and universal strategy for intracellular protein delivery.

Chemo-drugs in cell microparticles reset antitumor activity of macrophages by activating lysosomal P450 and nuclear hnRNPA2B1

Macrophages in tumors(tumor-associated macrophages,TAMs),a major population within most tumors,play key homeostatic functions by stimulating angiogenesis,enhancing tumor cell growth,and suppressing antitumor immunity.Resetting TAMs by simple,efficacious and safe approach(s)is highly desirable to enhance antitumor immunity and attenuate tumor cell malignancy.Previously,we used tumor cell-derived microparticles to package chemotherapeutic drugs(drug-MPs),which resulted in a significant treatment outcome in human malignant pleural effusions via neutrophil recruitments,implicating that drug-MPs might reset TAMs,considering the inhibitory effects of M2 macrophages on neutrophil recruitment and activation.Here,we show that drug-MPs can function as an antitumor immunomodulator by resetting TAMs with M1 phenotype and IFN-βrelease.Mechanistically,drug molecules in tumor MPs activate macrophage lysosomal P450 monooxygenases,resulting in superoxide anion formation,which further amplifies lysosomal ROS production and pH value by activating lysosomal NOX2.Consequently,lysosomal Ca^(2+)signaling is activated,thus polarizing macrophages towards M1.Meanwhile,the drug molecules are delivered from lysosomes into the nucleus where they activate DNA sensor hnRNPA2B1 for IFN-βproduction.This lysosomal-nuclear machinery fully arouses the antitumor activity of macrophages by targeting both lysosomal pH and the nuclear innate immunity.These findings highlight that drug-MPs can act as a new immunotherapeutic approach by revitalizing antitumor activity of macrophages.This mechanistic elucidation can be translated to treat malignant ascites by drug-MPs combined with PD-1 blockade.

Supramolecular G-quadruplex hydrogels:Bridging fabrication to biomedical application

G-quadruplex hydrogel is a class of self-assembled supramolecular hydrogel formed by guanine derivatives.As a biomimetic hydrogel,G-quadruplex hydrogels demonstrate wide biomedical applications,such as drug delivery,tissue engineering,and biosensing.The advantages of using G-quadruplex hydrogels include adequate biocompatibility and biodegradability,tunable multifunctionality,and cost-effective and large-scalable fabrication process.In this review,we focus on recent progress in the fabrication and characterization of G-quadruplex hydrogels to help readers understand the principles of G-quadruplex hydrogel formation.Meanwhile,the applications of G-quadruplex hydrogels in the biomedical area are discussed,aiming to pave the way for downward clinical or industry translation.The development of G-quadruplex hydrogel is still in its infancy.We hope this review will boost the development of this area and that more applications of G-quadruplex hydrogel will be developed.

Dynamic covalent nano-networks comprising antibiotics and polyphenols orchestrate bacterial drug resistance reversal and inflammation alleviation

New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms.This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks(aDCNs)composing antibiotics bearing multiple primary amines,polyphenols,and a cross-linker acylphenylboronic acid.Mechanistically,the iminoboronate bond drives the formation of aDCNs,facilitates their stability,and renders them highly responsive to stimuli,such as low pH and high H2O2 levels.Besides,the representative A1B1C1 networks,composed of polymyxin B1(A1),2-formylphenylboronic acid(B1),and quercetin(C1),inhibit biofilm formation of drug-resistant Escherichia coli,eliminate the mature biofilms,alleviate macrophage inflammation,and minimize the side effects of free polymyxins.Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model.The facile synthesis,excellent antimicrobial performance,and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.

Identification of methylated differentially expressed hub genes in systemic lupus erythematosus patients by WGCNA-based epigenome-wide and transcriptome-wide analysis

Systemic lupus erythematosus(SLE)is an autoimmune disease,characterized by the production of autoantibodies and the involvement of multi-systems.In order to explore its molecular mechanism,we,using bioinformatics analysis and wet lab experiments,identified two key genes in SLE patients.

HIF-1-modified BMSCs improve migration and reduce neuronal apoptosis after stroke in rats

Bone marrow-derived mesenchymal stem cells(BMSCs)have been demonstrated ameliorating neurologic deficits after stroke.Hypoxia-inducible factor-1(HIF-1),the key regulator of cellular responses to low oxygen concentration,can activate multiple genes involving in crucial aspects for neurologic recovery.In this study,we present that rat BMSCs overexpression of HIF-1showed higher expression of HIF-1 target genes in HIF-1-BMSCs,including CXCR4,EPO,and VEGF.BMSCs-mHIF-1 also exhibited an enhanced mobility towards the ischemic area within rat brain.Neural cell apoptosis in ischemic brain shown less severe in rats transplanted with HIF-1-BMSCs.Furthermore,the number of cells expressing neural progenitor markers PAX6 and DCX were increased in BMSCs-mHIF-1-transplanted rats.These results suggest that HIF-1 in BMSCs reduces neuronal apoptosis and promotes neurogenesis after stroke in rats.

Chinese herb microneedle patch for wound healing

Traditional Chinese medicine and Chinese herbs have a demonstrated value for disease therapy and sub-health improvement.Attempts in this area tend to develop new forms to make their applications more convenient and wider.Here,we propose a novel Chinese herb microneedle(CHMN)patch by integrating the herbal extracts,Premna microphylla and Centella asiatica,with microstructure of microneedle for wound healing.Such path is composed of sap extracted from the herbal leaves via traditional kneading method and solidified by plant ash derived from the brine induced process of tofu in a well-designed mold.Because the leaves of the Premna microphylla are rich in pectin and various amino acids,the CHMN could be imparted with medicinal efficacy of heat clearing,detoxicating,detumescence and hemostatic.Besides,with the excellent pharmaceutical activity of Asiatic acid extracted from Centella asiatica,the CHMN is potential in promoting relevant growth factor genes expression in fibroblasts and showing excellent performance in anti-oxidant,anti-inflammatory and anti-bacterial activity.Taking advantages of these pure herbal compositions,we have demonstrated that the derived CHMN was with dramatical achievement in anti-bacteria,inhibiting inflammatory,collagen deposition,angiogenesis and tissue reconstruction during the wound closure.These results indicate that the integration of traditional Chinese herbs with progressive technologies will facilitate the development and promotion of traditional Chinese medicine in modern society.

交换偏置多铁异质结中电场调控可逆性磁化反转的矢量分析研究

铁磁与反铁磁层间的交换偏置效应已在自旋电子器件中得到了广泛应用.目前,利用电场调控这一低能耗的方式已经实现了对交换偏置磁性多层膜中如交换偏置场和磁化值等宏观性质的调节.然而,交换偏置体系中磁畴如何随施加电场进行演化却鲜有报道.本文采用定量磁光克尔效应(MOKE)显微成像系统,实现了原位矢量分析CoFeB/IrMn/PMN-PT(011)交换偏置多铁异质结中电场作用下的可逆磁化反转.在保持偏置磁场于-80 Oe不变的情况下,外加电场驱动磁畴的磁化方向在160°方向与80°-120°方向区间内往复变化,对应磁畴的横向分量也于225°方向与45°方向间来回切换.同时,通过逐像素比对不同电场下的磁畴,进一步证实了电场调节磁化反转的可逆性.此外,在零偏置磁场下也实现了对磁化反转的可逆电场调节.电场调控交换偏置的矢量分析对于理解磁电效应以及发展下一代自旋电子器件具有重要意义.