Role of the membrane-associated accessory protein (MAAP) in adeno-associated virus (AAV) infection.

Adeno-associated viruses (AAVs) package a single-stranded (ss) DNA genome of 4.7 kb in their capsid of ~20 nm in diameter. AAV replication requires co-infection of a helper virus, such as adenovirus. During the optimization of recombinant AAV production, a small viral nonstructural protein, membrane-associated accessory protein (MAAP), was identified. However, the function of the MAAP in the context of AAV infection remains unknown. Here, we investigated the expression strategy and function of the MAAP during infection of both AAV2 and AAV5 in human embryonic kidney (HEK)293 cells. We found that AAV2 MAAP2 and AAV5 MAAP5 are expressed from the capsid gene (cap)-transcribing mRNA spliced from the donor to the second splice site that encodes VP2 and VP3. Thus, this AAV cap gene transcribes a multicistronic mRNA that can be translated to four viral proteins, MAAP, VP2, AAP, and VP3 in order. In AAV2 infection, MAAP2 predominantly localized in the cytoplasm, alongside the capsid, near the nuclear and plasma membranes, but a fraction of MAAP2 exhibited nuclear localization. In AAV5 infection, MAAP5 revealed a distinct pattern, predominantly localizing within the nucleus. In the cells infected with an MAAP knockout mutant of AAV2 or AAV5, both viral DNA replication and virus replication increased, whereas virus egress decreased, and the decrease in virus egress can be restored by providing MAAP in trans. In summary, MAAP, a novel AAV nonstructural protein translated from a multicistronic viral cap mRNA, not only facilitates cellular egress of AAV but also likely negatively affects viral DNA replication during infection. IMPORTANCE: Recombinant adeno-associated virus (rAAV) has been used as a gene delivery vector in clinical gene therapy. In current gene therapies employing rAAV, a high dose of the vector is required. Consequently, there is a high demand for efficient and high-purity vector production systems. In this study, we demonstrated that membrane-associated accessory protein (MAAP), a small viral nonstructural protein, is translated from the same viral mRNA transcript encoding VP2 and VP3. In AAV-infected cells, apart from its prevalent expression in the cytoplasm with localization near the plasma and nuclear membranes, the MAAP also exhibits notable localization within the nucleus. During AAV infection, MAAP expression increases the cellular egress of progeny virions and decreases viral DNA replication and progeny virion production. Thus, the choice of MAAP expression has pros and cons during AAV infection, which could provide a guide to rAAV production.

Identification of host essential factors for recombinant AAV transduction of the polarized human airway epithelium.

IMPORTANCE: The essential steps of successful gene delivery by recombinant adeno-associated viruses (rAAVs) include vector internalization, intracellular trafficking, nuclear import, uncoating, double-stranded (ds)DNA conversion, and transgene expression. rAAV2.5T has a chimeric capsid of AAV2 VP1u and AAV5 VP2 and VP3 with the mutation A581T. Our investigation revealed that KIAA0319L, the multiple AAV serotype receptor, is not essential for vector internalization but remains critical for efficient vector transduction to human airway epithelia. Additionally, we identified that a novel gene WDR63, whose cellular function is not well understood, plays an important role in vector transduction of human airway epithelia but not vector internalization and nuclear entry. Our study also discovered the substantial transduction potential of rAAV2.5T in basal stem cells of human airway epithelia, underscoring its utility in gene editing of human airways. Thus, the knowledge derived from this study holds promise for the advancement of gene therapy in the treatment of pulmonary genetic diseases.

SARS-CoV-2 infection of polarized human airway epithelium induces necroptosis that causes airway epithelial barrier dysfunction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause the ongoing pandemic of coronavirus disease 2019 (COVID19). One key feature associated with COVID-19 is excessive pro-inflammatory cytokine production that leads to severe acute respiratory distress syndrome. Although the cytokine storm induces inflammatory cell death in the host, which type of programmed cell death mechanism that occurs in various organs and cells remains elusive. Using an in vitro culture model of polarized human airway epithelium (HAE), we observed that necroptosis, but not apoptosis or pyroptosis, plays an essential role in the damage of the epithelial barrier of polarized HAE infected with SARS-CoV-2. Pharmacological inhibitors of necroptosis, necrostatin-2 and necrosulfonamide, efficiently prevented cell death and epithelial barrier dysfunction caused by SARS-CoV-2 infection. Moreover, the silencing of genes that are involved in necroptosis, RIPK1, RIPK3, and MLKL, ameliorated airway epithelial damage of the polarized HAE infected with SARS-CoV-2. This study, for the first time, confirms that SARS-CoV-2 infection triggers necroptosis that disrupts the barrier function of human airway epithelia in vitro.

Copper-Based Metal-Organic Framework Enables ROS Amplification and Drug Potency Activation.

Reactive oxygen species (ROS)-induced cancer therapy is extremely limited by tumor hypoxia, insufficient endogenous hydrogen peroxide (H2O2), overexpressed glutathione (GSH), and slower reaction rate. To address these challenges, in this paper, a hybrid nanomedicine (CaO2@Cu/ZIF-8-ICG@LA, CCZIL) is developed using a copper-based metal-organic framework (Cu/ZIF-8) for cancer synergistic therapy. H2O2/O2 self-supplementing, GSH-depleting, and photothermal properties multiply amplify ROS generation. Moreover, disulfiram (DSF) chemotherapy (CT) was activated by chelating with Cu2+ to synergize therapy. This novel strategy has enormous potential for ROS-involved synergistic antitumor therapy.

Identification of potential molecular mechanisms and candidate drugs for radiotherapy- and chemotherapy-induced mucositis.

BACKGROUND: Radiotherapy-induced oral mucositis (RIOM) and chemotherapy-induced oral mucositis (CIOM) are common complications in cancer patients, leading to negative clinical manifestations, reduced quality of life, and unsatisfactory treatment outcomes. OBJECTIVE: The present study aimed to identify potential molecular mechanisms and candidate drugs by data mining. METHODS: We obtained a preliminary list of genes associated with RIOM and CIOM. In-depth information on these genes was explored by functional and enrichment analyses. Then, the drug-gene interaction database was used to determine the interaction of the final enriched gene list with known drugs and analyze the drug candidates. RESULTS AND CONCLUSION: This study identified 21 hub genes that may play an important role in RIOM and CIOM, respectively. Through our data mining, bioinformatics survey, and candidate drug selection, TNF, IL-6, and TLR9 could play an important role in disease progression and treatment. In addition, eight candidate drugs (olokizumab, chloroquine, hydroxychloroquine, adalimumab, etanercept, golimumab, infliximab, and thalidomide) were selected by the drug-gene interaction literature search additionally, as candidates for treating RIOM and CIOM.

Robust Sparse Bayesian Two-Dimensional Direction-of-Arrival Estimation with Gain-Phase Errors.

To reduce the influence of gain-phase errors and improve the performance of direction-of-arrival (DOA) estimation, a robust sparse Bayesian two-dimensional (2D) DOA estimation method with gain-phase errors is proposed for L-shaped sensor arrays. The proposed method introduces an auxiliary angle to transform the 2D DOA estimation problem into two 1D angle estimation problems. A sparse representation model with gain-phase errors is constructed using the diagonal element vector of the cross-correlation covariance matrix of two submatrices of the L-shaped sensor array. The expectation maximization algorithm derives unknown parameter expression, which is used for iterative operations to obtain off-grid and signal precision. Using these parameters, a new spatial spectral function is constructed to estimate the auxiliary angle. The obtained auxiliary angle is substituted into a sparse representation model with gain and phase errors, and then the sparse Bayesian learning method is used to estimate the elevation angle of the incident signal. Finally, according to the relationship of the three angles, the azimuth angle can be estimated. The simulation results show that the proposed method can effectively realize the automatic matching of the azimuth and elevation angles of the incident signal, and improves the accuracy of DOA estimation and angular resolution.

Metal-Free Regioselective Hydrophosphorodithioation of Spirovinylcyclopropyl Oxindoles: Rapid Access to Allyl Dialkylphosphorodithioates.

Phosphorodithioates are important substructures due to their great use in bioactive compounds and functional materials. A metal-free 1,5-addition of spirovinylcyclopropyl oxindoles have been developed by choosing P4S10 and alcohol as nucleophiles through the regioselective ring-opening of spirovinylcyclopropyl oxindoles. This method provides access to allylic organothiophosphates with high efficiency, wide functional group tolerance, good chemo- and regioselectivity, and E-selectivity. 1,3-Addition products were also prepared in high yield. Furthermore, the resulting organothiophosphates could be readily transformed into other allylic derivatives.

Clinical efficacy of photodynamic therapy on halitosis: a systematic review and meta-analysis.

Halitosis is a widespread health problem with complex factors, and therapeutic effects sometimes are unsatisfactory. Plenty of clinical trials have tried to prove the effectiveness of photodynamic therapy (PDT), but the results are indeterminate. This study aimed to evaluate the clinical efficacy of PDT on halitosis. We searched PubMed, Cochrane Library, Embase, Web of Science, and Scopus from inception to August 10, 2022, and only studies about the PDT on halitosis were included. The criteria for meta-analysis comprised randomized controlled trials (RCTs) comparing the treatment of PDT with tongue scraper (TS) immediately after the halitosis therapy and during a 7-, 14-, 30-, and 90-day follow-up. Eight eligible studies involving 345 patients were included in this study. It was shown that PDT (MD = - 34.49, 95% CI [- 66.34, - 2.64], P = 0.03) or PDT + TS (MD = - 67.72, 95% CI [- 101.17, - 34.28], P < 0.001) had better efficacy than TS on the H2S concentration reduction immediately after the halitosis therapy. No significant differences were observed in reducing the H2S among TS, PDT alone, and PDT + TS at the follow-up. Besides, no difference between PDT and TS was found in the reduction of CH3SCH3 and CH3SH. Based on the current evidence, PDT and PDT + TS demonstrate efficacy in the treatment of halitosis in the short term, and PDT was shown to be a beneficial and promising therapeutic method.

The effect of ankyloglossia and tongue-tie division on speech articulation: A systematic review.

AIM: Ankyloglossia is a common congenital malformation characterized by a short, thick, or tight tongue frenulum, and its effect on speech articulation remains controversial. This study aimed to evaluate (a) the association between ankyloglossia and speech disorders, and (b) the effectiveness of surgical interventions on the articulation of patients with ankyloglossia. MATERIAL AND METHODS: A comprehensive search of PubMed was conducted. Randomized control trials (RCTs), cohort studies, case-control studies, and case series with more than five cases were included. RESULT: Of the 16 included studies, except for one cross-sectional study, all studies were small in sample size. The evidence quality was generally low, with an average of 3.88 in a 7-point system. Three studies investigated the occurrence of speech disorders in the ankyloglossia population and obtained different results. Fifteen studies assessed the effectiveness of surgery, among which eight self-control studies observed significant postoperative improvement, whereas three of four cohort studies with untreated controls reported no significant differences. Three RCTs compared surgical techniques and one pointed out the advantage of frenuloplasty over frenulotomy. CONCLUSION: There was no clear connection between ankyloglossia and speech disorders. More widely accepted uniform grading systems and well-designed clinical studies are needed.

Cellular Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Mediates Nuclear Import of Human Bocavirus 1 NP1 Protein and Modulates Viral Capsid Protein Expression.

Human bocavirus 1 (HBoV1), which belongs to the genus Bocaparvovirus of the Parvoviridae family, causes acute respiratory tract infections in young children. In vitro, HBoV1 infects polarized primary human airway epithelium (HAE) cultured at an air-liquid interface (HAE-ALI). HBoV1 encodes a small nonstructural protein, nuclear protein 1 (NP1), that plays an essential role in the maturation of capsid protein (VP)-encoding mRNAs and viral DNA replication. In this study, we determined the broad interactome of NP1 using the proximity-dependent biotin identification (BioID) assay combined with mass spectrometry (MS). We confirmed that two host mRNA processing factors, DEAH-box helicase 15 (DHX15) and cleavage and polyadenylation specificity factor 6 (CPSF6; also known as CFIm68), a subunit of the cleavage factor Im complex (CFIm), interact with HBoV1 NP1 independently of any DNA or mRNAs. Knockdown of CPSF6 significantly decreased the expression of capsid protein but not that of DHX15. We further demonstrated that NP1 directly interacts with CPSF6 in vitro and colocalizes within the virus replication centers. Importantly, we revealed a novel role of CPSF6 in the nuclear import of NP1, in addition to the critical role of CPSF6 in NP1-facilitated maturation of VP-encoding mRNAs. Thus, our study suggests that CPSF6 interacts with NP1 to escort NP1 imported into the nucleus for its function in the modulation of viral mRNA processing and viral DNA replication.IMPORTANCE Human bocavirus 1 (HBoV1) is one of the significant pathogens causing acute respiratory tract infections in young children worldwide. HBoV1 encodes a small nonstructural protein (NP1) that plays an important role in the maturation of viral mRNAs encoding capsid proteins as well as in viral DNA replication. Here, we identified a critical host factor, CPSF6, that directly interacts with NP1, mediates the nuclear import of NP1, and plays a role in the maturation of capsid protein-encoding mRNAs in the nucleus. The identification of the direct interaction between viral NP1 and host CPSF6 provides new insights into the mechanism by which a viral small nonstructural protein facilitates the multiple regulation of viral gene expression and replication and reveals a novel target for potent antiviral drug development.

Effectiveness and safety of Bifidobacterium in preventing dental caries: a systematic review and meta-analysis.

OBJECTIVES: The effectiveness and safety of Bifidobacterium in dental caries prevention are controversial. Thus, we performed this systematic review and meta-analysis to explore the preventive value of Bifidobacterium. METHODS: Eligible studies were identified from several databases, including PubMed, the Cochrane Library, Embase, Web of Science, and Scopus. Hand searches were also conducted in relevant bibliographies. We then extracted and pooled standardized mean difference (SMD) and risk ratio (RR) to analyze the anti-caries effect of Bifidobacterium with Stata 16.0 software. If the data obtained was not suitable for meta-analysis, qualitative descriptions were performed. RESULTS: Compared with the placebo control group, there was no statistically significant reduction in Streptococcus mutans and Lactobacilli counts in saliva in the test group. Also, there were no significant differences in Streptococcus mutans and Lactobacillus counts in dental plaque and no significant difference in caries incidence in deciduous teeth. There was no significant difference in the incidence of adverse events between the Bifidobacterium and control groups. CONCLUSIONS: Available evidence demonstrates that Bifidobacterium is neither effective in reducing Streptococcus mutans and Lactobacillus counts in the saliva or dental plaque nor in reducing the occurrence of caries in deciduous teeth. Evaluation of its safety requires further investigations. Therefore, Bifidobacterium is not a competent probiotic candidate to prevent dental caries.

Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer.

Androgen receptor (AR) splice variants (ARVs) are implicated in development of castration-resistant prostate cancer (CRPC). Upregulation of ARVs often correlates with persistent AR activity after androgen deprivation therapy (ADT). However, the genomic and epigenomic characteristics of ARV-dependent cistrome and the disease relevance of ARV-mediated transcriptome remain elusive. Through integrated chromatin immunoprecipitation coupled sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, we identified ARV-preferential-binding sites (ARV-PBS) and a set of genes preferentially transactivated by ARVs in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions harboring the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions containing the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in castration-resistant (CR) tumors in patients and ARV-preferentially activated genes were up-regulated in abiraterone-resistant patient specimens. Expression of ARV-PBS target genes, such as oncogene RAP2A and cell cycle gene E2F7, were significantly associated with castration resistance, poor survival and tumor progression. We uncover distinct genomic and epigenomic features of ARV-PBS, highlighting that ARVs are useful tools to depict AR-regulated oncogenic genome and epigenome landscapes in prostate cancer. Our data also suggest that the ARV-preferentially activated transcriptional program could be targeted for effective treatment of CRPC.

Effects of the PI3K/Akt signaling pathway on the apoptosis of early host cells infected with Eimeria tenella.

This study investigated the role of PI3K/Akt signaling pathway on host cell apoptosis in the early infection of Eimeria tenella. Chicken cecal epithelial cells were treated with apoptosis-inducer Actinomycin D (Act D) or PI3K/Akt signaling pathway inhibitor LY294002 and then infected with E. tenella. Results demonstrated that the E. tenella-infected group had less apoptosis 4-8 h after the infection and more apoptosis 12-20 h after the infection than the control group. At 4-20 h after the infection, the apoptotic/necrotic rate and the Caspase-3 activity in the Act D + E. tenella group were lower (P < 0.01) than those in the Act D-treated group. The p-Akt and NF-κB contents in the E. tenella-infected group were higher (P < 0.01) than those in the control group 4-12 h after the infection. However, the bad content and the Caspase-9/3 activity were lower (P < 0.05) in the E. tenella-infected group than in the control group. Compared with the E. tenella-infected group, the LY294002 + E. tenella group showed decreased p-Akt content and increased apoptotic/necrotic rate, bad content, NF-κB expression, membrane permeability transition pore (MPTP) openness, and Caspase-9/3 activity. Thus, the early development of E. tenella could inhibit host cell apoptosis by downregulating the Caspase-3 activity. Upregulating this activity promoted apoptosis. In addition, activating the PI3K/Akt signaling pathway inhibited the apoptosis of E. tenella host cells in the early infection by reducing the expression of the bad content, limiting the MPTP opening, and decreasing the Caspase-9 and Caspase-3 activities.

Potential factors affecting the success rate of indirect pulp therapy in primary molars with deep caries: a retrospective study.

Indirect pulp therapy (IPT) is a common conservative treatment for deep dental caries. However, the potential risk factors for the prognosis of IPT have not been well studied. This study retrospectively investigated the success rate of IPT in treating primary molars with deep caries and the factors potentially affecting the two-year success rate. A total of 303 primary molars in 202 children (106 boys and 96 girls) were included in this study. These primary molars were identified as having deep caries by clinical and radiographic examinations and were treated with IPT. The factors potentially affecting the IPT success rate were analyzed after two years of follow-up. The results indicated that the two-year IPT success rate was 86% (262/303). The success rate of primary molars with and without stainless steel crowns was 96% (120/125) and 80% (142/178), respectively. Primary molars treated with stainless steel crowns showed a significantly lower risk of failure (hazard ratio (HR) = 0.18, 95% confidence interval (CI): (0.10, 0.34), p = 0.01). There were no significant differences in other factors, including gender (male vs. female), age (preschool vs. school age), cooperation level (Frankl 2 vs. 3 or 4 scales), arch type (maxillary vs. mandibular), tooth type (first vs. second primary molar), or pulp capping material (calcium hydroxide vs. glass ionomer cement). IPT is an effective, conservative treatment modality for primary molars with deep caries. Stainless steel crowns could significantly improve the IPT success rate.

Improving biomass yields of microalgae biofilm by coculturing two microalgae species via forming biofilms with uniform microstructures and small cell-clusters.

Microalgae coculture has the potential to promote microalgae biofilm growth. Herein, three two-species cocultured biofilms were studied by determining biomass yields and detailed microstructure parameters, including porosity, average pore length, average cluster length, etc. It was found that biomass yields could reduce by 21-53 % when biofilm porosities decreased from about 35 % to 20 %; while at similar porosities (∼20 %), biomass yields of cocultured biofilms increased by 37 % when they possessed uniform microstructure and small cell-clusters (pores and clusters of 1 âˆ¼ 10 µm accounted for 96 % and 68 %, respectively). By analyzing morphologies and surface properties of cells, it was found that cells with small size, spherical shape, and reduced surface polymers could hinder the cell-clusters formation, thereby promoting biomass yields. The study provides new insights into choosing cocultured microalgae species for improving the biomass yield of biofilm via manipulating biofilm microstructures.

Use microalgae to treat coke wastewater for producing biofuel: Influence of phenol on photosynthetic properties and intracellular components of microalgae.

Using microalgae to treat coking wastewater has important application prospects and environmental significance. Previous studies have suggested that phycoremediation of pollutants from coking wastewater is feasible and can potentially enhance biodiesel production. This work investigates the effects of phenol in coking wastewater on C. pyrenoidosa and S. obliquus growth, photosynthesis activity, and intracellular components. The results indicated that when the phenol concentration was lower than 300 mg L-1, both microalgae maintained good photosynthetic and physiological activity, with a maximum quantum yield potential ranging from 0.6 to 0.7. At the phenol concentration of 300 mg L-1, the biomass of C. pyrenoidosa was 2.4 times that of the control group. For S. obliquus, at the phenol concentration of 150 mg L-1, the biomass was approximately 0.85 g L-1, which increased by 68% than that of the control group (0.58 g L-1). The lipid content in both microalgae increased with the phenol concentrations, with the maximum content exceeding 40%. The optimal phenol concentrations for C. pyrenoidosa and S. obliquus growth were determined to be 246.18 and 152.73 mg L-1, respectively, based on a developed kinetic model. This work contributes to further elucidating the effects of phenol on microalgae growth, photosynthesis, and intracellular components, and suggests that using microalgae to treat phenol-containing coking wastewater for producing biofuel is not only environmentally friendly but also holds significant energy promise.

YAP condensates are highly organized hubs.

YAP/TEAD signaling is essential for organismal development, cell proliferation, and cancer progression. As a transcriptional coactivator, how YAP activates its downstream target genes is incompletely understood. YAP forms biomolecular condensates in response to hyperosmotic stress, concentrating transcription-related factors to activate downstream target genes. However, whether YAP forms condensates under other signals, how YAP condensates organize and function, and how YAP condensates activate transcription in general are unknown. Here, we report that endogenous YAP forms sub-micron scale condensates in response to Hippo pathway regulation and actin cytoskeletal tension. YAP condensates are stabilized by the transcription factor TEAD1, and recruit BRD4, a coactivator that is enriched at active enhancers. Using single-particle tracking, we found that YAP condensates slowed YAP diffusion within condensate boundaries, a possible mechanism for promoting YAP target search. These results reveal that YAP condensate formation is a highly regulated process that is critical for YAP/TEAD target gene expression.

Transcriptional condensates and phase separation: condensing information across scales and mechanisms.

Transcription is the fundamental process of gene expression, which in eukaryotes occurs within the complex physicochemical environment of the nucleus. Decades of research have provided extreme detail in the molecular and functional mechanisms of transcription, but the spatial and genomic organization of transcription remains mysterious. Recent discoveries show that transcriptional components can undergo phase separation and create distinct compartments inside the nucleus, providing new models through which to view the transcription process in eukaryotes. In this review, we focus on transcriptional condensates and their phase separation-like behaviors. We suggest differentiation between physical descriptions of phase separation and the complex and dynamic biomolecular assemblies required for productive gene expression, and we discuss how transcriptional condensates are central to organizing the three-dimensional genome across spatial and temporal scales. Finally, we map approaches for therapeutic manipulation of transcriptional condensates and ask what technical advances are needed to understand transcriptional condensates more completely.

Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5' untranslated region.

One of the hallmarks of RNA viruses is highly structured untranslated regions (UTRs) in their genomes. These conserved RNA structures are often essential for viral replication, transcription, or translation. In this report, we discovered and optimized a new type of coumarin derivatives, such as C30 and C34, which bind to a four-way RNA helix called SL5 in the 5' UTR of the SARS-CoV-2 RNA genome. To locate the binding site, we developed a novel sequencing-based method namely cgSHAPE-seq, in which the acylating chemical probe was directed to crosslink with the 2'-OH groups of ribose at the ligand binding site. This crosslinked RNA could then create read-through mutations during reverse transcription (i.e., primer extension) at single-nucleotide resolution to uncover the acylation locations. cgSHAPE-seq unambiguously determined that a bulged G in SL5 was the primary binding site of C30 in the SARS-CoV-2 5' UTR, which was validated through mutagenesis and in vitro binding experiments. C30 was further used as a warhead in RNA-degrading chimeras to reduce viral RNA expression levels. We demonstrated that replacing the acylating moiety in the cgSHAPE probe with ribonuclease L recruiter (RLR) moieties yielded RNA degraders active in the in vitro RNase L degradation assay and SARS-CoV-2 5' UTR expressing cells. We further explored another RLR conjugation site on the E ring of C30/C34 and discovered improved RNA degradation activities in vitro and in cells. The optimized RNA-degrading chimera C64 inhibited live virus replication in lung epithelial carcinoma cells.

pH-responsive nanocatalyst for enhancing cancer therapy via H2O2 homeostasis disruption and disulfiram sensitization.

Due to the powerful redox homeostasis and inefficiency of monotherapy, chemodynamic therapy (CDT) is clinically limited. Despite great efforts, the design of CDT nanosystems with specific H2O2 homeostasis and effective integration of multiple treatments remains a great challenge. Therefore, herein, we engineer a novel pH-responsive nanocatalyst to disrupt intracellular H2O2 homeostasis through consuming glutathione (GSH), elevating H2O2 and restraining H2O2 elimination, as well as achieving a combination of CDT and chemotherapy (CT) through sensitized DSF. In the formulation, amplified CDT synergized enhanced CT significantly, strengthening the tumor therapeutic efficacy in vitro and in vivo. This work not only solves intracellular redox homeostasis disruption, but also realizes the re-use of old drugs, providing new insights for CDT-based multimodal cancer therapy.