Structural insights into the chloroplast protein import in land plants.

Chloroplast proteins are imported via the translocon at the outer chloroplast membrane (TOC)-translocon at the inner chloroplast membrane (TIC) supercomplex, driven by an ATPase motor. The Ycf2-FtsHi complex has been identified as the chloroplast import motor. However, its assembly and cooperation with the TIC complex during preprotein translocation remain unclear. Here, we present the structures of the Ycf2-FtsHi and TIC complexes from Arabidopsis and an ultracomplex formed between them from Pisum. The Ycf2-FtsHi structure reveals a heterohexameric AAA+ ATPase motor module with characteristic features. Four previously uncharacterized components of Ycf2-FtsHi were identified, which aid in complex assembly and anchoring of the motor module at a tilted angle relative to the membrane. When considering the structures of the TIC complex and the TIC-Ycf2-FtsHi ultracomplex together, it becomes evident that the tilted motor module of Ycf2-FtsHi enables its close contact with the TIC complex, thereby facilitating efficient preprotein translocation. Our study provides valuable structural insights into the chloroplast protein import process in land plants.

Conservation and specialization of the Ycf2-FtsHi chloroplast protein import motor in green algae.

The protein import motor in chloroplasts plays a pivotal role in their biogenesis and homeostasis by driving the translocation of preproteins into chloroplasts. While the Ycf2-FtsHi complex serves as the import motor in land plants, its evolutionary conservation, specialization, and mechanisms across photosynthetic organisms are largely unexplored. Here, we isolated and determined the cryogenic electron microscopy (cryo-EM) structures of the native Ycf2-FtsHi complex from Chlamydomonas reinhardtii, uncovering a complex composed of up to 19 subunits, including multiple green-algae-specific components. The heterohexameric AAA+ ATPase motor module is tilted, potentially facilitating preprotein handover from the translocon at the inner chloroplast membrane (TIC) complex. Preprotein interacts with Ycf2-FtsHi and enhances its ATPase activity in vitro. Integrating Ycf2-FtsHi and translocon at the outer chloroplast membrane (TOC)-TIC supercomplex structures reveals insights into their physical and functional interplay during preprotein translocation. By comparing these findings with those from land plants, our study establishes a structural foundation for understanding the assembly, function, evolutionary conservation, and diversity of chloroplast protein import motors.

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention.

An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

lncRNA directs cooperative epigenetic regulation downstream of chemokine signals.

lncRNAs are known to regulate a number of different developmental and tumorigenic processes. Here, we report a role for lncRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP1 and PNUTS in response to CCL21 releases the SNIP1's inhibition of p300-dependent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA Pol II via activation of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models. The findings reveal a disease-relevant lncRNA mechanism consisting of both direct coordinated protein recruitment and indirect regulation of transcription factors.

Structure of a step II catalytically activated spliceosome from Chlamydomonas reinhardtii.

Pre-mRNA splicing, a fundamental step in eukaryotic gene expression, is executed by the spliceosomes. While there is extensive knowledge of the composition and structure of spliceosomes in yeasts and humans, the structural diversity of spliceosomes in non-canonical organisms remains unclear. Here, we present a cryo-EM structure of a step II catalytically activated spliceosome (C* complex) derived from the unicellular green alga Chlamydomonas reinhardtii at 2.6 Å resolution. This Chlamydomonas C* complex comprises 29 proteins and four RNA elements, creating a dynamic assembly that shares a similar overall architecture with yeast and human counterparts but also has unique features of its own. Distinctive structural characteristics include variations in protein compositions as well as some noteworthy RNA features. The splicing factor Prp17, with four fragments and a WD40 domain, is engaged in intricate interactions with multiple protein and RNA components. The structural elucidation of Chlamydomonas C* complex provides insights into the molecular mechanism of RNA splicing in plants and understanding splicing evolution in eukaryotes.

Deep silicification-assisted long-term preservation of structural and genomic information across biospecies: From micro to macro.

The concurrent preservation of morphological, structural, and genomic attributes within biological samples is paramount for comprehensive insights into biological phenomena and disease mechanisms. However, current preservation methodologies (e.g., cryopreservation, chemical reagent fixation, and bioplasticization) exhibit limitations in simultaneously achieving these critical combined goals. To address this gap, inspired by natural fossilization, here we propose "deep silicification," a room temperature technology that eliminates fixation requirements and overcomes the cold chain problem. By harnessing the synergy between ethanol and dimethyl sulfoxide, deep silicification significantly enhances silica penetration and accumulation within bioorganisms, thereby reinforcing structural integrity. This versatile and cost-effective approach demonstrates remarkable efficacy in preserving organismal morphology across various scales. Accelerated aging experiments underscore a 4,723-fold enhancement in genomic information storage over millennia, with whole-genome sequencing confirming nearly 100% fidelity. With its simplicity and reliability, "deep silicification" represents a paradigm shift in biological sample storage.

Effective multi-modal clustering method via skip aggregation network for parallel scRNA-seq and scATAC-seq data.

In recent years, there has been a growing trend in the realm of parallel clustering analysis for single-cell RNA-seq (scRNA) and single-cell Assay of Transposase Accessible Chromatin (scATAC) data. However, prevailing methods often treat these two data modalities as equals, neglecting the fact that the scRNA mode holds significantly richer information compared to the scATAC. This disregard hinders the model benefits from the insights derived from multiple modalities, compromising the overall clustering performance. To this end, we propose an effective multi-modal clustering model scEMC for parallel scRNA and Assay of Transposase Accessible Chromatin data. Concretely, we have devised a skip aggregation network to simultaneously learn global structural information among cells and integrate data from diverse modalities. To safeguard the quality of integrated cell representation against the influence stemming from sparse scATAC data, we connect the scRNA data with the aggregated representation via skip connection. Moreover, to effectively fit the real distribution of cells, we introduced a Zero Inflated Negative Binomial-based denoising autoencoder that accommodates corrupted data containing synthetic noise, concurrently integrating a joint optimization module that employs multiple losses. Extensive experiments serve to underscore the effectiveness of our model. This work contributes significantly to the ongoing exploration of cell subpopulations and tumor microenvironments, and the code of our work will be public at https://github.com/DayuHuu/scEMC.

scEGG: an exogenous gene-guided clustering method for single-cell transcriptomic data.

In recent years, there has been significant advancement in the field of single-cell data analysis, particularly in the development of clustering methods. Despite these advancements, most algorithms continue to focus primarily on analyzing the provided single-cell matrix data. However, within medical contexts, single-cell data often encompasses a wealth of exogenous information, such as gene networks. Overlooking this aspect could result in information loss and produce clustering outcomes lacking significant clinical relevance. To address this limitation, we introduce an innovative deep clustering method for single-cell data that leverages exogenous gene information to generate discriminative cell representations. Specifically, an attention-enhanced graph autoencoder has been developed to efficiently capture topological signal patterns among cells. Concurrently, a random walk on an exogenous protein-protein interaction network enabled the acquisition of the gene's embeddings. Ultimately, the clustering process entailed integrating and reconstructing gene-cell cooperative embeddings, which yielded a discriminative representation. Extensive experiments have demonstrated the effectiveness of the proposed method. This research provides enhanced insights into the characteristics of cells, thus laying the foundation for the early diagnosis and treatment of diseases. The datasets and code can be publicly accessed in the repository at https://github.com/DayuHuu/scEGG.

scDFC: A deep fusion clustering method for single-cell RNA-seq data.

Clustering methods have been widely used in single-cell RNA-seq data for investigating tumor heterogeneity. Since traditional clustering methods fail to capture the high-dimension methods, deep clustering methods have drawn increasing attention these years due to their promising strengths on the task. However, existing methods consider either the attribute information of each cell or the structure information between different cells. In other words, they cannot sufficiently make use of all of this information simultaneously. To this end, we propose a novel single-cell deep fusion clustering model, which contains two modules, i.e. an attributed feature clustering module and a structure-attention feature clustering module. More concretely, two elegantly designed autoencoders are built to handle both features regardless of their data types. Experiments have demonstrated the validity of the proposed approach, showing that it is efficient to fuse attributes, structure, and attention information on single-cell RNA-seq data. This work will be further beneficial for investigating cell subpopulations and tumor microenvironment. The Python implementation of our work is now freely available at https://github.com/DayuHuu/scDFC.

A Versatile Nanozyme-Based NADH Circulating Oxidation Reactor for Tumor Therapy through Triple Cellular Metabolism Disruption.

Nanozyme-based metabolic regulation triggered by tumor-specific endogenous stimuli has emerged as a promising therapeutic strategy for tumors. The current efficacy, however, is constrained by the limited concentration of endogenous substrates and the metabolic plasticity of tumors. Consequently, the implementation of efficient metabolic regulation in tumor therapy is urgently needed. Herein, a versatile nanozyme-based nicotinamide adenine dinucleotide (NADH) circulating oxidation nanoreactor is reported. First, the synthesized cobalt-doped hollow carbon spheres (Co-HCS) possess NADH oxidase (NOX)-mimicking activity for the NADH oxidation to disrupt oxidative phosphorylation (OXPHOS) pathway of tumor cells. Second, the substrate-cycle manner of Co-HCS can be used for NADH circulating oxidation to overcome the limitation of substrate deficiency. Finally, 2-Deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) are introduced to block glycolysis and pentose phosphate pathway (PPP), thus creating a versatile nanozyme-based NADH circulating oxidation nanoreactor (Co-HCS/D/A) for tumor therapy through triple cellular metabolism disruption. In vitro and in vivo results demonstrate that the designed nanoreactor not only enhances the catalytic efficiency but also disrupts the tumor metabolic homeostasis, leading to efficient therapy outcome. This study develops a novel NADH circulating oxidation nanoreactor for tumor therapy through triple cellular metabolism disruption, which addresses the limitations of current nanozyme-based metabolism regulation for tumor therapy.

Microbiomes detected by cerebrospinal fluid metagenomic next-generation sequencing among patients with and without HIV with suspected central nervous system infection.

BACKGROUND: Opportunistic infections in the central nervous system (CNS) can be a serious threat to people living with HIV. Early aetiological diagnosis and targeted treatment are crucial but difficult. Metagenomic next-generation sequencing (mNGS) has significant advantages over traditional detection methods. However, differences in the cerebrospinal fluid (CSF) microbiome profiles of patients living with and without HIV with suspected CNS infections using mNGS and conventional testing methods have not yet been adequately evaluated. METHODS: We conducted a retrospective cohort study in the first hospital of Changsha between January 2019 and June 2022 to investigate the microbiomes detected using mNGS of the CSF of patients living with and without HIV with suspected CNS infections. The pathogens causing CNS infections were concurrently identified using both mNGS and traditional detection methods. The spectrum of pathogens identified was compared between the two groups. RESULTS: Overall, 173 patients (140 with and 33 without HIV) with suspected CNS infection were enrolled in our study. In total, 106 (75.7%) patients with and 16 (48.5%) patients without HIV tested positive with mNGS (p = 0.002). Among the enrolled patients, 71 (50.7%) with HIV and five (15.2%) without HIV tested positive for two or more pathogens (p < 0.001). Patients with HIV had significantly higher proportions of fungus (20.7% vs. 3.0%, p = 0.016) and DNA virus (59.3% vs. 21.2%, p < 0.001) than those without HIV. Epstein-Barr virus (33.6%) was the most commonly identified potential pathogen in the CSF of patients living with HIV using mNGS, followed by cytomegalovirus (20.7%) and torque teno virus (13.8%). The top three causative pathogens identified in patients without HIV were Streptococcus (18.2%), Epstein-Barr virus (12.1%), and Mycobacterium tuberculosis (9.1%). In total, 113 patients living with HIV were diagnosed as having CNS infections. The rate of pathogen detection in people living with HIV with a CNS infection was significantly higher with mNGS than with conventional methods (93.8% vs. 15.0%, p < 0.001). CONCLUSION: CSF microbiome profiles differ between patients living with and without HIV with suspected CNS infection. mNGS is a powerful tool for the diagnosis of CNS infection among people living with HIV, especially in those with mixed infections.

Double Direct C-H Bond Arylation of Thiophenes with Aryl Chlorides Catalyzed by the N-Heterocyclic Carbene-PdCl2-1-methylimidazole Complex.

With the combination of the N-heterocyclic carbene-PdCl2-1-methylimidazole complex and Cu2O, we succeeded in the first example of double direct C-H bond arylation reactions between thiophenes and aryl chlorides, giving the desired 2,5-diarylated thiophenes in moderate to high yields under suitable conditions, consistent with the density functional theory calculations.

Blood microbiota in HIV-infected and HIV-uninfected patients with suspected sepsis detected by metagenomic next-generation sequencing.

BACKGROUND: Information on the comparison of blood microbiota between human immunodeficiency virus (HIV)-infected and HIV-uninfected patients with suspected sepsis by metagenomic next-generation sequencing (mNGS) is limited. METHODS: Retrospectively analysis was conducted in HIV-infected and HIV-uninfected patients with suspected sepsis at Changsha First Hospital (China) from March 2019 to August 2022. Patients who underwent blood mNGS testing were enrolled. The blood microbiota detected by mNGS were analyzed. RESULTS: A total of 233 patients with suspected sepsis who performed blood mNGS were recruited in this study, including 79 HIV-infected and 154 HIV-uninfected patients. Compared with HIV-uninfected patients, the proportions of mycobacterium (p = 0.001), fungus (p < 0.001) and viruses (p < 0.001) were significantly higher, while the proportion of bacteria (p = 0.001) was significantly lower in HIV-infected patients. The higher positive rates of non-tuberculous mycobacteriosis (NTM, p = 0.022), Pneumocystis jirovecii (P. jirovecii) (p = 0.014), Talaromyces marneffei (T. marneffei) (p < 0.001) and cytomegalovirus (CMV) (p < 0.001) were observed in HIV-infected patients, compared with HIV-uninfected patients. In addition, compared with HIV-uninfected patients, the constituent ratio of T. marneffei (p < 0.001) in the fungus spectrum were significantly higher, while the constituent ratios of Candida (p < 0.001) and Aspergillus (p = 0.001) were significantly lower in HIV-infected patients. CONCLUSIONS: Significant differences in the blood microbiota profiles exist between HIV-infected and HIV-uninfected patients with suspected sepsis.

Effects of Kv1.3 knockout on pyramidal neuron excitability and synaptic plasticity in piriform cortex of mice.

Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca2+ influx evoked by high K+ solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.

Safety of different amphotericin B formulations among AIDS patients with invasive fungal disease: a retrospective observational study.

We conducted a retrospective, observational study among acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis or talaromycosis to assess AmB formulations-related adverse events (AEs). Total 205 eligible patients were enrolled. Of them, 139 received AmB therapy, 51 received liposomal AmB (L-AmB) therapy, and 15 received AmB cholesteryl sulfate complex (ABCD) therapy. The incidences of total AEs between the AmB, L-AmB and ABCD group had no significant differences. The ABCD group had significantly higher incidences of hepatotoxicity and hematological toxicity than the AmB and L-AmB groups. The incidence of grade 3-4 hematological toxicity in the ABCD group was significantly higher than that in the AmB and L-AmB groups. Multinomial logistic regression models showed that compared with AmB, ABCD had a higher risk for the occurrence of grade 3-4 hematological toxicity (aOR = 43.924, 95%CI 6.296-306.418; p < 0.001). We demonstrated that ABCD was more prone to hepatotoxicity and hematological toxicity than AmB and L-AmB among AIDS patients, which is worth noting.

People living with HIV with the Omicron variant infection have milder COVID-19 symptoms: results from a cross-sectional study.

BACKGROUND: China braces for coronavirus disease 2019 (COVID-19) surge after adjusting the "zero COVID" strategy. We aimed to evaluate and compare the prevalence of clinical symptoms of the Omicron variant infection among people living with HIV (PLWH) and HIV-free people. METHODS: A cross-sectional study was conducted in Wuchang District, Wuhan, Hubei Province, in December 2022 by a self-administered online survey during the Omicron wave. Participants aged ≥ 18 years with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis were recruited. PLWH managed by the local healthcare system were recruited, while HIV-free people were recruited by sending out online surveys through WeChat. We compared the prevalence of clinical symptoms of COVID-19 between PLWH and HIV-free people, and factors associated with symptom occurrence among PLWH were accessed. RESULTS: Total, 687 PLWH and 1222 HIV-free people were enrolled. After adjusting sex, age, body mass index, comorbidities and COVID-19 vaccination status, the prevalences of all symptoms, including higher degree and long duration of fever (aOR 0.51, 95%CI 0·42 - 0·61; aOR 0.52, 95%CI 0·43 - 0·63), were significantly lower among PLWH than among HIV-free people. Among PLWH, CD4+ T lymphocyte count (CD4 count) between 350 ~ 499 cells/µL and detectable HIV viral load (HIV-VL) were associated with significantly decreased risks of fever (aOR 0·63, 95%CI 0·40 - 0·97; aOR 0·56, 95%CI 0·33 - 0·94), headache (aOR 0·61, 95%CI 0·41 - 0·91; aOR 0·55, 95%CI 0·34 - 0·92) and muscle soreness (aOR 0·57, 95%CI 0·39 - 0·84; aOR 0·57, 95%CI 0·39 - 0·84). No apparent association between the symptoms prevalence and three/four doses of inactivated COVID-19 vaccination among PLWH was observed; both males and older age were associated with significantly decreased risks of nasal congestion/runny nose (aOR 0·52, 95%CI 0·32 - 0·82; aOR 0·97, 95%CI 0·96 - 0·99) and headache (aOR 0·58, 95%CI 0·36 - 0·92; aOR 0·96, 95%CI 0·95 - 0·98); older age was associated with significantly decreased risks of higher degree of fever (aOR 0·97, 95%CI 0·95 - 0·98). CONCLUSIONS: PLWH have significantly milder symptoms of the Omicron variant infection than HIV-free people. PLWH who are male, older, have low CD4 count, and detectable HIV-VL have reduced occurrence of COVID-19 symptoms. However, continuous monitoring should be conducted among PLWH during the COVID-19 pandemic.

Cryptotanshinone Inhibits Bladder Cancer Cell Malignant Progression in a Lipopolysaccharide-Induced Inflammatory Microenvironment through NLRP3 Inhibition.

Background: Bladder cancer (BC) is one of the most common malignancies of the urogenital system. This study assessed the nucleotide-binding oligomerization domain and leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) in BC as well as the effects of cryptotanshinone on changes in BC malignant behaviors and NLRP3 expression under a lipopolysaccharide (LPS)-induced inflammatory microenvironment. Methods: BC tissue specimens from 62 patients were collected for immunohistochemical detection of NLRP3 protein. BC and normal urothelial cell lines were cultured for the detection of NLRP3 mRNA and protein. Then, BC cells were pretreated with LPS to mimic the inflammatory tumor microenvironment. Next, these cells were incubated with a low or high dose of cryptotanshinone to assess its effects on tumor cell malignant behaviors as well as transfected with NLRP3 cDNA to confirm the role of NLRP3 in BC cells in vitro. Results: High NLRP3 expression was associated with larger tumor diameters (>2 cm), muscle invasion, and metastasis. The levels of NLRP3 mRNA and protein were greater in BC cells than in normal urothelial cells. LPS pretreatment significantly promoted NLRP3 and inflammatory cytokine expression in BC cells, and induced cell viability, migration, and invasion. However, cryptotanshinone was able to reduce the LPS-induced increase of NLRP3 and inflammatory cytokine expression as well as the BC cell malignant progression. NLRP3 overexpression using NLRP3 cDNA further promoted BC cell malignant progression after LPS stimulation and reversed cryptotanshinone-reduced LPS-induced BC cell malignant behaviors. Conclusion: NLRP3 might possess oncogenic activity in BC, and the antitumor activity of cryptotanshinone in BC in vitro might be related to its inhibition of NLRP3 expression.

Biodegradable Metal Complex-Gated Organosilica for Dually Enhanced Chemodynamic Therapy through GSH Depletions and NIR Light-Triggered Photothermal Effects.

Hollow silica spheres have been widely studied for drug delivery because of their excellent biosecurity and high porosity. However, difficulties with degradation in the tumor microenvironment (TME) and premature leaking during drug delivery limit their clinical applications. To alleviate these problems, herein, hollow organosilica spheres (HOS) were initially prepared using a "selective etching strategy" and loaded with a photothermal drug: new indocyanine green (IR820). Then, the Cu2+-tannic acid complex (Cu-TA) was deposited on the surface of the HOS, and a new nanoplatform named HOS@IR820@Cu-TA (HICT) was finally obtained. The deposition of Cu-TA can gate the pores of HOS completely to prevent the leakage of IR820 and significantly enhance the loading capacity of HOS. Once in the mildly acidic TME, the HOS and outer Cu-TA decompose quickly in response, resulting in the release of Cu2+ and IR820. The released Cu2+ can react with the endogenous glutathione (GSH) to consume it and produce Cu+, leading to the enhanced production of highly toxic ·OH through a Fenton-like reaction due to the overexpressed H2O2 in the TME. Meanwhile, the ·OH generation was remarkably enhanced by the NIR light-responsive photothermal effect of IR820. These collective properties of HICT enable it to be a smart nanomedicine for dually enhanced chemodynamic therapy through GSH depletions and NIR light-triggered photothermal effects.