DTNPD: A comprehensive database of drugs and targets for neurological and psychiatric disorders.

In response to the shortcomings in data quality and coverage for neurological and psychiatric disorders (NPDs) in existing comprehensive databases, this paper introduces the DTNPD database, specifically designed for NPDs. DTNPD contains detailed information on 30 NPDs types, 1847 drugs, 514 drug targets, 64 drug combinations, and 61 potential target combinations, forming a network with 2389 drug-target associations. The database is user-friendly, offering open access and downloadable data, which is crucial for network pharmacology studies. The key strength of DTNPD lies in its robust networks of drug and target combinations, as well as drug-target networks, facilitating research and development in the field of NPDs. The development of the DTNPD database marks a significant milestone in understanding and treating NPDs. For accessing the DTNPD database, the primary URL is http://dtnpd.cnsdrug.com, complemented by a mirror site available at http://dtnpd.lyhbio.com.

New anti-inflammatory limonoids from the fruits of Melia azedarach.

The phytochemical study of the fruits of Melia azedarach (Meliaceae) led to the isolation and characterisation of two novel natural limonoids1-deoxy- 3, 20-dicinnamoyl-11-methoxy-meliacarpinin (1) and 12ß- O- methyl nimbolinin A (2), along with twelve known limonoids. Its structure was identified by 1D- and 2D-NMR, HR-ESI-MS and comparison with published data. The anti-inflammatory effect of the compounds was measured in vitro in RAW 264.7 cells by evaluating the production of NO stimulated by LPS. Compounds 1, 8 and 14 indicated significant anti-inflammatory effect with inhibition rate of 11.76, 8.45 and 6.59 µM, respectively. Limonoid 1 significantly inhibited the production of NO, TNF-α and IL-1ß in RAW 264.7 cells. Therefore, limonoid derivative may be a promising source of bioactive metabolite for inflammatory diseases.

Irradiated tumour cell-derived microparticles upregulate MHC-I expression in cancer cells via DNA double-strand break repair pathway.

Radiotherapy (RT) is used for over 50 % of cancer patients and can promote adaptive immunity against tumour antigens. However, the underlying mechanisms remain unclear. Here, we discovered that RT induces the release of irradiated tumour cell-derived microparticles (RT-MPs), which significantly upregulate MHC-I expression on the membranes of non-irradiated cells, enhancing the recognition and killing of these cells by T cells. Mechanistically, RT-MPs induce DNA double-strand breaks (DSB) in tumour cells, activating the ATM/ATR/CHK1-mediated DNA repair signalling pathway, and upregulating MHC-I expression. Inhibition of ATM/ATR/CHK1 reversed RT-MP-induced upregulation of MHC-I. Furthermore, phosphorylation of STAT1/3 following the activation of ATM/ATR/CHK1 is indispensable for the DSB-dependent upregulation of MHC-I. Therefore, our findings reveal the role of RT-MP-induced DSBs and the subsequent DNA repair signalling pathway in MHC-I expression and provide mechanistic insights into the regulation of MHC-I expression after DSBs.

Induction of therapeutic immunity and cancer eradication through biofunctionalized liposome-like nanovesicles derived from irradiated-cancer cells.

Immunotherapy has revolutionized the treatment of cancer. However, its efficacy remains to be optimized. There are at least two major challenges in effectively eradicating cancer cells by immunotherapy. Firstly, cancer cells evade immune cell killing by down-regulating cell surface immune sensors. Secondly, immune cell dysfunction impairs their ability to execute anti-cancer functions. Radiotherapy, one of the cornerstones of cancer treatment, has the potential to enhance the immunogenicity of cancer cells and trigger an anti-tumor immune response. Inspired by this, we fabricate biofunctionalized liposome-like nanovesicles (BLNs) by exposing irradiated-cancer cells to ethanol, of which ethanol serves as a surfactant, inducing cancer cells pyroptosis-like cell death and facilitating nanovesicles shedding from cancer cell membrane. These BLNs are meticulously designed to disrupt both of the aforementioned mechanisms. On one hand, BLNs up-regulate the expression of calreticulin, an "eat me" signal on the surface of cancer cells, thus promoting macrophage phagocytosis of cancer cells. Additionally, BLNs are able to reprogram M2-like macrophages into an anti-cancer M1-like phenotype. Using a mouse model of malignant pleural effusion (MPE), an advanced-stage and immunotherapy-resistant cancer model, we demonstrate that BLNs significantly increase T cell infiltration and exhibit an ablative effect against MPE. When combined with PD-1 inhibitor (α-PD-1), we achieve a remarkable 63.6% cure rate (7 out of 11) among mice with MPE, while also inducing immunological memory effects. This work therefore introduces a unique strategy for overcoming immunotherapy resistance.

Serum Interleukin-6 and Serum Ferritin Levels Are the Independent Risk Factors for Pneumonia in Elderly Patients.

Pneumonia is a common infection in elderly patients. We explored the correlations of serum interleukin-6 (IL-6) and serum ferritin (SF) levels with immune function/disease severity in elderly pneumonia patients. Subjects were allocated into the mild pneumonia (MP), severe pneumonia (SP), and normal groups, with their age/sex/body mass index/ disease course and severity/blood pressure/comorbidities/medications/prealbumin (PA)/albumin (ALB)/C-reactive protein (CRP)/procalcitonin (PCT)/smoking status documented. The disease severity was evaluated by pneumonia severity index (PSI). T helper 17 (Th17)/regulatory T (Treg) cell ratios and IL-6/SF/immunoglobulin G (IgG)/Th17 cytokine (IL-21)/Treg cytokine (IL-10)/PA/ALB levels were assessed. The correlations between these indexes/independent risk factors in elderly patients with severe pneumonia were evaluated. There were differences in smoking and CRP/PCT/ALB/PA levels among the three groups, but only CRP/ALB were different between the MP/SP groups. Pneumonia patients exhibited up-regulated Th17 cell ratio and serum IL-6/SF/IL-21/IL-10/IgG levels, down-regulated Treg cell ratio, and greater differences were noted in severe cases. Serum IL-6/SF levels were positively correlated with disease severity, immune function, and IL-21/IL-10/IgG levels. Collectively, serum IL-6 and SF levels in elderly pneumonia patients were conspicuously positively correlated with disease severity and IL-21/IL-10/IgG levels. CRP, ALB, IL-6 and SF levels were independent risk factors for severe pneumonia in elderly patients.

Hydrogen-bonded cytosine-endowed supramolecular polymeric nanogels: Highly efficient cancer cell targeting and enhanced therapeutic efficacy.

We demonstrate that cytosine moieties within physically cross-linked supramolecular polymers not only manipulate drug delivery and release, but also confer specific targeting of cancer cells to effectively enhance the safety and efficacy of chemotherapy-and thus hold significant potential as a new perspective for development of drug delivery systems. Herein, we successfully developed physically cross-linked supramolecular polymers (PECH-PEG-Cy) comprised of hydrogen-bonding cytosine pendant groups, hydrophilic poly(ethylene glycol) side chains, and a hydrophobic poly(epichlorohydrin) main chain. The polymers spontaneously self-assemble into a reversibly hydrogen-bonded network structure induced by cytosine and directly form spherical nanogels in aqueous solution. Nanogels with a high hydrogen-bond network density (i.e., a higher content of cytosine moieties) exhibit outstanding long-term structural stability in cell culture substrates containing serum, whereas nanogels with a relatively low hydrogen-bond network density cannot preserve their structural integrity. The nanogels also exhibit numerous unique physicochemical characteristics in aqueous solution, such as a desirable spherical size, high biocompatibility with normal and cancer cells, excellent drug encapsulation capacity, and controlled pH-responsive drug release properties. More importantly, in vitro experiments conclusively indicate the drug-loaded PECH-PEG-Cy nanogels can selectively induce cancer cell-specific apoptosis and cell death via cytosine receptor-mediated endocytosis, without significantly harming normal cells. In contrast, control drug-loaded PECH-PEG nanogels, which lack cytosine moieties in their structure, can only induce cell death in cancer cells through non-specific pathways, which significantly inhibits the induction of apoptosis. This work clearly demonstrates that the cytosine moieties in PECH-PEG-Cy nanogels confer selective affinity for the surface of cancer cells, which enhances their targeted cellular uptake, cytotoxicity, and subsequent induction of programmed cell death in cancer cells.

Gut microbial CAZymes markers for depression.

Major depressive disorder (MDD) is a serious mental illness, characterized by disturbances of gut microbiome, it is required to further explore how the carbohydrate-active enzymes (CAZymes) were changed in MDD. Here, using the metagenomic data from patients with MDD (n = 118) and heath controls (HC, n = 118), we found that the whole CAZymes signatures of MDD were significantly discriminated from that in HC. α-diversity indexes of the two groups were also significantly different. The patients with MDD were characterized by enriched Glycoside Hydrolases (GHs) and Polysaccharide Lyases (PLs) relative to HC. A panel of makers composed of 9 CAZymes mainly belonging to GHs enabled to discriminate the patients with MDD and HC with AUC of 0.824. In addition, this marker panel could classify blinded test samples from the two groups with an AUC of 0.736. Moreover, we found that baseline 4 CAZymes levels also could predict the antidepressant efficacy after adjusted confounding factors and times of depressive episode. Our findings showed that MDD was associated with disturbances of gut CAZymes, which may help to develop diagnostic and predictive tools for depression.

Mapping crossover events of mouse meiotic recombination by restriction fragment ligation-based Refresh-seq.

Single-cell whole-genome sequencing methods have undergone great improvements over the past decade. However, allele dropout, which means the inability to detect both alleles simultaneously in an individual diploid cell, largely restricts the application of these methods particularly for medical applications. Here, we develop a new single-cell whole-genome sequencing method based on third-generation sequencing (TGS) platform named Refresh-seq (restriction fragment ligation-based genome amplification and TGS). It is based on restriction endonuclease cutting and ligation strategy in which two alleles in an individual cell can be cut into equal fragments and tend to be amplified simultaneously. As a new single-cell long-read genome sequencing method, Refresh-seq features much lower allele dropout rate compared with SMOOTH-seq. Furthermore, we apply Refresh-seq to 688 sperm cells and 272 female haploid cells (secondary polar bodies and parthenogenetic oocytes) from F1 hybrid mice. We acquire high-resolution genetic map of mouse meiosis recombination at low sequencing depth and reveal the sexual dimorphism in meiotic crossovers. We also phase the structure variations (deletions and insertions) in sperm cells and female haploid cells with high precision. Refresh-seq shows great performance in screening aneuploid sperm cells and oocytes due to the low allele dropout rate and has great potential for medical applications such as preimplantation genetic diagnosis.

Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers.

Colorectal cancer (CRC) is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of CRCs, we generated a high-quality single-cell chromatin accessibility atlas of epithelial cells for 29 patients. Abnormal chromatin states acquired in adenomas were largely retained in CRCs, which were tightly accompanied by opposite changes of DNA methylation. Unsupervised analysis on malignant cells revealed two epigenetic subtypes, exactly matching iCMS classification, and key iCMS-specific transcription factors were identified, including HNF4A, PPARA for iCMS2 tumors, and FOXA3, MAFK for iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets and contribute to both inter-patient similarities and diversities for both chromatin accessibilities and RNA expressions. Moreover, we identified CpG-island methylator phenotypes and pinpointed chromatin state signatures and TF regulators for CIMP-High subtype. Our work systematically revealed the epigenetic basis of the well-known iCMS and CIMP classifications of CRCs.

CT-based radiomics for differentiating peripherally located pulmonary sclerosing pneumocytoma from carcinoid.

BACKGROUND: Pulmonary sclerosing pneumocytoma (PSP) and pulmonary carcinoid (PC) are difficult to distinguish based on conventional imaging examinations. In recent years, radiomics has been used to discriminate benign from malignant pulmonary lesions. However, the value of radiomics based on computed tomography (CT) images to differentiate PSP from PC has not been well explored. PURPOSE: We aimed to investigate the feasibility of radiomics in the differentiation between PSP and PC. METHODS: Fifty-three PSP and fifty-five PC were retrospectively enrolled and then were randomly divided into the training and test sets. Univariate and multivariable logistic analyses were carried to select clinical predictor related to differential diagnosis of PSP and PC. A total of 1316 radiomics features were extracted from the unenhanced CT (UECT) and contrast-enhanced CT (CECT) images, respectively. The minimum redundancy maximum relevance and the least absolute shrinkage and selection operator were used to select the most significant radiomics features to construct radiomics models. The clinical predictor and radiomics features were integrated to develop combined models. Two senior radiologists independently categorized each patient into PSP or PC group based on traditional CT method. The performances of clinical, radiomics, and combined models in differentiating PSP from PC were investigated by the receiver operating characteristic (ROC) curve. The diagnostic performance was also compared between the combined models and radiologists. RESULTS: In regard to differentiating PSP from PC, the area under the curves (AUCs) of the clinical, radiomics, and combined models were 0.87, 0.96, and 0.99 in the training set UECT, and were 0.87, 0.97, and 0.98 in the training set CECT, respectively. The AUCs of the clinical, radiomics, and combined models were 0.84, 0.92, and 0.97 in the test set UECT, and were 0.84, 0.93, and 0.98 in the test set CECT, respectively. In regard to the differentiation between PSP and PC, the combined model was comparable to the radiomics model, but outperformed the clinical model and the two radiologists, whether in the test set UECT or CECT. CONCLUSIONS: Radiomics approaches show promise in distinguishing between PSP and PC. Moreover, the integration of clinical predictor (gender) has the potential to enhance the diagnostic performance even further.

A promising Artemisia capillaris Thunb. Leaf proteins with high nutrition, applicable function and excellent antioxidant activity.

The nutritional and functional properties of leaf proteins is a decisive factor for their use in food. This work was aimed to extract defatted Artemisia capillaris Thunb. (ACD) leaf proteins (ACLP), and assess ACLP nutritional quality, functional properties and in vitro antioxidant activity, as well characterize the structure. ACLP had a balanced amino acid profile and high bioavailability (protein digestibility corrected amino acid score (PDCAAS) 99.29 %). Solubility, foaming capacity and emulsifying ability of ACLP correlated positively with pH. Water and oil holding capacity were increased with temperature. Gel electrophoresis shown the protein molecular size was mainly ∼25 kDa, and random coil was the mainly secondary structure while ß-sheet was dominant regular conformation as indicated by circular dichroism (CD). ACLP performed in vitro antioxidant activity which was better after digestion. All data implied ACLP met the WHO/FAO protein quality expectations and had application potential in food.

Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment.

Background: The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods: The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro. RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8+ T cell-mediated antitumor immunity. Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.

Drivers of desert plant beta diversity on the Qinghai-Tibet plateau.

The desert ecosystem of the Qinghai-Tibet Plateau (QTP) is an important component of China's desert ecosystem. Studying the mechanisms shaping the taxonomic, phylogenetic, and functional beta diversity of plant communities in the QTP desert will help us to promote scientific conservation and management of the region's biodiversity. This study investigated the effects of environmental (including altitude, climate factors, and soil factors) and geographic distances on three facets of beta diversity as well as their turnover and nestedness components based on field survey data. The results showed that turnover components dominate the three facets of beta diversity. However, the turnover contributions to phylogenetic and functional beta diversity were lower than for taxonomic beta diversity. Environmental distance had a greater influence than geographic distance, with the former uniquely explaining 15.2%-22.8% of beta diversity and the latter explaining only 1.7%-2.4%. Additionally, the explanatory power of different factors for beta diversity differed between herbs and shrubs, with environmental distance being more important for the latter. Distance-based redundancy analysis suggested that soil total potassium content had a substantial impact on the beta diversity of three dimensions, with mean temperature of the coldest month and soil total phosphorus content having a substantial impact on taxonomic and functional beta diversity as well. Our results support that environmental sorting plays a predominant role in shaping plant community composition across QTP desert ecosystems. To maintain the plant diversity of this region, it is crucial to prioritize the conservation of its diverse environmental conditions and actively mitigate its degradation by anthropogenic pressures.

Inactivation of the TGF-ß1/ALK5 axis enhances club cell function and alleviates lung tissue damage to ameliorate COPD progression through the MEK/ERK signaling pathway.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and fatal disease worldwide. The function of club cells, which are considered progenitor/stem cells of the bronchial epithelium, and their secreted protein CC16, have been proposed as potential targets for COPD treatment. This study aimed to investigate the role of the TGF-ß1/ALK5 signaling pathway in club cell function and COPD progression. C57BL/6J mice were divided into Normal group (exposed to fresh air) and COPD group (exposed to incremental cigarette smoke extract for 12 weeks). The COPD mice were further divided into COPD group, DMSO group, and LY2109761 group (injected with 150 mg/kg LY2109761, a TGF-ß1 inhibitor). Tissue staining was used to assess lung damage, and the expression of CC16 was measured. The levels of inflammatory factors and DNA damage-related indicators were also measured. The involvement of the MEK/ERK signaling pathway was determined. COPD mice exhibited severe lung damage and impaired club cell function. Activation of the TGF-ß1/ALK5 and MEK/ERK pathways were observed in COPD mice. However, administration of LY2109761 in COPD mice inactivated the TGF-ß1/ALK5 and MEK/ERK pathways. Administration of LY2109761 also alleviated pulmonary fibrosis, downregulated the levels cleaved caspase-3, IL-4, IL-5, IL-13, IL-12, and IFN-γ, and limited the phosphorylation of Chk1. Moreover, LY2109761 enhanced CC16 expression and decreased lung cell apoptosis. Inactivation of the TGF-ß1/ALK5 axis inhibits the MEK/ERK signaling pathway, enhances club cell function, and alleviates lung tissue damage. These findings suggest that TGF-ß1 is a potential therapeutic target for COPD.

Impact of antifibrotic therapy on disease progression, all-cause mortality, and risk of acute exacerbation in non-IPF fibrosing interstitial lung diseases: evidence from a meta-analysis of randomized controlled trials and prospective controlled studies.

BACKGROUND: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited. OBJECTIVE: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs. DESIGN: Meta-analysis. DATA SOURCES AND METHODS: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment. RESULTS: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42-0.75; p < 0.0001; I2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55-1.03; p = 0.08; I2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48-0.98; p = 0.04; I2 = 0; low-certainty evidence). CONCLUSION: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. TRIAL REGISTRATION: This study protocol was registered with PROSPERO (registration number: CRD42023411272).

Determination of fatty acid methyl esters by two-color two-photon resonance-enhanced femtosecond ionization mass spectrometry.

A standard sample mixture containing thirty-seven fatty acid methyl esters (FAMEs) was measured by femtosecond laser ionization mass spectrometry. FAME molecules with double bonds were efficiently ionized via resonance-enhanced two-photon ionization by absorbing the first photon at 206 nm at the edge of the absorption band of the π→π* transition and subsequently ionized by absorbing the second photon at 257 nm. The intensity of the molecular radical ion was enhanced significantly using this two-color ionization scheme, which minimizes the excess energy in the ionized state, when compared with electron ionization mass spectrometry and vacuum-ultraviolet photoionization mass spectrometry. This approach was then used for the reliable identification of FAMEs contained in an actual sample of biofuel.

Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-NLGN3 axis.

BACKGROUND: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. It is an aggressive tumor characterized by rapid proliferation, diffuse tumor morphology, and poor prognosis. Unfortunately, current treatments, such as surgery, radiotherapy, and chemotherapy, are unable to achieve good outcomes. Therefore, there is an urgent need to explore new treatment targets. A detailed mechanistic exploration of the role of the nuclear pore transporter KPNB1 in GBM is lacking. This study demonstrated that KPNB1 regulated GBM progression through a transcription factor YBX1 to promote the expression of post-protrusion membrane protein NLGN3. This regulation was mediated by the deubiquitinating enzyme USP7. METHODS: A tissue microarray was used to measure the expression of KPNB1 and USP7 in glioma tissues. The effects of KPNB1 knockdown on the tumorigenic properties of glioma cells were characterized by colony formation assays, Transwell migration assay, EdU proliferation assays, CCK-8 viability assays, and apoptosis analysis using flow cytometry. Transcriptome sequencing identified NLGN3 as a downstream molecule that is regulated by KPNB1. Mass spectrometry and immunoprecipitation were performed to analyze the potential interaction between KPNB1 and YBX1. Moreover, the nuclear translocation of YBX1 was determined with nuclear-cytoplasmic fractionation and immunofluorescence staining, and chromatin immunoprecipitation assays were conducted to study DNA binding with YBX1. Ubiquitination assays were performed to determine the effects of USP7 on KPNB1 stability. The intracranial orthotopic tumor model was used to detect the efficacy in vivo. RESULTS: In this study, we found that the nuclear receptor KPNB1 was highly expressed in GBM and could mediate the nuclear translocation of macromolecules to promote GBM progression. Knockdown of KPNB1 inhibited the progression of GBM, both in vitro and in vivo. In addition, we found that KPNB1 could regulate the downstream expression of Neuroligin-3 (NLGN3) by mediating the nuclear import of transcription factor YBX1, which could bind to the NLGN3 promoter. NLGN3 was necessary and sufficient to promote glioma cell growth. Furthermore, we found that deubiquitinase USP7 played a critical role in stabilizing KPNB1 through deubiquitination. Knockdown of USP7 expression or inhibition of its activity could effectively impair GBM progression. In vivo experiments also demonstrated the promoting effects of USP7, KPNB1, and NLGN3 on GBM progression. Overall, our results suggested that KPNB1 stability was enhanced by USP7-mediated deubiquitination, and the overexpression of KPNB1 could promote GBM progression via the nuclear translocation of YBX1 and the subsequent increase in NLGN3 expression. CONCLUSION: This study identified a novel and targetable USP7/KPNB1/YBX1/NLGN3 signaling axis in GBM cells.

FBW7/GSK3ß mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer.

BACKGROUND: The development of radioresistance seriously hinders the efficacy of radiotherapy in lung cancer. However, the underlying mechanisms by which radioresistance occurs are still incompletely understood. The N6-Methyladenosine (m6A) modification of RNA is involved in cancer progression, but its role in lung cancer radioresistance remains elusive. This study aimed to identify m6A regulators involved in lung cancer radiosensitivity and further explore the underlying mechanisms to identify therapeutic targets to overcome lung cancer radioresistance. METHODS: Bioinformatic mining was used to identify the m6A regulator IGF2BP2 involved in lung cancer radiosensitivity. Transcriptome sequencing was used to explore the downstream factors. Clonogenic survival assays, neutral comet assays, Rad51 foci formation assays, and Annexin V/propidium iodide assays were used to determine the significance of FBW7/IGF2BP2/SLC7A5 axis in lung cancer radioresistance. Chromatin immunoprecipitation (ChIP)-qPCR analyses, RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP)-qPCR analyses, RNA pull-down analyses, co-immunoprecipitation analyses, and ubiquitination assays were used to determine the feedback loop between IGF2BP2 and SLC7A5 and the regulatory effect of FBW7/GSK3ß on IGF2BP2. Mice models and tissue microarrays were used to verify the effects in vivo. RESULTS: We identified IGF2BP2, an m6A "reader", that is overexpressed in lung cancer and facilitates radioresistance. We showed that inhibition of IGF2BP2 impairs radioresistance in lung cancer both in vitro and in vivo. Furthermore, we found that IGF2BP2 enhances the stability and translation of SLC7A5 mRNA through m6A modification, resulting in enhanced SLC7A5-mediated transport of methionine to produce S-adenosylmethionine. This feeds back upon the IGF2BP2 promoter region by further increasing the trimethyl modification at lysine 4 of histone H3 (H3K4me3) level to upregulate IGF2BP2 expression. We demonstrated that this positive feedback loop between IGF2BP2 and SLC7A5 promotes lung cancer radioresistance through the AKT/mTOR pathway. Moreover, we found that the ubiquitin ligase FBW7 functions with GSK3ß kinase to recognize and degrade IGF2BP2. CONCLUSIONS: Collectively, our study revealed that the m6A "reader" IGF2BP2 promotes lung cancer radioresistance by forming a positive feedback loop with SLC7A5, suggesting that IGF2BP2 may be a potential therapeutic target to control radioresistance in lung cancer.

Deubiquitinase USP7 stabilizes KDM5B and promotes tumor progression and cisplatin resistance in nasopharyngeal carcinoma through the ZBTB16/TOP2A axis.

Cisplatin-based chemotherapy improves the control of distant metastases in patients with nasopharyngeal carcinoma (NPC); however, around 30% of patients fail treatment due to acquired drug resistance. Epigenetic regulation is known to contribute to cisplatin resistance; nevertheless, the underlying mechanisms remain poorly understood. Here, we showed that lysine-specific demethylase 5B (KDM5B) was overexpressed and correlates with tumor progression and cisplatin resistance in patients with NPC. We also showed that specific inhibition of KDM5B impaired the progression of NPC and reverses cisplatin resistance, both in vitro and in vivo. Moreover, we found that KDM5B inhibited the expression of ZBTB16 by directly reducing H3K4me3 at the ZBTB16 promoter, which subsequently increased the expression of Topoisomerase II- α (TOP2A) to confer cisplatin resistance in NPC. In addition, we showed that the deubiquitinase USP7 was critical for deubiquitinating and stabilizing KDM5B. More importantly, the deletion of USP7 increased sensitivity to cisplatin by disrupting the stability of KDM5B in NPC cells. Therefore, our findings demonstrated that USP7 stabilized KDM5B and promoted cisplatin resistance through the ZBTB16/TOP2A axis, suggesting that targeting KDM5B may be a promising cisplatin-sensitization strategy in the treatment of NPC.

Meta-analysis of the systemic immune-inflammatory index and in-hospital mortality of COVID-19 patients.

Background: The potential significance of immunoinflammatory factors in the prognosis of individuals afflicted with coronavirus disease 2019 (COVID-19) is worthy of examination. The systemic immune-inflammatory index (SII), a recently developed immunoinflammatory metric based on the enumeration of neutrophils, platelets, and lymphocytes in blood samples, holds promise for elucidating this relationship. Consequently, in order to explore any possible correlation between the SII levels at admission and the in-hospital mortality of patients with COVID-19, we undertook a thorough systematic review and meta-analysis. Methods: In pursuit of accomplishing the aim of this meta-analysis, an extensive search was conducted to seek out pertinent observational studies featuring longitudinal follow-up across PubMed, Cochrane Library, Embase and the Web of Science databases. The I2 statistic was utilized to estimate the extent of heterogeneity and the Cochrane Q test was employed to evaluate heterogeneity between studies. The synthesis of outcomes involved the use of random-effects models, accounting for the possible influence of heterogeneity. Results: Our analysis included sixteen studies, encompassing 10,007 hospitalized COVID-19 patients. Among them, 1801 patients (18.0 %) succumbed during hospitalization. The pooled results indicated that a high SII at admission was substantially linked to a higher risk of all-cause mortality (risk ratio [RR]: 2.41, 95 % confidence interval: 1.78 to 3.24, p < 0.001; I2 = 86 %). Meta-regression analysis demonstrated a negative correlation between mean SII at baseline and patient mortality in individual studies (coefficients = -0.00023 and -0.030, p < 0.05), effectively explaining the observed heterogeneity. Furthermore, in patients with lower baseline SII (<1300) and a lower risk of mortality (<20 %), we observed a more pronounced association between high SII levels and the risk of all-cause mortality. Conclusion: The results of our study indicate that a high SII upon admission could potentially function as a prognostic indicator for mortality during hospitalization in patients diagnosed with COVID-19, particularly in individuals categorized as low risk.