Antigout effects and mechanisms of total flavonoids from prunus tomentosa.

BACKGROUND: In recent years, hyperuricemia and acute gouty arthritis have become increasingly common, posing a serious threat to public health. Current treatments primarily involve Western medicines with associated toxic side effects. OBJECTIVE: This study aims to investigate the therapeutic effects of total flavones from Prunus tomentosa (PTTF) on a rat model of gout and explore the mechanism of PTTF's anti-gout action through the TLR4/NF-κB signaling pathway. METHODS: We measured serum uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6) levels using an enzyme-linked immunosorbent assay (ELISA). Histopathological changes were observed using HE staining, and the expression levels of relevant proteins were detected through Western blotting. RESULTS: After PTTF treatment, all indicators improved significantly. PTTF reduced blood levels of UA, Cr, BUN, IL-1ß, IL-6, and TNF-α, and decreased ankle swelling. CONCLUSIONS: PTTF may have a therapeutic effect on animal models of hyperuricemia and acute gouty arthritis by reducing serum UA levels, improving ankle swelling, and inhibiting inflammation. The primary mechanism involves the regulation of the TLR4/NF-κB signaling pathway to alleviate inflammation. Further research is needed to explore deeper mechanisms.

Environmental fate and safety analysis of methoxyfenozide application to control litchi and longan pests.

Litchi and longan pests significantly affect crop yield and quality. Chemical prevention and control are very effective for production; therefore, it is crucial to study fate assessment and appropriate field efficacy before pesticide application on crops to appropriately assess the health and ecological risks linked with these agents. This study conducted Good Agricultural Practice (GAP) field trials and laboratory experiments to elucidate the dissipation, terminal residues, and efficacy of methoxyfenozide on litchi and longan in six locations throughout China. To detect methoxyfenozide residues on litchi and longan, a QuEChERS/UPLC-MS/MS-based method was designed. The initial methoxyfenozide levels in litchi and longan ranged from 2.21-2.86 to 0.83-0.95 mg kg-1 and indicated half-lives of 5.1-5.3 and 5.3-5.7 days, respectively. After 7 days of foliage treatment, the concentrations of terminal methoxyfenozide residue were 0.78-2.61 and 0.02-1.01 mg kg-1, which were less than the established maximum residue limit for methoxyfenozide in litchi and longan. The chronic (acceptable daily intake = 0.0055-0.0331%) dietary intake risk analysis for methoxyfenozide in longan and litchi indicated acceptable concentrations of terminal residue for the general population. Methoxyfenozide in litchi and longan was readily degraded in first-order kinetics models, the degradation rate on longan was higher than that on litchi, and their dietary risks were negligible to consumers. Two hundred forty grams per liter of methoxyfenozide suspension concentrate (SC) represents a highly efficacious insecticidal dose to control litchi and longan pests and indicates a significant application potential as it is rapidly degraded and linked with reduced post-treatment residue levels.

Apigenin suppresses epithelial-mesenchymal transition in high glucose-induced retinal pigment epithelial cell by inhibiting CBP/p300-mediated histone acetylation.

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.

Laponite-activated AIE supramolecular assembly with modulating multicolor luminescence for logic digital encryption and perfluorinated pollutant detection.

Recently, the non-covalently activated supramolecular scaffold method has become a prominent research area in the field of intelligent materials. Here, the inorganic clay (LP) promoted the AIE properties of 4,4',4″,4‴-(ethene-1,1,2,2-tetrayltetrakis(benzene-4,1-diyl))tetrakis(1-ethylpyridin-1-ium) (P-TPE), showing an astonishing 42-fold enhancement of the emission intensity of the yellow-green luminescence and a 34-fold increase of the quantum yield via organic-inorganic supramolecular strategy as well as the efficient light-harvesting properties (energy transfer efficiency up to 33 %) after doping with the dye receptor Rhodamine B. Furthermore, the full-color spectral regulation, including white light, was achieved by adjusting the ratio of the donor to the acceptor component and co-assembling with the carbon dots (CD). Interestingly, this TPE-based non-covalently activated full-color supramolecular light-harvesting system (LHS) could be achieved not only in aqueous media but also in the hydrogel and the solid state. More importantly, this panchromatic tunable supramolecular LHS exhibited the multi-mode and quadruple digital logic encryption property as well as the specific detection ability towards the perfluorobutyric acid and the perfluorobutanesulfonic acid, which are harmful to human health in drinking water. This result develops a simple, convenient and effective approach for the intelligent anti-counterfeiting and the pollutant sensing.

Uncovering the burden of hidradenitis suppurativa misdiagnosis and underdiagnosis: a machine learning approach.

Hidradenitis suppurativa (HS) is a chronic inflammatory follicular skin condition that is associated with significant psychosocial and economic burden and a diminished quality of life and work productivity. Accurate diagnosis of HS is challenging due to its unknown etiology, which can lead to underdiagnosis or misdiagnosis that results in increased patient and healthcare system burden. We applied machine learning (ML) to a medical and pharmacy claims database using data from 2000 through 2018 to develop a novel model to better understand HS underdiagnosis on a healthcare system level. The primary results demonstrated that high-performing models for predicting HS diagnosis can be constructed using claims data, with an area under the curve (AUC) of 81%-82% observed among the top-performing models. The results of the models developed in this study could be input into the development of an impact of inaction model that determines the cost implications of HS diagnosis and treatment delay to the healthcare system.

One-Step Multi-View Clustering With Diverse Representation.

Multi-View clustering has attracted broad attention due to its capacity to utilize consistent and complementary information among views. Although tremendous progress has been made recently, most existing methods undergo high complexity, preventing them from being applied to large-scale tasks. Multi-View clustering via matrix factorization is a representative to address this issue. However, most of them map the data matrices into a fixed dimension, limiting the model's expressiveness. Moreover, a range of methods suffers from a two-step process, i.e., multimodal learning and the subsequent k -means, inevitably causing a suboptimal clustering result. In light of this, we propose a one-step multi-view clustering with diverse representation (OMVCDR) method, which incorporates multi-view learning and k -means into a unified framework. Specifically, we first project original data matrices into various latent spaces to attain comprehensive information and auto-weight them in a self-supervised manner. Then, we directly use the information matrices under diverse dimensions to obtain consensus discrete clustering labels. The unified work of representation learning and clustering boosts the quality of the final results. Furthermore, we develop an efficient optimization algorithm with proven convergence to solve the resultant problem. Comprehensive experiments on various datasets demonstrate the promising clustering performance of our proposed method. The code is publicly available at https://github.com/wanxinhang/OMVCDR.

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP.

BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice. METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or ß-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging. RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP). CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Cell-free DNA assay for malignancy classification of high-risk lung nodules.

OBJECTIVE: Although low-dose computed tomography has been proven effective to reduce lung cancer-specific mortality, a considerable proportion of surgically resected high-risk lung nodules were still confirmed pathologically benign. There is an unmet need of a novel method for malignancy classification in lung nodules. METHODS: We recruited 307 patients with high-risk lung nodules who underwent curative surgery, and 247 and 60 cases were pathologically confirmed malignant and benign lung lesions, respectively. Plasma samples from each patient were collected before surgery and performed low-depth (5×) whole-genome sequencing. We extracted cell-free DNA (cfDNA) characteristics and determined radiomic features. We built models to classify the malignancy using our data and further validated models with two independent lung nodule cohorts. RESULTS: Our models using one type of profile were able to distinguish lung cancer and benign lung nodules (BLNs) at an area under the curve (AUC) metrics of 0.69-0.91 in the study cohort. Integrating all the five base models using cfDNA profiles, the cfDNA-based ensemble model achieved an AUC of 0.95 (95%CI: 0.92-0.97) in the study cohort and 0.98 (95%CI: 0.96-1.00) in the validation cohort. At a specificity of 95.0%, the sensitivity reached 80.0% in the study cohort. With the same threshold, the specificity and sensitivity had similar performances in both validation cohorts. Furthermore, the performance of AUC reached 0.97 both in the study and validation cohorts when considering the radiomic profile. CONCLUSIONS: The cfDNA profiles-based method is an efficient non-invasive tool to distinguish malignancies and high-risk but pathologically BLNs.

Dissipation and Safety Analysis of Dimethomorph Application in Lychee by High-Performance Liquid Chromatography-Tandem Mass Spectrometry with QuEChERS.

This study presents a method for analyzing dimethomorph residues in lychee using QuEChERS extraction and HPLC-MS/MS. The validation parameters for this method, which include accuracy, precision, linearity, and recovery, indicate that it meets standard validation requirements. Following first-order kinetics, the dissipation dynamic of dimethomorph in lychee was determined to range from 6.4 to 9.2 days. Analysis of terminal residues revealed that residues in whole lychee were substantially greater than those in the pulp, indicating that dimethomorph residues are predominantly concentrated in the peel. When applied twice and thrice at two dosage levels with pre-harvest intervals (PHIs) of 5, 7, and 10 days, the terminal residues in whole lychee ranged from 0.092 to 1.99 mg/kg. The terminal residues of the pulp ranged from 0.01 to 0.18 mg/kg, with the residue ratio of whole lychee to pulp consistently exceeding one. The risk quotient (RQ) for dimethomorph, even at the recommended dosage, was less than one, indicating that the potential for damage was negligible. This study contributes to the establishment of maximum residue limits (MRLs) in China by providing essential information on the safe application of dimethomorph in lychee orchards.

PVDF/ZnO piezoelectric nanofibers designed for monitoring of internal micro-pressure.

Organic piezoelectric materials are emerging as integral components in the development of advanced implantable self-powered sensors for the next generation. Despite their promising applications, a key limitation lies in their reduced mechanical force-to-electricity conversion efficiency. In this study, we present a breakthrough in the fabrication of soft poly(vinylidene fluoride) (PVDF) organic electrospun piezoelectric nanofibers (OEPNs) with exceptional piezoelectric performance achieved through the incorporation of zinc oxide nanorods (ZnO NR). The inclusion of ZnO NR proved instrumental in augmenting the nanocrystallization of PVDF organic electrospun piezoelectric nanofibers (OEPNs), leading to a highly efficient crystal phase transformation from the α phase to the ß/γ phase, serving as superior piezoelectric working dipoles. The resulting PVDF/ZnO NR OEPNs exhibited unparalleled piezoelectric output voltage and current density, particularly noteworthy under a micro-pressure of 1 kPa and a low frequency of 1.5 Hz. Utilizing the obtained PVDF/ZnO NR OEPNs as the piezoelectric working element, we engineered a soft self-powered micro-pressure sensor. This sensor was implanted simultaneously on the cardiovascular walls of the heart and femoral artery in pigs. The sensor demonstrated precise monitoring and recording capabilities for micro-pressure changes during various physiological states, spanning from wakefulness to coma, euthanasia, and notably, the formation of cardiac thrombus. These findings underscore the immense potential of the implantable self-powered sensor for the assessment and diagnosis of pressure-related cardiovascular diseases, such as thrombus and atherosclerosis, during the postoperative recovery phase. This innovative technology offers valuable insights into the dynamic physiological states, paving the way for enhanced postoperative care and management of cardiovascular conditions.

Traditional herbal medicine: Therapeutic potential in acute gouty arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute gouty arthritis (AGA) is characterized by a rapid inflammatory reaction caused by the build-up of monosodium urate (MSU) crystals in the tissues surrounding the joints. This condition often associated with hyperuricemia (HUA), is distinguished by its symptoms of intense pain, active inflammation, and swelling of the joints. Traditional approaches in AGA management often fall short of desired outcomes in clinical settings. However, recent ethnopharmacological investigations have been focusing on the potential of Traditional Herbal Medicine (THM) in various forms, exploring their therapeutic impact and targets in AGA treatment. AIM OF THE REVIEW: This review briefly summarizes the current potential pharmacological mechanisms of THMs - including active ingredients, extracts, and prescriptions -in the treatment of AGA, and discusses the relevant potential mechanisms and molecular targets in depth. The objective of this study is to offer extensive information and a reference point for the exploration of targeted AGA treatment using THMs. MATERIALS AND METHODS: This review obtained scientific publications focused on in vitro and in vivo studies of anti-AGA THMs conducted between 2013 and 2023. The literature was collected from various journals and electronic databases, including PubMed, Elsevier, ScienceDirect, Web of Science, and Google Scholar. The retrieval and analysis of relevant articles were guided by keywords such as "acute gouty arthritis and Chinese herbal medicine," "acute gouty arthritis herbal prescription," "acute gouty arthritis and immune cells," "acute gouty arthritis and inflammation," "acute gouty arthritis and NOD-like receptor thermoprotein domain associated protein 3 (NLRP3)," "acute gouty arthritis and miRNA," and "acute gouty arthritis and oxidative stress." RESULTS: We found that AGA has a large number of therapeutic targets, highlighting the effectiveness the potential of THMs in AGA treatment through in vitro and in vivo studies. THMs and their active ingredients can mitigate AGA symptoms through a variety of therapeutic targets, such as influencing macrophage polarization, neutrophils, T cells, natural killer (NK) cells, and addressing factors like inflammation, NLRP3 inflammasome, signaling pathways, oxidative stress, and miRNA multi-target interactions. The anti-AGA properties of THMs, including their active components and prescriptions, were systematically summarized and categorized based on their respective therapeutic targets. CONCLUSION: phenolic, flavonoid, terpenoid and alkaloid compounds in THMs are considered the key ingredients to improve AGA. THMs and their active ingredients achieve enhanced efficacy through interactions with multiple targets, of which NLRP3 is a main therapeutic target. Nonetheless, given the intricate composition of traditional Chinese medicine (TCM), additional research is required to unravel the underlying mechanisms and molecular targets through which THMs alleviate AGA.

Mechanism of Bazi Bushen capsule in delaying the senescence of mesenchymal stem cells based on network pharmacology and experimental validation.

Ageing is becoming an increasingly serious problem; therefore, there is an urgent need to find safe and effective anti-ageing drugs. Aims: To investigate the effects of Bazi Bushen capsule (BZBS) on the senescence of mesenchymal stem cells (MSCs) and explore its mechanism of action. Methods: Network pharmacology was used to predict the targets of BZBS in delaying senescence in MSCs. For in vitro studies, MSCs were treated with D-gal, BZBS, and NMN, and cell viability, cell senescence, stemness-related genes, and cell cycle were studied using cell counting kit-8 (CCK-8) assay, SA-ß-galactosidase (SA-ß-gal) staining, Quantitative Real-Time PCR (qPCR) and flow cytometry (FCM), respectively. Alkaline phosphatase (ALP), alizarin red, and oil red staining were used to determine the osteogenic and lipid differentiation abilities of MSCs. Finally, the expression of senescence-related genes and cyclin-related factors was detected by qPCR and western blotting. Results: Network pharmacological analysis suggested that BZBS delayed cell senescence by interfering in the cell cycle. Our in vitro studies suggested that BZBS could significantly increase cell viability (P < 0.01), decrease the quantity of ß-galactosidase+ cells (P < 0.01), downregulate p16 and p21 (P < 0.05, P < 0.01), improve adipogenic and osteogenic differentiation, and upregulate Nanog, OCT4 and SOX2 genes (P < 0.05, P < 0.01) in senescent MSCs. Moreover, BZBS significantly reduced the proportion of senescent MSCs in the G0/G1 phase (P < 0.01) and enhanced the expression of CDK4, Cyclin D1, and E2F1 (P < 0.05, P < 0.01, respectively). Upon treatment with HY-50767A, a CDK4 inhibitor, the upregulation of E2F1 was no longer observed in the BZBS group. Conclusions: BZBS can protect MSCs against D-gal-induced senescence, which may be associated with cell cycle regulation via the Cyclin D1/CDK4/E2F1 signalling pathway.

High-performance ferroelectric field-effect transistors with ultra-thin indium tin oxide channels for flexible and transparent electronics.

With the development of wearable devices and hafnium-based ferroelectrics (FE), there is an increasing demand for high-performance flexible ferroelectric memories. However, developing ferroelectric memories that simultaneously exhibit good flexibility and significant performance has proven challenging. Here, we developed a high-performance flexible field-effect transistor (FeFET) device with a thermal budget of less than 400 °C by integrating Zr-doped HfO2 (HZO) and ultra-thin indium tin oxide (ITO). The proposed FeFET has a large memory window (MW) of 2.78 V, a high current on/off ratio (ION/IOFF) of over 108, and high endurance up to 2×107 cycles. In addition, the FeFETs under different bending conditions exhibit excellent neuromorphic properties. The device exhibits excellent bending reliability over 5×105 pulse cycles at a bending radius of 5 mm. The efficient integration of hafnium-based ferroelectric materials with promising ultrathin channel materials (ITO) offers unique opportunities to enable high-performance back-end-of-line (BEOL) compatible wearable FeFETs for edge intelligence applications.

Restoring Treg/Th17 cell balance in ulcerative colitis through HRas silencing and MAPK pathway inhibition.

This study investigates HRas-dependent mechanisms in the disruption of regulatory T (Treg) cells and T helper 17 (Th17) cells balance in ulcerative colitis (UC). Comprehensive RNA sequencing and bioinformatics analyses revealed elevated HRas and MAPK pathway-related protein expression in UC samples. Using a murine UC model induced by dextran sulfate sodium (DSS), HRas silencing was found to promote Treg cell differentiation and suppress Th17 cell production, effectively restoring balance. Inactivation of the MAPK pathway played a pivotal role in this rebalancing effect. In vivo experiments further confirmed that HRas silencing mitigated colon tissue damage in DSS-induced mice, emphasizing its potential as a therapeutic strategy for UC.

Paeoniflorin promotes PPARγ expression to suppress HSCs activation by inhibiting EZH2-mediated histone H3K27 trimethylation.

BACKGROUND: The alleviating effect of paeoniflorin (Pae) on liver fibrosis has been established; however, the molecular mechanism and specific target(s) underlying this effect remain elusive. PURPOSE: This study was to investigate the molecular mechanism underlying the regulatory effect of Pae on hepatic stellate cells (HSCs) activation in liver fibrosis, with a specific focus on the role of Pae in modulating histone methylation modifications. METHODS: The therapeutic effect of Pae was evaluated by establishing in vivo and in vitro models of carbon tetrachloride (CCl4)-induced mice and transforming growth factor ß1 (TGF-ß1)-induced LX-2 cells, respectively. Molecular docking, surface plasmon resonance (SPR), chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and other molecular biological methods were used to clarify the molecular mechanism of Pae regulating HSCs activation. RESULTS: Our study found that Pae inhibited HSCs activation and histone trimethylation modification in liver of CCl4-induced mice and LX-2 cells. We demonstrated that the inhibitory effect of Pae on the activation of HSCs was dependent on peroxisome proliferator-activated receptor γ (PPARγ) expression and enhancer of zeste homolog 2 (EZH2). Mechanistically, Pae directly binded to EZH2 to effectively suppress its enzymatic activity. This attenuation leaded to the suppression of histone H3K27 trimethylation in the PPARγ promoter region, which induced upregulation of PPARγ expression. CONCLUSION: This investigative not only sheds new light on the precise targets that underlie the remission of hepatic fibrogenesis induced by Pae but also emphasizes the critical significance of EZH2-mediated H3K27 trimethylation in driving the pathogenesis of liver fibrosis.

A novel imprinted locus on bovine chromosome 18 homologous with human chromosome 16q24.1.

Genomic imprinting is an epigenetic regulation mechanism in mammals resulting in the parentally dependent monoallelic expression of genes. Imprinting disorders in humans are associated with several congenital syndromes and cancers and remain the focus of many medical studies. Cattle is a better model organism for investigating human embryo development than mice. Imprinted genes usually cluster on chromosomes and are regulated by different methylation regions (DMRs) located in imprinting control regions that control gene expression in cis. There is an imprinted locus on human chromosome 16q24.1 associated with congenital lethal developmental lung disease in newborns. However, genomic imprinting on bovine chromosome 18, which is homologous with human chromosome 16 has not been systematically studied. The aim of this study was to analyze the allelic expressions of eight genes (CDH13, ATP2C2, TLDC1, COTL1, CRISPLD2, ZDHHC7, KIAA0513, and GSE1) on bovine chromosome 18 and to search the DMRs associated gene allelic expression. Three transcript variants of the ZDHHC7 gene (X1, X2, and X5) showed maternal imprinting in bovine placentas. In addition, the monoallelic expression of X2 and X5 was tissue-specific. Five transcripts of the KIAA0513 gene showed tissue- and isoform-specific monoallelic expression. The CDH13, ATP2C2, and TLDC1 genes exhibited tissue-specific imprinting, however, COTL1, CRISLPLD2, and GSE1 escaped imprinting. Four DMRs, established after fertilization, were found in this region. Two DMRs were located between the ZDHHC7 and KIAA0513 genes, and two were in exon 1 of the CDH13 and ATP2C2 genes, respectively. The results from this study support future studies on the molecular mechanism to regulate the imprinting of candidate genes on bovine chromosome 18.

RECQL4 Inhibits Radiation-Induced Tumor Immune Awakening via Suppressing the cGAS-STING Pathway in Hepatocellular Carcinoma.

Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.

Top-down design of high-performance V-based MBene anode for Li/Na-ion batteries.

Two-dimensional (2D) MBenes have enormous potential in energy applications. Vanadium metal, with its versatile and tunable electronic states, can further enhance the electrochemical performance of MBenes. However, most MBenes are composed of a few atomic layers as the metal boron (MB) block, e.g., M2B2, which might lead to instability and poor mechanical response. Herein, we designed and predicted 2D V4B6 associated with different terminations (T = Cl, O, S) using a top-down method and global search for parental V4AB6. Among the A element candidates, the P-glued MAB phase exhibited high stability and easy synthesizability. Moreover, 2D V4B6 was feasibly formed and easily exfoliated owing to its weak V-P bonding. Most of the surface functionalization could improve both the mechanical and electrochemical properties of the V4B6 monolayer. In particular, 2D V4B6S2 exhibited a high potential as an anode material for lithium-ion batteries (LIBs) with high theoretical capacity (297 mA h g-1), low diffusion barrier (0.166 eV), and low open circuit voltage (0.136 V), outperforming a majority of MXenes and transition metal sulfide layers. This work offers a new strategy for designing desirable 2D layers from parental materials, and tuning their properties via composition and surface functionalization, which could shed light on the development of other 2D metal-ion anodes.

A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization.

Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.

Zhuifeng Tougu capsules in the treatment of knee osteoarthritis (cold dampness obstruction syndrome): a randomized, double blind, multicenter clinical study.

BACKGROUND: In Traditional Chinese Medicine (TCM) theory, cold dampness obstruction is one of the common syndromes of osteoarthritis. Therefore, in clinical practice, the main treatment methods are to dispel wind, remove dampness, and dissipate cold, used to treat knee osteoarthritis (KOA). This report describes a mulitercenter clinical study to assess Zhuifeng Tougu Capsule's efficacy and safety in the treatment of patients who are cold dampness obstruction syndrome in KOA, and to provide evidence-based medical for the rational use of Zhuifeng Tougu Capsules in clinical practice. METHODS: This randomized, parallel group controlled, double-blind, double dummy trial will include a total of 215 KOA patients who meet the study criteria. 215 patients underwent 1:1 randomisation, with 107 cases assigned the experimental group (Zhuifeng Tougu Capsules + Glucosamine Sulfate Capsules Simulator) and 108 assigned the control group (Glucosamine Sulfate Capsules + Zhuifeng Tougu Capsules Simulator). After enrolment, patients received 12 weeks of treatment. The main efficacy measure is the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain score. Visual analogue scale (VAS) pain score, Self-condition assessment VAS score, WOMAC KOA score, TCM syndrome score and TCM syndrome efficacy, ESR level, CRP level, suprapatellar bursa effusion depth, use of rescue drugs, and safety indicators are secondary efficacy indicators. RESULTS: Compared with before treatment, WOMAC pain score, VAS pain score, Self-condition assessment VAS score, WOMAC KOA score, and TCM syndrome score decreased significantly in both groups (P < 0.01). Also, the experimental group showed significant differences in the above indicators compared to control (P < 0.01). However, after treatment, no significant differences were showed in the ESR level, CRP level, and suprapatellar bursa effusion depth between the two groups (P > 0.05). No any serious adverse effects showed in the experimental group and control group. CONCLUSIONS: Zhuifeng Tougu Capsules can effectively improve knee joint function and significantly alleviate the pain of KOA. TRIAL REGISTRATION: Clinical trial registration was completed with the China Clinical Trial Registration Center for this research protocol (No. ChiCTR2000028750) on January 2, 2020.