Activation of PPAR-α attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis and mitochondrial injury via upregulating 14-3-3η.

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.

Screening of potentially active compounds against rheumatoid arthritis in the Juan-Bi decoction using systems pharmacology and animal experiments.

Background: The Juan-Bi decoction (JBD) is a classic traditional Chinese medicines (TCMs) prescription for the treatment of rheumatoid arthritis (RA). However, the active compounds of the JBD in RA treatment remain unclear. Aim: The aim of this study is to screen effective compounds in the JBD for RA treatment using systems pharmacology and experimental approaches. Method: Botanical drugs and compounds in the JBD were acquired from multiple public TCM databases. All compounds were initially screened using absorption, distribution, metabolism, excretion, and toxicity (ADMET) and physicochemical properties, and then a target prediction was performed. RA pathological genes were acquired from the DisGeNet database. Potential active compounds were screened by constructing a compound-target-pathogenic gene (C-T-P) network and calculating the cumulative interaction intensity of the compounds on pathogenic genes. The effectiveness of the compounds was verified using lipopolysaccharide (LPS)-induced RAW.264.7 cells and collagen-induced arthritis (CIA) mouse models. Results: We screened 15 potentially active compounds in the JBD for RA treatment. These compounds primarily act on multiple metabolic pathways, immune pathways, and signaling transduction pathways. Furthermore, in vivo and in vitro experiments showed that bornyl acetate (BAC) alleviated joint damage, and inflammatory cells infiltrated and facilitated a smooth cartilage surface via the suppression of the steroid hormone biosynthesis. Conclusion: We screened potential compounds in the JBD for the treatment of RA using systems pharmacology approaches. In particular, BAC had an anti-rheumatic effect, and future studies are required to elucidate the underlying mechanisms.

Design, synthesis, and evaluation of benzodioxolane compounds for antitumor activity.

This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.

Scientific Discovery Framework Accelerating Advanced Polymeric Materials Design.

Organic polymer materials, as the most abundantly produced materials, possess a flammable nature, making them potential hazards to human casualties and property losses. Target polymer design is still hindered due to the lack of a scientific foundation. Herein, we present a robust, generalizable, yet intelligent polymer discovery framework, which synergizes diverse capabilities, including the in situ burning analyzer, virtual reaction generator, and material genomic model, to achieve results that surpass the sum of individual parts. Notably, the high-throughput analyzer created for the first time, grounded in multiple spectroscopic principles, enables in situ capturing of massive combustion intermediates; then, the created realistic apparatus transforming to the virtual reaction generator acquires exponentially more intermediate information; further, the proposed feature engineering tool, which embedded both polymer hierarchical structures and massive intermediate data, develops the generalizable genomic model with excellent universality (adapting over 20 kinds of polymers) and high accuracy (88.8%), succeeding discovering series of novel polymers. This emerging approach addresses the target polymer design for flame-retardant application and underscores a pivotal role in accelerating polymeric materials discovery.

Trehalose along with ABA promotes the salt tolerance of Avicennia marina by regulating Na+ transport.

Mangroves grow in tropical/subtropical intertidal habitats with extremely high salt tolerance. Trehalose and trehalose-6-phosphate (T6P) have an alleviating function against abiotic stress. However, the roles of trehalose in the salt tolerance of salt-secreting mangrove Avicennia marina is not documented. Here, we found that trehalose was significantly accumulated in A. marina under salt treatment. Furthermore, exogenous trehalose can enhance salt tolerance by promoting the Na+ efflux from leaf salt gland and root to reduce the Na+ content in root and leaf. Subsequently, eighteen trehalose-6-phosphate synthase (AmTPS) and 11 trehalose-6-phosphate phosphatase (AmTPP) genes were identified from A. marina genome. Abscisic acid (ABA) responsive elements were predicted in AmTPS and AmTPP promoters by cis-acting elements analysis. We further identified AmTPS9A, as an important positive regulator, that increased the salt tolerance of AmTPS9A-overexpressing Arabidopsis thaliana by altering the expressions of ion transport genes and mediating Na+ efflux from the roots of transgenic A. thaliana under NaCl treatments. In addition, we also found that ABA could promote the accumulation of trehalose, and the application of exogenous trehalose significantly promoted the biosynthesis of ABA in both roots and leaves of A. marina. Ultimately, we confirmed that AmABF2 directly binds to the AmTPS9A promoter in vitro and in vivo. Taken together, we speculated that there was a positive feedback loop between trehalose and ABA in regulating the salt tolerance of A. marina. These findings provide new understanding to the salt tolerance of A. marina in adapting to high saline environment at trehalose and ABA aspects.

Highly Selective Electrocatalytic CO2 Conversion to Tailored Products through Precise Regulation of Hydrogenation and C-C Coupling.

The electrochemical reduction reaction of carbon dioxide (CO2RR) into valuable products offers notable economic benefits and contributes to environmental sustainability. However, precisely controlling the reaction pathways and selectively converting key intermediates pose considerable challenges. In this study, our theoretical calculations reveal that the active sites with different states of copper atoms (1-3-5-7-9) play a pivotal role in the adsorption behavior of the *CHO critical intermediate. This behavior dictates the subsequent hydrogenation and coupling steps, ultimately influencing the formation of the desired products. Consequently, we designed two model electrocatalysts comprising Cu single atoms and particles supported on CeO2. This design enables controlled *CHO intermediate transformation through either hydrogenation with *H or coupling with *CO, leading to a highly selective CO2RR. Notably, our selective control strategy tunes the Faradaic efficiency from 61.1% for ethylene (C2H4) to 61.2% for methane (CH4). Additionally, the catalyst demonstrated a high current density and remarkable stability, exceeding 500 h of operation. This work not only provides efficient catalysts for selective CO2RR but also offers valuable insights into tailoring surface chemistry and designing catalysts for precise control over catalytic processes to achieve targeted product generation in CO2RR technology.

Functional Identification of Malus halliana MhbZIP23 Gene Demonstrates That It Enhances Saline-Alkali Stress Tolerance in Arabidopsis thaliana.

Saline-alkali stress is a significant abiotic stress that restricts plant growth globally. Basic region leucine zipper (bZIP) transcription factor proteins are widely involved in plants in response to abiotic stress such as saline-alkali stress. Based on transcriptome and quantitative real-time PCR (qRT-PCR), we found that the MhbZIP23 gene could respond to saline-alkali stress. Despite this discovery, the underlying mechanism by which the MhbZIP23 transcription factor responds to saline-alkaline stress remains unexplored. To address this gap in knowledge, we successfully cloned the MhbZIP23 (MD05G1121500) gene from Malus halliana for heterologous expression in Arabidopsis thaliana, facilitating the investigation of its functional role in stress response. Compared to the wild type (WT), Arabidopsis plants demonstrated enhanced growth and a lower degree of wilting when subjected to saline-alkali stress. Furthermore, several physiological indices of the plants altered under such stress conditions. The transgenic Arabidopsis plants (OE-5, 6, and 8), which grew normally, exhibited a higher chlorophyll content and had greater root length in comparison to the control check (CK). MhbZIP23 effectively regulated the levels of the osmoregulatory substance proline (Pro), enhanced the activities of antioxidant enzymes such as peroxidase (POD) and superoxide dismutase (SOD), and reduced the levels of malondialdehyde (MDA) and relative conductivity (REC). These actions improved the ability of plant cells in transgenic Arabidopsis to counteract ROS, as evidenced by the decreased accumulation of O2- and hydrogen peroxide (H2O2). In summary, the MhbZIP23 gene demonstrated effectiveness in alleviating saline-alkali stress in M. halliana, presenting itself as an outstanding resistance gene for apples to combat saline-alkali stress.

[N2O Emission Factors from Wastewater Treatment Plants Based on Literature Statistics and Model Fitting].

The emission of nitrous oxide （N2O） during wastewater treatment cannot be ignored. The analysis of statistical data from literature based on 126 empirical studies revealed that the geographical factors of wastewater treatment plants （WWTPs） had a significant impact on N2O emission factors. However, the N2O emission factors of WWTPs in all regions of the world were generally lower than the Intergovernmental Panel on Climate Change （IPCC） recommended values. In China, the N2O emission factors （in N2O-N/Ninfluent） of WWTPs were approximately 0.000 35-0.065 20 kg·kg-1. Meanwhile, the N2O emission factors of different wastewater treatment processes were also significantly different, especially since the sequencing batch reactor （SBR） process had higher emissions. The use of uniform default emission factors for accounting was prone to overestimate N2O emissions, and it is recommended that countries conduct actual monitoring or modeling studies to develop categorical emission factors suitable for local conditions. In addition, the N2O emission factor based on total nitrogen （TN） removal was weakly negatively correlated with TN removal in 126 empirical data, which was more in line with bioprocessing stoichiometry and could provide an accurate accounting method for N2O. To this end, a digital twin model was developed to dynamically simulate a case anaerobic-anoxic-aerobic （AAO） WWTP to comprehensively quantify the dynamic emission behavior of N2O, which demonstrated that N2O emissions had significant seasonal and daily variability and were only equivalent to 11% of the calculated value of the emission factor based on the IPCC recommendation. Comparing the scatter linear fitting and categorical mean exponential fitting methods, it was found that the latter could more accurately reflect the negative correlation between the N2O emission factors and the TN removal rate, and an exponential regression equation between the average N2O emission factor based on the amount of TN removed and the TN removal rate was further developed to predict the N2O emission. The dynamic simulation and categorical index fitting methods provided in this study are important references for the accurate accounting of N2O emissions in similar WWTPs and provide help for understanding and responding to the N2O emission problems.

SIRT3/AMPK signaling pathway regulates lipid metabolism and improves vulnerability to atrial fibrillation in Dahl salt sensitive rats.

BACKGROUND: Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3) / AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either high-salt diet (8% NaCl; DSH group) or normal diet (0.3% NaCl; DSN group). Then DSH group were administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of SBP, the expression levels of lipid metabolism-related biomarker, pathological examination of atrial fibrosis and lipid accumulation, as well as AF inducibility and AF duration. RESULTS: DSH decrease SIRT3, phosphorylation-AMPK and VLCAD expression, increased FASN and FABP4 expression and concentrations of FFA and TG, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS: We have confirmed that high-salt diet can result in hypertension, associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.

Cervical cancer segmentation based on medical images: a literature review.

Background and Objective: Cervical cancer clinical target volume (CTV) outlining and organs at risk segmentation are crucial steps in the diagnosis and treatment of cervical cancer. Manual segmentation is inefficient and subjective, leading to the development of automated or semi-automated methods. However, limitation of image quality, organ motion, and individual differences still pose significant challenges. Apart from numbers of studies on the medical images' segmentation, a comprehensive review within the field is lacking. The purpose of this paper is to comprehensively review the literatures on different types of medical image segmentation regarding cervical cancer and discuss the current level and challenges in segmentation process. Methods: As of May 31, 2023, we conducted a comprehensive literature search on Google Scholar, PubMed, and Web of Science using the following term combinations: "cervical cancer images", "segmentation", and "outline". The included studies focused on the segmentation of cervical cancer utilizing computed tomography (CT), magnetic resonance (MR), and positron emission tomography (PET) images, with screening for eligibility by two independent investigators. Key Content and Findings: This paper reviews representative papers on CTV and organs at risk segmentation in cervical cancer and classifies the methods into three categories based on image modalities. The traditional or deep learning methods are comprehensively described. The similarities and differences of related methods are analyzed, and their advantages and limitations are discussed in-depth. We have also included experimental results by using our private datasets to verify the performance of selected methods. The results indicate that the residual module and squeeze-and-excitation blocks module can significantly improve the performance of the model. Additionally, the segmentation method based on improved level set demonstrates better segmentation accuracy than other methods. Conclusions: The paper provides valuable insights into the current state-of-the-art in cervical cancer CTV outlining and organs at risk segmentation, highlighting areas for future research.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents.

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

Brain gliomas: Diagnostic and therapeutic issues and the prospects of drug-targeted Nano-delivery technology.

Glioma is the most common intracranial malignant tumor, with severe difficulty in treatment and a low patient survival rate. Due to the heterogeneity and invasiveness of tumors, lack of personalized clinical treatment design, and physiological barriers, it is often difficult to accurately distinguish gliomas, which dramatically affects the subsequent diagnosis, imaging treatment, and prognosis. Fortunately, nano-delivery systems have demonstrated unprecedented capabilities in diagnosing and treating gliomas in recent years. They have been modified and surface modified to efficiently traverse BBB/BBTB, target lesion sites, and intelligently release therapeutic or contrast agents, thereby achieving precise imaging and treatment. In this review, we focus on nano-delivery systems. Firstly, we provide an overview of the standard and emerging diagnostic and treatment technologies for glioma in clinical practice. After induction and analysis, we focus on summarizing the delivery methods of drug delivery systems, the design of nanoparticles, and their new advances in glioma imaging and treatment in recent years. Finally, we discussed the prospects and potential challenges of drug-delivery systems in diagnosing and treating glioma.

Discriminative feature analysis of dairy products based on machine learning algorithms and Raman spectroscopy.

Discriminant analysis of similar food samples is an important aspect of achieving food quality control. The effective combination of Raman spectroscopy and machine learning algorithms has become an extremely attractive approach to develop intelligent discrimination techniques. Feature spectral analysis can help researchers gain a deeper understanding of the data patterns in food quality discrimination. Herein, this work takes the discrimination of three brands of dairy products as an example to investigate the Raman spectral feature based on the support vector machines (SVM), extreme learning machines (ELM) and convolutional neural network (CNN) algorithms. The results show that there are certain differences in the optimal spectral feature interval corresponding to different machine learning algorithms. Selecting the appropriate spectral feature interval can maintain high recognition accuracy and improve the computational efficiency of the algorithm. For example, the SVM algorithm has a recognition accuracy of 100% in the 890-980 cm-1, 1410-1500 cm-1 fusion spectral range, which takes about 200 s. The ELM algorithm also has a recognition accuracy of 100% in the 890-980 cm-1, 1410-1500 cm-1 fusion spectral range, which takes less than 0.3 s. The CNN algorithm has a recognition accuracy of 100% in the 890-980 cm-1, 1050-1180 cm-1, 1410-1500 cm-1 fusion spectral range, which takes about 80 s. In addition, by analyzing the distribution of spectral feature intervals based on Euclidean distance, the distribution of experimental samples based on feature spectra is visually displayed. Through the spectral feature analysis process of similar samples, a set of analysis strategies is provided to deeply reveal the data foundation of classification algorithms, which can provide reference for the analysis of relevant discriminative research patterns.

Recovery of Metal Ions (Cd2+, Co2+, and Ni2+) from Nitrate and Sulfate on Laser-Induced Graphene Film Using Applied Voltage and Its Application.

The urgent removal of Cd, Co, and Ni from nitrate and sulfate is essential to mitigate the potential risk of chemical pollution from large volumes of industrial wastewater. In this study, these metal ions were rapidly recovered through applying voltage on nitrate and sulfate, utilizing laser-induced graphene/polyimide (LIG/PI) film as the electrode. Following the application of external voltage, both the pH value and conductivity of the solution undergo changes. Compared to Co2+ and Ni2+, Cd2+ exhibits a lower standard electrode potential and stronger reducibility. Consequently, in both nitrate and sulfate solutions, the reaction sequence follows the order of Cd2+ > Co2+ > Ni2+, with the corresponding electrode adsorption quantities in the order of Cd2+ > Co2+ ~ Ni2+. Additionally, using the recovered Co(OH)2 as the raw material, a LiCoO2 composite was prepared. The assembled battery with this composite exhibited a specific capacity of 122.8 mAh g-1, meeting practical application requirements. This research has significance for fostering green development.

Conversion of estriol to estrone: A bacterial strategy for the catabolism of estriol.

Natural estrogens, including estrone (E1), 17ß-estradiol (E2), and estriol (E3), are potentially carcinogenic pollutants commonly found in water and soil environments. Bacterial metabolic pathway of E2 has been studied; however, the catabolic products of E3 have not been discovered thus far. In this study, Novosphingobium sp. ES2-1 was used as the target strain to investigate its catabolic pathway of E3. The metabolites of E3 were identified by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS) combined with stable 13C3-labeling. Strain ES2-1 could almost completely degrade 20 mg∙L-1 of E3 within 72 h under the optimal conditions of 30°C and pH 7.0. When inoculated with strain ES2-1, E3 was initially converted to E1 and then to 4-hydroxyestrone (4-OH-E1), which was then cleaved to HIP (metabolite A6) via the 4, 5-seco pathway or cleaved to the B loop via the 9,10-seco pathway to produce metabolite with a long-chain ketone structure (metabolite B4). Although the ring-opening sequence of the above two metabolic pathways was different, the metabolism of E3 was achieved especially through continuous oxidation reactions. This study reveals that, E3 could be firstly converted to E1 and then to 4-OH-E1, and finally degraded into small molecule metabolites through two alternative pathways, thereby reducing E3 pollution in water and soil environments.

Network pharmacology and experimental verification to decode the action of Qing Fei Hua Xian Decotion against pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua Xian Decotion (QFHXD), a traditional Chinese medicine formula applied for treating PF in COVID-19 survivors, is unclear. This study aimed to uncover the mechanisms related to the anti-PF effect of QFHXD through analysis of network pharmacology and experimental verification. METHODS: The candidate chemical compounds of QFHXD and its putative targets for treating PF were achieved from public databases, thereby we established the corresponding "herb-compound-target" network of QFHXD. The protein-protein interaction network of potential targets was also constructed to screen the core targets. Furthermore, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict targets, and pathways, then validated by in vivo experiments. RESULTS: A total of 188 active compounds in QFHXD and 50 target genes were identified from databases. The key therapeutic targets of QFHXD, such as PI3K/Akt, IL-6, TNF, IL-1ß, STAT3, MMP-9, and TGF-ß1 were identified by KEGG and GO analysis. Anti-PF effects of QFHXD (in a dose-dependent manner) and prednisone were confirmed by HE, Masson staining, and Sirius red staining as well as in vivo Micro-CT and immunohistochemical analysis in a rat model of bleomycin-induced PF. Besides, QFXHD remarkably inhibits the activity of PI3K/Akt/NF-κB and TGF-ß1/Smad2/3. CONCLUSIONS: QFXHD significantly attenuated bleomycin-induced PF via inhibiting inflammation and epithelial-mesenchymal transition. PI3K/Akt/NF-κB and TGF-ß1/Smad2/3 pathways might be the potential therapeutic effects of QFHXD for treating PF.

Efficacy and safety of remimazolam versus propofol for intraoperative sedation during regional anesthesia: A phase II, multicenter, randomized, active-controlled, single-blind clinical trial.

This study aimed to evaluate the efficacy and safety of remimazolam for intraoperative sedation during regional anesthesia. It was a phase II-multicenter, randomized, single-blind, parallel-group, active-controlled clinical trial (No. ChiCTR2100054956). From May 6, 2021 to July 4, 2021, patients were randomly enrolled from 17 hospitals in China. A total of 105 patients aged 18-65 years who underwent selective surgery under regional anesthesia were included. Patients received different sedatives with different dosages: 0.1 mg/kg remimazolam (HR), 0.05 mg/kg remimazolam (LR), or 1.0 mg/kg propofol (P) group, followed by a maintenance infusion. Main outcome measures included the efficacy of sedation measured by Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) levels (1-4, 1-3, 2-3, 3, and 2-4) during the sedation procedure (the duration percentage) and incidence of adverse reactions. It showed that the duration percentage of MOAA/S levels 1-4 was 100.0 [8.1]% (median [interquartile range]), 89.9 [20.2]%, 100.0 [7.7]% in the HR, LR, and P groups, respectively. The percentage of patients in the HR, LR, and P groups who achieved MOAA/S levels 1-4 within 3 min after administration was 85.7%, 58.8%, and 82.9%, respectively. However, the time to recovery from anesthesia after withdrawal of sedatives (7.9 ± 5.7 min), incidence of anterograde amnesia (75%), and adverse effects were not statistically significant among the three groups. These findings suggest that a loading dose of remimazolam 0.1 mg/kg followed by a maintenance infusion of 0-3 mg/kg/h provides adequate sedation for patients under regional anesthesia without increasing adverse reactions.

Inflammation-Responsive Mesoporous Silica Nanoparticles with Synergistic Anti-inflammatory and Joint Protection Effects for Rheumatoid Arthritis Treatment.

PURPOSE: Joint destruction is a major burden and an unsolved problem in rheumatoid arthritis (RA) patients. We designed an intra-articular mesoporous silica nanosystem (MSN-TP@PDA-GlcN) with anti-inflammatory and joint protection effects. The nanosystem was synthesized by encapsulating triptolide (TP) in mesoporous silica nanoparticles and coating it with pH-sensitive polydopamine (PDA) and glucosamine (GlcN) grafting on the PDA. The nano-drug delivery system with anti-inflammatory and joint protection effects should have good potency against RA. METHODS: A template method was used to synthesize mesoporous silica (MSN). MSN-TP@PDA-GlcN was synthesized via MSN loading with TP, coating with PDA and grafting of GlcN on PDA. The drug release behavior was tested. A cellular inflammatory model and a rat RA model were used to evaluate the effects on RA. In vivo imaging and microdialysis (MD) system were used to analyze the sustained release and pharmacokinetics in RA rats. RESULTS: TMSN-TP@PDA-GlcN was stable, had good biocompatibility, and exhibited sustained release of drugs in acidic environments. It had excellent anti-inflammatory effects in vitro and in vivo. It also effectively repaired joint destruction in vivo without causing any tissue toxicity. In vivo imaging and pharmacokinetics experiments showed that the nanosystem prolonged the residence time, lowered the Cmax value and enhanced the relative bioavailability of TP. CONCLUSIONS: These results demonstrated that MSN-TP@PDA-GlcN sustained the release of drugs in inflammatory joints and produced effective anti-inflammatory and joint protection effects on RA. This study provides a new strategy for the treatment of RA.

Genome sequencing, comparative analysis, and gene expression responses of cytochrome P450 genes in Oryzias curvinotus provide insights into environmental adaptation.

The mangrove fish (Oryzias curvinotus) serves as a model for researching environmental adaptation and sexual development. To further such research, we sequenced and assembled a high-quality 842 Mb reference genome for O. curvinotus. Comparative genomic analysis revealed 891 expanded gene families, including significantly expanded cytochrome P450 (CYP) detoxification genes known to be involved in xenobiotic defense. We identified 69 O. curvinotus CYPs (OcuCYPs) across 18 families and 10 clans using multiple methods. Extensive RNA-seq and qPCR analysis demonstrated diverse spatiotemporal expression patterns of OcuCYPs by developmental stage, tissue type, sex, and pollutant exposure (17ß-estradiol (E2) and testosterone (MT)). Many OcuCYPs exhibited sexual dimorphism in gonads, suggesting reproductive roles in steroidogenesis, while their responsiveness to model toxicants indicates their importance in environmental adaptation through enhanced detoxification. Pathway analysis highlighted expanded CYP genes in arachidonic acid metabolism, drug metabolism, and steroid hormone biosynthesis. This chromosome-level genomic resource provides crucial biological insights to elucidate the functional roles of expanded CYPs in environmental adaptation, sexual development, early life history, and conservation in the anthropogenically impacted mangrove habitats of O. curvinotus. It also enables future ecotoxicology research leveraging O. curvinotus as a pollution sentinel species.