ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch.

BACKGROUND: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in ß-aminopropionitrile fumarate (BAPN)-induced TAD. METHODS: A mouse model of TAD induced by BAPN and IL-1ß -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. RESULTS: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. CONCLUSION: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Gender differences in behavioral and emotional problems among school children and adolescents in China: National survey findings from a comparative network perspective.

BACKGROUND: Behavioral and emotional problems are common and often co-occur during childhood and adolescence. The aim of this study was to assess gender differences in the network structures of behavioral and emotional problems of children and adolescents in China based on a national survey. METHODS: The Parent version of Achenbach's Child Behavior Checklist (CBCL) was used to assess behavioral and emotional problems. To account for potential confounding factors between boys and girls, propensity score matching was utilized. Network model differences were assessed with a Network Comparison Test (NCT). RESULTS: Data from 60,715 children and adolescents were included for analyses. Boys exhibited more severe total behavioral and emotional problems compared to girls. While several edges showed significant differences between boys and girls, the strongest association was consistently found between "Attention problems" (CBCL6) and "Aggressive behavior"(CBCL8) in both boys and girls, regardless of age. Network centrality was higher among adolescents compared to children. The most central problems commonly found across different genders and age groups were "Aggressive behavior" (CBCL8) (centrality values were 1.142 for boys aged 6-11 years, 1.051 for boys aged 12-16 years, 1.148 for girls aged 6-11 years, and 1.028 for girls aged 12-16 years), "Anxious/depressed" (CBCL1) (centrality values of 0.892 for boys aged between 6 and 11 years, 1.031 for boys aged 12-16 years, 0.951 for girls aged 6-11 years, and 1.099 for girls aged 12-16 years) and "Social problems" (CBCL4) (centrality values of 1.080 for boys aged 6-11 years, 0.978 for boys aged 12-16 years, 1.086 for girls aged between 6 and 11 years, and 0.929 for girls aged 12-16 years). CONCLUSION: Development of interventions that address aggressive behavior, anxiety/depression, and social problems may be beneficial for reducing risk of psychopathology among children and adolescents.

Upregulation of serum miR-4429 discriminates chronic heart failure patients and regulates cardiomyocyte injury via modulating HAPLN1.

BACKGROUND: Chronic heart failure (CHF) is the outcome of various cardiac diseases. Due to the unobvious symptoms of early-stage CHF, the screening of CHF remains a challenging problem. This study focused on the dysregulated miR-4429 and evaluated its significance in the diagnosis and development of CHF, aiming to explore a novel biomarker for CHF. METHODS: A total of 103 CHF patients and 71 healthy individuals with matched clinicopathological features were enrolled. Serum miR-4429 levels were analyzed by PCR and its significance in discriminating CHF patients was evaluated by receiver operatinf curve (ROC). Cardiomyocyte was treated with H2O2 to mimic cell injury during CHF, the regulatory effect and the underlying mechanism of miR-4429 was investigated by cell transfection and cell counting kit-8 assay. RESULTS: miR-4429 was significantly upregulated in CHF patients (P< 0.0001), which sensitively and specifically discriminated CHF patients from healthy individuals (AUC=0.803, 95% CI=0.735-0.872). miR-4429 was closely associated with the decreased cardiac function of CHF patients (r>0.5, P<0.0001). H2O2 induced increased miR-4429 and reduced HAPLN1 in cardiomyocytes (P<0.001). H2O2-treated cardiomyocytes showed inhibited proliferation and increased reactive oxygen species (ROS) levels, and silencing miR-4429 could alleviate cardiomyocyte injury caused by H2O2 (P<0.0001). miR-4429 negatively regulated HAPLN1, and the knockdown of HAPLN1 could reverse the protective effect of silencing miR-4429 on cardiomyocyte injury (P<0.0001). CONCLUSIONS: The upregulation of miR-4429 served as a biomarker discriminating CHF patients and indicating severe disease conditions. Silencing miR-4429 could alleviate cardiomyocyte injury via negatively regulating HAPLN1.

Characterization and identification of the wide-polarity multicomponents from Prunella vulgaris by offline two-dimensional liquid chromatography and hydrophilic interaction chromatography coupled to ion mobility-quadrupole time-of-flight mass spectrometry.

Metabolites identification is crucial to develop functional foods or perform quality control. Prunella vulgaris (Xia-Ku-Cao) is a medicinal and edible plant used as the herbal medicine or main additive in functional beverage. However, current analytical strategies can only on-line characterize tens of compounds, restricted by insufficient chromatographic resolution and low coverage of the mass spectrometric scan methods. This work was designed to characterize the wide-polarity components from the ear of P. vulgaris. The total extract was fractionated by semi-preparative high-performance liquid chromatography into the retained medium-polarity fraction and unretained polar fraction, which were further analyzed by offline two-dimensional liquid chromatography (2D-LC) and hydrophilic interaction chromatography, respectively. Data-independent high-definition MSE of the Vion™ ion mobility time-of-flight mass spectrometer was utilized enabling the high-coverage acquisition of collision-induced dissociation-MS2 data. The offline 2D-LC, configuring the XBridge Amide and HSS T3 columns, gave high orthogonality (0.81) and effective peak capacity (1555). Automatic peak annotation facilitated by the UNIFI™ bioinformatics platform and comparison with 62 reference compounds achieved the efficient and more reliable structural elucidation. We could characterize 255 compounds from P. vulgaris, with numerous phenylpropanoid phenolic acids and triterpenoid O-glycosides newly reported. Especially, collision cross section (CCS) prediction and targeted isolation of three compounds assisted in the identification of 39 groups of isomers. Additionally, 17 hydrophilic compounds, involving oligosaccharides and organic acids, were characterized from the unretained polar fraction. Conclusively, the in-depth metabolites identification of P. vulgaris was accomplished, and the results can benefit the development and better quality control of this valuable plant.

Does mental fatigue affect performance in racket sports? A systematic review.

Mental fatigue impairs performance across several sports domains. However, a systematic review on its effects on racket sports performance has been lacking due to the previous scarcity of studies. This review aims to provide a comprehensive review the effects of mental fatigue on racket players' performance, with a discussion of the underlying mechanisms. A thorough search was conducted across five databases, including Web of Science, PubMed, SCOPUS, SPORTDiscus (via EBSCOhost), and the Psychological and Behavioral Science Collection (via EBSCOhost). The PICOS framework established the inclusion criteria: (1) healthy racket sports players; (2) induction of mental fatigue in both field and laboratory settings; (3) comparison of mental fatigue interventions with a control group (e.g., watching a movie or reading a magazine); (4) assessment of performance outcomes, including physical performance, skilled performance, and perceptual-cognitive performance; and (5) randomized controlled trials (RCTs), non-randomized controlled trials (non-RCTs), and non-randomized non-controlled trials. Mental fatigue manipulation, subjective evaluation, and (neuro)physiological markers were synthesized to support the successful induction of mental fatigue. Performance was categorized into tennis, table tennis, badminton, and padel based on the characteristics of specific racket sports domains. Secondary outcomes, such as the rate perception of effort (RPE) and motivation, were synthesized to explain the mechanisms based on the prominent theory of the Psychobiological model of endurance performance. Six studies revealed that mental fatigue impacts stroke performance in table tennis, affecting speed, accuracy, faults, and only second-serve accuracy in tennis. The response time of psychomotor performance increased in table tennis, padel, and badminton. Meanwhile, mental fatigue increased the RPE and remained unchanged in heart rate, blood glucose, and lactate, consistent with the Psychobiological model of endurance performance. Additionally, attention is suggested as a significant underlying psychobiological factor.

Study on the chemical composition and anti-fungi activities of anthraquinones and its glycosides from Rumex japonicus Houtt.

Fungi, such as Trichophyton rubrum (T. rubrum) and Microsporum canis Bodin Anamorph (M. canis Bodin Anamorph) are the main pathogens of dermatophysis. According to ancient books records, Rumex japonicus Houtt. (RJH) has a miraculous effect on the treatment of dermatophysis. To reveal the anti-fungi (T. rubrum and M. canis Bodin Anamorph) components and its mechanism of the Rumex japonicus Houtt. The vinegar extraction and alcohol precipitation, HPLC and nuclear magnetic resonance spectroscopy (NMR) were employed for analyzing the chemical compositions of RJH; in vitro anti-fungal experiment was investigated including test the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC), spore germination rate, nucleic acid, protein leakage rate, biofilm structure, and the mechanism of anti-fungal and anti-fungal biofilms in RJH. Seven anthraquinones and their glycoside compounds were obtained in this study respectively, such as chrysophanol, physcion, aloe-emodin, emodin, rhein, emodin-8-O-ß-D-glucoside and chrysophanol-8-O-ß-D-glucoside. In vitro anti-fungal experiment results showed that RJH extracts have good anti-fungal activity for dermatophytic fungi. Among them, the MIC of the rhein, emodin and aloe-emodin against T. rubrum are 1.9 µg/ml, 3.9 µg/ml and 15.6 µg/ml, respectively; the MIC of emodin and aloe-emodin against M. canis Bodin Anamorph are 7.8 µg/ml and 62.5 µg/ml, respectively. In addition, its active components can inhibit fungal spore germination and the formation of bud tube, change cell membrane permeability, prevent hyphal growth, destroy biofilm structure, and down-regulate the expression of agglutinin-like sequence family 1 of the adhesion phase of biofilm growth. The study shows that RJH play a fungicidal role.

GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway.

Sepsis is a systemic inflammatory response syndrome triggered by infection, presenting with symptoms such as fever, increased heart rate, and low blood pressure. In severe cases, it can lead to multiple organ dysfunction, posing a life-threatening risk. Sepsis-induced cardiomyopathy (SIC) is a critical factor in the poor prognosis of septic patients, leading to myocardial dysfunction characterized by cell death, inflammation, and diminished cardiac function. Ferroptosis, an iron-dependent form of programmed cell death, is a key mechanism causing cardiomyocyte damage in SIC. Growth differentiation factor 15 (GDF15), a member of the TGF-ß superfamily, is associated with various cardiovascular diseases and can inhibit oxidative stress, reduce reactive oxygen species (ROS), and suppress ferroptosis. Elevated serum GDF15 levels in sepsis are correlated with organ injuries, suggesting its potential as a therapeutic target. However, its role and mechanisms in SIC remain unclear. Glutathione peroxidase 4 (GPX4), the only enzyme capable of reducing lipid peroxides within cells, protects cells by reducing lipid peroxidation levels and inhibiting ferroptosis. Investigating the regulatory factors of GPX4 may provide a theoretical basis for SIC treatment. In this study, a mouse SIC model revealed that elevated GDF15 exerts a protective effect. Antagonizing GDF15 exacerbates myocardial damage. Through transcriptomic analysis and other methods, we confirmed that GDF15 inhibits the expression of SOCS1 by activating the ALK5-SMAD2/3 pathway, thereby activates the JAK2/STAT3 pathway, promotes the transcription of GPX4, inhibits ferroptosis in cardiomyocytes, and plays a myocardial protective role in SIC.

Molecular definition of the endogenous Toll-like receptor signalling pathways.

Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease1. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24 h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.

The effects of plyometric training on physical fitness and skill-related performance in female basketball players: a systematic review and meta-analysis.

Objective: This study aims to analyze the effects of plyometric training (PT) on physical fitness and skill-related performance in female basketball players. Method: Five databases, including Web of Science, Scopus, PubMed, EBSCOhost, and Google Scholar, were used to select articles published up to 20 December 2023, using a combination of keywords related to PT and female basketball players. The risk of bias and the certainty of evidence in included articles were assessed using the Cochrane risk of bias (RoB2) tool and "The Grading of Recommendations Assessment, Development, and Evaluation" (GRADE). Results: Ten studies were included for the systematic review, and eight for the meta-analysis, totalling 246 female basketball players aged 14.5-22.5 years. Most of these players were highly trained. Most of the included studies exhibited concerns regarding the risk of bias. The PT programs lasted 4-8 weeks, conducted 2-3 sessions per week, with sessions lasting 20-90 min and including 29-190 jumps. In the systematic review, most studies showed that PT significantly improved performance in countermovement jump (CMJ), squat jump (SJ), Sargent jump, standing long jump, lateral hop, medicine ball throw, t-Test, Illinois agility, lane agility drill, linear 20-m sprint, stable and dynamic leg balance, dribbling, passing, shooting, and various basketball-specific tests, as well as increased muscle volume and thigh cross-sectional area. However, some studies showed PT to induce no significant changes in performance during CMJ, t-Test, Illinois agility, knee extensor/flexor strength, linear sprint, and single leg balance tests. In the meta-analysis, CMJ height (ES = 0.37; p = 0.036), vertical jump (VJ) peak power (ES = 0.57; p = 0.015), VJ peak velocity (ES = 0.26; p = 0.004), and t-Test performance time (ES = 0.32; p = 0.004) were significantly improved with small effects following PT. Conclusion: The effect of PT on performance in female basketball players was mixed. Most studies indicated that PT could improve various measures of physical fitness and skill-related performance, but performance remained unchanged in some tests. More studies with established tests are needed to investigate the effect of PT on female basketball players in the future. Systematic Review Registration: https://inplasy.com/, Identifier INPLASY2023120078.

Measuring Carbon Content in Airway Macrophages Exposed to Carbon-Containing Particulate Matters.

Pulmonary macrophages exhibit a dose-dependent pattern in phagocytizing particles. Following engulfment, these macrophages are subsequently excreted with sputum, rendering macrophages and particles visible and quantifiable under light microscopy. Notably, elemental carbon within the mammalian body originates exclusively from external contaminants. Consequently, the carbon content in airway macrophages (CCAM) serves as a valid exposure biomarker, accurately estimating individual exposure to carbon-containing particulate matter (PM). This article delineates a protocol involving sputum collection, preservation, processing, slide preparation, and staining, as well as macrophage photo acquisition and analysis. After removing the macrophage nuclei, the proportion of cytoplasm area occupied by carbon particles (PCOC) was calculated to quantify carbon content in each macrophage. The results indicate an elevation in CCAM levels after exposure to carbon-containing PM. In summary, this non-invasive, precise, reliable, and standardized method enables the direct measurement of carbon particles within target cells and is utilized for large-scale quantification of individual CCAM through induced sputum.

Relative Contribution of Diagnostic Testing to the Diagnosis of Respiratory Syncytial Virus in Hospitalized Adults in the United States.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illness (ARI) in older adults. Optimizing diagnosis could improve understanding of RSV burden. METHODS: We enrolled adults ≥50 years of age hospitalized with ARI and adults of any age hospitalized with congestive heart failure or chronic obstructive pulmonary disease exacerbations at two hospitals during two respiratory seasons (2018-2020). We collected nasopharyngeal (NP) and oropharyngeal (OP) swabs (n=1558), acute and convalescent sera (n=568), and expectorated sputum (n=153) from participants, and recorded standard-of-care (SOC) NP results (n=805). We measured RSV antibodies by two immunoassays and performed BioFire testing on respiratory specimens. RESULTS: Of 1,558 eligible participants, 92 (5.9%) tested positive for RSV by any diagnostic method. Combined NP/OP PCR yielded 58 positives, while separate NP and OP testing identified 11 additional positives (18.9% increase). Compared to Study NP/OP PCR alone, the addition of paired serology increased RSV detection by 42.9% (28 vs 40) among those with both specimen types, while the addition of SOC swab RT-PCR results increased RSV detection by 25.9% (47 vs 59). CONCLUSIONS: The addition of paired serology testing, SOC swab results, and separate testing of NP and OP swabs improved RSV diagnostic yield in hospitalized adults.

Lingdan: enhancing encoding of traditional Chinese medicine knowledge for clinical reasoning tasks with large language models.

OBJECTIVE: The recent surge in large language models (LLMs) across various fields has yet to be fully realized in traditional Chinese medicine (TCM). This study aims to bridge this gap by developing a large language model tailored to TCM knowledge, enhancing its performance and accuracy in clinical reasoning tasks such as diagnosis, treatment, and prescription recommendations. MATERIALS AND METHODS: This study harnessed a wide array of TCM data resources, including TCM ancient books, textbooks, and clinical data, to create 3 key datasets: the TCM Pre-trained Dataset, the Traditional Chinese Patent Medicine (TCPM) Question Answering Dataset, and the Spleen and Stomach Herbal Prescription Recommendation Dataset. These datasets underpinned the development of the Lingdan Pre-trained LLM and 2 specialized models: the Lingdan-TCPM-Chat Model, which uses a Chain-of-Thought process for symptom analysis and TCPM recommendation, and a Lingdan Prescription Recommendation model (Lingdan-PR) that proposes herbal prescriptions based on electronic medical records. RESULTS: The Lingdan-TCPM-Chat and the Lingdan-PR Model, fine-tuned on the Lingdan Pre-trained LLM, demonstrated state-of-the art performances for the tasks of TCM clinical knowledge answering and herbal prescription recommendation. Notably, Lingdan-PR outperformed all state-of-the-art baseline models, achieving an improvement of 18.39% in the Top@20 F1-score compared with the best baseline. CONCLUSION: This study marks a pivotal step in merging advanced LLMs with TCM, showcasing the potential of artificial intelligence to help improve clinical decision-making of medical diagnostics and treatment strategies. The success of the Lingdan Pre-trained LLM and its derivative models, Lingdan-TCPM-Chat and Lingdan-PR, not only revolutionizes TCM practices but also opens new avenues for the application of artificial intelligence in other specialized medical fields. Our project is available at https://github.com/TCMAI-BJTU/LingdanLLM.

Hybrid nanoflower-based electrochemical lateral flow immunoassay for Escherichia coli O157 detection.

An electrochemical biosensor has been developed for detection of Escherichia coli O157 by integrating lateral flow with screen-printed electrodes. The screen-printed electrodes were attached under the lateral flow detection line, and organic-inorganic nanoflowers prepared from E. coli O157-specific antibodies as an organic component were attached to the lateral flow detection line. In the presence of E. coli O157, an organic-inorganic nanoflower-E. coli O157-antimicrobial peptide-labelled ferrocene sandwich structure is formed on the lateral flow detection line. Differential pulse voltammetry is applied using a smartphone-based device to monitor ferrocene on the detection line. The resulting electrochemical biosensor could specifically detect E. coli O157 with a limit of detection of 25 colony-forming units mL-1. Through substitution of antibodies of organic components in organic-inorganic nanoflowers, biosensors have great potential for the detection of other pathogens in biomedical research and clinical diagnosis.

Lithium isotopic records of anthropogenic activity in the Xiaoqing River basin, eastern China.

The environmental impact of the discharge of lithium (Li) by anthropogenic activity has been overlooked. By analyzing Li concentrations and isotope compositions (δ7Li) of water and sediment samples, this study evaluates the influence of anthropogenic Li discharge on the Xiaoqing River and Laizhou Bay, which are heavily polluted areas in China. High Li concentrations of the river water (up to 7.8 µmol/L) should be linked to anthropogenic Li discharge. However, no profound δ7Li anomalies were observed, preventing identification of the exact discharge sources. In the river sediments, Li concentrations (19.0-45.0 µg/g) were weakly correlated with Zn, Cu, and Cr concentrations, whereas δ7Li values ranged from 0.6 ‰ to 13.9 ‰ with high values being accompanied by high contents of total organic carbon and heavy Cr isotope compositions (δ53Cr). All these point to significant influence of anthropogenic activity on the Li budget of river sediments. A simple mass balance calculation indicates that smelters, Li-bearing therapeutic drugs, and secondary Li-ion batteries are the main anthropogenic Li sources. In contrast to river sediments, marine sediments in the Laizhou Bay were broadly homogeneous at both spatial and temporal scales, indicating no significant influence of anthropogenic Li discharge. Overall, our data indicate that Li isotope systematics in river sediments, especially sediments near intense anthropogenic activity, are effective at tracing potential Li pollution and can help obtain accurate results for environmental inspection.

Gastrodin Improves the Activity of the Ubiquitin-Proteasome System and the Autophagy-Lysosome Pathway to Degrade Mutant Huntingtin.

Gastrodin (GAS) is the main chemical component of the traditional Chinese herb Gastrodia elata (called "Tianma" in Chinese), which has been used to treat neurological conditions, including headaches, epilepsy, stroke, and memory loss. To our knowledge, it is unclear whether GAS has a therapeutic effect on Huntington's disease (HD). In the present study, we evaluated the effect of GAS on the degradation of mutant huntingtin protein (mHtt) by using PC12 cells transfected with N-terminal mHtt Q74. We found that 0.1-100 µM GAS had no effect on the survival rate of Q23 and Q74 PC12 cells after 24-48 h of incubation. The ubiquitin-proteasome system (UPS) is the main system that clears misfolded proteins in eukaryotic cells. Mutated Htt significantly upregulated total ubiquitinated protein (Ub) expression, decreased chymotrypsin-like, trypsin-like and caspase-like peptidase activity, and reduced the colocalization of the 20S proteasome with mHtt. GAS (25 µM) attenuated all of the abovementioned pathological changes, and the regulatory effect of GAS on mHtt was found to be abolished by MG132, a proteasome inhibitor. The autophagy-lysosome pathway (ALP) is another system for misfolded protein degradation. Although GAS downregulated the expression of autophagy markers (LC3II and P62), it increased the colocalization of LC3II with lysosomal associated membrane protein 1 (LAMP1), which indicates that ALP was activated. Moreover, GAS prevented mHtt-induced neuronal damage in PC12 cells. GAS has a selective effect on mHtt in Q74 PC12 cells and has no effect on Q23 and proteins encoded by other genes containing long CAGs, such as Rbm33 (10 CAG repeats) and Hcn1 (>30 CAG repeats). Furthermore, oral administration of 100 mg/kg GAS increased grip strength and attenuated mHtt aggregates in B6-hHTT130-N transgenic mice. This is a high dose (100 mg/kg GAS) when compared with experiments on HD mice with other small molecules. We will design more doses to evaluate the dose-response relationship of the inhibition effect of GAS on mHtt in our next study. In summary, GAS can promote the degradation of mHtt by activating the UPS and ALP, making it a potential therapeutic agent for HD.

Apabetalone, a BET protein inhibitor, inhibits kidney damage in diabetes by preventing pyroptosis via modulating the P300/H3K27ac/PLK1 axis.

Many inflammatory disorders, including diabetic kidney disease (DKD), are associated with pyroptosis, a type of inflammation-regulated cell death. The purpose of this work was to ascertain the effects of apabetalone, which targets BRD4, a specific inhibitor of the bromodomain (BRD) and extra-terminal (BET) proteins that target bromodomain 2, on kidney injury in DKD. This study utilized pharmacological and genetic approaches to investigate the effects of apabetalone on pyroptosis in db/db mice and human tubular epithelial cells (HK-2). BRD4 levels were elevated in HK-2 cells exposed to high glucose and in db/db mice. Modulating BRD4 levels led to changes in the generation of inflammatory cytokines and cell pyroptosis linked to NLRP3 inflammasome in HK-2 cells and db/db mice. Likewise, these cellular processes were mitigated by apabetalone through inhibition BRD4. Apabetalone or BRD4 siRNA suppressed PLK1 expression in HK-2 cells under high glucose by P300-dependent H3K27 acetylation on the PLK1 gene promoter, as demonstrated through chromatin immunoprecipitation and immunoprecipitation assays. To summarize, apabetalone relieves renal proptosis and fibrosis in DKD. BRD4 regulates the P300/H3K27ac/PLK1 axis, leading to the activation of the NLRP3 inflammasome and subsequent cell pyroptosis, inflammation, and fibrosis. These results may provide new perspectives on DKD treatment.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Physiological Basis for the Mechanism of Selectivity of Tripyrasulfone between Rice (Oryza sativa) and Barnyard Grass (Echinochloa crus-galli).

Tripyrasulfone is currently the only HPPD-inhibiting herbicide that possesses outstanding selectivity even for direct-seeded rice (Oryza sativa) when applied POST to control grass weeds; however, the underlying mechanisms remain unclear. In this study, the inhibitory effects of the real active HDT of tripyrasulfone on recombinant 4-hydroxyphenylpyruvate dioxygenase (HPPDs) from rice and barnyard grass (Echinochloa crus-galli) were similar, with consistent structural interactions and similar binding energies predicted by molecular docking. However, the HPPD expression level in rice was significantly greater than that in barnyard grass after tripyrasulfone treatment. Tripyrasulfone was rapidly taken up and hydrolyzed into HDT, which was similarly distributed within the whole plants of rice and barnyard grass at 24 h after treatment. Compared with barnyard grass, rice has more uniform epicuticular wax in the cuticle of its leaves, absorbing less tripyrasulfone and metabolizing much more tripyrasulfone. Overall, to a greater extent, the different sensitivities to tripyrasulfone between barnyard grass and rice resulted from metabolic variations.

Bisphosphonate-Anchored Self-Assembled Molecules with Larger Dipole Moments for Efficient Inverted Perovskite Solar Cells with Excellent Stability.

In the fabrication of inverted perovskite solar cells (PSCs), the wettability, adsorbability, and compactness of self-assembled monolayers (SAMs) on conductive substrates have critical impacts on the quality of the perovskite films and the defects at the buried perovskite-substrate interface, which control the efficiency and stability of the devices. Herein, three bisphosphonate-anchored indolocarbazole (IDCz)-derived SAMs, IDCz-1, IDCz-2, and IDCz-3, are designed and synthesized by modulating the position of the two nitrogen atoms of the IDCz unit to improve the molecular dipole moments and strengthen the π-π interactions. Regulating the work functions (WF) of FTO electrodes through molecular dipole moments and energy levels, the perovskite band bends upwards with a small offset for ITO/IDCz-3/perovskite, thereby promoting hole extraction and blocking electrons. As a result, the inverted PSC employing IDCz-3 as hole-collecting layer exhibits a champion PCE of 25.15%, which is a record efficiency for the multipodal SAMs-based PSCs. Moreover, the unencapsulated device with IDCz-3 can be stored for at least 1800 h with little degradation in performance.