Notoginsenoside R1 targets PPAR-γ to inhibit hepatic stellate cell activation and ameliorates liver fibrosis.

BACKGROUND: Hepatic fibrosis, a common pathological process that occurs in end-stage liver diseases, is a serious public health problem and lacks effective therapy. Notoginsenoside R1 (NR1) is a small molecule derived from the traditional Chinese medicine Sanqi, exhibiting great potential in treating diverse metabolie disorders. Here we aimed to enquired the role of NR1 in liver fibrosis and its underlying mechanism in hepatoprotective effects. METHODS: We investigated the anti-fibrosis effect of NR1 using CCl4-induced mouse mode of liver fibrosis as well as TGF-ß1-activated JS-1, LX-2 cells and primary hepatic stellate cell. Cell samples treated by NR1 were collected for transcriptomic profiling analysis. PPAR-γ mediated TGF-ß1/Smads signaling was examined using PPAR-γ selective inhibitors and agonists intervention, immunofluorescence staining and western blot analysis. Additionally, we designed and studied the binding of NR1 to PPAR-γ using molecular docking. RESULTS: NR1 obviously attenuated liver histological damage, reduced serum ALT, AST levels, and decreased liver fibrogenesis markers in mouse mode. Mechanistically, NR1 elevated PPAR-γ and decreased TGF-ß1, p-Smad2/3 expression. The TGF-ß1/Smads signaling pathway and fibrotic phenotype were altered in JS-1 cells after using PPAR-γ selective inhibitors and agonists respectively, confirming PPAR-γ played a pivotal protection role inNR1 treating liver fibrosis. Further molecular docking indicated NR1 had a strong binding tendency to PPAR-γ with minimum free energy. CONCLUSIONS: NR1 attenuates hepatic stellate cell activation and hepatic fibrosis by elevating PPAR-γ to inhibit TGF-ß1/Smads signalling. NR1 may be a potential candidate compound for reliving liver fibrosis.

Remarkable Toughening of Plastic with Monodispersed Nano-CaCO3: From Theoretical Predictions to Experimental Validation.

The structure-property relationship of poly(vinyl chloride) (PVC)/CaCO3 nanocomposites is investigated by all-atom molecular dynamics (MD) simulations. MD simulation results indicate that the dispersity of nanofillers, interfacial bonding, and chain mobility are imperative factors to improve the mechanical performance of nanocomposites, especially toughness. The tensile behavior and dissipated work of the PVC/CaCO3 model demonstrate that 12 wt % CaCO3 modified with oleate anion and dodecylbenzenesulfonate can impart high toughness to PVC due to its good dispersion, favorable interface interaction, and weak migration of PVC chains. Under the guidance of MD simulation, we experimentally prepared a transparent PVC/CaCO3 nanocomposite with good mechanical properties by in situ polymerization of monodispersed CaCO3 in vinyl chloride monomers. Interestingly, experimental tests indicate that the optimum toughness of a nanocomposite (a 368% increase in the elongation at break and 204% improvement of the impact strength) can be indeed realized by adding 12 wt % CaCO3 modified with oleic acid and dodecylbenzenesulfonic acid, which is remarkably consistent with the MD simulation prediction. In short, this work provides a proof-of-concept of using MD simulation to guide the experimental synthesis of PVC/CaCO3 nanocomposites, which can be considered as an example to develop other functional nanocomposites.

Combination Epicardial Adipose Tissue and left atrial Low Voltage Areas Predicting Atrial Fibrillation Recurrence after radiofrequency ablation.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia, with radiofrequency catheter ablation (RFCA) being first-line therapy. However, the high rate of post-ablation recurrence necessitates the identification of predictors for recurrence risk. Left atrial low-voltage areas (LA-LVASs), reflecting atrial fibrosis, have been confirmed to be related to recurrence of atrial fibrillation. Recently, epicardial adipose tissue (EAT) has been studied due to its role in initiating and maintaining atrial fibrillation. In this study, we try to evaluate the significance of the combined use of LA-EAT and percentage of LA-LVAs (LA-LVAs%) for predicting the recurrence of atrial fibrillation. METHODS: A total of 387 patients with AF who had undergone RFCA for the first time were followed up for 3, 6, and 12 months. They were divided into two groups: the recurrence group (n=90) and the non-recurrence group (n=297). Before the ablation, all patients underwent computed tomography angiography (CTA) examination of the left atrium, and the left atrial epicardial adipose tissue (LA-EAT) was measured using medical software (Advantage Workstation 4.6, GE, USA). After circumferential pulmonary vein isolation， a three-dimensional mapping system was used to map the left atrial endocardium and evaluate the LA-LVAs in sinus rhythm. RESULTS: After a median follow-up of 10.2 months, 90 patients developed AF recurrence after RFCA. Compared to patients without recurrence, the volume of LA-EAT (33.45±13.65 vs. 26.27±11.38; p<0.001) and the LA-LVAs% (1.60% (0%, 9.99%) vs. 0.00% (0%, 2.46%); p<0.001) were significantly higher. Multivariate analysis indicated that non-paroxysmal AF, LA-EAT volume, and LA-LVAs% were independent predictors. Compared to LA-EAT volume (AUC 0.655; specificity 0.675; sensitivity 0.586) or LA-LVAs% (AUC 0.659; specificity 0.836; sensitivity 0.437), the combined use of LA-EAT volume and LA-LVAs% offers higher accuracy for predicting AF recurrence after ablation (AUC 0.738; specificity 0.761; sensitivity 0.621). CONCLUSION: The combined LA-EAT and LA-LVAs% can effectively predict the risk of AF recurrence after radiofrequency ablation.

ALKBH5-mediated m6A demethylation of pri-miR-199a-5p exacerbates myocardial ischemia/reperfusion injury by regulating TRAF3-mediated pyroptosis.

Myocardial ischemia‒reperfusion injury (MI/RI) is closely related to pyroptosis. alkB homolog 5 (ALKBH5) is abnormally expressed in the MI/RI models. However, the detailed molecular mechanism of ALKBH5 in MI/RI has not been elucidated. In this study, rats and H9C2 cells served as experimental subjects and received MI/R induction and H/R induction, respectively. The abundance of the targeted molecules was evaluated using RT-qPCR, Western blotting, immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assay. The heart functions of the rats were evaluated using echocardiography, and heart injury was evaluated. Cell viability and pyroptosis were determined using cell counting Kit-8 and flow cytometry, respectively. Total m6A modification was measured using a commercial kit, and pri-miR-199a-5p m6A modification was detected by Me-RNA immunoprecipitation (RIP) assay. The interactions among the molecules were validated using RIP and luciferase experiments. ALKBH5 was abnormally highly expressed in H/R-induced H9C2 cells and MI/RI rats. ALKBH5 silencing improved injury and inhibited pyroptosis. ALKBH5 reduced pri-miR-199a-5p m6A methylation to block miR-199a-5p maturation and inhibit its expression. TNF receptor-associated Factor 3 (TRAF3) is a downstream gene of miR-199a-5p. Furthermore, in H/R-induced H9C2 cells, the miR-199a-5p inhibitor-mediated promotion of pyroptosis was reversed by ALKBH5 silencing, and the TRAF3 overexpression-mediated promotion of pyroptosis was offset by miR-199a-5p upregulation. ALKBH5 silencing inhibited pri-miR-199a-5p expression and enhanced pri-miR-199a-5p m6A modification to promote miR-199a-5p maturation and enhance its expression, thereby suppressing pyroptosis to alleviate MI/RI through decreasing TRAF3 expression.

RBM15 activates glycolysis in M1-type macrophages to promote the progression of aortic aneurysm and dissection.

Aortic aneurysm and dissection (AD) represent a critical cardiovascular emergency with an alarmingly high mortality rate. Recent research has spotlighted the overexpression of genes associated with the m6A modification in AD patients, linking them to the presence of inflammatory M1-type macrophages. Moreover, glycolysis is widely recognized as a key feature of inflammatory M1-type macrophages, but biomarkers linking glycolysis and macrophage function to promote disease progression in AD have not been reported. We conducted an analysis of aortic immune cell infiltration, macrophages, and m6A-related biomarkers in AD patients using bioinformatics techniques. Subsequently, we employed a combination of RT-PCR, WB, and immunofluorescence assays to elucidate the alterations in the expression of M1- and M2-type macrophages, as well as markers of glycolysis, following the overexpression of key biomarkers. These findings were further validated in vivo through the creation of a rat model of AD with knockdown of the aforementioned key biomarkers. The findings revealed that the m6A-modified related gene RBM15 exhibited heightened expression in AD samples and was correlated with macrophage polarization. Upon overexpression of RBM15 in macrophages, there was an observed increase in the expression of M1-type macrophage markers CXCL9 and CXCL10, alongside a decrease in the expression of M2-type macrophage markers CCL13 and MRC1. Furthermore, there was an elevation in the expression of glycolytic enzymes GLUT1 and Hexokinase, as well as HIF1α, GAPDH, and PFKFB3 after RBM15 overexpression. Moreover, in vivo knockdown of RBM15 led to an amelioration of aortic aneurysm in the rat AD model. This knockdown also resulted in a reduction of the M1-type macrophage marker iNOS, while significantly increasing the expression of the M2-type macrophage marker CD206. In conclusion, our findings demonstrate that RBM15 upregulates glycolysis in macrophages, thus contributing to the progression of AD through the promotion of M1-type macrophage polarization. Conversely, downregulation of RBM15 suppresses M1-type macrophage polarization, thereby decelerating the advancement of AD. These results unveil potential novel targets for the treatment of AD.

Lens power, cornea power and association with refractive error in children with moderate to high hyperopia.

OBJECTIVE: This study aimed to profile ocular biometry parameters and predictors of spherical equivalent refraction (SER) among children with moderate to high hyperopia. METHODS: Individuals <18 years of age with moderate to high hyperopia were enrolled from November 2015 to November 2021. Participants underwent a series of comprehensive ocular examinations, and were classified as having low hyperopia, that is, SER +0.5 to < +2.0 D or moderate to high hyperopia, that is, SER ≥ +2.0 D. RESULTS: A total of 459 and 230 eyes with moderate to high hyperopia and low hyperopia, respectively, were included. Moderate to high hyperopic eyes had a shorter axial length, stronger lens power (24.78 ± 5.47 D vs. 18.74 ± 1.63 D, p < 0.001) and weaker corneal power (42.82 ± 1.75 D vs. 43.31 ± 1.55 D, p < 0.001) than low hyperopic eyes. When comparing values before and after 5 years of age, both lens power and axial length differed significantly in the moderate to high hyperopia group, whereas in the low hyperopia group, they only differed significantly after 9 years of age. Lens power was negatively associated with AL in eyes with axial lengths between 20 and 22 mm. A multiple linear regression model which included axial length (standardised ß = -0.80, p < 0.001), corneal power (standardised ß = -0.47, p < 0.001) and lens power (standardised ß = 0.23, p < 0.001) explained 81.2% of the variance in SER. CONCLUSIONS: Differences in lens power and axial length in moderate to high hyperopic eyes became significantly smaller after 5 years of age, at least 4 years earlier than for the low hyperopia. Lens power could offset the axial elongation in participants with axial lengths between 20 and 22 mm, suggesting that children with moderate to high hyperopia might have different ocular growth patterns. Axial length, corneal power and lens power were the main predictors of SER in moderate to high hyperopia.

Systematic Assessment of Chinese Medicine Compounds for Mitigating Anthracycline-Induced Cardiotoxicity.

Background: Anthracycline chemotherapy is highly effective in treating various cancers but is associated with significant cardiotoxicity. Chinese herbal compounds have shown promise in mitigating this adverse effect, warranting systematic evaluation for clinical applicability. Objective: This study seeks to systematically assess the effectiveness of Chinese herbal compounds in managing anthracycline-induced cardiotoxicity via meta-analysis. The objective is to establish an evidence-based framework for their clinical use in preventing and treating this condition. Methods: This study employed a systematic review and meta-analysis design. A comprehensive search strategy was implemented across multiple databases, including CNKI, VIP, PubMed, Embase, and the Cochrane Library, to identify relevant randomized controlled trials (RCTs). Data collection involved extracting information on the efficacy of Chinese herbal compounds in treating anthracycline-induced cardiotoxicity. The primary outcome measures included left ventricular ejection fraction (LVEF), serum levels of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), creatine kinase (CK), and ST-T abnormality. The risk of bias in these studies was assessed following Cochrane Handbook guidelines. Meta-analysis of outcome indicators was conducted utilizing RevMan 5.4. Results: A total of 10 RCTs involving 748 patients met the inclusion criteria. Findings indicate that Chinese herbal compounds significantly enhance left ventricular ejection fraction (LVEF) while reducing serum levels of cTnI, CK-MB, and CK. Additionally, the compounds demonstrate a significant improvement in ST-T abnormality. Conclusions: Chinese herbal compounds exhibit promising potential in ameliorating anthracycline-induced cardiotoxicity. These findings underscore the potential utility of Chinese herbal medicine as an adjunctive therapy in managing this condition. Further research is warranted to explain the underlying mechanisms and optimize their clinical application.

Immunogenicity of novel DNA vaccines encoding receptor-binding domain (RBD) dimer-Fc fusing antigens derived from different SARS-CoV-2 variants of concern.

The continuously emerging of severe acute respiratory syndrome coronavirus-2 variants of concern (VOCs) led to a decline in effectiveness of the first-generation vaccines. Therefore, optimized vaccines and vaccination strategies, which show advantages in protecting against VOCs, are urgently needed. Here we constructed an optimized DNA vaccine plasmid containing built-in CpG adjuvant, and designed vaccine candidates encoding five forms of antigens derived from Wuhan-Hu-1. The results showed that plasmid with receptor binding domain (RBD) dimer-Fc fusing antigen (2RBD-Fc) induced the highest level of RBD-specific IgG and neutralizing antibodies in mice. Then 2dRBD-Fc and 2omRBD-Fc vaccines, respectively derived from delta and omicron VOCs, were constructed. The 2dRBD-Fc induced potent humoral and cellular immune responses, while the immunogenicity of 2omRBD-Fc was low. We also observed that sequential immunization with 2RBD-Fc, 2dRBD-Fc and 2omRBD-Fc effectively elicited neutralizing antibodies against each immunized strain, and RBD-specific T cell responses. To be noted, the Wuhan-Hu-1, delta and omicron neutralizing antibody titers induced by sequential immunization were comparable to that induced by repetitive immunization with 2RBD-Fc, 2dRBD-Fc or 2omRBD-Fc respectively. The results suggest that sequential immunization with DNA vaccines encoding potent antigens derived from different VOCs, may be a promising strategy to elicit immune responses against multiple variants.

Cardiac MRI Left Atrial Strain Associated With New-Onset Atrial Fibrillation in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Left atrial (LA) strain is associated with structural remodeling of the LA. Whether there is an association between LA strain obtained by cardiac magnetic resonance imaging (MRI) and new-onset atrial fibrillation (AF) after ST-segment elevation myocardial infarction (STEMI) is unclear. PURPOSE: To investigate the relationship between LA strain and new-onset AF after STEMI. STUDY TYPE: Retrospective. POPULATION: Three hundred and seventy-nine STEMI patients were enrolled, of which 26 had new-onset AF. FIELD STRENGTH/SEQUENCE: 3.0 T, balanced turbo field echo sequence. ASSESSMENT: Patients were divided into w/o AF group and new-onset AF group. Cardiac MRI images were analyzed using cardiovascular imaging software CVI 42 (Circle Cardiovascular Imaging, Canada). An automatic tracing algorithm was applied to obtain strain values. The reservoir strain, conduit strain, and booster strain were included in model 1, model 2, and model 3, respectively. STATISTICAL TESTS: Student's t-test, Mann-Whiney U test, and chi-square test were performed. Variables with a P ≤ 0.05 were incorporated into the logistic regression analysis. Area under curve of receiver operating characteristic was used to assess the ability of LA strain to identify new-onset AF. Bayesian information criterion, Akaike information criterion, and C-index were used to make comparisons between three models. P < 0.05 was considered statistically significant. RESULTS: Three models were used to assess LA strain identification ability for new-onset AF. After including multiple factors, right coronary artery (RCA), LVEF, and reservoir strain were still risk factors for new-onset AF in model 1. In model 2, age, RCA, LVEF, and conduit strain were still risk factors for new-onset AF. In model 3, RCA, LVEF, LVEDVi, and booster strain were still risk factors for new-onset AF. Model 2 has a stronger identification ability than others. DATA CONCLUSION: LA strain associated with new-onset AF after STEMI. The model including conduit strain was the best-fit one. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

Development and Validation of a Nomogram Model Affecting the ACT Targeting Rate During Radiofrequency Ablation of Atrial Fibrillation in China.

CONTEXT: A nomogram model affecting the activated clotting time (ACT) targeting rate during radiofrequency ablation of atrial fibrillation (RFCA) in China. PURPOSE: The aim of this study is to develop and validate a nomogram model for predicting the activated clotting time targeting rate after the initial bolus heparin dosages during the radiofrequency catheter ablation of atrial fibrillation in China. METHODS AND RESULTS: A retrospective observational study was conducted on the data of 465 patients with atrial fibrillation who underwent radiofrequency catheter ablation (RFCA) from October 2019 to June 2022. All patients were randomized into a training cohort (70%; n = 325) and a validation cohort (30%; n = 140). Independent risk factors were identified using univariate and multifactorial logistic regression analysis. The predictive nomogram model was established using R software. The nomogram was developed and evaluated based on differentiation, calibration, and clinical efficacy using concordance statistic (C-statistic), calibration plots, and decision curve analysis (DCA), respectively. The nomogram was established using three variables, including sex (OR 1.01, 95% CI 0.29-1.76, P = 0.007), heparin dose (OR 0.04; 95%CI 0.02-0.05, P < 0.001), and the baseline ACT (OR 0.03; 95%CI 0.02-0.04, P < 0.001). The C-statistic of the nomogram was 0.736 (95%CI 0.675-0.732) in the training cohort and 0.700 (95%CI 0.622-0.721) in the validation cohort. The calibration plots showed good agreement between the predictions and observations in the training and validation cohorts. The clinical decision curve also proves that the map is useful in clinical settings. CONCLUSION: The nomogram model has good discrimination and accuracy, which can screen attainment groups intuitively and individually, and has a certain predictive value for the probability of ACT reaching the target after the adequate dosage of initial heparin in Chinese patients with atrial fibrillation.

The Dopamine D1 Receptor Attenuates Titanium Particle-Induced Inhibition of Osteogenesis by Activating the Wnt Signaling Pathway.

Periprosthetic osteolysis (PPO), caused by wear particles, has become a major cause of joint replacement failure. Secondary surgery after joint replacement poses a serious threat to public health worldwide. Therefore, determining how to effectively inhibit wear particle-induced PPO has become an urgent issue. Recently, the interaction between osteogenic inhibition and wear particles at the biological interface of the implant has been found to be an important factor in the pathological process. Previous studies have found that the central nervous system plays an important role in the regulation of bone formation and bone remodeling. Dopamine (DA), an important catecholamine neurotransmitter, plays an integral role in the physiological and pathological processes of various tissues through its corresponding receptors. Our current study found that upregulation of dopamine first receptors could be achieved by activating the Wnt/ß-catenin pathway, improving osteogenesis in vivo and in vitro, and significantly reducing the inhibition of titanium particle-induced osteogenesis. Overall, these findings suggest that dopamine first receptor (D1R) may be a plausible target to promote osteoblast function and resist wear particle-induced PPO.

Evaluation of late gadolinium enhancement cardiac MRI using deep learning reconstruction.

BACKGROUND: Deep learning (DL)-based methods have been used to improve the imaging quality of magnetic resonance imaging (MRI) by denoising. PURPOSE: To assess the effects of DL-based MR reconstruction (DLR) method on late gadolinium enhancement (LGE) image quality. MATERIAL AND METHODS: A total of 85 patients who underwent cardiovascular magnetic resonance (CMR) examination, including LGE imaging using conventional construction and DLR with varying levels of noise reduction (NR) levels, were included. Both magnitude LGE (MLGE) and phase-sensitive LGE (PSLGE) images were reviewed independently by double-blinded observers who used a 5-point Likert scale for multiple measures regarding image quality. Meanwhile, the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and edge sharpness of images were calculated and compared between conventional LGE imaging and DLR LGE imaging. RESULTS: Both MLGE and PSLGE with DLR at 50% and 75% noise reduction levels received significantly higher scores than conventional imaging for overall imaging quality (all P < 0.01). In addition, the SNR, CNR, and edge sharpness of all DLR LGE imaging are higher than conventional imaging (all P < 0.01). The highest subjective score and best image quality is obtained when the DLR noise reduction level is at 75%. CONCLUSION: DLR reduced image noise while improving image contrast and sharpness in the cardiovascular LGE imaging.

Characterization of sonicated gluten protein and subsequent rheological properties of model dough and noodles.

BACKGROUND: The present study aimed to investigate the effects of the thermo-mechanical and rheological properties of a wheat gluten-sonicated model dough and noodles, as well as the effects of ultrasonic frequency (20, 28, 40, 68 and 80 kHz) on the functional properties and structural features of gluten. RESULTS: Water absorption, stability and developmental time, and viscoelastic behavior of gluten-sonicated model dough were all found to be improved. Water absorption, tensile resistance and stretching distance of noodles increased markedly, whereas cooking loss decreased. Ultrasonication at different frequencies also significantly affected gluten structure, including its surface hydrophobicity, micro-network structure, and secondary and tertiary structures. These alterations then caused changes in its functional characteristics. Compared to untreated gluten, sonicated gluten exhibited significantly increased oil and water capacities (8.75-15.26% and 100.65-127.71% higher than the untreated gluten, respectively), foaming and emulsifying properties, and increased solubility (63.46-98.83% higher than control). In addition, these findings indicated that 40 kHz was the likely resonance frequency of the cavitation bubble in the gluten solution. However, sodium dodecyl sulfate-polyacrylamide gel electrophoresis electropherograms revealed that such treatments did not affect the molecular weight of gluten, which was also consistent with its unchanged disulfide bond content. CONCLUSION: The present study clarified the impact of frequency on the properties of gluten and model dough. The best frequency for modification of gluten was 40 kHz. Collectively, these findings suggest that ultrasonic technology has the potential for use in modifying wheat gluten and commercial noodle processing. © 2022 Society of Chemical Industry.

Purinergic Signaling Controls Spontaneous Activity in the Auditory System throughout Early Development.

Spontaneous bursts of electrical activity in the developing auditory system arise within the cochlea before hearing onset and propagate through future sound-processing circuits of the brain to promote maturation of auditory neurons. Studies in isolated cochleae revealed that this intrinsically generated activity is initiated by ATP release from inner supporting cells (ISCs), resulting in activation of purinergic autoreceptors, K+ efflux, and subsequent depolarization of inner hair cells. However, it is unknown when this activity emerges or whether different mechanisms induce activity during distinct stages of development. Here we show that spontaneous electrical activity in mouse cochlea from both sexes emerges within ISCs during the late embryonic period, preceding the onset of spontaneous correlated activity in inner hair cells and spiral ganglion neurons, which begins at birth and follows a base to apex developmental gradient. At all developmental ages, pharmacological inhibition of P2Y1 purinergic receptors dramatically reduced spontaneous activity in these three cell types. Moreover, in vivo imaging within the inferior colliculus revealed that auditory neurons within future isofrequency zones exhibit coordinated neural activity at birth. The frequency of these discrete bursts increased progressively during the postnatal prehearing period yet remained dependent on P2RY1. Analysis of mice with disrupted cholinergic signaling in the cochlea indicate that this efferent input modulates, rather than initiates, spontaneous activity before hearing onset. Thus, the auditory system uses a consistent mechanism involving ATP release from ISCs and activation of P2RY1 autoreceptors to elicit coordinated excitation of neurons that will process similar frequencies of sound.SIGNIFICANCE STATEMENT In developing sensory systems, groups of neurons that will process information from similar sensory space exhibit highly correlated electrical activity that is critical for proper maturation and circuit refinement. Defining the period when this activity is present, the mechanisms responsible and the features of this activity are crucial for understanding how spontaneous activity influences circuit development. We show that, from birth to hearing onset, the auditory system relies on a consistent mechanism to elicit correlate firing of neurons that will process similar frequencies of sound. Targeted disruption of this activity will increase our understanding of how these early circuits mature and may provide insight into processes responsible for developmental disorders of the auditory system.

Activation of dopamine receptor D1 promotes osteogenic differentiation and reduces glucocorticoid-induced bone loss by upregulating the ERK1/2 signaling pathway.

BACKGROUND: The inhibition of osteogenic differentiation is a major factor in glucocorticoid-induced bone loss, but there is currently no effective treatment. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of the neuroendocrine system in bone metabolism has emerged, the precise effects of dopamine receptor signaling on osteoblastogenesis remain unknown. METHODS: In vitro, western blotting and immunofluorescence staining were used to observe the expression of dopamine receptors in MC3T3-E1 and BMSCs cells treated with dexamethasone (Dex). In addition, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining and western blotting were used to evaluate the effect of D1R activation on osteogenic differentiation in Dex-induced MC3T3-E1 cells via the ERK1/2 signaling pathway. In vivo, micro-CT and hematoxylin and eosin (H&E), toluidine blue and immunohistochemical staining were used to determine the effect of D1R activation on Dex-induced bone loss. RESULTS: We demonstrated that the trend in D1R but not D2-5R was consistent with that of osteogenic markers in the presence of Dex. We also demonstrated that the activation of D1R promoted Dex-induced osteogenic differentiation by activating the ERK1/2 pathway in vitro. We further demonstrated that a D1R agonist could reduce Dex-induced bone loss, while pretreatment with a D1R inhibitor blocked the effect of a D1R agonist in vivo. CONCLUSIONS: Activation of D1R promotes osteogenic differentiation and reduces Dex-induced bone loss by activating the ERK1/2 pathway. Hence, D1R could serve as a potential therapeutic target for glucocorticoid-induced osteoporosis.

A zinc finger protein SlSZP1 protects SlSTOP1 from SlRAE1-mediated degradation to modulate aluminum resistance.

In acidic soils, aluminum (Al) toxicity is the main factor inhibiting plant root development and reducing crops yield. STOP1 (SENSITIVE TO PROTON RHIZOTOXICITY 1) was a critical factor in detoxifying Al stress. Under Al stress, STOP1 expression was not induced, although STOP1 protein accumulated, even in the presence of RAE1 (STOP1 DEGRADATION E3-LIGASE). How the Al stress triggers and stabilises the accumulation of STOP1 is still unknown. Here, we characterised SlSTOP1-interacting zinc finger protein (SlSZP1) using a yeast-two-hybrid screening, and generated slstop1, slszp1 and slstop1/slszp1 knockout mutants using clustered regularly interspaced short palindromic repeats (CRISPR) in tomato. SlSZP1 is induced by Al stress but it is not regulated by SlSTOP1. The slstop1, slszp1 and slstop1/slszp1 knockout mutants exhibited hypersensitivity to Al stress. The expression of SlSTOP1-targeted genes, such as SlRAE1 and SlASR2 (ALUMINUM SENSITIVE), was inhibited in both slstop1 and slszp1 mutants, but not directly regulated by SlSZP1. Furthermore, the degradation of SlSTOP1 by SlRAE1 was prevented by SlSZP1. Al stress increased the accumulation of SlSTOP1 in wild-type (WT) but not in slszp1 mutants. The overexpression of either SlSTOP1 or SlSZP1 did not enhance plant Al resistance. Altogether, our results show that SlSZP1 is an important factor for protecting SlSTOP1 from SlRAE1-mediated degradation.

The transcription factor SlWRKY37 positively regulates jasmonic acid- and dark-induced leaf senescence in tomato.

Initiation and progression of leaf senescence are triggered by various environmental stressors and phytohormones. Jasmonic acid (JA) and darkness accelerate leaf senescence in plants. However, the mechanisms that integrate these two factors to initiate and regulate leaf senescence have not been identified. Here, we report a transcriptional regulatory module centred on a novel tomato WRKY transcription factor, SlWRKY37, responsible for both JA- and dark-induced leaf senescence. The expression of SlWRKY37, together with SlMYC2, encoding a master transcription factor in JA signalling, was significantly induced by both methyl jasmonate (MeJA) and dark treatments. SlMYC2 binds directly to the promoter of SlWRKY37 to activate its expression. Knock out of SlWRKY37 inhibited JA- and dark-induced leaf senescence. Transcriptome analysis and biochemical experiments revealed SlWRKY53 and SlSGR1 (S. lycopersicum senescence-inducible chloroplast stay-green protein 1) as direct transcriptional targets of SlWRKY37 to control leaf senescence. Moreover, SlWRKY37 interacted with a VQ motif-containing protein SlVQ7, and the interaction improved the stability of SlWRKY37 and the transcriptional activation of downstream target genes. Our results reveal the physiological and molecular functions of SlWRKY37 in leaf senescence, and offer a target gene to retard leaf yellowing by reducing sensitivity to external senescence signals, such as JA and darkness.

Association of Soluble Suppression of Tumorigenicity 2 with New-Onset Atrial Fibrillation in Acute Myocardial Infarction.

BACKGROUND: The combination of acute myocardial infarction (AMI) and atrial fibrillation (AF) is still a thorny problem in the clinic. At present, there are few reports on the role of soluble suppression of tumorigenicity 2 (sST2) in AF after AMI. This study was to explore the predictive value of sST2 in patients with AMI for new-onset AF. METHODS: This is a single-center retrospective clinical observation study. We continuously included AMI patients from September 2019 to November 2021. The concentration of sST2 in blood samples was determined. During admission, a suspicious heart rhythm was recorded by electrocardiogram (ECG) monitoring, and new-onset AF was confirmed by immediate body surface ECG. RESULTS: After multiple factors were included, age, right coronary artery, high-sensitivity C-reactive protein, left ventricular ejection fraction, and sST2 were still risk factors for new-onset AF. The area under curve value of age and sST2 was more than 0.7, which showed good diagnostic value. For reevaluation, the sST2 was added to the clinical new-onset AF prediction model. It was found that the integrated discrimination improvement and net reclassification index in the model were improved significantly. CONCLUSION: sST2 is an independent predictor of new-onset AF in patients with AMI and can improve the accuracy of the AF risk model.

A comprehensive analysis of potential gastric cancer prognostic biomarker ITGBL1 associated with immune infiltration and epithelial-mesenchymal transition.

BACKGROUND: Integrin, beta-like 1 (ITGBL1) is involved in a variety of human malignancies. However, the information on the involvement of ITGBL1 in gastric carcinoma (GC) is limited. Hence, this study aimed further to explore the functions and mechanisms of ITGBL1 in GC. METHODS: First, multiple bioinformatics databases, including Oncomine, Tumor Immune Estimation Resource, UALCAN, and Kaplan-Meier Plotter, were used to predict the expression level and prognostic value of ITGBL1, as well as its association with immune infiltration and epithelial-mesenchymal transition (EMT) in GC. Quantitative reverse transcription-polymerase chain reaction and immunohistochemical analysis were used to detect the expression of ITGBL1 in both GC tissues and cells. Then, targeted silencing of ITGBL1 in GC cells was further used to examine the biological functions of ITGBL1. RESULTS: These databases revealed that ITGBL1 was overexpressed and affected the overall survival in GC. Besides, the expression of ITGBL1 positively correlated with immune-infiltrating cells and EMT-related markers. Subsequently, molecular biology experiments verified these predictions. In GC tissues and cells, ITGBL1 was notably overexpressed. Loss-of-function studies showed that the knockdown of ITGBL1 significantly suppressed migration and invasion but promoted apoptosis in MGC803 GC cells. Furthermore, the inhibition of ITGBL1 resulted in remarkably increased protein expression levels of cadherin 1, while the expression of Vimentin, Snail, and transforming growth factor-ß1 was downregulated, indicating the initiation and progression of GC caused by ITGBL1 partly via inducing EMT. CONCLUSIONS: To sum up, the findings indicated that ITGBL1 acted as a valuable oncogenic factor in GC.

Nonatrial Fibrillation Patients With Complete P Wave Disappearance: An Overlooked Population With High Stroke Risk.

BACKGROUND AND PURPOSE: Complete P wave disappearance (CPWD) in patients without atrial fibrillation is an uncommon clinical phenomenon. We aimed to study the relationship between CPWD and thromboembolism. METHODS: Between July 2007 and December 2018, consecutive patients with CPWD on surface ECG and 24-hour Holter recording were recruited into the study from 4 centers in China. All recruited patients underwent transesophageal echocardiography or cardiac computed tomography to screen for atrial thrombus. Atrial electrical activity and scar were assessed by electrophysiological study (EPS) and 3-dimensional electroanatomic mapping. Cardiac structure and function were assessed by multimodality cardiac imaging. RESULTS: Twenty-three consecutive patients (8 male; mean age 48.5±14.7 years) with CPWD were included. Only 3 patients demonstrated complete atrial electrical silence with atrial noncapture. Thirteen patients who had invasive atrial endocardial mapping demonstrated extensive scar. Pulse-wave mitral inflow Doppler demonstrated absent and dampened A waves in 18 and 5 patients, respectively. Pulse-wave tricuspid inflow Doppler showed absent and dampened A waves in 19 and 4 patients, respectively. Upon recruitment, 8 patients had previous stroke and 3 patients had atrial thrombus. Warfarin was prescribed to all patients. During median follow-up of 42.0 months, 2 patients developed massive ischemic stroke due to warfarin discontinuation. CONCLUSIONS: Our study suggested that CPWD reflects extensive atrial electrical silence and significantly impaired atrial mechanical function. It was strongly associated with thromboembolism and the clinical triad of CPWD-atrial paralysis-stroke was proposed. Anticoagulation should be recommended in such patients.