Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to inves-tigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar.We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation.Spatial transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods.During the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue repair.ST analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling activation.Moreover,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar formation.The combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN alone.At the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this.The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH.Inversely,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy.This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.

Objective To investigate the effect of state anxiety and trait anxiety on attentional orienting of heroin addicts. Methods State anxiety and trait anxiety was measured by State-Trait Anxiety Inventory (STAI). Forty heroin ad?dicts (36 males and 4 females) and 40 healthy controls (36 males and 4 females) participated in cue-target task. Atten?tional orienting and reorienting were measured in valid cue trials and invalid cue trails. Results Heroin addicts had sig?nificantly greater state anxiety [(42.65 ± 6.58) vs. (36.60 ± 8.91)] and trait anxiety [(44.43 ± 7.67) vs. (37.00 ± 8.63)] values than controls (P<0.05). The state anxiety was significantly correlated with orientation RT difference (r=-0.259, P=0.020) and disengaging/reorientation RT difference (r=0.333, P=0.003) in heroin addicts. Trait anxiety was also significantly cor?related with orientation RT difference (r=-0.248, P=0.026) and disengaging/reorientation RT difference (r=0.356, P=0.001) in heroin addicts. Conclusion Heroin addicts have significantly greater anxiety than healthy controls. Both their state anxiety and trait anxiety are associated with attentional orienting and disengaging/reorienting.

Objective To investigate the clinical value of color Doppler ultrasound (CDFI) in the diagnosis of carotid atherosclerosis lesion in patients with acute stroke.Methods Totally 60patients with acute cerebral infarction were examined with CDFI to observe vessel diameter and stenosis degree of common carotid artery,internal carotid artery and external carotid artery and the results were compared with digital subtraction angiography (DSA) test.Results Among 60patients,normal ultrasound diagnosis was in 28 cases,occlusion and stenosis in 32 cases,stenosis in 25 cases; mild,moderate and severe stenosis were in 18,20,12 vessels,occlusion in 7 cases,14vessels.DSA examination results showed normal in 29 cases,stenosis and occlusion in 31 cases,stenosis in 26 cases,mild,moderate and severe stenosis of the 18,16,18 vessels; occlusion in 5 cases,10 vessels.The consistency test results between carotid artery color Doppler ultrasound and DSA were Kappa=0.786,0.667(P＜0.05).All carotid DSA results were considered as gold standard,CDFI diagnosis of moderate to severe stenosis was in high accuracy compared with DSA.Conclusions CDFI in the diagnosis of different degrees of carotid stenosis is in good agreement with DSA diagnosis,and may replace invasive DSA diagnosis of moderate to severe stenosis.

Objective To explore the clinical significance of the disagreement between transmitral pulsed wave Doppler (PWD) and mitral annulus Doppler tissue imaging (DTI) in the estimation of left ventricular (LV) filling pressures. Methods One hundred and eighty-two sinus rhythm patients without arrhythmia, congenital heart disease and valvular disease underwent routine echocardiography and synchronous electrocardiogram for assessment of LV function. Early and late diastolic velocities of LV, which were composed of e and a waves, were recorded using DTI at the mitral annulus. Six sites at the mitral annuli were selected corresponding to the septal, lateral, anterior septal, posterior, inferior, and anterior walls of LV from apical 4-, 3-and 2-chamber views. Transmitral diastolic flow velocity, which was represented by E and A wave, was measured with PWD from apical 4-chamber view. Ratio of early and late diastolic transmitral valve (MV-E/A), ratio of DTI-e/a-ann and ratio of E/e-ann were calculated, respectively. The mean value of e-ann from the above 6 sites was selected to describe the early diastolic velocities of mitral annular. Results According to the results of MV-E/A ratio and DTI-e/a-ann ratios of the 6 sites, these 182 patients were divided into 4 groups: groupⅠ(n=68): MV-E/A＜1.0, DTI-e/a-ann＜1.0 at all the 6 sites at the same time, with mean MV-E/A ratio being 0.71±0.16 and mean E/e-ann ratio 15.91±6.78; groupⅡ(n=38): MV-E/A＜1.0, DTI-e/a-ann≥1.0 at 1-6 sites among the total sites, with mean MV-E/A ratio being 0.76±0.12 and mean E/e-ann ratio 10.37±2.63; group Ⅲ(n=23): MV-E/A≥1.0, DTI-e/a-ann≥1.0 at all the 6 sites at the same time, with mean MV-E/A ratio being 1.74±0.42 and mean E/e-ann ratio 9.57±2.39; group Ⅳ(n=53): MV-E/A≥1.0, DTI-e/a-ann＜1.0 at 1-6 sites among the total sites, with mean MV-E/A ratio being 1.31±0.31 and mean E/e-ann ratio 13.27±9.46. The mean ages of group Ⅰ, Ⅱand Ⅳ were older than that of group Ⅲ. Although there was no obvious difference between group Ⅰand groupⅡ in the mean age and mean MV-E/A (P＞0.05), the mean E/e-ann was much higher in group Ⅰthan that in groupⅡ (P＜0.05). The mean MV-E/A was similar in group Ⅲ and group Ⅳ (P＞0.05), but the mean age and mean E/e-ann in the latter were older and higher than those in the former (P＜0.05), respectively. The mean age in group Ⅳ was younger than that in group Ⅰand Ⅱ, while the mean E/e-ann in group Ⅳ was higher than that in group Ⅱ, but lower than group Ⅰ (P＜0.05). Conclusion ①Ratio of MV-E/A ＜1.0 and ratios of DTI-e/a-ann ＜1.0 at all the 6 sites indicates increasing LV filling pressures; ②MV-E/A≥1.0 and DTI-e/a-ann＜1.0 at 1-6 sites among the total sites predicts a tendency of high LV filling pressures; ③Wide variability may present in those with MV-E/A＜1.0, DTI-e/a-ann≥1.0 at 1-6 sites among the total 6 sites or MV-E/A≥1.0, DTI-e/a-ann≥1.0 at all the 6 sites at the same time; ④Age of the patient has great influence on the measurement of MV-E/A ratio and DTI-e/a-ann ratio.

Aim To investigate the pharmacokinetics of dipfluzine hydrochloride,a novel piperazines calcium antagonist.Methods Eighteen Beagle dogs were randomly divided into three groups,which were administered with dipfluzine hydrochloride at iv single dose of 1.5,3.0 and 6.0 mg?kg-1,respectively.The blood was collected at different time.A RP-HPLC method was developed to determine the concentration of dipfluzine hydrochloride in plasma.The pharmacokinetic parameters were calculated by 3P97 software.Results The specificity,lowest limit of detection and quantification,extraction recoveries,the precision of intra-and inter-day and stability were qualified to the pharmacokinetic study.The concentration-time courses of dipfluzine hydrochloride were best fitted to a two-compartment open model at three doses.The main pharmacokinetic parameters at three doses were 24.7,24.2 and 29.6 h for T12?,0.44,1.12 and 2.86 g?min?L-1 for AUC,1.30,1.22 and 1.28 L?kg-1 for Vc,and 3.4?10-3,2.7?10-3 and 2.1?10-3 L?kg-1?min-1 for CL,respectively.Conclusions The developed RP-HPLC method for determination of dipfluzine hydrochloride in plasma can satisfy the requirement of pharmacokinetic study after iv dipfluzine hydrochloride.Analysis of plasma concentration-time curves indicates a biphasic decrease.There was a linear relationship between AUC and dosage.