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.

OBJECTIVE: Exposure to polycyclic aromatic hydrocarbons (PAHs) or metal(loid)s individually has been associated with neural tube defects (NTDs). However, the impacts of PAH and metal(loid) co-exposure and potential interaction effects on NTD risk remain unclear. We conducted a case-control study in China among population with a high prevalence of NTDs to investigate the combined effects of PAH and metal(loid) exposures on the risk of NTD. METHODS: Cases included 80 women who gave birth to offspring with NTDs, whereas controls were 50 women who delivered infants with no congenital malformations. We analyzed the levels of placental PAHs using gas chromatography and mass spectrometry, PAH-DNA adducts with ³²P-post-labeling method, and metal(loid)s with an inductively coupled plasma mass spectrometer. Unconditional logistic regression was employed to estimate the associations between individual exposures and NTDs. Least absolute shrinkage and selection operator (LASSO) penalized regression models were used to select a subset of exposures, while additive interaction models were used to identify interaction effects. RESULTS: In the single-exposure models, we found that eight PAHs, PAH-DNA adducts, and 28 metal(loid)s were associated with NTDs. Pyrene, selenium, molybdenum, cadmium, uranium, and rubidium were selected through LASSO regression and were statistically associated with NTDs in the multiple-exposure models. Women with high levels of pyrene and molybdenum or pyrene and selenium exhibited significantly increased risk of having offspring with NTDs, indicating that these combinations may have synergistic effects on the risk of NTDs. CONCLUSION Our findings suggest that individual PAHs and metal(loid)s, as well as their interactions, may be associated with the risk of NTDs, which warrants further investigation.
Humans ; Neural Tube Defects/chemically induced* ; Polycyclic Aromatic Hydrocarbons/adverse effects* ; Female ; Case-Control Studies ; China/epidemiology* ; Adult ; Pregnancy ; Environmental Pollutants ; Maternal Exposure/adverse effects* ; Metals/toxicity* ; Young Adult ; Risk Factors

Objective: To evaluate the predictive value of the proportion of hibernating myocardium (HM) in total perfusion defect (TPD) on reverse left ventricle remodeling (RR) after coronary artery bypass graft (CABG) in patients with heart failure with reduced ejection fraction (HFrEF) by ^99mTc-methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) combined with ¹⁸F-flurodeoxyglucose (FDG) gated myocardial imaging positron emission computed tomography (PET). Methods: Inpatients diagnosed with HFrEF at the Cardiac Surgery Center, Anzhen Hospital of Capital Medical University from January 2016 to January 2022 were prospectively recruited. MPI combined with ¹⁸F-FDG gated PET was performed before surgery for viability assessment and the patients received follow-up MPI and ¹⁸F-FDG gated PET at different stages (3-12 months) after surgery. Δ indicated changes (post-pre). Left ventricular end-systolic volume (ESV) reduced at least 10% was defined as RR, patients were divided into reverse remodeling (RR+) group and the non-reverse group (RR-). Binary logistic regression analysis was used to identify predictors of RR. Receiver operating characteristic (ROC) curve analysis was performed and the area under the curve (AUC) was calculated to assess the cut-off value for predicting RR. Additionally, we retrospectively enrolled inpatients with HFrEF at the Cardiac Surgery Center, Anzhen Hospital of Capital Medical University from January 2021 to January 2022 as the validation group, who underwent MPI and ¹⁸F-FDG gated PET before surgery. Echocardiography was performed before CABG and after CABG (3-12 months). In the validation group, the reliability of obtaining the cut-off value for the ROC curve was verified. Results: A total of 28 patients with HFrEF (26 males; age (56.9±8.7) years) were included in the prospective cohort. HM/TPD was significantly higher in the RR+ group than in the RR- group ((51.8%±17.9%) vs. (35.7%±13.9%), P=0.016). Binary logistic regression analysis revealed that HM/TPD was an independent predictor of RR (Odds ratio=1.073, 95% Confidence interval: 1.005-1.145, P=0.035). ROC curve analysis revealed that HM/TPD=38.3% yielded the highest sensitivity, specificity, and accuracy (all 75%) for predicting RR and the AUC was 0.786 (P=0.011). Meanwhile, a total of 100 patients with HFrEF (90 males; age (59.7±9.6) years) were included in the validation group. In the validation group, HM/TPD=38.3% predicted RR in HFrEF patients after CABG with the highest sensitivity, specificity and accuracy (82%, 60% and 73% respectively). Compared with the HFrEF patients in the HM/TPD<38.3% group (n=36), RR and cardiac function improved more significantly in the HM/TPD≥38.3% group (n=64) (all P<0.05). Conclusions: Preoperative HM/TPD ratio is an independent factor for predicting RR in patients with HFrEF after CABG, and HM/TPD≥38.3% can accurately predict RR and the improvement of cardiac function after CABG.
Male ; Humans ; Middle Aged ; Aged ; Stroke Volume ; Heart Failure ; Fluorodeoxyglucose F18 ; Retrospective Studies ; Reproducibility of Results ; Prospective Studies ; Coronary Artery Bypass ; Ventricular Dysfunction, Left ; Tomography, Emission-Computed, Single-Photon ; Perfusion ; Myocardium

Objective: To establish a purge and trap-gas chromatography-mass spectrometry method based on soil analysis model for the determination of six benzene homologues (benzene, toluene, ethylbenzene, m-xylene, p-xylene and o-xylene) in human blood. Methods: From September 2020 to May 2021, diatomite was used as a dispersant to add 2.0 ml blood sample and fully mixed. The sample was directly injected into the purging and collecting bottle after purging. The gas chromatography column was used for separation. The retention time locking was used for qualitative analysis and the selected ion scanning mode (SIM) was used for detection. The detection limit and recovery rate of the method were analyzed. Results: The linear range of the method for the determination of six benzene homologues in human blood was 0.02-10.00 ng/ml, the correlation coefficient was 0.9927-0.9968, the detection limit was 0.006-0.016 ng/ml, the recovery rate of sample spiking was 84.39%-102.41%, and the precision of the method was 3.06%-6.90%. Conclusion: Purge and trap-gas chromatography-mass spectrometry can simultaneously determine the contents of six benzene homologues in human blood. The pretreatment method is simple, time-saving, and the method has low detection limit, which provides a scientific basis for the detection of benzene homologues in human body.
Humans ; Benzene/analysis* ; Gas Chromatography-Mass Spectrometry/methods* ; Xylenes/analysis* ; Benzene Derivatives/analysis* ; Toluene/analysis*

The expression, function and prognostic significance of epoxide hydrolase 2 (EPHX2) in hepatocellular carcinoma (HCC) were comprehensively analyzed through collecting HCC tissues and public database. The GEO and MitoCarta databases were used to identify the mitochondria-related differentially expressed genes (DEGs) in HCC. The Cancer Genome Atlas (TCGA) database was applied to analyze the expression levels of DEGs in HCC, including EPHX2 and its co-expressed genes. The R package was applied to draw the Kaplan-Meier survival curve and gene function enrichment analysis. The STRING database and GSEA software were used to analyze the protein-protein interaction (PPI) network and gene set enrichment analysis. qPCR and GEO database were applied to verify the expression level of EPHX2 in HCC. In the present study, a total of 15 mitochondria-related DEGs were identified in HCC. The expression of EPHX2 in HCC was significantly decreased compared to the normal liver tissues (P < 0. 01). The expression of EPHX2 was related to gender, tumor stage and grade in HCC, but not associated with age, T stage, et al in HCC. Moreover, compared with the patients with lower expression of EPHX2, patients with higher expression of EPHX2 had a better prognosis. EPHX2 was associated with fatty acid degradation. In addition, PPI results indicated that HAO1, AGXT, ACOX1, GSTκ1, SCP-2, CAT, CYP2C8, CYP2C9, CYP2B6, and CYP2J2 were co-expressed with EPXH2 in HCC. Furthermore, GSEA results showed that the group with lower expression of EPHX2 was positively correlated with the gene set of liver cancer cell proliferation and liver cancer recurrence. qPCR and GEO database results verified that the expression of EPHX2 was significantly decreased in HCC. The expression of EPHX2 was decreased in HCC, strongly suggesting that EPHX2 might function as a tumor suppressor gene in HCC. However, the potential mechanism of EPHX2 in HCC needs to be further verified.

Objective To study the clinical events and risk factors of in stent restenosis (ISR) during the ＞1 year follow-up period after vertebral artery stenting.Methods Forty-six patients with 48 stents implanted from the Shaoxing No.2 Hospital between January 2010 and October 2016were divided into ISR group (n=8) and ISR-free group (n=38) or clinical events group (n=8)and clinical events-free group (n=38).The influencing factors for their long-term clinical outcome were analyzed after vertebral artery stenting.Results The mean stenosis length was (7.7 ± 4.6mm,the stenosis severity was 80.7％±14.2％,and the residual stenosis was 3.0％±8.4％ before stenting.The mean angiographic follow-up time was 31.6±20.8 months,during which ISR occurred in 8 patients (17.4％).The mean clinical follow-up time was 53.8±27.0 months,during which clinical events occurred in 8 patients (17.4％).Survival analysis showed that ISR usually occurred in the first 20 months and no clinical events occurred in 23 patiemts (50.0％) after vertebral artery stenting.The stenosis was significantly longer in ISR group than in ISR-free group (6.00±2.00 mm vs 2.76±4.14 mm,P=0.003).The diameter of stents was significantly shorter in clinical events group than in clinical events-free group (3.53±0.93 mm vs 4.18±0.67 mm,P=0.024).Conclusion The long-term clinical follow-up outcome is associated with the length and diameter of stents in patients after vertebral artery stenting.

Objective To study the characteristics and mechanism of mine blast injury that wading in shoal of different depths through an animal model.Methods Ninety-six healthy adult New Zealand white rabbits weighing 2.19 ± 0.12kg were randomly divided into land group (n=16),limb wading group (n=16,the water depth reaching up the middle of the thighs of rabbits),and chest wading group (n=16,the water depth reaching up the thoracic xiphoid),stress test group (n=30),fake injury group (n=18).Punctiform burster was used to simulate landmine.Electric ignited the simulated mine away,causing landmine explosion injury to rabbits' one-sided hind limbs in upright state.High-speed photography was used to observe the movement of water accompanying the simulated mine explosion.Arterial blood serum markers of myocardial injury (CK-MB,cTnⅠ) and nerve injury (MBP,NSE) were detected before injury,and 3,6 and 12h after injury,and echocardiography,electrocardiography,CT,DSA and other examinations were implemented at the same time.Survival animals were killed 12h after injury for anatomy to record their injuries to the limbs and distant organs.The histopathological examination was done to define the injury characteristics furthen Results Feet and distal tibia were broken,and closed femoral fractures and arterial damage were often found away from the stump in limb wading group.This type of injury was different from the mop-like tearing tissue in the land group.Chest,abdominal organs and the brain,spinal cord injury in wading group were more severe than those in land group.There were higher incidences of chest,abdominal organs and spinal cord injury in chest wading Group.Conclusion The energy transfer of underwater explosion is affected by water depth and limbs or trunk mutually,which is an important mechanism of the complex and serious injuries in the wading group.The wading depth is an important factor affecting severity of the injury.Based on characteristics and unique mechanism of wading explosion,emergency treatment and the principle of early treatment for injury warrant further explored.

Objective To develop a digital management system in the pulmonary function test room to realize pulmonary function data sharing between the outpatient department,ward,medical examination facility and community hospital.Methods The system was developed with Microsoft Visual Studio 2010 and enterprise-version SQL Server database,and the integration of pulmonary function test devices and HIS was achieved by linking up the spirometer,bluetooth height & weight digital measuring equipment,barcode scanner,back tracking system and the switch to HIS.Results The system contributed to enhancing the flow and efficiency of clinical service.Conclusion The system standardizes the flow and quality control of pulmonary function test,implements patient data sharing between the outpatient department and ward and facilitates scientific research data acquisition,and thus is worthy promoting clinically.

OBJECTIVETo investigate the effect of Xuezhikang (, XZK) on renal cell apoptosis in diabetic rats and the possible mechanism.

METHODSSixty-six rats were randomly divided into 3 groups: the normal, model and XZK groups. In each group, the rats were further randomly divided into 3-month and 6-month subgroups, respectively. Diabetes of rats was induced by a single intraperitoneal injection of 1% streptozocin at 60 mg/kg body weight. Rats in the XZK group received gastric perfusion of XZK (1200 mg/kg body weight) everyday for 3 or 6 months, while rats in the normal and model groups received equal volume of saline. Twenty-four hours' urine was collected for urinary albumin excretion (UAE) measurement. Periodic acid-Schiff (PAS) and Masson's trichrome staining were used for saccharides and collagen detection. Cell apoptosis of renal cortex was investigated by TdT-mediated dUTP nick end labeling (TUNEL) staining. Bax and Bcl-2 expressions were detected by immunohistochemistry and Western blot, respectively. Cytochrome C (Cyt C) and caspase-9 concentration were detected by Western blot.

RESULTSCompared with the model group, XZK treatment could significantly decrease the kidney hypertrophy index, 24 h UAE, renal cell apoptosis, cytoplasmic Cyt C level and active caspase-9 level, as well as suppress the increment of Bax and up-regulate the expression of Bcl-2, leading to the suppression of Bax/Bcl-2 ratio at 3 and 6 months (P<0.05 or P<0.01). Moreover, XZK treatment could alleviate the deposition of PAS-stained saccharides and Masson's trichromestained collagen to different extent.

CONCLUSIONSRenal cell apoptosis was observed in diabetic kidney, in which mitochondrial apoptotic pathway might be involved. XZK treatment could attenuate pathological changes in diabetic kidney and reduce renal cell apoptosis, probably via the suppression of Bax/Bcl-2 ratio, which lead to inhibition of Cyt C release and following caspase-9 activation.

Albuminuria ; blood ; complications ; Animals ; Apoptosis ; drug effects ; Blood Glucose ; metabolism ; Caspase 9 ; metabolism ; Cytochromes c ; metabolism ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hypertrophy ; In Situ Nick-End Labeling ; Kidney ; drug effects ; pathology ; Kidney Glomerulus ; pathology ; Lipids ; blood ; Male ; Mesangial Cells ; drug effects ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats, Sprague-Dawley ; Streptozocin ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo evaluate the expression of interleukin-6 (IL-6) and its clinicopathological significance in Castleman's disease (CD).

METHODSClinical data and paraffin blocks of 92 CD patients and 20 cases of lymph node reactive hyperplasia (LRH) as a control group were collected from department of pathology of Peking University Health Science Center. The expression of IL-6 was detected by using immunohistochemical method.

RESULTSThe 92 patients were composed of 42 multicentric variant (MCDs) and 50 unicentric variant (UCDs) clinically, and 30 hyaline-vascular variant (HV-CDs) and 62 plasma cell variant (PC-CDs) morphologically. None of them was positive for HIV tests. There were 56 males and 36 females, and their ages ranged from 4 years to 90 years with the median 41 years. IL-6 was expressed in 77 (83.7%) of 92 CD cases and 1 (5.0%) of 20 LRH cases. The expression rate of IL-6 was 90.5% in MCDs, 78.0% in UCDs, 93.6% in PC-CDs and 63.4% in HV-CDs, respectively. PC-CD cases showed a significantly higher expression rate of IL-6 than HV-CD cases (P = 0.001). All cases with positive IL-6 expression in plasmacytes were PC-CDs, showing obviously higher expression in MCDs than that in UCDs (P = 0.003). Compared with HV-CD cases, much more PC-CD cases showed IL-6 positivity in endothelial cells (P = 0.008). However, IL-6 was rarely expressed by both FDCs and macrophages, with only 3.3% and 10.9% positive cases, respectively. There are 53.2% (41/77) of the IL-6 positive cases and 20.0% (3/15) of IL-6 negative cases suffered from systemic symptoms, showing a significant difference between the two groups (P = 0.018). Cases with IL-6 expression in plasmacytes and macrophages were more likely to suffer from systemic symptoms, especially B type symptoms (P < 0.05).

CONCLUSIONThere is a high expression rate of IL-6 in CD, which is different from LRH. The expression of IL-6 has close relationship with CD subtypes and the presence of systemic symptoms. In all, the evaluation of interleukin-6 is of great value to guide the diagnosis and therapy of CD.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Castleman Disease ; metabolism ; pathology ; Child ; Child, Preschool ; Female ; Humans ; Interleukin-6 ; metabolism ; Male ; Middle Aged ; Young Adult