ObjectiveTo investigate the regulatory effect and potential mechanisms of isocitrate dehydrogenase 3A （IDH3A） on cardiomyocyte hypertrophy. MethodsThe expression of IDH3A in the myocardium of healthy volunteers （n=10） and patients with heart failure （HF） （n=10）， and in the myocardium of mice subjected to transverse aortic constriction （TAC） surgery and sham operation， as well as in phenylephrine （PE）-induced neonatal rat ventricular cardiomyocytes （NRVCs）， was assessed by real-time quantitative polymerase chain reaction （RT-qPCR） and Western blot assay. The effect of adenovirus-mediated overexpression of IDH3A on the expression of hypertrophy-related genes in PE-induced NRVCs was also evaluated. The effect of IDH3A on NRVCs area was examined by phalloidin staining assay. A mutant of IDH3A with abolished enzymatic activity， IDH3A_D208A， was generated through site-directed mutagenesis. The impact of this IDH3A mutant on the hypertrophic phenotype， ATP and ROS levels in NRVCs was evaluated to investigate whether the regulatory role of IDH3A in cardiomyocyte hypertrophy was dependent on its enzymatic activity. The effect of exogenous α-ketoglutaric acid （AKG） on cardiomyocyte hypertrophy was also detected by Western blot and phalloidin staining assay， respectively. ResultsIDH3A was significantly decreased in the myocardium of HF patients， in the myocardium of TAC-operated mice， and in PE-induced NRVCs （P = 0.005 2，P = 0.026 6，P = 0.041 3 and P = 0.006 6， respectively）. Overexpression of IDH3A markedly suppressed the expression of hypertrophy-related genes and the increase of cell size of PE-induced NRVCs （P < 0.000 1， P = 0.000 1 and P = 0.000 2， respectively）. The ATP and ROS analysis indicated that IDH3A inhibited the increases of ATP and ROS levels in PE-induced NRVCs （P = 0.001 2 and P<0.000 1， respectively）， whereas the enzymatically inactive IDH3A mutant lacked this effect. Exogenous AKG provision could， but overexpression of IDH3A mutant failed to suppress PE-induced NRVCs hypertrophy. ConclusionIDH3A inhibits cardiomyocyte hypertrophy via elevating AKG level， providing scientific evidence for study on IDH3A-based treatment of cardiac hypertrophy.

ObjectiveTo investigate the regulatory effect of circular RNA circ_0120051 on the fibrotic phenotype of cardiac fibroblasts and the potential mechanism involved. MethodsThe expression of circ_0120051 and its host gene of solute carrier family 8 member A1（SLC8A1） mRNA in the myocardium of healthy organ donors （n=24） and heart failure （HF） patients （n=21） were assessed by real-time quantitative polymerase chain reaction （RT-qPCR） assay. RNA stability of circ_0120051 was identified by RNase R exonuclease digestion assay. The cytoplasmic and nuclear distribution of circ_0120051 in human cardiomyocyte AC16 was detected by RT-qPCR assay. The expression of fibrosis-related genes in mouse cardiac fibroblasts （mCFs） with adenovirus-mediated overexpression of circ_0120051 was detected by RT-qPCR and Western blot assay， respectively. The effect of overexpression of circ_0120051 on the migration activity of mCFs was evaluated by wound-healing assay. RNA co-immunoprecipitation （RIP） was conducted to detect the interaction between circ_0120051 and miR-144-3p. The binding site of miR-144-3p in the 3'-UTR of isocitrate dehydrogenase 2 （Idh2） mRNA was identified by the dual luciferase reporter gene assay. ResultsCirc_0120051 was significantly up-regulated in the myocardium of HF patients， while the mRNA expression of its host gene SLC8A1 was not changed. Circ_0120051 was mainly located in the cytoplasm of human AC16 cells. Results of RNase R exonuclease digestion revealed that circ_0120051 possesses the characteristic stability of circular RNA compared to the linear SLC8A1 mRNA. Overexpression of circ_0120051 could inhibit the expression of fibrosis-related gene in mCFs and mCFs migration. RIP assay confirmed the specific interaction between circ_0120051 and miR-144-3p. Transfection of miR-144-3p mimic could efficiently promote the expression of fibrosis-related genes in mCFs and reverse the inhibitory effect of circ_0120051 on the fibrotic phenotype of mCFs. Results of the dual luciferase reporter gene assay confirmed the interaction between miR-144-3p and the 3'-UTR of Idh2. Transfection of miR-144-3p transcriptionally inhibited Idh2 expression， and overexpression of circ_0120051 enhanced IDH2 expression in mCFs. MiR-144-3p mimic and Idh2 small interfering RNA （siRNA） could consistently reverse the inhibitory effects of circ_0120051 on fibrosis-related genes expression in mCFs and mCFs migration. ConclusionsCirc_0120051 inhibits the fibrotic phenotype of cardiac fibroblasts via sponging miR-144-3p to enhance the target gene of IDH2 expression.

Objective:To automatically synthesize Al 18F-fibroblast activation protein inhibitor (FAPI)-74, and explore its value of clinical application. Methods:Al 18F-FAPI-74 was synthesized automatically by the commercial synthesis module CFN-MPS-100, and its yield, radiochemical purity and stability were determined. Sixteen normal Kunming (KM) mice were randomly divided into 4 groups and euthanized at 10, 30, 60 and 90 min after Al 18F-FAPI-74 injection, and the biodistribution was measured. MicroPET/CT dynamic scanning (60 min) was performed in 5 rat pancreatic tumor-bearing BALB/c nude mice to observe the tumor uptake. Al 18F-FAPI-74 PET/CT imaging was performed on 3 volunteers (1 male, 2 females; age: 37, 41, 43 years) to evaluate the clinical application value of Al 18F-FAPI-74. Results:The automated synthesis time of Al 18F-FAPI-74 was about 35 min, with the synthesis yield of (21.34±3.86)% (without attenuation correction, n=5) and the radiochemical purity more than 99%. The radiochemical purity was still more than 96% after placement at 37 ℃ for 6 h. Biodistribution in normal mice and microPET/CT dynamic scanning in tumor-bearing nude mice showed that consistently high uptake in the kidneys and bladder, and the tumor uptake was the highest at 20 min, and the maximum tumor-to-muscle ratio was 3.16±0.01 at 60 min. PET/CT imaging on volunteers showed that there was a small amount of uptake in myocardium, most organs such as the liver and lung had background uptake, and the maximum SUV max of persistent high uptake of tumor was 17.08. Conclusions:Al 18F-FAPI-74 has the advantages of simple synthesis, high yield, stable quality and good imaging performance in mice and volunteers. It is a kind of imaging agent that meets the requirements of clinical diagnosis.

Hepatocellular carcinoma is a common malignant disease in clinical practice, and portal vein tumor thrombosis (PVTT) is one of the important factors affecting the prognosis of hepatocellular carcinoma. PVTT has strong oncologic characteristics and is highly susceptible to extrahepatic metastasis, complicating portal hypertension, leading to gastrointestinal bleeding or liver failure and causing death. In this paper, we review the formation mechanism of hepatocellular carcinoma combined with PVTT in terms of local anatomy, hemodynamics, molecular biology and tumor microenvironment to provide effective reference for clinical treatment.

Hepatocellular carcinoma is one of the common malignant tumors in China, which seriously threatens the life and health of the nation. Hepatic vein tumor thrombosis (HVTT) is one of the common clinical manifestations. The prognosis of hepatocellular carcinoma combined with HVTT is extremely poor, and there is no unanimous opinion on its treatment in China and abroad. Currently, Asian guidelines recommend multidisciplinary treatment for patients with vascular invasion. This article reviewed the current progress in the treatment of hepatocellular carcinoma combined with HVTT.

Hepatic hydrothorax (HH) is a challenging complication of liver cirrhosis associated with portal hypertension, and its pathogenesis and therapeutic measures remain unknown. This article summarizes and reviews the advances and challenges in the research on the pathogenesis, clinical manifestations, diagnosis, and treatment of HH and proposes a multidisciplinary treatment strategy, including reducing the production of ascites, preventing effusion from entering the thoracic cavity, removing pleural effusion, occluding the pleural cavity, and performing liver transplantation, so as to provide a reference for more clinicians.

ObjectiveTo investigate the influence of endoplasmic reticulum stress (ERS) on some inflammatory mediators during the progression of hepatic alveolar echinococcosis (HAE) and its clinical significance. MethodsA total of 15 patients with HAE who underwent partial liver resection in Qinghai University Affiliated Hospital from June 2018 to September 2019 were enrolled, and the marginal zone of HAE lesion was resected as AE group; 15 normal liver tissue samples collected during the same period of time were selected as control group. Western blot and qRT-PCR were used to measure the protein and mRNA expression of protein kinase R-like ER kinase (PERK), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and glucose-regulated protein-78 (GRP-78), and q-PCR was used to measure the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the t-test was used for comparison of normally distributed continuous data between two groups; a Pearson correlation analysis was performed to investigate the correlation between two variables. ResultsCompared with the control group, the AE group had significantly higher protein expression levels of PERK, CHOP, caspase-12, and GRP78 (U=4.165, 3.461, 2.577, and 3.344, all P＜0.001) and their mRNA expression levels (t= 34003, 4.461, 53.573, and 55.224, all P＜0.001). The AE group had significantly higher mRNA expression levels of IL-1β, IL-6, and TNF than the control group (t=6.090, 12.578, and 53.573, all P＜0.001). The protein expression levels of PERK, CHOP, caspase-12, and GRP-78 were positively correlated with the mRNA expression levels of IL-1β, IL-6, and TNF (all r＞0.700, all P≤0.05). ConclusionPositive correlation is observed between the activation of ERS and inflammatory mediators in HAE, and excessive activation of ERS can change the secretion of several inflammatory mediators to exacerbate liver injury, while further studies are needed to clarify the specific mechanism.

Endoplasmic reticulum stress (ERS) manifests as the aggregation of misfolded and unfolded proteins in the endoplasmic reticulum lumen and disorder of calcium balance and can activate the signaling pathways involved in unfolded protein response, endoplasmic reticulum overload reaction, and sterol regulatory cascade response. ERS can not only exert a protective effect by inducing the expression of endoplasmic reticulum molecular chaperones such as glucose-regulated protein 78 and glucose-regulated protein 94, but also induce cell apoptosis. At present, there is still no systematic understanding of ERS involvement in the development and progression of liver diseases. This article summarizes the research advances in ERS-related signaling pathways and related liver diseases and elaborates on the role of ERS-mediated cell apoptosis in liver diseases. The intervention of ERS signaling pathways may provide a reference for the research and treatment of liver diseases in the future.

Objective:To investigate the factors affecting the application of systemic glucocorticoids in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with carbon dioxide (CO 2) retention, and to guide the formulation of a strategy to reduce systemic glucocorticoid exposure. Methods:The AECOPD patients with CO 2 retention admitted to the Ningde Municipal Hospital of Fujian Medical University from January 2017 to December 2019 were enrolled. The general information, past history, times of acute exacerbations within 1 year, pneumonia on admission, causes of COPD, heart failure, blood gas analysis, eosinophil count (EOS), albumin (Alb) and apolipoprotein E (ApoE) levels, exhaled nitric oxide (FeNO) level, inhaled glucocorticoid and non-invasive mechanical ventilation treatment at acute exacerbation were collected. The patients were divided into recommended dosage group (exposure levels in the recommended dosage range, cumulative prednisone dosage ≤ 200 mg) and exceeded group (exposure levels exceeded the recommended dose, cumulative prednisone dosage > 200 mg) according to cumulative systemic glucocorticoid exposure dosage of the patients during hospitalization. The clinical data of patients between the two groups were compared, and possible factors with P < 0.1 in univariate analysis were included in multivariate Logistic regression analysis to screen the related factors of systemic glucocorticoid exposure level in AECOPD patients with CO 2 retention. Results:According to the order of hospitalization, 151 AECOPD patients with CO 2 retention were enrolled, 8 patients were excluded, and 143 patients were enrolled in the analysis. Of the 143 patients, 68 received the recommended dose of systemic glucocorticoid, and 75 received excessive systemic glucocorticoid. Age, percentage of forced expiratory volume in 1 second (FEV1%) at stable phase, frequency of acute exacerbation within 1 year, heart failure ratio, oxygen index (PaO 2/FiO 2), arterial partial pressure of carbon dioxide (PaCO 2), serum EOS and ApoE levels at admission, the ratio of aerosolized inhaled glucocorticoids and non-invasive mechanical ventilation showed statistical differences between the two groups. Multivariate Logistic regression analysis showed that related factors affecting systemic glucocorticoid exposure levels of AECOPD patients with CO 2 retention were FEV1% at stable phase [odds ratio ( OR) = 0.957, 95% confidence interval (95% CI) was 0.921-0.994, P = 0.023], acute exacerbation frequency within 1 year ( OR = 1.530, 95% CI was 1.121-2.088, P = 0.007), heart failure ( OR = 3.022, 95% CI was 1.263-7.231, P = 0.013), PaCO 2 ( OR = 1.062, 95% CI was 1.010-1.115, P = 0.018) and EOS at admission ( OR = 0.103, 95% CI was 0.016-0.684, P = 0.019), aerosolized inhaled glucocorticoids ( OR = 0.337, 95% CI was 0.145-0.783, P = 0.011) and non-invasive mechanical ventilation at acute exacerbation ( OR = 0.422, 95% CI was 0.188-0.948, P = 0.037), of which high FEV1% at stable phase, high EOS at admission, aerosolized inhaled glucocorticoid and non-invasive mechanical ventilation at acute exacerbation were protective factors, while high frequency of acute exacerbation within 1 year, heart failure and high PaCO 2 were risk factors. Conclusions:For AECOPD patients with CO 2 retention, high FEV1% at stable phase, high EOS level at admission, aerosolized inhaled glucocorticoid and non-invasive mechanical ventilation at acute exacerbation can reduce systemic glucocorticoid exposure. In addition, high frequency of acute exacerbation within 1 year, heart failure, and high PaCO 2 can increase systemic glucocorticoid exposure.