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Background. Acute ST-segment elevation myocardial infarction (STEMI) is a serious multiple acute cardiovascular disease. This study investigated the effect of statins on the efficacy and prognosis of STEMI patients after emergency PCI. Methods. From October 2019 to January 2021, 98 patients with STEMI in our hospital were selected and divided into study group and control group. The study group took atorvastatin 40 mg 2 hours before surgery, 40 mg/day after surgery, and 20 mg/day 1 week later. The control group received 20 mg of atorvastatin every night after admission. The cardiac output, left ventricular ejection fraction, blood flow classification, vagus nerve function, heart rate deceleration force and chemoreflex sensitivity were compared between the two groups, and recorded the incidence of adverse reactions before and after treatment and 3 months after treatment. The number of major adverse cardiac events (MACEs) was also recorded. Results. Before treatment, there were no differences in CO, CI, and LVEF between the study and control groups. After treatment, CO, CI, and LVEF in the study group were significantly higher than those in the control group. Before treatment, there was no significant difference in TIMI blood flow classification among the groups, and after treatment, the study group was better than the control group. DC and ChRS were significantly higher in the study group than in the control group. There was no difference in the incidence of adverse reactions between the study group and the control group. However, the incidence of MACE in the study group was lower than that in the control group. Conclusion. Enhanced-dose atorvastatin for STEMI patients improved PCI treatment effect, cardiac function, and vagus nerve function and reduced the incidence of adverse cardiac events. Thus, statins are safe and worth considering. [ABSTRACT FROM AUTHOR]

Objective. To explore the potential and mechanism of action of poricoic acid A (PAA) in treatment of cardiorenal injury and fibrosis due to cardiorenal syndrome (CRS). Materials and Methods. A CRS rat model was established by transabdominal subtotal nephrectomy (STNx). The experimental group was treated by gavage of PAA (10 mg/kg/day). After 8 weeks of treatment, echocardiography was utilized for detecting heart-related indexes in rats. HE and Masson staining were conducted to detect the degree of pathological damage and fibrosis in rat kidney tissue, respectively. In addition, serum blood urea nitrogen (BUN), serum creatinine (SCr), and 24-hour urine protein were measured biochemically. Also, the levels of inflammatory factors (IL-1β, IL-6, and IL-10) in rat kidneys were measured using ELISA. Western blot was used to examine the expression of NF-κB/MAPK pathway-related proteins. Results. In this study, a CRS rat model was successfully established by STNx surgery. PAA treatment could significantly alleviate the damage of heart and kidney function in CRS rats and reduce the pathological damage of kidney tissue and renal fibrosis. Meanwhile, PAA could also inhibit the renal inflammatory response through downregulating IL-1β and IL-6 levels in the kidney tissue and upregulating IL-10 level. Further mechanism exploration showed that the NF-κB/MAPK signaling pathway was significantly activated in CRS rats, while PAA treatment could markedly inhibit the NF-κB/MAPK signaling pathway activity in CRS rats. Conclusion. PAA can obviously improve the pathological damage and fibrosis of renal tissue in CRS rats and maintain the function of the heart and kidney. The above functions of PAA may be achieved by inhibiting the NF-κB/MAPK signaling pathway activity. Briefly speaking, PAA can serve as a potential drug for CRS treatment. [ABSTRACT FROM AUTHOR]

Summary: Macrophages are professional antigen‐presenting cells relying on the expression of class II major histocompatibility complex (MHC II) genes. Interferon‐γ (IFN‐γ) activates MHC II transcription via the assembly of an enhanceosome centred on class II trans‐activator (CIITA). In the present study, we investigated the role of the forkhead transcription factor FOXO3a in IFN‐ γ‐induced MHC II transcription in macrophages. Knockdown of FOXO3a, but not FOXO1 or FOXO4, diminished IFN‐γ‐induced MHC II expression in RAW cells. On the contrary, over‐expression of FOXO3a, but neither FOXO1 nor FOXO4, enhanced CIITA‐mediated trans‐activation of the MHC II promoter. IFN‐γ treatment promoted the recruitment of FOXO3a to the MHC II promoter. Co‐immunoprecipitation and RE‐ChIP assays showed that FOXO3a was a component of the MHC II enhanceosome forming interactions with CIITA, RFX5, RFXB and RFXAP. FOXO3a contributed to MHC II transcription by altering histone modifications surrounding the MHC II promoter. Of interest, FOXO3a was recruited to the type IV CIITA promoter and directly activated CIITA transcription by interacting with signal transducer of activation and transcription 1 in response to IFN‐γ stimulation. In conclusion, our data unveil a novel role for FOXO3a in the regulation of MHC II transcription in macrophages. [ABSTRACT FROM AUTHOR]

Summary: Background: Liver fibrosis is the strongest histological risk factor for liver‐related complications and mortality in metabolic dysfunction‐associated fatty liver disease (MAFLD). Second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) is a powerful tool for label‐free two‐dimensional and three‐dimensional tissue visualisation that shows promise in liver fibrosis assessment. Aim: To investigate combining multi‐photon microscopy (MPM) and deep learning techniques to develop and validate a new automated quantitative histological classification tool, named AutoFibroNet (Automated Liver Fibrosis Grading Network), for accurately staging liver fibrosis in MAFLD. Methods: AutoFibroNet was developed in a training cohort that consisted of 203 Chinese adults with biopsy‐confirmed MAFLD. Three deep learning models (VGG16, ResNet34, and MobileNet V3) were used to train pre‐processed images and test data sets. Multi‐layer perceptrons were used to fuse data (deep learning features, clinical features, and manual features) to build a joint model. This model was then validated in two further independent cohorts. Results: AutoFibroNet showed good discrimination in the training set. For F0, F1, F2 and F3‐4 fibrosis stages, the area under the receiver operating characteristic curves (AUROC) of AutoFibroNet were 1.00, 0.99, 0.98 and 0.98. The AUROCs of F0, F1, F2 and F3‐4 fibrosis stages for AutoFibroNet in the two validation cohorts were 0.99, 0.83, 0.80 and 0.90 and 1.00, 0.83, 0.80 and 0.94, respectively, showing a good discriminatory ability in different cohorts. Conclusion: AutoFibroNet is an automated quantitative tool that accurately identifies histological stages of liver fibrosis in Chinese individuals with MAFLD. [ABSTRACT FROM AUTHOR]

Efficient presentation of alien antigens triggers activation of T lymphocytes and robust host defense against invading pathogens. This pathophysiological process relies on the expression of major histocompatibility complex (MHC) molecules in antigen presenting cells such as macrophages. Aberrant MHC II transactivation plays a crucial role in the pathogenesis of atherosclerosis. Class II transactivator (CIITA) mediates MHC II induction by interferon gamma (IFN-γ). CIITA activity can be fine-tuned at the post-translational level, but the mechanisms are not fully appreciated. We investigated the role of protein arginine methyltransferase 1 (PRMT1) in this process. We report here that CIITA interacted with PRMT1. IFN-γ treatment down-regulated PRMT1 expression and attenuated PRMT1 binding on the MHC II promoter. Over-expression of PRMT1 repressed MHC II promoter activity while PRMT1 depletion enhanced MHC II transactivation. Mechanistically, PRMT1 methylated CIITA and promoted CIITA degradation. Therefore, our data reveal a previously unrecognized role for PRMT1 in suppressing CIITA-mediated MHC II transactivation. [ABSTRACT FROM AUTHOR]

Background: Due to the low incidence and histological heterogeneity, the molecular features and underlying carcinogenic mechanisms of thymic epithelial tumors (TETs) are yet to be fully elucidated, especially for different subtypes of TETs. Methods: Tumor tissue samples of 43 TETs with distinct histological subtypes were collected. We analyzed the molecular characteristics in different subtypes based on whole exome sequencing data. Results: The mutational profiles of the different subtypes of TETs varied. Compared with thymomas, thymic carcinomas (TCs) had a higher mutation frequency of MYO16 (33% vs. 3%, p = 0.024) and a lower frequency of ZNF729 mutations (0% vs. 35%, p = 0.044). No significant difference was observed in the median tumor mutation burden across different subtypes. The value of copy number variation burden, weighted genome instability index, and the number of amplified segments were all higher in TCs than thymomas, and they also tended to be higher in B3 thymoma than in non‐B3 thymomas, while they had no significant differences between B3 thymoma and TCs. Clustering analyses revealed that Wnt, MAPK, Hedgehog, AMPK, and cell junction assembly signaling pathways were exclusively enriched in non‐B3 thymomas, lysine degradation pathway in B3 thymoma, and extracellular matrix‐receptor (ECM‐receptor) interaction, positive regulation of cell cycle process, and activation of innate immune response pathways in TCs. Conclusions: This study revealed distinct molecular landscapes of different subtypes of TETs, suggesting diverse pathogenesis of non‐B3 thymomas, B3 thymomas, and TCs. Our findings warrant further validation in future large‐scale studies and may provide a theoretical basis for potential personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Two Ag-MOCPs with different dimensional electron transfer Channels were used for electrocatalytic conversion CO 2 to CO. [Display omitted] • New Ag-MOCP materials for CO 2 RR electrocatalysts were synthesized. • CO 2 -to-CO conversion was boosted with the regulation of the electron transfer channel. • The FE CO for Ag-MOCP-2 with multi-dimensional electron transfer channels is higher than that for Ag-MOCP-1 with single channel at most given potentials. • The mechanism of its reaction was further explored by DFT calculation. Although, electrons transfer plays an important role in achieving the electrocatalytic CO 2 reduction reaction (CO 2 RR), it is scarce to regulate the electron transfer channels for enhancing the performance of CO 2 RR via rational design. Here, based on different solvothermal conditions, two metal–organic coordination polymers (MOCPs, Ag-MOCP-1 and Ag-MOCP-2) electrocatalyst for CO 2 RR were obtained by the same Ag ions and 5-phenyltetrazolium ligands. Single crystal X-ray diffraction showed Ag-MOCP-2 with intra-&inter-layer C H···π and π···π interactions, while Ag-MOCP-1 with intra-layer π···π interactions. The intra-&inter-layer π interactions in Ag-MOCP-2 makes it show multi-dimensional electron transfer channels, which enable Ag-MOCP-2 with higher electron conductivities and lower band gap than Ag-MOCP-1. And the Faradaic efficiency of CO for Ag-MOCP-2 with 78.3 % is higher than that for Ag-MOCP-1 with 69.1 % at −1.08 V vs RHE, and the maximum difference can reach 22 % at −1.48 V vs RHE. Based on the same central metal and organic ligands of the two MOCPs, we believe that multi-dimensional electron transfer channels make a predominant contribution for improving CO 2 RR performance in this work. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a comorbidity commonly presenting with metabolic-dysfunction-associated fatty liver disease (MAFLD); however, few tests for interaction have been reported. Our target was to evaluate the prognostic implications of DM in patients with different forms of MAFLD. Methods: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) in the United States, we screened 14,797 participants aged 20–74 who received ultrasound examinations from 1988–1994. Among them, 4599 patients met the diagnosis of MAFLD, and we defined mortality as the outcome event. Survival analysis of competitive risk events was performed using Cox regression and sub-distributed risk ratio (SHR). Results: During 21.1 years of follow-up, cardiovascular diseases seemed to be the most common cause of death among MAFLD patients. Of them, DM was present in 25.48% and was independently associated with increased risk of all-cause mortality (HRs: 1.427, 95% CIs: 1.256–1.621, p < 0.001) and cause-specific mortality (cardiovascular-related mortality (HRs: 1.458, 95% CIs: 1.117–1.902, p = 0.005), non-cardiovascular-related mortality (HRs: 1.423, 95% CIs: 1.229–1.647, p < 0.001), and non-cancer-related mortality (HRs: 1.584, 95% CIs: 1.368–1.835, p < 0.001), respectively). Surprisingly, this association was more significant for young patients (p-value for interaction <0.001). Moreover, DM had a greater risk of all-cause and cause-specific mortality among overweight and obese MAFLD patients (p-value for interaction <0.001). Conclusions: DM increased the risk of all-cause and cause-specific mortality (cardiovascular-related, non-cardiovascular-related, and non-cancer-related) in MAFLD patients, especially in younger patients with excess obesity. [ABSTRACT FROM AUTHOR]

Trans-differentiation, or activation, of hepatic stellate cells (HSCs) is a hallmark event in liver fibrosis although the underlying mechanism is not fully appreciated. Serum response factor (SRF) is a pleiotropic sequence-specific transcription factor with a ubiquitous expression pattern. In the present study, we investigated the effect of HSC-specific ablation of SRF on liver fibrosis in vivo and the underlying mechanism. We report that SRF bound to the promoter regions of pro-fibrogenic genes, including collagen type I (Col1a1/Col1a2) and alpha smooth muscle actin (Acta2), with greater affinity in activated HSCs compared to quiescent HSCs. Ablation of SRF in HSCs in vitro downregulated the expression of fibrogenic genes by dampening the accumulation of active histone marks. SRF also interacted with MRTF-A, a well-documented co-factor involved in liver fibrosis, on the pro-fibrogenic gene promoters during HSC activation. In addition, SRF directly regulated MRTF-A transcription in activated HSCs. More importantly, HSC conditional SRF knockout (CKO) mice developed a less robust pro-fibrogenic response in the liver in response to CCl4 injection and BDL compared to wild-type littermates. In conclusion, our data demonstrate that SRF may play an essential role in HSC activation and liver fibrosis. Key messages: • SRF deficiency decelerates activation of hepatic stellate cells (HSCs) in vitro. • SRF epigenetically activates pro-fibrogenic transcription to promote HSC maturation. • SRF interacts with MRTF-A and contributes to MRTF-A transcription. • Conditional SRF deletion in HSCs attenuates BDL-induced liver fibrosis in mice. • Conditional SRF ablation in HSCs attenuates CCl4-induced liver fibrosis in mice. [ABSTRACT FROM AUTHOR]

Fibrosis is a common pathophysiological process following liver injury and can lead to, if left unattended to, irreversible end-stage liver disease such as cirrhosis. Hepatic stellate cells (HSCs) are a major contributor to liver fibrosis. Here we investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in HSC activation and the underlying mechanisms. Aggf1 expression was down-regulated in the livers in three different mouse models of liver fibrosis following injury. Aggf1 expression was also suppressed in activated HSCs when compared to quiescent HSCs. Over-expression of Aggf1 alleviated liver fibrosis in mice and in cultured HSCs. RNA-sequencing (RNA-seq) analysis performed in HSCs revealed that Aggf1-dependent transcription regulates several key fibrogenic pathways. Mechanistically, Aggf1 regulated liver fibrogenesis by forming a complex with the inhibitor SMAD protein (SMAD7) thereby leading to diminished SMAD3 binding to the pro-fibrogenic gene promoters. On the contrary, SMAD7 knockdown abrogated the effect of Aggf1 and rescued HSC activation. Aggf1 expression was silenced during HSC activation/liver fibrogenesis as a result of DNA methylation. Treatment with a DNA methyltransferase inhibitor (5-Azacytidine) restored Aggf1 expression and repressed liver fibrosis in an Aggf1-dependent manner. In conclusion, our data illustrate a previously unknown role for Aggf1 and shed light on the development of novel therapeutic solutions against liver fibrosis. [ABSTRACT FROM AUTHOR]

Background: Using fluorescence in situ hybridisation (FISH) to detect any gain of chromosomes 3, 7, or 17 and loss of the 9p21 locus has been proven to be sensitive in the diagnosis of pancreatobiliary tumors. However, both genetic and environmental factors contribute to the pathogenesis of pancreatobiliary tumors. Therefore, it is unknown whether this method is suitable for Chinese patients with pancreatobiliary tumors. This study aims to compare the sensitivity, specificity, predictive values and accuracy of cytology, ERCP/MRCP and FISH based on Chinese patients with pancreatobiliary tumors,and to analyze differences between brushing-based and formalin-fixed paraffin-embedded (FFPE)-based FISH.Methods: A total of 66 brush cytology specimens obtained during ERCP were detected by FISH and cytology test respectively to compare the sensitivity, specificity, predictive values and accuracy. Besides, FFPE-based FISH was performed on 46 corresponding paraffin sections of pancreatobiliary tumors obtained by surgical resection.Results: Our findings demonstrate that FISH greatly improves diagnostic sensitivity and negative predictive value compared to ERCP/MRCP and cytology without much reduction in specificity and positive predictive value. However, our results also indicate that FFPE-based FISH could not effectively identify the false-negative of brushing-based FISH.Conclusions: We believe that FISH can effectively distinguish true positive and false positive results of cytological or radiological suspicions of malignancy. However, FFPE-based FISH still does not precisely recognize the false-negative of brushing-based FISH. Both cytology-based and PPFE-based FISH had limitation in some specimens. [ABSTRACT FROM AUTHOR]