The Hidden Agony of the Pancreas: A Comprehensive Case Study of Paraduodenal Pancreatitis.

Paraduodenal pancreatitis (PP), also known as groove pancreatitis (GP), is a rare and distinct variant of chronic pancreatitis and presents significant diagnostic and therapeutic challenges. This comprehensive case study explores a 54-year-old male patient's journey, highlighting the intricate relationship between clinical presentation, diagnostic modalities, and management strategies. Despite a history of smoking and alcohol consumption, the diagnosis of PP was primarily reliant on advanced imaging techniques, including computed tomography and magnetic resonance imaging, which revealed characteristic findings of GP. The case underscores the importance of a high index of suspicion and a step-up approach to management, starting with conservative treatment and progressing to surgical intervention as necessary. This study contributes to the growing body of knowledge on PP, emphasizing the need for awareness and understanding of this rare condition to improve patient outcomes.

Macrophages-derived exo-miR-4449 induced by Cryptococcus affects HUVEC permeability and promotes pyroptosis in BEAS-2B via the HIC1 pathway.

Macrophages have recently been discovered to assume a significant role in the progression of cryptococcosis. However, the potential involvement of macrophage-derived exosomes in the pathogenesis of cryptococcosis remains uncertain. In this study, we investigated the changes of microRNAs in macrophage exosomes (exo-miRNAs) in cryptococcal infections and the role of markedly altered exo-miRNAs in the modulation of Human Umbilical Vein Endothelial Cells (HUVEC) permeability and ROS accumulation and pyroptosis in Human Bronchial Epithelioid Cells (BEAS-2B). Techniques such as microarray analysis and real-time quantitative PCR were used to detect different exo-miRNAs and to screen for the most highly expressed exo-miRNAs. Then its mimics were transfected into HUVEC to study its effect on the monolayer permeability of HUVEC. Finally, the relationship between this exo-miRNAs and the ROS accumulation and pyroptosis was verified by bioinformatics analysis. The results showed that five exo-miRNAs were overexpressed and two exo-miRNAs were reduced, among which, exo-miR-4449 was expressed at the highest level. Exo-miR-4449 could be internalized by HUVEC and enhanced its monolayer permeability. Moreover, exo-miR-4449 was found to promote ROS accumulation and pyroptosis in BEAS-2B through HIC1 pathway. Thus, exo-miR-4449 plays an important role in the pathogenesis of cryptococcosis and holds promise as a significant biomarker for treatment.

TBUnet: A Pure Convolutional U-Net Capable of Multifaceted Feature Extraction for Medical Image Segmentation.

Many current medical image segmentation methods utilize convolutional neural networks (CNNs), with some extended U-Net-based networks relying on deep feature representations to achieve satisfactory results. However, due to the limited receptive fields of convolutional architectures, they are unable to explicitly model the varying range dependencies present in medical images. Recently, advancements in large kernel convolution have allowed for the extraction of a wider range of low frequency information, making this task more achievable. In this paper, we propose TBUnet for solving the problem of difficult to accurately segment lesions with heterogeneous structures and fuzzy borders, such as melanoma, colon polyps and breast cancer. The TBUnet is a pure convolutional network with three branches for extracting high frequency information, low frequency information, and boundary information, respectively. It is capable of extracting features in various areas. To fuse the feature maps from the three branches, TBUnet presents the FL (fusion layer) module, which is based on threshold and logical operation. We design the FE (feature enhancement) module on the skip-connection to emphasize the fine-grained features. In addition, our method varies the number of input channels in different branches at each stage of the network, so that the relationship between low and high frequency features can be learned. TBUnet yields 91.08 DSC on ISIC-2018 for melanoma segmentation, and achieves better performance than state-of-the-art medical image segmentation methods. Furthermore, experimental results with 82.48 DSC and 89.04 DSC obtained on the BUSI dataset and the Kvasir-SEG dataset show that TBUnet outperforms the advanced segmentation methods. Experiments demonstrate that TBUnet has excellent segmentation performance and generalisation capability.

Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients.

OBJECTIVE: This study aims to analyze whether there are any differences in clinicopathological features and prognosis between HER2 ultra-low, HER2-null, and HER2-low expression in Chinese breast cancer (BC) patients. METHODS: The clinicopathological data of 1363 HER2-negative BC patients were retrospectively collected (from January 2018 to December 2019). HER2 status was further classified into HER2-null, HER2 ultra-low, and HER2-low. HER2-null expression is defined as infiltrating cancer cells completely free of staining. HER2 ultra-low expression is defined as ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining. HER2-low expression is defined as HER2 immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH) assay. RESULTS: Of 1363 patients, there were 86 (6.3%) HER2-null patients, 395 (29.0%) HER2 ultra-low patients, and 882 (64.7%) HER2-low patients. HER2 ultra-low patients were different from HER2-low patients in terms of N stage, hormone receptor (HR) status, Ki-67 expression, and type of surgery. There were also significant differences in histologic type and postoperative endocrine therapy between HER2 ultra-low and HER2-null patients. HR+ (81.0%) tumors was more common than HR- (19.0%) in HER2 ultra-low patients. In addition, there was a significant difference in HR status between HER2 ultra-low and HER2-low patients (P = 0.001). The survival analysis showed that HER2 status had no effect on disease-free survival (DFS) in HER2-negative patients (all P > 0.05). However, regardless of HER2 status, HR+ patients had better DFS than HR- patients (P = 0.003). Cox multivariate analysis revealed that age (HR [95% CI] = 0.950 [0.928, 0.972], P < 0.001), HR status (HR [95% CI] = 3.342 [1.658, 6.736], P = 0.001), and postoperative endocrine therapy (HR [95% CI] = 0.048 [0.048, 0.023], P < 0.001) were important influencing factors of DFS in HER2-negative BC patients. CONCLUSION: HER2 ultra-low BC patients demonstrated distinct clinicopathological features from HER2-null and HER2-low tumors; while, HER2 status (null, ultra-low, or low) had no prognostic value in these HER2-negative BC population. Consistent with the published literature, HR status was an independent prognostic factor for DFS in HER2-negative BC patients.

The Fe-S cluster assembly protein IscU2 increases α-ketoglutarate catabolism and DNA 5mC to promote tumor growth.

IscU2 is a scaffold protein that is critical for the assembly of iron-sulfur (Fe-S) clusters and the functions of Fe-S-containing mitochondrial proteins. However, the role of IscU2 in tumor development remains unclear. Here, we demonstrated that IscU2 expression is much higher in human pancreatic ductal adenocarcinoma (PDAC) tissues than in adjacent normal pancreatic tissues. In PDAC cells, activated KRAS enhances the c-Myc-mediated IscU2 transcription. The upregulated IscU2 stabilizes Fe-S cluster and regulates the activity of tricarboxylic acid (TCA) cycle enzymes α-ketoglutarate (α-KG) dehydrogenase and aconitase 2, which promote α-KG catabolism through oxidative and reductive TCA cycling, respectively. In addition to promoting mitochondrial functions, activated KRAS-induced and IscU2-dependent acceleration of α-KG catabolism results in reduced α-KG levels in the cytosol and nucleus, leading to an increase in DNA 5mC due to Tet methylcytosine dioxygenase 3 (TET3) inhibition and subsequent expression of genes including DNA polymerase alpha 1 catalytic subunit for PDAC cell proliferation and tumor growth in mice. These findings underscore a critical role of IscU2 in KRAS-promoted α-KG catabolism, 5mC-dependent gene expression, and PDAC growth and highlight the instrumental and integrated regulation of mitochondrial functions and gene expression by IscU2 in PDAC cells.

Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells.

Rationale: Mitochondria generate ATP via the oxidative phosphorylation system, which mainly comprises five respiratory complexes found in the inner mitochondrial membrane. A high-order assembly of respiratory complexes is called a supercomplex. COX7A2L is a supercomplex assembly factor that has been well-investigated for studying supercomplex function and assembly. To date, the effects of mitochondrial supercomplexes on cell metabolism have not been elucidated. Methods: We depleted COX7A2L or Cox7a2l in human and mouse cells to generate cell models lacking mitochondrial supercomplexes as well as in DBA/2J mice as animal models. We tested the effect of impaired supercomplex assembly on cell proliferation with different nutrient supply. We profiled the metabolic features in COX7A2L-/- cells and Cox7a2l-/- mice via the combined use of targeted and untargeted metabolic profiling and metabolic flux analysis. We further tested the role of mitochondrial supercomplexes in pancreatic ductal adenocarcinoma (PDAC) through PDAC cell lines and a nude mouse model. Results: Impairing mitochondrial supercomplex assembly by depleting COX7A2L in human cells reprogrammed metabolic pathways toward anabolism and increased glutamine metabolism, cell proliferation and antioxidative defense. Similarly, knockout of Cox7a2l in DBA/2J mice promoted the use of proteins/amino acids as oxidative carbon sources. Mechanistically, impaired supercomplex assembly increased electron flux from CII to CIII/CIV and promoted CII-dependent respiration in COX7A2L-/- cells which further upregulated glutaminolysis and glutamine oxidation to accelerate the reactions of the tricarboxylic acid cycle. Moreover, the proliferation of PDAC cells lacking COX7A2L was inhibited by glutamine deprivation. Conclusion: Our results reveal the regulatory role of mitochondrial supercomplexes in glutaminolysis which may fine-tune the fate of cells with different nutrient availability.

Regulation of endothelial-to-mesenchymal transition by histone deacetylase 3 posttranslational modifications in neointimal hyperplasia.

Background: Endothelial-to-mesenchymal transition (EndMT) is the process by which endothelial cells lose their specific markers and acquire mesenchymal or myofibroblastic phenotypes. Studies have demonstrated the importance of endothelial-derived vascular smooth muscle cells (VSMCs) through EndMT in neointimal hyperplasia. Histone deacetylases (HDACs) are epigenetic modification enzymes involved in the epigenetic control of important cellular functions. Recent studies found that HDAC3, a class I HDAC, causes posttranslational modifications, including deacetylation and decrotonylation. However, the effect of HDAC3 on EndMT in neointimal hyperplasia via posttranslational modifications remains to be seen. Therefore, we investigated the effects of HDAC3 on EndMT in carotid artery-ligated mice and human umbilical vein endothelial cells (HUVECs) and the underlying posttranslational modifications. Methods: HUVECs were treated with transforming growth factor (TGF)-ß1 or the inflammatory cytokine tumor necrosis factor (TNF)-α at different concentrations and durations. In HUVECs, HDAC3 expression, the expression of endothelial and mesenchymal markers, and posttranslational modifications were analyzed with Western blotting, quantitative real-time polymerase chain reaction (PCR), and immunofluorescence. C57BL/6 mice underwent left carotid artery ligation. Mice were treated with the HDAC3-selective inhibitor RGFP966 (10 mg/kg, i.p.) from 1 day before to 14 days after ligation. Then, the sections of the carotid arteries were examined histologically using hematoxylin and eosin (HE) and immunofluorescence staining. The carotid arteries from other mice were examined for the expression of EndMT markers and inflammatory cytokines. Furthermore, the acetylation and crotonylation of carotid arteries were immunostained in mice. Results: In HUVECs, TGF-ß1 and TNF-α induced EndMT by decreasing CD31 expression and increasing α-smooth muscle actin expression. TGF-ß1 and TNF-α also upregulated HDAC3 expression in HUVECs. The in vivo study in mice indicated that RGFP966 significantly alleviated neointimal hyperplasia of the carotid artery compared with vehicle treatment. Furthermore, RGFP966 suppressed EndMT and the inflammatory response in carotid artery-ligated mice. Further investigation revealed that HDAC3 regulated EndMT by posttranslational modifications of deacetylation and decrotonylation. Conclusions: These results suggest that HDAC3 regulates EndMT in neointimal hyperplasia through posttranslational modifications.

Application Effect of Modified Through and Through Suture in Anterior Chondrectomy of Auricular Pseudocyst.

Objective: To introduce a novel method of modified through and through suture with collagen sutures in conjunction with anterior chondrectomy of auricular pseudocyst and assess its therapeutic efficacy. Subjects and Methods: The study comprised 87 patients with unilateral auricular pseudocyst, treated in our department from December 2019 to November 2021. Following anterior chondrectomy of the cyst, modified through and through suture was performed using collagen sutures. Evaluation of successful resolution of the problem, assessment of complications, recurrence, and ultimate ear cosmesis was undertaken with a minimum of 6 months follow-up. Results: There were 83 males and 4 females, ages ranged from 26-78 years old, with a median age of 41 years. The right and left ears were affected in, 52 and 35 patients, respectively. Local skin color deepening was found in 15 patients within 3 months, which returned to normal within 5 months. During the follow-up, such complications as anaphylaxis, hematocele in the surgical cavity, incision infection, and deformity were not observed in any patients. All patients were cured with a single operation without relapse. Conclusion: The modified through and through suture with collagen sutures in conjunction with anterior chondrectomy of an auricular pseudocyst is characterized by a straightforward, single-stage operation, with no relapses, few complications, restoration of normal ear cosmesis, and high patient acceptance.

Impact of MAFLD on the complications after hepatectomy in patients with HBV-related hepatocellular carcinoma.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a term that was proposed in 2020 by a group of international experts. However, the impact of MAFLD on complications after hepatectomy in patients with hepatocellular carcinoma is not clear. The aim of this study is to explore the influence of MAFLD on the complications after hepatectomy in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). Patients with HBV-HCC who underwent hepatectomy between January 2019 and December 2021 were consecutively enrolled. The predictors of complications after hepatectomy in HBV-HCC patients were retrospectively analyzed. Among the 514 eligible HBV-HCC patients, 117 (22.8%) were diagnosed with concurrent MAFLD. Post hepatectomy complications occurred in 101 patients (19.6%), including 75 patients (14.6%) with infectious complications and 40 patients (7.8%) with major complications. Univariate analysis showed that MAFLD was not the risk factor for complications after hepatectomy in patients with HBV-HCC (P > .05). However, univariate and multivariate analysis revealed that lean-MAFLD was an independent risk factor for post hepatectomy complications in patients with HBV-HCC (odds ratio 2.245; 95% confidence interval 1.243-5.362, P = .028). Similar results were found in the analysis of predictors for infectious and major complications after hepatectomy in patients with HBV-HCC. MAFLD commonly coexists with HBV-HCC and is not directly associated with complications after hepatectomy, but lean-MAFLD is an independent risk factor for post hepatectomy complications in patients with HBV-HCC.

Weighted Gene Co-Expression Network Analysis to Explore Hub Genes of Resveratrol Biosynthesis in Exocarp and Mesocarp of 'Summer Black' Grape.

Resveratrol is a polyphenol compound beneficial to human health, and its main source is grapes. In the present study, the molecular regulation of resveratrol biosynthesis in developing grape berries was investigated using weighted gene co-expression network analysis (WGCNA). At the same time, the reason for the resveratrol content difference between grape exocarp (skin) and mesocarp (flesh) was explored. Hub genes (CHS, STS, F3'5'H, PAL, HCT) related to resveratrol biosynthesis were screened with Cytoscape software. The expression level of hub genes in the exocarp was significantly higher than that in the mesocarp, and the expressions of the hub genes and the content of resveratrol in exocarp peaked at the maturity stage. While the expression levels of PAL, CHS and STS in the mesocarp, reached the maximum at the maturity stage, and F3'5'H and HCT decreased. These hub genes likely play a key role in resveratrol biosynthesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further indicated that resveratrol biosynthesis was related to flavonoid biosynthesis, phenylalanine metabolism, phenylpropanoid biosynthesis, and stilbene biosynthesis pathways. This study has theoretical significance for exploring genes related to resveratrol biosynthesis in the exocarp and mesocarp of grapes, and provides a theoretical basis for the subsequent function and regulatory mechanism of hub genes.

Electroacupuncture treatment of benign prostatic hyperplasia: A case report.

Benign prostatic hyperplasia (BPH) is characterized by symptoms such as frequent urination and difficulty in urination. Currently, treatment is mainly carried out using medications and surgery, but all of these methods can lead to certain adverse effects. In this case, a ninety-year-old male elderly patient came to our acupuncture clinic for treatment of urinary tract occlusion due to BPH. According to the patient's condition, we adopted the eletroacupuncture treatment protocol of Prof. Zhanglian Wang, a famous experienced Chinese medicine doctor. After six weeks of acupuncture treatment, the patient's urinary status improved significantly. This case suggests that acupuncture may be an effective complementary alternative therapy for BPH.

The impact of metabolic dysfunction-associated fatty liver disease on the prognosis of patients with hepatocellular carcinoma after radical resection.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is recently proposed an entity by a group of international experts. However, the impact of MAFLD on the prognosis of patients with hepatocellular carcinoma (HCC) is not clear. The aim of this study was to explore the influence of MAFLD for the prognosis of HCC after radical resection. METHODS: HCC patients who received radical resection were enrolled. The recurrence-free survival (RFS) and overall survival (OS) were compared between MAFLD and non-MAFLD. RESULTS: A total of 576 HCC patients were included, and among them 114 (19.8%) met the diagnostic criteria of MAFLD. The median RFS was 34.0 months in the MAFLD group and 19.0 months in the non-MAFLD group. The 1-, 3-, and 5-year RFS rates were 64.9%, 49.1% and 36.1% in the MAFLD group, which were higher than those of the non-MAFLD group (59.4%, 35.3% and 26.5%, respectively, P = 0.01). The mean OS was 57.0 months in the MAFLD group and 52.2 months in the non-MAFLD group. There was no statistical difference in OS rate between the MAFLD group and non-MAFLD group. Similar results were found in HBV-related HCC patients in the subgroup analysis. Univariate analysis revealed that MAFLD was a protective factor for RFS in HCC patients after radical resection (P < 0.05), and there was no association between MAFLD and OS rate (P > 0.05). Multivariate analysis demonstrated that MAFLD was not an independent protective factor for HCC patients with radical resection. CONCLUSIONS: MAFLD improves RFS rate in HCC patients with radical resection, but is not an independent protective factor and not associated with OS rate.

Acupuncture treatment for lumbar disc herniation with scoliosis: A case report.

INTRODUCTION: Lumbar disc herniation (LDH) with scoliosis usually refers to lumbar disc herniation caused by scoliosis, which is a postural compensatory deformity to reduce low back and leg pain, mostly with nonstructural changes. Scoliosis may disappear after the treatment of LDH. PATIENT CONCERNS: At present, this kind of scoliosis is mainly treated with medicine and surgery, but all these methods may have some adverse effects. DIAGNOSIS: A 24-year-old female patient was admitted to the acupuncture department of our hospital due to unbearable pain caused by LDH. INTERVENTIONS: According to the patient condition, the acupuncture treatment plan was adopted by Professor Wang Zhanglian, a famous Chinese medicine practitioner. OUTCOMES: After 12 weeks of acupuncture treatment, the patient low back pain was significantly relieved. CONCLUSION: This case suggests that acupuncture may be an effective alternative treatment for LDH.

Combined Shikonin-Loaded MPEG-PCL Micelles Inhibits Effective Transition of Endothelial-to-Mesenchymal Cells.

Introduction: Shikonin is well known for its anti-inflammatory activity in cardiovascular diseases. However, the application of shikonin is limited by its low water solubility and poor bioavailability. Methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) (MPEG-PCL) is considered a promising delivery system for hydrophobic drugs. Therefore, in this study, we prepared shikonin-loaded MPEG-PCL micelles and investigated their effect on endothelial-to-mesenchymal transition (EndMT) induced by inflammatory cytokines. Methods: Shikonin was encapsulated in MPEG-PCL micelles using an anti-solvent method and the physiochemical characteristics of the micelles (particle size, zeta potential, morphology, critical micelle concentration (CMC), drug loading and encapsulation efficiency) were investigated. Cellular uptake of micelles in human umbilical vein endothelial cells (HUVECs) was evaluated using fluorescence microscopy. In vitro EndMT inhibition was explored in HUVECs by quantitative real-time PCR analysis. Results: The average particle size of shikonin-loaded MPEG-PCL micelles was 54.57±0.13 nm and 60 nm determined by dynamic light scattering and transmission electron microscopy, respectively. The zeta potential was -6.23±0.02 mV. The CMC of the micelles was 6.31×10-7mol/L. The drug loading and encapsulation efficiency were 0.88±0.08% and 43.08±3.77%, respectively. The MPEG-PCL micelles significantly improved the cellular uptake of cargo with low water solubility. Real-time PCR analysis showed that co-treatment with TNF-α and IL-1ß successfully induced EndMT in HUVECs, whereas this process was significantly inhibited by shikonin and shikonin-loaded MPEG-PCL micelles, with greater inhibition mediated by the shikonin-loaded MPEG-PCL micelles. Conclusion: Shikonin-loaded MPEG-PCL micelles significantly improved the EndMT-inhibiting effect of the free shikonin. MPEG-PCL is suitable for use more generally as a lipophilic drug carrier.

Evaluation of the risk factors for severe complications and surgery of intestinal foreign bodies in adults: a single-center experience with 180 cases.

Background: Foreign bodies (FBs) lodged in the intestine or causing intestinal complications are uncommon in clinical practice but may pose diagnostic difficulties and prove life-threatening. This study aimed to evaluate the risk factors for severe complications and surgery to aid clinicians in the diagnosis and management of intestinal FBs. Methods: We performed a retrospective analysis of patients in whom FBs were lodged in the intestine or caused complications from 2010 to 2020 in the First Affiliated Hospital of Wenzhou Medical University (Zhejiang, China). The characteristics of the patients and FBs, symptoms, imaging findings, diagnostics, treatment strategies, and clinical outcomes were analysed. Furthermore, the risk factors for complications and surgery were investigated. Results: In total, 180 patients were included in our study. Most patients (76.1%) were unable to provide a history of ingestion. Bezoars were the most common FBs (35.6%). The FBs were mainly located in the duodenum (32.8%) and the ileum (27.8%). Surgical removal of FBs was successful in 89 (49.4%) patients and endoscopic removal in 54 (30.0%) patients. Eleven with perforations were treated conservatively. FBs located in the jejunum or ileum were more likely to cause severe complications than those located in the duodenum. FBs located in the jejunum, ileum, or sigmoid colon were more likely to undergo surgery, and severe complications were an independent risk factor for surgery. Conclusion: Intestinal FBs, often localized in angulation, are likely to be misdiagnosed because most patients do not provide a history of FB ingestion. Surgery and endoscopic therapy are the most commonly used treatment modalities. Surgery is not mandatory in clinically stable patients with small and contained perforations. FBs located in the jejunum or ileum are risk factors for both complications and surgery.

The modified computed tomography severity index combined with low skeletal muscle mass can better predict the severity of hypertriglyceridemia-induced pancreatitis.

BACKGROUND: Body composition parameters are associated with hypertriglyceridemia-induced pancreatitis (HTGP). This study investigated the association between the quantity of muscle assessed using computed tomography (CT) and the severity of HTGP. METHODS: The modified CT severity index (MCTSI) was calculated from admission examination data. Patients' characteristics and body composition parameters were collected. Univariate and multivariate logistic regression analyses were also performed. The receiver operating characteristic curves and corresponding area under the curves (AUC) were calculated to test the efficiency of the model. A nomogram was then constructed. RESULTS: Of the 175 included patients, 138 were male, of which 85 had moderately severe to severe HTGP. Patients with low skeletal muscle mass (LSMM) and high MCTSI were significantly more likely to have moderately severe to severe HTGP. Patients with LSMM had lower body mass index, lower HDL-C level, higher amylase level, prevalence of surgery, shorter umbilical waist circumference, and longer length of hospital stay. Univariate and multivariate logistic regression analyses confirmed that female sex, lipase, total cholesterol, LSMM-MCTSI (P = .004, odds ratio = 23.105), and albumin were risk factors. The TOTAL model that combined LSMM-MCTSI and clinical risk parameters performed best (AUCs = 0.875), followed by other models (LSMM-MCTSI: AUCs = 0.762, MCTSI: AUCs = 0.728). The Delong test revealed significant difference. Finally, a nomogram was developed to predict the severity of HTGP. CONCLUSION: The performance of MCTSI in predicting severity can be improved by considering LSMM, which is a promising strategy for the treatment of HTGP.

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells.

Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE-/- mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

BMSCs mediates endothelial cell autophagy by upregulating miR-155-5p to alleviate ventilator-induced lung injury.

In this study, we explored to detect the effects and mechanism of bone-marrow-derived mesenchymal stem cells (BMSCs) on ventilator-induced lung injury (VILI). We transplanted BMSCs in mice and then induced VILI using mechanical ventilation (MV) treatment. The pathological changes, the content of PaO2 and PaCO2 , wet/dry weight ratio (W/D) of the lung, levels of tumor necrosis factor-α and interleukin-6 in bronchoalveolar lavage fluid, and apoptosis were detected. The autophagy-associated factor p62, LC3, and Beclin-1 expression were analyzed by western blot. The quantitative polymerase chain reaction was applied to detect abnormally expressed microRNAs, including miR-155-5p. Subsequently, we overexpressed miR-155-5p in VILI mice to detect the effects of miR-155-5p on MV-induced lung injury. Then, we carried out bioinformatics analysis to verify the BMSCs-regulated miR-155-5p that target messenger RNA. It was observed that BMSCs transplantation mitigated the severity of VILI in mice. BMSCs transplantation reduced lung inflammation, strengthened the arterial oxygen partial pressure, and reduced apoptosis and the W/D of the lung. BMSCs promoted autophagy of pulmonary endothelial cells accompanied by decreased p62 and increased LC3 II/I and Beclin-1. BMSCs increased the levels of miR-155-5p in VILI mice. Overexpression of miR-155-5p alleviated lung injury in VILI mice following reduced apoptosis and increased autophagy. Finally, TAB2 was identified as a downstream target of miR-155-5p and regulated by miR-155-5p. BMSCs may protect lung tissues from MV-induced injury, inhibit lung inflammation, promote autophagy through upregulating of miR-155-5p.

Preparation of controlled degradation of insulin-like growth factor 1/spider silk protein nanofibrous membrane and its effect on endothelial progenitor cell viability.

The present study aimed to prepare a kind of controlled-releasing insulin-like growth factor 1 (IGF-1)/spider silk protein nanofibrous membrane using a electrostatic spinning method and evaluated its effect on the cell viability of endothelial progenitor cells (EPCs). Recombinant spidroin named as GMCDRSSP-IgF-1 was electro-spun into nanofibrous membrane which can be degraded by protease and be capable of sustained-release of IGF-1. The membrane can be degraded after being treated with thrombin. The release assay results showed that IGF-1 concentration could be maintained at 20 ng/ml for a long time with treatment of Tobacco Etch Virus (TEV) protease. The viability of EPCs on GMCDRSSP-IgF-1 nanofibrous membrane was significantly increased with the presence of TEV protease. The controlled and sustained release of IGF-1 from the nanofibrous membrane could promote the adhesion and viability of EPCs. In summary, the nanofibrous membrane that exhibits controlled degradation and sustained release of IGF-1 was prepared with electrostatic spinning from genetically modified recombinant spider silk protein. The nanofibrous membrane exhibited good blood compatibility and cytocompatibility. With the presence of TEV protease, the sustained-release of IGF-1 significantly promoted the adhesion and viability of EPCs. The new nanofibrous membrane can be potentially used as a scaffold for EPCs culture in vitro and future in vivo studies.

SIRT6 inhibits endothelial-to-mesenchymal transition through attenuating the vascular endothelial inflammatory response.

Endothelial-to-mesenchymal transition (EndMT) is a process of transdifferentiation in which endothelial cells gradually adopt the phenotypic characteristics of mesenchymal cells. Emerging studies demonstrate the importance of EndMT in endothelial dysfunction during inflammation. Sirtuin 6 (SIRT6), a member of the mammalian NAD+-dependent deacetylase sirtuin family, plays a critical role in cardiovascular diseases by regulating the inflammatory response. However, little is known about the effect of SIRT6 on EndMT during vascular inflammation. Therefore, we aimed to investigate the effect of SIRT6 on EndMT in endothelium-specific SIRT6 knockout (ecSIRT6-/-) mice and human umbilical vein endothelial cells (HUVECs) stimulated with inflammatory cytokines. First, we found that TNF-α and IL-1ß co-treatment induced EndMT and down-regulated SIRT6 expression in HUVECs. Adenovirus-mediated SIRT6 overexpression suppressed inflammation-induced EndMT in HUVECs. In contrast, SIRT6 knockdown further promoted EndMT. Our findings also revealed that SIRT6 attenuated the inflammatory response of HUVECs. Additionally, vascular inflammation was induced by carotid artery ligation in ecSIRT6-/- mice. Results showed that the intima of ligated carotid arteries in ecSIRT6-/- mice was significantly thickened compared to that in ecSIRT6+/+ ligated mice. Moreover, endothelium-specific SIRT6 knockout promoted EndMT and increased the expression of proinflammatory cytokines in the carotid arteries of mice. These results suggest that SIRT6 inhibits EndMT through attenuating the vascular endothelial inflammatory response. These findings may have significance for reducing the occurrence of EndMT and ameliorating certain aspects of vascular inflammation.