Piceatannol protects against myocardial ischemia/reperfusion injury by inhibiting ferroptosis via Nrf-2 signaling-mediated iron metabolism.

Myocardial tissue ischemia damages myocardial cells. Although reperfusion is an effective technique to rescue myocardial cell damage, it may also exacerbate myocardial cell damage. Ferroptosis, an iron-dependent cell death, occurs following myocardial ischemia-reperfusion (I/R). Piceatannol (PCT) is a natural stilbene compound with excellent antioxidant properties that protect against I/R injury and exerts protective effects against ferroptosis-induced cardiomyocytes following I/R injury; however, the exact mechanism remains to be elucidated. PURPOSE: This study aims to investigate the protective effect and mechanism of PCT on myocardial ischemia-reperfusion injury. METHODS: An ischemia-reperfusion model was established via ligation of the left anterior descending branch of mice's hearts and hypoxia-reoxygenation (H/R) of cardiomyocytes. RESULTS: During ischemia-reperfusion, Nuclear factor E2-related factor 2 (Nrf-2) expression was downregulated, the left ventricular function was impaired, intracellular iron and lipid peroxidation product levels were elevated, and cardiomyocytes underwent ferroptosis. Furthermore, ferroptosis was enhanced following treatment with an Nrf-2 inhibitor. After PCT treatment, Nrf-2 expression significantly increased, intracellular ferrous ions and lipid peroxidation products significantly reduced, Ferroportin1 (FPN1) expression increased, and transferrin receptor-1 (TfR-1) expression was inhibited. CONCLUSIONS: PCT regulates iron metabolism through Nrf-2 to protect against myocardial cell ferroptosis induced by myocardial I/R injury.

SPINT2 is involved in the proliferation, migration and phenotypic switching of aortic smooth muscle cells: Implications for the pathogenesis of thoracic aortic dissection.

Thoracic aortic dissection (TAD) is a severe and extremely dangerous cardiovascular disease. Proliferation, migration and phenotypic switching of vascular smooth muscle cells (SMCs) are major pathogenetic mechanisms involved in the development of TAD. The present study was designed to investigate the expression and potential function of serine peptidase inhibitor Kunitz type 2 (SPINT2) in TAD. The gene expression profile data for ascending aorta from patients with TAD were downloaded from the GEO database with the accession number GSE52093. Bioinformatics analysis using GEO2R indicated that the differentially expressed SPINT2 was prominently decreased in TAD. The expression levels of SPINT2 mRNA and protein in aortic dissection specimens and normal aorta tissues were measured using reverse transcription-quantitative PCR and western blotting. SPINT2 expression was downregulated in clinical samples from aortic dissection specimens of patients with TAD compared with the corresponding expression noted in tissues derived from patients without TAD. In vitro, platelet-derived growth factor BB (PDGF-BB) was applied to induce the isolated primary mouse aortic SMC phenotypic modulation (a significant upregulation in the expression levels of synthetic markers), and the SMCs were infected with the adenoviral vector, Ad-SPINT2, to construct SPINT2-overexpressed cell lines. SMC viability was detected by an MTT assay and SMC proliferation was detected via the presence of Ki-67-positive cells (immunofluorescence staining). To explore the effects of SPINT2 on SMC migration, a wound healing assay was conducted. ELISA and western blotting assays were used to measure the content and expression levels of MMP-2 and MMP-9. The expression levels of vimentin, collagen I, α-SMA and SM22α were measured using western blotting. The PDGF-BB-induced proliferation and migration of SMCs were recovered by SPINT2 overexpression. The increase in the expression levels of SPINT2 reduced the expression levels of active matrix metalloproteinases (MMPs), MMP-2 and MMP-9. Overexpression of SPINT2 suppressed SMC switching from a contractile to a synthetic type, as evidenced by decreased vimentin and collagen I expression levels along with increased α-smooth muscle actin and smooth muscle protein 22-α expression levels. Furthermore, activation of ERK was inhibited in SPINT2-overexpressing SMCs. A specific ERK agonist, 12-O-tetradecanoylphorbol-13-acetate, reversed the SPINT2-mediated inhibition of SMC migration and the phenotypic switching. Collectively, the data indicated that SPINT2 was implicated in the proliferation, migration and phenotypic switching of aortic SMCs, suggesting that it may be involved in TAD progression.

Low tidal volume ventilation alleviates ventilator-induced lung injury by regulating the NLRP3 inflammasome.

PURPOSE: Low tidal volume ventilation (LTVV) is a well-known ventilation mode which can improve ventilator-induced lung injury (VILI). However, the mechanism of LTVV ameliorating VILI has not yet been elucidated. In this study, we aimed to reveal LTVV protected against VILI by inhibiting the activation of the NLRP3 inflammasome in bronchoalveolar lavage fluid (BALF) from humans and lungs from mice. MATERIALS AND METHODS: Twenty-eight patients scheduled for video-assisted thoracoscopic esophagectomy were randomized to receive high-tidal-volume ventilation [Vt = 10 mL/kg without positive end-expiratory pressure (PEEP)] or LTVV (Vt = 5 mL/kg along with 5 cm of H2O PEEP) during one-lung ventilation. BALF was collected before and at the end of surgery. Male C57BL/6 mice received high-tidal-volume ventilation, LTVV or MCC950 (an inhibitor of NLRP3). The activation of the formation of NLRP3 inflammasome in BALF from patients and in lungs from mice were analyzed. RESULTS: LTTV decreased the peak airway pressure (Ppeak), plateau airway pressure (Pplat) and driving pressure (ΔP) during one-lung ventilation. Additionally, LTVV not only inhibited pulmonary infiltration and inflammation caused by mechanical ventilation, but also suppressed the NLRP3 inflammasome activation in BALF from humans. In mice, ventilator-induced inflammatory response and pulmonary edema were suppressed by LTVV with an efficacy comparable to that of MCC950 treatment. Furthermore, LTVV, similar to MCC950, clearly decreased ventilator-induced NLRP3 inflammasome activation. CONCLUSION: Our study showed that LTVV played a protective role in ventilator-induced lung injury by suppressing the activation of the NLRP3 inflammasome. TRIAL REGISTRATION: This study was registered in The Chinese Clinical Trial Registry, ChiCTR1900026190 on 25 September 2019.

Endovascular Repair for Giant Right Subclavian Artery Aneurysm With Gore Viabahn and Pull-Through Procedure: A Case Report.

Background: Giant true subclavian artery aneurysms (SAAs) (>5 cm) are rare. Technical and anatomical considerations complicate the endovascular treatment of SAAs and pose some challenges. Here, we present a giant right SAA that was successfully excluded using stent grafts with the pull-through technique after two interventional steps and discuss the pull-through technique details as well as the lessons to be learned from this case. Methods: A 50-year-old man presented at our department complaining of dyspnea and hoarseness. Computed tomography angiography (CTA) showed a giant right SAA with partial intraluminal thrombus and severe angulated aneurysm necks originating from the proximal right subclavian artery, approximately 70 × 71 mm in size. Outcomes: An 8 × 100-mm Gore Viabahn was selected to exclude the SAA. A decision was made to stabilize the wire tension using the pull-through technique. Final angiography showed that the SAA was essentially excluded, and slight endoleak was observed. At 6 months, imaging showed that the aneurysm was not obviously shrinking, there was still an endoleak and stent graft dislodgement was observed. Angiography confirmed a type Ia endoleak, which was managed by the placement of a 10 × 50-mm Gore Viabahn, again with the assistance of the pull-through technique. At the 25-month follow-up, CTA showed that the SAA was satisfactorily excluded, with no endoleak, and the SAA was reduced in size. Conclusions: Endovascular treatment of SAAs is a safe, reliable and minimally invasive approach. The pull-through technique may improve wire tension and device stabilization. Additionally, size selection and positioning should be reappraised under a severely angulated aneurysm neck.

Effects of silver foam combined with Dermlin wound healing dressing on inflammation and quality of life in patients with diabetic lower limb ulcers.

OBJECTIVE: To investigate the effects of silver foam combined with Dermlin wound healing dressing on concentrations of inflammatory factors of wound surface and quality of life of the patients with diabetic lower limb ulcers. METHODS: A total of 60 patients with diabetic lower limb ulcers admitted to the First Affiliated Hospital of Anhui Medical University during January 2020 and December 2020 were retrospectively enrolled in this study. According to the different treatments, they were divided into a control group (30 cases treated with Dermlin wound healing dressing only), and a research group (30 cases treated with silver foam combined with Dermlin dressing). The clinical efficacy, wound healing status, pain intensity (visual analog scale (VAS) scores), concentrations of inflammatory factor (high-sensitivity C-reactive protein (hsCRP), leukocyte interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT)), angiogenesis factors levels (basic fibroblast growth factor (BFGF), vascular endothelial growth factor (VEGF)), oxidative stress reaction indexes (advanced protein oxidation products (AOPP), malondialdehyde (MDA) and superoxide dismutase (SOD)) and quality of life (SF-36 scale) were compared between two groups. The bacterial removal rate was calculated based on the results of bacterial culture before and after treatment. The central granulated tissue was collected after the granulation tissue coverage rate was calculated. RESULTS: The research group had significantly higher overall response rate (96.67% vs 73.33%), shorter wound healing time and higher wound healing rate than the control group (all P<0.05). The VAS scores were decreased in both Groups 1, 3 and 7 d after treatment as compared with those before treatment, and the VAS scores were significantly lower in the research group than in the control group during the same period (all P<0.05). After treatment, the concentrations of hsCRP, IL-6, TNF-α, PCT, AOPP and MDA were decreased in both groups, while the levels of bFGF, VEGF, l TGF-ß1, SOD and SF-36 scores were increased significantly (all P<0.05). The above-mentioned indicators of the research group improved significantly compared with those of the control group (all P<0.05). The bacterial removal rate and granulation tissue coverage rate of the research group were significantly higher than those of the control group (both P<0.05). CONCLUSION: The treatment of diabetic lower limb ulcers with silver foam combined with Dermlin dressing can effectively promote wound healing, reduce pain intensity, and improve quality of life in patients with diabetic lower limb ulcers. Such effects may be attributed to lower levels of inflammatory factor levels, regulation of oxidative stress, and improvement of angiogenesis.

GPR30 Promotes the Phenotypic Switching of Vascular Smooth Muscle Cells via Activating the AKT and ERK Pathways.

BACKGROUND: Lower extremity varicose veins (LEVVs) are a common venous disorder of venous dilation and tortuosity. The functional integrity of vascular smooth muscle cells (VSMCs), the majority of the cells in venous tissues, and their phenotypic differences play important roles in the occurrence and development of LEVV. However, the underlying mechanism remains unclear. METHODS: The expression of estrogen receptors ERα and ERß and G-protein-coupled receptor 30 (GPR30) in LEVV tissues and the role of GPR30 in VSMC phenotypic switching were examined by Western blotting and quantitative real-time PCR. Finally, the related mechanisms underlying LEVVs were explored by Western blotting. RESULTS: The serum estradiol content was increased in LEVV patients compared with normal control patients, but the mRNA levels of ERα and ERß were not significantly different. GPR30 was overexpressed in LEVVs, and high expression of GPR30 promoted the maintenance of a synthetic phenotype in which OPN, MMP-1 and MMP-9 were highly expressed and α-SMA was poorly expressed in VSMCs. Finally, the mechanism by which GPR30 promotes the phenotypic switching of VSMCs is dependent on the ERK1/2 and AKT pathways. CONCLUSION: GPR30 may contribute to the pathogenesis of LEVVs by promoting the maintenance of a synthetic phenotype in VSMCs by activating the ERK1/2 and AKT pathways, and GPR30 might be a novel therapeutic target for clinical LEVV treatment.

A meta-analysis of combined proximal stent grafting with or without adjunctive distal bare stent for the management of aortic dissection.

BACKGROUND: The efficacy and safety of placement of a proximal covered stent graft combined with a distal bare stent are controversial because of the lack of evidence. This systematic review and meta-analysis compared the outcomes of combined proximal covered stent grafting with distal bare stenting (BS group) and proximal covered stent grafting without distal bare stenting (non-BS group). METHODS: The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and key references were searched up to January 26, 2019. Predefined outcomes of interest were mortality, morbidity, and postoperative assessment of aortic remodeling. We pooled risk ratios (RRs) of the outcomes of interest using fixed effects model or random effects model. RESULTS: Overall, eight observational studies involving 914 patients were included. There were no significant differences in overall aorta-related mortality (RR, 0.54; confidence interval [CI], 0.24-1.24; P = .15), complete thoracic false lumen (FL) thrombosis rate (RR, 1.23; CI, 0.83-1.81; P = .30), or complete abdominal FL thrombosis rate (RR, 1.96; CI, 0.68-5.69; P = .21) between the BS group and the non-BS group. The BS group had a lower rate of partial thoracic FL thrombosis (RR, 0.40; CI, 0.25-0.65; P = .0002), a lower stent graft-induced new entry rate (RR, 0.08; CI, 0.02-0.41; P = .003), and a lower reintervention rate (RR, 0.42; CI, 0.26-0.69; P = .0005). CONCLUSIONS: Combined proximal covered stent grafting with distal adjunctive bare stenting had the potential to reduce the partial thoracic FL thrombosis rate and the rates of stent graft-induced new entry and reintervention but was not associated with lower aorta-related mortality or the complete FL thrombosis rate. Further research with a stricter methodology is needed.

Systematic Review and Meta-Analysis of Iliofemoral Stenting for Post-thrombotic Syndrome.

OBJECTIVE: Stent placements are considered as a treatment for post-thrombotic syndrome (PTS) with iliofemoral obstruction, but the application of these iliofemoral venous stents has also caused a lot of controversy. The purpose of this systematic review and meta-analysis was to summarise the efficacy and safety of venous stents in PTS with obstruction in iliofemoral venous segments. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register for Controlled Trials databases and key references were searched up to 15 January 2018. The main relevant outcomes included technical success, peri-operative complications, symptom resolution, a change of symptom scores, and long-term patency of the stents. RESULTS: Overall, 504 limbs of 489 patients from seven studies were included in this study. A GRADE assessment showed the quality of the evidence was "very low" for 11 relevant outcomes. The technical success rate was 95%. The pooled rate of complications including 30 day thrombotic event, per-operative venous injury, and back pain was 3.4%, 18.14%, and 52%, respectively. The rates of ulcer healing, pain and oedema relief were 75.66%, 52%, and 42%, respectively. The primary, assisted primary and secondary patency rates were 83.36%, 90.59%, and 94.32%, respectively, at 12 months and 67.98%, 82.26%, and 86.10%, respectively, at 36 months. CONCLUSIONS: Endovenous stenting has the potential to be effective and has a low risk of peri-operative complications. The quality of evidence to support this treatment is very low. Endovenous iliofemoral stenting should be considered a treatment option for PTS with iliofemoral obstruction.

miR-335-5p targeting ICAM-1 inhibits invasion and metastasis of thyroid cancer cells.

miRNAs is a kind of noncoding small RNAs with negative regulation function. Some miRNAs play a crucial role in the growth of tumor cells. In this study, we analyzed the role of miR-335-5p and its target gene intercellular adhesion molecule 1 (ICAM-1) in thyroid cancer. Real-time polymerase chain reaction (PCR) results showed that the expression level of ICAM-1 in cancer tissues was higher than that in their adjacent tissues. The expression level of ICAM-1 in papillary thyroid carcinoma was also significantly higher than that in other types of tumors. However, the expression of miR-335-5p is opposite to that of ICAM-1. In human thyroid cancer cell lines TPC-1, FTC-133, TT and human thyroid follicular cell line Nthyori 3-1, the expression level of ICAM-1 in TPC-1 was significantly higher than that of other cells, while the expression level of miR-335-5p in TPC-1 was significantly lower than that of other cells. When ICAM-1 expression was downregulated and miR-335-5p expression was upregulated in TPC-1 cells, ICAM-1 expression was upregulated and miR-335-5p expression was downregulated in FTC-133 cells, we found that ICAM-1 could promote the proliferation of thyroid cancer cells, while miR-335-5p could inhibit the proliferation of thyroid cancer cells. miR-335-5p could combine with 3'UTR of ICAM-1 by bioinformatics prediction. Luciferase reporter gene analysis and Western blotting detection further confirmed that miR-335-5p could target ICAM-1 and inhibit its expression. The expression level of miR-335-5p was downregulated, while the expression level of ICAM-1 was upregulated in thyroid cancer. This study will help us better understand the pathogenesis of thyroid cancer and provide new insights into the treatment of this disease.

Association between Clinical and Ultrasonic Characteristics of Varicocele and Lower Extremity Varicose Vein in Men.

BACKGROUND: The study investigated the association between lower extremity varicose veins in men and varicocele. METHODS: A total of 100 patients who presented to the Department of Vascular Surgery in the First Affiliated Hospital of Anhui Medical University with the diagnosis of lower extremity varicose veins were included in the study group. A total of 100 adults without vascular disease were included as controls. The prevalence of varicocele between the study group and the control group was compared. We compared the prevalence of varicocele and the mean diameter of spermatic veins between the patients with and without reflux in the saphenofemoral junctions. We analyzed the association between the maximum spermatic vein diameter and the maximum diameter of lower extremity varicose veins in patients who had both lower extremity varicose vein and varicocele in the study group. According to their clinic signs, patients with lower extremity varicose veins were divided into C1-C6 by clinic sign grade of Clinical-Etiology-Anatomy-Pathophysiology (CEAP), and we investigated the trend of the incidence of varicocele and the mean diameter of spermatic veins in different grades. RESULTS: The patients with lower extremity varicose veins had a statistically significant (χ2 = 20.05, P < 0.01) higher rate of varicocele when compared with controls. We compared the prevalence of varicocele and the mean diameter of spermatic veins between the patients with and without reflux in the saphenofemoral junctions and found no statistically significant differences between them (prevalence of varicocele P > 0.05, diameter P > 0.05). We found a linear correlation between the maximum spermatic vein diameter and the maximum diameter of lower extremity varicose veins in the patients who had both lower extremity varicose veins and varicocele in the study group (coefficient of rank correlation r = 0.4072, P < 0.01). The patients in the study group were classified into 6 grades by CEAP. After the analysis by trend chi-square, we found that the prevalence of varicocele had no statistical trend in different grades (χ2 = 0.8798, P > 0.05), and the mean diameter of spermatic vein also had no statistical trend in different grades (F = 1.59, P > 0.05). CONCLUSIONS: In conclusion, we demonstrated that the prevalence of varicocele is higher in patients with varicose veins in lower extremity than the patients without vascular diseases. The reason for the association between varicose vein in lower extremity and varicocele remains uncertain.

Characteristic gene expression profiles in the progression from liver cirrhosis to carcinoma induced by diethylnitrosamine in a rat model.

BACKGROUND: Liver cancer is a heterogeneous disease in terms of etiology, biologic and clinical behavior. Very little is known about how many genes concur at the molecular level of tumor development, progression and aggressiveness. To explore the key genes involved in the development of liver cancer, we established a rat model induced by diethylnitrosamine to investigate the gene expression profiles of liver tissues during the transition to cirrhosis and carcinoma. METHODS: A rat model of liver cancer induced by diethylnitrosamine was established. The cirrhotic tissue, the dysplasia nodules, the early cancerous nodules and the cancerous nodules from the rats with lung metastasis were chosen to compare with liver tissue of normal rats to investigate the differential expression genes between them. Affymetrix GeneChip Rat 230 2.0 arrays were used throughout. The real-time quantity PCR was used to verify the expression of some differential expression genes in tissues. RESULTS: The pathological changes that occurred in the livers of diethylnitrosamine-treated rats included non-specific injury, fibrosis and cirrhosis, dysplastic nodules, early cancerous nodules and metastasis. There are 349 upregulated and 345 downregulated genes sharing among the above chosen tissues when compared with liver tissue of normal rats. The deregulated genes play various roles in diverse processes such as metabolism, transport, cell proliferation, apoptosis, cell adhesion, angiogenesis and so on. Among which, 41 upregulated and 27 downregulated genes are associated with inflammatory response, immune response and oxidative stress. Twenty-four genes associated with glutathione metabolism majorly participating oxidative stress were deregulated in the development of liver cancer. There were 19 members belong to CYP450 family downregulated, except CYP2C40 upregulated. CONCLUSION: In this study, we provide the global gene expression profiles during the development and progression of liver cancer in rats. The data obtained from the gene expression profiles will allow us to acquire insights into the molecular mechanisms of hepatocarcinogenesis and identify specific genes (or gene products) that can be used for early molecular diagnosis, risk analysis, prognosis prediction, and development of new therapies.