Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice.

AIMS: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. METHODS AND RESULTS: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and inflammation). Transcriptome and biochemical analyses revealed that the ageing-controlling protein p66Shc and metabolism of mitochondrial reactive oxygen species (mROS) contributed to SIRT2 function in vascular ageing. Sirtuin 2 repressed p66Shc activation and mROS production by deacetylating p66Shc at lysine 81. Elimination of reactive oxygen species by MnTBAP repressed the SIRT2 deficiency-mediated aggravation of vascular remodelling and dysfunction in angiotensin II-challenged and aged mice. The SIRT2 coexpression module in aortas was reduced with ageing across species and was a significant predictor of age-related aortic diseases in humans. CONCLUSION: The deacetylase SIRT2 is a response to ageing that delays vascular ageing, and the cytoplasm-mitochondria axis (SIRT2-p66Shc-mROS) is important for vascular ageing. Therefore, SIRT2 may serve as a potential therapeutic target for vascular rejuvenation.

A Meta-Analysis of Prognostic Factors in Patients with Posterior Circulation Stroke after Mechanical Thrombectomy.

BACKGROUND: Posterior circulation stroke is characterized by poor prognosis because its optimal thrombolysis "time window" is always missed. After mechanical thrombectomy (MT), the recanalization rate of posterior circulation obstruction is significantly increased, but prognosis remains poor. To best manage patients, prognostic factors are needed to inform MT triaging after posterior circulation stroke. METHODS: A systematic literature search was done for the period through April 2020. Studies included those with posterior circulation stroke cases that underwent MT. The primary outcome measure in this study was the modified Rankin Scale on day 90. RESULTS: No outcome differences were found in gender, atrial fibrillation, smoking, and coronary artery disease (OR = 1.07, 95% CI: 0.90-1.28; OR = 1.02, 95% CI: 0.82-1.26; OR = 1.26, 95% CI: 0.94-1.68; and OR = 0.84, 95% CI: 0.58-1.22, respectively). Hypertension, diabetes mellitus, and previous stroke correlated with poorer prognosis (OR = 0.61, 95% CI: 0.48-0.77; OR = 0.60, 95% CI: 0.50-0.73; and OR = 0.74, 95% CI: 0.55-0.99, respectively). However, hyperlipidemia correlated with better prognosis (OR = 1.28, 95% CI: 1.04-1.58). CONCLUSION: Our analysis indicates that hypertension, diabetes mellitus, or previous stroke correlate with poorer outcomes. Intriguingly, hyperlipidemia correlates with better prognosis. These factors may help inform triage decisions when considering MT for posterior circulation stroke patients. However, large, multicenter, randomized controlled trials are needed to validate these observations.

Long noncoding RNA SNHG14 promotes osteosarcoma progression via miR-433-3p/FBXO22 axis.

Long noncoding RNA small nucleolus RNA host gene 14 (SNHG14) has been shown to exert oncogenic functions in seceral cancers, but its role in osteosarcoma still unclear. In this present study, we found that SNHG14 was significantly upregulated in osteosarcoma tissues and cell lines. Knockdown SNHG14 expression significantly inhibited osteosarcoma cell proliferation through inducing apoptosis. Further functional assays revealed that SNHG14 knockdown dramatically suppressed cell migration and invasion. Bioinformatics analysis and luciferase assays identified that microRNA-433-3p (miR-433-3p) was a direct target of SNHG14, and directly targeted F-box only protein 22 (FBXO22). Mechanistic analysis demonstrated that SNHG14 acted as a ceRNA in modulating osteosarcoma proliferation, migration and invasion by decoying miR-433-3p to upregulate FBXO22 expression. We also observed that knockdown of FBXO22 and SNHG14 and overexpression of miR-433-3p both dramatically suppressed osteosarcoma cell proliferation, migration and invasion, but induced cell apoptosis. Moreover, the suppresive effect of SNHG14 knockdown on osteosarcoma cell proliferation, invasion and migration was attenuated by miR-433-3p inhibitor. Our findings demonstrated that SNHG14 promoted osteosarcoma progression by acting as a ceRNA for miR-433-3p to regulate FBXO22 expression, suggesting that SNHG14 may serve as a potential therapeutic target in osteosarcoma patients.

Expression of the Long Intergenic Non-Coding RNA (lincRNA) of the NED25 Gene Modulates the microRNA-125b, STAT3, Nitric Oxide, and Procalcitonin Signaling Pathways in Patients with Sepsis.

BACKGROUND The aim of this study was to investigate the long intergenic non-coding RNA (lincRNA) of the NED25 gene, and the microRNA (miR)-125b, STAT3, nitric oxide (NO), and procalcitonin (PCT) pathway in sepsis. MATERIAL AND METHODS Seventy-five age-matched and sex-matched patients were divided into three groups: 25 patients with sepsis only; 25 patients with septic shock; and 25 healthy control subjects. Computational analysis and a luciferase assay confirmed that the STAT3 and PCT genes were target genes of miR-125b, whereas the lincRNA of the NED25 gene was validated as an endogenous lincRNA competing with miR-125b for binding to STAT3 and PCT. Real-time polymerase chain reaction (PCR) and Western blot measured the expression of miR-125b, STAT3, and PCT in peripheral blood monocytes (PBM) transfected with miR-125b mimics, miR-125b inhibitors, or small interfering (siRNA). RESULTS The expression of miR-125b, the PCT position ratio, the expression of PCT mRNA and protein were increased when compared with healthy individuals. When compared with the siRNA negative control, miR-125b and the lincRNA of the NED25 gene mimics, as well as STAT3 siRNA significantly downregulated the mRNA and protein expression of STAT3 and PCT; mRNA and protein expression of STAT3 and PCT in cells transfected with miR-125b inhibitors were significantly increased. Intracellular nitric oxide (NO) production was upregulated by miR-125b inhibitors and downregulated by miR-125b mimics or siRNA. CONCLUSIONS Downregulation of the lincRNA of the NED25 gene was associated with sepsis in patients by modulating the signaling pathways downstream of miR-125b/STAT3/PCT/NO signaling pathway.

Tenuifolin improves learning and memory by regulating long-term potentiation and dendritic structure of hippocampal CA1 area in healthy female mice but not male mice.

Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.

Identification of immune-associated biomarker for predicting lung adenocarcinoma: bioinformatics analysis and experiment verification of PTK6.

BACKGROUND: Abnormal expression of protein tyrosine kinase 6 (PTK6) has been proven to be involved in the development of gynecological tumors. However, its immune-related carcinogenic mechanism in other tumors remains unclear. OBJECTIVE: The aim of this study was to identify PTK6 as a novel prognostic biomarker in pan-cancer, especially in lung adenocarcinoma (LUAD), which is correlated with immune infiltration, and to clarify its clinicopathological and prognostic significance. METHODS: The prognostic value and immune relevance of PTK6 were investigated by using bio-informatics in this study. PTK6 expression was validated in vitro experiments (lung cancer cell lines PC9, NCI-H1975, and HCC827; human normal lung epithelial cells BEAS-2B). Western blot (WB) revealed the PTK6 protein expression in lung cancer cell lines. PTK6 expression was inhibited by Tilfrinib. Colony formation and the Cell Counting Kit-8 (CCK-8) assay were used to detect cell proliferation. The wound healing and trans-well were performed to analyze the cell migration capacity. Then flow cytometry was conducted to evaluate the cell apoptosis. Eventually, the relationship between PTK6 and immune checkpoints was examined. WB was used to estimate the PD-L1 expression at different Tilfrinib doses. RESULTS: PTK6 was an independent predictive factor for LUAD and was substantially expressed in LUAD. Pathological stage was significantly correlated with increased PTK6 expression. In accordance with survival analysis, poor survival rate in LUAD was associated with a high expression level of PTK6. Functional enrichment of the cell cycle and TGF-ß signaling pathway was demonstrated by KEGG and GSEA analysis. Moreover, PTK6 expression considerably associated with immune infiltration in LUAD, as determined by immune analysis. Thus, the result of vitro experiments indicated that cell proliferation and migration were inhibited by the elimination of PTK6. Additionally, PTK6 suppression induced cell apoptosis. Obviously, PD-L1 protein expression level up-regulated while PTK6 was suppressed. CONCLUSION: PTK6 has predictive value for LUAD prognosis, and could up regulated PD-L1.

Glutamine supplementation attenuates intestinal apoptosis by inducing heat shock protein 70 in heatstroke rats.

BACKGROUND: Heatstroke is the most hazardous heat-related illness and has a high fatality rate. We investigated whether glutamine supplementation could have a protective effect on heatstroke rats. METHODS: Twenty-five 12-week-old male Wistar rats (weight 305±16 g) were randomly divided into a control group (n=5), heatstroke (HS) group (n=10), and heatstroke+glutamine (HSG) group (n=10). Seven days before heat exposure, glutamine (0.4 g/[kg·d]) was administered to the rats in the HSG group by gavage every day. Three hours after heat exposure, serum samples were collected to detect white blood cells, coagulation indicators, blood biochemical indicators, and inflammatory cytokines in the rats. The small intestine tissue was stained to analyze pathological structural changes and apoptosis. Finally, immunohistochemistry and Western blotting were used to analyze the expression levels of heat shock protein 70 (HSP70). Multiple comparisons were analyzed by using one-way analysis of variance, and the Bonferroni test was conducted for the post hoc comparisons. RESULTS: After heat exposure, the core temperature of the HS group (40.65±0.31 °C) was higher than the criterion of heatstroke, whereas the core temperature of the HSG group (39.45±0.14 °C) was lower than the criterion. Glutamine supplementation restored the increased white blood cells, coagulation indicators, blood biochemical indicators, and inflammatory cytokines that were induced by heatstroke to normal levels. The intestinal mucosa was injured, and the structure of tight junctions was damaged in the HS group; however, the structure of intestinal mucosal epithelial cells was stable in the HSG group. Glutamine supplementation alleviated intestinal apoptosis and up-regulated HSP70 expression. CONCLUSION: Glutamine supplementation may alleviate intestinal apoptosis by inducing the expression of HSP70 and have a protective effect on heatstroke rats.

Thoracic endovascular aortic repair under venoarterial extracorporeal membrane oxygenation for acute aortic dissection patients: a case report.

Background: Open repair and replacement of the diseased aorta is still the standard treatment for type A aortic dissection (TAAD) in most patients. In endovascular treatment alone, ensuring adequate blood supply to the brain while covering the dissection with a stent is difficult. Case presentation: This study includes a 71-year-old male patient with type A aortic dissection presented at a recent follow-up examination after having undergone thoracic endovascular aortic repair (TEVAR) plus left subclavian artery chimney stent reconstruction for descending aortic dissection 5 years ago. Preoperative computed tomographic angiography, computed tomographic perfusion, and transcranial Doppler showed an intact cerebral arterial ring and good collateral circulation. We successfully performed an endovascular repair of the thoracic aorta with venoarterial extracorporeal membrane oxygenation (V-A ECMO) to protect the craniocerebral blood supply, greatly increase the safety of the operation, and ensure a good prognosis. Conclusion: TEVAR under V-A ECMO protection is beneficial for patients with TAAD because of its minimal trauma, rapid recovery, few complications, and low mortality.

Femoral artery variation was found during V-A ECMO catheterization.

BACKGROUND: High bifurcation of the deep femoral artery (DFA) is rare in clinical practice, and patients with this variation are less likely to receive venoarterial extracorporeal membrane oxygenation (V-A ECMO) treatment. Therefore, the method by which V-A ECMO is introduced in patients with vascular variation is very important. CASE PRESENTATION: A 52-year-old male patient had ST elevation myocardial infarction due to coronary heart disease. Angiography showed tripartite coronary artery lesions, and coronary artery stenting supported by V-A ECMO was needed. Vascular evaluation before ECMO catheterization revealed high bifurcation of the bilateral DFA located at the inguinal ligament. After discussion, the perfusion cannula was placed in the left superficial femoral artery (SFA) towards the heart, and the distal perfusion catheter (DPC) was placed in the left SFA towards the distal end. Nevertheless, after the patient's heart recovered, necrosis of the toe of the left lower limb still occurred. CONCLUSION: Common femoral artery assessment must be performed before V-A ECMO for patients with high bifurcation of the DFA. Incision catheterization and DPC placement are recommended. After decannulation, arterial repair under direct visualisation is recommended, and rigorous distal vascular assessment and management are needed.

Diurnal oscillations of endogenous H2O2 sustained by p66Shc regulate circadian clocks.

Redox balance, an essential feature of healthy physiological steady states, is regulated by circadian clocks, but whether or how endogenous redox signalling conversely regulates clockworks in mammals remains unknown. Here, we report circadian rhythms in the levels of endogenous H2O2 in mammalian cells and mouse livers. Using an unbiased method to screen for H2O2-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous H2O2 oscillations is required for proper intracellular clock function. Importantly, perturbations in the rhythm of H2O2 levels induced by the loss of p66Shc, which oscillates rhythmically in the liver and suprachiasmatic nucleus (SCN) of mice, disturb the rhythmic redox control of CLOCK function, reprogram hepatic transcriptome oscillations, lengthen the circadian period in mice and modulate light-induced clock resetting. Our findings suggest that redox signalling rhythms are intrinsically coupled to the circadian system through reversible oxidative modification of CLOCK and constitute essential mechanistic timekeeping components in mammals.