Berberine ameliorates chronic intermittent hypoxia-induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling.

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.

Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1.

Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.

Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development.

Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.

RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling.

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule neuron progenitors (CGNPs) and its mis-regulation is linked to various disorders, including the cerebellar cancer medulloblastoma (MB). We recently identified RNF220, a ubiquitin E3 ligase promoting K63-linked polyubiquitylation and nuclear exportation of Gli transcription factors, as an Shh/Gli regulator involved in ventral neural patterning. Here, we report that RNF220 is required for the proliferation of CGNPs and Daoy cells (an Shh-grouped MB cell line), working as a positive regulator of Shh signaling. Mechanistic investigation demonstrated that RNF220 promotes Shh target gene expression by targeting the PRC2 component EED, and alters levels of epigenetic modification marks on Shh target promoters. We provided evidence that RNF220+/-; Ptch1+/- mice showed lower spontaneous MB occurrence compared with Ptch1+/- mice. Furthermore, in human clinical MB samples, RNF220 expression correlated well with that of GAB1, an Shh-group MB marker. Our findings provide new insights into the epigenetic regulation of Shh signaling and identify RNF220 as a potential new diagnostic marker and therapeutic target for Shh-group MB.

2022 CMICS Expert Consensus on the Management of Isolated Tricuspid Regurgitation after Left-Sided Valve Surgery.

Tricuspid regurgitation (TR) may occur late after left-sided valve surgery (LSVS). Isolated tricuspid regurgitation after left-sided valve surgery (iTR-LSVS) refers to isolated TR without significant lesions in the mitral and/or aortic position late after mitral and/or aortic replacement or repair. Severe TR has a negative impact on long-term prognosis and requires surgical or transcatheter treatment. However, there is no clear recommendation on when and how intervention should be performed for patients with iTR-LSVS in the current guidelines for the management of valvular heart disease. The historically high operative mortality may be reduced by current minimally invasive techniques and transcatheter therapy. To further understand iTR-LSVS, standardize the treatment, improve the prognosis, and promote the collaboration, the Chinese Minimally Invasive Cardiovascular Surgery Committee (CMICS) wrote this expert consensus on the management of iTR-LSVS from the aspects of etiology, preoperative evaluation, indications for intervention, surgical treatment, transcatheter therapy, and postoperative management.

Increasing coverage of mono-layer graphene grown on hexagonal boron nitride.

Graphene sitting on hexagonal boron nitride (h-BN) always exhibits excellent electrical properties. And the properties of graphene onh-BN are often dominated by its domain size and boundaries. Chemical vapor deposition (CVD) is a promising approach to achieve large size graphene crystal. However, the CVD growth of graphene onh-BN still faces challenges in increasing coverage of monolayer graphene because of a weak control on nucleation and vertical growth. Here, an auxiliary source strategy is adapted to increase the nucleation density of graphene onh-BN and synthesis continuous graphene films. It is found that both silicon carbide and organic polymer e.g. methyl methacrylate can assist the nucleation of graphene, and then increases the coverage of graphene onh-BN. By optimizing the growth temperature, vertical accumulation of graphitic materials can be greatly suppressed. This work provides an effective approach for preparing continuous graphene film onh-BN, and may bring a new sight for the growth of high quality graphene.

Cost-effectiveness of stereotactic body radiotherapy versus conventional fractionated radiotherapy for medically inoperable, early-stage non-small cell lung cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is a novel radio-therapeutic technique that has recently emerged as standard-of-care treatment for medically inoperable, early-stage non-small cell lung cancer (NSCLC). In this study, we compared the cost-effectiveness of SBRT with that of conventional fractionated radiotherapy (CFRT) in patients with medically inoperable, early-stage NSCLC from the perspective of the Chinese health system. METHODS: A Markov model was developed to describe health states of patients after treatment with SBRT and CFRT. The recurrence risks, treatment toxicities, and utilities inputs were obtained from the literature. The costs were based on listed prices and real-world evidence. A simulation was conducted to determine the post-treatment lifetime years. For each treatment, the total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) per QALY were calculated. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters. RESULTS: In the base case analysis, SBRT was associated with a mean cost of USD16,933 and 2.05 QALYs, whereas CFRT was associated with a mean cost of USD17,726 and 1.61 QALYs. SBRT is a more cost-effective strategy compared with CFRT for medically inoperable, early-stage NSCLC, with USD 1802 is saved for every incremental QALY. This result was validated by DSA and PSA, in which SBRT remained the most cost-effective option. CONCLUSIONS: The findings suggested that, compared to CFRT, SBRT may be considered a more cost-effective strategy for medically inoperable, early-stage NSCLC.

The association between parental risks and childhood development: findings from a community-based survey in East China.

BACKGROUND: Nurturing care is necessary for optimal early childhood development. This study aimed to investigate the prevalence of parental risks in rural East China and assess their impacts on early development in children younger than three years old. METHODS: This community-based cross-sectional survey was conducted among 3852 caregiver-child pairs in Zhejiang Province from December 2019 to January 2020. Children aged 0 to 3 years were recruited from China's Early Childhood Development Program (ECD). Local child health care providers conducted face-to-face interviews with the primary caregivers. Demographic information of the participants was collected by questionnaire. Each child was screened for parental risk through the Parental Risk Checklist designed by the ECD program. The Ages and Stages Questionnaire (ASQ) was used to identify children with potential developmental delays. Multinomial logistic regression model and linear trend test were applied to assess the association between parental risks and suspected developmental delays. RESULTS: Among the 3852 children included in the analyses, 46.70% had at least one parental risk and 9.01% presented suspected developmental delays in any domain of ASQ. Parental risk was statistically associated with the overall suspected developmental delay in young children (Relative Risk Ratio (RRR): 1.36; 95% confidence interval (CI): 1.08, 1.72; P = 0.010) after adjusting potential confounders. Compared with children with no parental risk, children exposed to 3 or more parental risks had 2.59, 5.76, 3.95, and 2.84 times higher risk of the suspected developmental delay in overall ASQ, communication, problem-solving, and personal-social domain, respectively (P values < 0.05). The linear trend tests found that the more parental risks, the higher possibility of developmental delay (P values < 0.05). CONCLUSIONS: Parental risks are prevalent among children under three years in rural East China, which may increase the risk of developmental delays in children. Meanwhile, parental risk screening can be used to recognize poor nurturing care in primary health care settings. Targeted interventions are warranted to improve nurturing care for optimal early childhood development.

Probiotics Improve Cognitive Impairment by Decreasing Bacteria-Related Pattern Recognition Receptor-Mediated Inflammation in the Gut-Brain Axis of Mice.

INTRODUCTION: Some studies have found that probiotics can improve cognitive impairment in Alzheimer's disease, although the specific molecular mechanism by which this occurs has not been reported. Our previous research found that probiotics inhibited bacteria-related Toll-like receptor 4- and retinoic-acid-inducible gene-I-mediated nuclear factor-κB signaling pathways to improve cognitive impairment. However, it is unclear whether probiotics have similar effects on other pattern recognition receptors that respond to bacteria. METHODS: Nine-month-old senescence-accelerated mouse prone 8 (SAMP8) mice received ProBiotic-4 (a mixture of Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus casei, and Bifidobacterium lactis) orally for 12 weeks. The effects on other bacteria-related pattern recognition receptors were then investigated. RESULTS: ProBiotic-4-treated SAMP8 mice showed improvement in memory deficits, synaptic and cerebral neuronal injuries, and microglial activation. ProBiotic-4 also markedly increased the expression of intestinal tight junction proteins (i.e., claudin-1, occludin, and zonula occluden-1), decreased the expression of interleukin-1ß at both the mRNA and protein levels, and reduced the expression of caspase-11, cleaved caspase-1, and α-kinase 1 (ALPK1) in the intestine and brain. CONCLUSIONS: These findings suggest that probiotics may have therapeutic potential for the treatment of inflammation in the gut-brain axis and for cognitive impairment. The mechanism of action of probiotics appears to be related to inhibition of the caspase-11/caspase-1 pathway and reduction of ALPK1 expression.

Long-Term Results and Risk Factors of Treatment for Post-Infarction Ventricular Septal Rupture: A Single-Center Experience.

BACKGROUND: Ventricular septal rupture (VSR) following myocardial infarction (MI) is a rare but lethal complication. We analyzed the long-term results and risk factors for survival in the treatment of VSR. METHODS: From January 2012 to December 2021, 115 consecutive patients with post-MI VSR were admitted to our hospital. Depending on different treatment methods patients were divided into following three groups: medical, transcatheter intervention, and surgical repair. During the study, relevant clinical data, operation-related conditions, and follow-up data were analyzed. The Kaplan-Meier method and log-rank test were used to determine the cumulative incidence of mortality. The independent risk factors for patient mortality were evaluated by multivariate logistic regression. RESULTS: The mean follow-up time was 43.4 ± 34.7 months. The overall in-hospital, 30-day, and long-term mortality rates were 24.3%, 38.3%, and 51.3%, respectively. In the medical group, the in-hospital and 30-day mortality rates were 46.7 % (21/45) and 82.2 % (37/45), respectively, with only three patients alive at follow-up. In the transcatheter intervention group, 30-day and long-term mortality rates were 12% and 28%, respectively. In the surgical repair group, 30-day and long-term mortality rates were 8.9% and 22.2%, respectively. Compared with the surgery-group patients, patients with transcatheter intervention had a longer time from VSR to intervention. Logistic regression analysis revealed that age, previous infarction, Killip class, serum creatinine, Troponin T, N-terminal pro-B-type natriuretic peptide, and medical strategy were risk factors for all-cause mortality. CONCLUSIONS: The 30-day and long-term outcomes of patients treated with surgical repair and transcatheter intervention were significantly better than medically treated patients.

RasI/R Quorum Sensing System Controls the Virulence of Ralstonia solanacearum Strain EP1.

Quorum sensing (QS) is a widely conserved bacterial regulatory mechanism that relies on production and perception of autoinducing chemical signals to coordinate diverse cooperative activities, such as virulence, exoenzyme secretion, and biofilm formation. In Ralstonia solanacearum, a phytopathogen causing severe bacterial wilt diseases in many plant species, previous studies identified the PhcBSR QS system, which plays a key role in regulation of its physiology and virulence. In this study, we found that R. solanacearum strain EP1 contains the genes encoding uncharacterized LuxI/LuxR (LuxI/R) QS homologues (RasI/RasR [designated RasI/R here]). To determine the roles of the RasI/R system in strain EP1, we constructed a specific reporter for the signals catalyzed by RasI. Chromatography separation and structural analysis showed that RasI synthesized primarily N-(3-hydroxydodecanoyl)-homoserine lactone (3-OH-C12-HSL). In addition, we showed that the transcriptional expression of rasI is regulated by RasR in response to 3-OH-C12-HSL. Phenotype analysis unveiled that the RasI/R system plays a critical role in modulation of cellulase production, motility, biofilm formation, oxidative stress response, and virulence of R. solanacearum EP1. We then further characterized this system by determining the RasI/R regulon using transcriptome sequencing (RNA-seq) analysis, which showed that this newly identified QS system regulates the transcriptional expression of over 154 genes associated with bacterial physiology and pathogenic properties. Taken together, the findings from this study present an essential new QS system in regulation of R. solanacearum physiology and virulence and provide new insight into the complicated regulatory mechanisms and networks in this important plant pathogen. IMPORTANCE Quorum sensing (QS) is a key regulator of virulence factors in many plant-pathogenic bacteria. Previous studies unveiled two QS systems (i.e., PhcBSR and SolI/R) in several R. solanacearum strains. The PhcBSR QS system is known for its key roles in regulation of bacterial virulence, and the LuxI/LuxR (SolI/R) QS system appears dispensable for pathogenicity in a number of R. solanacearum strains. In this study, a new functional QS system (i.e., RasI/R) was identified and characterized in R. solanacearum strain EP1 isolated from infected eggplants. Phenotype analyses showed that the RasI/R system plays an important role in regulation of a range of biological activities associated with bacterial virulence. This QS system produces and responds to the QS signal 3-OH-C12-HSL and hence regulates critical bacterial abilities in survival and infection. To date, multiple QS signaling circuits in R. solanacearum strains are still not well understood. Our findings from this study provide new insight into the complicated QS regulatory networks that govern the physiology and virulence of R. solanacearum and present a valid target and clues for the control and prevention of bacterial wilt diseases.

The systemic-immune-inflammation index predicts the recurrence of atrial fibrillation after cryomaze concomitant with mitral valve surgery.

BACKGROUND AND AIMS: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). The systemic inflammation indexes are easily evaluated and predict AF development. However, it's role in prediction of recurrence of AF is unknown. We aim to explore the association between the systemic inflammation indexes and recurrence of AF in patients underwent cryoablation (CryoMaze) concomitant with mitral valve surgery. METHODS: We examined systemic inflammation indexes during perioperative period in 122 patients between 2015 and 2018. Systemic inflammation indexes were developed by systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio. Univariate and multivariate analyses were performed to examine the association of each markers with recurrence of AF. RESULTS: Of the 122 patients included in this study, 22 patients (18%) experienced AF recurrence after CryoMaze concomitant with mitral valve surgery. There is no significant difference between each systemic inflammation indexes before surgery and recurrence of AF. In univariate analysis, MLR after surgery 3 days, PLR, MPLR, NLR, SII after surgery 7 days were able to predict recurrence of AF. In multivariate analyses, SII ≥ 1696 independently predicted recurrence (OR, 3.719; 95% CI, 1.417-9.760). Interestingly, baseline SII showed no significant in prediction of recurrence. It was sharply elevated after surgery and dropped slowly. In patients of recurrence, SII after 7 days of surgery increased again. CONCLUSIONS: The raised SII again was associated with an increased risk of the postoperative recurrence of AF and independently predicted the late recurrence of AF after CryoMaze concomitant with mitral valve surgery.

Surgical treatment for Behcet's disease with acute superior vena cava syndrome.

BACKGROUND AND AIM OF THE STUDY: Behcet's disease (BD) is a multisystem vasculitis with unknown etiology. The involvement of superior vena cava (SVC) is reported in less than 2% of patients with BD. METHODS: We report a patient with acute edema of neck and face associated with dyspnea as the primary manifestation. So a diagnosis of superior Vena Cava syndrome (SVCS) was made and the thickening wall of SVC was resected. An Operation was performed under cardiopulmonary bypass to remove the mass and thrombus for avoiding for pulmonary embolism. RESULTS: The diagnosis of Behcet's disease (BD) didn't not be made until the recurrent oral and genital ulceration occurred 2 weeks later. The patient taked aspirin and prednisolone orally as prescribed and no recurrence were observed during the 30 months follow-up. CONCLUSIONS: BD should be suspected in patients presenting with SVCS, when there is thickening of SVC, whether thrombosis or not. Early diagnosis and treatment are essential for management of BD.

Moderate Hypothermic Circulatory Arrest Model in Rats: A New Model with Hyperkalemia-Induced Cardioplegia.

BACKGROUND: Moderate hypothermic circulatory arrest (MHCA) is a safe and effective method of cardiopulmonary bypass (CPB). However, most present rat models involve a deep hypothermic circulatory arrest, which cannot exactly reflect the clinical situation. The aim of this study was to establish a novel and safe rat model of MHCA with hyperkalemia-induced cardioplegia to study the pathophysiology of potential complications. METHODS: Ten adult male Sprague-Dawley rats (age, 16-18 weeks; weight, 450-550 g) were used. The entire CPB circuit consisted of a reservoir, peristaltic pump, membrane oxygenator, heat exchanger, and hemoconcentrator, all of which were connected via silicon tubing. The prime solution was approximately 19 mL. The right jugular vein, right femoral artery, and left femoral artery were cannulated. Blood was drained from the right atrium through the right jugular vein and perfused to the rats via the left femoral artery. CPB was commenced at a full flow rate. The rats were cooled to a rectal temperature of 25°C, and cardioplegia was induced by systemic hyperkalemia. After that, MHCA was carried out for 30 min. At the same time, system self-ultrafiltration was carried out to decrease the concentration of potassium by a hemoconcentrator. The circulatory arrest was followed by reperfusion and over 30 min of rewarming. CPB carefully was terminated. Blood in the circuit slowly was centrifuged for autotransfusion. Blood gas and hemodynamic parameters were recorded at each time point before CPB, before MHCA, at 10 min after the initiation of rewarming, and after CPB. RESULTS: All CPB and MHCA procedures successfully were achieved. One rat died of respiratory failure. Cardioplegia with systemic hyperkalemia was induced by 1 mL of 10% potassium chloride injected into the reservoir, and the concentration of potassium was maintained at 17 ± 3 mmol/L. Cardiac function and blood pressure were stable after the operation. CONCLUSIONS: A novel and safe rat model of MHCA with hyperkalemia-induced cardioplegia successfully was established.

Imaging Dual-Moiré Lattices in Twisted Bilayer Graphene Aligned on Hexagonal Boron Nitride Using Microwave Impedance Microscopy.

Moiré superlattices (MSLs) formed in van der Waals materials have become a promising platform to realize novel two-dimensional electronic states. Angle-aligned trilayer structures can form two sets of MSLs which could potentially interfere. In this work, we directly image the moiré patterns in both monolayer and twisted bilayer graphene aligned on hexagonal boron nitride (hBN), using combined scanning microwave impedance microscopy and conductive atomic force microscopy. Correlation of the two techniques reveals the contrast mechanism for the achieved ultrahigh spatial resolution (<2 nm). We observe two sets of MSLs with different periodicities in the trilayer stack. The smaller MSL breaks the 6-fold rotational symmetry and exhibits abrupt discontinuities at the boundaries of the larger MSL. Using a rigid atomic-stacking model, we demonstrate that the hBN layer considerably modifies the MSL of twisted bilayer graphene. We further analyze its effect on the reciprocal space spectrum of the dual-moiré system.

A Modified Maze Versus Cut-and-Sew Maze for Long-Standing Persistent Atrial Fibrillation Concomitant with Mitral Valve Surgery: A Propensity Score-Matched Cohort Study.

BACKGROUND: The cut-and-sew maze (CSM) procedure has an excellent efficacy for the elimination of long-standing persistent atrial fibrillation (AF) concomitant with mitral valve surgery. Because of the complexity and prolongation of cardiopulmonary bypass, CSM has not been widely used. The aim of this study was to examine a modified maze procedure that preserves the "cut-and-sew" procedure in the left atrium and uses cryoablation in the right atrium along with cavotricuspid isthmus. METHODS: From December 2013 to December 2018, 229 patients underwent CSM, and 43 underwent the modified maze procedure during mitral valve surgery. Propensity score matching analysis was used to perform selective 1:2 ratio matching of the 43 patients undergoing the modified maze procedure with 86 patients undergoing CSM. Early operative outcomes were analysed for differences. The absence of AF recurrence without the use of anti-arrhythmic drugs was calculated at 2 years by a generalised linear model analysis. RESULTS: One (1.1%) early death occurred in the CSM group, and no deaths occurred in the modified maze group (p=0.722). The aortic cross-clamp durations were 76.30±8.86 minutes for the modified maze and 92.38±10.88 for the CSM procedure (p<0.001). There were no late strokes or deaths during the 2-year follow-up. The modified maze group showed similar rates of absence of AF without the use of anti-arrhythmic drugs as the CSM group within the 2 years (p=0.332). CONCLUSION: This modified maze simplifies the "cut-and-sew" procedure and reduces operating time while retaining the efficacy of CSM.

Cardioprotective effects of melatonin against myocardial ischaemia/reperfusion injury: Activation of AMPK/Nrf2 pathway.

Although reperfusion is the most effective therapy for patients with acute myocardial infarction, reperfusion injury limits the therapeutic effects of early reperfusion. Oxidative stress plays a crucial role in myocardial ischaemia/reperfusion (I/R) injury. Melatonin, a circulating hormone, is well-known as an antioxidant in cardiovascular diseases. In this short communication, we show that melatonin significantly improves post-ischaemic cardiac function, reduces infarct size and decreases oxidative stress. Furthermore, melatonin markedly increases AMPK activation and Nrf2 nuclear translocation. Nevertheless, these melatonin-induced changes are abrogated by compound C. In addition, ML-385, an Nrf2 inhibitor, also withdraws the antioxidative effects of melatonin but has little effect on AMPK activation. In conclusion, our results demonstrate that melatonin alleviates myocardial I/R injury by inhibiting oxidative stress via the AMPK/Nrf2 signalling pathway.

RNF220-mediated ubiquitination promotes aggresomal accumulation and autophagic degradation of cytoplasmic Gli via HDAC6.

Sonic hedgehog acts as a key mitogen to drive cell proliferation and as a morphogen to direct cell differentiation during embryonic development and adult tissue maintenance by controlling the activities of its transcriptional effectors Glis. We previously reported that RNF220 controls the nuclear translocation and subcellular localization of Glis by promoting their K63-linked polyubiquitination, through which it fine tunes Shh/Gli gradients during ventral spinal cord patterning. RNF220 also epigenetically regulates Shh signaling by targeting epifactor EED in cerebellar development. Here, we continued to study the molecular events underlying RNF220-mediated Shh regulation in the cytoplasm. The results showed that HDAC6 is required for RNF220-induced Gli accumulation in the cytoskeletal fraction and inclusion in aggresomes. In the cytoplasm, Glis polyubiquitinated by RNF220 are prone to interact with p62 and destined for autophagy-mediated degradation. Additionally, we showed that RNF220 inhibits the processing of Gli2 and Gli3 both in vitro and in vivo. Collectively, our studies shed new light on Shh signaling regulation.

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: Role of SIRT6.

Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high-fat diet-streptozotocin-induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling. After the induction of diabetes, adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long-term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients.

Smartphone-based application to improve medication adherence in patients after surgical coronary revascularization.

BACKGROUND: Secondary preventive therapies play a key role in the prevention of adverse events after coronary artery bypass grafting (CABG). However, adherence to secondary preventive drugs after CABG is often poor. With the increasing penetration of smartphones, health-related smartphone applications might provide an opportunity to improve medication adherence. We aimed to evaluate the effectiveness and feasibility of using a smartphone-based application to improve medication adherence in patients after CABG. METHODS: The Measurement and Improvement Studies of Surgical coronary revascularizatION: medication adherence (MISSION-2) study is a multicenter randomized controlled trial that planned to enroll over 1000 patients who underwent isolated CABG at one of four large teaching hospitals in China; all enrolled participants had access to a smartphone and were able to operate at least three smartphone applications. The investigators randomly assigned the participants to one of two groups: (1) the intervention group with an advanced smartphone application for 6 months which was designed specifically for this trial and did not exist before. Participants could receive medication reminders and cardiac health education by the smartphone application or (2) the control group with usual care. The primary outcome was CABG secondary preventive medication adherence as measured by the translated Chinese version of the 8-item Morisky Medication Adherence Scale (MMAS-8) at 6 months after randomization. The secondary outcomes were mortality, major adverse cardiovascular and cerebrovascular events (MACCE), cardiovascular rehospitalization, self-reported secondary preventive medication use after 6 months of follow-up, blood pressure (BP), body mass index (BMI), and self-reported smoking status. All analyses were conducted using the intention-to-treat principle. RESULTS: A total of 1000 patients (mean age, 57.28 [SD, 9.09] years; 85.5% male) with coronary heart disease after CABG were enrolled between September 2015 and September 2016 and were randomly assigned to the intervention (n = 501) or control group (n = 499). At 6 months, the proportion of low-adherence participants, categorized by MMAS-8 scores, was 11.8% in the intervention group and 11.7% in the control group (RR = 1.005, 95% CI 0.682 to 1.480, P = 1.000). Similar results were found in sensitivity analyses that considered participants who withdrew from the study, or were lost to follow-up as nonadherent. There were no significant differences in the secondary clinical outcome measures, and there were no significant differences in the primary outcome across the subgroups tested. In the intervention group, the proportion of participants who used and operated the application during the first month after CABG was 88.1%; however, the use rate decreased sharply from 42.5% in the second month to 9.2% by the end of the study (6 months). CONCLUSIONS: A smartphone-based application supporting secondary prevention among patients after CABG did not lead to a greater adherence to secondary preventive medications. The limited room for improvement in medication adherence and the low participants' engagement with the smartphone applications might account for these non-significant outcomes.