HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling.

Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1 cardiac stromal cells (CSCs) for myocardial injury.

ctDNA-adjusted bTMB as a predictive biomarker for patients with NSCLC treated with PD-(L)1 inhibitors.

Background: In non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs), higher blood tumor mutational burden (bTMB) was usually associated with better progression-free survival (PFS) and objective response rate (ORR). However, the association between bTMB and overall survival (OS) benefit remains undefined. It has been reported that patients harboring a high level of circulating tumor DNA (ctDNA) had poor survival.

N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice.

N-n-Butyl haloperidol iodide (F) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl) or thioacetamide (TAA).

A novel human S10F-Hsp20 mutation induces lethal peripartum cardiomyopathy.

Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac-specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice.

Identification of the Functional Autophagy-Regulatory Domain in HCLS1-Associated Protein X-1 That Resists Against Oxidative Stress.

HCLS1 Associated Protein X-1 (HAX1) promotes cell survival through attenuation of the damaged signals from endoplasmic reticulum and mitochondria, which are known as prominent intracellular compartments for the autophagic process under stress conditions. This study investigates whether autophagy can be upregulated in response to HAX1 overexpression and identifies the functional motif in HAX1 responsible for the autophagic induction. Autophagosome accumulation, mitochondrial membrane potential (Δψm), and apoptosis were assessed in HEK293 cells post transduction with full-length or truncated HAX1-encoding genes, while empty vector-transduced cells served as control.

[Influence of age on the effectiveness of revascularization in immature permanent teeth].

Purpose: To evaluate the effect of age on the potential of dental pulp regeneration in young permanent teeth with periapical periodontitis.

Methods: A total of 30 mandibular premolars from 9-18 years old patients with pulp necrosis were divided into 2 groups, group A (younger age group): 9-13 years old, and group B (older age group): 14-18 years old. Revascularization procedures were performed for all patients.

HAX-1 regulates SERCA2a oxidation and degradation.

Ischemia/reperfusion injury is associated with contractile dysfunction and increased cardiomyocyte death. Overexpression of the hematopoietic lineage substrate-1-associated protein X-1 (HAX-1) has been shown to protect from cellular injury but the function of endogenous HAX-1 remains obscure due to early lethality of the knockout mouse. Herein we generated a cardiac-specific and inducible HAX-1 deficient model, which uncovered an unexpected role of HAX-1 in regulation of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) in ischemia/reperfusion injury.

Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6 mutant.

HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified a human mutant of HSPB6 (HSPB6) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression of this mutant in mouse hearts resulted in remodeling and dysfunction, which progressed to heart failure and early death.

Biomechanical Simulation of Stress Concentration and Intraocular Pressure in Corneas Subjected to Myopic Refractive Surgical Procedures.

Recent advances in the analysis of corneal biomechanical properties remain difficult to predict the structural stability before and after refractive surgery. In this regard, we applied the finite element method (FEM) to determine the roles of the Bowman's membrane, stroma, and Descemet's membrane in the hoop stresses of cornea, under tension (physiological) and bending (nonphysiological), for patients who undergo radial keratotomy (RK), photorefractive keratectomy (PRK), laser-assisted in situ keratomileusis (LASIK), or small incision lenticule extraction (SMILE). The stress concentration maps, potential creak zones, and potential errors in intraocular pressure (IOP) measurements were further determined.

Paracrine effect of CXCR4-overexpressing mesenchymal stem cells on ischemic heart injury.

It has been reported that CXCR4-overexpressing mesenchymal stem cells (MSC ) can repair heart tissue post myocardial infarction. This study aims to investigate the MSCCX4-derived paracrine cardio-protective signaling in the presence of myocardial infarction. Mesenchymal stem cells (MSCs) were divided into 3 groups: MSC only, MSC , and CXCR4 gene-specific siRNA-transduced MSC.

The N-butyl alcohol extract from Hibiscus rosa-sinensis L. flowers enhances healing potential on rat excisional wounds.

Ethno-pharmacological Relevance: Hibiscus rosa-sinensis L. (HRS), a folk medicine named Zhujin in China, possess anti-tumor, antioxidant, antibacterial, low density lipoprotein oxidation prevention and macrophage death prevention effects. The leaves and red flowers of HRS have been traditionally used to treat with furuncle and ulceration.

Repair Injured Heart by Regulating Cardiac Regenerative Signals.

Cardiac regeneration is a homeostatic cardiogenic process by which the sections of malfunctioning adult cardiovascular tissues are repaired and renewed employing a combination of both cardiomyogenesis and angiogenesis. Unfortunately, while high-quality regeneration can be performed in amphibians and zebrafish hearts, mammalian hearts do not respond in kind. Indeed, a long-term loss of proliferative capacity in mammalian adult cardiomyocytes in combination with dysregulated induction of tissue fibrosis impairs mammalian endogenous heart regenerative capacity, leading to deleterious cardiac remodeling at the end stage of heart failure.

Manipulating the Hippo-Yap signal cascade in stem cells for heart regeneration.

The Hippo-Yap pathway was originally recognized as a crucial signal cascade controlling organ size, and more recently identified as an important component involved in the regulation of cardiomyocyte survival, proliferation, and regeneration. Negative stress responses can activate mammalian sterile 20-like kinase 1 (Mst1) to suppress protective autophagy and promote cardiomyocyte apoptosis via phosphorylation and inhibition of Bcl-xL. Moreover, decreased Yap activity and nuclear entry will decrease upon Mst1 activation, ultimately suppressing cardiomyocytes proliferation and regeneration.

Induced Pluripotent Stem Cells derived Muscle Progenitors Effectively Mitigate Muscular Dystrophy through Restoring the Dystrophin Distribution.

Background: Duchenne Muscular Dystrophy (DMD) is a recessive form of muscular disorder, resulting from the dystrophin gene mutations in X-chromosome. Application of embryonic stem cells or adult stem cells has demonstrated the therapeutic effects on DMD through both cell-based and non-cell based mechanisms. In this study, we proposed that Myogenic Progenitor Cells from Induced Pluripotent Stem Cells (iPSC-MPCs) would be more effective in repairing muscle damage caused by muscular dystrophy.

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart.

The major underpinning of massive cell death associated with myocardial infarction involves opening of the mitochondrial permeability transition pore (mPTP), resulting in disruption of mitochondria membrane integrity and programmed necrosis. Studies in human lymphocytes suggested that the hematopoietic-substrate-1 associated protein X-1 (HAX-1) is linked to regulation of mitochondrial membrane function, but its role in controlling mPTP activity remains obscure. Herein we used models with altered HAX-1 expression levels in the heart and uncovered an unexpected role of HAX-1 in regulation of mPTP and cardiomyocyte survival.

Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility.

Aims: Impaired sarcoplasmic reticulum (SR) Ca(2+) cycling and depressed contractility, a hallmark of human and experimental heart failure, has been partially attributed to increased protein phosphatase 1 (PP-1) activity, associated with down-regulation of its endogenous inhibitor-1. The levels and activity of inhibitor-1 are reduced in failing hearts, contributing to dephosphorylation and inactivation of key calcium cycling proteins. Therefore, we investigated the mechanisms that mediate decreases in inhibitor-1 by post-transcriptional modification.

A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia.

Aims: Depressed sarcoplasmic reticulum (SR) Ca(2+) cycling, a universal characteristic of human and experimental heart failure, may be associated with genetic alterations in key Ca(2+)-handling proteins. In this study, we identified a novel PLN mutation (R25C) in dilated cardiomyopathy (DCM) and investigated its functional significance in cardiomyocyte Ca(2+)-handling and contractility.

Methods And Results: Exome sequencing identified a C73T substitution in the coding region of PLN in a family with DCM.

CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia-reperfusion injury.

The chemokine (C-X-C motif) receptor 4 (CXCR4) is expressed on native cardiomyocytes and can modulate isolated cardiomyocyte contractility. This study examines the role of CXCR4 in cardiomyocyte response to ischaemia-reperfusion (I/R) injury. Isolated adult rat ventricular cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) to simulate I/R injury.

Attitudinal changes toward control measures in live poultry markets among the general public and live poultry traders, Guangzhou, China, January-February, 2014.

Two sets of cross-sectional surveys were conducted among the general public and live poultry traders (LPTs) during January-February, 2014, to monitor attitudes toward human cases of avian influenza A(H7N9)-related control measures among these 2 parties in Guangzhou, China. We found generally high support for regular market rest days among the general public and LPTs, but only limited support for permanent central slaughtering of poultry. LPTs' support for relevant control measures declined after the citywide wet market closure.

[An epidemiological investigation on a food-born outbreak of noroviru caused by Sydney 2012 G II.4 strain].

Objective: To identify the source of infection, route of transmission and risk factors related to a cluster of acute gastroenteritis cases in a university of Guangzhou.

Methods: Cases were identified according to the definition. Descriptive epidemiological approaches and case-control study designs were employed in the analysis.

[Risk evaluation on H7N9 avian influenza in Guangzhou, China].

Objective: We conducted both quick surveillance and evaluation programs within one week after the novel H7N9 influenza cases had been released by the Ministry of Health (MOH), to get the basic information on H7N9 virus in Guangzhou.

Methods: We sampled live birds from food markets and the natural habitat of birds to detect H7N9, H5 and H9 viruses. We interviewed workers from both markets and natural habitats.

[Investigation on the source of infection regarding an avian influenza (H5N1) case in Hong Kong that returning from Guangzhou].

Objective: We conducted an epidemiologic investigation to determine the source of infection on an avian influenza (H5N1) case who returned from Guangzhou, in Hong Kong.

Methods: Data related to epidemiologic investigation, medical observation on close contacts, Syndromic Surveillance on poultry salesmen, emergency monitoring, detection of the samples, source tracing on potential Avian influenza virus (H5, H7, H9) infected people, situation on environment pollution by avian influenza virus in the markets etc. were gathered.

Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging.

The activity of protein phosphatase-1 (PP1) inhibitor-1 (I-1) is antithetically modulated by the cAMP-protein kinase A (PKA) and Ca(2+)-protein kinase C (PKC) signaling axes. β-adrenergic (β-AR) stimulation results in PKA-phosphorylation of I-1 at threonine 35 (Thr35) and depressed PP1 activity, while PKC phosphorylation at serine 67 (Ser67) and/or Thr75 increases PP1 activity. In heart failure, pThr35 is decreased while pSer67 and pThr75 are elevated.

Ablation of junctin or triadin is associated with increased cardiac injury following ischaemia/reperfusion.

Aims: Junctin and triadin are calsequestrin-binding proteins that regulate sarcoplasmic reticulum (SR) Ca(2+) release by interacting with the ryanodine receptor. The levels of these proteins are significantly down-regulated in failing human hearts. However, the significance of such decreases is currently unknown.

Intracellular or extracellular heat shock protein 70 differentially regulates cardiac remodelling in pressure overload mice.

Aims: Innate and adaptive immune responses are associated with the development of hypertension-induced myocardial hypertrophy and fibrosis. As a result, we investigated whether heat shock protein (HSP) 70, which is a molecule of damage-associated molecular patterns, could induce inflammation in the myocardium and promote the development of hypertension-induced cardiac hypertrophy and fibrosis.

Methods And Results: We found that HSP70 serum levels, as well as the amount of HSP70 translocation to the cardiomyocyte membranes and the interstitial space, were elevated in the hypertensive mice caused by abdominal aortic constriction (AAC).