[Association of ventricular septal defect with rare variations of the HAND2 gene]. / 室间隔缺损与HAND2åŸºå› ç½•è§å˜å¼‚çš„å ³è”åˆ†æž.

OBJECTIVES: To study the association of ventricular septal defect (VSD) with rare variations in the promoter region of HAND2 gene, as well as related molecular mechanisms. METHODS: Blood samples were collected from 349 children with VSD and 345 healthy controls. The target fragments were amplified by polymerase chain reaction and sequenced to identify the rare variation sites in the promoter region of the HAND2 gene. Dual-luciferase reporter assay was used to perform a functional analysis of the variation sites. Electrophoretic mobility shift assay (EMSA) was used to investigate related molecular mechanisms. TRANSFAC and JASPAR databases were used to predict transcription factors. RESULTS: Sequencing revealed that three variation sites (g.173530852A>G, g.173531173A>G, and g.173531213C>G) were only observed in the promoter region of the HAND2 gene in 10 children with VSD, among whom 4 children had only one variation site. The dual-luciferase reporter assay revealed that g.173531213C>G reduced the transcriptional activity of the HAND2 gene promoter. EMSA and transcription factor prediction revealed that g.173531213C>G created a binding site for transcription factor. CONCLUSIONS: The rare variation, g.173531213C>G, in the promoter region of the HAND2 gene participates in the development and progression of VSD possibly by affecting the binding of transcription factors.

A review of the current research on in vivo and in vitro detection for alpha-synuclein: a biomarker of Parkinson's disease.

Parkinson's disease is a health-threatening neurodegenerative disease of the elderly with clinical manifestations of motor and non-motor deficits such as tremor palsy and loss of smell. Alpha-synuclein (α-Syn) is the pathological basis of PD, it can abnormally aggregate into insoluble forms such as oligomers, fibrils, and plaques, causing degeneration of nigrostriatal dopaminergic neurons in the substantia nigra in the patient's brain and the formation of Lewy bodies (LBs) and Lewy neuritis (LN) inclusions. As a result, achieving α-Syn aggregate detection in the early stages of PD can effectively stop or delay the progression of the disease. In this paper, we provide a brief overview and analysis of the molecular structures and α-Syn in vivo and in vitro detection methods, such as mass spectrometry, antigen-antibody recognition, electrochemical sensors, and imaging techniques, intending to provide more technological support for detecting α-Syn early in the disease and intervening in the progression of Parkinson's disease.

A potential association between immunosenescence and high COVID-19 related mortality among elderly patients with cardiovascular diseases.

Elderly patients with cardiovascular diseases account for a large proportion of Corona virus Disease 2019(COVID-19)related deaths. COVID-19, as a new coronavirus, mainly targets the patient's lung triggering a cascade of innate and adaptive immune responses in the host. The principal causes of death among COVID-19 patients, especially elderly subjects with cardiovascular diseases, are acute respiratory distress syndrome(ARDS), multiple organ dysfunction syndrome (MODS), and microvascular thrombosis. All prompted by an excessive uncontrolled systemic inflammatory response. Immunosenescence, characterized by systemic and chronic inflammation as well as innate/adaptive immune imbalance, presents both in the elderly and cardiovascular patients. COVID-19 infection further aggravates the existing inflammatory process and lymphocyte depletion leading to uncontrollable systemic inflammatory responses, which is the primary cause of death. Based on the higher mortality, this study attempts to elucidate the pathophysiological mechanisms of COVID-19 in elderly subjects with cardiovascular diseases as well as the cause of the high mortality result from COVID-19.

BuShenKangShuai Tablet Alleviates Hepatic Steatosis via Improving Liver Adiponectin Resistance in ApoE-/- Mice.

BuShenKangShuai tablet (BSKS) is a Chinese herbal compound, which has been used to treat nonalcoholic fatty liver disease and cardiovascular diseases in clinic for over four decades. This study intends to explore whether BSKS administration can alleviates hepatic steatosis via improving liver adiponectin resistance in ApoE-/- mice. ApoE-/- mice were fed with western-type diet for 6 weeks and then were administrated with BSKS or atorvastatin for 6 weeks by gavage, and then blood and liver were collected for analysis. The results showed that BSKS attenuated hepatic steatosis, decreased blood lipids, and increased the serum level of adiponectin. We also found that adiponectin resistance in the liver was improved by BSKS, while the expression of TLR4 and NF-κB p65 was inhibited, followed by the suppression of proinflammatory mediators of TNF-α. Our data provided evidence that BSKS was able to alleviate hepatic steatosis in vivo. The underlying mechanism of BSKS was focused on improving liver adiponectin resistance, thereby regulating dyslipidemia and inhibiting inflammatory signaling pathway.

Bushenkangshuai Tablet Reduces Atherosclerotic Lesion by Improving Blood Lipids Metabolism and Inhibiting Inflammatory Response via TLR4 and NF-κB Signaling Pathway.

Bushenkangshuai tablet (BSKS) is a Chinese herbal compound which has been used for the treatment of cardiovascular and cerebrovascular diseases in China for decades. This study intends to explore the molecular mechanism of BSKS against atherosclerosis in ApoE-/- mice. ApoE-/- mice were fed with western-type diet for 6 weeks and then were given BSKS for 6 weeks. The results showed that BSKS attenuated the size of the atherosclerotic lesion, reduced visceral adipose content, and decreased blood lipids. We also found that BSKS promoted the expression of adiponectin and its receptors, inhibited the expression of Toll-like receptor 4 and nuclear factor-kappa B, decreased the levels of interleukin-1 beta, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1, and increased the levels of interleukin-10 and adiponectin. Our data provided evidence that BSKS exerted an antiatherosclerotic effect by lowering blood lipids and inhibiting inflammatory response via TLR4 and NF-κB signaling pathway.

Laser-assisted in situ synthesis of graphene-based magnetic-responsive hybrids for multimodal imaging-guided chemo/photothermal synergistic therapy.

Magnetic graphene-based hybrids are being increasing recognized as an effective nanotheranostic agent in biomedicine. Conventional technologies for their synthesis have drawbacks not only from a synthetic standpoint, mainly requiring high temperatures and multi-step processes, but also from a biological perspective, chemical precursors or surfactants involved in the chemical process are toxic to cells. Herein, we report a novel approach for one-step fabricating magnetic graphene hybrid nanocomposites based on laser irradiation of an Fe target in GO-PEG aqueous solution at room temperature without using any other chemical reagent. TEM, XPS, FT-IR, XRD, Mossbauer spectrum and VSM observation reveal that γ-Fe2O3 nanoparticles were directly grown on the surface of GO-PEG with uniform morphology and superior dispersibility. These GO-PEG-γ-Fe2O3 nanocomposites (labeled as GPF) showed low cytotoxicity in vitro compared to chemically synthesized nanoparticles since the pulsed-laser-ablation-in-liquid (PLAL) process is free of toxic agents. After tail vein injection of the nanotheranostics, the tumor was clearly mapped by T2-weighted magnetic resonance of γ-Fe2O3, photothermal imaging of graphene and fluorescence imaging of loaded antitumor DOX. Meanwhile the tumor cells both in vitro and in vivo achieved highly superior inhibition by the synergistic chemo/photothermal therapeutic effect which provided an intense heating effect and enhanced DOX release upon 808 nm NIR light exposure. The results revealed that the magnetic graphene-based hybrids prepared by PLAL is competent for future multi-modal imaging assisted tumor targeted chemo/photothermal synergistic therapy of cancer.

Synthesis of permeable yolk-shell structured gadolinium-doped quantum dots as a potential nanoscale multimodal-visible delivery system.

Developing a nanoscale drug delivery system with magnetic resonance imaging (MRI)/fluorescence imaging (FL) visibility to optimize the delivery efficiency and therapeutic efficacy under image guidance has attracted great attentions in the area of nanomedicine. Herein, a novel permeable yolk-shell structured gadolinium-doped quantum dots nanocomposite was synthesized as a theranostic nanocarrier via an indirectly doping method. The as-prepared permeable nanoparticles with tunable color fluorescent emission, paramagnetic and accessible mesoporous channels could be developed as a novel nanomedical platform for integrated multimodal diagnosis and therapy. The hydrophilic nanocomposites exhibited tunable fluorescence as well as high longitudinal relaxivity (r1 = 17.32mM-1s-1) in water with good colloidal stability. In vivo animal experiments further verified CSSP could achieve FL/MRI dual modality imaging. The widely used antineoplastic anthracycline drug doxorubicin (DOX) was absorbed into the permeable nanospheres with 95.3% loading efficiency and released in a pH-sensitive pattern. In vitro cancer cell cytotoxicity tests verified that the DOX-loaded nanocomposites had enhanced cytotoxicity compared with free DOX at the same concentration. The as-prepared nanocomposites present great potential as MRI/FL-visible nanoscale drug carrier to realize imaging-guided personalized therapy.

Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects.

BACKGROUND: Congenital heart disease (CHD) is the most common human birth defect. Genetic causes for CHD remain largely unknown. GATA transcription factor 5 (GATA 5) is an essential regulator for the heart development. Mutations in the GATA5 gene have been reported in patients with a variety of CHD. Since misregulation of gene expression have been associated with human diseases, we speculated that changed levels of cardiac transcription factors, GATA5, may mediate the development of CHD. METHODS: In this study, GATA5 gene promoter was genetically and functionally analyzed in large cohorts of patients with ventricular septal defect (VSD) (n=343) and ethnic-matched healthy controls (n=348). RESULTS: Two novel and heterozygous DNA sequence variants (DSVs), g.61051165A>G and g.61051463delC, were identified in three VSD patients, but not in the controls. In cultured cardiomyocytes, GATA5 gene promoter activities were significantly decreased by DSV g.61051165A>G and increased by DSV g.61051463delC. Moreover, fathers of the VSD patients carrying the same DSVs had reduced diastolic function of left ventricles. Three SNPs, g.61051279C>T (rs77067995), g.61051327A>C (rs145936691) and g.61051373G>A (rs80197101), and one novel heterozygous DSV, g.61051227C>T, were found in both VSD patients and controls with similar frequencies. CONCLUSION: Our data suggested that the DSVs in the GATA5 gene promoter may increase the susceptibility to the development of VSD as a risk factor.

Tetrodotoxin attenuates isoproterenol-induced hypertrophy in H9c2 rat cardiac myocytes.

Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either α- or ß- adrenergic stimulation. The present study was carried out to determine whether the reversible sodium channel blocker tetrodotoxin (TTX) exerts a direct anti-hypertrophic effect on isoproterenol (ISO)-induced cell hypertrophy and find the underlying mechanism that regulate [Na(+)]( i ). The experiments were performed on cultured H9c2 cells exposed to ISO (10 µM) alone or combined with TTX (1 µM) for 48 h. Our results showed that ISO significantly increased cell surface area by 30 % and atrial natriuretic peptide gene expression by nearly twofold (p < 0.05 for both). These effects were associated with a significant reduction in the gene expression of Na(+)/K(+)-ATPase isoforms α2 and α3, whereas the α1 isoform was unaffected. Conversely, ISO increased Na(+)-H(+) exchanger 1 (NHE-1) gene expression by approximately 40 % and significantly increased [Na(+)]( i ) level by 50 % (p < 0.05 for both). ISO was also found to significantly increase aquaporin 4 gene expression by nearly ninefold (p < 0.05). All these effects were prevented when identical experiments were carried out in the presence of TTX, but the expression of NHE-1. The expression of sodium channel protein type 5 subunit alpha was unaffected by either ISO or TTX. When taken together, these studies show that TTX attenuates the hypertrophic effect of ISO and suggest a possible approach to limiting ISO-induced hypertrophy in clinical treatment.