Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described. METHODS: Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further. RESULTS: Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events. CONCLUSIONS: The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

Damage Effect of Amorphous Carbon Black Nanoparticle Aggregates on Model Phospholipid Membranes: Surface Charge, Exposure Concentration and Time Dependence.

Commercial nano-scale carbon blacks (CB) are being harnessed widely and may impose potentially hazardous effects because of their unique properties, especially if they have been modified to grow reactive functional groups on their surface. Cytotoxicity of CB has been well studied but the membrane damage mechanisms and role of surface modification are still open to debate. Negatively and positively charged giant unilamellar vesicles (GUVs) were prepared using three lipids as model cell membranes to examine the mechanistic damage of CB and MCB (modified by acidic potassium permanganate) aggregates. Optical images showed that both anionic CB and MCB disrupted the positively charged but not the negatively charged GUVs. This disruption deteriorated with the rise and extension of exposure concentration and time. Lipids extraction caused by CBNs (CB and MCB together are called CBNs) was found. MCB caused more severe disruption than CB. MCB was enveloped into vesicles through an endocytosis-like process at 120 mg/L. MCB mediated the gelation of GUVs, perhaps through C-O-P bonding bridges. The lower hydrodynamic diameter and more negative charges may have been responsible for the distinction effect of MCB over CB. The adhesion and bonding of CBNs to the membrane were favored by electrostatic interaction and the practical application of CBNs warrants more attention.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction.

BACKGROUND: Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS: The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS: A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS: The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

[Anti-tumor effect of Huaier extract supernatant on human gastric cancer HGC-27 and MGC-803 cells].

The purpose of this study was to investigate the effect of Huaier extract supernatant(HES) on the proliferation, apoptosis, autophagy, and migration of human gastric cancer HGC-27 and MGC-803 cells and its molecular mechanisms. The main components in HES were preliminarily analyzed by high-performance liquid chromatography-mass spectrometry(HPLC-MS). Methyl thiazolyl tetrazolium(MTT) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine(EdU) staining assay were used to explore the effect of HES on the proliferation of human gastric cancer HGC-27 and MGC-803 cells. Hoechst staining and flow cytometry assay were used to determine the effect of HES on apoptosis of human gastric cancer HGC-27 and MGC-803 cells. Acridine orange staining and cell scratch assay were used to determine the effect of HES on autophagy and migration of human gastric cancer HGC-27 and MGC-803 cells, respectively. Western blot was used to investigate the regulatory effect of HES on the expression levels of proteins related to apoptosis, epithelial-mesenchymal transition(EMT), and signaling pathways in human gastric cancer HGC-27 and MGC-803 cells. The results showed that HES mainly contained some components with high polarities. HES significantly reduced the cell viability of human gastric cancer cells in a dose-and time-dependent manner. The IC_(50 )values after 48 h of HES treatment in human gastric cancer HGC-27 and MGC-803 cells were 7.56 and 10.77 g·L~(-1), respectively. Meanwhile, HES inhibited the colony-forming ability and short-term proliferation of human gastric cancer cells. The apoptosis rates of HGC-27 and MGC-803 cells treated with 8 g·L~(-1) HES for 72 h were 62.13%±8.92% and 54.50%±3.26%, respectively. HES also promoted autophagy in human gastric cancer cells and impaired their migration ability in vitro. Moreover, HES up-regulated the cleavage of the apoptosis marker poly ADP-ribose polymerase(PARP) and the protein expression level of the epithelial cell marker E-cadherin, and down-regulated the protein levels of phosphorylated-mammalian target of rapamycin(p-mTOR), phosphorylated-S6(p-S6), and phosphorylated-extracellular signal-regulated kinase(p-ERK) in human gastric cancer cells. Therefore, HES is one of the effective anti-tumor components of Huaier, which inhibits the proliferation and migration of human gastric cancer cells, and induces apoptosis and autophagy. Moreover, the mTOR signal and ERK signal may be involved in the anti-gastric cancer effect of HES. This study provides novel references for the in-depth research and clinical application of Huaier. It is also of great significance to promote the scientific development and utilization of Huaier.

Prevalence and Clinical Characteristics of Fabry Disease in Chinese Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The prevalence of Fabry disease (FD) in Chinese patients with hypertrophic cardiomyopathy (HCM) is unclear. We aimed to evaluate the prevalence, clinical characteristics, and outcomes of FD in Chinese patients with HCM. METHODS: Of 217 patients with HCM, FD probands were screened by next-generation sequencing at Fuwai Hospital. Medical data from α-galactosidase A activity, electrocardiography, echocardiography, coronary angiography, cardiac magnetic resonance, pathological examination, and follow up was analyzed. RESULTS: Two FD probands were observed (0.93% of patients with HCM), both of which were diagnosed with symptomatic obstructive HCM at 49 years of age. One proband had a GLA mutation (c.887T>C [p.M296T]) with a late-onset cardiac variant, which was characterized by dual ventricular hypertrophy and conduction disease with a permanent pacemaker. The other patient had a GLA mutation (c.758T>C [p.I253T]) with a classic phenotype and dual ventricular hypertrophy, atrioventricular block, renal failure, and recurrent cerebral infarction. Both probands had late gadolinium enhancement mainly in the basal segment of the inferolateral wall. Follow up revealed no exertional symptoms or outflow obstruction after surgical septal myectomy in the two probands, and stable renal function was observed after 6 months of migalastat therapy in the later one. A family study revealed six female carriers and three sudden cardiac deaths. CONCLUSIONS: FD is not uncommon in Chinese patients with HCM. Multiple organic involvement, dual ventricular hypertrophy, and conduction disease provide clinical clues for suspected FD, and early genetic screening is necessary. Surgical septal myectomy and migalastat improve the long-term prognosis of patients with FD.

[Research progress on anti-tumor effect of Chinese dragon's blood].

As a traditional Chinese medicine, Chinese dragon's blood has multiple effects, such as activating blood to remove blood stasis, softening and dispelling stagnation, astringent and hemostasis, clearing swelling and relieving pain, regulating menstruation and rectifying the blood, so it is called "an effective medicine of promoting blood circulation". It has been widely used clinically to treat a variety of diseases. With the further research on Chinese dragon's blood, its anti-tumor medicinal value is gradually emerging. Modern pharmacological studies have shown that Chinese dragon's blood exerts anti-tumor effects mainly by inhibiting cell proliferation, inducing apoptosis, inducing DNA damage and cell cycle arrest, inducing senescence and autophagy of tumor cells, inhibiting metastasis and angiogenesis, as well as reversing multidrug resistance. This article focuses on the research progress on anti-tumor effects of Chinese dragon's blood extract and its chemical components, with a view to provide new references for the in-depth research and reasonable utilization of Chinese dragon's blood.

Etiology spectrum and clinical characteristics of renal artery stenosis in a Chinese cohort.

OBJECTIVE: To analyze the causes of renal artery stenosis (RAS) and compare the clinical characteristics in accordance with the primary disease among patients aged from 30 to 50. METHODS: Patients were grouped by etiologies of RAS. Groups were retrospectively examined and compared regarding demographic data, clinical manifestations, laboratory findings, and imaging findings. RESULTS: A total of 152 patients (74 females, 78 males; mean age: 40.70 ± 6.01 years) were enrolled, including 84 patients (55.3%) with atherosclerosis (AS), 46 patients (30.3%) with Takayasu arteritis (TA), 18 patients (11.8%) with fibromuscular dysplasia (FMD), and four patients (2.6%) with other etiologies. Patients in AS group had greater body mass index, higher prevalence of comorbidities and higher rate of smoking and drinking history. TA patients showed more constitutional symptoms and vascular findings, and higher erythrocyte sedimentation rate. RAS in both AS group and TA group mainly located on ostia and proximal segments, but RAS in FMD group mainly involved middle to distal segment of renal artery. The AS group had significantly lesser stenosis than the other groups. Although renal function evaluated by the estimated glomerular filtration rate did not significantly differ among the groups, the incidence of kidney shrinkage was significantly higher in the TA and FMD groups (39.1% and 50%, respectively) than in the AS group (8.3%). The FMD group had milder cardiac damage than other groups. CONCLUSIONS: AS was the most common cause of RAS in patients aged from 30 to 50, followed by TA and FMD. The etiology of RAS should be carefully distinguished based on clinical manifestations, laboratory findings, and imaging to ensure that proper treatment is provided.

[Effect of Huaier aqueous extract on growth and metastasis of human non-small cell lung cancer NCI-H1299 cells and its underlying mechanisms].

This study aims to investigate the effect of Huaier aqueous extract on the growth and metastasis of human non-small cell lung cancer NCI-H1299 cells and its underlying mechanisms. MTT assay was used to detect the effect of Huaier aqueous extract on the proliferation of NCI-H1299 cells. Flow cytometry was used to examine the effect of Huaier aqueous extract on the apoptosis, cell cycle, and ROS level of NCI-H1299 cells. Wound healing assay was used to evaluate the effect of Huaier aqueous extract on the migration ability of NCI-H1299 cells. Western blot was used to detect the levels of proteins involving apoptosis, epithelial-mesenchymal transition(EMT), and MAPK signaling pathway in NCI-H1299 cells exposed to Huaier aqueous extract. The results showed that Huaier aqueous extract inhibited the proliferation of NCI-H1299 cells, and induced cell-cycle arrest at the phase S. Huaier aqueous extract promoted the apoptosis of NCI-H1299 cells by down-regulating the expression of anti-apoptotic protein Bcl-2. Moreover, Huaier aqueous extract increased ROS level and induced ferroptosis in NCI-H1299 cells. EMT played a critical role in cancer metastasis. Huaier aqueous extract reduced the migration ability of NCI-H1299 cells by inhibiting EMT of NCI-H1299 cells. In addition, this study revealed that Huaier aqueous extract inhibited MAPK signaling pathway in human non-small cell lung cancer NCI-H1299 cells, which may be one of Huaier's mechanisms in inhibiting growth and metastasis of NCI-H1299 cells. This study provides a new theoretical basis for the clinical treatment of lung cancer with Huaier, and important reference significance for further studies on the anti-tumor mechanisms of Huaier.

Combined toxicity of functionalized nano-carbon black and cadmium on Eisenia fetida coelomocytes: The role of adsorption.

Little is known about the potential threats of functionalized nano-carbon black (FNCB) combined with cadmium (Cd) to soil invertebrates. In this study, immunocompetent coelomocytes from Eisenia fetida are harnessed, and the joint cytotoxicity types of FNCB and Cd co-exposure are analyzed. The extracellular interaction mechanisms of FNCB and Cd were completely explored using adsorption kinetics and thermodynamics accompanied by isotherm batch experiments and Fourier infrared spectroscopy. The results indicated that functional amorphous carbon nanoparticles up to certain dose may injure cells due to their surface oxygen-containing groups. The MIXTOX model and the combination index suggested that the combined action of FNCB and Cd exhibited antagonism at the low dose/effect-level and synergism at the high dose/effect-level. FNCB decreased the intracellular free Cd2+ content at a low mixture dose, while it increased it at a high mixture dose. The adsorption of Cd on FNCB followed pseudo-second-kinetics and the Langmuir isotherm, hence better indicating a chemisorption, which was also supported by the activation energy (Ea = 36.6 kJ/mol), enthalpy change (ΔH = -98.4 kJ/mol), and functional group changes. Coordination binding should be responsible for the subsequent interaction of toxicity.

Liraglutide Ameliorates Lipotoxicity-Induced Oxidative Stress by Activating the NRF2 Pathway in HepG2 Cells.

Although glucagon-like peptide-1 (GLP-1) analogue has been reported to suppress oxidative stress in non-alcoholic fatty liver disease (NAFLD), an effective therapeutic agent for NAFLD is currently unavailable. Therefore, in this study, we aimed to investigate the protective effects of the GLP-1 analogue liraglutide against lipotoxicity-induced oxidative stress in HepG2 cells and to elucidate the underlying mechanisms. HepG2 cells were cultured for 48 hours and treated with a free fatty acid (FFA) mixture: FFA mixture and liraglutide or FFA mixture, liraglutide, and exendin (9-39). Lipid accumulation was examined by oil red O staining. Oxidative stress was assessed by measuring the levels of intracellular reactive oxygen species using 2',7'-dichlorofluorescein diacetate and thiobarbituric acid-reactive substances, whereas antioxidant capacity was assessed by measuring the activity of superoxide dismutase and catalase. Expression of the nuclear factor erythroid-2-related factor 2 (NRF2) gene and the genes encoding antioxidant enzymes was analyzed using quantitative RT-PCR. Cellular and nuclear NRF2 expression levels were assessed using immunofluorescence cell staining and western blotting. Liraglutide treatment reduced high fat-induced lipid formation and the levels of oxidative stress markers and increased antioxidant enzyme activity in HepG2 cells. Liraglutide treatment increased the mRNA expression of NRF2 target genes, induced NRF2 nuclear translocation, and increased nuclear NRF2 levels without altering NRF2 mRNA expression. Collectively, these results indicate that liraglutide exhibits a protective effect against lipotoxicity-induced oxidative stress, possibly via modulation of NRF2 and expression of antioxidant enzymes in liver cells.

Effect of Nano-Carbon Black Surface Modification on Toxicity to Earthworm (Eisenia fetida) Using Filter Paper Contact and Avoidance Test.

Engineered nanomaterials (NMs) may enter the soil through various channels and pose potential harm to soil animals, especially those proactively applied for soil heavy metal remediation. Effects of nano-carbon black (CB) and surface modified carbon black (MCB) on catalase (CAT) activity and malondialdehyde (MDA) content in earthworms exposed on filter paper for 48 h were tested. Avoidance test was used to determine hazard of soil treated with 0.015% and 1.5% CB and MCB. Surface properties of NMs were also characterized. MCB has a significant effect on CAT activity at 70 and 1000 mg/L (1.1 and 15.7 µg/cm2), but has no impact on MDA content in earthworm. Strongly avoidance behavior of worms was also found in soil added 1.5% MCB. Negative charges and oxygen functional groups increased for MCB and its adverse effect on earthworm was higher than CB. The application of MCB in soil remediation warrants more attention.

[Clinical application features of Fufang Kushen injection in treating malignant esophageal tumor： real world study based on hospital information system].

To analyze the clinical application features of Fufang Kushen injection in treating malignant esophageal tumors in the real world by using hospital information system database, and provide reference for clinical application of Fufang Kushen injection. The electronic medical data from 2 550 patients with malignant esophageal tumors using Fufang Kushen injection from 22 large-scale hospitals nationwide were extracted based on the hospital information system (HIS) established by Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences. Then the descriptive analysis based on frequency and rate was conducted for general characteristics, diagnostic characteristics, characteristics of dosage and medication information, characteristics of drug combination, and discharge outcome characteristics. The results showed that the average age of patients treated with Fufang Kushen injection for malignant esophageal tumors was 62.3 years old; more males than females; admitted to hospital mainly in department of cardiology, oncology and digestology first. The total efficiency was 47.15% based on the discharge outcome characteristics; the most common dosage was 10-20 mL for single use; the course of treatment was mainly 4-7 d; and the common drugs in drug combinations included dexamethasone, tropisetron injection, thymosin injection, compound amino acid injection, pantoprazole sodium injection, fluorouracil, et al. The characteristics of the crowd using Fufang Kushen injection to treat the malignant esophageal tumors were clear and in line with the general rule of malignant esophageal tumors; its clinical dosage and scope of treatment for malignant esophageal tumors in the real world were basically consistent with the specification; and the types of clinical drug use combinations were more extensive.

The role of inflammation in coronary artery calcification.

Vascular calcification is an age-dependent, common finding in human coronary arteries and begins as early as the second decade of life, just after fatty streak formation. Previous studies have showed that the severity of coronary calcification is closely related to atherosclerotic plaque burden and cardiac event rate. In the past few decades, coronary calcification has been considered passive and degenerative. With recent clinical and basic research, however, there is increasing recognition that coronary calcification is an active, regulated process. Current diagnostic methods for coronary artery calcification (CAC) are usually traditional coronary angiography, intravascular ultrasound (IVUS), electron beam computed tomography (EBCT) and multi-slice computed tomography (MSCT) while treatment for patients with calcified coronary arteries is troublesome. Several lines of evidence suggest that inflammation plays a major role in the development of atherosclerosis as well as its clinical manifestations. Recent study showed that inflammatory process might be also involved in coronary calcification. Accordingly, measurements of inflammatory markers such as C-reactive protein (CRP) may in part reflect indices of atherosclerosis, such as coronary calcification, and are likely to provide distinct information regarding cardiovascular risk. In this article, we review the current evidence of relationship between coronary calcification and inflammation for purpose of drawing the more attention on the inflammatory mechanism of coronary calcification, which may change our research as well as therapeutic strategies for coronary calcification in the future.