Aims: Obstructive sleep apnea syndrome (OSAS) has been increasingly recognized as an independent risk factor for aortic dissection (AD) and it is strongly associated with the extent of intermittent hypoxia and re-oxygenation (IH).This study aimed to clarify role of ROS-HIF-1α-MMPs pathway in the pathogenesis of AD and whether the HIF-1α inhibitor attenuates AD formation.Methods and results: 8-week-old male ApoE -/mice were given β-aminopropionitrile at a concentration of 0.1 % for 3 weeks and infused via osmotic mini pumps with either saline or 2,500 ng/min/kg angiotensin II (Ang II) for 2 weeks.To mimic the OSAS, one group was exposed to IH, which consisted of alternating cycles of 20.9% O2/8% O2 FiO2 (30 episodes per hour) with 20 s at the nadir FiO2 during the 12-h light phase, 2 weeks before Ang II infusion.After Ang II infusion, we assessed remodeling in the aorta by echocardiography, histological and immunohistochemical analysis.IH treatment resulted in significant enlargement of the luminal area, destruction of the media, marked thickening of the adventitia, higher incidence of AD formation and lower survival rate in compared with the Ang II only group.Moreover, IH exposure markedly increased the aortic ROS production and subsequent HIF-1α expression, which in turn promoted the expressions of VEGF, MMP2 and MMP9 and finally leading to the progression of AD.Besides, in vitro study confirmed that IH induced HIF-1α expression plays an important role in the induction of MMPs and that is regulated by the PI3K/AKT/FRAP pathway.Intriguingly, a selective HIF-1α inhibitor KC7F2 could significantly ameliorate IH exposure induced aforementioned deleterious effects in vitro and in vivo.Conclusion: OSAS induced IH can promote the occurrence and progression of AD via a ROS-HIF-1α-MMPs associated pathway.The selective HIF-1α inhibitor KC7F2 could be a novel therapeutic agent for AD patient with OSAS.
Male osteoporosis is primarily caused by a decrease in testicular testosterone production. Male osteoporosis remains a disease with insufficient diagnosis and treatment, and its consequences are severe, especially in older patients. The gut microbiota plays a crucial role in its occurrence and development. Our study found that the relative abundance of Lactobacillus salivarius in the fecal microbiota of male patients with osteoporosis was significantly lower than that in healthy volunteers. Animal experiments have shown that orchiectomy (ORX) can induce osteoporosis and disrupt the intestinal mucosal barrier, and intestinal microbiota. In addition, we discovered a potential etiological connection between the decreased abundance of the intestinal bacterium L. salivarius and the occurrence of ORX-induced osteoporosis. Cohousing or direct colonization of the intestinal microbiota from healthy rats or direct oral administration of the bacteria alleviated ORX-induced osteoporosis and repaired the intestinal mucosal barrier. Finally, we demonstrated that the extracellular vesicles (EVs) of L. salivarius could be transported to the bones and mitigate ORX-induced osteoporosis in rats. Our results indicate that the gut microbiota participates in protecting bones by secreting and delivering bacterial EVs, and that the reduction of L. salivarius and its EVs is closely related to the development of androgen deficiency-related osteoporosis.
The overall outcome of patients with hepatocellular carcinoma (HCC) is still very poor due to its high metastasis and recurrence rate. During metastasis, trans-endothelial migration (TEM) of HCC cells is a key step. Heparanase (HPSE) is an endo-beta-glucuronidase and exerts prometastatic properties for normal and tumor-derived cells. However, it is remains unclear that HPSE contributes to TEM of HCC cells. In this study, human umbilical vein endothelial cells-C (HUVEC-C) was used to simulate vascular endothelial cells (VECs), and the HCCLM3 cells with high HPSE expression were chosen and used for in vitro TEM assay and in vivo experiment. As results, we found that HCCLM3 cells showed higher TEM rate compared with other HCC cells. Downregulation or inhibition of HPSE activity resulted in suppression of TEM of HCC cells both in vitro and in vivo. Our findings suggest that HPSE contributes to TEM of HCC cells, which may be a new biological function of HPSE.
Abstract Purpose The aim of this study was to investigate myocardial dysfunction and mechanical abnormalities in young patients with Graves' disease before therapy, using two‐dimensional speckle tracking echocardiography. Methods We performed a comprehensive transthoracic echocardiographic examination, including segmental and global radial strain, and time‐to‐peak radial strain, in 47 young patients with hyperthyroidism and 34 healthy adults. The time‐to‐peak radial strain was corrected by RR interval. The variables derived from radial myocardial deformation by the six‐basal, six‐mid, and six‐apical segmental model were compared to investigate the difference of the myocardial function between the two groups. Results Early diastolic mitral inflow velocity, E/A ratio, early diastolic mitral annular velocity, and e′/a′ ratio were lower in patients with Graves' disease than in controls. The left ventricular end‐diastolic volume, left ventricular end‐systolic volume, stroke volume, cardiac output, heart rate, late diastolic mitral inflow velocity, and late diastolic mitral annular velocity were slightly higher in patients than in controls. Radial strain, global radial strain, and corrected time‐to‐peak radial strain were lower in the patient group. Conclusions The decreased radial strain, global radial strain, and corrected time‐to‐peak radial strain in young patients with newly diagnosed hyperthyroidism due to Graves' disease could serve as an early sign of subclinical cardiac involvement.
97% of drug-indication pairs that are tested in clinical trials in oncology never advance to receive FDA approval.While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not wellunderstood.Using CRISPR/Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing.We show that -contrary to previous reports obtained predominantly with RNAi and small-molecule inhibitors -the proteins ostensibly targeted by these drugs are non-essential for cancer cell proliferation.Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects.By applying a genetic target-deconvolution strategy, we discovered that the mischaracterized anti-cancer agent OTS964 is actually a potent inhibitor of the cyclindependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression.We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. One-sentence summary:CRISPR reveals that many cancer drug targets are dispensable for cell proliferation and identifies CDK11 as the target of one mischaracterized agent.
Objective To investigate the cardiac structural and functional characteristics in the patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM),and predict the factors influencing the characteristics. Methods A total of 783 HFpEF patients diagnosed in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from April 2009 to December 2020 were enrolled in this study.Echocardiography and tissue Doppler technique were employed to evaluate cardiac structure and function.According to the occurrence of T2DM,the patients were assigned into a HFpEF+T2DM group (n=332) and a HFpEF group (n=451).Propensity score matching (PSM)(in a 1∶1 ratio) was adopted to minimize confounding effect.According to urinary albumin excretion rate (UAER),the HFpEF+T2DM group was further divided into three subgroups with UAER<20 μg/min,of 20-200 μg/min,and>200 μg/min,respectively.The comorbidities,symptoms and signs,and cardiac structure and function were compared among the groups to clarify the features of diabetes related HFpEF.Multivariate linear regression was conducted to probe the relationship of systolic blood pressure,blood glucose,glycosylated hemoglobin,and UARE with cardiac structural and functional impairment. Results The HFpEF+T2DM group had higher prevalence of hypertension (P=0.001) and coronary heart disease (P=0.036),younger age (P=0.020),and larger body mass index (P=0.005) than the HFpEF group,with the median diabetic course of 10 (3,17) years.After PSM,the prevalence of hypertension and coronary heart disease,body mass index,and age had no significant differences between the two groups(all P>0.05).In addition,the HFpEF+T2DM group had higher interventricular septal thickness (P=0.015),left ventricular posterior wall thickness (P=0.040),and left ventricular mass (P=0.012) and lower early diastole velocity of mitral annular septum (P=0.030) and lateral wall (P=0.011) than the HFpEF group.Compared with the HFpEF group,the HFpEF+T2DM group showed increased ratio of early diastolic mitral filling velocity to early diastolic mitral annular velocity (E/e') (P=0.036).Glycosylated hemoglobin was correlated with left ventricular mass (P=0.011),and the natural logarithm of UAER with interventricular septal thickness (P=0.004),left ventricular posterior wall thickness (P=0.006),left ventricular mass (P<0.001),and E/e' ratio (P=0.049). Conclusion The patients with both T2DM and HFpEF have thicker left ventricular wall,larger left ventricular mass,more advanced left ventricular remodeling,severer impaired left ventricular diastolic function,and higher left ventricular filling pressure than the HFpEF patients without T2DM.Elevated blood glucose and diabetic microvascular diseases might play a role in the development of the detrimental structural and functional changes of the heart.
OBJECTIVE: Recently H5N1 subtype avian influenza virus (AIV) is capable of mortality to aquatic bird. The molecular basis for the virulence of this virus is still poorly understood. METHODS: We characterized two H5N1 subtype viruses, A/mallard/Huadong/Y/2003 (Y) is nonpathogenic to mallard whereas A/mallard/Huadong/S/2005 (S) is highly pathogenic to mallard. Using reverse genetics, we constructed a series of single-gene or multiple-gene reassortants from these two viruses. RESULTS: Substitution of single-gene for PB2, PB1, PA (3P), HA and of combination for 3P gene resulted in complete attenuation of S virus in mallard. However, these corresponding substitutions only slightly increased virulence of Y virus in mallard. Other gene segments had little contribution to the virulence of both viruses. CONCLUSION: These results indicate that the pathogenicity of H5N1 AIV to mallard was regulated by multiple gene segments, and these regulations had more sensitive effect on highly pathogenic virus backbone than on low pathogenic virus backbone.
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