Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study

Abstract Background and aims Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction. Methods and results In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/A〔(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012〕and the smaller LV end-diastolic diameter〔(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030〕. And the non-obese NAFLD group had a higher prevalence of E/A < 1 than control group (83.3% vs 68.9%, X2 = 5.802, p = 0.016) while two groups had similar proportions of LV diastolic dysfunction (58.3% vs 53.7%, X2 = 0.484, p = 0.487). Multivariate logistic regression analysis showed that non-obese NAFLD was associated with an increase in E/A < 1 (OR = 6.562, 95%CI 2.014, 21.373, p = 0.002). Conclusions Non-obese NAFLD was associated with decrease of E/A, while more research will be necessary to evaluate risk of non-obese NAFLD for LV diastolic dysfunction in future

Correlation between Nonalcoholic Fatty Liver Disease and Early Left Ventricular Diastolic Dysfunction

Background As the most common chronic liver disease, nonalcoholic fatty liver disease (NAFLD) has been reported to be associated with significant changes in myocardial structure and function, but it is still a controversial issue whether it is an independent risk factor for abnormalities in cardiac structure and function. Objective To assess the correlation of NAFLD with early left ventricular diastolic dysfunction by comparing left ventricular structure and functional indices between NAFLD and non-NAFLD patients. Methods A total of 519 inpatients from Geriatric Medicine Unit, Peking University People&apos;s Hospital were enrolled during 2018 to 2020, and divided into NAFLD group and non-NAFLD group according to the results of abdominal ultrasound or CT examination. Left ventricular structural and functional indices of two groups were comparatively analyzed. Early left ventricular diastolic dysfunction was defined as the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave &lt;1. Multivariate Logistic regression was used to assess the correlation between NAFLD and early left ventricular diastolic dysfunction. FIB-4 index was used to assess the risk of liver fibrosis in NAFLD patient〔low risk (&lt;1.30) , medium risk (1.30-3.25) , and high risk (&gt;3.25) 〕. NAFLD patients were divided into low-risk subgroup (n=81) and medium-high risk subgroup (n=100) according to whether FIB-4 index &lt;1.30. Results Compared with the non-NAFLD patients (n=338) , NAFLD patients had lower E/A ratio〔 (0.79±0.25) vs (0.87±0.34) , t=2.607, P=0.009) 〕 and greater end-diastolic interventricular septal thickness〔 (0.92±0.13) cm vs (0.89±0.13) cm, t=-2.525, P=0.012〕. Multivariate Logistic regression analysis showed that NAFLD was independently associated with the risk of early left ventricular diastolic dysfunction〔OR=2.941, 95%CI (1.736, 4.981) , P&lt;0.001〕. NAFLD patients with medium-high risk subgroup had lower E/A ratio〔 (0.75±0.21) vs (0.84±0.28) , t=2.275, P=0.024〕 and higher left ventricular mass index than did those with low-risk subgroup〔 (80.22±14.92) g/m2 vs (74.72±16.83) g/m2, t=-2.327, P=0.021〕. Conclusion NAFLD may be an independent risk factor for early left ventricular diastolic dysfunction. The higher risk of advanced fibrosis in NAFLD patients, the worse was the left ventricular diastolic function

Engineering of Bacillus thuringiensis Cry Proteins to Enhance the Activity against Western Corn Rootworm

A novel Bacillus thuringiensis Cry protein, Cry8Hb, active against Diabrotica virgifera virgifera (Western corn rootworm, WCRW) was discovered. Unexpectedly, the anti-rootworm activity of the Cry8Hb toxin was enhanced significantly by fusing Escherichia coli maltose binding protein (MBP) to this Cry toxin. While the exact mechanism of the activity enhancement remains indefinite, it is probable that the enhancement is a result of increased solubility of the MBP-Cry8Hb fusion in the rootworm midgut. This hypothesis was examined using a synthetic Cry3 protein called IP3-1, which was not soluble at a neutral pH like Cry8Hb and marginally active to WCRW. When IP3-1 was fused to MBP, its anti-WCRW activity was enhanced 13-fold. To further test the hypothesis, DNA shuffling was performed on IP3-1 to increase the solubility without MBP. Screening of shuffled libraries found six new IP3 variants showing very high anti-WCRW activity without MBP. Sequence and 3D structure analysis of those highly active, shuffled IP3 variants revealed several charge-altering mutations such as Lys to Glu on the putative MBP-attaching side of the IP3 molecule. It is likely that those mutations make the protein acidic to substitute the functions of MBP including enhancing the solubility of IP3 at a neutral pH

Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling

The extracellular matrix (ECM) serves as signals that regulate specific cell states in tumor tissues. Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression. In this study, we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status. Experiments were conducted using 3D collagen, fibrinogen, and Matrigel matrices to investigate the role of mechanical force in tumor development. Integrin-cytoskeleton-AIRE and DDR-STAT signals were examined using RNA sequencing and western blotting. Data from 1358 patients and 86 clinical specimens were used for ECM signature-prognosis analysis. Our findings revealed that ECM-derived mechanical force regulated tumor stemness and cell quiescence in breast cancer cells. A mechanical force of ~45 Pa derived from the extracellular substrate activated integrin β1/3 receptors, stimulating stem cell signaling pathways through the cytoskeleton/AIRE axis and promoting tumorigenic potential and stem-like phenotypes. However, excessive mechanical force (450 Pa) could drive stem-like cancer cells into a quiescent state, with the removal of mechanical forces leading to vigorous proliferation in quiescent cancer stem cells. Mechanical force facilitated cell cycle arrest to induce quiescence, dependent on DDR2/STAT1/P27 signaling. Therefore, ECM-derived mechanical force governs breast cancer cell status and proliferative characteristics through stiffness alterations. We further established an ECM signature based on the fibrinogen/fibronectin/vitronectin/elastin axis, which efficiently predicts patient prognosis in breast cancer. Our findings highlight the vital role of ECM-derived mechanical force in governing breast cancer cell stemness/quiescence transition and suggest the novel use of ECM signature in predicting the clinical prognosis of breast cancer

PRR15 deficiency facilitates malignant progression by mediating PI3K/Akt signaling and predicts clinical prognosis in triple-negative rather than non-triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast neoplasms with a higher risk of recurrence and metastasis than non-TNBC. Nevertheless, the factors responsible for the differences in the malignant behavior between TNBC and non-TNBC are not fully explored. Proline rich 15 (PRR15) is a protein involved in the progression of several tumor types, but its mechanisms are still controversial. Therefore, this study aimed to investigate the biological role and clinical applications of PRR15 on TNBC. PRR15 gene was differentially expressed between TNBC and non-TNBC patients, previously described as an oncogenic factor in breast cancer. However, our results showed a decreased expression of PRR15 that portended a favorable prognosis in TNBC rather than non-TNBC. PRR15 knockdown facilitated the proliferation, migration, and invasive ability of TNBC cells in vitro and in vivo, which was abolished by PRR15 restoration, without remarkable effects on non-TNBC. High-throughput drug sensitivity revealed that PI3K/Akt signaling was involved in the aggressive properties of PRR15 silencing, which was confirmed by the PI3K/Akt signaling activation in the tumors of PRR15Low patients, and PI3K inhibitor reversed the metastatic capacity of TNBC in mice. The reduced PRR15 expression in TNBC patients was positively correlated with more aggressive clinicopathological characteristics, enhanced metastasis, and poor disease-free survival. Collectively, PRR15 down-regulation promotes malignant progression through the PI3K/Akt signaling in TNBC rather than in non-TNBC, affects the response of TNBC cells to antitumor agents, and is a promising indicator of disease outcomes in TNBC