Biomedical reports最新文献

Sestrin 2 (SESN2) is a conserved protein whose expression is upregulated under various cellular stresses including hepatic injury. In the injured liver, hepatic stellate cells (HSCs) become activated and produce collagen, contributing to fibrosis; however, SESN2 overexpression has been shown to suppress collagen synthesis. Amino acids are known to influence SESN2 expression; however, their specific effects remain unclear. In the present study, it was investigated whether specific amino acids regulate SESN2 expression and the function of quiescent RI-T HSCs, which are responsible for collagen production, using reverse transcription-quantitative PCR, western blotting, and cell proliferation assay. It was found that supplementation with asparagine (Asn) and proline (Pro) (AP), both non-essential amino acids, led to a complete reduction in SESN2 and activating transcription factor 4 (ATF4) mRNA levels after 5 h of incubation. Additionally, AP partially reduced collagen type I α1 (COL1A1) mRNA levels. However, knockdown of SESN2 or ATF4 resulted in a more substantial reduction in COL1A1 mRNA levels than the supplementation with AP. These results suggest that SESN2, which is induced by amino acid insufficiency, contributes to the upregulation of COL1A1 mRNA levels and that AP may increase COL1A1 mRNA levels through pathways independent of SESN2. The COL1A1-inducing effect of SESN2 contrasted with the inhibitory effect of SESN2 on activated HSCs. In long-term cultures, AP supplementation increased COL1A1 mRNA and protein levels, as well as RI-T cell proliferation, while SESN2 and ATF4 mRNA levels remained suppressed. These findings suggested that the absence of AP induces relative amino acid starvation, leading to increased ATF4/SESN2 expression. By contrast, long-term AP supplementation alleviated this stress, promoting cell proliferation and COL1A1 synthesis. The present results indicate that SESN2 function in quiescent HSCs may differ from its role in activated cells, providing new insights into its regulatory mechanisms in collagen production.

Progressive right ventricle (RV) failure and death in connective tissue disease (CTD) are related to RV hypertrophy (RVH) and dilation, irrespective of pulmonary arterial hypertension (PAH). Therefore, detecting cardiac impairment before RVH and determining RVH predictors is crucial for timely intervention. The present prospective cohort study aimed to identify cardiac markers that occur before RVH and to investigate predictors of RVH. CTD was diagnosed based on clinical features, laboratory findings and imaging data. The cardiac functions of patients with CTD were evaluated using echocardiography, cardiovascular magnetic resonance (CMR) and multi-modality cardiac imaging studies, including RV wall thickness, systolic functions, late gadolinium enhancement, T1 maps and biventricular strain analysis. A total of 52 patients with CTD with non-right ventricular hypertrophy (non-RVH), 34 patients with RVH and 50 healthy individuals were prospectively included. The impaired cardiac indices in patients with RVH included RV ejection fraction, ventricular dimensions, global myocardial deformation, late gadolinium enhancement and ventricular extracellular volume (ECV). The cardiac death rate did not differ significantly between the RVH and non-RVH groups (P=0.14). Conventional parameters, including serum cardiac markers and the left ventricular ejection fraction, showed no significant changes in the non-RVH group compared with the control group. Regarding fibrosis assessment using CMR, an elevated native T1 value (1,362±72 msec in the non-RVH group vs. 1,268±42 in the control group; P<0.001) and ECV (31±4% in the non-RVH group vs. 25±3% in the control group; P<0.001) were observed. By contrast, T1 myocardium/msec 15 min post-contrast of the left ventricle in the RVH group was significantly decreased compared with that in the non-RVH group, indicating an increase in the extracellular matrix at this stage. RVH was predicted by pulmonary arterial pressure (PAP) in patients in the non-RVH group (t-statistic, 2.84; P=0.01), whereas after RVH presentation, RV end-systolic volume (RVESV) became a progression predictor of RVH (t-statistic, 7.98; P<0.0001). No other cardiac imaging or laboratory findings predicted RVH. To the best of our knowledge, the present study was the first to highlight the non-invasive detection of cardiac tissue impairment using CMR and provide support for cardiac treatment initiation before RVH detection. The predictors of RVH vary with the heart disease stage. PAP in the non-RVH stage and incompetence of RVESV in the RVH stage predicted the progression of RVH. The present study was part of a clinical trial (NCT03271385), which was registered on July 1, 2017, and started on September 1, 2017.

Gallein is a known Gβγ subunit inhibitor, but its function in bone metabolism, especially in osteoblasts, and its molecular mechanism remains to be elucidated. Osteoprotegerin (OPG), which is secreted from osteoblasts, binds to nuclear factor kB receptor activator (RANK) ligand (RANKL) as a decoy receptor, prevents RANKL-RANK binding, and inhibits bone resorption. IL-6 is not only a bone resorption factor but also as a bone metabolism regulator. Prostaglandin F2α (PGF2α) promotes p44/p42 MAPK, p38 MAPK and stress-activated protein kinase/JNK phosphorylation in osteoblast-like MC3T3-E1 cells. In MC3T3-E1 cells, activated p44/p42 and p38 MAPKs promote IL-6 secretion and activated p44/p42 and p38 MAPKs and JNK promote OPG secretion. The present study aimed to investigate the effect and mechanism of gallein on PGF2α-induced OPG and IL-6 secretion using an osteoblastic MC3T3-E1 cell line. It was found that gallein significantly increased PGF2α-induced OPG and IL-6 secretion in the MC3T3-E1 cell. By contrast, fluorescein, which is a gallein-like compound that does not bind to Gβγ, did not affect PGF2α-induced OPG and IL-6 secretion. Gallein significantly improved the PGF2α-induced OPG and IL-6 mRNA expression levels. Gallein did not affect the PGF2α-activated phosphorylation of p44/p42 and p38 MAPKs and JNK. Gallein increased PGF2α-induced OPG and IL-6 secretion in osteoblasts, indicating that gallein may regulate bone remodeling via OPG/IL-6 in bone metabolism.