Transgenic mice were generated in which the cDNA for the human insulin-like growth factor 1B (IGF-1B) was placed under the control of a rat a-myosin heavy chain promoter. In mice heterozygous for the transgene, IGF-1B mRNA was not detectable in the fetal heart at the end of gestation, was present in modest levels at 1 day after birth, and increased progressively with postnatal maturation, reaching a peak at 75 days. Myocytes isolated from transgenic mice secreted 1.15 + 0.25 ng of IGF-1 per 106 cells per 24 hr versus 0.27 ± 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 increased 84% in transgenic mice. Heart weight was comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, and 300 days, respectively, after birth. At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgenic and control mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart. Insulin-like growth factor-1 (IGF-1) belongs to the insulin family of peptides and acts as a growth factor in many tissues and tumors (1). Limited information is available on the effects of IGF-1 on the growth of cardiac myocytes. In neonatal ventricular myocytes in culture, lGF-1 activates DNA synthesis (2, 3) and the expression of myosin light chain-2, troponin, and a-skeletal actin (4), which are consistent with a hyperplastic and hypertrophic response of these cells. However, long-term cultures of adult myocytes react to the addition of IGF-1 by increasing only the formation of myofibrils in the cytoplasm (5). An up-regulation of IGF-1 mRNA in the myocardium occurs in pressure overload hypertrophy in vivo (6, 7), and this adaptation has been linked to myocyte hypertrophy. Recent observations have reported that acute ventricular failure is characterized by enhanced expression of IGF-1 and IGF-1 receptor (IGF-1R) in the stressed myocytes, which is followed by DNA replication, nuclear mitotic division, and cell proliferation (8,9). In line with these findings, the decline in DNA synthesis and cellular hyperplasia with postnatal myocardial development (10) is accompanied by attenuation in the expression of IGF-1 and IGF-1 receptor in myocytes in spite of ongoing cellular hypertrophy (11). However, a cause and effect relationship between IGF-1 and myocyte growth in vivo has not been established. For this purpose, a construct was made in which the human IGF-1B cDNA was placed under the control of the rat a-myosin heavy chain (a-MHC) promoter (12), which was then introduced as a transgene in FVB/N mice. This communication presents the effects that this transgene has on cardiac myocytes and on the whole animal, in heterozygous mice, designated as FVB.Igf+/-. Moreover, the consequences of this transgene on the hemodynamic characterist...

Discogenic low back pain is a common cause of disability, but its pathogenesis is poorly understood. We collected 19 specimens of lumbar intervertebral discs from 17 patients with discogenic low back pain during posterior lumbar interbody fusion, 12 from physiologically ageing discs and ten from normal control discs. We investigated the histological features and assessed the immunoreactive activity of neurofilament (NF200) and neuropeptides such as substance P (SP) and vasoactive-intestinal peptide (VIP) in the nerve fibres.The distinct histological characteristic of the painful disc was the formation of a zone of vascularised granulation tissue from the nucleus pulposus to the outer part of the annulus fibrosus along the edges of the fissures. SP-, NF-and VIP-immunoreactive nerve fibres in the painful discs were more extensive than in the control discs. Growth of nerves deep into the annulus fibrosus and nucleus pulposus was observed mainly along the zone of granulation tissue in the painful discs. This suggests that the zone of granulation tissue with extensive innervation along the tears in the posterior part of the painful disc may be responsible for causing the pain of discography and of discogenic low back pain.

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.

Cell-cell adhesion protein αE-catenin inhibits skin squamous cell carcinoma (SCC) development; however, the mechanisms responsible for this function are not completely understood. We report here that αE-catenin inhibits β4 integrin-mediated activation of SRC tyrosine kinase. SRC is the first discovered oncogene, but the protein substrate critical for SRC-mediated transformation has not been identified. We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. We uncovered a marked increase in this YAP1 phosphorylation in human and mouse SCC tumors with low/negative expression of αE-catenin. We demonstrate that the tumor suppressor function of αE-catenin involves negative regulation of the β4 integrin-SRC signaling pathway and that SRC-mediated phosphorylation and activation of YAP1 are an alternative to the canonical Hippo signaling pathway that directly connect oncogenic tyrosine kinase signaling with YAP1.

Complexity of heartbeat interval series is typically measured by entropy. Recent studies have found that sample entropy (SampEn) or fuzzy entropy (FuzzyEn) quantifies essentially the randomness, which may not be uniformly identical to complexity. Additionally, these entropy measures are heavily dependent on the predetermined parameters and confined to data length. Aiming at improving the robustness of complexity assessment for short-term RR interval series, this study developed a novel measure--distribution entropy (DistEn). The DistEn took full advantage of the inherent information underlying the vector-to-vector distances in the state space by probability density estimation. Performances of DistEn were examined by theoretical data and experimental short-term RR interval series. Results showed that DistEn correctly ranked the complexity of simulated chaotic series and Gaussian noise series. The DistEn had relatively lower sensitivity to the predetermined parameters and showed stability even for quantifying the complexity of extremely short series. Analysis further showed that the DistEn indicated the loss of complexity in both healthy aging and heart failure patients (both p < 0.01), whereas neither the SampEn nor the FuzzyEn achieved comparable results (all p ≥ 0.05). This study suggested that the DistEn would be a promising measure for prompt clinical examination of cardiovascular function.