Translation is the process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals and the public, ranging from diagnostics and ...therapeutics to medical procedures and behavioral changes. Translational research is defined as the effort to traverse a particular step of the translation process for a particular target or disease. Translational science is a newly emerging science, distinct from basic and clinical sciences in biology and medicine, and is a field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process. Advances in translational science will increase the efficacy and safety of translational research in all diagnostic and therapeutic areas. This report examines translational research on novel hormones, the natriuretic peptide family and leptin, which have achieved clinical applications or for which studies are still ongoing, and also emphasizes the lessons that translational science has learned from more than 30 years’ experience in translational research.
Summary The mammalian natriuretic peptide family consists of atrial (ANP), brain B-type; BNP and C-type natriuretic peptide (CNP) and three receptors, natriuretic receptors-A (NPR-A), -B (NPR-B) and ...-C (NPR-C). Both ANP and BNP are abundantly expressed in the heart and are secreted mainly from the atria and ventricles, respectively. By contrast, CNP is mainly expressed in the central nervous system, bone and vasculature. Plasma concentrations of both ANP and BNP are elevated in patients with cardiovascular disease, though the magnitude of the increase in BNP is usually greater than the increase in ANP. This makes BNP is a clinically useful diagnostic marker for several pathophysiological conditions, including heart failure, ventricular remodeling and pulmonary hypertension, among others. Recent studies have shown that in addition to BNP-32, proBNP-108 also circulates in human plasma and that levels of both forms are increased in heart failure. Furthermore, proBNP-108 is O -glycosylated and circulates at higher levels in patients with severe heart failure. In this review we discuss recent progress in our understanding of the biochemistry, molecular biology and clinical relevance of the natriuretic peptide system.
Lifestyle interventions can substantially improve obesity and cardiometabolic risks. However, evidence of long-term benefits of national intervention is sparse. We aimed to evaluate the long-term ...effectiveness of a nationwide program for abdominal obesity.
A retrospective cohort study was performed using a longitudinal nationwide individual data in subjects aged 40-74 years who underwent checkups in fiscal year (FY) 2008. Lifestyle interventions were provided via interview in subjects with abdominal obesity and at least one cardiometabolic risk factor. Subjects who attended the lifestyle intervention (participants) were compared to those who did not attend (non-participants). Outcomes were waist circumferences (WC) and body mass index (BMI) reduction, reversal of metabolic syndrome (MetS), and changes in cardiometabolic risks. We used a three-step process with robust analytic approaches to account for selection bias that included traditional multivariate analysis, propensity-score matching and instrumental variable (IV) analyses.
Of 19,969,722 subjects, 4,370,042 were eligible for analyses; 111,779 participants and 907,909 non-participants. A higher percentage of participants had ≥5% reductions in obesity profiles at year 3, compared to non-participants (WC, 21.4% vs 16.1%; BMI, 17.6% vs 13.6%; p<0.001 each). Participants also had higher reversal for MetS (adjusted odds ratio 1.31; 95% confidence interval: 1.29-1.33; p<0.001). Greater reductions in cardiometabolic risks were observed in participants. Those results were confirmed in analyses using a propensity score-matched cohort (n = 75,777, each) and IV analyses. Limitations of this work include the use of non-randomized national data in Japan to assess the effectiveness of the nationwide preventive program.
In the nationwide lifestyle intervention for abdominal obesity, the at-risk population achieved significant reductions in WC, BMI, and cardiometabolic risks in 3 years. This study provides evidence that the nationwide program effectively achieved long-term improvement in abdominal obesity and cardiometabolic risks.
Reactivation of the fetal cardiac gene program in adults is a reliable marker of cardiac hypertrophy and heart failure. Normally, genes within this group are expressed in the fetal ventricles during ...development, but are silent after birth. However, their expression is re-induced in the ventricular myocardium in response to various cardiovascular diseases, and potentially plays an important role in the pathological process of cardiac remodeling. Thus, analysis of the molecular mechanisms that govern the expression of fetal cardiac genes could lead to the discovery of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. In this review we will summarize what is currently known about the transcriptional regulation of the fetal cardiac gene program.
Background
Methods that facilitate muscle quality measurement may improve the diagnosis of sarcopenia. Current research has focused on the phase angle (PhA) obtained through bioelectrical impedance ...analysis (BIA) as an indicator of cellular health, particularly cell membrane integrity and cell function. The current study therefore aimed to evaluate the relationship between the PhA and muscle quality and muscle‐related parameters and to determine factors associated with the PhA. Moreover, we attempted to determine the cut‐off value of PhA for predicting sarcopenia.
Methods
First‐year university students (830 male students, 18.5 ± 0.6 years old; 422 female students, 18.3 ± 0.5 years old) and community‐dwelling elderly individuals (70 male individuals, 74.4 ± 5.5 years old; 97 female individuals, 73.1 ± 6.4 years old) were included. PhA and other body composition data were measured using BIA, while muscle quality was calculated by dividing handgrip strength by upper limbs muscle mass. The relationship between PhA and the aforementioned parameters were then analysed, after which the cut‐off value of PhA for predicting sarcopenia was examined.
Results
Multiple linear regression analysis revealed that age, skeletal muscle mass index (SMI), and muscle quality were independently associated with PhA in both sexes male (age: standardized regression coefficient (β) = −0.43, P < 0.001, SMI: β = 0.61, P < 0.001, muscle quality: β = 0.13, P < 0.001) and female (age: β = −0.56, P < 0.001, SMI: β = 0.52, P < 0.001, muscle quality: β = 0.09, P = 0.007). Participants with sarcopenia had a significantly lower PhA compared with those without it (sarcopenia vs. non‐sarcopenia: young male participants, 5.51 ± 0.41° vs. 6.25 ± 0.50°, P < 0.001; young female participants, 4.88 ± 0.16° vs. 5.37 ± 0.44°, P = 0.005; elderly female participants: 4.14 ± 0.29° vs. 4.63 ± 0.42°, P = 0.009). Although no significant findings were observed in elderly male participants, the same tendency was noted. Receiver operating characteristic (ROC) curve analysis indicated that PhA had good predictive ability for sarcopenia in young male, elderly male, young female, and elderly female participants (area under the ROC curve of 0.882, 0.838, 0.865, and 0.850, with cut‐off PhA values of 5.95°, 5.04°, 5.02°, and 4.20° for predicting sarcopenia, respectively).
Conclusions
The PhA reflected muscle quality and exhibited good accuracy in detecting sarcopenia, suggesting its utility as an index for easily measuring muscle quality, which could improve the diagnosis of sarcopenia.
Genetic remodeling contributes to the progression of heart failure by affecting myocardial cellular function and survival. In our investigation of the transcriptional regulation of cardiac gene ...expression, we found several transcriptional pathways involved in pathological cardiac remodeling. A transcriptional repressor, neuron-restrictive silencer factor (NRSF), regulates expression of multiple fetal cardiac genes through the activity of histone deacetylases (HDACs). Inhibition of NRSF in the heart results in cardiac dysfunction and sudden arrhythmic death accompanied by re-expression of a number of fetal genes, including those encoding fetal ion channels, such as the T-type Ca2+ channel. In the pathological calcineurin – nuclear factor of activated T-cells (NFAT) signaling pathway, transient receptor potential cation channel, subfamily C, member 6 (TRPC6) is a key component of a Ca2+-dependent regulatory loop. Indeed, inhibition of TRPC significantly ameliorates this pathological process in a mouse model of cardiac hypertrophy. Moreover, we recently showed that myocardin-related transcription factor-A (MRTF-A), a coactivator of serum response factor (SRF), mediates prohypertrophic signaling by linking the small GTPase Rho-actin dynamics signaling pathway to cardiac gene transcription. Collectively, our studies have revealed the transcriptional network involved in the development of cardiac dysfunction and potential therapeutic targets for the treatment of heart failure.
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) ...results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.
Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones. During cardiac development, their expression is a maker of cardiomyocyte differentiation and is under tight ...spatiotemporal regulation. After birth, however, their ventricular expression is only up-regulated in response to various cardiovascular diseases. As a result, analysis of ANP and BNP gene expression has led to discoveries of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. Studies using genetically engineered mice have shed light on the molecular mechanisms regulating ANP and BNP gene expression, as well as the physiological and pathophysiological relevance of the cardiac natriuretic peptide system. In this review we will summarize what is currently known about their regulation and the significance of ANP and BNP as hormones derived from the heart.
Background There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan. Methods We examined the epidemiology of GEP-NETs pancreatic endocrine ...tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs) in Japan in 2005 using a nationwide stratified random sampling method. Results A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (>2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (>1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis. Conclusion Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.
We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial ...CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell-specific CNP knockout and vascular smooth muscle cell-specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell-specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell-specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell-specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell-specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell-specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.
PDF
