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Irisin is a recently identified myokine which brings increases in energy expenditure and contributes to the beneficial effects of exercise through the browning of white adipose tissues. However, its effects in the heart remains unknown. This study sought to determine the effects of irisin on hypoxia/reoxygenation injury and its relationship with HDAC4. Wild type and stable HDAC4-overexpression cells were generated from H9c2 cardiomyoblasts. HDAC4 overexpression cells and wild type H9c2 cells were exposed to 24 hours of hypoxia followed by one hour of reoxygenation in vitro in the presence or absence of irisin (5 ng/ml). Cell cytotoxicity, apoptosis, mitochondrial respiration, and mitochondrial permeability transition pore (mPTP) were determined. Western blotting was employed to determine active-caspase 3, annexin V, and HDAC4 expression. As compared to wild type H9c2 group, HDAC4 overexpression remarkably led to a great increase in cell death as evident by the increased lactate dehydrogenase (LDH) leakage, ratio of caspase-3-positive cells as well as the upregulated levels of active-caspase 3 and annexin V shown by western blot analysis. In addition, HDAC4 overexpression also induced much severe mitochondrial dysfunction, as indicated by apoptotic mitochondria and increased mPTP. However, irisin treatment significantly attenuated all of these effects. Though irisin treatment did not influence the expression of HDAC4 at the transcriptional level, western blot analysis showed that HDAC4 protein levels decreased in a time-dependent way after administration of irisin, which is associated with the degradation of HDAC4 mediated by small ubiquitin-like modification (SUMO). Our results are the first to demonstrate that the protective effects of irisin in cardiomyoblasts exposed to hypoxia/reoxygenation might be associated with HDAC4 degradation.

Ultrasound imaging is a vital component of high-quality Obstetric care. In rural and under-resourced communities, the scarcity of ultrasound imaging results in a considerable gap in the healthcare of pregnant mothers. To increase access to ultrasound in these communities, we developed a new automated diagnostic framework operated without an experienced sonographer or interpreting provider for assessment of fetal biometric measurements, fetal presentation, and placental position. This approach involves the use of a standardized volume sweep imaging (VSI) protocol based solely on external body landmarks to obtain imaging without an experienced sonographer and application of a deep learning algorithm (U-Net) for diagnostic assessment without a radiologist. Obstetric VSI ultrasound examinations were performed in Peru by an ultrasound operator with no previous ultrasound experience who underwent 8 hours of training on a standard protocol. The U-Net was trained to automatically segment the fetal head and placental location from the VSI ultrasound acquisitions to subsequently evaluate fetal biometry, fetal presentation, and placental position. In comparison to diagnostic interpretation of VSI acquisitions by a specialist, the U-Net model showed 100% agreement for fetal presentation (Cohen’s κ 1 (p<0.0001)) and 76.7% agreement for placental location (Cohen’s κ 0.59 (p<0.0001)). This corresponded to 100% sensitivity and specificity for fetal presentation and 87.5% sensitivity and 85.7% specificity for anterior placental location. The method also achieved a low relative error of 5.6% for biparietal diameter and 7.9% for head circumference. Biometry measurements corresponded to estimated gestational age within 2 weeks of those assigned by standard of care examination with up to 89% accuracy. This system could be deployed in rural and underserved areas to provide vital information about a pregnancy without a trained sonographer or interpreting provider. The resulting increased access to ultrasound imaging and diagnosis could improve disparities in healthcare delivery in under-resourced areas.

Irisin is a myokine that primarily targets adipose tissue, where it increases energy expenditure and contributes to the beneficial effects of exercise through the browning of white adipose tissue. As our knowledge has deepened in recent years, muscle has been found to be a major target organ for irisin as well. Several studies have attempted to characterize the role of irisin in muscle to improve glucose metabolism through mechanisms such as reducing insulin resistance. Although they are very intriguing reports, some contradictory results make it difficult to grasp the whole picture of the action of irisin on muscle. In this review, we attempted to organize the current knowledge of the role of irisin in muscle glucose metabolism. We discussed the direct effects of irisin on glucose metabolism in three types of muscle, that is, skeletal muscle, smooth muscle, and the myocardium. We also describe irisin’s effects on mitochondria and its interactions with other hormones. Furthermore, to consider the relationship between the irisin-induced improvement of glucose metabolism in muscle and systemic disorders of glucose metabolism, we reviewed the results from animal interventional studies and human clinical studies.

Irisin, a newly identified peptide, is critical to regulating metabolism, thermogenesis, and reducing oxidative stresses. Our recent works demonstrated that irisin protected the heart against myocardial ischemic injury and preserved the function of mitochondria. However, whether irisin preserves myocardial performance and attenuates insulin resistance in type II diabetes remains unknown. Effects of irisin on type II diabetes-induced cardiac dysfty unction and insulin resistance in db/db mice were studied. Methods: Homozygous db/db mice (n=5/each group) for spontaneous mutation ( ) and heterozygous (heterozygous) mice (n=5/each group) for control were used to assess for cardiac performance and impairment of insulin resistance. Homozygous and heterozygous controls received a treatment with either irisin (100 mg/kg, intraperitoneal injection, every other day) or vehicle control (PBS) for 4 weeks at 16 weeks of age. Insulin tolerance test and glucose tolerance test were employed to determine insulin resistance in mice. Cardiac function was assessed by echocardiography. Metabolic features including hyperglycemia and body growth were also examined. Immunohistochemical analysis was employed to determine myocardial hypertrophy and interstitial fibrosis. Immunoblots were employed to determine the signaling pathway associated with irisin treatment. Homozygous db/db mice developed an impairment in insulin sensitivity as indicated by Insulin tolerance test (ITT), glucose tolerance test (GTT) (p<0.05 vs non-irisin treatment), hyperglycemia (p<0.05 vs heterozygous control), and hyperinsulinemia (serum insulin: 0.81 ± 0.065 ng/ml in heterozygous control vs. 8.33 ± 0.69 ng/ml in homozygous db/db control, p<0.0001), which were attenuated by the administration of irisin (serum insulin 8.32 ± 0.68 ng/ml in homozygous db/db control vs 6.56 ± 0.38 ng/ml in homozygous db/db irisin treatment, p<0.0001). Furthermore, as compared to heterozygous control, db/db mice manifested a depression in cardiac performance [ejection fraction (EF): 91.9% ± 0.44 in heterozygous control vs 79.1% ± 2.0 in homozygous db/db control, p< 0.001] in associated myocardial remodeling (cardiac fibrosis 1.89% ± 0.09 in heterozygous control vs. 5.39% ± 0.22 in homozygous db/db control, p<0.001). Notably, the depression of cardiac function in EF (79.2% ± 2.0 homozygous db/db control vs. 88.6% ± 1.9 in homozygous db/db + irisin, p<0.01) and fractional shortening (FS) (42.2% ± 1.8 in homozygous db/db control vs. 53.2% ± 2.7 in homozygous db/db+irisin, p<0.01) and remodeling were markedly attenuated by the administration of irisin. Western blotting shows that irisin treatment prevented an approximate two-fold decrease in p38 phosphorylation and increase in histone deacetylase 4 (HDAC4) in the homozygous db/db myocardium (p<0.05 vs homozygous db/db control). Irisin preserves myocardial performance and insulin resistance in db/db mice, which is related to p38 phosphorylation and HDAC reduction.

Irisin, a cleaved product of the fibronectin type III domain containing protein-5, is produced in the muscle tissue, which plays an important role in modulating insulin resistance. However, it remains unknown if irisin provides a protective effect against the detrimental outcomes of hemorrhage. Hemorrhages were simulated in male CD-1 mice to achieve a mean arterial blood pressure of 35–45 mmHg, followed by resuscitation. Irisin (50 ng/kg) and the vehicle (saline) were administrated at the start of resuscitation. Cardiac function was assessed by echocardiography, and hemodynamics were measured through femoral artery catheterization. A glucose tolerance test was used to evaluate insulin sensitivity. An enzyme-linked immunosorbent assay was performed to detect inflammatory factors in the muscles and blood serum. Western blot was carried out to assess the irisin production in skeletal muscles. Histological analyses were used to determine tissue damage and active-caspase 3 apoptotic signals. The hemorrhage suppressed cardiac performance, as indicated by a reduced ejection fraction and fractional shortening, which was accompanied by enhanced insulin resistance and hyperinsulinemia. Furthermore, the hemorrhage resulted in a marked decrease in irisin and an increase in the production of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). Additionally, the hemorrhage caused marked edema, inflammatory cell infiltration and active-caspase 3 positive signals in skeletal muscles and cardiac muscles. Irisin treatment led to a significant improvement in the cardiac function of animals exposed to a hemorrhage. In addition, irisin treatment improved insulin sensitivity, which is consistent with the suppressed inflammatory cytokine secretion elicited by hemorrhages. Furthermore, hemorrhage-induced tissue edema, inflammatory cell infiltration, and active-caspase 3 positive signaling were attenuated by irisin treatment. The results suggest that irisin protects against damage from a hemorrhage through the modulation of insulin sensitivity.

Background: p38 regulated/activated protein kinase (PRAK) plays a crucial role in modulating cell death and survival. However, the role of PRAK in the regulation of metabolic stress remains unclear. We examined the effects of PRAK on cell survival and mitochondrial function in C2C12 myoblasts in response to high glucose stresses. Methods: PRAK of C2C12 myoblasts was knocked out by using CRISPR/Cas-9 genome editing technology. Both wild type and PRAK −/− C2C12 cells were exposed to high glucose at the concentration of 30 mmol/L to induce metabolic stress. The effect of irisin, an adipomyokine, on both wild type and PRAK −/− cells was determined to explore its relationship with RPAK. Cell viability, ATP product, glucose uptake, mitochondrial damage, and insulin signaling were assessed. Results : PRAK knockout decreased C2C12 viability in response to high glucose stress as evident by MTT assay in association with the reduction of ATP and glucose uptake. PRAK knockout enhanced apoptosis of C2C12 myoblasts in response to high glucose, consistent with an impairment in mitochondrial function, by decreasing mitochondrial membrane potential. PRAK knockout induced impairment of mitochondrial and cell damage were rescued by irisin. PRAK knockout caused decrease in phosphorylated PI3 kinase at Tyr 485, IRS-1 and AMPKα and but did not affect non-phosphorylated PI3 kinase, IRS-1 and AMPKα signaling. High glucose caused the further reduction of phosphorylated PI3 kinase, IRS-1 and AMPKα. Irisin treatment preserved phosphorylated PI3 kinase, IRS-1by rescuing PRAK in high glucose treatment. Conclusion: Our finding indicates a pivotal role of PRAK in preserving cellular survival, mitochondrial function, and high glucose stress.

Background Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy. Methods Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control , Control  +  Sodium butyrate ( NaBu ) , STZ and STZ  +  Sodium butyrate ( NaBu ), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments. Results Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice. Conclusion HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.

Background Recent evidence has demonstrated that cardiac progenitor cells play an essential role in the induction of angiomyogenesis in infarcted myocardium. We and others have shown that engraftment of c-kit + cardiac stem cells (CSCs) into infarcted hearts led to myocardium regeneration and neovascularization, which was associated with an improvement of ventricular function. The purpose of this study is aimed at investigating the functional role of transcription factor (TF) Oct3/4 in facilitating CSCs to promote myocardium regeneration and preserve cardiac performance in the post-MI heart. Methods c-kit + CSCs were isolated from adult hearts and re-introduced into the infarcted myocardium in which the mouse MI model was created by permanent ligation of the left anterior descending artery (LAD). The Oct3/4 of CSCs was inhibited by transfection of Oct3/4 siRNA, and transfection of CSCs with control siRNA serves as control groups. Myocardial functions were evaluated by echocardiographic measurement. Histological analysis was employed to assess newly formed cardiogenesis, neovascularization, and cell proliferations. Terminal deoxynucleotidyltransferase (TdT) nick-end labeling (TUNEL) was carried out to assess apoptotic cardiomyocytes. Real time polymerase chain reaction and Western blot were carried out to evaluate the level of Oct 3/4 in CSCs. Results Two weeks after engraftment, CSCs increased ventricular functional recovery as shown by a serial echocardiographic measurement, which is concomitant with the suppression of cardiac hypertrophy and attenuation of myocardial interstitial fibrosis. Suppression of Oct 3/4 of CSCs abrogated functional improvements and mitigated the hypertrophic response and cardiac remodeling. Transplantation of c-kit + CSCs into MI hearts promoted cardiac regeneration and neovascularization, which were abolished with the knockdown of Oct3/4. Additionally, suppression of Oct3/4 abrogated myocyte proliferation in the CSC-engrafted myocardium. Conclusion Our results indicate that CSCs-derived cardiac regeneration improves the restoration of cardiac function and is mediated through Oct 3/4.

Background: Warts are a common dermatologic complaint with an increased incidence within the pediatric population. Warts are caused by multiple strains of the human papillomavirus (HPV). There is little research on how a patient's HPV immunization status affects the response to treatment of warts in pediatric patients. Aims: The purpose of this study is to investigate the relationship between HPV vaccination status and wart resolution. Materials and Methods: This is a retrospective chart review that investigates the relationship between response to routine treatment of warts and a subject's HPV vaccination status. Results: There was no significant relationship found between HPV vaccination status and resolution of warts (p = 0.797). However, there was a significant positive correlation between having the HPV vaccine and number of visits for the treatment of warts (r = 0.180, P = 0.024). Conclusion: This study did not show a significant correlation between HPV vaccination status and wart resolution, although it demonstrated a significant positive relationship between those immunized with the HPV vaccine and an increased number of treatment visits. Possible explanations for this unexpected correlation include the variation in HPV vaccine formulation, vaccination status, and frequency of office visits, since vaccinated patients are more likely to be compliant with office visits.