Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases.

The mechanistic target of rapamycin (mTOR) is evolutionarily conserved from yeast to humans and is one of the most fundamental pathways of living organisms. Since its discovery three decades ago, mTOR has been recognized as the center of nutrient sensing and growth, homeostasis, metabolism, life span, and aging. The role of dysregulated mTOR in common diseases, especially cancer, has been extensively studied and reported. Emerging evidence supports that mTOR critically regulates innate immune responses that govern the pathogenesis of various cardiovascular diseases. This review discusses the regulatory role of mTOR in macrophage functions in acute inflammation triggered by ischemia and in atherosclerotic cardiovascular disease (ASCVD) and heart failure with preserved ejection fraction (HFpEF), in which chronic inflammation plays critical roles. Specifically, we discuss the role of mTOR in trained immunity, immune senescence, and clonal hematopoiesis. In addition, this review includes a discussion on the architecture of mTOR, the function of its regulatory complexes, and the dual-arm signals required for mTOR activation to reflect the current knowledge state. We emphasize future research directions necessary to understand better the powerful pathway to take advantage of the mTOR inhibitors for innovative applications in patients with cardiovascular diseases associated with aging and inflammation.

Matricellular Protein Cilp1 Promotes Myocardial Fibrosis in Response to Myocardial Infarction.

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The mechanistic target of rapamycin complex 1 critically regulates the function of mononuclear phagocytes and promotes cardiac remodeling in acute ischemia.

Monocytes and macrophages are cellular forces that drive and resolve inflammation triggered by acute myocardial ischemia. One of the most important but least understood regulatory mechanisms is how these cells sense cues from the micro-milieu and integrate environmental signals with their response that eventually determines the outcome of myocardial repair. In the current study, we investigated if the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) plays this role. We present evidence that support a robustly activated mTORC1 pathway in monocytes and macrophages in the infarcting myocardium.. Specific mTORC1 inhibition transformed the landscape of cardiac monocytes and macrophages into reparative cells that promoted myocardial healing. As the result, mTORC1 inhibition diminished remodeling and reduced mortality from acute ischemia by 80%. In conclusion, our data suggest a critical role of mTORC1 in regulating the functions of cardiac monocytes and macrophages, and specific mTORC1 inhibition protects the heart from inflammatory injury in acute ischemia. As mTOR/mTORC1 is a master regulator that integrates external signals with cellular responses, the study sheds light on how the cardiac monocytes and macrophages sense and respond to the ischemic environment..

Left lung cancer in a patient with congenital unilateral absence of the left pulmonary artery: a case report and literature review.

BACKGROUND: Unilateral absence of pulmonary artery (UAPA) is a rare congenital disease of pulmonary circulation, which is often accompanied by other cardiovascular anomalies. Infrequently, it may remain undiagnosed until adulthood. More rarely, it is to be found with lung cancer in the ipsilateral or contralateral lung simultaneously. CASE PRESENTATION: A 56-year-old man with complaints of intermittent left chest pain for 2 months was referred to our hospital. Chest computed tomography(CT) revealed a cavitary lesion measuring 5.5 cm × 5.7 cm in the superior segment of the left lower lobe. Absence of left pulmonary artery and right-sided aortic arch were found on chest computed tomography angiography (CTA). The tumor was successfully removed via left pneumonectomy, and postoperative histopathology showed that the tumor was a squamous cell carcinoma (T2bN1). At a postoperative 24-month follow-up, the patient was free of disease and no evidence of recurrence or metastasis. Based on literature review, this is the ninth case of lung cancer in UAPA patients. CONCLUSIONS: Lung cancer and UAPA occurred ipsilaterally in 66.7% of these cases (6/9), including the present case. For those patients who occurred contralaterally, surgical treatment may be more challenging. CT and CTA could provide an accurate diagnosis for this disease entity. Identification and recognition of this rare and special disease entity may facilitate timely diagnosis and appropriate treatment.

Cytosolic DNA Sensing Promotes Macrophage Transformation and Governs Myocardial Ischemic Injury.

BACKGROUND: Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood. METHODS: Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role. RESULTS: We report that ischemic myocardial injury, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance. CONCLUSIONS: These results reveal, for the first time, that the cytosolic DNA receptor cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.

Spectral broadband anastigmatic Wadsworth imaging spectrometer.

A new advanced optical design based on the Wadsworth mounting for a broadband stigmatic, coma-free practical spectrometer with high imaging quality is presented. By the addition of an inclined cylindrical lens with a wedge angle, the stigmatic imaging conditions in a broad waveband have been obtained by our analysis. An example which presents excellent optical performances over a spectral broadband of 380nm centered at 570nm has been designed to certify the analysis.

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy.

Histone deacetylases (HDACs) regulate cardiac plasticity; however, their molecular targets are unknown. As autophagy contributes to pathological cardiac remodeling, we hypothesized that HDAC inhibitors target autophagy. The prototypical HDAC inhibitor (HDACi), trichostatin A (TSA), attenuated both load- and agonist-induced hypertrophic growth and abolished the associated activation of autophagy. Phenylephrine (PE)-triggered hypertrophy and autophagy in cultured cardiomyocytes were each blocked by a panel of structurally distinct HDAC inhibitors. RNAi-mediated knockdown of either Atg5 or Beclin 1, two essential autophagy effectors, was similarly capable of suppressing ligand-induced autophagy and myocyte growth. RNAi experiments uncovered the class I isoforms HDAC1 and HDAC2 as required for the autophagic response. To test the functional requirement of autophagic activation, we studied mice that overexpress Beclin 1 in cardiomyocytes. In these animals with a fourfold amplified autophagic response to TAC, TSA abolished TAC-induced increases in autophagy and blunted load-induced hypertrophy. Finally, we subjected animals with preexisting hypertrophy to HDACi, finding that ventricular mass reverted to near-normal levels and ventricular function normalized completely. Together, these data implicate autophagy as an obligatory element in pathological cardiac remodeling and point to HDAC1/2 as required effectors. Also, these data reveal autophagy as a previously unknown target of HDAC inhibitor therapy.

Amyand's hernia in a neonate: A case report.

Acute appendicitis secondary to hernia incarceration presenting as scrotal swelling is exceptionally rare in neonates. We report a neonate who presented with tender swelling in the right scrotum. Ultrasonography detected features of a rare Amyand's hernia. Surgical exploration and histopathological examination confirmed the diagnosis.

Planning skills moderate the intention-planning cognitions-behaviour relation: a longitudinal study on physical activity in Chinese adolescents.

Our objective is to examine the role of planning skills for translating intentions into physical activity via planning cognitions. A study with 534 adolescents was conducted. Over 4 weeks, intention, planning cognitions (prospective anticipation of when, where, and how to perform activities), planning skills (successful past planning experiences), and physical activity were assessed. The results were that skills correlated with intention, planning cognitions, and subsequent physical activity. Planning cognitions were found to mediate the intention-behavior relation, whereas skills moderated the mediating role of planning cognitions: If students reported high skills, they were more likely to translate their intentions into plans and behavior. We conclude that having more skills makes it more likely that adolescents successfully translate their intentions into plans. Promotion of physical activity should improve planning cognitions but also planning skills. Only with planning cognitions and skills might adolescents better be able to act in accordance with their intentions and perform physical activity.

Multiple organ dysfunction syndrome associated with Mycoplasma pneumoniae infection.

In this study, we report one case of a three-year-old boy infected with Mycoplasma pneumonia (MP) and presenting concomitant multiple organ damage of the heart, kidney, lung and liver, among others, together with a brief review for the diagnosis and treatment of MP infection with multiple organ dysfunction syndrome (MODS).

FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases.

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.

Cardiomyocyte autophagy: remodeling, repairing, and reconstructing the heart.

Autophagy is an evolutionarily conserved catabolic pathway of lysosome-dependent turnover of damaged proteins and organelles. When nutrients are in short supply, bulk removal of cytoplasmic components by autophagy replenishes depleted energy stores, a process critical for maintaining cellular homeostasis. However, prolonged activation of autophagic pathways can result in cell death. Longstanding evidence has linked the stimulation of lysosomal pathways to pathologic cardiac remodeling and a number of cardiac diseases, including heart failure and ischemia. Only recently, however, has work begun to parse cytoprotective autophagy from autophagy that contributes to disease pathogenesis. Current thinking suggests that the effects of autophagy exist on a continuum, with the eliciting triggers, the duration and amplitude of autophagic flux, and possibly the targeted intra-cellular cargo as critical determinants of the end result. Deciphering how autophagy participates in basal homeostasis of the heart, in aging, and in disease pathogenesis may uncover novel insights with clinical relevance in the treatment of heart disease.

Mutations in VP0 and 2C Proteins of Duck Hepatitis A Virus Type 3 Attenuate Viral Infection and Virulence.

Duck hepatitis A virus (DHAV) is prevalent worldwide and has caused significant economic losses. As the predominant serotype in China, DHAV-3 has become a major challenge to the local duck industry. Here the genetics and pathogenesis of a virulent DHAV-3 strain and its embryo-passaged strain were assessed. There were only two amino acid substitutions (Y164N in VP0 protein and L71I in 2C protein) introduced during the adaptation process. The pathogenicity of these strains was further evaluated in vivo. Clinical signs, gross pathology, and histopathological analysis showed that the embryo-passaged strain was attenuated. Meanwhile, the viral RNA loads were significantly lower in the liver tissues of the ducklings infected with the attenuated strain. As expected, infection with the virulent and attenuated strains led to the activation of different innate immune genes. We suspected that the loss of replication efficiency in ducklings was responsible for the attenuation phenotype of the embryo-passaged strain. In addition, different innate immune responses in the liver of ducklings were at least partly responsible for the differential infectivity phenotype. These findings provide new insights into the genetics and pathogenesis of DHAV-3, which may aid the development of new vaccines and the implementation of immunization strategies.

The role of plasma D-dimer levels for predicting lymph node and mediastinal lymph node involvement in non-small cell lung cancer.

INTRODUCTION: Elevated plasma D-dimer levels have been suggested as a predictor of poor prognosis in NSCLC. But rare study showed the relationship between D-dimer levels and lymph node involvement. OBJECTIVES: To evaluate the role of plasma D-dimer levels in predicting lymph node and mediastinal lymph node involvement in NSCLC. METHODS: Preoperative plasma D-dimer levels were quantified in 253 NSCLC patients that underwent radical lung resection with systemic lymph node dissection. Patients were classified as lymph node negative (N0) versus lymph node positive (N1 + N2) and mediastinal lymph node negative (N0 + N1) versus mediastinal lymph node positive (N2). RESULTS: Median plasma D-dimer level was significantly lower in Group N0 (94.0 µg/L) compared to Group N1 + N2 (177.0 µg/L) and in Group N0 + N1 (122.0 µg/L) compared to Group N2 (198.0 µg/L). Similar results were found in patients stratified by age, sex, smoking status and histological type, expect in patients with squamous carcinoma. The Receiver Operating Characteristic (ROC) curve for plasma D-dimer levels of N0 versus N1 + N2 showed an area under the curve (AUC) of 0.757 and when a cutoff value was 124.0 µg/L DDU, the sensitivity and specificity was 0.80 and 0.68. The ROC curve for plasma D-dimer levels of N0 + N1 versus N2 showed an AUC of 0.720 and when a cutoff value was 147.0 µg/L DDU, the sensitivity and specificity was 0.75 and 0.67. CONCLUSIONS: Plasma D-dimer level has utility for predicting lymph node and mediastinal lymph node status in patients with operable NSCLC.