Resistance exercise upregulates Irisin expression and suppresses myocardial fibrosis following myocardial infarction via activating AMPK-Sirt1 and inactivating TGFß1-Smad2/3.

AIM: To reveal the contribution of Irisin in the beneficial effects of resistance exercise on myocardial fibrosis (MF) and cardiac function in the mice with myocardial infarction (MI). METHODS: The MI model was built by ligating the left anterior descending coronary artery in Fndc5 knockout mice (Fndc5-/-). Resistance exercise was started one week after surgery and continued for four weeks. In addition, H2O2, AICAR, recombinant human Irisin protein (rhIRISIN), and Sirt1 shRNA lentivirus (LV-Sirt1 shRNA) were used to intervene primary isolated cardiac fibroblasts (CFs). MF was observed through Masson staining, and apoptosis was assessed using TUNEL staining. MDA and T-SOD contents were detected by biochemical kits. The expression of proteins and genes was detected by Western blotting and RT-qPCR. RESULTS: Resistance exercise increased Fndc5 mRNA level, inhibited the activation of TGFß1-TGFßR2-Smad2/3 pathway, activated AMPK-Sirt1 pathway, reduced the levels of oxidative stress, apoptosis, and MF in the infarcted heart, and promoted cardiac function. However, Fndc5 knockout attenuated the protective effects of resistance exercise on the MI heart. Results of the in vitro experiments showed that AICAR and rhIRISIN intervention activated the AMPK-Sirt1 pathway and inactivated the TGFß1-Smad2/3 pathway, and promoted apoptosis in H2O2-treated CFs. Notably, these effects of rhIRISIN intervention, except for the TGFßR2 expression, were attenuated by LV-Sirt1 shRNA. CONCLUSION: Resistance exercise upregulates Fndc5 expression, activates AMPK-Sirt1 pathway, inhibits the activation of TGFß1-Smad2/3 pathway, attenuates MF, and promotes cardiac function after MI.

Manipulation of Glutamatergic Neuronal Activity in the Primary Motor Cortex Regulates Cardiac Function in Normal and Myocardial Infarction Mice.

Cardiac function is under neural regulation; however, brain regions in the cerebral cortex responsible for regulating cardiac function remain elusive. In this study, retrograde trans-synaptic viral tracing is used from the heart to identify a specific population of the excitatory neurons in the primary motor cortex (M1) that influences cardiac function in mice. Optogenetic activation of M1 glutamatergic neurons increases heart rate, ejection fraction, and blood pressure. By contrast, inhibition of M1 glutamatergic neurons decreased cardiac function and blood pressure as well as tyrosine hydroxylase (TH) expression in the heart. Using viral tracing and optogenetics, the median raphe nucleus (MnR) is identified as one of the key relay brain regions in the circuit from M1 that affect cardiac function. Then, a mouse model of cardiac injury is established caused by myocardial infarction (MI), in which optogenetic activation of M1 glutamatergic neurons impaired cardiac function in MI mice. Moreover, ablation of M1 neurons decreased the levels of norepinephrine and cardiac TH expression, and enhanced cardiac function in MI mice. These findings establish that the M1 neurons involved in the regulation of cardiac function and blood pressure. They also help the understanding of the neural mechanisms underlying cardiovascular regulation.

Application of nanotechnology in bladder cancer diagnosis and therapeutic drug delivery.

Bladder cancer (BC) is one of the most common malignant tumors in the urinary system, and its high recurrence rate is a great economic burden to patients. Traditional diagnosis and treatment methods have the disadvantages of insufficient targeting, obvious side effects and low sensitivity, which seriously limit the accurate diagnosis and efficient treatment of BC. Due to their small size, easy surface modification, optical properties such as plasmon resonance, and surface enhanced Raman scattering, good electrical conductivity and photothermal conversion properties, nanomaterials have great potential application value in the realization of specific diagnosis and targeted therapy of BC. At present, the application of nanomaterials in the diagnosis and treatment of BC is attracting great attention and achieving rich research results. Therefore, this paper summarizes the recent research on nanomaterials in the diagnosis and treatment of BC, clarifies the existing advantages and disadvantages, and provides theoretical guidance for promoting the accurate diagnosis and efficient treatment of BC.

FNDC5/Irisin Inhibits the Inflammatory Response and Mediates the Aerobic Exercise-Induced Improvement of Liver Injury after Myocardial Infarction.

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.

Irisin and ALCAT1 mediated aerobic exercise-alleviated oxidative stress and apoptosis in skeletal muscle of mice with myocardial infarction.

Skeletal muscle in patients with heart failure (HF) exhibits altered structure, function and metabolism. Myocardial infarction (MI) is the most common cause of HF. Oxidative stress and cell apoptosis are involved in the pathophysiology of MI/HF-induced skeletal muscle atrophy. It is well recognized that aerobic exercise (AE) could prevent skeletal muscle atrophy after MI, but the underlying mechanism and molecular targets are still not fully clarified. In this study, Fndc5-/- and Alcat1-/- mice were used to establish the MI model and subjected to six weeks of moderate-intensity AE. C2C12 cells were treated with H2O2 and recombinant human Irisin (rhIrisin), or transduced with a lentiviral vector to mediate the overexpression of ALCAT1 (LV-Alcat1). Results showed that MI reduced Irisin expression and antioxidant capacity of skeletal muscle, increased ALCAT1 expression, induced protein degradation and cell apoptosis, which were partly reversed by AE; Knockout of Fndc5 further aggravated MI-induced oxidative stress and cell apoptosis in skeletal muscle, and partly weakened the beneficial effects of AE. In contrast, knockout of Alcat1 reduced MI-induced oxidative stress and cell apoptosis and strengthened the beneficial effects of AE. rhIrisin and AICAR intervention inhibited ALCAT1 expression, oxidative stress and cell apoptosis, which induced by H2O2 or LV-Alcat1 in C2C12 cells. These findings reveal that AE could alleviate the levels of oxidative stress and apoptosis in skeletal muscle following MI, partly via up-regulating Irisin and inhibiting ALCAT1 expression.

Exercise Training Enhances Myocardial Mitophagy and Improves Cardiac Function via Irisin/FNDC5-PINK1/Parkin Pathway in MI Mice.

Myocardial infarction is the major cause of death in cardiovascular disease. In vitro and in vivo models are used to find the exercise mode which has the most significant effect on myocardial irisin/FNDC5 expression and illuminate the cardioprotective role and mechanisms of exercise-activated myocardial irisin/FNDC5-PINK1/Parkin-mediated mitophagy in myocardial infarction. The results indicated that expression of irisin/FNDC5 in myocardium could be up-regulated by different types of exercise and skeletal muscle electrical stimulation, which then promotes mitophagy and improves cardiac function and the effect of resistance exercise. Resistance exercise can improve cardiac function by activating the irisin/FNDC5-PINK1/Parkin-LC3/P62 pathway, regulating mitophagy and inhibiting oxidative stress. OPA1 may play an important role in the improvement of cardiac function and mitophagy pathway in myocardial infarction mice by irisin-mediated resistance exercise. Resistance exercise is expected to become an effective therapeutic way to promote myocardial infarction rehabilitation.

Aerobic exercise alleviates oxidative stress-induced apoptosis in kidneys of myocardial infarction mice by inhibiting ALCAT1 and activating FNDC5/Irisin signaling pathway.

Aerobic exercise involves in ameliorating kidney injury, but the underlying mechanisms are not fully clarified. In this study, we elucidated the potential mechanisms of aerobic exercise in ameliorating kidney injury following myocardial infarction (MI). In vivo, wildtype and alcat1 knockout mice were used to establish the MI model, and subjected to six-week moderate-intensity aerobic exercise. In vitro, Normal Rat Kidney (NRK) cells treated with H2O2 and recombinant human Irisin (rhIrisin) were used for exploring potential mechanisms. Our results showed that Irisin expression was up-regulated by aerobic exercise in kidneys after MI, while ALCAT1 was reduced. In alcat1 knockout mice, we found that ALCAT1 involved in the progressions of oxidative stress and apoptosis in impaired kidney tissues of MI mice, but aerobic exercise reversed these changes. Furthermore, in vitro, we observed that Irisin inhibited both H2O2-treatment or overexpression of alcat1-induced oxidative stress and apoptosis in NRK cells, partially via AMPK-Sirt1-PGC-1α pathway. These findings reveal that aerobic exercise participates in alleviating the levels of oxidative stress and apoptosis in impaired kidney tissues following MI, partially via activating FNDC5/Irisin-AMPK-Sirt1-PGC-1α signaling pathway and inhibiting ALCAT1 expression.