AMPA receptor inhibition alleviates inflammatory response and myocardial apoptosis after myocardial infarction by inhibiting TLR4/NF-κB signaling pathway.

Myocardial infarction leads to myocardial inflammation and apoptosis, which are crucial factors leading to heart failure and cardiovascular dysfunction, eventually resulting in death. While the inhibition of AMPA receptors mitigates inflammation and tissue apoptosis, the effectiveness of this inhibition in the pathophysiological processes of myocardial infarction remains unclear. This study investigated the role of AMPA receptor inhibition in myocardial infarction and elucidated the underlying mechanisms. This study established a myocardial infarction model by ligating the left anterior descending branch of the coronary artery in Sprague-Dawley rats. The findings suggested that injecting the AMPA receptor antagonist NBQX into myocardial infarction rats effectively alleviated cardiac inflammation, myocardial necrosis, and apoptosis and improved their cardiac contractile function. Conversely, injecting the AMPA receptor agonist CX546 into infarcted rats exacerbated the symptoms and tissue damage, as reflected by histopathology. This agonist also stimulated the TLR4/NF-κB pathway, further deteriorating cardiac function. Furthermore, the investigations revealed that AMPA receptor inhibition hindered the nuclear translocation of P65, blocking its downstream signaling pathway and attenuating tissue inflammation. In summary, this study affirmed the potential of AMPA receptor inhibition in countering inflammation and tissue apoptosis after myocardial infarction, making it a promising therapeutic target for mitigating myocardial infarction.

Dapagliflozin attenuates the vulnerability to atrial fibrillation in rats with lipopolysaccharide-induced myocardial injury.

BACKGROUND: Oxidative stress is an essential component participating in the development and maintenance of atrial fibrillation (AF). Dapagliflozin, a SGLT2 inhibitor, has been shown to exert cardioprotective effects by ameliorating oxidative stress in multiple heart disease models. However, its potential to attenuate lipopolysaccharide (LPS)-induced myocardial injury in rats remains unknown. AIM: This study aims to investigate the role of dapagliflozin in LPS-induced myocardial injury and the potential mechanisms involved. METHODS: Rats were intraperitoneally administered LPS to induce sepsis-like condition. The intervention was conducted with intraperitoneal injection of dapagliflozin or saline 1 h in advance. The effects of dapagliflozin were detected by electrophysiological recordings, western blot, qPCR, ELISA, HE staining, immunohistochemistry and fluorescence. We further validated the mechanism in vitro using HL-1 cells. RESULTS: Dapagliflozin significantly improved LPS-induced myocardial injury, reduced susceptibility to AF, and mitigated atrial tissue inflammatory cell infiltration and atrial myocyte apoptosis. These were correlated with the Nrf2/HO-1 signaling pathway, which subsequently reduced oxidative stress. Subsequently, we used a specific inhibitor of the Nrf2/HO-1 pathway in vitro, reversed the anti-oxidative stress effects of dapagliflozin on HL-1 cells, further confirming the Nrf2/HO-1 pathway's pivotal role in dapagliflozin-mediated cardioprotection. CONCLUSION: Dapagliflozin ameliorated myocardial injury and susceptibility to AF induced by LPS through anti-oxidative stress, which relied on upregulation of the Nrf2/HO-1 pathway.

A distribution-based selective optimization method for eliminating periodic defects in harmonic signals.

Due to environmental interference and defects in measured objects, measurement signals are frequently affected by unpredictable noise and periodic defects. Moreover, there is a lack of effective methods for accurately distinguishing defect components from measurement signals. In this study, a distribution-based selective optimisation method (SOM) is proposed to mitigate the effects of noise and defect components. The SOM can be seen as a binary- or multiple-class signal classifier based on an error distribution, which can simultaneously eliminate periodic defect components of measurement signals and proceed with signal-fitting regression. The effectiveness, accuracy, and feasibility of the SOM are verified in theoretical and realworld measurement settings. Based on theoretical simulations under various parameter conditions, some criteria for selecting operation variables among a selection of parameter conditions are explained in detail. The proposed method is capable of separating defect components from measurement signals while also achieving a satisfactory fitting curve for the measurement signals. The proposed SOM has broad application prospects in signal processing and defect detection for mechanical measurements, electronic filtering, instrumentation, part maintenance, and other fields.

Dapagliflozin ameliorates sepsis-induced heart injury by inhibiting cardiomyocyte apoptosis and electrical remodeling through the PI3K/Akt pathway.

BACKGROUND: Sepsis-induced heart injury is one of the leading causes of circulation disorders worldwide. Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor mainly used for controlling blood glucose, has been shown to exert a protective effect on cardiomyocytes. However, the protective effect of dapagliflozin against sepsis-induced cardiac injury and the underlying mechanism needs to be studied. AIM: This study aims to investigate the effect of dapagliflozin on sepsis-induced cardiomyopathy and the potential mechanisms involved. METHODS: The rat model of sepsis was constructed by intraperitoneal injection of lipopolysaccharide. Echocardiography and electrophysiological studies were performed to detect changes in cardiac function and electrical activity. Cardiac pathological alternation and cardiomyocyte apoptosis were measured by H&E staining, serological analysis, immunohistochemical, immunofluorescence, and TUNEL assays. Western blot and qRT-PCR were performed to elucidate the underlying mechanism of dapagliflozin. Additionally, corresponding experiments in H9c2 cells were performed to further validate the mechanisms in vitro. RESULTS: Dapagliflozin improved cardiac dysfunction and reduced the susceptibility to ventricular arrhythmias in sepsis rats by ameliorating cardiac inflammation, suppressing cardiomyocyte apoptosis, and alleviating ventricular electrical remodeling. The PI3K/Akt signaling pathway inhibitor inhibited the anti-apoptotic effect of dapagliflozin, indicating that the protective effect was related to the activation of the PI3K/Akt pathway. CONCLUSION: Dapagliflozin ameliorated sepsis-induced cardiac injury by suppressing electrical remodeling and cardiomyocyte apoptosis, which could be attributed to the PI3K/Akt pathway.

Theoretical investigation of pure-state single-photon and large-bandwidth-correlation biphoton generation from micro/nanofiber.

Pure-state single photons and large-bandwidth-correlation biphotons are fundamental resources for quantum information processing. The dispersion properties of micro/nanofiber (MNF) can be tailored by carefully choosing its diameter, resulting in a flexibly tailored biphoton spectrum. We theoretically investigate pure-state single photons and large-bandwidth-correlation biphotons produced by degenerate spontaneous four-wave mixing in MNF. In our simulation, a single-photon state with a purity of 99% will be theoretically attained by choosing the appropriate pump bandwidth and center wavelength with respect to the diameter and length of the MNF. Further, when an appropriate diameter with a negligible curvature at the zero dispersion wavelength is chosen, even a narrow pump bandwidth is capable of motivating remarkably broadband correlation biphotons, e.g., for a MNF diameter of 0.7 µm, the theoretical full width at half maximum is 473 nm. In practice, the application of a MNF-based quantum light source is dependent on the technologies that precisely control and measure the diameter. Our theoretical investigation will guide the experimental realization of high-quality quantum light sources based on MNF.

Characterization of the Internal Stress Evolution of an EB-PVD Thermal Barrier Coating during a Long-Term Thermal Cycling.

Electron beam physical vapour deposition (EB-PVD) technology is a standard industrial method for the preparation of a thermal barrier coating (TBC) deposition on aeroengines. The internal stress of EB-PVD TBCs, including stress inside the top coating (TC) and thermal oxidation stress during long-term service is one of the key reasons for thermal barrier failures. However, research on the synergistic characterization of the internal stress of EB-PVD TBCs is still lacking. In this work, the stress inside the TC layer and the thermal oxidation stress of EB-PVD TBC during long-term thermal cycles were synergistically detected, combining Cr3+-PLPS and THz-TDS technologies. Based on a self-built THz-TDS system, stress-THz coefficients c1 and c2 of the EB-PVD TBC, which are the core parameters for stress characterization, were calibrated for the first time. According to experimental results, the evolution law of the internal stress of the TC layer was similar to that of the TGO stress, which were interrelated and influenced by each other. In addition, the internal stress of the TC layer was less than that of the TGO stress due to the columnar crystal microstructure of EB-PVD TBCs.

Experimental study on the coupling between the piezoelectric and streaming potential in wet bone.

The stress-generated potential (SGP) of bone is one of the mechanisms affecting bone remodeling including piezoelectricity and streaming potential. To explore the interactions between the piezoelectric and streaming potential, an experimental setup was designed that simultaneously applied a concentrated force and liquid pressure to wet bone. Using this device, the stress-generated potential of wet bone under the two types of loads was measured. The experimental results show that under a constant liquid pressure, the measured potential curves increase over time, and its increasing rate decrease as the concentrated force increase. The measured peak amplitudes of potential decrease as the liquid pressure increase under the same concentrated force whether loading or unloading. To explain the coupling mechanism of the found phenomena, an equivalent model with two voltage sources and three equivalent resistances was established, and the equivalent electrical relationship between the piezoelectric and streaming potential was obtained by analyzing the model. The analysis discussion implies that various factors have influence on the coupling relationship between streaming and piezoelectric potentials, and the factors can be summarized as the changes of the three equivalent resistances caused by piezoelectric and streaming potentials.

The characterization of bovine compact bone fatigue damage using terahertz spectroscopy.

Fatigue can cause cracks to propagate from the micro- to the macroscale, which results in a decrease of Young's modulus of the bone. Non-destructive measurements of bone fatigue damage are of great importance for bone quality assessment and fracture prevention. Unfortunately, there is still a lack of effective nondestructive methods sensitive to the initial deterioration during damage accumulation, particularly in the field of orthopedics and biomechanics. In this study, terahertz spectroscopy was adopted to evaluate microscale bone damage. Specifically, the refractive index and Young's modulus of bone samples subjected to different degrees of fatigue damage were tested at a fixed area. Both parameters are found to decrease in two stages under cycled fatigue loading, which is attributed to the initial onset and subsequent development of microdamage during fatigue loading. The change in refractive index reflects the accumulation of fatigue damage as well as the decrease in Young's modulus.

miR-216b-5p regulates proliferation and apoptosis of ox-LDL-stimulated VSMCs and HUVECs via IGF2.

Atherosclerosis (AS) is one of the principal causes of cardiovascular disorder. Reportedly, vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) play key roles in AS development, and microRNAs (miRNAs) regulate their functions. The function of miR-216b-5p in AS remains unknown. Human VSMCs and human HUVECs were treated with ox-LDL to establish the in vitro model of AS. MiR-216b-5p and IGF2 expressions in VSMCs and HUVECs were probed by qRT-PCR and western blot. The viability, cell cycle progression, and apoptosis of VSMCs and HUVECs were evaluated by Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine, and flow cytometry assays, respectively. The binding sites between IGF2 3'UTR and miR-216b-5p were validated by dual-luciferase reporter assay. miR-216b-5p expression was declined in ox-LDL-induced VSMCs and HUVECs. In VSMCs, miR-216b-5p overexpression inhibited excessive proliferation and induced apoptosis. MiR-216b-5p could markedly restrain the viabiblity of VSMCs induced by ox-LDL and enhanced the viability of HUVECs. Additionally, IGF2 was confirmed as the direct target of miR-216b-5p and transfection of IGF2 overexpression plasmids rescued the effects of miR-216b-5p on VSMCs and HUVECs. miR-216b-5p alleviates the dysfunction of VSMCs and HUVECs caused by ox-LDL via repressing IGF2, and exerts protective functions to block the development of AS.

Activation of the sigma-1 receptor exerts cardioprotection in a rodent model of chronic heart failure by stimulation of angiogenesis.

BACKGROUND: Angiogenesis plays a critical role on post-infarction heart failure (PIHF), the presence of which facilitates additional blood supply to maintain the survival of residual cardiomyocytes. The sigma-1 receptor (S1R) has been substantiated to stimulate angiogenesis, with the effect on a model of PIHF remaining unknown. AIMS: This study aims to investigate the effects of S1R on PIHF and the underlying mechanisms involved. METHODS: Rats were implemented left anterior descending artery ligation followed by rearing for 6 weeks to induce a phenotype of heart failure. Daily intraperitoneal injection of S1R agonist or antagonist for 5 weeks was applied from 2nd week after surgery. The effects exerted by S1R were detected by echocardiography, hemodynamic testing, western blot, Sirius red dyeing, ELISA, immunohistochemistry and fluorescence. We also cultured HUVECs to verify the mechanisms in vitro. RESULTS: Stimulation of S1R significantly ameliorated the cardiac function resulted from PIHF, in addition to the observation of reduced fibrosis in the peri-infarct region and the apoptosis of residual cardiomyocytes, which were associated with augmentation of microvascular density in peri-infarct region through activation of the JAK2/STAT3 pathway. We also indicated that suppression of JAK2/STAT3 pathway by specific inhibitor in vitro reversed the pro-angiogenic effects of S1R on HUVECs, which further confirmed that angiogenesis, responsible for PIHF amelioration, by S1R stimulation was in a JAK2/STAT3 pathway-dependent manner. CONCLUSION: S1R stimulation improved PIHF-induced cardiac dysfunction and ventricular remodeling through promoting angiogenesis by activating the JAK2/STAT3 pathway.

Corrigendum: The Reversal Effect of Sigma-1 Receptor (S1R) Agonist, SA4503, on Atrial Fibrillation After Depression and Its Underlying Mechanism.

[This corrects the article DOI: 10.3389/fphys.2019.01346.].

Chronic Sigma 1 receptor activation alleviates right ventricular dysfunction secondary to pulmonary arterial hypertension.

Sigma 1 receptor (S1R) has shown a preferable protective effect on left ventricular function, but whether it protects right ventricular (RV) function is still elusive.This study aimed to determine the effects of S1R on RV dysfunction secondary to pulmonary arterial hypertension.Sixty wild-type male Sprague-Dawley rats were randomly divided into the control group, the fluvoxamine group, the pulmonary arterial hypertension group and the pulmonary arterial hypertension combined with fluvoxamine group. Monocrotaline (60 mg/kg) was administered to induce pulmonary arterial hypertension, and fluvoxamine was given for 21 consecutive days to activate S1R after one week of monocrotaline administration. Echocardiographic, serologic, and histologic parameters, qRT-PCR, and western blotting were conducted after 4 weeks of monocrotaline administration.The expression of S1R was decreased in the right ventricle in pulmonary arterial hypertension. TAPSE, and the FAC of the right ventricle were significantly decreased, and RV EDP and the plasma concentration of N-terminal pro-B-type natriuretic peptide was increased in the pulmonary arterial hypertension group, but fluvoxamine partly restored those abnormalities (all P < 0.05). Moreover, pulmonary arteriole remodeling, and fibrosis and hypertrophy in the RV were shown in the pulmonary arterial hypertension group; interestingly, fluvoxamine recovered RV structural remodeling (all P < 0.05) but neither alleviated pulmonary arteriole remodeling nor reduced pulmonary artery pressure. Furthermore, S1R activation protects RV function by upgrading the NRF 2/HO 1-mediated antioxidant stress pathway. In conclusion, chronic S1R activation ameliorates structural remodeling and RV dysfunction secondary to pulmonary arterial hypertension without altering pulmonary artery pressure.

Metal-Free Reductive Coupling of para-Quinone Methides with 4-Cyanopyridines Enabled by Pyridine-Boryl Radicals: Access to Pyridylated Diarylmethanes with Anti-Cancer Activity.

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B2 pin2 ) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.

Pinocembrin mediates antiarrhythmic effects in rats with isoproterenol-induced cardiac remodeling.

BACKGROUND: High levels of circulating catecholamines are related to raise risk of cardiac arrhythmias. In addition, our recent studies have suggested that pinocembrin could decrease the susceptibility to arrhythmias in several rat models, including chronic ischemic heart failure, myocardial infarction and depression. In this research, the effects of pinocembrin on ventricular fibrillation (VF) susceptibility were investigated in rats treated with isoproterenol (ISO) and further explored the possible mechanism. METHODS: Cardiac remodeling was induced by intraperitoneally injection ISO (5 mg/kg) 7 days. Simultaneously, Rats were received pinocembrin (5 mg/kg) or saline by tail vein injection. The effects of pinocembrin were evaluated by electrocardiogram parameters, ventricular electrophysiological parameters, echocardiographic, western blot, ventricular histology, biochemical examinations. In vitro, we cultured H9C2 cardiomyocytes to further define the mechanisms. RESULTS: Compared with ISO group, pinocembrin remarkably decreased VF inducibility rate, attenuated the shortening of QT and corrected QT (QTc) interval, action potential duration (APD), ventricular effective refractory period (ERP), and increased the protein levels of Kv4.2 and Kv4.3 and Cav1.2 and decreased phosphorylated Ca2+ calmodulin-dependent kinase Ⅱ (p-CaMK Ⅱ). Pinocembrin also alleviated ventricular fibrosis, hypertrophy and increased expression of connexin protein 43 (Cx43). In addition, pinocembrin markedly downregulated levels of malondialdehyde (MDA), hydrogen peroxide (H2O2), oxidized glutathione (GSSG) and increased the activity of superoxide dismutase (SOD) and glutathione (GSH) levels in circulation and cardiac tissue. Pinocembrin reduced the reactive oxygen species (ROS) levels. Furthermore, after treatment of pinocembrin the content of NADPH Oxidase-4 (NOX4) and NADPH Oxidase-2 (NOX2) was significantly lower and the level of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly higher. In vitro, we found that Nrf2 inhibitor remarkably reduced the antioxidant effects of pinocembrin, which further demonstrated that the effect of pinocembrin was related to activation of Nrf2. CONCLUSION: Our data demonstrate that pinocembrin decreases ventricular electrical remodeling, ion remodeling, ventricular fibrosis, hypertrophy and suppresses isoproterenol-induced oxidative stress. The findings shown that pinocembrin mediates antiarrhythmic effects in rats with isoproterenol-induced cardiac remodeling related to Nrf2/HO-1 pathway.

[Effect of Selenoprotein Thioredoxin Reductase 3 on the Survival Prognosis of Tumor Patients].

Objective To investigate the expression of thioredoxin reductase 3(TXNRD3),a selenoprotein,in 33 human malignant tumors and then analyze its effect on the survival prognosis.Methods We employed the genotype-tissue expression project database,the cancer cell line encyclopedia,and the cancer genome atlas to explore the expression of TXNRD3 gene in 33 human malignant tumors and analyze its impact on the survival prognosis.Further,we explored the correlations of TXNRD3 with immune cells and immune infiltration in the tumor microenvironment,as well as with neoantigens,immune checkpoint genes,tumor mutational burden,and microsatellite instability.Subsequently,human samples were classified into high-and low-expression groups according to TXNRD3 gene expression levels,and the enrichment analysis of biological functions and signaling pathways was performed.Results The analysis with multiple databases showed that TXNRD3 was highly expressed in 15 tumors.The survival analysis showed that TXNRD3 was significantly associated with poor prognosis in pancreatic cancer patients.In addition,the expression level of TXNRD3 was correlated with immune infiltration in tumor microenvironment,neoantigens,immune checkpoint genes,tumor mutational burden,and microsatellite instability.TXNRD3 affected the expression of DNA mismatch repair genes.The gene set enrichment indicated that TXNRD3 was involved in regulating multiple signaling pathways associated with tumor metabolism and tumor immunity.Conclusion TXNRD3 is widely expressed in tumors and has a clinical value for the survival prognosis prediction and treatment of multiple tumors,demonstrating the potential of being a promising biomarker for targeted treatment of multiple tumors.

Retrospective cohort study of new-onset atrial fibrillation in acute pulmonary embolism on prognosis.

OBJECTIVES: To investigate the characteristics of new-onset atrial fibrillation (AF) and its impact on prognosis in acute pulmonary embolism (aPE). DESIGN: A retrospective cohort study SETTING: The study cohort included patients diagnosed with aPE who were admitted to the Renmin Hospital of Wuhan University from January 2017 to January 2019. PARTICIPANTS: Patients were ≥18 years of age and hospitalised for aPE. OUTCOME MEASURES: AF was diagnosed based on an ECG recording or a Holter monitor during hospitalisation. aPE was diagnosed by CT pulmonary angiography. The prescription was determined from the discharge medication list. All-cause mortality was observed after 6-month follow-up. The logistic regression model and Cox proportional hazards model were used to study the risk factor of the new-onset AF and the predictor of all-cause mortality, respectively. RESULTS: A total of 590 patients with aPE were enrolled, 23 (3.9%) in the new-onset paroxysmal AF group, 31 (5.3%) in the new-onset persistent AF group and 536 (90.8%) in the sinus rhythm (SR) group. The incidence of the new-onset AF was 9.2% (54/590). A significant difference in age, heart rate, cardiac troponin I ultra, amino-terminal pro-brain natriuretic peptide, D-dimer, left atrial diameter, left ventricular ejection fraction, pulmonary infection, venous thromboembolism, congestive heart failure, chronic cor pulmonale and ischaemic heart disease was found among the three groups (p<0.05). Risk factors for the new-onset AF were massive PE, ischaemic heart disease and congestive heart failure. The survival rate of the paroxysmal and persistent AF group was significantly lower than that of the SR group within 6 months (60.9% and 51.6% vs 88.8%, p<0.001). New-onset persistent AF (OR 2.73; 95% CI 1.28 to 5.81; p=0.009) was an independent predictor affecting the 6-month survival in aPE patients. CONCLUSIONS: Massive PE, ischaemic heart disease and congestive heart failure are high-risk factors which were related to new-onset AF in aPE. New-onset persistent AF was an independent predictor for 6-month all-cause mortality in PE patients.

Pinocembrin ameliorates post-infarct heart failure through activation of Nrf2/HO-1 signaling pathway.

BACKGROUND: Oxidative stress is an important factor involved in the progress of heart failure. The current study was performed to investigate whether pinocembrin was able to ameliorate post-infarct heart failure (PIHF) and the underlying mechanisms. METHODS: Rats were carried out left anterior descending artery ligation to induce myocardial infarction and subsequently raised for 6 weeks to produce chronic heart failure. Then pinocembrin was administrated every other day for 2 weeks. The effects were evaluated by echocardiography, western blot, Masson's staining, biochemical examinations, immunohistochemistry, and fluorescence. In vitro we also cultured H9c2 cardiomyocytes and cardiac myofibroblasts to further testify the mechanisms. RESULTS: We found that PIHF-induced deteriorations of cardiac functions were significantly ameliorated by administrating pinocembrin. In addition, the pinocembrin treatment also attenuated collagen deposition and augmented vascular endothelial growth factor receptor 2 in infarct border zone along with an attenuated apoptosis, which were related to an amelioration of oxidative stress evidenced by reduction of reactive oxygen species (ROS) in heart tissue and malondialdehyde (MDA) in serum, and increase of superoxide dismutase (SOD). This were accompanied by upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) pathway. In vitro experiments we found that specific Nrf2 inhibitor significantly reversed the effects resulted from pinocembrin including antioxidant, anti-apoptosis, anti-fibrosis and neovascularization, which further indicated the amelioration of PIHF by pinocembrin was in a Nrf2/HO-1 pathway-dependent manner. CONCLUSION: Pinocembrin ameliorated cardiac functions and remodeling resulted from PIHF by ROS scavenging and Nrf2/HO-1 pathway activation which further attenuated collagen fibers deposition and apoptosis, and facilitated angiogenesis.

Effects of Fatigue Damage on the Microscopic Modulus of Cortical Bone Using Nanoindentation.

Alterations to the bone structure from cycle loadings can undermine its damage resistance at multiple scales. The accumulation of fatigue damage in a bone is commonly characterized by the reduction in the elastic modulus. In this study, nano-indentation was used for investigating microscopic damage evolution of bovine tibia samples subjected to fatigue loading. Indentation tests were conducted in the same 60 µm × 120 µm area with different degrees of damage, including fracture, and the evolution of reduced modulus was observed. The results showed that bone's reduced modulus decreased significantly during the initial 40% of the life fraction, whereas it proceeded slowly during the remaining period. As the size of the residual indentations was about 4 µm in length, the degradation of bone's reduced modulus reflected the accumulation of fatigue damage at smaller scales.

Pinocembrin ameliorates arrhythmias in rats with chronic ischaemic heart failure.

OBJECTIVE: Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism. METHODS: Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure. RESULTS: Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43). CONCLUSION: We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.

Pinocembrin alleviates lipopolysaccharide-induced myocardial injury and cardiac dysfunction in rats by inhibiting p38/JNK MAPK pathway.

AIM: Recent studies have shown that, with its excellent anti-inflammatory and antioxidant effects, pinocembrin can reduce the occurrence of arrhythmia in myocardial infarction rats. However, whether it can alleviate lipopolysaccharide (LPS)-induced myocardial injury in rats has not been reported. Therefore, the purpose of this study was to investigate whether pinocembrin could alleviate myocardial injury and arrhythmia in rats with sepsis. MATERIALS AND METHODS: Rats were intraperitoneally injected with LPS to simulate animal sepsis, and the caudal vein was injected with pinocembrin or normal saline for intervention. Transthoracic echocardiography, inflammatory factors, electrophysiological recording, histological analysis, and western-blot analysis were performed. KEY FINDINGS: Compared with the control group, the rats in the LPS group had myocardial injury and cardiac dysfunction, and the incidence of ventricular arrhythmia increased. In addition, LPS resulted in the increase of p-c-Jun N-terminal kinase (JNK), p-p38 proteins in the myocardium, the levels of inflammatory factors in the blood and the apoptosis rate of left ventricular cardiomyocytes. And all these adverse effects were eliminated, thus confirming that pinocembrin has an excellent protective effect on the heart. SIGNIFICANCE: Reducing the inflammatory response and cell apoptosis by inhibiting p38/JNK mitogen-activated protein kinase (MAPK) signaling pathway, pinocembrin can alleviate myocardial injury, cardiac dysfunction, and ventricular arrhythmia induced by LPS.