Itaconic acid regulation of TFEB-mediated autophagy flux alleviates hyperoxia-induced bronchopulmonary dysplasia.

BACKGROUND: Premature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. METHODS: Plasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. RESULTS: An imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. CONCLUSION: The metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.

Correlation of vitamin A levels in umbilical cord blood with neonatal pulmonary diseases.

OBJECTIVE: To study the relationship between umbilical cord blood vitamin A (VA) and neonatal lung diseases and explore the impact of umbilical cord blood VA on neonatal lung diseases. METHOD: Umbilical vein blood was collected at birth, and its VA content was measured. According to the VA levels in umbilical cord blood, a VA deficiency (VAD) group, a marginal deficiency group and a normal group were created and followed up until 28 days after birth. RESULTS: The umbilical cord blood VA level in the neonatal group with lung disease was 0.13 ± 0.05 mg/L, while the result for the VA level in the non-lung disease group was 0.15 ± 0.05 mg/L. The umbilical cord blood VA levels in the neonatal lung disease group were significantly lower than those in the non-lung disease group. The incidence of neonatal pulmonary diseases was highest in the VAD group, and the incidence decreased as the level of VA in umbilical cord blood increased. Umbilical cord blood VAD and premature birth were found to be independent risk factors for neonatal respiratory disease. CONCLUSION: Umbilical cord blood VAD and premature birth are independent risk factors for neonatal pulmonary diseases. The lower the level of VA in umbilical cord blood, the more susceptible infants will be to neonatal respiratory infections in the neonatal period.

Epigenetic and transcriptional landscapes during cerebral cortex development in a microcephaly mouse model.

The cerebral cortex is a pivotal structure integral to advanced brain functions within the mammalian central nervous system. DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'-hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in the early stages profoundly alters the epigenetic regulation program, which provides unique insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.

Single-cell sequencing highlights heterogeneity and malignant progression in actinic keratosis and cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent of the keratinocyte-derived malignancies with actinic keratosis (AK) as a precancerous lesion. To comprehensively delineate the underlying mechanisms for the whole progression from normal skin to AK to invasive cSCC, we performed single-cell RNA sequencing (scRNA-seq) to acquire the transcriptomes of 138,982 cells from 13 samples of six patients including AK, squamous cell carcinoma in situ (SCCIS), cSCC, and their matched normal tissues, covering comprehensive clinical courses of cSCC. We identified diverse cell types, including important subtypes with different gene expression profiles and functions in major keratinocytes. In SCCIS, we discovered the malignant subtypes of basal cells with differential proliferative and migration potential. Differentially expressed genes (DEGs) analysis screened out multiple key driver genes including transcription factors along AK to cSCC progression. Immunohistochemistry (IHC)/immunofluorescence (IF) experiments and single-cell ATAC sequencing (scATAC-seq) data verified the expression changes of these genes. The functional experiments confirmed the important roles of these genes in regulating cell proliferation, apoptosis, migration, and invasion in cSCC tumor. Furthermore, we comprehensively described the tumor microenvironment (TME) landscape and potential keratinocyte-TME crosstalk in cSCC providing theoretical basis for immunotherapy. Together, our findings provide a valuable resource for deciphering the progression from AK to cSCC and identifying potential targets for anticancer treatment of cSCC.

Material Extrusion Filament Width and Height Prediction via Design of Experiment and Machine Learning.

The dimensions of material extrusion 3D printing filaments play a pivotal role in determining processing resolution and efficiency and are influenced by processing parameters. This study focuses on four key process parameters, namely, nozzle diameter, nondimensional nozzle height, extrusion pressure, and printing speed. The design of experiment was carried out to determine the impact of various factors and interaction effects on filament width and height through variance analysis. Five machine learning models (support vector regression, backpropagation neural network, decision tree, random forest, and K-nearest neighbor) were built to predict the geometric dimension of filaments. The models exhibited good predictive performance. The coefficients of determination of the backpropagation neural network model for predicting line width and line height were 0.9025 and 0.9604, respectively. The effect of various process parameters on the geometric morphology based on the established prediction model was also studied. The order of influence on line width and height, ranked from highest to lowest, was as follows: nozzle diameter, printing speed, extrusion pressure, and nondimensional nozzle height. Different nondimensional nozzle height settings may cause the extruded material to be stretched or squeezed. The material being in a stretched state leads to a thin filament, and the regularity of processing parameters on the geometric size is not strong. Meanwhile, the nozzle diameter exhibits a significant impact on dimensions when the material is in a squeezing state. Thus, this study can be used to predict the size of printing filament structures, guide the selection of printing parameters, and determine the size of 3D printing layers.

Unveiling sub-bandgap energy-level structures on machined optical surfaces based on weak photo-luminescence.

Sub-bandgap defect energy levels (SDELs) introduced by the point defects located in surface defect areas are considered the main factors in decreasing laser-induced damage thresholds (LIDTs). The suppression of SDELs could greatly increase LIDTs. However, no available method could detect SDELs, limiting the characterization and suppression of SDELs. Herein, a self-designed photo-luminescence detection system is developed to explore the weak transient-steady photo-luminescence properties of machined surfaces. Based on the excitation laser wavelength dependence of photo-luminescence properties, a sub-bandgap energy-level structure (SELS) containing SDELs is unveiled for the first time. Based on the developed mathematical model for predicting LIDTs, the feasibility of the detection method was verified. In summary, this work provides a novel approach to characterize SDELs on machined surfaces. This work could construct electronic structures and explore the transition behaviors of electrons, which is vital to laser-induced damage. Besides, this work could predict the LIDTs of the machined surfaces based on their PL properties, which provides convenience for evaluating the LIDTs of various optical elements in industrial production. Moreover, this work provides a convenient method for raising the LIDTs of various optical elements through monitoring and suppressing the SDELs on machined surfaces.

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.

[Artesunate alleviates hypoxic-ischemic brain damage in neonatal rats by inhibiting NLRP3 inflammasome activation and inflammatory cytokine secretion].

Objective To investigate the protective effect of artesunate on hypoxic-ischemic brain damage (HIBD) and its mechanism in neonatal rats. Methods 7-day-old neonatal SD rats were randomly divided into sham operation group, model group, artesunate 5 mg/kg group, artesunate 10 mg/kg group, artesunate 20 mg/kg group and dexamethasone 6 mg/kg group, with 18 rats in each group. HIBD models were established in groups except for the sham operation group. The sham operation group only needed to separate the left common carotid artery without ligation and nitrogen-oxygen mixed gas ventilation. Each group was injected with drug intraperitoneally right after surgery and the rats in the sham operation group and the model group were injected with an equal volume of normal saline (once a day for a total of 5 times). One hour after the last injection, the rats in each group were scored for neurological defects. After the rats were sacrificed, the brain water content was measured and the pathological changes of the brain tissues of rats were observed. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) was used to detect the neuronal cell apoptosis, and ELISA was applied to detect the levels of IL-1ß, IL-6 and TNF-α in brain tissues and peripheral blood of each group of rats. Western blot analysis was adopted to detect the protein expression levels of NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 in the rats brain tissues of each group. Results Compared with the model group, the neurological deficit score was decreased; the pathological damage of brain tissues was relieved; the brain water content was significantly reduced; the apoptosis number of hippocampal neurons was decreased significantly; the levels of IL-1ß, IL-6 and TNF-α in brain tissues and peripheral blood were significantly reduced; the protein expression levels of NLRP3, ASC and caspase-1 were significantly lowered in the middle-dose and high-dose artesunate groups and the dexamethasone group. Conclusion Artesunate can improve the neurological function, relieve the brain damage, and alleviate the brain edema in neonatal rats with HIBD. It can protect the HIBD, which may be related to the inhibition of NLRP3 inflammasome activation and reduction of inflammatory cytokine secretion.

Pan-cancer analysis revealed H3K4me1 at bivalent promoters premarks DNA hypermethylation during tumor development and identified the regulatory role of DNA methylation in relation to histone modifications.

BACKGROUND: DNA hypermethylation at promoter CpG islands (CGIs) is a hallmark of cancers and could lead to dysregulation of gene expression in the development of cancers, however, its dynamics and regulatory mechanisms remain elusive. Bivalent genes, that direct development and differentiation of stem cells, are found to be frequent targets of hypermethylation in cancers. RESULTS: Here we performed comprehensive analysis across multiple cancer types and identified that the decrease in H3K4me1 levels coincides with DNA hypermethylation at the bivalent promoter CGIs during tumorigenesis. Removal of DNA hypermethylation leads to increment of H3K4me1 at promoter CGIs with preference for bivalent genes. Nevertheless, the alteration of H3K4me1 by overexpressing or knockout LSD1, the demethylase of H3K4, doesn't change the level or pattern of DNA methylation. Moreover, LSD1 was found to regulate the expression of a bivalent gene OVOL2 to promote tumorigenesis. Knockdown of OVOL2 in LSD1 knockout HCT116 cells restored the cancer cell phenotype. CONCLUSION: In summary, our work identified a universal indicator that can pre-mark DNA hypermethylation in cancer cells, and dissected the interplay between H3K4me1 and DNA hypermethylation in detail. Current study also reveals a novel mechanism underlying the oncogenic role of LSD1, providing clues for cancer therapies.

Evolution of the point defects involved under the action of mechanical forces on mechanically machined fused silica surfaces.

Point defects with different species are concentrated on most mechanically machined fused silica optical surfaces with surface defects, which would sharply decrease the laser damage resistance under intense laser irradiation. Various point defects have distinct roles in affecting the laser damage resistance. Especially, the proportions of various point defects have not been identified, posing the challenge in relating the intrinsic quantitative relationship among various point defects. To fully reveal the comprehensive effect of various point defects, it is necessary to systematically explore the origins, evolution laws and especially the quantitative relationship among point defects. Herein, seven types of point defects are determined. The unbonded electrons in point defects are found to tend to be ionized to induce laser damage and there is a definite quantitative relationship between the proportions of oxygen-deficient point defects and that of peroxide point defects. The conclusions are further verified based on the photoluminescence (PL) emission spectra and the properties (e.g., reaction rule and structural feature) of the point defects. On basis of the fitted Gaussian components and electronic-transition theory, the quantitative relationship between PL and the proportions of various point defects is constructed for the first time. E'-Center accounts for the highest proportion among them. This work is beneficial for fully revealing the comprehensive action mechanisms of various point defects and providing new insights in elucidating the defect-induced laser damage mechanisms of optical components under intense laser irradiation from the atomic scale.

Short sleep duration associated with increased risk for new-onset cardiovascular diseases in individuals with metabolic syndromes: Evidence from the China Health and Retirement Longitudinal Study.

To explore the impact and risk of short sleep duration (sleep duration < 6 h/night) on new-onset cardiovascular and cerebrovascular diseases (CVDs) in people with metabolic syndromes (Mets), this study used the 2011 baseline and 2015 follow-up data from the China Longitudinal Study of Health and Retirement (CHARLS) to conduct a prospective study of people aged ≥ 45 years in China. A total of 5,530 individuals without pre-existing CVDs in baseline were included. Mets were defined according to the harmonized criteria. We applied the Logistic Regression (LR), the Deep Neural Networks (DNN), and the Adaptive Boosting (AdaBoost), to evaluate the association between Mets components, short sleep, and the risk of new-onset CVDs, and the importance of multiple variates for new-onset CVDs. During the 4-year follow-up period, 512 individuals developed CVDs, and short sleep increased the risk of CVD in individuals with Mets. The odds ratio for prevalent CVD in Mets with short sleep group was 3.73 (95%CI 2.95-4.71; P < 0.001) compared to the normal group, and 1.99 (95% CI 1.58-2.51; P < 0.001) compared to the Mets without short sleep group. The DNN method reached the highest precision of 92.24% and f1-score of 95.86%, and the Adaboost method reached the highest recall of 99.92%. Both DNN and Adaboost have better predictive performance than LR and revealed short sleep duration and components of Mets are all the strongest predictors of CVD onset.

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.

m6A Topological Transition Coupled to Developmental Regulation of Gene Expression During Mammalian Tissue Development.

N6-methyladenosine (m6A) is the most prevalent internal modification and reversible epitranscriptomic mark in messenger RNAs (mRNAs) and plays essential roles in a variety of biological processes. However, the dynamic distribution patterns of m6A and their significance during mammalian tissue development are poorly understood. Here, we found that based on m6A distribution patterns, protein-coding genes were classified into five groups with significantly distinct biological features and functions. Strikingly, comparison of the m6A methylomes of multiple mammalian tissues between fetal and adult stages revealed dynamic m6A topological transition during mammalian tissue development, and identified large numbers of genes with significant m6A loss in 5'UTRs or m6A gain around stop codons. The genes with m6A loss in 5'UTRs were highly enriched in developmental stage-specific genes, and their m6A topological transitions were strongly associated with gene expression regulation during tissue development. The genes with m6A gain around the stop codons were associated with tissue-specific functions. Our findings revealed the existence of different m6A topologies among protein-coding genes that were associated with distinct characteristics. More importantly, these genes with m6A topological transitions were crucial for tissue development via regulation of gene expression, suggesting the importance of dynamic m6A topological transitions during mammalian tissue development.

Pinocembrin Decreases Atrial Fibrillation Susceptibility in a Rodent Model of Depression.

Background: Depression is often comorbid with cardiovascular diseases and contributes to the development and maintenance of atrial fibrillation (AF). Ample research demonstrated that pinocembrin had protective effects on the neuropsychiatric and cardiovascular systems via its pharmacological properties. However, whether pinocembrin protects from AF in depression models is not known. The present research investigated antiarrhythmic effects of pinocembrin and the underlying mechanisms in depressed rats. Methods: One hundred and ten male Sprague Dawley rats were randomly divided into six groups: the CTL group (the normal rats administered saline), the CTP group (the normal rats administered pinocembrin), the MDD group (the depressed rats administered saline), the MDP group (the depressed rats administered pinocembrin), the MDA group (the depressed rats administered apocynin), and the MPA group (the depressed rats administered both pinocembrin and apocynin). Chronic unpredictable mild stress (CUMS) was performed for 28 days to establish the depression model. Pinocembrin was administered via gavage from Day 8 to Day 28, and apocynin was administered via intraperitoneal injection from Day 1 to Day 28. The effects were evaluated using behavioral measurements, in vitro electrophysiological studies, whole-cell patch-clamp recordings, biochemical detection, Western blot, and histological studies. Results: Pinocembrin treatment significantly attenuated the abnormality of heart rate variability (HRV), the prolongation of action potential duration (APD), the shortening of the effective refractory period (ERP), the reduction of transient outward potassium current (Ito), and the increase in L-type calcium current (ICa-L), which increase susceptibility to AF in a rat model of depression. Compared to the depressed rats, pinocembrin also increased the content of Kv4.2, Kv4.3, and atrial gap junction channel Cx40 and decreased the expression level of Cav1.2, which ameliorated oxidative stress and inhibited the ROS/p-p38MAPK pro-apoptotic pathway and the ROS/TGF-ß1 pro-fibrotic pathway. Conclusion: Pinocembrin is a therapeutic strategy with great promise for the treatment of AF in depressed patients by reducing oxidative stress.

Study on mechanism of improving efficiency of permanent-magnet small ball-end magnetorheological polishing by increasing magnetorheological fluid temperature.

Permanent-magnet small ball-end magnetorheological polishing method can be used to polish the small part with complex structure. However, the material removal rate of this method is low, which is difficult to improve the output and reduce the cost. In this research, the effect of magnetorheological fluid temperature on the material removal rate is theoretically analyzed by measuring the effect of temperature on the flow properties of magnetorheological fluid, establishing the hydrodynamic model of polishing zone and solving the material removal parameters. It is found that with the increase of the magnetorheological fluid temperature, the polishing relative velocity increases accordingly, which can promote the improvement of material removal rate. But the shear stress decreases accordingly, which inhibits the improvement of material removal rate. The verification experiment results show that the promoting effect can exceeds the inhibitory effect, so that the material removal rate increases with the increase of magnetorheological fluid temperature. When the magnetorheological fluid temperature increases to 60 °C, the material removal rate is improved by 108.4% and the polished surface roughness Sa can reach 14.9 nm. Therefore, increasing the magnetorheological fluid temperature can significantly improve the efficiency of permanent-magnet small ball-end magnetorheological polishing and obtain high quality polished surface.

Bacterial diacetyl suppresses abiotic stress-induced senescence in Arabidopsis.

Premature plant senescence induced by abiotic stresses is a major cause of agricultural losses worldwide. Tools for suppressing stress-induced plant senescence are limited. Here, we report that diacetyl, a natural compound emitted by the plant-beneficial bacterium Bacillus amyloliquefaciens, suppresses abscisic acid -mediated foliar senescence in Arabidopsis thaliana under various abiotic stress conditions. Our results establish diacetyl as an effective protector against stress-induced plant senescence and reveal a molecular mechanism for bacteria-enhanced plant stress resistance.

Customer Relationship Management Based on SPRINT Classification Algorithm under Data Mining Technology.

Under the advance of computational intelligence, customer relationship management system based on data mining technology can not only bring more economic benefits to an enterprise but also improve the management and decision-making level of Chinese enterprises. In this paper, the application of data mining technology in customer relationship management (CRM) is analyzed, and four data mining modes are realized: customer classification, cross-marketing, customer acquisition, and customer retention. In the data mining module, SPRINT classification algorithm is used in customer classification. At the same time, FP-growth, an association rule algorithm without candidate set, is applied in cross-marketing, which enhances the practicability of the system. The algorithm of optimal customer retention strategy under digital intelligence technology is adopted in customer retention, which makes up for the shortcomings of traditional CRM system and helps enterprises to better operate and adjust marketing strategies.

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.

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.

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.