Catalpol alleviates myocardial ischemia reperfusion injury by activating the Nrf2/HO-1 signaling pathway.

PURPOSE: Myocardial ischemia/reperfusion injury (MI/RI) is a major problem in the clinical treatment of ischemic cardiomyopathy, and its specific underlying mechanisms are complicated and still unclear. A number of studies have indicated that the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxidase-1(HO-1) signaling pathway might serve as an important target for the management of MI/RI. Catalpol is a kind of iridoid glucoside that has been found to exhibit diverse anti-inflammatory and antioxidant properties. This study was aimed at investigating the role of Catalpol in targeting MI/RI and its related mechanisms in an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro and a preclinical ischemia/reperfusion (I/R) model. METHODS: This study using both in vitro and in vivo models investigated the possible role and underlying mechanisms used by Catalpol for modulating of MI/RI. The potential effects of Catalpol on the viability of cardiomyocytes were measured by cell counting kit-8 (CCK-8) assays. The phenotypes of myocardial injury, oxidative stress and inflammation markers were measured by western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) etc. Nrf2/HO-1 signaling pathway was detected by immunofluorescence and western blot analysis. RESULTS: We found that Catalpol significantly suppressed the process of MI/RI and protected OGD/R-treated cardiomyocytes by inhibiting the various markers of inflammation and suppressing oxidative stress. Additionally, mechanistically it was also demonstrated that Catalpol could effectively activate Nrf2/HO-1 signaling pathway to suppress the damage caused by inflammation and oxidative stress in MI/RI. CONCLUSION: In summary, the findings suggest that Catalpol exerted significant cardioprotective effects following myocardial ischemia, possibly through the activation of the Nrf2/HO-1 signaling pathway.

The Role of miR-23b in Cancer and Autoimmune Disease.

Short-stranded miRNAs are single-stranded RNA molecules involved in the regulation of gene expression. miRNAs are involved in a variety of cellular physiological processes, including cell proliferation, differentiation, and apoptosis. miR-23b have been identified to act both as oncogenes and as tumor suppressors. In addition, miR-23b is related to inflammation resistance to various autoimmune diseases and restrained inflammatory cell migration. The characterization of the specific alterations in the patterns of miR-23b expression in cancer and autoimmune disease has great potential for identifying biomarkers for early disease diagnosis, as well as for potential therapeutic intervention in various diseases. In this review, we summarize the ever-expanding role of miR-23b and its target genes in different models and offer insight into how this multifunctional miRNA modulates tumor cell proliferation and apoptosis or inflammatory cell activation, differentiation, and migration.

Diagnostic value of pulse oximetry combined with cardiac auscultation in screening congenital heart disease in neonates.

OBJECTIVE: This study aimed to investigate the feasibility and reliability of pulse oximetry combined with cardiac auscultation in screening neonatal congenital heart disease (CHD). METHODS: This was a retrospective, observational, screening study. All newborns included in the study were at the Second Affiliated Hospital of Wenzhou Medical University from July 2019 to January 2020. Primary screening of CHD was conducted by pulse oximetry combined with cardiac auscultation assays. Indices, including sensitivity, specificity, the positive/negative predictive value, the positive/negative likelihood ratio, and the diagnostic odds ratio, were calculated. The area under the relative operating characteristic curve of the subjects was measured. RESULTS: A total of 3327 neonates were enrolled, among whom 139 were diagnosed with CHD and the incidence of CHD was 4.2%. The sensitivity, specificity, diagnostic odds ratio, and area under the relative operating characteristic curve of pulse oximetry combined with cardiac auscultation were 89.9%, 94.7%, 169.0, and 0.923, respectively. CONCLUSIONS: Pulse oximetry combined with cardiac auscultation is a novel screening method with acceptable accuracy and feasibility for neonatal CHD. This combination method is worth promoting widely.

Targeting TFE3 Protects Against Lysosomal Malfunction-Induced Pyroptosis in Random Skin Flaps via ROS Elimination.

Increasing evidence indicates that pyroptosis, a new type of programmed cell death, may participate in random flap necrosis and play an important role. ROS-induced lysosome malfunction is an important inducement of pyroptosis. Transcription factor E3 (TFE3) exerts a decisive effect in oxidative metabolism and lysosomal homeostasis. We explored the effect of pyroptosis in random flap necrosis and discussed the effect of TFE3 in modulating pyroptosis. Histological analysis via hematoxylin-eosin staining, immunohistochemistry, general evaluation of flaps, evaluation of tissue edema, and laser Doppler blood flow were employed to determine the survival of the skin flaps. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays were used to calculate the expressions of pyroptosis, oxidative stress, lysosome function, and the AMPK-MCOLN1 signaling pathway. In cell experiments, HUVEC cells were utilized to ensure the relationship between TFE3, reactive oxygen species (ROS)-induced lysosome malfunction and cell pyroptosis. Our results indicate that pyroptosis exists in the random skin flap model and oxygen and glucose deprivation/reperfusion cell model. In addition, NLRP3-mediated pyroptosis leads to necrosis of the flaps. Moreover, we also found that ischemic flaps can augment the accumulation of ROS, thereby inducing lysosomal malfunction and finally initiating pyroptosis. Meanwhile, we observed that TFE3 levels are interrelated with ROS levels, and overexpression and low expression of TFE3 levels can, respectively, inhibit and promote ROS-induced lysosomal dysfunction and pyroptosis during in vivo and in vitro experiments. In conclusion, we found the activation of TFE3 in random flaps is partially regulated by the AMPK-MCOLN1 signal pathway. Taken together, TFE3 is a key regulator of ROS-induced pyroptosis in random skin flaps, and TFE3 may be a promising therapeutic target for improving random flap survival.

Microarray analysis reveals a potential role of lncRNA expression in remote ischemic preconditioning in myocardial ischemia-reperfusion injury.

The challenge to avoid or reduce cardiopulmonary bypass-related injuries in cardiovascular surgery remains a major issue. Remote ischemic preconditioning (RIPC) remains a promising strategy whose clinical applications appear to be significantly more realistic and extensive as compared with other conservative or surgical strategies. However, considering its underlying mechanism(s) are still unclear, novel ideas and methods must be explored to enhance its potential in clinical applications. Long noncoding RNAs (LncRNAs) are a kind of RNAs that have been implicated in the occurrence and development of cardiovascular diseases. The differently expressed LncRNAs and their biological effects during RIPC have not been explored previously. In this study, mouse and human LncRNA microarrays were used to investigate the expression signatures of LncRNAs and mRNAs in the myocardial tissue after RIPC. Therafter, homology comparisons were used to screen homologous genes from differentially expressed LncRNAs. Competing endogenous RNA (ceRNA) mechanism analysis were employed to find the matching relationship among homologous LncRNA, mRNA and microRNA. 554 differentially expressed mouse LncRNAs (281 up-regulated/273 down-regulated) and 1392 differentially expresssed human LncRNAs (635 up-regulated/757 down-regulated) were selected for further analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to quantify these LncRNAs, homology comparison and ceRNA mechanism analysis provided a pair of homologous LncRNAs (ENST00000574727 & ENSMUST00000123752) for further research investigation. Overall, in this study, a number of differentially expressed LncRNAs were identified which may play an important role the regulation of both inflammation and cell proliferation. The findings may thus unveil the mystery of RIPC and discover a novel protective mechanism for the mitigation of cardiovascular ischemia-reperfusion disease.

Apelin/APJ-Manipulated CaMKK/AMPK/GSK3ß Signaling Works as an Endogenous Counterinjury Mechanism in Promoting the Vitality of Random-Pattern Skin Flaps.

A random-pattern skin flap plays an important role in the field of wound repair; the mechanisms that influence the survival of random-pattern skin flaps have been extensively studied but little attention has been paid to endogenous counterinjury substances and mechanism. Previous reports reveal that the apelin-APJ axis is an endogenous counterinjury mechanism that has considerable function in protecting against infection, inflammation, oxidative stress, necrosis, and apoptosis in various organs. As an in vivo study, our study proved that the apelin/APJ axis protected the skin flap by alleviating vascular oxidative stress and the apelin/APJ axis works as an antioxidant stress factor dependent on CaMKK/AMPK/GSK3ß signaling. In addition, the apelin/APJ-manipulated CaMKK/AMPK/GSK3ß-dependent mechanism improves HUVECs' resistance to oxygen and glucose deprivation/reperfusion (OGD/R), reduces ROS production and accumulation, maintained the normal mitochondrial membrane potential, and suppresses oxidative stress in vitro. Besides, activation of the apelin/APJ axis promotes vascular migration and angiogenesis under relative hypoxia condition through CaMKK/AMPK/GSK3ß signaling. In a word, we provide new evidence that the apelin/APJ axis is an effective antioxidant and can significantly improve the vitality of random flaps, so it has potential be a promising clinical treatment.

Pomegranate peel extract ameliorates the severity of experimental autoimmune encephalomyelitis via modulation of gut microbiota.

Multiple sclerosis (MS) is a CNS autoimmune disease characterized by demyelination and inflammatory infiltration with a high disability rate. Increasing evidence has demonstrated the importance of gut microbiota as an environmental risk factor in MS and its animal model experimental autoimmune encephalomyelitis (EAE). Diet is the main determinant of gut microbiota composition and function, which greatly affects the shaping of microbial structure. Pomegranate peel, a waste product in the production of juice, is rich in health-promoting compounds. However, its individual constituents, immunoregulatory activities, and action associated with bacterial diversity in the gut microbiota are largely unknown. Here, the main nutrient ingredients of pomegranate peel extract (PPE) were identified as phenols, flavonoids, amino acids, carbohydrates, fatty acids, lipids, nucleotides, organic acids, alcohols, and vitamins via metabolomics evaluation. We found, for the first time, oral PPE (100 mg/kg/day) not only effectively relieves EAE, inhibits CNS inflammatory factor infiltration and myelin loss, but also reshapes gut microbiota. Furthermore, recipient EAE mice with fecal transplantation from the PPE-treated donor delayed the disease development significantly. 16S rRNA gene sequencing revealed the increased gut microbiota richness in PPE-treated group. Among them, Lactobacillaceae enriched significantly, while Alcaligenaceae and Acidaminococcacea decreased remarkably. In conclusion, our data demonstrated that gut microbiota mediated the beneficial effects of oral PPE on EAE, and provided new ideas for developing the prebiotic value of pomegranate peel for the treatment of autoimmune diseases.