RNase P Ribozymes Inhibit the Replication of Human Cytomegalovirus by Targeting Essential Viral Capsid Proteins.

An engineered RNase P-based ribozyme variant, which was generated using the in vitro selection procedure, was used to target the overlapping mRNA region of two proteins essential for human cytomegalovirus (HCMV) replication: capsid assembly protein (AP) and protease (PR). In vitro studies showed that the generated variant, V718-A, cleaved the target AP mRNA sequence efficiently and its activity was about 60-fold higher than that of wild type ribozyme M1-A. Furthermore, we observed a reduction of 98%-99% in AP/PR expression and an inhibition of 50,000 fold in viral growth in cells with V718-A, while a 75% reduction in AP/PR expression and a 500-fold inhibition in viral growth was found in cells with M1-A. Examination of the antiviral effects of the generated ribozyme on the HCMV replication cycle suggested that viral DNA encapsidation was inhibited and as a consequence, viral capsid assembly was blocked when the expression of AP and PR was inhibited by the ribozyme. Thus, our study indicates that the generated ribozyme variant is highly effective in inhibiting HCMV gene expression and blocking viral replication, and suggests that engineered RNase P ribozyme can be potentially developed as a promising gene-targeting agent for anti-HCMV therapy

Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling

Diabetic cardiomyopathy (DCM) leads to heart failure and death in diabetic patients, no effective treatment is available. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and our previous studies have showed cardioprotective and neuroprotective effects of NGR1. However, its role in protecting against DCM remains unexplored. Herein, we examine potential effects of NGR1 on cardiac function of diabetic db/db mice and H9c2 cardiomyocytes treated by advanced glycation end products (AGEs). In vitro experiments revealed that pretreatment with NGR1 significantly decreased AGEs-induced mitochondria injury, limited an increase in ROS, and reduced apoptosis in H9c2 cells. NGR1 eliminated ROS by promoting estrogen receptor α expression, which subsequently activated Akt and Nrf2-mediated anti-oxidant enzymes. In vivo investigation demonstrated that NGR1 significantly reduced serum lipid levels, insulin resistance, the expression of enzymes related to cardiomyopathy, and the expression of apoptotic proteins. Finally, NGR1 improved cardiac dysfunction and attenuated histological abnormalities, as evidenced by elevating ejection fraction and fractional shortening, and reducing cardiac fibrosis. Mechanistically, NGR1 promoted ERα expression, which led to the activation of Akt-Nrf2 signaling and the inhibition of the TGFβ pathway. Collectively, these results strongly indicate that NGR1 exerts cardioprotective effects against DCM through its inhibition of oxidative stress and apoptosis, and eventually suppresses cardiac fibrosis and hypertrophy, which suggests that NGR1 is a potential therapeutic medicine for the treatment of DCM

Uniqueness of self-similar very singular solution for non-Newtonian polytropic filtration equations with gradient absorption

Uniqueness of self-similar very singular solutions with compact support are proved for the non-Newtonian polytropic filtration equation with gradient absorption $$\frac{\partial u}{\partial t} =\hbox{div}(|\nabla u^m|^{p-2}\nabla u^m) -|\nabla u|^{q},\quad x\in \mathbb{R}^N,\quad t>0,$$ where $m>0$, $p>1$, $m(p-1)>1$ and $q>1$

Protective effect of Guanxin Danshen formula on myocardial ischemiareperfusion injury in rats

ABSTRACT Purpose: Myocardial ischemia/reperfusion injury (MIRI) leads to myocardial tissue necrosis, which will increase the size of myocardial infarction. The study examined the protective effect and mechanism of the Guanxin Danshen formula (GXDSF) on MIRI in rats. Methods: MIRI model was performed in rats; rat H9C2 cardiomyocytes were hypoxia-reoxygenated to establish a cell injury model. Results: The GXDSF significantly reduced myocardial ischemia area, reduced myocardial structural injury, decreased the levels of interleukin (IL-1β, IL-6) in serum, decreased the activity of myocardial enzymes, increased the activity of superoxide dismutase (SOD), and reduced glutathione in rats with MIRI. The GXDSF can reduce the expression of nucleotide- binding oligomerization domain, leucine-rich repeat and pyrin domain containing nod-like receptor family protein 3 (NLRP3), IL-1β, caspase-1, and gasdermin D (GSDMD) in myocardial tissue cells. Salvianolic acid B and notoginsenoside R1 protected H9C2 cardiomyocytes from hypoxia and reoxygenation injury and reduced the levels of tumor necrosis factor α (TNF-α) and IL-6 in the cell supernatant, decreasing the NLRP3, IL-18, IL-1β, caspase-1, and GSDMD expression in H9C2 cardiomyocytes. GXDSF can reduce the myocardial infarction area and alleviate the damage to myocardial structure in rats with MIRI, which may be related to the regulation of the NLRP3. Conclusions: GXDSF reduces MIRI in rat myocardial infarction injury, improves structural damage in myocardial ischemia injury, and reduces myocardial tissue inflammation and oxidative stress by lowering inflammatory factors and controlling focal cell death signaling pathways

TNS1: Emerging Insights into Its Domain Function, Biological Roles, and Tumors

Tensins are a family of cellular-adhesion constituents that have been extensively studied. They have instrumental roles in the pathogenesis of numerous diseases. The mammalian tensin family comprises four members: tensin1 (TNS1), tensin2, tensin3, and tensin4. Among them, TNS1 has recently received attention from researchers because of its structural properties. TNS1 engages in various biological processes, such as cell adhesion, polarization, migration, invasion, proliferation, apoptosis, and mechano-transduction, by interacting with various partner proteins. Moreover, the abnormal expression of TNS1 in vivo is associated with the development of various diseases, especially tumors. Interestingly, the role of TNS1 in different tumors is still controversial. Here, we systematically summarize three aspects of TNS1: the gene structure, the biological processes underlying its action, and the dual regulatory role of TNS1 in different tumors through different mechanisms, of which we provide the first overview

Hydroxysafflor Yellow A Ameliorates Myocardial Ischemia/Reperfusion Injury by Suppressing Calcium Overload and Apoptosis

Myocardial ischemia/reperfusion injury (MI/RI) is an urgent problem with a great impact on health globally. However, its pathological mechanisms have not been fully elucidated. Hydroxysafflor yellow A (HSYA) has a protective effect against MI/RI. This study is aimed at further clarifying the relationship between HSYA cardioprotection and calcium overload as well as the underlying mechanisms. We verified the protective effect of HSYA on neonatal rat primary cardiomyocytes (NPCMs) and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from hypoxia-reoxygenation (HR) injury. To explore the cardioprotective mechanism of HSYA, we employed calcium fluorescence, TUNEL assay, JC-1 staining, and western blotting. Finally, cardio-ECR and patch-clamp experiments were used to explain the regulation of L-type calcium channels (LTCC) in cardioprotection mediated by HSYA. The results showed that HSYA reduced the levels of myocardial enzymes and protected NPCMs from HR injury. HSYA also restored the contractile function of hiPSC-CMs and field potential signal abnormalities caused by HR and exerted a protective effect on cardiac function. Further, we demonstrated that HSYA protects cardiomyocytes from HR injury by decreasing mitochondrial membrane potential and inhibiting apoptosis and calcium overload. Patch-clamp results revealed that MI/RI caused a sharp increase in calcium currents, which was inhibited by pretreatment with HSYA. Furthermore, we found that HSYA restored contraction amplitude, beat rate, and field potential duration of hiPSC-CMs, which were disrupted by the LTCC agonist Bay-K8644. Patch-clamp experiments also showed that HSYA inhibits Bay-K8644-induced calcium current, with an effect similar to that of the LTCC inhibitor nisoldipine. Therefore, our data suggest that HSYA targets LTCC to inhibit calcium overload and apoptosis of cardiomyocytes, thereby exerting a cardioprotective effect and reducing MI/RI injury

Role of Adiponectin in Cardiovascular Diseases Related to Glucose and Lipid Metabolism Disorders

Lifestyle changes have led to increased incidence of cardiovascular disease (CVD); therefore, potential targets against CVD should be explored to mitigate its risks. Adiponectin (APN), an adipokine secreted by adipose tissue, has numerous beneficial effects against CVD related to glucose and lipid metabolism disorders, including regulation of glucose and lipid metabolism, increasing insulin sensitivity, reduction of oxidative stress and inflammation, protection of myocardial cells, and improvement in endothelial cell function. These effects demonstrate the anti-atherosclerotic and antihypertensive properties of APN, which could aid in improving myocardial hypertrophy, and reducing myocardial ischemia/reperfusion (MI/R) injury and myocardial infarction. APN can also be used for diagnosing and predicting heart failure. This review summarizes and discusses the role of APN in the treatment of CVD related to glucose and lipid metabolism disorders, and explores future APN research directions and clinical application prospects. Future studies should elucidate the signaling pathway network of APN cardiovascular protective effects, which will facilitate clinical trials targeting APN for CVD treatment in a clinical setting

Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

Hyperglycemia, as well as diabetes mellitus, has been shown to trigger cardiac cell apoptosis. We have previously demonstrated that myricitrin prevents endothelial cell apoptosis. However, whether myricitrin can attenuate H9c2 cell apoptosis remains unknown. In this study, we established an experiment model in H9c2 cells exposed to high glucose. We tested the hypothesis that myricitrin may inhibit high glucose (HG)-induced cardiac cell apoptosis as determined by TUNEL staining. Furthermore, myricitrin promoted antioxidative enzyme production, suppressed high glucose-induced reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) in H9c2 cells. This agent significantly inhibited apoptotic protein expression, activated Akt and facilitated the transcription of NF-E2-related factor 2 (Nrf2)-mediated protein (heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1) expression as determined by Western blotting. Significantly, an Akt inhibitor (LY294002) or HO-1 inhibitor (ZnPP) not only inhibited myricitrin-induced HO-1/NQO-1 upregulation but also alleviated its anti-apoptotic effects. In summary, these observations demonstrate that myricitrin activates Nrf2-mediated anti-oxidant signaling and attenuates H9c2 cell apoptosis induced by high glucose via activation of Akt signaling

The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress

Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca2+ overload induced by ATO in vivo and vitro. Moreover, Sal A increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity and expression, alleviated [Ca2+]ER depletion, and decreased ER stress-related protein expression. Sal A protects the heart from ATO-induced injury and its administration correlates with the modulation of SERCA, the recovery of Ca2+ homeostasis, and the down-regulation of ER stress-mediated apoptosis