scholarly journals The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through A1AR Positive Allosteric Modulation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1242 ◽  
Author(s):  
Fabrizio Vincenzi ◽  
Silvia Pasquini ◽  
Stefania Gessi ◽  
Stefania Merighi ◽  
Romeo Romagnoli ◽  
...  
Keyword(s):  
Pc12 Cells ◽  
Adenosine Receptor ◽  
Therapeutic Strategy ◽  
Cell Injury ◽  
Allosteric Modulation ◽  
The Novel ◽  
Positive Allosteric Modulator ◽  
Endogenous Adenosine ◽  
Mitochondrial Membrane Potential Loss

Glutamate cytotoxicity is implicated in neuronal death in different neurological disorders including stroke, traumatic brain injury, and neurodegenerative diseases. Adenosine is a nucleoside that plays an important role in modulating neuronal activity and its receptors have been identified as promising therapeutic targets for glutamate cytotoxicity. The purpose of this study is to elucidate the role of adenosine and its receptors on glutamate-induced injury in PC12 cells and to verify the protective effect of the novel A1 adenosine receptor positive allosteric modulator, TRR469. Flow cytometry experiments to detect apoptosis revealed that adenosine has a dual role in glutamate cytotoxicity, with A2A and A2B adenosine receptor (AR) activation exacerbating and A1 AR activation improving glutamate-induced cell injury. The overall effect of endogenous adenosine in PC12 cells resulted in a facilitating action on glutamate cytotoxicity, as demonstrated by the use of adenosine deaminase and selective antagonists. However, enhancing the action of endogenous adenosine on A1ARs by TRR469 completely abrogated glutamate-mediated cell death, caspase 3/7 activation, ROS production, and mitochondrial membrane potential loss. Our results indicate a novel potential therapeutic strategy against glutamate cytotoxicity based on the positive allosteric modulation of A1ARs.

scholarly journals Targeting circPTPN12/1 miR-21-5p/ΔNp63α pathway as a therapeutic strategy for human endometrial fibrosis

2021 ◽  
Author(s):  
Minmin Song ◽  
Guangfeng Zhao ◽  
Haixiang Sun ◽  
Simin Yao ◽  
Zhenhua Zhou ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rnas ◽  
The Novel ◽  
Mesenchymal Transition ◽  
Organ Fibrosis ◽  
Endometrial Epithelial Cells ◽  
Expression And Activity ◽  
Uterine Infertility

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5p to inhibit miR-21-5p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT. Our findings reveal the novel mechanism in the pathogenesis of endometrium fibrosis and the potential therapeutic strategy for endometrium fibrosis via targeting circPTPN12/miR-21-5p/∆Np63α pathway.

Hypoxia-induced vasodilation of the feline superior mesenteric artery is not adenosine mediated

1990 ◽  
Vol 259 (4) ◽  
pp. G605-G610 ◽  
Author(s):  
L. K. Lockhart ◽  
W. W. Lautt
Keyword(s):  
Superior Mesenteric Artery ◽  
Vascular Resistance ◽  
Hollow Fiber ◽  
Adenosine Receptor ◽  
Mesenteric Artery ◽  
Receptor Blockade ◽  
Pentobarbital Sodium ◽  
Endogenous Adenosine ◽  
Similar Decrease

The role of adenosine in hypoxia-induced vasodilation was examined in the intestine of pentobarbital sodium-anesthetized cats. A hollow-fiber fetal oxygenator was used to selectively reduce the PO2 of the blood supplying the superior mesenteric artery, thereby inducing hypoxia in the intestines. Decreasing the PO2 from 109 to 38 Torr caused vascular resistance to decrease from 10.2 to 7.5 Torr.kg.min.ml-1, a decrease of 2.7 Torr.kg.min.ml-1 or 24%. During selective adenosine receptor blockade with 8-phenyltheophylline, the same decrease in PO2 (from 109 to 40 Torr) produced a similar decrease in resistance from 5.7 to 3.4 Torr.kg.min.ml-1 or a difference of 2.3 Torr.kg.min.ml-1 (-36%). Thus adenosine is not the mediator of hypoxia-induced vasodilation in the feline intestine because blockade of the vasodilating effects of exogenous and presumably endogenous adenosine did not affect the observed decrease in resistance.

scholarly journals Role of MicroRNA in Governing Synaptic Plasticity

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Yuqin Ye ◽  
Hongyu Xu ◽  
Xinhong Su ◽  
Xiaosheng He
Keyword(s):  
Synaptic Plasticity ◽  
Neurological Disorders ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Synaptic Function ◽  
The Novel ◽  
Individual Mirnas ◽  
Underlying Mechanisms ◽  
And Function

Although synaptic plasticity in neural circuits is orchestrated by an ocean of genes, molecules, and proteins, the underlying mechanisms remain poorly understood. Recently, it is well acknowledged that miRNA exerts widespread regulation over the translation and degradation of target gene in nervous system. Increasing evidence suggests that quite a few specific miRNAs play important roles in various respects of synaptic plasticity including synaptogenesis, synaptic morphology alteration, and synaptic function modification. More importantly, the miRNA-mediated regulation of synaptic plasticity is not only responsible for synapse development and function but also involved in the pathophysiology of plasticity-related diseases. A review is made here on the function of miRNAs in governing synaptic plasticity, emphasizing the emerging regulatory role of individual miRNAs in synaptic morphological and functional plasticity, as well as their implications in neurological disorders. Understanding of the way in which miRNAs contribute to synaptic plasticity provides rational clues in establishing the novel therapeutic strategy for plasticity-related diseases.

Inhibition of the Heat Shock Transcription Factor 1 as a Potential New Therapeutic Strategy to Target Multiple Oncogenic Heat Shock Proteins in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2829-2829
Author(s):  
Tanja Heimberger ◽  
Mindaugas Andrulis ◽  
Stephanie Fischbach ◽  
Thorsten Stühmer ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Cell Lines ◽  
Therapeutic Strategy ◽  
The Novel ◽  
Pharmacological Inhibition ◽  
Shock Proteins ◽  
Transcription Factor 1

Abstract Abstract 2829 Poster Board II-805 Introduction: We could recently show that the heat shock proteins (HSP) HSP90 and HSP70 are frequently overexpressed in multiple myeloma (MM), stabilize as molecular chaperones various oncogenic proteins and contribute to survival of MM cells. Currently, several clinical Phase I/II studies are under way to evaluate the concept of pharmacological HSP90 blockade in human cancer. Under cellular stress conditions the heat shock transcription factor 1 (HSF1) has a key regulatory role for the up-regulation of HSP. Importantly, it has been observed that treatment with the proteasome inhibitor bortezomib, a clinically effective anti-MM agent, induces up-regulation of HSP90, HSP70 and HSP27. Furthermore, it has recently been demonstrated that HSF1 can protect cells from oncogene-driven malignant transformation. We therefore analyzed the role of HSF1 for the malignant growth of MM cells. Methods: Western analyses were performed to determine HSF1 expression and regulation in different human MM cell lines. To examine the expression of HSF1 and different HSP like HSP90, HSP70 and HSP27 in situ, samples from 60 bone marrow biopsies obtained from MM patients were immunohistochemically stained. To analyze the role of HSF1 for the survival of MM cells, HSF1 was either selectively depleted by siRNA-mediated knockdown using a pSUPER-based siRNA expression vector or targeted by treatment with a novel pharmacological HSF1 inhibitor triptolide. In addition, pharmacological inhibition of HSF1 was combined with concomitant pharmacological inhibition of either HSP90 (with the novel inhibitor NVP-AUY922) or bortezomib. Furthermore, gene expression analyses with an Affymetrix GeneChip were performed to identify HSF1 target genes in MM cells. Results: Here, we show that HSF1 is frequently overexpressed in MM cell lines in vitro and in the majority of the analyzed MM biopsies in situ, but not in MGUS or in normal plasma cells. Blockade of HSF1 either by siRNA-mediated knockdown or treatment with the novel pharamacological HSF1 inhibitor triptolide led to a strong induction of apoptosis in cells of the MM cell lines INA-6 and MM.1s. Importantly, also primary MM cells showed apoptosis induction after triptolide treatment. HSF1 inhibition led to downregulation of HSP70, HSP27 and HSP90. Gene expression analysis revealed a number of additional molecular targets of HSF1 involved in apoptosis regulation. Furthermore, initial experiments indicated that the apoptotic effect of pharmacological HSF1 inhibition is enhanced by the concomitant pharmacological inhibition of either HSP90 or the proteasome. Conclusion: We demonstrate that HSF1 is overexpressed in MM, contributes to the survival of MM cells and controls the activity of oncogenic HSP like HSP90, HSP70 and HSP27. Targeting HSF1 may therefore represent an attractive potential therapeutic strategy in MM, in particular in combination with HSP90 or proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

Correction: Structural modeling and role of HAX-1 as a positive allosteric modulator of human serine protease HtrA2

2020 ◽  
Vol 477 (2) ◽  
pp. 459-459
Author(s):  
Lalith K. Chaganti ◽  
Shubhankar Dutta ◽  
Raja Reddy Kuppili ◽  
Mriganka Mandal ◽  
Kakoli Bose
Keyword(s):  
Serine Protease ◽  
Structural Modeling ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator

ROLE OF THE NOVEL INTRODUCED PAN-INTESTINAL CAPSULE ENDOSCOPY SYSTEM IN CELIAC DISEASE

2019 ◽  
Author(s):  
F Foerster ◽  
K Mönkemüller ◽  
PR Galle ◽  
H Neumann
Keyword(s):  
Celiac Disease ◽  
Capsule Endoscopy ◽  
The Novel

Patterns: Rosamond Lehmann

2018 ◽  
Author(s):  
Vike Martina Plock
Keyword(s):  
Coming Of Age ◽  
Public Image ◽  
Market Forces ◽  
The Novel ◽  
Fashion Industry ◽  
To The Lighthouse ◽  
Fashion Magazines ◽  
Female Authorship ◽  
Rosamond Lehmann

This chapter analyzes the role of fashion as a discursive force in Rosamond Lehmann’s 1932 coming-of-age novel Invitation to the Waltz. Reading the novel alongside such fashion magazines as Vogue, it demonstrates Lehmann’s awareness that 1920s fashion, in spite of its carefully stylized public image as harbinger of originality, emphasized the importance of following preconceived (dress) patterns in the successful construction of modern feminine types. Invitation to the Waltz, it argues, opposes the production of patterned types and celebrates difference and disobedience in its stead. At the same time, the novel’s formal appearance is nonetheless dependent on the very same tenets it criticizes. On closer scrutiny, it is seen to reveal its resemblance to Virginia Woolf’s To the Lighthouse (1927). A tension between imitation and originality determines sartorial fashion choices. This chapter shows that female authorship in the inter-war period was subjected to the same market forces that controlled and sustained the organization of the fashion industry.

SARS-COV2 virus and Coronavirus disease (COVID-19)

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 977-982
Author(s):  
Mohamed J. Saadh ◽  
Bashar Haj Rashid M ◽  
Roa’a Matar ◽  
Sajeda Riyad Aldibs ◽  
Hala Sbaih ◽  
...  
Keyword(s):  
Close Contact ◽  
Antiviral Agents ◽  
Health Concern ◽  
The Novel ◽  
Global Public Health ◽  
Fatal Disease ◽  
Mild Disease ◽  
Life Threatening ◽  
Novel Coronavirus

SARS-COV2 virus causes Coronavirus disease (COVID-19) and represents the causative agent of a potentially fatal disease that is of great global public health concern. The novel coronavirus (2019) was discovered in 2019 in Wuhan, the market of the wet animal, China with viral pneumonia cases and is life-threatening. Today, WHO announces COVID-19 outbreak as a pandemic. COVID-19 is likely to be zoonotic. It is transmitted from bats as intermediary animals to human. Also, the virus is transmitted from human to human who is in close contact with others. The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is nearly supportive; the role of antiviral agents is yet to be established. The SARS-COV2 virus spreads faster than its two ancestors, the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. In this article, we aimed to summarize the transmission, symptoms, pathogenesis, diagnosis, treatment, and vaccine to control the spread of this fatal disease.

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