Targeting cAMP-pathway in Regeneration-Competent Cells of Nervous Tissue: Potential to Create a Novel Drug for Treatment of Ethanol-Induced Neurodegeneration

2021 ◽  
Vol 21 ◽  
Author(s):  
Gleb Nikolaevich Zyuz’kov ◽  
Larisa Arkad`evna ◽  
Tatyana Yur`evna Polykova ◽  
Elena Vladislavovna Simanina ◽  
Larisa Alexandrovna Stavrova
Keyword(s):  
Glial Cells ◽  
Intracellular Signaling ◽  
Nervous Tissue ◽  
Adenosine Monophosphate ◽  
Growth Potential ◽  
Microglial Cells ◽  
Camp Pathway ◽  
Competent Cells

Background: Existing neuroprotective drugs are not effective enough to treat alcoholic encephalopathy. This makes the development of novel pharmacological approaches to treating patients with ethanol-induced neurodegeneration(EIN) relevant. Therefore, the search for new targets among intracellular signaling molecules of regeneration-competent cells of nervous tissue is promising. Objective: This study aims to explore the involvement of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the realization of the functions of nervous tissue progenitors and glial cells in EIN. Methods: Experiments were conducted on mice of C57B1/6. EIN was modeled in vitro and in vivo. The effects of the adenylate cyclase (AC) and PKA inhibitors on the colony-forming capacity of neural stem cells (NSC) and neuronal-committed progenitors (NCP), their proliferative activity, and intensity of specialization were investigated. The secretion of neurotrophins by astrocytes, oligodendrocytes, and microglial cells was also evaluated. Individual fractions of cells were obtained using the immunomagnetic separation method. Results: The cAMP/PKA signaling is shown to stimulate the proliferation of the NSC and inhibit the mitotic activity of the NCP under the conditions of their optimal vital activity. cAMP reduces the specialization intensity of both types of progenitors. EIN leads to the inversion of the role of the cAMP/PKA-pathway in the regulation of NSC functions. cAMP-pathway has varying influences on the secretion of neurotrophic growth factors by glial cells depending on their living conditions. AC blockage stimulates the realization of the NSC and NCP growth potential and production of neurotrophins by astrocytes and microglial cells in EIN. Conclusion: These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.

scholarly journals Prospects for the Use of NF-кb Inhibitors to Stimulate the Functions of Regeneration-Competent Cells of Nerve Tissue and Neuroregeneration in Ethanol-Induced Neurodegeneration

2020 ◽  
Vol 11 (1) ◽  
pp. 8065-8074
Keyword(s):  
Intracellular Signaling ◽  
Alcohol Intoxication ◽  
Growth Potential ◽  
Nerve Tissue ◽  
Competent Cells ◽  
Pharmacological Targets ◽  
Intracellular Signaling Molecules

The implementation of the concept of drug therapy of neurological disorders in chronic alcohol intoxication is, in some cases, unsuccessful. Promising is the search for new pharmacological targets among the intracellular signaling molecules of regenerating-competent cells. In the conditions of in vitro and in vivo modeling of ethanol-induced neurodegeneration, the role of NF-кВ in the realization of the growth potential of neural progenitors and the secretion of neurotrophins by glial elements was studied. The absence of participation of NF-кВ in the regulation of mitotic activity of neural SC (NSC) and of neuronal-committed progenitors (NCP) in their optimal living conditions and in the influence of ethanol in vitro is shown. At the same time, NF-кВ hinders the implementation of the NSC specialization process. The prolonged introduction of ethanol per os mice was accompanied by the appearance of an inhibitory value in NF-кВ in relation to the intensity of progenitors proliferation. The blockade of NF-кВ of NSC and NCP animals with neurodegeneration caused the progression of their cell cycle. The participation of NF-кВ in the secretory function of astrocytes and oligodendrogliocytes has been established. The inactivation of the nuclear transcription factor led to a decrease in their production of neurotrophins, including in the case of ethanol. At the same time, there were no changes from the microglia functioning.

Intracellular signaling molecules of nerve tissue progenitors as pharmacological targets for treatment of ethanol-induced neurodegeneration

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Gleb Nikolaevich Zyuz’kov ◽  
Larisa Arkad`evna Miroshnichenko ◽  
Elena Vladislavovna Simanina ◽  
Larisa Alexandrovna Stavrova ◽  
Tatyana Yur`evna Polykova
Keyword(s):  
Stem Cells ◽  
Alcohol Abuse ◽  
Intracellular Signaling ◽  
Signaling Molecules ◽  
Growth Potential ◽  
Nerve Tissue ◽  
Intracellular Signaling Molecules

Abstract Objectives The development of approaches to the treatment of neurodegenerative diseases caused by alcohol abuse by targeted pharmacological regulation of intracellular signaling transduction of progenitor cells of nerve tissue is promising. We studied peculiarities of participation of NF-кB-, сАМР/РКА-, JAKs/STAT3-, ERK1/2-, p38-pathways in the regulation of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in the simulation of ethanol-induced neurodegeneration in vitro and in vivo. Methods In vitro, the role of signaling molecules (NF-кB, сАМР, РКА, JAKs, STAT3, ERK1/2, p38) in realizing the growth potential of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in ethanol-induced neurodegeneration modeled in vitro and in vivo was studied. To do this, the method of the pharmacological blockade with the use of selective inhibitors of individual signaling molecules was used. Results Several of fundamental differences in the role of certain intracellular signaling molecules (SM) in proliferation and specialization of NSC and NCP have been revealed. It has been shown that the effect of ethanol on progenitors is accompanied by the formation of a qualitatively new pattern of signaling pathways. Data have been obtained on the possibility of stimulation of nerve tissue regeneration in ethanol-induced neurodegeneration by NF-кB and STAT3 inhibitors. It has been found that the blockage of these SM stimulates NSC and NCP in conditions of ethanol intoxication and does not have a «negative» effect on the realization of the growth potential of intact progenitors (which will appear de novo during therapy). Conclusions The results may serve as a basis for the development of fundamentally new drugs to the treatment of alcoholic encephalopathy and other diseases of the central nervous system associated with alcohol abuse.

scholarly journals Loss of AMP-Activated Protein Kinase Induces Mitochondrial Dysfunction and Proinflammatory Response in Unstimulated Abcd1-Knockout Mice Mixed Glial Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jaspreet Singh ◽  
Hamid Suhail ◽  
Shailendra Giri
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Dysfunction ◽  
Glial Cells ◽  
Adenosine Monophosphate ◽  
Proinflammatory Response ◽  
Inflammatory Protein ◽  
Lower Oxygen ◽  
Amp Activated Protein Kinase

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations and/or deletions in the ABCD1 gene. Similar mutations/deletions can give rise to variable phenotypes ranging from mild adrenomyeloneuropathy (AMN) to inflammatory fatal cerebral adrenoleukodystrophy (ALD) via unknown mechanisms. We recently reported the loss of the anti-inflammatory protein adenosine monophosphate activated protein kinase (AMPKα1) exclusively in ALD patient-derived cells. X-ALD mouse model (Abcd1-knockout (KO) mice) mimics the human AMN phenotype and does not develop the cerebral inflammation characteristic of human ALD. In this study we document that AMPKα1 levelsin vivo(in brain cortex and spinal cord) andin vitroin Abcd1-KO mixed glial cells are similar to that of wild type mice. Deletion of AMPKα1 in the mixed glial cells of Abcd1-KO mice induced spontaneous mitochondrial dysfunction (lower oxygen consumption rate and ATP levels). Mitochondrial dysfunction in ALD patient-derived cells and in AMPKα1-deleted Abcd1-KO mice mixed glial cells was accompanied by lower levels of mitochondrial complex (1-V) subunits. More importantly, AMPKα1 deletion induced proinflammatory inducible nitric oxide synthase levels in the unstimulated Abcd1-KO mice mixed glial cells. Taken together, this study provides novel direct evidence for a causal role for AMPK loss in the development of mitochondrial dysfunction and proinflammatory response in X-ALD.

scholarly journals A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism

2019 ◽  
Vol 116 (8) ◽  
pp. 1500-1513
Author(s):  
Carly Jones ◽  
Malik Bisserier ◽  
Carlos Bueno-Beti ◽  
Guillaume Bonnet ◽  
Susana Neves-Zaph ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Adenosine Monophosphate ◽  
Cell Types ◽  
Pulmonary Vasculature ◽  
Intracellular Camp ◽  
Camp Pathway ◽  
Extracellular Camp

Abstract Aims Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodelling in the pathogenesis of pulmonary hypertension (PH). Methods and results The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodelling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo PH models prevented and reversed pulmonary and cardiac remodelling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway. Conclusions Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signalling pathway to limit pulmonary vascular remodelling and PH.

Nanocurcumin: A Double-Edged Sword for Microcancers

2020 ◽  
Vol 26 (45) ◽  
pp. 5783-5792
Author(s):  
Kholood Abid Janjua ◽  
Adeeb Shehzad ◽  
Raheem Shahzad ◽  
Salman Ul Islam ◽  
Mazhar Ul Islam
Keyword(s):  
Intracellular Signaling ◽  
Dosage Forms ◽  
The Body ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Anticancer Activities ◽  
Road Map ◽  
Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

scholarly journals The Role of Melatonin on NLRP3 Inflammasome Activation in Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1020
Author(s):  
Burak Ibrahim Arioz ◽  
Emre Tarakcioglu ◽  
Melis Olcum ◽  
Sermin Genc
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intracellular Signaling ◽  
Metabolic Diseases ◽  
Metabolic Stress ◽  
Clinical Importance ◽  
Rapid Identification ◽  
In Vivo Studies ◽  
Inflammasome Activation

NLRP3 inflammasome is a part of the innate immune system and responsible for the rapid identification and eradication of pathogenic microbes, metabolic stress products, reactive oxygen species, and other exogenous agents. NLRP3 inflammasome is overactivated in several neurodegenerative, cardiac, pulmonary, and metabolic diseases. Therefore, suppression of inflammasome activation is of utmost clinical importance. Melatonin is a ubiquitous hormone mainly produced in the pineal gland with circadian rhythm regulatory, antioxidant, and immunomodulatory functions. Melatonin is a natural product and safer than most chemicals to use for medicinal purposes. Many in vitro and in vivo studies have proved that melatonin alleviates NLRP3 inflammasome activity via various intracellular signaling pathways. In this review, the effect of melatonin on the NLRP3 inflammasome in the context of diseases will be discussed.

Neuroprotective Effects of the FGF21 Analogue LY2405319

2021 ◽  
pp. 1-13
Author(s):  
Claire Rühlmann ◽  
David Dannehl ◽  
Marcus Brodtrück ◽  
Andrew C. Adams ◽  
Jan Stenzel ◽  
...  
Keyword(s):  
Glial Cells ◽  
Neuroprotective Effect ◽  
Amyloid Β ◽  
Fibroblast Growth Factor 21 ◽  
Neuroprotective Effects ◽  
Organotypic Brain Slice ◽  
Brain Slice Cultures ◽  
Abca1 Mrna

Background: To date, there are no effective treatments for Alzheimer’s disease (AD). Thus, a significant need for research of therapies remains. Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.

scholarly journals Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

2016 ◽  
Vol 38 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Mingfeng He ◽  
Hongquan Dong ◽  
Yahui Huang ◽  
Shunmei Lu ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Microglial Activation ◽  
Culture Media ◽  
Microglial Cells ◽  
Migration Ability ◽  
Migration Assay ◽  
Tnf Α

Background/Aims: Microglia are an essential player in central nervous system inflammation. Recent studies have demonstrated that the astrocytic chemokine, CCL2, is associated with microglial activation in vivo. However, CCL2-induced microglial activation has not yet been studied in vitro. The purpose of the current study was to understand the role of astrocyte-derived CCL2 in microglial activation and to elucidate the underlying mechanism(s). Methods: Primary astrocytes were pre-treated with CCL2 siRNA and stimulated with TNF-α. The culture medium (CM) was collected and added to cultures of microglia, which were incubated with and without CCR2 inhibitor. Microglial cells were analyzed by quantitative RT-PCR to determine whether they polarized to the M1 or M2 state. Microglial migratory ability was assessed by transwell migration assay. Results: TNF-α stimulated the release of CCL2 from astrocytes, even if the culture media containing TNF-α was replaced with fresh media after 3 h. CM from TNF-α-stimulated astrocytes successfully induced microglial activation, which was ascertained by increased activation of M1 and enhanced migration ability. In contrast, CM from astrocytes pretreated with CCL2 siRNA showed no effect on microglial activation, compared to controls. Additionally, microglia pre-treated with RS102895, a CCR2 inhibitor, were resistant to activation by CM from TNF-α-stimulated astrocytes. Conclusion: This study demonstrates that the CCL2/CCR2 pathway of astrocyte-induced microglial activation is associated with M1 polarization and enhanced migration ability, indicating that this pathway could be a useful target to ameliorate inflammation in the central nervous system.

scholarly journals Cellular basis of urothelial squamous metaplasia

2005 ◽  
Vol 171 (5) ◽  
pp. 835-844 ◽  
Author(s):  
Feng-Xia Liang ◽  
Maarten C. Bosland ◽  
Hongying Huang ◽  
Rok Romih ◽  
Solange Baptiste ◽  
...  
Keyword(s):  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Squamous Metaplasia ◽  
Culture Conditions ◽  
Growth Potential ◽  
Basal Cells ◽  
Cellular Basis ◽  
Proximal Urethra

Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency. Moreover, these cells remain phenotypically distinct even after they have been serially passaged under identical culture conditions, thus ruling out local mesenchymal influence as the sole cause of their in vivo differences. During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium. These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

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