scholarly journals Sex-Dependent Signaling Pathways Underlying Seizure Susceptibility and the Role of Chloride Cotransporters

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 448 ◽  
Author(s):  
Pavel A. Kipnis ◽  
Brennan J. Sullivan ◽  
Shilpa D. Kadam
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Electrical Response ◽  
Developmental Expression ◽  
Seizure Susceptibility ◽  
Early Postnatal Development ◽  
Inhibitory Neurotransmitter ◽  
Neuroscience Research ◽  
Cation Chloride Cotransporters

Seizure incidence, severity, and antiseizure medication (ASM) efficacy varies between males and females. Differences in sex-dependent signaling pathways that determine network excitability may be responsible. The identification and validation of sex-dependent molecular mechanisms that influence seizure susceptibility is an emerging focus of neuroscience research. The electroneutral cation-chloride cotransporters (CCCs) of the SLC12A gene family utilize Na+-K+-ATPase generated electrochemical gradients to transport chloride into or out of neurons. CCCs regulate neuronal chloride gradients, cell volume, and have a strong influence over the electrical response to the inhibitory neurotransmitter GABA. Acquired or genetic causes of CCCs dysfunction have been linked to seizures during early postnatal development, epileptogenesis, and refractoriness to ASMs. A growing number of studies suggest that the developmental expression of CCCs, such as KCC2, is sex-dependent. This review will summarize the reports of sexual dimorphism in epileptology while focusing on the role of chloride cotransporters and their associated modulators that can influence seizure susceptibility.

The Signaling Pathways in Nitric Oxide Production by Neutrophils Exposed to N-nitrosodimethylamine

2018 ◽  
Vol 16 (2) ◽  
pp. 194-199
Author(s):  
Wioletta Ratajczak-Wrona ◽  
Ewa Jablonska
Keyword(s):  
Nitric Oxide ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Polymorphonuclear Neutrophils ◽  
Microbial Pathogens ◽  
Human Neutrophils ◽  
No Production ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Background: Polymorphonuclear neutrophils (PMNs) play a crucial role in the innate immune system’s response to microbial pathogens through the release of reactive nitrogen species, including Nitric Oxide (NO). </P><P> Methods: In neutrophils, NO is produced by the inducible Nitric Oxide Synthase (iNOS), which is regulated by various signaling pathways and transcription factors. N-nitrosodimethylamine (NDMA), a potential human carcinogen, affects immune cells. NDMA plays a major part in the growing incidence of cancers. Thanks to the increasing knowledge on the toxicological role of NDMA, the environmental factors that condition the exposure to this compound, especially its precursors- nitrates arouse wide concern. Results: In this article, we present a detailed summary of the molecular mechanisms of NDMA’s effect on the iNOS-dependent NO production in human neutrophils. Conclusion: This research contributes to a more complete understanding of the mechanisms that explain the changes that occur during nonspecific cellular responses to NDMA toxicity.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms

2021 ◽  
Vol 12 (2) ◽  
pp. 212-227
Author(s):  
V. V. Povoroznyuk ◽  
N. V. Dedukh ◽  
M. A. Bystrytska ◽  
V. S. Shapovalov
Keyword(s):  
Growth Factors ◽  
Bone Resorption ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Molecular Mechanisms ◽  
Signaling Molecules ◽  
Physiological Conditions ◽  
Bone Cell Differentiation ◽  
Repressive Effect

This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.

scholarly journals STAT3, a Hub Protein of Cellular Signaling Pathways, Is Triggered by β-Hexaclorocyclohexane

2018 ◽  
Vol 19 (7) ◽  
pp. 2108 ◽  
Author(s):  
Elisabetta Rubini ◽  
Fabio Altieri ◽  
Silvia Chichiarelli ◽  
Flavia Giamogante ◽  
Stefania Carissimi ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cellular Signaling ◽  
Environmental Pollutants ◽  
Altered Expression ◽  
Exposed Population ◽  
Wide Range ◽  
Hepg2 Cell Lines

Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study carried out on exposed population in the “Valle del Sacco” found correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination. Taking into account the pleiotropic role of the protein signal transducer and activator of transcription 3 (STAT3), its function as a hub protein in cellular signaling pathways triggered by β-HCH was investigated in different cell lines corresponding to tissues that are especially vulnerable to damage by environmental pollutants. Materials and Methods: Human prostate cancer (LNCaP), human breast cancer (MCF-7 and MDA-MB 468), and human hepatoma (HepG2) cell lines were treated with 10 μM β-HCH in the presence or absence of specific inhibitors for different receptors. All samples were subjected to analysis by immunoblotting and RT-qPCR. Results and Conclusions: The preliminary results allow us to hypothesize the involvement of STAT3, through both its canonical and non-canonical pathways, in response to β-HCH. Moreover, we ascertained the role of STAT3 as a master regulator of energy metabolism via the altered expression and localization of HIF-1α and PKM2, respectively, resulting in a Warburg-like effect.

scholarly journals The Role of MicroRNAs in Hepatoblastoma Tumors

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 409 ◽  
Author(s):  
Ion Cristóbal ◽  
Marta Sanz-Álvarez ◽  
Melani Luque ◽  
Cristina Caramés ◽  
Federico Rojo ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Therapeutic Strategies ◽  
Substantial Contribution ◽  
Hepatic Malignancy ◽  
Recent Advances

Hepatoblastoma is the most common hepatic malignancy during childhood. However, little is still known about the molecular mechanisms that govern the development of this disease. This review is focused on the recent advances regarding the study of microRNAs in hepatoblastoma and their substantial contribution to improv our knowledge of the pathogenesis of this disease. We show here that miRNAs represent valuable tools to identify signaling pathways involved in hepatoblastoma progression as well as useful biomarkers and novel molecular targets to develop alternative therapeutic strategies in this disease.

scholarly journals Androgen action in cell fate and communication during prostate development at single-cell resolution

Development ◽  
2020 ◽  
pp. dev.196048
Author(s):  
Dong-Hoon Lee ◽  
Adam W. Olson ◽  
Jinhui Wang ◽  
Won Kyung Kim ◽  
Jiaqi Mi ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Bud Formation ◽  
Master Regulators ◽  
Prostate Development ◽  
Dynamic Cell ◽  
Cell Signaling Networks

Androgens/androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, and regeneration. Specifically, stromal AR-signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were characterized in regulating prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation mesenchymal rather than epithelial cells dysregulates the expression of the master regulators and significantly impairs prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling as cellular niches controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.

scholarly journals Effect of nerve growth factor on the proliferation in newborn bovine testicular Sertoli cells

Reproduction ◽  
2020 ◽  
Vol 160 (3) ◽  
pp. 405-415
Author(s):  
Qiaoge Niu ◽  
Maosheng Cao ◽  
Chenfeng Yuan ◽  
Yuwen Huang ◽  
Zijiao Zhao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Male Reproduction ◽  
Nerve Growth ◽  
And Function

Nerve growth factor (NGF) has been proved to play important roles in male reproductive physiology, but the molecular mechanisms of NGF action remain unclear. In this study, the effects of NGF on the growth of newborn bovine testicular Sertoli (NBS) cells and the related signaling pathways were investigated. The NBS cells were treated in vitro with NGF (100 ng/mL) for 18 h. The expression levels of cell proliferation related genes, INHBB, and cytoplasmic specialization related gene were determined using real-time PCR and Western blot. The roles of PI3K/AKT and MAPK/ERK pathways in NGF-induced cell proliferation were investigated. It was found that NGF regulates proliferation and function of NBS cells via its receptor NTRK1 by activating the PI3K/ATK and MAPK/ERK signaling pathways. The study will help to further understand the role of NGF in male reproduction and provide new therapeutic targets for reproductive dysfunctions in male animals.

scholarly journals Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

2020 ◽  
Author(s):  
Stefano Ratti ◽  
Isabella Rusciano ◽  
Sara Mongiorgi ◽  
Eric Owusu Obeng ◽  
Alessandra Cappellini ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Neurodegenerative Disorder ◽  
Nuclear Lamina ◽  
Cellular Models ◽  
Lamin B1 ◽  
Nuclear Alterations ◽  
First Time

Abstract Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.

scholarly journals The Role of Small Molecules and Their Effect on the Molecular Mechanisms of Early Retinal Organoid Development

2021 ◽  
Vol 22 (13) ◽  
pp. 7081
Author(s):  
Philip E. Wagstaff ◽  
Andrea Heredero Berzal ◽  
Camiel J. F. Boon ◽  
Peter M. J. Quinn ◽  
Anneloor L. M. A. ten Asbroek ◽  
...  
Keyword(s):  
Small Molecules ◽  
Signaling Pathways ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Retinal Development ◽  
Comprehensive Overview ◽  
Or Efficiency

Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.

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