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

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.

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

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180426121503 ◽

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.

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

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180723104340 ◽

2019 ◽

Vol 14 (3) ◽

pp. 219-225 ◽

Cited By ~ 6

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.

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Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22115722 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5722

Author(s):

Alessandro de Sire ◽

Nicola Marotta ◽

Cinzia Marinaro ◽

Claudio Curci ◽

Marco Invernizzi ◽

...

Keyword(s):

Signaling Pathways ◽

Synergistic Effects ◽

Molecular Pathways ◽

Epigenetic Changes ◽

Pathological Features ◽

Oxidative Signaling ◽

Cartilage Extracellular Matrix ◽

Wide Range ◽

Comprehensive Picture

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

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Molecular mechanisms of the juvenile form of Batten disease: important role of MAPK signaling pathways (ERK1/ERK2, JNK and p38) in pathogenesis of the malady

Biology Direct ◽

10.1186/s13062-018-0212-y ◽

2018 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Elena K. Shematorova ◽

Dmitry G. Shpakovski ◽

Anna D. Chernysheva ◽

George V. Shpakovski

Keyword(s):

Signaling Pathways ◽

Molecular Mechanisms ◽

Batten Disease ◽

Mapk Signaling ◽

Juvenile Form ◽

Mapk Signaling Pathways

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

Regulatory Mechanisms in Biosystems ◽

10.15421/022130 ◽

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.

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The Role of MicroRNAs in Hepatoblastoma Tumors

Cancers ◽

10.3390/cancers11030409 ◽

2019 ◽

Vol 11 (3) ◽

pp. 409 ◽

Cited By ~ 7

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.

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Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

Biochemical Journal ◽

10.1042/bj20110949 ◽

2011 ◽

Vol 439 (3) ◽

pp. 349-378 ◽

Cited By ~ 212

Author(s):

Anthony J. Morgan ◽

Frances M. Platt ◽

Emyr Lloyd-Evans ◽

Antony Galione

Keyword(s):

Molecular Mechanisms ◽

Cellular Processes ◽

Late Endosomes ◽

Wide Range ◽

Health And Disease ◽

Lysosome Related Organelles ◽

Cellular Compartments ◽

Endosomal Vesicles ◽

Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

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Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Glycobiology ◽

10.1093/glycob/cwaa110 ◽

2020 ◽

Author(s):

Kaitlyn A Dorsett ◽

Michael P Marciel ◽

Jihye Hwang ◽

Katherine E Ankenbauer ◽

Nikita Bhalerao ◽

...

Keyword(s):

Cancer Cells ◽

Translational Regulation ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Sialic Acids ◽

Invasion Resistance ◽

Cell Behaviors ◽

Molecular Events ◽

Wide Range

Abstract The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress, and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional, and post-translational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

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The Role of Sirtuins in Kidney Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21186686 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6686

Author(s):

Yu Ah Hong ◽

Ji Eun Kim ◽

Minjee Jo ◽

Gang-Jee Ko

Keyword(s):

Histone Deacetylases ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Kidney Diseases ◽

Expression Profiles ◽

Kidney Injury ◽

Class Iii ◽

Cellular Functions ◽

Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

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