scholarly journals Encapsulating TGF-β1 Inhibitory Peptides P17 and P144 as a Promising Strategy to Facilitate Their Dissolution and to Improve Their Functionalization

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 421 ◽  
Author(s):  
Nemany A. N. Hanafy ◽  
Isabel Fabregat ◽  
Stefano Leporatti ◽  
Maged El Kemary
Keyword(s):  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Biological Efficiency ◽  
Therapeutic Applications ◽  
Smad Phosphorylation ◽  
Therapeutic Molecules ◽  
Hydrophobic Molecule ◽  
Health And Disease ◽  
Highly Hydrophobic

Transforming growth factor-beta (TGFβ1) is considered as a master regulator for many intracellular signaling pathways, including proliferation, differentiation and death, both in health and disease. It further represents an oncogenic factor in advanced tumors allowing cancer cells to be more invasive and prone to move into the metastatic process. This finding has received great attention for discovering new therapeutic molecules against the TGFβ1 pathway. Among many TGFβ1 inhibitors, peptides (P17 and P144) were designed to block the TGFβ1 pathway. However, their therapeutic applications have limited use, due to lack of selection for their targets and their possible recognition by the immune system and further due to their potential cytotoxicity on healthy cells. Besides that, P144 is a highly hydrophobic molecule with less dissolution even in organic solution. Here, we aimed to overcome the dissolution of P144, as well as design nano-delivery strategies to protect normal cells, to increase cellular penetration and to raise the targeted therapy of both P17 and P144. Peptides were encapsulated in moieties of polymer hybrid protein. Their assembly was investigated by TEM, microplate spectrum analysis and fluorescence microscopy. SMAD phosphorylation was analyzed by Western blot as a hallmark of their biological efficiency. The results showed that the encapsulation of P17 and P144 might improve their potential therapeutic applications.

scholarly journals Transforming growth factor-β1 and activin A generate antiproliferative signaling in thyroid cancer cells

2006 ◽  
Vol 190 (1) ◽  
pp. 141-150 ◽  
Author(s):  
Sílvia Emiko Matsuo ◽  
Suzana Garcia Leoni ◽  
Alison Colquhoun ◽  
Edna Teruko Kimura
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Carcinoma Cell ◽  
Transforming Growth Factor Β1 ◽  
Activin A ◽  
Antiproliferative Signaling ◽  
Tgf Β1

Transforming growth factor-beta 1 (TGF-β1) and activin A (ActA) induce similar intracellular signaling mediated by the mothers against decapentaplegic homolog (SMAD) proteins. TGF-β1 is a potent antimitogenic factor for thyroid follicular cells, while the role of ActA is not clear. In our study, the proliferation of TPC-1, the papillary thyroid carcinoma cell line, was reduced by both recombinant ActA and TGF-β1. Due to the concomitant expression of TGF-β1 and ActA in thyroid tumors, we investigated the effects of either TGF-β1 or ActA gene silencing by RNA interference in TPC-1 cells in order to distinguish the specific participation of each in proliferation and intracellular signaling. An increased proliferation and reduced SMAD2, SMAD3, and SMAD4 mRNA expression were observed in both TGF-β1 and ActA knockdown cells. Recombinant TGF-β1 and ActA increased the expression of inhibitory SMAD7, whereas they reduced c-MYC. Accordingly, we detected a reduction in SMAD7 expression in knockdown cells while, unexpectedly, c-MYC was reduced. Our data indicate that both TGF-β1 and ActA generate SMADs signaling with each regulating the expression of their target genes, SMAD7 and c-MYC. Furthermore, TGF-β1 and ActA have an antiproliferative effect on thyroid papillary carcinoma cell, exerting an important role in the control of thyroid tumorigenesis.

The Potential Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Epilepsy Pathogenesis

2020 ◽  
Vol 20 ◽  
Author(s):  
Ali N. Kamali ◽  
Zeineb Zian ◽  
José M. Bautista ◽  
Haleh Hamedifar ◽  
Nikoo Hossein-Khannazer ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Brain Disorder ◽  
Necrosis Factor Alpha ◽  
Proinflammatory Mediators ◽  
Inflammatory Protein ◽  
Cytokine Levels ◽  
Inflammatory Processes ◽  
Factor Alpha

Abstract:: Within the pathophysiology of epilepsy, as a chronic brain disorder, neuroinflammation has been extensively implied. Recurrent seizures of epilepsy have been associated with elevated levels of immune mediators that seem to play a pivotal role in triggering them. Neurons, glia, and endothelial cells of the blood-brain barrier (BBB) take part in such inflammatory processes by expressing receptors of associated mediators through autocrine and paracrine stimulation of intracellular signaling pathways. In this milieu, elevated cytokine levels in serum and brain tissue have been reported in patients with an epileptic profile. Noteworthy, interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) are the proinflammatory cytokines mostly associated, in literature, with the pathogenesis of epilepsies. In this review, we examine the function of these cytokines in connection with transforming growth factor-beta (TGF-β), IL-8, IL-12, IL-18, and macrophage inflammatory protein (MIP) as potential proinflammatory mediators in the neuropathology of epilepsy.

scholarly journals The TGF-β /NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2312
Author(s):  
Macarena Herranz-Itúrbide ◽  
Irene Peñuelas-Haro ◽  
Rut Espinosa-Sotelo ◽  
Esther Bertran ◽  
Isabel Fabregat
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cell Biology ◽  
Transforming Growth Factor ◽  
Relevant Factor ◽  
Nadph Oxidases ◽  
The Family ◽  
Nox Inhibitors ◽  
Health And Disease ◽  
Growth Factor Beta ◽  
Therapeutic Tools

The Transforming Growth Factor-beta (TGF-β) pathway plays essential roles in liver development and homeostasis and become a relevant factor involved in different liver pathologies, particularly fibrosis and cancer. The family of NADPH oxidases (NOXs) has emerged in recent years as targets of the TGF-β pathway mediating many of its effects on hepatocytes, stellate cells and macrophages. This review focuses on how the axis TGF-β/NOXs may regulate the biology of different liver cells and how this influences physiological situations, such as liver regeneration, and pathological circumstances, such as liver fibrosis and cancer. Finally, we discuss whether NOX inhibitors may be considered as potential therapeutic tools in liver diseases.

Dynamic Tensile Loading Activates TGF and BMP Signaling in Mesenchymal Stem Cells on Aligned Nanofibrous Scaffolds

2012 ◽  
Author(s):  
Su-Jin Heo ◽  
Tristan P. Driscoll ◽  
Robert L. Mauck
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Transforming Growth Factor Beta ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Nanofibrous Scaffolds ◽  
Smad Phosphorylation

Mesenchymal stem cells (MSCs) are a promising cell source for tissue engineering applications, given their ease of isolation and multi-potential differentiation capacity [1]. External mechanical cues directly influence MSC lineage commitment [2]. However, it is not yet clear how these physical cues are transduced to the cell nucleus, an understanding of which may prove essential for orthopaedic tissue engineering. Transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP), members of the TGF beta superfamily, regulate cellular processes including growth and differentiation [3, 4]. TGF and/or BMP ligand binding initiate SMAD phosphorylation, translocation to the nucleus, and transcriptional activation of target genes [4]. Additionally, both ligands can influence the organization of chromatin and the Lamin A/C (LMAC) nucleoskeletal network [5]. For example, we have recently shown that TGF-β3 leads to corticalized LMAC, marked increases in heterochromatin (HTC), and increased nuclear stiffness [6]. Interestingly, dynamic tensile stretch of MSCs on aligned nanofibrous scaffolds, in the absence of these differentiation factors, resulted in many of these same nuclear transformations [6, 7]. The objective of this study was to identify how dynamic tensile stress is transduced in MSCs on aligned nanofibrous scaffolds, and further, to ascertain whether these mechanoregulatory changes are coordinated through TGFβ/BMP signaling pathways.

scholarly journals Mechanistic Insight into Orthodontic Tooth Movement Based on Animal Studies: A Critical Review

2021 ◽  
Vol 10 (8) ◽  
pp. 1733
Author(s):  
Hyeran Helen Jeon ◽  
Hellen Teixeira ◽  
Andrew Tsai
Keyword(s):  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Tooth Movement ◽  
Wnt Signaling Pathway ◽  
Orthodontic Tooth Movement ◽  
Sterile Inflammation ◽  
Mechanistic Insight ◽  
Alveolar Bone Remodeling ◽  
Insight Into

Alveolar bone remodeling in orthodontic tooth movement (OTM) is a highly regulated process that coordinates bone resorption by osteoclasts and new bone formation by osteoblasts. Mechanisms involved in OTM include mechano-sensing, sterile inflammation-mediated osteoclastogenesis on the compression side and tensile force-induced osteogenesis on the tension side. Several intracellular signaling pathways and mechanosensors including the cilia and ion channels transduce mechanical force into biochemical signals that stimulate formation of osteoclasts or osteoblasts. To date, many studies were performed in vitro or using human gingival crevicular fluid samples. Thus, the use of transgenic animals is very helpful in examining a cause and effect relationship. Key cell types that participate in mediating the response to OTM include periodontal ligament fibroblasts, mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. Intercellular signals that stimulate cellular processes needed for orthodontic tooth movement include receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-α (TNF-α), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), sclerostin, transforming growth factor beta (TGF-β), and bone morphogenetic proteins (BMPs). In this review, we critically summarize the current OTM studies using transgenic animal models in order to provide mechanistic insight into the cellular events and the molecular regulation of OTM.

scholarly journals Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Jelena Krstic ◽  
Juan F. Santibanez
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinases ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tumor Stroma ◽  
System Response ◽  
Health And Disease ◽  
Growth Factor Beta ◽  
Tumor Growth And Metastasis

Transforming growth factor-beta (TGF-β) is a pleiotropic factor with several different roles in health and disease. In tumorigenesis, it may act as a protumorigenic factor and have a profound impact on the regulation of the immune system response. Matrix metalloproteinases (MMPs) are a family that comprises more than 25 members, which have recently been proposed as important regulators acting in tumor stroma by regulating the response of noncellular and cellular microenvironment. Tumor stroma consists of several types of resident cells and infiltrating cells derived from bone marrow, which together play crucial roles in the promotion of tumor growth and metastasis. In cancer cells, TGF-βregulates MMPs expression, while MMPs, produced by either cancer cells or residents’ stroma cells, activate latent TGF-βin the extracellular matrix, together facilitating the enhancement of tumor progression. In this review we will focus on the compartment of myeloid stroma cells, such as tumor-associated macrophages, neutrophils, and dendritic and mast cells, which are potently regulated by TGF-βand produce large amounts of MMPs. Their interplay and mutual implications in the generation of pro-tumorigenic cancer microenvironment will be analyzed.

scholarly journals Vitamin D Prevents Pancreatic Cancer-Induced Apoptosis Signaling of Inflammatory Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1055 ◽  
Author(s):  
Stefania Moz ◽  
Nicole Contran ◽  
Monica Facco ◽  
Valentina Trimarco ◽  
Mario Plebani ◽  
...  
Keyword(s):  
Vitamin D ◽  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Ductal Adenocarcinoma ◽  
Drug Candidate ◽  
Immune Effector ◽  
Induced Apoptosis

Combined approaches based on immunotherapy and drugs supporting immune effector cell function might increase treatment options for pancreatic ductal adenocarcinoma (PDAC), vitamin D being a suitable drug candidate. In this study, we evaluated whether treatment with the vitamin D analogue, calcipotriol, counterbalances PDAC induced and SMAD4-associated intracellular calcium [Ca2+]i alterations, cytokines release, immune effector function, and the intracellular signaling of peripheral blood mononuclear cells (PBMCs). Calcipotriol counteracted the [Ca2+]i depletion of PBMCs induced by SMAD4-expressing PDAC cells, which conditioned media augmented the number of calcium flows while reducing whole [Ca2+]i. While calcipotriol inhibited spontaneous and PDAC-induced tumor necrosis factor alpha (TNF-α) release by PBMC and reduced intracellular transforming growth factor beta (TGF-β), it did not counteract the lymphocytes proliferation induced in allogenic co-culture by PDAC-conditioned PBMCs. Calcipotriol mainly antagonized PDAC-induced apoptosis and partially restored PDAC-inhibited NF-κB signaling pathway. In conclusion, alterations induced by PDAC cells in the [Ca2+]i of immune cells can be partially reverted by calcipotriol treatment, which promotes inflammation and antagonizes PBMCs apoptosis. These effects, together with the dampening of intracellular TGF-β, might result in an overall anti-tumor effect, thus supporting the administration of vitamin D in PDAC patients.

scholarly journals Atypical TGF-β Signaling Controls Neuronal Guidance in Caenorhabditis elegans

2020 ◽  
Author(s):  
Oguzhan Baltaci ◽  
Mikael Egebjerg Pedersen ◽  
Tessa Sherry ◽  
Ava Handley ◽  
Goda Snieckute ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Caenorhabditis Elegans ◽  
Transforming Growth Factor Beta ◽  
Intracellular Signaling ◽  
Neuronal Development ◽  
Transforming Growth Factor ◽  
Type I ◽  
Coordinated Expression ◽  
Dauer Formation ◽  
Neuronal Guidance

AbstractCoordinated expression of cell adhesion and signaling molecules is crucial for brain development. Here, we report that the Caenorhabditis elegans transforming growth factor-beta (TGF-β) type I receptor SMA-6 (small-6) acts independently of its cognate TGF-β type II receptor DAF-4 (dauer formation-defective-4) to control neuronal guidance. SMA-6 directs neuronal development from the epidermis through interactions with three, orphan, TGF-β ligands. Intracellular signaling downstream of SMA-6 limits expression of NLR-1, an essential Neurexin-like cell adhesion receptor, to enable neuronal guidance. Together, our data identify an atypical TGF-β-mediated regulatory mechanism to ensure correct development of the nervous system.

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