Genomic Profiles of Damage and Protection in Human Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) produces a high rate of death and disability. The molecular mechanisms of damage in perihematomal tissue in humans have not been systematically characterized. This study determines the gene expression profile and molecular networks that are induced in human perihematomal tissue through molecular analysis of tissue obtained from endoscopic clot evacuation. Differentially expressed genes and their cellular origin were confirmed in a mouse model of ICH. A total of 624 genes showed altered regulation in human ICH. Bioinformatic analysis shows that these genes form interconnected networks of proinflammatory, anti-inflammatory, and neuronal signaling cascades. Intracerebral hemorrhage evokes coordinated upregulation of proinflammatory signaling through specific cytokines and chemokines and their downstream molecular pathways. Anti-inflammatory networks are also induced by ICH, including annexins A1 and A2 and transforming growth factor beta (TGF β) and their intracellular cascades. Intracerebral hemorrhage downregulates many neuronal signaling systems, including the N-methyl-D-aspartic acid (NMDA) receptor complex and membrane ion channels. Select portions of these molecular networks were confirmed in the mouse, and the proteins in a subset of these networks localized to subsets of neurons, oligodendrocytes, or leukocytes. These inflammatory and anti-inflammatory networks interact at several key points in neutrophil signaling, apoptotic cell death, and protease responses, and indicate that secondary damage in ICH activates opposing molecular systems.

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The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

Biomolecules ◽

10.3390/biom10030453 ◽

2020 ◽

Vol 10 (3) ◽

pp. 453

Author(s):

Susana M. Chuva de Sousa Lopes ◽

Marta S. Alexdottir ◽

Gudrun Valdimarsdottir

Keyword(s):

Stem Cell ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Cell Model ◽

Embryonic Stem ◽

Model Systems ◽

Special Focus ◽

Placental Development

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

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Role of Harmaline as Adiponectin Modulator in Defeating Liver Cirrhosis Induced By Thioacetamide in Mice

Biomedical & Pharmacology Journal ◽

10.13005/bpj/2106 ◽

2021 ◽

Vol 14 (1) ◽

pp. 123-131

Author(s):

Doha M. Beltagy ◽

Khloud Gamal Abdelsalam ◽

Tarek M Mohamed ◽

Mai M. El-Keey

Keyword(s):

Oxidative Stress ◽

Liver Cirrhosis ◽

Transforming Growth Factor Beta ◽

Liver Tissue ◽

Cell Activation ◽

Transforming Growth Factor ◽

Stellate Cell ◽

Matrix Deposition ◽

Anti Inflammatory ◽

Tgf Β1

Liver cirrhosis is currently the 11th most common cause of death which includes inflammatory, oxidative damage, and immune response. Harmaline has antioxidant and anti-inflammatory mechanisms which can defeat against hepatic cirrhosis pathways. The present work aimed to evaluate the ameliorating effect of harmaline against liver cirrhosis induced by thioacetamide in mice. The study was carried out on sixty male mice divided into three main groups. Control and harmaline groups (GIa and GIb), thioacetamide-group (GII) and harmaline co-treated and treated groups (GIIIa and GIIIb). By the end of the experiment, adiponectin concentrations were measured in serum and liver tissue. Gene expression of adiponectin, transforming growth factor beta-1 (TGF-β1), tissue inhibitor metalloprotease-1(TIMP-1) and peroxisome proliferator activated receptor-gamma (PPAR-γ) were assessed. Some oxidative stress biomarkers as malondialdehyde, reduced glutathione, catalase, superoxide dismutase and nitric oxide were determined. The results indicated that harmaline administration cause significant suppression of oxidative stress and inflammatory response.Inhibition of hepatic stellate cell activation and extracellular matrix deposition were also noticed with a significant decrease in the expression of the profibrotic markers(TGF-β1 and TIMP-1) which have direct effects on adiponectin activation. These results were confirmed by the histological studies in liver tissue. In Conclusion,Harmaline has excellent protective role against liver cirrhosis induced by thioacetamide in mice via its antioxidant and anti-inflammatory properties.It can be therapeutically used as a safe liver support by a dose of 10 mg/kg after furtherin vivo studies.

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Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽

10.7554/elife.02172 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 40

Author(s):

Hiroshi Yamaguchi ◽

Toshihiko Maruyama ◽

Yoshihiro Urade ◽

Shigekazu Nagata

Keyword(s):

Adenosine Receptor ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Adenosine Monophosphate ◽

Receptor Activation ◽

Death Process ◽

Apoptotic Cells ◽

Dependent Manner ◽

A2a Adenosine Receptor ◽

Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

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Local and systemic influence of toxic levels of airborne ozone on the inflammatory response in rats

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0051 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Małgorzata Chmielewska-Krzesińska ◽

Krzysztof Wąsowicz

Keyword(s):

Inflammatory Response ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Interleukin 1 ◽

Interleukin 10 ◽

Necrosis Factor Alpha ◽

Genes Expression ◽

Factor Alpha ◽

Anti Inflammatory ◽

Necrosis Factor

Abstract Introduction Ozone is not harmful itself; however, it directly oxidises biomolecules and produces radical-dependent cytotoxicity. Exposure to ozone is by inhalation and therefore the lungs develop the main anti-inflammatory response, while ozone has an indirect impact on the other organs. This study investigated the local and systemic effects of the ozone-associated inflammatory response. Material and Methods Three groups each of 5 Wistar Han rats aged 6 months were exposed for 2h to airborne ozone at 0.5 ppm and a fourth identical group were unexposed controls. Sacrifice was at 3h after exposure for control rats and one experimental group and at 24 h and 48 h for the others. Lung and liver samples were evaluated for changes in expression of transforming growth factor beta 1, anti-inflammatory interleukin 10, pro-inflammatory tumour necrosis factor alpha and interleukin 1 beta and two nuclear factor kappa-light-chain-enhancer of B cells subunit genes. Total RNA was isolated from the samples in spin columns and cDNA was synthesised in an RT-PCR. Expression levels were compared to those of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and analysed statistically. Results All variables changed non-linearly over time comparing experimental groups to the control. Conspicuous expression changes in the subunit genes and cytokines were observed in both evaluated organs. Conclusion Locally and systemically, inflammation responses to ozone inhalation include regulation of certain genes’ expression. The mechanisms are unalike in lungs and liver but ozone exerts a similar effect in both organs. A broader range of variables influential on ozone response should be studied in the future.

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Characteristics of epidemiological and molecular relationships between allergic diseases and helminth disorders in Opisthorchis endemic region

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2008-4-37-44 ◽

2008 ◽

Vol 7 (4) ◽

pp. 37-44

Author(s):

L. M. Ogorodova ◽

O. S. Fyodorova ◽

M. B. Freidin ◽

M. B. Vasil’yeva ◽

N. A. Cherevko ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Phenotypic Variability ◽

Allergic Diseases ◽

Endemic Region ◽

Gene Differential Expression ◽

Atopic Bronchial Asthma ◽

Growth Factor Beta ◽

Molecular Relationships

To elucidate the molecular mechanisms of O. felineus impact into phenotypic variability of allergic diseases in the opisthorchis endemic region, we studied 104 patients with opisthorchosis, 92 patients with atopic bronchial asthma, 52 patients with a combination of both diseases, and 120 healthy persons. Standard clinical, immunological, and genetic methods were used. An association of opisthorchis invasion with the improvement of lung function signs and bronchial hyperreactivity was found. It was established, that IL-4-dependent mechanisms of atopy were suppressed by O. felineus antigens, in particular due to hyperproduction of IL-10 and transforming growth factor-beta. However, IL-5-dependant mechanisms were supported. A phenomenology of the cytokine gene differential expression was established, disclosing the molecular basis of the immune system function in diseases with polar immune response in the helminth endemic region.

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The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽

10.1098/rsob.130067 ◽

2013 ◽

Vol 3 (6) ◽

pp. 130067 ◽

Cited By ~ 16

Author(s):

Gopal P. Sapkota

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

Mesenchymal Transition ◽

Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

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The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0338 ◽

2018 ◽

Vol 96 (12) ◽

pp. 1308-1317 ◽

Cited By ~ 9

Author(s):

Heba M. Mansour ◽

Abeer A.A. Salama ◽

Rania M. Abdel-Salam ◽

Naglaa A. Ahmed ◽

Noha N. Yassen ◽

...

Keyword(s):

Liver Fibrosis ◽

Inflammatory Cytokines ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Interleukin 1 ◽

Health Concern ◽

Dependent Manner ◽

Serum Transaminases ◽

Anti Inflammatory

Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.

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Disruption of Smad4 in Odontoblasts Causes Multiple Keratocystic Odontogenic Tumors and Tooth Malformation in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.00706-09 ◽

2009 ◽

Vol 29 (21) ◽

pp. 5941-5951 ◽

Cited By ~ 34

Author(s):

Yuanrong Gao ◽

Guan Yang ◽

Tujun Weng ◽

Juan Du ◽

Xuejiu Wang ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Hedgehog Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Bmp Signaling ◽

Odontogenic Tumors ◽

High Recurrence Rate ◽

Signal Molecules ◽

Cystic Tumors ◽

Keratocystic Odontogenic Tumors

ABSTRACT Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocyte-specific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-β/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.

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Contextual Regulation of TGF-β Signaling in Liver Cancer

Cells ◽

10.3390/cells8101235 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1235 ◽

Cited By ~ 4

Author(s):

Tu ◽

Huang ◽

Luo ◽

Yan

Keyword(s):

Liver Cancer ◽

Cancer Progression ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Early Stage ◽

Primary Liver Cancer ◽

Receptor Activation ◽

Membrane Receptors ◽

Cancer Cell Survival

Primary liver cancer is one of the leading causes for cancer-related death worldwide. Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that signals through membrane receptors and intracellular Smad proteins, which enter the nucleus upon receptor activation and act as transcription factors. TGF-β inhibits liver tumorigenesis in the early stage by inducing cytostasis and apoptosis, but promotes malignant progression in more advanced stages by enhancing cancer cell survival, EMT, migration, invasion and finally metastasis. Understanding the molecular mechanisms underpinning the multi-faceted roles of TGF-β in liver cancer has become a persistent pursuit during the last two decades. Contextual regulation fine-tunes the robustness, duration and plasticity of TGF-β signaling, yielding versatile albeit specific responses. This involves multiple feedback and feed-forward regulatory loops and also the interplay between Smad signaling and non-Smad pathways. This review summarizes the known regulatory mechanisms of TGF-β signaling in liver cancer, and how they channel, skew and even switch the actions of TGF-β during cancer progression.

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TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms21082735 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2735 ◽

Cited By ~ 1

Author(s):

Enaam Chleilat ◽

Abhishek Pethe ◽

Dietmar Pfeifer ◽

Kerstin Krieglstein ◽

Eleni Roussa

Keyword(s):

Oxidative Stress ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Cell Function ◽

Dorsal Raphe ◽

Conditional Knockout ◽

Serotonergic Neurons ◽

Dorsal Raphé

Calcium homeostasis is a cellular process required for proper cell function and survival, maintained by the coordinated action of several transporters, among them members of the Na+/Ca2+-exchanger family, such as SLC8A3. Transforming growth factor beta (TGF-β) signaling defines neuronal development and survival and may regulate the expression of channels and transporters. We investigated the regulation of SLC8A3 by TGF-β in a conditional knockout mouse with deletion of TGF-β signaling from Engrailed 1-expressing cells, i.e., in cells from the midbrain and rhombomere 1, and elucidated the underlying molecular mechanisms. The results show that SLC8A3 is significantly downregulated in developing dopaminergic and dorsal raphe serotonergic neurons in mutants and that low SLC8A3 abundance prevents the expression of the anti-apoptotic protein Bcl-xL. TGF-β signaling affects SLC8A3 via the canonical and p38 signaling pathway and may increase the binding of Smad4 to the Slc8a3 promoter. Expression of the lipid peroxidation marker malondialdehyde (MDA) was increased following knockdown of Slc8a3 expression in vitro. In neurons lacking TGF-β signaling, the number of MDA- and 4-hydroxynonenal (4-HNE)-positive cells was significantly increased, accompanied with increased cellular 4-HNE abundance. These results suggest that TGF-β contributes to the regulation of SLC8A3 expression in developing dopaminergic and dorsal raphe serotonergic neurons, thereby preventing oxidative stress.

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