scholarly journals Heavy Metals in the Environment and Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4052
Author(s):  
Fiorenza Gianì ◽  
Roberta Masto ◽  
Maria Antonietta Trovato ◽  
Pasqualino Malandrino ◽  
Marco Russo ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Low Levels ◽  
Causative Link

In recent decades, the incidence of thyroid cancer has increased more than most other cancers, paralleling the generalized worldwide increase in metal pollution. This review provides an overview of the evidence supporting a possible causative link between the increase in heavy metals in the environment and thyroid cancer. The major novelty is that human thyroid stem/progenitor cells (thyrospheres) chronically exposed to different metals at slightly increased environmentally relevant concentrations show a biphasic increase in proliferation typical of hormesis. The molecular mechanisms include, for all metals investigated, the activation of the extracellular signal-regulated kinase (ERK1/2) pathway. A metal mixture, at the same concentration of individual metals, was more effective. Under the same conditions, mature thyrocytes were unaffected. Preliminary data with tungsten indicate that, after chronic exposure, additional abnormalities may occur and persist in thyrocytes derived from exposed thyrospheres, leading to a progeny population of transformation-prone thyroid cells. In a rat model predisposed to develop thyroid cancer, long-term exposure to low levels of metals accelerated and worsened histological signs of malignancy in the thyroid. These studies provide new insight on metal toxicity and carcinogenicity occurring in thyroid cells at a low stage of differentiation when chronically exposed to metal concentrations that are slightly increased, albeit still in the “normal” range.

scholarly journals Thyroid Stem Cells But Not Differentiated Thyrocytes Are Sensitive to Slightly Increased Concentrations of Heavy Metals

2021 ◽  
Vol 12 ◽  
Author(s):  
Fiorenza Gianì ◽  
Roberta Masto ◽  
Maria Antonietta Trovato ◽  
Annarita Franco ◽  
Giuseppe Pandini ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Thyroid Cancer ◽  
Response Curve ◽  
Living Cells ◽  
Human Thyroid ◽  
Target Cells ◽  
Volcanic Area ◽  
Thyroid Cells ◽  
Biphasic Pattern ◽  
Thyroid Cancer Incidence

Thyroid cancer incidence is markedly increased in volcanic areas where residents are biocontaminated by chronic lifelong exposure to slightly increased metals in the environment. Metals can influence the biology of living cells by a variety of mechanisms, depending not only on the dose and length of exposure but also on the type and stage of differentiation of target cells. We explored the effect of five heavy metals (Cu, Hg, Pd, W and Zn) at nanomolar concentrations (the biocontamination level in residents of the volcanic area in Sicily where thyroid cancer is increased) on stimulating the proliferation of undifferentiated (thyrospheres) and differentiated human thyroid cells. Thyrosphere proliferation was significantly increased after exposure to each individual metal and a greater stimulating effect was observed when a mixture of the examined metals was used. No effect was seen in differentiated thyrocytes. For all metals, the dose-response curve followed a biphasic pattern that is typical of hormesis. Thyrosphere growth concerned the size rather than number, except with the metal mixture. An altered morphology was also observed in metal-treated thyrospheres. Metal-induced proliferation was due to activation of the ERK1/2 pathway, as confirmed by growth inhibition when ERK1/2 signaling was blocked. These studies show that stem/precursor thyroid cells are sensitive to small increases in environmental metal concentrations that are harmless for differentiated thyrocytes.

Senkyunolide I Relieves Neuropathic Pain Induced by Chronic Constriction Injury by Inhibiting Activation of Microglia

2021 ◽  
Vol 20 (2) ◽  
pp. 253-258
Author(s):  
Xiaomin Huang ◽  
Miao Huo
Keyword(s):  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Biological Activities ◽  
Bioactive Components ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induced Apoptosis ◽  
Kinase Pathway ◽  
Senkyunolide I

As an alternative to the use of narcotics, generally refractory to long-term effectiveness, for the management of neuropathic pain, we have explored the utility of senkyunolide I. Senkyunolide I is one of the bioactive components isolated from Ligusticum chuanxiong Hort known to exhibit multiple biological activities. In this study, we report senkyunolide I inhibition of chronic constriction injury induced neuropathic pain. Mechanistically, senkyunolide I inhibited chronic constriction injury induced apoptosis and the activity of microglia via extracellular signal regulated kinase pathway. We therefore suggest that senkyunolide I could serve as a promising drug for the treatment of neuropathic pain.

scholarly journals Stimulation of Phosphorylation of ERK and CREB by Phellopterin and Auraptene Isolated from Citrus junos

2014 ◽  
Vol 9 (10) ◽  
pp. 1934578X1400901 ◽  
Author(s):  
Mitsuhiro Nakamura ◽  
Tomoko Suzuki ◽  
Mai Takagi ◽  
Hirotoshi Tamura ◽  
Toshiya Masuda
Keyword(s):  
Camp Response Element Binding ◽  
Long Term Memory ◽  
Camp Response Element ◽  
Extracellular Signal Regulated Kinase ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Citrus Junos ◽  
Element Binding Protein ◽  
Methyl Ferulate

Bioactive compounds from citrus fruits contribute many benefits to human health. Extracellular signal-regulated kinase (ERK) signaling plays an important role in the regulation of multiple cellular processes. Activation of the ERK-cAMP response element binding protein (CREB) signaling is required for long-term memory formation. In this study, auraptene, phellopterin, thymol, coniferyl alcohol 9-methyl ether and methyl ferulate were isolated from Citrus junos. Among the five compounds isolated, auraptene and phellopterin increased the phosphorylation of ERK and CREB. This study provides, to our knowledge, the first evidence that phellopterin potently stimulates the phosphorylation of ERK and CREB. Phellopterin could be a novel neuroprotective agent.

scholarly journals Histone deacetylation of NIS promoter underlies BRAF V600E-promoted NIS silencing in thyroid cancer

2013 ◽  
Vol 21 (2) ◽  
pp. 161-173 ◽  
Author(s):  
Zongjing Zhang ◽  
Dingxie Liu ◽  
Avaniyapuram Kannan Murugan ◽  
Zhimin Liu ◽  
Mingzhao Xing
Keyword(s):  
Thyroid Cancer ◽  
Histone Acetylation ◽  
Underlying Mechanism ◽  
Histone Deacetylation ◽  
Braf V600e ◽  
Epigenetic Mechanism ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Rat Thyroid

The BRAF V600E mutation causes impaired expression of sodium iodide symporter (NIS) and radioiodine refractoriness of thyroid cancer, but the underlying mechanism remains undefined. In this study, we hypothesized that histone deacetylation at the NIS (SLC5A5) promoter was the mechanism. Using the chromatin immunoprecipitation approach, we examined histone acetylation status on the lysine residues H3K9/14, H3K18, total H4, and H4K16 at the NIS promoter under the influence of BRAF V600E. We found that expression of stably or transiently transfected BRAF V600E inhibited NIS expression while the deacetylase inhibitor SAHA stimulated NIS expression in PCCL3 rat thyroid cells. Although BRAF V600E enhanced global histone acetylation, it caused histone deacetylation at the NIS promoter while SAHA caused acetylation in the cells. In human thyroid cancer BCPAP cells harboring homozygous BRAF V600E mutation, BRAF V600E inhibitor, PLX4032, and MEK inhibitor, AZD6244, increased histone acetylation of the NIS promoter, suggesting that BRAF V600E normally maintained histone in a deacetylated state at the NIS promoter. The regions most commonly affected with deacetylation by BRAF V600E were the transcriptionally active areas upstream of the translation start that contained important transcription factor binding sites, including nucleotides −297/−107 in the rat NIS promoter and −692/−370 in the human NIS promoter. Our findings not only reveal an epigenetic mechanism for BRAF V600E-promoted NIS silencing involving histone deacetylation at critical regulatory regions of the NIS promoter but also provide further support for our previously proposed combination therapy targeting major signaling pathways and histone deacetylase to restore thyroid gene expression for radioiodine treatment of thyroid cancer.

scholarly journals Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qin Song ◽  
Qiheng Gou ◽  
Yuxin Xie ◽  
Zhen Zhang ◽  
Chaomei Fu
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Periplaneta Americana ◽  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Nuclear Factor ◽  
Protective Function ◽  
Extracellular Signal Regulated Kinase ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal

Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-κB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IκBα and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-κB and ERK signaling.

scholarly journals Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

2010 ◽  
Vol 23 (3) ◽  
pp. 590-615 ◽  
Author(s):  
Soichiro Kanoh ◽  
Bruce K. Rubin
Keyword(s):  
Nuclear Factor Kappa B ◽  
Biological Activities ◽  
Mechanisms Of Action ◽  
Nuclear Factor ◽  
Diffuse Panbronchiolitis ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Regulation Of Cell Cycle ◽  
Immunomodulatory Therapies

SUMMARY Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

Activation of Triggering Receptor Expressed on Myeloid Cells-1 Protects Monocyte from Apoptosis through Regulation of Myeloid Cell Leukemia-1

2013 ◽  
Vol 118 (5) ◽  
pp. 1140-1149 ◽  
Author(s):  
MeiTing Cai ◽  
QiXing Chen ◽  
Chi Chen ◽  
XiWang Liu ◽  
JinChao Hou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cell Leukemia ◽  
Proinflammatory Response ◽  
Extracellular Signal Regulated Kinase ◽  
Viral Oncogene ◽  
Extracellular Signal ◽  
Monocyte Apoptosis ◽  
Oncogene Homologue

Abstract Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. Methods: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. Results: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal–regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. Conclusions: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal–regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1–mediated hyperinflammatory response in monocytes.

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