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Uterine fibroids and the endometrium
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Deborah E. Ikhena, Serdar E. Bulun
Depending on their size, uterine fibroids can place tremendous stress and stretch on the nearby myometrium and overlying endometrium. Fibroids are characterized by increased deposition of ECM, which accounts for most of their size. Fibroids express higher levels of AKAP13, which activates Rho and is associated with the cytoskeleton of fibroid cells (67). Additionally, expression of the stress response gene, activating transcription factor 3 (ATF3), is altered in the presence of uterine fibroids (68). Data suggest that there is abnormal communication between the external mechanical environment and RhoA-mediated reorganization of the actin cytoskeleton in fibroid cells (69).
Venous ulcer formation and healing at cellular levels
Published in Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Fedor Lurie, Thomas W. Wakefield, Monika L. Gloviczki, Handbook of Venous and Lymphatic Disorders, 2017
In addition to PDGF receptors, the TGF-β type II receptors have also been studied. TGF-β is very important in fibroblasts’ regulation of extracellular proteins, proliferation, and differentiation during wound healing.50 In a study evaluating venous ulcer fibroblasts versus control fibroblasts, the investigators found that there was no difference in incorporation of proline into procollagen, the synthesis of total TGF, or mRNA levels of procollagen or TGF-β. However, when the fibroblasts were stimulated with exogenous TGF-β and collagen synthesis was measured, the venous ulcer fibroblasts failed to respond, whereas the normal cells showed a more than 60% increase in collagen production (P = 0.0001). Venous ulcer fibroblasts showed a fourfold reduction in TGF-β type II receptors, which could partly explain the absence of TGF-β-induced synthesis of collagen. It is unclear why the receptors are downregulated, but it has an effect on the response to TGF-β. This finding could explain the lack of appropriate extracellular matrix (ECM) deposition needed for re-epithelialization and wound healing in VLUs.51 In a recent study, the TGF-β signaling pathway was examined in patients with VLUs. The critical findings of this study were suppression of TGF-β RI, TGF-β RII, and TGF-β RIII receptors, and complete absence of phosphorylated Smad2, which is important in TGF-β signal transduction. Transcriptional factors for cell proliferation and function (GADD45β, ATF3, and ZFP36L1), which are usually stimulated by TGF-β, were suppressed in VLUs, while genes suppressed by TGF-β (FABP5, CSTA, and S100A8) were induced in VLUs. These data indicate that TGF-β signaling is functionally blocked in VLUs by the downregulation of TGF-β receptors and the attenuation of Smad signaling, with deregulation of TGF-β target genes. Furthermore, application of exogenous TGF-β would likely not benefit ulcer healing.52
Patulin
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Alejandro Hernández, Alicia Rodríguez, Santiago Ruiz-Moyano, Francisco Pérez-Nevado, Juan J. Córdoba, Alberto Martín
Apart from genotoxicity, other mechanisms may contribute to the cytotoxic effects of patulin. Heussner et al. [89] showed cytotoxic effects on porcine renal cell line LLC-PK1 exposure to this mycotoxin. Later, studies on HEK293 cell line verified that patulin causes cell death by activating a major mitogen-activated protein kinases (MAPKs: ERK1/2, p38, and JUN kinase proteins) signaling cascade [86,90–91]. In an animal model, Saxena et al. [92] demonstrated this mycotoxin could be a potential dermal carcinogenic mycotoxin inducing DNA damage and lead to cell cycle arrest along with intrinsic mitochondrial pathway-mediated apoptosis through modulation of Bax, p53, and p21/WAF1 proteins. Although these previous works have already correlated ERK1/2, p53, and p21/WAF1 signaling pathways with patulin-mediated ROS generation, Kwon et al. [93] arrested the cell cycle at the G2/M phase and activated apoptotic protein cascades through increased oxidative stress, which induces phosphorylation of a transcription factor EGR-1 for elevated expression of ATF3, in colorectal cancer cell assays added with patulin. This capacity of patulin to trigger apoptosis of tumor cells makes it a candidate for cancer treatment. More recently, Jin et al. [88] showed that p53 activation is correlated with the induction of apoptosis of patulin through mechanisms involved in its transcriptional-dependent activation of mitochondrial pathway and increase of ROS-mediated p38 activation. However, Wu et al. [94] using HL-60 cell line, where p53 is natural absence, and in HEK293 with the suppression of p53 expression, reported that patulin can trigger mitochondria-dependent apoptosis through a p53-independent pathway. In addition, other mechanistic insights in the signaling pathways caused by patulin in HEK293 and also in human colon carcinoma cells (HCT116) were reported by Boussabbeh et al. [95], who showed that patulin cytotoxicity by a ROS-dependent mechanism involves an endoplasmic reticulum stress pathway in addition to activation of a mitochondrial apoptotic pathway. These findings have been confirmed in several works that have demonstrated the capacity of this mycotoxin to inhibit the cell viability in vitro on cell line HEK293 experiments. For example, Zhang et al. [96], after treatment with concentrations varying from 2.5 to 15 μM, reported inhibition and apoptosis caused by the stress oxidative due to the increase of ROS and malondialdehyde and loss in the activity of glutathione, catalase, and superoxide dismutase. Likewise, Pillay et al. [97] observed that patulin caused a dose-dependent decrease in cell viability, and also, activation of the innate cell survival mechanisms to adapt to oxidative stress was detected. In another kind of cell, erythrocyte, which lack mitochondria and nuclei and cannot experience apoptosis by mitochondrial pathway and DNA fragmentation [98], patulin stimulates Ca2+ entry into the cell with subsequent cell membrane scrambling and cell shrinkage triggering suicidal erythrocyte death [99].
Liver transcriptome analysis reveals biological pathways and transcription factors in response to high ammonia exposure
Published in Inhalation Toxicology, 2022
Daojie Li, Shuangzhao Chen, Chun Liu, Baoxing Wei, Xiaoping Li
A previous study showed that ammonia exposure induced apoptosis in chicken livers (Xu et al. 2020). In this study, some core genes (ACTG1, PIK3CA, RB1, TAF1, KAT5, FOS, JUNB, and ATF3) that were related with apoptosis changed their expression after ammonia exposure. ACTG1 is a member of the actin family and the decrease of its expression promoted apoptosis (Zhou et al. 2020; Wu et al. 2021). In our transcriptome data, ACTG1 was a significantly down-regulated gene, indicating that it may be involved in the apoptosis process in pig liver under 80 ppm ammonia exposure. PIK3CA gene encode an important subunit of phosphatidylinositol-3-kinases (PI3Ks), and PI3K pathway is known to be important for apoptosis (Hellwinkel et al. 2008). RB1, TAF1, and KAT5 genes were also reported to play key roles in apoptosis (Indovina et al. 2015; Oh et al. 2017; Humbert et al. 2020). FOS and JUNB encode components of the dimeric transcription factor AP-1 (Rassidakis et al. 2005; Takada et al. 2010). AP-1 is an essential regulator of cell proliferation, inflammation and apoptosis. In addition, transcription factor ATF3, encoded by ATF3 gene, regulates inflammatory response and apoptosis under a stress condition (Jang et al. 2012). In our results, the changed expression of these genes indicated that ammonia may induce apoptosis in pig livers.
Identification of genes and miRNAs in paclitaxel treatment for breast cancer
Published in Gynecological Endocrinology, 2021
Jie Wu, Yijian Zhang, Maolan Li
ATF3 is induced by a variety of signals, including many of those encountered by cancer cells [24]. Avraham et al. found that ATF3 regulated the expression of essential tumor promoting factors induced by fibroblasts within the tumor microenvironment, and thus restrained tumor growth [25]. Moreover, Zhou et al. indicated ATF3 was upregulated by inhibiting miR-513a-5p, thereby increasing nasopharyngeal cancer paclitaxel chemosensitivity [26]. In our study, we observed that ATF3 was significantly upregulated in posttreatment samples, and high expression of ATF3 indicated longer survival of breast cancer. This was consistent with previous findings. We also found that ATF3 was regulated by hsa-miR-584. It is reported that miR-584 could target oncogene ROCK1 to suppress thyroid carcinoma and miR-584 as a molecular marker in cancer [27]. Fils-Aimé et al. found that miR-584 as a potential tumor suppressor was negatively regulated by TGF-β in the breast cancer cells, suggesting miR-584 and its downstream target-phosphatase and actin regulator 1 were involved in cell migration in invasive breast cancer cells [28]. Thus, the upregulated ATF3 was connected with paclitaxel used and clinical improvement. However, the role of miR-584 in the breast cancer treatment has not been confirmed, and the mechanism of how miR-584 played therapeutic effect still need further research.
Inflammasomes: a preclinical assessment of targeting in atherosclerosis
Published in Expert Opinion on Therapeutic Targets, 2020
Jeremiah Stitham, Astrid Rodriguez-Velez, Xiangyu Zhang, Se-Jin Jeong, Babak Razani
High‐density lipoprotein (HDL) exerts many different and antagonistic effects on cholesterol crystal (CC)-induced inflammasome activation. While HDL binds directly to CCs, this interaction did not dissipate CC formation, nor did it prevent phagocytosis or inhibit cellular uptake [125,126]. Niyonzima and colleagues demonstrated that HDL blocks complement deposition to the surface of CC and this resulted in the suppression of markers of activation in monocytes [126]. HDL has specifically been shown to inhibit complement C3b deposition on the surface of CCs [61,126]. High‐density lipoprotein (HDL) suppresses inflammasome activation in response to a wide range of activators, including ATP and nigericin (microbial toxin derived from Streptomyces), and stabilizes lysosomal integrity in response to treatment with CCs. Loss of lysosomal integrity activates lysosomal cathepsins capable of generating secondary messengers that trigger NLRP3 with resultant activation of caspase‐1 and pro‐IL‐1β cleavage [127]. Decreased transcription of NLRP3 and IL-1β genes in monocyte‐derived macrophages has been observed following treatment with lipopolysaccharide (LPS) and HDL [125,128]. Some have shown this to be mediated through activation of ATF3.