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A, HuR protein expression in eutopic endometrial glands according to the menstrual cycle phase. HSCORE analysis was performed to quantitate endometrial glandular expression of HuR from biopsy samples. B, HuR protein expression in eutopic endometrial stromal cells according to the menstrual cycle phase. HSCORE analysis was performed to quantitate endometrial stromal cell expression of HuR from biopsy samples. EP indicates early proliferative (n ¼ 5); MP-LP, mid-proliferative þ late proliferative (n ¼ 4); ES-LS, early secretory þ mid-secretory (n ¼ 11); LS, late secretory (n ¼ 3).
Source publication
Cytokines modulate turnover of the endometrium during the menstrual cycle and contribute to the pathogenesis of endometriosis. Gene expression for cytokines is often regulated by proteins that bind to adenosine- and uridine-rich elements (AREs) in their transcripts to stabilize or destabilize bound messenger RNAs (mRNAs). HuR/ELAVL1 is an RNA-bindi...
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Citations
... These results showed that HuR could be a causal factor of ER-α regulation and may induce the hormone-dependent endometrial carcinoma. They are concordant with a study showing that HuR immunoreactivity was significantly lower in the endometrium of early proliferative and late secretory phases, compared to the mid-late proliferative and early-mid secretory phases [22]. ...
HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001), correlating with worse overall survival (OS) (p = 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and correlated with better OS (p = 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and non-significantly correlated with increased OS (p = 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.
... Immunohistochemical results were evaluated according to the intensity and extent of staining in the tissue as follows: Mild (+); moderate (++); or intense (+++). [13] RESULTS ...
... [15][16][17] Five regions that showed positive immunoreactivity were analyzed for staining intensity using a modified histoscore (H-SCORE), ranging from 0 to 300 points, according to the literature. [18] Sections were assessed in a blinded fashion by the same histologist. Intraobserver reliability was assessed by histopathologic and immunohistochemical measurements of all subjects repeated twice at one-month intervals by the same histologist. ...
Objectives
The purpose of this study was to investigate whether hydroxychloroquine (HCQ) sulfate causes oxidative stress (OS) and its effect on fracture healing in an experimental rat model.
Materials and methods
In this experimental study, open diaphyseal femur fractures were induced in 24 eight-week-old male rats (mean weight: 225±25 g; range, 200 to 250 g) and then fixed with K-wire. The rats were divided into four groups: HCQ-2, control-2 (C-2), HCQ-4, and control-4 (C-4). During the study period, rats in the HCQ groups received an HCQ solution (160 mg/kg/day), whereas rats in the control groups received saline. The HCQ-2 and C-2 groups were sacrificed on the 14th day, and the HCQ-4 and C-4 groups were sacrificed on the 28th day. After sacrifice, malondialdehyde levels induced by OS were calculated for each rat, and fracture healing was evaluated radiographically, histomorphometrically, histopathologically, and immunohistochemically.
Results
Malondialdehyde levels were higher in the HCQ groups than in the control groups (p<0.05). Hydroxychloroquine caused OS in rats. The ratio of total callus diameter to femur bone diameter was lower in HCQ groups compared to control groups (p<0.05). No differences were observed when comparing radiological and histological healing results between the control and HCQ groups. Alkaline phosphatase levels were lower in the HCQ-4 group than the C-4 group at week four (p<0.05), although osteocalcin and osteopontin levels did not differ between groups (p>0.05). Oxidative stress had no adverse effects on histologic healing outcomes and osteoblast functions. Cathepsin K and tartrate-resistant acid phosphatase-5b levels were higher in the HCQ-4 group than in the C-4 group (p<0.05). While the number and function of osteoclasts increased due to OS in callus tissue, a decrease in the number of chondrocytes was observed.
Conclusion
Hydroxychloroquine-induced OS increases the number and function of osteoclasts and decreases the number of hypertrophic chondrocytes and endochondral ossification but has no significant effect on mid-late osteoblast products and histological fracture healing scores.
... The monoclonal and polyclonal antibodies against Cluster of differentiation (CD) CD 34 and vascular endothelial growth factor (VEGF) proteins were used on the femoral sections. Five regions showing positive immunolabeling with relevant antigens were analyzed in terms of staining intensity by using semiquantitative modified H-SCORE according to the literature [26]. Two researchers gave scores between 0 and 300 for five regions, and the scores were averaged. ...
Aim:
Our study aimed to examine the effects of Linagliptin, Pioglitazone, and their combination on fracture healing in a diabetes rat femur fracture model.
Material and methods:
Type 2 diabetes mellitus (T2DM) induced rats were randomly divided into four groups: non-treated diabetes group (TD), Pioglitazone group (P), Linagliptin group (L), and Pioglitazone and Linagliptin group (PL). Daily oral dosage of pioglitazone (10 mg/kg/day), linagliptin (10 mg/kg/day), and their combination were administered. Femur fractures were stabilized intramedullary. At weeks 2 and 6, rats were sacrificed for evaluation radiologically, biomechanically, histopathologically, histomorphometrically, and immunohistochemically.
Results:
Flexural strength of the L and PL groups were significantly higher compared to the P group. The highest healing score was in the L group and lowest in the P group, while the highest inflammation score was in the P group and lowest in the L group. A cluster of differentiation (CD) CD 34 reactivity was highest in the L group and lowest in the PL group.
Conclusion:
Linagliptin treatment significantly increased histological healing scores, callus volume, biomechanical strength, and vascularity, however, minimized the inflammatory process, which was increased by pioglitazone. The combination of linagliptin and pioglitazone restored BMD and increased biomechanical strength. Linagliptin monotherapy is rarely indicated; hence, T2DM patients with a high risk of bone fractures can be considered for combined therapy of pioglitazone and linagliptin.
... Immunohistochemical results were evaluated according to the intensity and extent of staining in the tissue as follows: negative (0); mild (1); moderate (2); or intense (3). Femoral localizations of staining were identified, and the changes in protein expression and regional differences were detected semi-quantitatively. [22] ...
Objectives:
The aim of this study was to investigate the radiological, biomechanical, histopathological and immunohistochemical effects of theranekron on fracture healing in an experimental rat model.
Materials and methods:
Forty-eight male albino Wistar rats were used. Four groups were formed, with 12 rats in each of theranekron groups 1 and 2, and control groups 1 and 2. After a fracture was created in the right femur of the rats included in the study, fixation was performed with an intramedullary Kirschner wire. Theranekron was administered subcutaneously to theranekron groups 1 and 2 at a dose of 0.3 mg/kg on days 0, 5 and 10. After radiographic analysis of the femurs of theranekron group 1 and control group 1 rats at four weeks of the study was performed, both groups were divided into two equal subgroups (six femurs in each group). Histopathological and immunohistochemical examinations were performed in one subgroup and biomechanical examination in the other subgroup. At the end of six weeks, the rats in theranekron group 2 and control group 2 were evaluated after applying the same procedure as in the fourth week.
Results:
When the mean radiological scores of the theranekron and control groups were compared, a statistically significant difference was found in favor of the theranekron group at four and six weeks (p=0.028 and p=0.006, respectively). At four weeks, statistically significant higher biomechanical forces were obtained in the theranekron group compared to the control group (p=0.030). In the histopathological evaluation, the inflammation value of the control group at four weeks was statistically significantly higher than the theranekron group (p=0.027). The angiogenesis, osteoblast proliferation, and bone formation values of the theranekron group were significantly higher than the control group (p=0.014, p=0.014, and p=0.005, respectively). At six weeks, the bone formation values of the theranekron group were statistically significantly higher than the control group (p=0.021). The difference between the theranekron group and the control group scores of the immunohistochemical evaluation were statistically significantly different at four and six weeks (p=0.006 and p=0.011, respectively).
Conclusion:
Theranekron may play a role in accelerating fracture healing by reducing acute inflammation process in the early period of fracture union, increasing fracture strength, angiogenesis, osteoblast proliferation, and bone formation.
... Five regions were evaluated by two researchers for positive immune marking of bone morphogenic protein (BMP)-4, BMP-7 and cluster of differentiation (CD) 34 and scored between 0-300 with semiquantitative histoscore (H-score) (Figure 4). [10] H-score is a combined semiquantitative scoring system determined by adding the results of multiplication of the percentage of cells with staining intensity ordinal value (scored from 0 for no signal to 3 for strong signal) with 300 possible values. [11] Staining intensity ordinal values of BMP-4, BMP-7 and CD34 proteins on osteoblasts, chondroblasts and fibroblasts of all groups were evaluated and scored by H-score scoring system. ...
Objectives:
This study aims to evaluate and compare radiological, biomechanical, histopathological, histomorphometric and immunohistochemical effects of povidone iodine (PVP-I), hydrogen peroxide (HPO) and chlorhexidine gluconate (CHG) on fracture healing in their minimum cytotoxic and most efficient concentrations.
Materials and methods:
This experimental animal study, conducted between April 2018 and January 2019, included 48 male Sprague Dawley® rats (aging 9 weeks; weighing 356 g) which were randomly divided into four groups: control (saline), HPO, PVP-I and CHG. Rat model of femoral fracture was established and intramedullary fixation was applied. Solutions were applied to fracture region in determined concentration and time, and all subjects were sacrificed on Day 28. Extracted femurs were investigated radiologically by micro-computed tomography. Then, all groups were divided into two random groups to be evaluated biomechanically, histopathologically, histomorphometrically and immunohistochemically.
Results:
In histopathological evaluation, inflammation score of CHG group was significantly lower than other groups, and inflammation score of PVP-I group was significantly lower than control and HPO groups (p<0.05). Biomechanically, flexural strength (σbend) (megapascal) values of CHG and control groups showed similar results, but there was no significant difference between all groups (p>0.05). In immunohistochemical localization of bone morphogenic protein (BMP)-4, osteoblast and chondroblast histoscores (H-scores) of HPO group were significantly lower than other groups, and chondroblast H-score in CHG group was lower than control and PVP-I groups (p<0.05). In immunohistochemical localization of BMP-7, osteoblast H-score was significantly higher in CHG group than other groups (p<0.05).
Conclusion:
We determined that CHG 0.05% solution had no negative effect on the fourth week of fracture healing histopathologically, immunohistochemically and biomechanically, and is an alternative irrigative to normal saline.
... The investigators were blinded to the tissue type and source. These scores were averaged to generate the data presented by Karipcin et al. [15]. ...
... As a summary, the proliferation, inflammation, and differentiation play important roles in wound healing process [10]. The process also involves a series of genes such as p53, AP-1 and MMPs [15], as confirmed by this study. The induction or inhibition of mentioned genes has role in the acceleration of wound healing [16]. ...
Aims
Lucilia sericata larvae have been successfully used on healing of wounds in the diabetics. However, the involvement of the extraction/secretion (ES) products of larvae in the treatment of diabetic wounds is still unknown. Activator protein-1 (AP-1) transcription, composed of c-jun and c-Fos proteins, has been shown to be the principal regulator of multiple MMP transcriptions under a variety of conditions, also in diabetic wounds. Specifically, MMP-2 and MMP-9’s transcriptions are known to be modulated by AP-1. c-jun has been demonstrated to be a repressor of p53 in immortalized fibroblasts. The aim of the present study is to investigate the effects of L. sericata ES on the expression of AP-1 (c-jun), p53, MMP-2, and MMP-9 in wound biopsies dissected from streptozotocin induced diabetic rats.
Methods
The expression levels of MMP-2, MMP-9, c-jun and p53 in dermal tissues were determined at days 0, 3, 7 and 14 after wounding, using immunohistochemical analysis and quantitative real-time PCR.
Results
The treatment with ES significantly decreased through inflammation-based induction of MMP-2 and MMP-9 expression levels in the wounds of diabetic groups, compared to control groups at the third day of wound healing. At the 14th day, there were dramatic decreases in expression of c-jun, MMP-9, and p53 in ES-treated groups, compared to the diabetic group (P < 0.001, P < 0.05 and P < 0.01, respectively).
Conclusion
ES products of L. sericata may enhance the process of wound healing in phases of inflammation, proliferation, and re-epithelization, essentially via regulating c-jun expression and modulating MMP-2 and MMP-9 expressions.
... To determine the specificity of immunostaining, sections were processed as described above, using control serum in place of the primary antibody. Immunohistochemical staining was evaluated semi-quantitatively using a modified H-SCORE analysis that assigned numerical values of 0-300 to the staining intensity [18]. Each slide was assigned H-SCORE values for 10 different areas by two investigators at different times. ...
... The investigators were blinded to the tissue type and source. These scores were averaged to generate the data presented by Karipcin et al. (Figures 1, 2) [18]. ...
Purpose:
Preeclampsia is a multisystem disorder and its etiology remains still unclear. Recent hypotheses rely on imbalance between angiogenic and antiangiogenic factors and disruption of endothelial function of spiral arteries. In addition; increased VTE (venous thromboembolism) risk is still unclear in preeclampsia. Our aim was to investigate the relationship between endothelial dysfunction, adipocytokines, platelet function, and vasculogenesis in preeclampsia.
Methods:
Plasma angiogenic (PlGF, VEGF), antiangiogenic factors (sflt-1, endoglin) with adipocytokines (leptin, adiponectin, ghrelin), endothelial dysfunction markers (vWF, NO), and platelet function markers (ADP and collagen induced platelet aggregation, P-selectin) were examined in 30 early-onset, 22 late-onset preeclampsia, and 27 healthy pregnants. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum biomarker levels except NO. NO levels were determined using colorimetric method.
Results:
Endoglin, leptin, and vWF levels were increased in preeclampsia (P < 0.001), whereas PlGF, P-selectin (P < 0.001), and col-induced platelet aggregation slope (P < 0.05) were decreased in the same counterpart as compared to healthy pregnants. Endoglin also correlated with sflt-1 in preeclamptic patients.
Conclusion:
Increase in the levels of antiangiogenic factors and leptin herewith decline in the level of other angiogenic factor PlGF, did not affect nitric oxide and platelet aggregation markers significantly. Increased levels of vWF and endoglin might be result of endothelial dysfunction, so our findings suggest that an impaired angiogenesis may address endothelial dysfunction, but not platelet aggregation for preeclampsia.
... RNABP mRNAs are expressed in the reproductive tract of humans and mice and are influenced by menstrual/estrous cycles. 58,59 Female mice with mutations in ZFP36L2 were unable to ovulate even under pharmacological conditions, and attempts to mature oocytes from these mice ex vivo was hindered because of meiotic arrest imposed by cAMP. 60 Using the TTP knockout mouse model, it has also been demonstrated that TTP is critically involved in mouse meiosis, chromosomal arrangement, spindle morphology, and polar body extrusion, all of which are critical events for oocyte maturation. ...
... Women with endometriosis present decreased TIA-1 and HuR expression, both of which are RNABPs responsible for modulation of proinflammatory cytokines, in the eutopic and ectopic endometrium compared to normal healthy controls. 59,69 Decreases in regulatory molecules of inflammation likely contribute to the pathogenesis and pathophysiology of endometriosis by contributing to the inflammatory milieu in the peritoneal cavity and symptoms of pain and infertility observed in endometriosis patients. Another RNABP that has been implicated in the pathogenesis of endometriosis is Musashi-1. ...
RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction.
... In other animal models, inflammation has been related to an impairment in spiral artery remodelling [34]. Studies have investigated similar RNA binding proteins in other human-associated reproductive tract pathologies such as endometriosis [35,36]. Therefore, our aims were to 1) characterize expression of tristetraprolin in murine placental trophoblast cells and to 2) investigate whether RNA binding proteins are involved in a mouse model of LPS-induced abortion at the placental site. ...
Recurrent pregnancy loss is a major reproductive pathology affecting 1-5% of pregnant women worldwide. A distinct feature of this reproductive pathology is involvement of key inflammatory cytokines and transcription factors such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and nuclear factor kappa beta (NF-κB). Special classes of RNA-binding proteins regulate the transcripts of many of these important cytokines and regulatory factors via binding to the 3' untranslated regions (UTRs) and/or poly(A) tail and destabilizing/stabilizing the transcript. The tristetraprolin (TTP/ZFP36) family have been found to be potent destabilizers of the aforementioned inflammatory and cellular response cytokines. The aim of this study was to evaluate whether tristetraprolin is expressed in the placenta and involved in modulating inflammation in mouse model of lipopolysaccharide (LPS)-induced fetal loss. In this study, Swiss-albino mice were injected with LPS at gestational day 15.5 and placental tissues were harvested 6 hours post-LPS injection. Histopathology and immunohistochemistry analyses clearly revealed cellular stress and death in LPS treated placentas compared to controls. TTP protein was downregulated, while targets TNF-α and IL-6 were upregulated in LPS group compared to controls. We observed increased TTP nuclear immunolocalization corresponding with higher NF-κB nuclear localization in trophoblasts from LPS treated placentas. Our results suggest that RNA-binding proteins such as TTP are expressed and perhaps involved in the modulation of inflammation-induced pregnancy pathologies.
