1,721,018 research outputs found
ANALYSIS OF TIGHT JUNCTIONS IN PLACENTAS AFFECTED BY CHORIOAMNIONITIS: IN VIVO AND IN VITRO ANALYSIS
No full textLa corionamnionite è una patologica gestazionale dovuta alla presenza di batteri, provenienti dal tratto vaginale, nel liquido amniotico. Questa patologia è caratterizzata da infiammazione acuta della membrana amniocorionica, della placenta e da elevate concentrazioni di citochine infiammatorie come IL-1β, IL-6, IL-8 e TGF-β nel liquido amniotico. È noto che le molecole infiammatorie sono coinvolte nelle alterazioni delle giunzioni cellulari ma, ad oggi, non è mai stato studiato il ruolo di queste citochine nella corionamnionite.
Le giunzioni strette (Tight Junctions) e le giunzioni aderenti (Adherens Junctions) sono giunzioni intercellulari cruciali per l’adesione e la regolazione della permeabilità degli epiteli in una vasta gamma di tessuti e organi.
In questo studio abbiamo analizzato l’espressione delle proteine e dei rispettivi mRNA che compongono le giunzioni strette (zonula occludent-1 e Occludina) e le giunzioni aderenti (VE-caderina e β-catenina) nelle placente e membrane fetali in gravidanze complicate da corionamnionite rispetto a gravidanze idiopatiche.
I risultati ottenuti hanno mostrato una significativa diminuzione dell’occudina nelle placente e membrane affette da corioamnionite mentre non sono state evidenziate differenze significative per le proteine ZO-1, VE-caderina e β-catenina. Dal momento che le concentrazioni di IL-1β, IL-6, IL-8 e TGF-β sono elevate nel liquido amniotico delle gravidanze con corioamnionite, abbiamo valutato il ruolo di queste citochine sull’espressione dell’occludina utilizzando colture HUVEC. I nostri risultati hanno evidenziato un ruolo chiave dell’ IL-1β e TGF-β nel regolare la localizzazione dell’occludina. In conclusione, in questo studio abbiamo evidenziato un ruolo dell’ IL-1β e del TGF-β nel regolare le giunzioni strette, facilitando le infezioni intra-placentari e alterando le membrane amniotiche portando alla rottura della membrana amniotica e parto pretermine
Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers
No full textCervical and endometrial cancers are among the most dangerous gynaecological malignancies, with high fatality and recurrence rates due to frequent diagnosis at an advanced stage and chemoresistance onset. The NRF2/KEAP1 signalling pathway plays an important role in protecting cells against oxidative damage due to increased reactive oxygen species (ROS) levels. NRF2, activated by ROS, induces the expression of antioxidant enzymes such as heme oxygenase, catalase, glutathione peroxidase and superoxide dismutase which neutralize ROS, protecting cells against oxidative stress damage. However, activation of NRF2/KEAP1 signalling in cancer cells results in chemoresistance, inactivating drug-mediated oxidative stress and protecting cancer cells from drug-induced cell death. We review the literature on the role of the NRF2/KEAP1 pathway in cervical and endometrial cancers, with a focus on the expression of its components and downstream genes. We also examine the role of the NRF2/KEAP1 pathway in chemotherapy resistance and how this pathway can be modulated by natural and synthetic modulators
Natural and synthetic compounds in Ovarian Cancer: A focus on NRF2/KEAP1 pathway
No full textAmong gynecologic malignancies, ovarian cancer is one of the most dangerous, with a high fatality rate and relapse due to the occurrence of chemoresistance. Many researchers demonstrated that oxidative stress is involved in tumor occurrence, development and procession. Nuclear factor erythroid 2-related factor 2 (NRF2) is an important transcription factor playing an important role in protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) activate NRF2 signaling inducing the expression of antioxidant enzymes such as heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) that protect cells against oxidative stress. However, NRF2 activation in cancer cells is responsible for the development of chemoresistance inactivating drug-mediated oxidative stress that normally leads cancer cells to death. In this review we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 (Kelch Like ECH Associated Protein 1) pathway in in vitro models of ovarian cancer. In particular, we reported how these compounds can modulate chemotherapy response
Signaling Pathways in Pregnancy
Full text linkWe are pleased to present this Special Issue of Cells, entitled ‘Signaling Pathways in Pregnancy’ [...
Pathology of Urologic Cancers
Full text linkWe are pleased to present this Special Issue of Cancers, entitled “Pathology of Urologic Cancers” [...
Disruption of BMP9 signalling contributes to altered acid ceramidase expression and processing in preeclampsia
No full textSphingolipids are critical bioactive mediators of cellular events. Ceramide (CER) is central to sphingolipid metabolism and its levels are kept in balance via the action of key regulatory enzymes that function by modulating its synthesis and breakdown in a variety of patho-physiological conditions. In particular, lysosomal acid ceramidase (ASAH1) is responsible for hydrolyzing CER into sphingosine (SPH). We have recently reported that altered sphingolipid metabolism in preeclampsia and IUGR, is in part due to impaired TGFß signaling. Bone morphogenetic protein 9 is a member of the TGFß superfamily that functions as a high affinity ligand for the Activin Receptor-like Kinase 1(ALK1) thereby activating R-SMAD1 signalling. Herein, we investigated the role of BMP9 in regulating ASAH1 expression in physiological and pathological conditions. Human choriocarcinoma JEG3 cells were treated with BMP9 (5–10 ng/ml) or control vehicle and examined ASAH1 protein expression by Western Blotting. Exposure of JEG3 cells to BMP9 resulted in increased ASAH1 protein expression. Inhibition of ALK1 signalling using the ALK1 inhibitor Dorsomorphin reversed the BMP9 stimulatory effect and led to an accumulation of inactive ASAH1 precursors. Immunoprecipitation of ASAH1 followed by immunoblotting with concanavalin A (identifies N-glycans) revealed decreased ASAH1 glycosylation following dorsomorphin treatment indicating an ALK1 signalling dependent regulation of ASAH1 maturation. Immunofluorescence analysis showed that dorsomorphin treatment resulted in co-localization of ASAH1with the endoplasmic reticulum marker (ER) calreticulin, in line with reduced glycosylation and trafficking of ASAH1 from the ER to the lysosomes. Of clinical relevance, BMP9, ALK1 and pophorylated SMAD1 protein expression levels were markedly decreased in preeclamptic placentae relative to age-matched controls. Our data implicates a novel role for BMP9 signaling via ALK1 in regulating ASAH1 expression, processing and trafficking in the human placenta. Disruption of this signalling pathway may in part contribute to altered sphingolipid metabolism found in preeclampsia. (Supported by CIHR
NRF2 modulation in TRAMP mice: an in vivo model of prostate cancer
No full textBackground Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis. Methods and results We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention. Conclusion We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis
Cellular Modulators of the NRF2/KEAP1 Signaling Pathway in Prostate Cancer
Full text linkProstate cancer is the second most common malignancy in men worldwide. Prostate cancer can be treated by surgery, radiotherapy and hormone therapy. The latter, in the form of androgen-deprivation therapy is needed to reduce prostate cancer progression at an advanced stage. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development and progression and the Nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway is affected by reactive oxygen species (ROS). Furthermore, the NRF2/KEAP1 signaling pathway has been investigated by several studies related to anti-androgen therapy, biochemical recurrence and radiotherapy. In this review we analysed the current literature regarding the indirect modulators involved in NRF2/KEAP1 pathway regulation and their role as possible therapeutic targets in prostate cancer cells
Role of CD93 in Health and Disease
Full text link: CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies
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