Interaction of heat shock protein (hsp90) with the cytoskeleton: potential implication in intracellular transport

In this article we will summarize the details concerning the association of 90kD heat shock protein (hsp90) with cytoskeletal structures and we will discuss the potential involvement of these interactions in the translocation of steroid hormone receptors to the cell nucleus. In cultured mammalian cells hsp90 has been found to be colocalized with both microtubules and cytokeratin intermediate filaments, whereas no association with actin filaments and vimentin intermediate filaments has been established. The colocalization of hsp90 with microtubules and cytokeratin in intact cells rises the possibility that cytoskeletal structures could serve as "rails" for the direct movement of the steroid hormone receptor via association-dissociation with hsp90 molecules from the cytoplasmic site of synthesis to the nuclear site of action.Biomedical Reviews 1994; 3: 27-37

The floods in Greece: the case of Mandra in Attica

Οι πλημμύρες είναι από τις συνηθέστερες φυσικές καταστροφές και εξαιρετικά επικίνδυνες σε παγκόσμια κλίμακα καθώς μπορούν να προκαλέσουν εκτεταμένες ζημιές σε περιουσίες και σε απώλεια ανθρώπινων ζωών. Σύμφωνα με πολλούς ειδικούς επιστήμονες, η αλλαγή του κλίματος έχει οδηγήσει στην αύξηση των πλημμυρικών φαινομένων τα τελευταία χρόνια παγκοσμίως, όπως και στην Ελλάδα. Στόχος της παρούσας εργασίας είναι να εξετάσει το πλημμυρικό γεγονός που έλαβε χώρα στις 14-15 Νοεμβρίου του 2017 στην περιοχή της Μάνδρας, Αττική (Ελλάδα). Η μέγιστη πλημμυρική παροχή των ρεμάτων Αγίας Αικατερίνης και Σούρες υπολογίσθηκε με τη χρήση της ορθολογικής μεθόδου (Giandotti) για περιόδους επαναφοράς ίσων με 10, 100 και 1000 έτη. Μελετήθηκαν τα χαρακτηριστικά των ρεμάτων και ερευνήθηκε η συμπεριφορά τους κατά τη διάρκεια της πλημμύρας. Αποδόθηκαν πολλές από τις συνέπειες στην ανθρώπινη παρέμβαση στις κοίτες των ρεμάτων.Floods are one of the most common natural disasters and are extremely dangerous in a global range since they can cause extensive damage to properties or losses in human lives. According to the opinion of many expert scientists, climate change has led to the increase of flooding phenomena over the last years worldwide, as well as in Greece. The aim of this paper is to examine the flooding event that occurred in Mandra area, Attica (Greece) on 14-15 November of 2017. The peak discharge of the Agia Ekaterini and Soures streams was calculated using the rational method (Giandotti) for return periods equal to 10, 100 and 1000 years. The stream characteristics were studied and their behavior during the flood was investigated. Many of the impacts were attributed to the human intervention in the streambeds

Opioid peptides in the female reproductive system: physiological implications

All endogenous opioid peptides derive from three precursor molecules i.e. proopiomelanocortin, proenkephalin and prodynorphin. The endogenous opioid peptides exert their biological effects through opioid receptors. Each endogenous opioid peptide exhibits higher binding affinity towards a specific type of opioid receptors. Current evidence suggests that endogenous opioid peptides play important regulatory roles in reproduction. Endogenous opioid peptides are present through the hypothalamic-pituitary-gonadal axis. The hypothalamic opioidergic mechanism represents one of the important central control systems of gonadotropin-releasing hormone and gonadotropin release. Opioids mediate the sex steroid effect exerted on gonadotropin-releasing hormone and luteinizing hormone secretion and play a crucial role in the integration of several neuroendocrine mechanisms. There is also evidence that suprahypothalamic mechanism enhances endogenous opioid inhibition of gonadotropin-releasing hormone. The genes of the endogenous opioid peptides are also expressed in peripheral reproductive tissues such as the endometrium and placenta. At least part of the endogenous opioid peptides effects may be paracrine or autocrine in nature. The possible roles of opioids in various physiological processes of the female reproductive system are also reviewed.Biomedical Reviews 1995; 4: 71-83

Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress

Expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) is up-regulated by several types of cell stress, such as ischemia, radiation and hyperosmotic shock. The SGK1 protein is activated by a signaling cascade involving phosphatidylinositide-3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin (mTOR). SGK1 up-regulates Na+/K+-ATPase, a variety of carriers including Na+-,K+-,2Cl–– cotransporter (NKCC), NaCl cotransporter (NCC), Na+/H+ exchangers, diverse amino acid transporters and several glucose carriers such as Na+-coupled glucose transporter SGLT1. SGK1 further up-regulates a large number of ion channels including epithelial Na+ channel ENaC, voltage-gated Na+ channel SCN5A, Ca2+ release-activated Ca2+ channel (ORAI1) with its stimulator STIM1, epithelial Ca2+ channels TRPV5 and TRPV6 and diverse K+ channels. Furthermore, SGK1 influences transcription factors such as nuclear factor kappa-B (NF-κB), p53 tumor suppressor protein, cAMP responsive element-binding protein (CREB), activator protein-1 (AP-1) and forkhead box O3 protein (FOXO3a). Thus, SGK1 supports cellular glucose uptake and glycolysis, angiogenesis, cell survival, cell migration, and wound healing. Presumably as last line of defense against tissue injury, SGK1 fosters tissue fibrosis and tissue calcification replacing energy consuming cells

Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Recently we have reported membrane androgen receptors-induced apoptotic regression of prostate cancer cells regulated by Rho/ROCK/actin signaling. In the present study we explored the specificity of these receptors and we analyzed downstream effectors controlling survival and apoptosis in hormone refractory DU145-prostate cancer cells stimulated with membrane androgen receptor-selective agonists.</p> <p>Results</p> <p>Using membrane impermeable conjugates of serum albumin covalently linked to testosterone, we show here down-regulation of the activity of pro-survival gene products, namely PI-3K/Akt and NF-κB, in DU145 cells. Testosterone-albumin conjugates further induced FasL expression. A FasL blocking peptide abrogated membrane androgen receptors-dependent apoptosis. In addition, testosterone-albumin conjugates increased caspase-3 and Bad protein activity. The actin cytoskeleton drug cytochalasin B and the ROCK inhibitor Y-27632 inhibited FasL induction and caspase-3 activation, indicating that the newly identified Rho/Rock/actin signaling may regulate the downstream pro-apoptotic effectors in DU145 cells. Finally, other steroids or steroid-albumin conjugates did not interfere with these receptors indicating testosterone specificity.</p> <p>Conclusion</p> <p>Collectively, our results provide novel mechanistic insights pointing to specific pro-apoptotic molecules controlling membrane androgen receptors-induced apoptotic regression of prostate cancer cells and corroborate previously published observations on the potential use of membrane androgen receptor-agonists as novel anti-tumor agents in prostate cancer.</p

Functional membrane androgen receptors in colon tumors trigger pro-apoptotic responses in vitro and reduce drastically tumor incidence in vivo

<p>Abstract</p> <p>Background</p> <p>Membrane androgen receptors (mAR) have been implicated in the regulation of cell growth, motility and apoptosis in prostate and breast cancer. Here we analyzed mAR expression and function in colon cancer.</p> <p>Results</p> <p>Using fluorescent mAR ligands we showed specific membrane staining in colon cell lines and mouse xenograft tumor tissues, while membrane staining was undetectable in healthy mouse colon tissues and non-transformed intestinal cells. Saturation/displacement assays revealed time- and concentration-dependent specific binding for testosterone with a K_Dof 2.9 nM. Stimulation of colon mAR by testosterone albumin conjugates induced rapid cytoskeleton reorganization and apoptotic responses, even in the presence of anti-androgens. The actin cytoskeleton drug cytochalasin B effectively inhibited the pro-apoptotic responses and caspase-3 activation. Interestingly, <it>in vivo </it>studies revealed that mAR activation resulted in a 65% reduction of tumor incidence in chemically induced Balb/c mice colon tumors.</p> <p>Conclusion</p> <p>Our results demonstrate for the first time that functional mARs are predominantly expressed in colon tumors and that their activation results in induction of anti-tumor responses <it>in vitro </it>and extensive reduction of tumor incidence <it>in vivo</it>.</p

Phosphate Homeostasis, Inflammation and the Regulation of FGF-23

Fibroblast growth factor 23 (FGF23) is released primarily from osteoblasts/osteocytes in bone. In cooperation with the transmembrane protein Klotho, FGF23 is a powerful inhibitor of 1α 25OH Vitamin D Hydroxylase (Cyp27b1) and thus of the formation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). As 1,25(OH)2D3 up-regulates intestinal calcium and phosphate absorption, the downregulation of 1,25(OH)2D3 synthesis counteracts phosphate excess and tissue calcification. FGF23 also directly inhibits renal phosphate reabsorption. Other actions of FGF23 include triggering of cardiac hypertrophy. FGF23 formation and/or release are stimulated by 1,25(OH)2D3, phosphate excess, Ca2+, PTH, leptin, catecholamines, mineralocorticoids, volume depletion, lithium, high fat diet, iron deficiency, TNFα and TGFß2. The stimulating effect of 1,25(OH)2D3 on FGF23 expression is dependent on RAC1/PAK1 induced actin-polymerisation. Intracellular signaling involved in the stimulation of FGF23 release also includes increases in the cytosolic Ca2+ concentration ([Ca2+]i) following intracellular Ca2+ release and store-operated Ca2+ entry (SOCE). SOCE is accomplished by the Ca2+ release-activated calcium channel protein 1 (Orai1) and its stimulator stromal interaction molecule 1 (STIM1). Expression of Orai1, SOCE and FGF23-formation are up-regulated by the proinflammatory transcription factor NFκB. The present brief review describes the cellular mechanisms involved in FGF23 regulation and its sensitivity to both phosphate metabolism and inflammation. The case is made that up-regulation of FGF23 by inflammatory mediators and signaling may amplify inflammation by inhibiting formation of the anti-inflammatory 1,25(OH)2D3