Novel actions of progesterone: what we know today and what will be the scenario in the future?

Kaore, Shilpa N.; Langade, Deepak; Yadav, Vijay K.; Sharma, Parag; Thawani, Vijay; Sharma, Raj Kishore

doi:10.1111/j.2042-7158.2012.01464.x

Cited by 31 publications

(17 citation statements)

References 257 publications

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“…Our laboratory and others have demonstrated that in many pre-clinical studies progesterone has substantial neuroprotective effects against brain injury, including traumatic brain injury (TBI) and ischemic stroke (Sayeed et al, 2007; Ishrat et al, 2009; Kaore et al, 2012; Won et al, 2014). Progesterone has been shown to reduce infarct volume, edema, global inflammation and behavioral deficits in both permanent and transient rodent models of middle cerebral artery occlusion (MCAO) compared to vehicle-injected controls (Sayeed et al, 2007; Gibson et al, 2009; Ishrat et al, 2009; Jiang et al, 2009; Ishrat et al, 2012; Kaore et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Progesterone has been shown to reduce infarct volume, edema, global inflammation and behavioral deficits in both permanent and transient rodent models of middle cerebral artery occlusion (MCAO) compared to vehicle-injected controls (Sayeed et al, 2007; Gibson et al, 2009; Ishrat et al, 2009; Jiang et al, 2009; Ishrat et al, 2012; Kaore et al, 2012). As previously reported, progesterone significantly reduces infarct volume 72 hours after transient (t)MCAO (Sayeed et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

Remus

Sayeed

Won

et al. 2015

Experimental Neurology

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The neuroprotective effects of progesterone after ischemic stroke have been established, but the role of progesterone in promoting cerebrovascular repair remains under-explored. Male Sprague–Dawley rats underwent transient middle cerebral artery occlusion (tMCAO) for 90 min followed by reperfusion for 3 days. Progesterone (8 mg/kg/day) was administered intraperitoneally at 1 hour after initial occlusion followed by subcutaneous injections at 6, 24 and 48 hours post-occlusion. Rats were euthanized after 72 hours and brain endothelial cell density and macrophage infiltration were evaluated within the cerebral cortex. We also assessed progesterone’s ability to induce macrophage migration towards hypoxic/reoxygenated cultured endothelial cells. We found that progesterone treatment post-tMCAO protects ischemic endothelial cells from macrophage infiltration. We further demonstrate that infiltration of monocytes/macrophages can be induced by potent chemotactic factors such as monocyte chemoattractant protein-1 (MCP-1) and the chemokine ligand 1 (CXCL1), secreted by hypoxic/reoxygenated endothelial cells. Progesterone blunts secretion of MCP-1 and CXCL1 from endothelial cells after hypoxia/reoxygenation injury and decreases leukocyte infiltration. The treatment protects ischemic endothelial cells from macrophage infiltration and thus preserves vascularization after ischemic injury.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

Remus

Sayeed

Won

et al. 2015

Experimental Neurology

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“…In recent years, a number of reports have identified nongenomic cell responses initiated by the activation of steroid hormones-induced membrane signaling [Falkenstein et al, 2000;Losel and Wehling, 2003;Simoncini and Genazzani, 2003;Norman et al, 2004]. Nongenomic steroid hormone actions have been described for rapid effects of estrogen, progesterone, glucocorticoids, mineralcorticoids and androgens (for recent reviews see [Song and Buttgereit, 2006;Michels and Hoppe, 2008;Vasudevan and Pfaff, 2008;Papadopoulou et al, 2009;Dooley et al, 2012;Kaore et al, 2012;Lee et al, 2012;Wendler et al, 2012;Lang et al, 2013]. The nongenomic steroid hormone actions are initiated either by (a) specific steroid hormone membrane receptors, distinct from the classical receptors [Zhu et al, 2003], (b) the classical steroid receptors internalized in the plasma membrane [Freeman et al, 2005;Pedram et al, 2007;Razandi et al, 2010;Yu et al, 2012], (c) G-protein coupled receptors (GPCR) interacting with steroid hormones that may govern the rapid, non-genomic actions [Thomas et al, 2006;Pi et al, 2010;Gonzalez-Velazquez et al, 2012], or (d) possible crosstalk of steroid hormones with other specific membrane receptors such as the erythropoietin receptor EPOR [Pelekanou et al, 2010], the EGF-receptor [Bonaccorsi et al, 2004;Sen et al, 2010] the opioid receptors [Kampa et al, 2004] or NGF receptors [Anagnostopoulou et al, 2013].…”

Section: Introductionmentioning

confidence: 99%

The actin cytoskeleton in rapid steroid hormone actions

et al. 2014

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Early actin cytoskeleton reorganization is an important regulatory step of membrane-initiated, non-genomic steroid hormone actions. Specific intracellular signaling cascades control the rapid alterations of actin polymerization in a variety of cell models. Moreover, actin remodeling is a decisive component in the signaling of hormone-induced early and late cellular responses. This article briefly summarizes the current knowledge on the steroid hormone-induced early actin cytoskeleton rearrangements. It focuses on the current progress to characterize the glucocorticoid-and androgen-initiated, tissue-specific actin signaling pathways and discusses the plethora of cellular responses that are regulated by the early actin redistribution. It also provides insights into the potential clinical significance of actin dynamics and actin-specific molecular signaling for nongenomic steroid hormone actions on tumor cells. V C 2014 Wiley Periodicals, Inc.

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“…CBG's physiological ligands are steroid hormones, and it has a moderately high affinity for progesterone [44]. Since the 1980s, the synthetic progestin, megestrol acetate, has been used in the treatment of some forms of prostatic hyperplasia because it lowers the levels of testosterone, luteinising hormone and follicle-stimulating hormone, which are responsible for stimulating the unwanted proliferation of tissue in the prostate gland [45]–[49]. It also functions as an androgen receptor antagonist, starving prostate carcinomas of the testosterone and dihydrotestosterone required for their growth and maintenance [45], [48].…”

Section: Resultsmentioning

confidence: 99%

Towards Engineering Hormone-Binding Globulins as Drug Delivery Agents

2014

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The treatment of many diseases such as cancer requires the use of drugs that can cause severe side effects. Off-target toxicity can often be reduced simply by directing the drugs specifically to sites of diseases. Amidst increasingly sophisticated methods of targeted drug delivery, we observed that Nature has already evolved elegant means of sending biological molecules to where they are needed. One such example is corticosteroid binding globulin (CBG), the major carrier of the anti-inflammatory hormone, cortisol. Targeted release of cortisol is triggered by cleavage of CBG's reactive centre loop by elastase, a protease released by neutrophils in inflamed tissues. This work aimed to establish the feasibility of exploiting this mechanism to carry therapeutic agents to defined locations. The reactive centre loop of CBG was altered with site-directed mutagenesis to favour cleavage by other proteases, to alter the sites at which it would release its cargo. Mutagenesis succeeded in making CBG a substrate for either prostate specific antigen (PSA), a prostate-specific serine protease, or thrombin, a key protease in the blood coagulation cascade. PSA is conspicuously overproduced in prostatic hyperplasia and is, therefore, a good way of targeting hyperplastic prostate tissues. Thrombin is released during clotting and consequently is ideal for conferring specificity to thrombotic sites. Using fluorescence-based titration assays, we also showed that CBG can be engineered to bind a new compound, thyroxine-6-carboxyfluorescein, instead of its physiological ligand, cortisol, thereby demonstrating that it is possible to tailor the hormone binding site to deliver a therapeutic drug. In addition, we proved that the efficiency with which CBG releases bound ligand can be increased by introducing some well-placed mutations. This proof-of-concept study has raised the prospect of a novel means of targeted drug delivery, using the serpin conformational change to combat the problem of off-target effects in the treatment of diseases.

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Novel actions of progesterone: what we know today and what will be the scenario in the future?

Cited by 31 publications

References 257 publications

Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

The actin cytoskeleton in rapid steroid hormone actions

Towards Engineering Hormone-Binding Globulins as Drug Delivery Agents

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