The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

/pdf/photodynamic-therapy-of-cancer-an-update-4fcrlehb17.pdf

Photodynamic therapy of cancer: An update†‡

Thereisgrowinginterestinthepossiblehealththreatposedbyendocrine-disruptingchemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor , retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness. (Endocrine Reviews 30: 293–342, 2009)

/pdf/endocrine-disrupting-chemicals-an-endocrine-society-3fgbtp8gql.pdf

Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement

5-Noncoding sequences have been tabulated for 211 messenger RNAs from higher eukaryotic cells. The 5'-proximal AUG triplet serves as the initiator codon in 95% of the mRNAs examined. The most conspicuous conserved feature is the presence of a purine (most often A) three nucleotides upstream from the AUG initiator codon; only 6 of the mRNAs in the survey have a pyrimidine in that position. There is a predominance of C in positions -1, -2, -4 and -5, just upstream from the initiator codon. The sequence CCAGCCAUG (G) thus emerges as a consensus sequence for eukaryotic initiation sites. The extent to which the ribosome binding site in a given mRNA matches the -1 to -5 consensus sequence varies: more than half of the mRNAs in the tabulation have 3 or 4 nucleotides in common with the CCACC consensus, but only ten mRNAs conform perfectly.

Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs

Inhibitors of programmed cell death (apoptosis) aberrantly prolonging cell viability may contribute to cancer by facilitating the insurgence of mutations and by promoting resistance to therapy Despite the identification of several new apoptosis inhibitors related to bcl-2 or to the baculovirus IAP gene, it is not clear whether apoptosis inhibition plays a general role in neoplasia Here, we describe a new human gene encoding a structurally unique IAP apoptosis inhibitor, designated survivin Survivin contains a single baculovirus IAP repeat and lacks a carboxyl-terminal RING finger Present during fetal development, survivin is undetectable in terminally differentiated adult tissues However, survivin becomes prominently expressed in transformed cell lines and in all the most common human cancers of lung, colon, pancreas, prostate and breast, in vivo Survivin is also found in approximately 50% of high-grade non-Hodgkin's lymphomas (centroblastic, immunoblastic), but not in low-grade lymphomas (lymphocytic) Recombinant expression of survivin counteracts apoptosis of B lymphocyte precursors deprived of interleukin 3 (IL-3) These findings suggest that apoptosis inhibition may be a general feature of neoplasia and identify survivin as a potential new target for apoptosis-based therapy in cancer and lymphoma

A novel anti-apoptosis gene, survivin , expressed in cancer and lymphoma

There are three known isoforms of the rat thyroid hormone receptor, TR alpha-1, TR beta-1, and TR beta-2. The first two are expressed in all tissues, whereas TR beta-2 appears to be expressed only in the pituitary. The differences in the roles of the three receptor isoforms are unknown, but may involve preferential interaction with different subsets of thyroid hormone-regulated genes in different tissues. We tested the binding of the three TR isoforms to putative thyroid hormone response elements (TREs) from genes that are expressed in the pituitary or other tissues and are regulated by thyroid hormone. In vitro translated 35S-labeled rat TR alpha-1, rat TR beta-2, and human TR beta-1 receptors were bound to a battery of biotinylated synthetic deoxyribonucleotides containing naturally occurring putative TREs from genes expressed either in only pituitary (rat glycoprotein hormone alpha-subunit, TSH beta-subunit, and GH) or in nonpituitary (rat alpha-myosin heavy chain, malic enzyme, and Moloney murine leukemia virus promoter) tissues. All three receptor forms bound to each of the TREs. TR beta-2 did not show preferential binding to TREs of pituitary-specific genes compared to TR beta-1. Additionally, TR alpha-1 had a similar TRE-binding pattern as the TR beta s, except for possibly less binding to rat glycoprotein hormone alpha-subunit TRE. Finally, rat pituitary and liver nuclear extracts enhanced TR binding to TREs, with the greatest enhancement seen with the alpha-subunit TRE. These studies suggest that all TR isoforms bind similarly to native TREs. Also, TR binding to TREs can be differentially enhanced by interactions with nuclear proteins.

Basal and thyroid hormone receptor auxiliary protein-enhanced binding of thyroid hormone receptor isoforms to native thyroid hormone response elements.

The effect of cycloguanil pamoate (CI-501) against a chlorguanide-resistant Chesson strain of Plasmodium vivax.

Thyroid hormone (Ts) stimulates gene transcription by activation of thyroid hormone receptors (TRs), which bind to thyroid hormone response elements in T,-regulated genes. Retinoid-X receptors (RXRs), major members of the TR auxiliary proteins, have recently been shown to form TR-RXR heterodimers, to enhance the binding of the TRs to thyroid hormone response elements, and to augment TRmediated transcriptional activation. In this report, we provide evidence that a putative adaptor(s), other than RXR, may be involved in Ts-stimulated gene transcription. First, To-stimulated, but not basal, transcription from the rat GH promoter was progressively and specifically inhibited by the addition of increasing amounts of either GST-TRB or GST-RXR6 in a cell-free in vitro transcription. Second, this specific transcriptional inhibition is not due to disruption of the DNA-binding activity of the endogenous TR-RXR complex. These results suggest that inhibition of Ts-stimulated transcription may be due to the sequestration of a limiting adaptor molecule(s). Hence, we hypothesize that a limiting adaptor(s), which may act as a bridging molecule between the TR-RXR complex and the basal transcriptional machinery, may be sequestered by either GST-TR6 or GSTRXRP, resulting in the inhibition of Ts-stimulated transcription. (Endocri

Adaptor(s) May Be Required in Thyroid Hormone-Stimulated Gene Transcription in Vitro

The course of Plasmodium inui and Babesia microti infections was studied in seven splenectomized squirrel monkeys (Saimiri sciureus) of Guyanan or Bolivian origin. Three of the monkeys were infected with P. inui either by the inoculations of parasitized blood or by the bite of infected mosquitoes. The remaining four monkeys were infected by the inoculation of parasitized blood, containing P. inui and B. microti in three and with B. microti only in one. The infection in all seven animals was severe, terminating fatally.

Plasmodium inui and Babesia microti infections in the squirrel monkey, Saimiri sciureus.

Two genes, c-ErbA alpha and c-ErbA beta, generate at least three functional T3 receptor (TR) isoforms in the rat: TR alpha-1, TR beta-1, and TR beta-2. The latter is an N-terminal splice variant of TR beta-1 whose expression is high in the pituitary gland, whereas the other isoforms are more widely expressed. It is believed that TR beta-2 might play an important role in the pituitary, but no specific biological activities have been defined. Using in vitro translated receptors, we were unable to detect striking isoform-specific differences in T3 binding, DNA binding, homodimerization and heterodimerization activities with retinoid X receptor in the electrophoretic mobility assay, or T3-dependent repression and activation of basal transcription in transfection assays. The N-terminus of TR beta is completely dispensible for these activities. However, we found that unliganded TR alpha-1 and TR beta-1, but not TR beta-2, can repress glucocorticoid receptor-mediated transcriptional activation if the reporter gene promoter contains binding sites for both receptor species. TR beta-2 also synergizes most efficiently with the glucocorticoid receptor in the presence for the of T3. The TR beta-2-specific N-terminus is required for these effects. This result indicates that the relative abundance of specific TR isoforms may determine the with the glucocorticoid receptor in the presence of T3. The TR beta-2 specific N-terminus is required for these effects. This result indicates that the relative abundance of specific TR isoforms may determine the quantitative response of a gene that is regulated by T3 and glucocorticoids. In particular, pituitary TR beta-2 may be an important mediator of GH gene expression, which is regulated by both of these hormones.

Repression of glucocorticoid receptor-mediated transcriptional activation by unliganded thyroid hormone receptor (TR) is TR isoform-specific

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