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Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions.

The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions.

1051 related Products with: Vasoactive Intestinal Peptide Immunoregulatory Role at the Periapex: Associative and Mechanistic Evidences from Human and Experimental Periapical Lesions.

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Effects of glucocorticoid and noradrenergic activity on spatial learning and spatial memory in healthy young adults.

Acute stress leads to a rapid release of noradrenaline and glucocorticoids, which in turn influence cognitive functions such as spatial learning and memory. However, few studies have investigated noradrenergic and glucocorticoid effects on spatial learning and memory in humans. Therefore, we examined the separate and combined effects of noradrenergic and glucocorticoid stimulation on spatial learning and memory.

2257 related Products with: Effects of glucocorticoid and noradrenergic activity on spatial learning and spatial memory in healthy young adults.

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Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia.

We describe the clinical features and biochemical characteristics of a unique population of severely affected untreated patients with congenital adrenal hyperplasia (CAH) from an Indonesian population with proven cortisol deficiency but without clinical signs of cortisol deficiency. We evaluated the in vitro glucocorticoid activity of all relevant adrenal steroid precursors occurring in patients with CAH.

2741 related Products with: Glucocorticoid Activity of Adrenal Steroid Precursors in Untreated Patients With Congenital Adrenal Hyperplasia.

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Rational design of anti-GITR-based combination immunotherapy.

Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses. However, many patients still do not benefit from checkpoint blockade, highlighting the need for targeting of alternative immune pathways. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (T) functions and hamper regulatory T cell (T) suppression. On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others, we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral T cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite T reductions and increased T:T ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ).

1514 related Products with: Rational design of anti-GITR-based combination immunotherapy.

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Adrenocortical hypofunction with simultaneous primary aldosteronism: A case report.

Cases of adrenocortical hyperfunction combined with primary aldosteronism have been reported in the literature, and the underlying mechanism involves the secretion of aldosterone and glucocorticoids by a tumor or an adenoma. However, adrenocortical hypofunction and coexisting primary aldosteronism have not been reported until now. Herein, we report a case of adrenocortical hypofunction combined with primary aldosteronism.

2206 related Products with: Adrenocortical hypofunction with simultaneous primary aldosteronism: A case report.

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Endothelial Cell Growth Promoting Activity in Graves' Disease Sera is Neutralized by Anti-Basic Fibroblast Growth Factor Antibodies in Patients with Fat Expansive but Not Infiltrative Orbitopathy.

To report a case of orbital fat expansion leading to globe prolapse in a Graves' disease patient undergoing high-dose glucocorticoid therapy. To evaluate the growth factor receptor specificities of plasma autoantibodies in Graves' disease patients who exhibited contrasting subtypes of thyroid-associated ophthalmopathy, i.e. orbital fat expansion-type . infiltrative.

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PI3K inhibitors protect against glucocorticoid-induced skin atrophy.

Skin atrophy is a major adverse effect of topical glucocorticoids. We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, are induced by glucocorticoids in mouse and human skin and are central drivers of steroid skin atrophy. Thus, we hypothesized that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids.

1566 related Products with: PI3K inhibitors protect against glucocorticoid-induced skin atrophy.

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Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors.

Several bisphenol A (BPA) analogues have been detected in environmental samples, foodstuffs, and/or human biological samples, and there is concern regarding their potential endocrine-disrupting effects. In this study, we characterized the agonistic and/or antagonistic activities of BPA and eight its analogues against human estrogen receptors (ERα/β), androgen receptor (AR), glucocorticoid receptor (GR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR). All the test compounds, except for bisphenol P (BPP), showed both ERα and ERβ agonistic activities, with bisphenol AF (BPAF) being the most potent. On the other hand, BPAF and BPP showed ERα and ERβ antagonistic activities. Interestingly, their ER activities demonstrated a preference toward ERβ. All the test compounds, except for bisphenol S, showed AR antagonistic activities, with bisphenol E being the most potent. Weak GR antagonistic activities were also found in BPA and five its analogues. PXR agonistic activity was observed in the six compounds, with bisphenol Z being the most potent. Results of the CAR assay revealed that BPA and five its analogues acted as CAR inverse agonists. Taken together, these results suggested that BPA analogues demonstrate multiple effects via human nuclear receptors in a similar manner to BPA, and several analogues might have more potent endocrine-disrupting activity than does BPA.

1989 related Products with: Profiling of bisphenol A and eight its analogues on transcriptional activity via human nuclear receptors.

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DNA methylation levels are associated with CRF receptor antagonist treatment outcome in women with post-traumatic stress disorder.

We have previously evaluated the efficacy of the CRF receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup.

1882 related Products with: DNA methylation levels are associated with CRF receptor antagonist treatment outcome in women with post-traumatic stress disorder.

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GCDB: a glaucomatous chemogenomics database for in silico drug discovery.

Glaucoma is a group of neurodegenerative diseases that can cause irreversible blindness. The current medications, which mainly reduce intraocular pressure to slow the progression of disease, may have local and systemic side effects. Recently, medications with possible neuroprotective effects have attracted much attention. To assist in the identification of new glaucoma drugs, we created a glaucomatous chemogenomics database (GCDB; http://cadd.pharmacy.nankai.edu.cn/gcdb/home) in which various glaucoma-related chemogenomics data records are assembled, including 275 genes, 105 proteins, 83 approved or clinical trial drugs, 90 206 chemicals associated with 213 093 records of reported bioactivities from 22 324 corresponding bioassays and 5630 references. Moreover, an improved chemical similarity ensemble approach computational algorithm was incorporated in the GCDB to identify new targets and design new drugs. Further, we demonstrated the application of GCDB in a case study screening two chemical libraries, Maybridge and Specs, to identify interactions between small molecules and glaucoma-related proteins. Finally, six and four compounds were selected from the final hits for in vitro human glucocorticoid receptor (hGR) and adenosine A3 receptor (A3AR) inhibitory assays, respectively. Of these compounds, six were shown to have inhibitory activities against hGR, with IC50 values ranging from 2.92-28.43 μM, whereas one compoundshowed inhibitory activity against A3AR, with an IC50 of 6.15 μM. Overall, GCDB will be helpful in target identification and glaucoma chemogenomics data exchange and sharing, and facilitate drug discovery for glaucoma treatment.

1833 related Products with: GCDB: a glaucomatous chemogenomics database for in silico drug discovery.

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