NR4A1 (Nur77) mediates thyrotropin-releasing hormone-induced stimulation of transcription of the thyrotropin β gene: analysis of TRH knockout mice

Thyrotropin-releasing hormone (TRH) is a major stimulator of thyrotropin-stimulating hormone (TSH) synthesis in the anterior pituitary, though precisely how TRH stimulates the TSHβ gene remains unclear. Analysis of TRH-deficient mice differing in thyroid hormone status demonstrated that TRH was critical for the basal activity and responsiveness to thyroid hormone of the TSHβ gene. cDNA microarray and K-means cluster analyses with pituitaries from wild-type mice, TRH-deficient mice and TRH-deficient mice with thyroid hormone replacement revealed that the largest and most consistent decrease in expression in the absence of TRH and on supplementation with thyroid hormone was shown by the TSHβ gene, and the NR4A1 gene belonged to the same cluster as and showed a similar expression profile to the TSHβ gene. Immunohistochemical analysis demonstrated that NR4A1 was expressed not only in ACTH- and FSH- producing cells but also in thyrotrophs and the expression was remarkably reduced in TRH-deficient pituitary. Furthermore, experiments in vitro demonstrated that incubation with TRH in GH4C1 cells increased the endogenous NR4A1 mRNA level by approximately 50-fold within one hour, and this stimulation was inhibited by inhibitors for PKC and ERK1/2. Western blot analysis confirmed that TRH increased NR4A1 expression within 2 h. A series of deletions of the promoter demonstrated that the region between bp -138 and +37 of the TSHβ gene was responsible for the TRH-induced stimulation, and Chip analysis revealed that NR4A1 was recruited to this region. Conversely, knockdown of NR4A1 by siRNA led to a significant reduction in TRH-induced TSHβ promoter activity. Furthermore, TRH stimulated NR4A1 promoter activity through the TRH receptor. These findings demonstrated that 1) TRH is a highly specific regulator of the TSHβ gene, and 2) TRH mediated induction of the TSHβ gene, at least in part by sequential stimulation of the NR4A1-TSHβ genes through a PKC and ERK1/2 pathway.     

Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.     

Effects of regularizing sleep-wake schedules on daytime autonomic functions and psychological states in healthy university students with irregular sleep-wake habits

Sleep and Biological Rhythms - The present study examined the effects of regularizing sleep-wake schedules on sleep, autonomic function and mood/emotional and personality states in 14 habitually...     

Adult Mortality Attributable to Preventable Risk Factors for Non-Communicable Diseases and Injuries in Japan: A Comparative Risk Assessment

Background

The population of Japan has achieved the longest life expectancy in the world. To further improve population health, consistent and comparative evidence on mortality attributable to preventable risk factors is necessary for setting priorities for health policies and programs. Although several past studies have quantified the impact of individual risk factors in Japan, to our knowledge no study has assessed and compared the effects of multiple modifiable risk factors for non-communicable diseases and injuries using a standard framework. We estimated the effects of 16 risk factors on cause-specific deaths and life expectancy in Japan.

Methods and Findings

We obtained data on risk factor exposures from the National Health and Nutrition Survey and epidemiological studies, data on the number of cause-specific deaths from vital records adjusted for ill-defined codes, and data on relative risks from epidemiological studies and meta-analyses. We applied a comparative risk assessment framework to estimate effects of excess risks on deaths and life expectancy at age 40 y. In 2007, tobacco smoking and high blood pressure accounted for 129,000 deaths (95% CI: 115,000–154,000) and 104,000 deaths (95% CI: 86,000–119,000), respectively, followed by physical inactivity (52,000 deaths, 95% CI: 47,000–58,000), high blood glucose (34,000 deaths, 95% CI: 26,000–43,000), high dietary salt intake (34,000 deaths, 95% CI: 27,000–39,000), and alcohol use (31,000 deaths, 95% CI: 28,000–35,000). In recent decades, cancer mortality attributable to tobacco smoking has increased in the elderly, while stroke mortality attributable to high blood pressure has declined. Life expectancy at age 40 y in 2007 would have been extended by 1.4 y for both sexes (men, 95% CI: 1.3–1.6; women, 95% CI: 1.2–1.7) if exposures to multiple cardiovascular risk factors had been reduced to their optimal levels as determined by a theoretical-minimum-risk exposure distribution.

Conclusions

Tobacco smoking and high blood pressure are the two major risk factors for adult mortality from non-communicable diseases and injuries in Japan. There is a large potential population health gain if multiple risk factors are jointly controlled. Please see later in the article for the Editors'' Summary     

Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation

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Highlights? Palmitate induces β cell dysfunction by activating inflammatory processes in islets ? β cells sense palmitate via the TLR4 pathway and recruit M1 macrophages to islets ? M1 macrophages play a pivotal role in palmitate-induced β cell dysfunction ? M1 macrophages and inflammation also play a role in β cell dysfunction in T2D models     

Synthesis of quinolinomorphinan derivatives as highly selective δ opioid receptor ligands

We have reported previously the novel δ opioid agonist KNT-127 which showed high affinity and selectivity for the δ receptor. Moreover, the analgesic effect of subcutaneously administered KNT-127 was more potent than that of a prototypical δ agonist (?)-TAN-67 in the acetic acid writhing test. This study of the structure–activity relationship of KNT-127 derivatives focused on the introduction of substituents onto the 5′-, 6′-, 7′- or 8′-position of the quinoline ring and revealed that many derivatives with 5′- or 8′-substituents showed high affinities and selectivities for the δ receptor. Especially, SYK-153 with an 8′-OH group showed the highest affinity and the most balanced and highest selectivity for the δ receptor among the synthesized compounds.