Prostaglandin E₂ promotes Th1 differentiation via synergistic amplification of IL-12 signalling by cAMP and PI3-kinase

T helper 1 (Th1) cells have critical roles in various autoimmune and proinflammatory diseases. cAMP has long been believed to act as a suppressor of IFN-γ production and Th1 cell-mediated immune inflammation. Here we show that cAMP actively promotes Th1 differentiation by inducing gene expression of cytokine receptors involved in this process. PGE(2) signalling through EP2/EP4 receptors mobilizes the cAMP-PKA pathway, which induces CREB- and its co-activator CRTC2-mediated transcription of IL-12Rβ2 and IFN-γR1. Meanwhile, cAMP-mediated suppression of T-cell receptor signalling is overcome by simultaneous activation of PI3-kinase through EP2/EP4 and/or CD28. Loss of EP4 in T cells restricts expression of IL-12Rβ2 and IFN-γR1, and attenuates Th1 cell-mediated inflammation in vivo. These findings clarify the molecular mechanisms and pathological contexts of cAMP-mediated Th1 differentiation and have clinical and therapeutic implications for deployment of cAMP modulators as immunoregulatory drugs

Early diagnosis of malignant-transformed ovarian mature cystic teratoma: fat-suppressed MRI findings

The most common form of malignant transformation developing from a mature cystic teratoma is squamous cell carcinoma, representing 80% of malignant transformations, while adenocarcinoma accounts for approximately 5%. Because of this rarity, few reports exist of preoperative diagnosis of this tumor by magnetic resonance imaging, in particular with fat suppression techniques. Here, we report magnetic resonance imaging findings and clinical features of a 79-year-old woman with mucinous adenocarcinoma arising from a mature cystic teratoma (measuring 5×6 cm), classified as surgical stage IA. Because of the poor prognosis of malignant transformation, when mature cystic teratomas are detected (even smaller than 5 cm tumor size) in postmenopausal women, serum tumor marker carcinoembryonic antigen levels and fat-suppressed magnetic resonance imaging may be potential indicators of malignant transformation

Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3.

植物由来成分であるプテロシンBはSIK3を阻害し変形性関節症の治療薬開発のリード化合物となる. 京都大学プレスリリース. 2016-03-31.Yahara, Y., Takemori, H., Okada, M. et al. Correction: Corrigendum: Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. Nat Commun 7, 12117 (2016).Osteoarthritis is a common debilitating joint disorder. Risk factors for osteoarthritis include age, which is associated with thinning of articular cartilage. Here we generate chondrocyte-specific salt-inducible kinase 3 (Sik3) conditional knockout mice that are resistant to osteoarthritis with thickened articular cartilage owing to a larger chondrocyte population. We also identify an edible Pteridium aquilinum compound, pterosin B, as a Sik3 pathway inhibitor. We show that either Sik3 deletion or intraarticular injection of mice with pterosin B inhibits chondrocyte hypertrophy and protects cartilage from osteoarthritis. Collectively, our results suggest Sik3 regulates the homeostasis of articular cartilage and is a target for the treatment of osteoarthritis, with pterosin B as a candidate therapeutic

The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector

Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB. Here, we describe a signaling module that mediates the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a CREB coactivator. This module consists of the calcium-regulated phosphatase calcineurin and the Ser/Thr kinase SIK2, both of which associate with TORC2. Under resting conditions, TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupts TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increases calcineurin activity, whereas cAMP inhibits SIK2 kinase activity. Our results illustrate how a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal cues

The Effects of Self-compassion and Help-Seeking on Stress Response in Adolescents

The purpose of this study was to examine the effect of self-compassion on help-seeking and stress response. Six-hundred seventeen junior high school students (315 men and 302 women) participated. Results suggested that high "positive attitude" and "fear and disinclination" forhelp-seeking associated with stress response. These results indicated that increasing positive attitude for help-seeking would not be able to lead improved mental health, but decreasing fear and disinclination for help-seeking would improve it. Self-compassion has negative impact for fear and disinclination for help-seeking, but doesn’t increasing positive attitude for help-seeking. increasing self-compassion will elicit adaptive help-seeking for improving mental health.本研究ではセルフ・コンパッションと被援助志向性およびストレス反応の関連について，中学生617名（男性315名，女性302名）を対象とする質問紙調査によって検討した。その結果，被援助志向性のうち他者に援助を求めることに対する抵抗感・期待感のどちらもストレス反応に促進的な影響をあたえることが示された。つまり，他者に援助を求めることに対する期待感を高めるだけでは精神的健康の向上にはつながらず，抵抗感を低減させることが精神的健康の改善を促すと考えられる。セルフ・コンパッションは他者に援助を求めることに対する抵抗感に抑制的に働くが，期待感には促進的に働かないことが示唆されており，セルフ・コンパッションを向上させることは，精神的健康を改善するうえで適応的な援助要請につながると考えられる

A multicenter randomized controlled trial to evaluate the efficacy and safety of nelfinavir in patients with mild COVID-19

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms