The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stressrelated disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3 0 -deoxyadenosine (cordycepin) towards cell survival. 3 0 -Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3 0 -Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2a signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2a, and dephosphorylation of eIF2a by salubrinal mimicked the anti-apoptotic effect of 3 0 -deoxyadenosine. Unexpectedly, although 3 0 -deoxyadenosine caused activation of eIF2a, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3 0 -deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3 0 -deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3 0 -deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders. Endoplasmic reticulum (ER) stress-mediated tissue injury is implicated in a wide range of pathologies including cancers, infection, atherosclerosis, ischemia, neurodegenerative disorders and metabolic diseases such as diabetes mellitus.

BACKGROUND AND PURPOSECordyceps militaris has the potential to suppress differentiation of pre-adipocytes. However, the active entities in the extract and the underlying mechanisms of its action are not known. Hence, we investigated whether and how cordycepin (3′-deoxyadenosine), a constituent of C. militaris, inhibits adipogenesis. EXPERIMENTAL APPROACHDifferentiation of 3T3-L1 pre-adipocytes and pre-adipocytes in primary cultures was induced by Insulin, dexamethasone and IBMX, and these were used as in vitro models of adipogenesis. The effects of cordycepin on adipogenesis were examined with particular focus on the regulation of CCAAT/enhancer-binding protein b (C/EBPb) and PPARg. KEY RESULTSCordycepin suppressed the lipid accumulation and induction of adipogenic markers that occurred on differentiation of pre-adipocytes and also blocked the down-regulation of a pre-adipocyte marker. This anti-adipogenic effect was reversible and mediated by an adenosine transporter, but not A1, A2 or A3 adenosine receptors. This effect of cordycepin was not reproduced by other adenosine-related substances, including ATP, ADP and adenosine. Early induction of the adipogenic C/EBPb-PPARg pathway was suppressed by cordycepin. Blockade of mTORC1 via inhibition of PKB (Akt) and activation of AMP kinase was identified as the crucial upstream event targeted by cordycepin. In addition to its negative effect on adipogenesis, cordycepin suppressed lipid accumulation in mature adipocytes. CONCLUSIONS AND IMPLICATIONSThese results suggest that the anti-adipogenic effects of cordycepin occur through its intervention in the mTORC1-C/EBPb-PPARg pathway. Cordycepin, by blocking both adipogenesis and lipid accumulation, may have potential as a therapeutic agent for effective treatment of obesity and obesity-related disorders.

Edited by Noboru MizushimaKeywords: MG132 NF-jB Endoplasmic reticulum (ER) stress Unfolded protein response (UPR) C/EBPb a b s t r a c t Proteasome inhibitor MG132 blocks activation of NF-jB by preventing degradation of IjB. In this report, we propose an alternative mechanism by which MG132 inhibits cytokine-triggered NF-jB activation. We found that MG132 induced endoplasmic reticulum (ER) stress, and attenuation of ER stress blunted the suppressive effect of MG132 on NF-jB. Through ER stress, MG132 up-regulated C/EBPb mRNA transiently and caused sustained accumulation of its translational products liver activating protein (LAP) and liver-enriched inhibitory protein (LIP), both of which were identified as suppressors of NF-jB. Our results disclosed a novel mechanism underlying inhibition of NF-jB by MG132.

Objectives To reveal the utility of motion artifact reduction with convolutional neural network (MARC) in gadoxetate disodium–enhanced multi-arterial phase MRI of the liver. Methods This retrospective study included 192 patients (131 men, 68.7 ± 10.3 years) receiving gadoxetate disodium–enhanced liver MRI in 2017. Datasets were submitted to a newly developed filter (MARC), consisting of 7 convolutional layers, and trained on 14,190 cropped images generated from abdominal MR images. Motion artifact for training was simulated by adding periodic k-space domain noise to the images. Original and filtered images of pre-contrast and 6 arterial phases (7 image sets per patient resulting in 1344 sets in total) were evaluated regarding motion artifacts on a 4-point scale. Lesion conspicuity in original and filtered images was ranked by side-by-side comparison. Results Of the 1344 original image sets, motion artifact score was 2 in 597, 3 in 165, and 4 in 54 sets. MARC significantly improved image quality over all phases showing an average motion artifact score of 1.97 ± 0.72 compared to 2.53 ± 0.71 in original MR images (p < 0.001). MARC improved motion scores from 2 to 1 in 177/596 (29.65%), from 3 to 2 in 119/165 (72.12%), and from 4 to 3 in 34/54 sets (62.96%). Lesion conspicuity was significantly improved (p < 0.001) without removing anatomical details. Conclusions Motion artifacts and lesion conspicuity of gadoxetate disodium–enhanced arterial phase liver MRI were significantly improved by the MARC filter, especially in cases with substantial artifacts. This method can be of high clinical value in subjects with failing breath-hold in the scan. Key Points • This study presents a newly developed deep learning–based filter for artifact reduction using convolutional neural network (motion artifact reduction with convolutional neural network, MARC). • MARC significantly improved MR image quality after gadoxetate disodium administration by reducing motion artifacts, especially in cases with severely degraded images. • Postprocessing with MARC led to better lesion conspicuity without removing anatomical details.

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IntroductionEarly intervention in type 2 diabetes can prevent exacerbation of insulin resistance. More effective interventions can be implemented by early and precise prediction of the change in glycated haemoglobin A1c (HbA1c). Artificial intelligence (AI), which has been introduced into various medical fields, may be useful in predicting changes in HbA1c. However, the inability to explain the predictive factors has been a problem in the use of deep learning, the leading AI technology. Therefore, we applied a highly interpretable AI method, random forest (RF), to large-scale health check-up data and examined whether there was an advantage over a conventional prediction model.Research design and methodsThis study included a cumulative total of 42 908 subjects not receiving treatment for diabetes with an HbA1c <6.5%. The objective variable was the change in HbA1c in the next year. Each prediction model was created with 51 health-check items and part of their change values from the previous year. We used two analytical methods to compare the predictive powers: RF as a new model and multivariate logistic regression (MLR) as a conventional model. We also created models excluding the change values to determine whether it positively affected the predictions. In addition, variable importance was calculated in the RF analysis, and standard regression coefficients were calculated in the MLR analysis to identify the predictors.ResultsThe RF model showed a higher predictive power for the change in HbA1c than MLR in all models. The RF model including change values showed the highest predictive power. In the RF prediction model, HbA1c, fasting blood glucose, body weight, alkaline phosphatase and platelet count were factors with high predictive power.ConclusionsCorrect use of the RF method may enable highly accurate risk prediction for the change in HbA1c and may allow the identification of new diabetes risk predictors.

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Cordyceps militaris has been used in Eastern countries for the treatment of various diseases including chronic kidney diseases. However, there are no reports that identified its active entities and molecular mechanisms underlying its therapeutic effectiveness. 3 0 -Deoxyadenosine is a major nucleoside derivative isolated from C. militaris. Some reports suggested that both C. militaris and 3 0 -deoxyadenosine have anti-inflammatory and anti-fibrotic effects. In the present report, we investigated whether and how 3 0 -deoxyadenosine interferes with fibrogenic processes in the kidney. For this purpose, we examined effects of 3 0 -deoxyadenosine on the expression of collagens triggered by transforming growth factor-b (TGF-b1) and bone morphogenetic protein-4 (BMP-4), especially focusing on the regulation of Smad signaling in vitro and in vivo. We found that 3 0 -deoxyadenosine suppressed expression of collagens induced by TGF-b1 and BMP-4 dose dependently. This suppression occurred at the transcriptional level and was correlated with blunted activation of the CAGA box and the BMP-responsive element. The suppressive effect on the TGF-b/BMP signaling was mediated mainly by adenosine transporter and partially by the A3 adenosine receptor, but not A1/A2 adenosine receptors. 3 0 -Deoxyadenosine reduced levels of both phosphorylated and total Smad proteins (Smad1, 2 and 3) dose dependently. It was mainly ascribed to transcriptional suppression, but not to enhanced protein degradation and eIF2a-mediated translational suppression. Consistent with the in vitro results, in vivo administration with 3 0 -deoxyadenosine reduced the levels of phosphorylated and total Smad proteins, as well as the levels of Smad mRNAs, in the kidney subjected to unilateral ureteral obstruction. It was associated with blunted induction of type I collagen and a-smooth muscle actin, a decrease in the number of interstitial myofibroblasts and reduced fibrotic area. These results suggest that 3 0 -deoxyadenosine interferes with the TGF-b and BMP signaling via downregulation of Smads, which may underlie the anti-fibrotic effect of this agent. 3 0 -Deoxyadenosine may be useful for therapeutic intervention in various TGF-b-related fibrotic disorders.