Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue

Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#22020030, #22800049), Sumitomo Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, The Pharmacological Research Foundation Tokyo, Daiichi-Sankyo Foundation of Life Science, and The Naito Foundation

Attenuation of indirect markers of eccentric exercise-induced muscle damage by curcumin

Purpose: Polyphenolic curcumin is known to have potent anti-inflammatory effects; thus the present study investigated the hypothesis that curcumin ingestion would attenuate muscle damage after eccentric exercise. Methods: Fourteen untrained young men (24 ± 1 years) performed 50 maximal isokinetic (120°/s) eccentric contractions of the elbow flexors of one arm on an isokinetic dynamometer and the same exercise with the other arm 4 weeks later. They took 150 mg of curcumin (theracurmin) or placebo (starch) orally before and 12 h after each eccentric exercise bout in a randomised, crossover design. Maximal voluntary contraction (MVC) torque of the elbow flexors, range of motion of the elbow joint, upper-arm circumference, muscle soreness, serum creatine kinase (CK) activity, and plasma interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) concentration were measured before, immediately after, and 24, 48, 72 and 96 h after each eccentric exercise. Changes in these variables over time were compared between curcumin and placebo conditions by two-way repeated measures ANOVA. Results: MVC torque decreased smaller and recovered faster (e.g., 4 days post-exercise: −31 ± 13 % vs. −15 ± 15 %), and peak serum CK activity was smaller (peak: 7684 ± 8959 IU/L vs. 3398 ± 3562 IU/L) for curcumin than placebo condition (P \u3c 0.05). However, no significant differences between conditions were evident for other variables, and no significant changes in IL-6 and TNF-α were evident after exercise. Conclusion: It is concluded that theracurmin ingestion attenuates some aspects of muscle damage such as MVC loss and CK activity increase

Unfolded protein response, activated by OASIS family transcription factors, promotes astrocyte differentiation

OASIS is a member of the CREB/ATF family of transcription factors and modulates cell- or tissue-specific unfolded protein response signalling. Here we show that this modulation has a critical role in the differentiation of neural precursor cells into astrocytes. Cerebral cortices of mice specifically deficient in OASIS (Oasis−/−) contain fewer astrocytes and more neural precursor cells than those of wild-type mice during embryonic development. Furthermore, astrocyte differentiation is delayed in primary cultured Oasis−/− neural precursor cells. The transcription factor Gcm1, which is necessary for astrocyte differentiation in Drosophila, is revealed to be a target of OASIS. Introduction of Gcm1 into Oasis−/− neural precursor cells improves the delayed differentiation of neural precursor cells into astrocytes by accelerating demethylation of the Gfap promoter. Gcm1 expression is temporally controlled by the unfolded protein response through interactions between OASIS family members during astrocyte differentiation. Taken together, our findings demonstrate a novel mechanism by which OASIS and its associated family members are modulated by the unfolded protein response to finely control astrocyte differentiation.This work was partly supported by grants from the Japan Society for the Promotion of Science KAKENHI (#22020030, #22800049), Sumitomo Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Astellas Foundation for Research on Metabolic Disorders, Takeda Science Foundation, The Pharmacological Research Foundation Tokyo, Daiichi-Sankyo Foundation of Life Science, The Naito Foundation, Senri Life Science Foundation, Hokuto Foundation for Bioscience, and The Japan Prize Foundation

Automated classification of pulmonary nodules through a retrospective analysis of conventional CT and two-phase PET images in patients undergoing biopsy

Objective(s): Positron emission tomography/computed tomography (PET/CT) examination is commonly used for the evaluation of pulmonary nodules since it provides both anatomical and functional information. However, given the dependence of this evaluation on physician’s subjective judgment, the results could be variable. The purpose of this study was to develop an automated scheme for the classification of pulmonary nodules using early and delayed phase PET/ CT and conventional CT images.Methods: We analysed 36 early and delayed phase PET/CT images in patients who underwent both PET/CT scan and lung biopsy, following bronchoscopy. In addition, conventional CT images at maximal inspiration were analysed. The images consisted of 18 malignant and 18 benign nodules. For the classification scheme, 25 types of shape and functional features were first calculated from the images. The random forest algorithm, which is a machine learning technique, was used for classification.Results: The evaluation of the characteristic features and classification accuracy was accomplished using collected images. There was a significant difference between the characteristic features of benign and malignant nodules with regard to standardised uptake value and texture. In terms of classification performance, 94.4% of the malignant nodules were identified correctly assuming that 72.2% of the benign nodules were diagnosed accurately. The accuracy rate of benign nodule detection by means of CT plus two-phase PET images was 44.4% and 11.1% higher than those obtained by CT images alone and CT plus early phase PET images, respectively.Conclusion: Based on the findings, the proposed method may be useful to improve the accuracy of malignancy analysis

Age, Symptomatic Metastatic Disease, and Malignant Pleural Effusion as Predictors of Poor Prognosis in Patients with Differentiated Thyroid Carcinoma Treated with Lenvatinib.

Background: Lenvatinib is one of the few therapeutic options available for radioiodine-refractory thyroid cancer. However, the factors that determine the therapeutic outcomes remain unknown.Methods: Patients with thyroid carcinoma treated with lenvatinib who had been dead or who had survived for longer than a halfyearwere retrospectively compared. We evaluated the clinical parameters when lenvatinib was started, and also studied the tumor volume reduction ratio, the duration until re-growth of the largest metastatic lesion, the thyroglobulin (Tg) reduction rate,and the duration until re-elevation of Tg after lenvatinib between survivors and dead patients.Results: We identified 16 patients, with an average age of 73.1±7.6 yrs and a male-to-female ratio of 5 to 11, who had advanced differentiated thyroid cancer that was treated with lenvatinib. Nine patients had died after 8.9±6.1 months, whereas 7 survived for 13.0±2.0 months after starting lenvatinib. The patients who died were older than the survivors (76.7±6.5 vs. 68.6±6.6 yrs, p=0.03).Malignant pleural effusion (p=0.017) and symptomatic metastatic disease (SMD) (p=0.039) were associated with death in a Kaplan-Meier survival analysis. Age (p=0.012, HR 1.150, CI 1.030-1.320) and SMD (p=0.014, HR 8.069, CI 1.503-61.34) wereassociated with poor outcome in a multivariate Cox proportional hazard model. The duration until the re-elevation of Tg waslonger in survivors than in patients who died (6.43±4.55 vs. 2.17±1.39 months, p=0.025).Conclusions: We identified multiple factors, including SMD, that were related to poor outcomes after lenvatinib treatment. This study suggests that lenvatinib might be started before patients develop SMD

Pharmacologic characterization of TBP1901, a prodrug form of aglycone curcumin, and CRISPR-Cas9 screen for therapeutic targets of aglycone curcumin

プロドラッグ型クルクミン注射製剤の抗腫瘍効果及び治療標的の包括的な解析 --安全性の高い抗がん薬としての開発に期待--. 京都大学プレスリリース. 2022-10-21.Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin β-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In β-glucuronidase (GUSB)-proficient mice, both curcumin β-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin β-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation

大腸杯細胞の最終分化における小胞体ストレスセンサーOASISの役割

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora