Deubiquitination and Stabilization of PD-L1 by CSN5

Lim, Seung-Oe,Li, Chia-Wei,Xia, Weiya,Cha, Jong-Ho,Chan, Li-Chuan,Wu, Yun,Chang, Shih-Shin,Lin, Wan-Chi,Hsu, Jung-Mao,Hsu, Yi-Hsin,Kim, Taewan,Chang, Wei-Chao,Hsu, Jennifer L.,Yamaguchi, Hirohito,Ding Elsevier 2016 Cancer cell Vol.30 No.6

<P><B>Summary</B></P> <P>Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation </LI> <LI> Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization </LI> <LI> CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination </LI> <LI> Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

AT1 Receptor Modulator Attenuates the Hypercholesterolemia-Induced Impairment of the Myocardial Ischemic Post-Conditioning Benefits

Yun-Wei Li,Yan-Ming Li,Yan Hon,Qi-Lin Wan,Rui-Li He,Zhi-Zhong Wang,Cui-Hua Zhao 대한심장학회 2017 Korean Circulation Journal Vol.47 No.2

Background and Objectives: Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature’s protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats. Materials and Methods: HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff’s perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts. Results: Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N5-(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS). Conclusion: Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC.

An Arabidopsis SUMO E3 Ligase, SIZ1, Negatively Regulates Photomorphogenesis by Promoting COP1 Activity

Lin, Xiao-Li,Niu, De,Hu, Zi-Liang,Kim, Dae Heon,Jin, Yin Hua,Cai, Bin,Liu, Peng,Miura, Kenji,Yun, Dae-Jin,Kim, Woe-Yeon,Lin, Rongcheng,Jin, Jing Bo Public Library of Science 2016 PLoS genetics Vol.12 No.4

<P>COP1 (CONSTITUTIVE PHOTOMORPHOGENIC 1), a ubiquitin E3 ligase, is a central negative regulator of photomorphogenesis. However, how COP1 activity is regulated by post-translational modifications remains largely unknown. Here we show that SUMO (small ubiquitin-like modifier) modification enhances COP1 activity. Loss-of-function siz1 mutant seedlings exhibit a weak constitutive photomorphogenic phenotype. SIZ1 physically interacts with COP1 and mediates the sumoylation of COP1. A K193R substitution in COP1 blocks its SUMO modification and reduces COP1 activity in vitro and in planta. Consistently, COP1 activity is reduced in siz1 and the level of HY5, a COP1 target protein, is increased in siz1. Sumoylated COP1 may exhibits higher transubiquitination activity than does non-sumoylated COP1, but SIZ1-mediated SUMO modification does not affect COP1 dimerization, COP1-HY5 interaction, and nuclear accumulation of COP1. Interestingly, prolonged light exposure reduces the sumoylation level of COP1, and COP1 mediates the ubiquitination and degradation of SIZ1. These regulatory mechanisms may maintain the homeostasis of COP1 activity, ensuing proper photomorphogenic development in changing light environment. Our genetic and biochemical studies identify a function for SIZ1 in photomorphogenesis and reveal a novel SUMO-regulated ubiquitin ligase, COP1, in plants.</P>

Staged Improvement in Awareness of Disease for Elderly Cancer Patients in Southern China

Li, Xing,Dong, Min,Wen, Jing-Yun,Wei, Li,Ma, Xiao-Kun,Xing, Yan-Fang,Deng, Yun,Chen, Zhan-Hong,Chen, Jie,Ruan, Dan-Yun,Lin, Ze-Xiao,Wang, Tian-Tian,Wu, Dong-Hao,Liu, Xu,Hu, Hai-Tao,Lin, Jia-Yu,Li, Zhu Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.15

Background: In mainland China, awareness of disease of elderly cancer patients largely relies on the patients' families. We developed a staged procedure to improve their awareness of disease. Materials and Methods: Participants were 224 elderly cancer patients from 9 leading hospitals across Southern China. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between family and patients, patient awareness of their disease and participation in medical decision-making. After first cycles of treatment, increased information of disease was given to patients with cooperation of the family. Then patient awareness of their disease and participation in medical decision-making was documented. Results: Among the 224 cancer elderly patients, 26 (11.6%) made decisions by themselves and 125 (55.8%) delegated their rights of decision-making to their family. Subordinate family members tended to play a passive role in decision-making significantly. Patients participating more in medical decision-making tended to know more about their disease. However, in contrast to the awareness of disease, patient awareness of violation of medical recommendations was reversely associated with their participation in medical decision-making. Improvement in awareness of diagnosis, stages and prognosis was achieved in about 20% elderly cancer patients. About 5% participated more actively in medical decision-making. Conclusions: Chinese elderly cancer patient awareness of disease and participation in medical decision-making is limited and relies on their family status. The staged procedure we developed to improve patient awareness of disease proved effective.

Hepatitis B Virus DNA Negativity Acts as a Favorable Prognostic Factor in Hepatocellular Carcinoma Patients

Li, Xing,Zhong, Xiang,Chen, Zhan-Hong,Xing, Yan-Fang,Wu, Dong-Hao,Chen, Jie,Ma, Xiao-Kun,Lin, Qu,Wen, Jing-Yun,Wei, Li,Wang, Tian-Tian,Ruan, Dan-Yun,Lin, Ze-Xiao,Wu, Xiang-Yuan,Dong, Min Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.22

Background: This retrospective study was aimed to investigate the efficacy of prophylactic agents in hepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine and entecavir. Materials and Methods: A consecutive series of 203 HBV-related HCC patients receiving TACE were analyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation and progression free survival (PFS) were the main endpoints. Results: Some 48 (69.6%) reached virologic response. Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%, p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as compared to those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significant variables associated with virologic events. In addition, prophylaxis was the only independent protective factor for hepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver Italian Program score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudine demonstrated similar efficacy as entecavir. Conclusions: Prophylactic agents are efficacious for prevention of HBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayed a significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA and hepatitis B flares might be causes of tumor progression in these patients.

Correction to: Amelioration of radiation‑induced liver damage by p-coumaric acid in mice

Yun-Hong Li,Jiang-Xue Wu,Qian He,Jia Gu,Lin Zhang,Hao-Zhi Niu,Xin-Wen Zhang,Han-Ting Zhao,Jia-Ying Xu,Li-qiang Qin 한국식품과학회 2023 Food Science and Biotechnology Vol.32 No.5

In the original publication, incorrect versions of Figs. 2 , 3 ,4 and 5 were published. Specifi cally, the arrows in Figs. 2 , 3and 4 were moved outside the representative images, and theFig. 5 was wrongly replaced by another fi gure. The correctversion of Figs. 2 , 3 , 4 , and 5 , were shown below.

Efficacy of Prophylactic Entecavir for Hepatitis B Virus-Related Hepatocellular Carcinoma Receiving Transcatheter Arterial Chemoembolization

Li, Xing,Zhong, Xiang,Chen, Zhan-Hong,Wang, Tian-Tian,Ma, Xiao-Kun,Xing, Yan-Fang,Wu, Dong-Hao,Dong, Min,Chen, Jie,Ruan, Dan-Yun,Lin, Ze-Xiao,Wen, Jing-Yun,Wei, Li,Wu, Xiang-Yuan,Lin, Qu Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.18

Background and Aims: Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. Methods: A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. Results: Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. Conclusion: Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.

Pomelo fruit wastes are potentially valuable antioxidants, anti-inflfl ammatories, antihypertensives, and antihyperglycemics

Li-Yun Lin,Chi-Yun Huang,Kuan-Chou Chen,Robert Y. Peng 한국원예학회 2021 Horticulture, Environment, and Biotechnology Vol.62 No.3

Grapefruit (G) parts contain abundant phenolic acids and fl avonoids (PPNs and FLVs). The wastes created from exocarps,mesocarps (G wastes, GW) and waste blanching water (WBW) lead to a considerable loss of PPNs and FLVs. Here, weassessed Buntan (CB), Buntan Hayata (CBH), and Peiyu (CP) cultivars and observed considerable amounts of PPNs andFLVs. The ethanolic extracts of GW (GWE) and WBW contained gallic acid, protocatechuic acid, chlorogenic acid, caff eicacid, ferulic acid, coumaric acid, naringin, hesperidin, diosmin, quercetin, hesperetin, nobiletin, and tangeretin (GWC). GWEhas previously been reported to be a relatively active antioxidant, anti-infl ammatory (based on the expression of TNF-αin Raw264.7 cells), antihypertensive, and anti-hyperglycemic compound. The IC 50 values for antihyperglycemic activitywith WBW for α-amylase were as follows: CB (27.96 ± 0.03 mg/mL) < CP (28.13 ± 0.19 mg/mL) < CBH (41.60 ± 0.16 mg/mL), and those for α-glucosidase were CB (1.80 ± 0.03 mg/mL) < CP (2.97 ± 0.29 mg/mL) < CBH (9.10 ± 0.51 mg/mL). GWC upregulated Glut4 in HepG2 cells, as well as the insulin secretion capability, and intracellular levels in RIN-m5Fcells, and it downregulated DPP4 in HepG2 cells. The IC 50 values for the angiotensin-converting enzyme activity were:CBP (5.10 ± 0.02 mg/mL) < CB (7.24 ± 0.65 mg/mL) < CP (8.60 ± 2.03 mg/mL). Our results indicate that PPNs and FLVspresent in GW are worth reclaiming.

Amelioration of radiation-induced liver damage by p-coumaric acid in mice

Yun-Hong Li,Jiang-Xue Wu,Qian He,Jia Gu,Lin Zhang,Hao-Zhi Niu,Xin-Wen Zhang,Han-Ting Zhao,Jia-Ying Xu,Li-qiang Qin 한국식품과학회 2022 Food Science and Biotechnology Vol.31 No.10

Radiation-induced liver damage (RILD) is a spiny problem in radiotherapy or other circumstances that exposure to radiation. The need for radioprotective agent is increasing to protect liver tissue. This study aimed to explore the hepatoprotective effect of p-coumaric acid (CA) against RILD. C57BL/6 male mice were exposed to 4 Gy irradiation and administrated with CA for 4 days starting on the same day of irradiation. Mice were sacrificed to obtain blood and liver tissues on day 3.5 or 14 post irradiation, respectively. The blood and liver tissues were collected. As compared with the only irradiated group, CA supplementation improved liver morphology, decreased serum alanine aminotransferase and aspartate aminotransferase, inhibited BCL2-associated X (BAX) protein expression, and improved the mice hematopoietic function. CA at the dose of 100 mg/kg body weight showed better effect compared to the other doses. Thus, CA might possess potential to protect against RILD.

Establishment and Validation of a Nomogram for Nasopharyngeal Carcinoma Patients Concerning the Prognostic Effect of Parotid Lymph Node Metastases

Chao Lin,Xue-Song Sun,Sai-Lan Liu,Xiao-Yun Li,Nian Lu,Xin-Ling Li,Lin-Quan Tang,Ling Guo 대한암학회 2020 Cancer Research and Treatment Vol.52 No.3

Purpose The prognosis of nasopharyngeal carcinoma (NPC) patients with parotid lymph node (PLN) metastasis remains unclear. This study was performed to investigate the prognostic significance and optimal staging category of PLN metastasis and develop a nomogram for estimating individual risk. Materials and Methods Clinical data of 7,084 non-metastatic NPC patients were retrospectively reviewed. Overall survival (OS) was the primary endpoint. A nomogram was established based on the Cox proportional hazards regression model. The accuracy and calibration ability of this nomogram was evaluated by C-index and calibration curves with bootstrap validation. Results Totally, 164/7,084 NPC patients (2.3%) presented with PLNs. Multivariate analyses showed that PLN metastasis was a negative prognostic factor for OS, progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRFS). Patients with PLN metastasis had a worse prognosis than N3 disease. Five independent prognostic factors were included in the nomogram, which showed a C-index of 0.743. The calibration curves for probability of 3- and 5-year OS indicated satisfactory agreement between nomogram-based prediction and actual observation. All results were confirmed in the validation cohort. Conclusion NPC patient with PLN metastasis had poorer survival outcome (OS, PFS, DMFS, and LRFS) than N3 disease. We developed a nomogram to provide individual prediction of OS for patients with PLN metastasis.