Publications by authors named "Guoli Li"

109 Publications

Effects of palmitic acid and eicosapentaenoic acid on angiogenesis of porcine vascular endothelial cells.

Vet Med Sci 2021 Sep 21. Epub 2021 Sep 21.

Innovative Institute of Animal Healthy Breeding, Zhongkai University of Agriculture and Engineering, Guangzhou, China.

Restricted placental angiogenesis is an important cause of intrauterine growth retardation in piglets. During pregnancy, sow obesity can result in an increase in placental lipid deposition, subsequently inhibiting placental angiogenesis and fetal development. However, the effect of different types of fatty acids on placental angiogenesis is still unclear. Trophoblast cells and vascular endothelial cells constitute two important types of placental tissue. In this study, we used palmitic acid (C16:0) and eicosapentaenoic acid (C20:5, n-3), respectively, to treat porcine trophectoderm cells (pTr2) and porcine iliac artery endothelial cells (PIEC) to study the effects of saturated fatty acids and n-3 polyunsaturated fatty acids (PUFAs) on placental angiogenesis in vitro. We found that C16:0 caused significant cytotoxicity in pTr2 and PIEC (p < 0.01) and inhibited the proliferation and migration of PIEC (p < 0.01), whereas C20:5 treatment exhibited very low cytotoxicity and minimal inhibition of cellular proliferation. Meanwhile, a low concentration of C16:0 had no effect on the tube formation in PIEC, whereas C20:5 significantly promoted tube formation of PIEC (p < 0.01). These results suggested that saturated fatty acids and n-3 PUFAs had different effects on placental angiogenesis. As essential functional fatty acid, n-3 PUFA might be effective measure in alleviating the placental lipotoxicity caused by sow obesity during pregnancy.
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http://dx.doi.org/10.1002/vms3.577DOI Listing
September 2021

The effects of albumin-bound paclitaxel combined with cisplatin injections on patients with advanced laryngeal cancer and serum survivin.

Am J Transl Res 2021 15;13(8):9802-9807. Epub 2021 Aug 15.

Department of Otolaryngology, Cangzhou Central Hospital Cangzhou, China.

Objective: To explore the effects of the TP (Taxol plus Platinol) regimen and the PF (Platinol plus fluorouracil) regimen on patients with advanced laryngeal cancer and on the patients' VEGF-C (vascular endothelial growth factor C) and survivin genes.

Methods: 42 patients with locally advanced laryngeal cancer treated in our hospital from June 2018 to October 2020 were recruited as the study cohort. The patients were assigned into a control group (21 cases) or an observation group (21 cases). The control group was administered the PF regimen, and the observation group was administered the TP regimen. Both groups were treated for four consecutive courses. The clinical efficacy of the two groups of patients was observed, and the two groups' treatment effects, their serum VEGF-C, and survivin levels, and their adverse reactions were compared.

Results: A superior clinical efficacy was observed in the observation group (85.7%) than in the control group (57.1%) (P<0.05). Before the treatment, the two groups' serum VEGF-C and survivin levels showed no significant differences (P>0.05). After the treatment, apparently lower serum VEGF-C and survivin levels in the observation group were measured, and both groups witnessed a decline in their levels (P<0.05). We measured higher overall survival times and tumor-free survival times in the patients in the observation group compared to the control group (P<0.05). There was no significant difference in the incidences of adverse reactions between the two groups of patients (P>0.05).

Conclusion: The TP regimen in the treatment of laryngeal cancer can reduce the VEGF-C and survivin levels in patients and has a better therapeutic effect, so it is worthy of clinical promotion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430087PMC
August 2021

Angelica Polysaccharide Antagonizes 5-FU-Induced Oxidative Stress Injury to Reduce Apoptosis in the Liver Through Nrf2 Pathway.

Front Oncol 2021 16;11:720620. Epub 2021 Aug 16.

Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, China.

Oxidative stress induced by chemotherapeutic agents causes hepatotoxicity. 5-Fluorouracil (5-FU) has been found to have a variety of side effects, but its toxic effect on the liver and the mechanism are still unclear. Angelica polysaccharide (ASP), the main active ingredient of Dang Gui, has antioxidative stress effects. In this study, we investigated the antagonistic effects of ASP on 5-FU-induced injury in the mouse liver and human normal liver cell line MIHA and the possible mechanism. Our results show that ASP inhibited 5-FU-induced the decrease in Bcl-2 protein and the increase in Bax protein. ASP alleviated 5-FU-induced the increase in alanine aminotransferase (ALT), triglyceride (TG), and aspartate aminotransferase (AST) content; hepatic steatosis; and liver fibrosis. ASP restored 5-FU-induced swelling of mitochondria and the endoplasmic reticulum. 5-FU promoted the expression of Keap1 and increased the binding to NF-E2-related factor 2 (Nrf2) to reduce the nuclear translocation of Nrf2, thereby weakening the transcriptional activity of Nrf2 to inhibit the expression of HO-1; reducing the activity of GSH, SOD, and CAT to increase ROS content; and aggravating DNA damage (indicated by the increase in 8-OHdG). However, ASP reversed these reactions. In conclusion, ASP attenuated the 5-FU-induced Nrf2 pathway barrier to reduce oxidative stress injury and thereby inhibit the disorder of lipid anabolism and apoptosis. The study provides a new protectant for reducing the hepatic toxicity caused by 5-FU and a novel target for treating the liver injury.
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http://dx.doi.org/10.3389/fonc.2021.720620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415481PMC
August 2021

Adaptive friction compensation robust control for permanent magnet spherical actuator under compound disturbance.

Rev Sci Instrum 2021 Jul;92(7):075006

National Engineering Laboratory of Energy-Saving Motor and Control Technology, Anhui University, Hefei 230601, China.

The permanent magnet spherical actuator (PMSA) is a multi-variable featured and strongly coupled nonlinear system, and its motion control will unavoidably be affected by various factors. In order to reduce the influence of model uncertainty, friction, and external disturbance on the actual control during the position tracking of PMSA, this paper proposes a novel adaptive friction compensation robust control method under compound disturbance to improve the motion stability of PMSA. In this method, an adaptive compensator is designed to compensate for the unmodeled friction with unknown but constant parameters, and a robust compensator is used to deal with friction parameter variation and non-parametric interference factors that cannot be modeled. The combination of the two controllers can achieve better friction compensation and interference suppression with smaller feedback gain, thus reducing the trajectory tracking errors. In addition, in order to add the smoothness of the velocity value during the experiment, a first-order filter is introduced into the controller. Finally, the stability of the designed controller for the closed-loop system is proved by the Lyapunov method. Furthermore, a simulation model is established and experiments are conducted on the research prototype, and the feasibility and effectiveness under compound disturbance of the proposed control method are verified by comparing with the simulation and experimental results of other controllers.
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http://dx.doi.org/10.1063/5.0059367DOI Listing
July 2021

The efficacy of cisplatin and low-temperature plasma radiofrequency ablation in advanced laryngeal cancer patients and on the serum survivin levels.

Am J Transl Res 2021 15;13(6):7394-7399. Epub 2021 Jun 15.

Department of Otolaryngology, Cangzhou Central Hospital Cangzhou, China.

Objective: To investigate the effect of cisplatin injections combined with low-temperature plasma radiofrequency ablation on the clinical efficacy and serum survivin levels in advanced laryngeal cancer patients.

Methods: A total of 42 patients with locally advanced laryngeal cancer treated in our hospital from January 2018 to June 2020 were recruited as the study cohort and placed in a control group (21 cases) or a treatment group (21 cases) according to the medication administered to each patient. The patients in the control group were treated with CO laser resections under laryngoscopy combined with cisplatin injections, and the patients in the observation group were treated with low-temperature plasma radiofrequency ablation combined with cisplatin injections. The clinical efficacies in the two groups were observed and the WHOQOL-BREF scores, tumor marker levels, and serum survivin levels were compared.

Results: After the treatment, the ORR and CBR in the control group were 33.3% and 61.9%, respectively, levels that were significantly lower than the 66.7% and 90.5% in the observation group (P<0.05). The observation group's physiological, psychological, and social relations dimension scores were significantly higher than the corresponding scores in the control group (P<0.05). The tumor markers in the observation group were significantly lower in the serum CA72-4, CA19-9, and SCC-Ag levels than they were in the control group (P<0.05). The observation group exhibited lower serum survivin levels than the control group (P<0.05). Conclusion Cisplatin injections combined with low-temperature plasma radiofrequency ablation has a significant effect on the treatment of locally advanced laryngeal cancer. It can improve patients' quality of life, reduce the tumor marker levels in the body, and inhibit the serum survivin levels.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290673PMC
June 2021

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

Lancet Oncol 2021 08 9;22(8):1081-1092. Epub 2021 Jul 9.

Department of General Surgery, The First Hospital Affiliated to Army Medical University, Chongqing, China.

Background: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.

Methods: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral capecitabine 1000 mg/m twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.

Findings: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.

Interpretation: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.

Funding: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00297-7DOI Listing
August 2021

Separated parabiont reveals the fate and lifespan of peripheral-derived immune cells in normal and ischaemia-induced injured kidneys.

Open Biol 2021 Jun 9;11(6):200340. Epub 2021 Jun 9.

Division of Nephrology, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, People's Republic of China.

Immune cell infiltration plays a key role in acute kidney injury (AKI) to chronic kidney disease (CKD) progression. T lymphocytes, neutrophils, monocytes/macrophages and other immune cells regulate inflammation, tissue remodelling and repair. To determine the kinetics of accumulation of various immune cell populations, we established an animal model combining parabiosis and separation surgery to explore the fate and lifespan of peripheral leucocytes that migrate to the kidney. We found that peripheral T lymphocytes could survive for a long time (more than 14 days), whereas peripheral neutrophils survived for a short time in both healthy and ischaemia-induced damaged kidneys. Nearly half of the peripheral-derived macrophages disappeared after 14 days in normal kidneys, while their existing time in the inflammatory kidneys was prolonged. A fraction of F4/80 macrophages were renewed from the circulating monocyte pool. In addition, we found that after renal ischaemia reperfusion, neutrophils increased significantly in the early phase, and T lymphocytes mainly accumulated in the late stage, whereas macrophages infiltrated throughout AKI-CKD progression and were sustained longer in injured as opposed to normal kidneys. In conclusion, peripheral-derived macrophages, T lymphocytes and neutrophils exhibit different lifespans in the kidney, which may play different roles during AKI-CKD progression.
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http://dx.doi.org/10.1098/rsob.200340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187026PMC
June 2021

Distinct durability of IgM/IgG antibody responses in COVID-19 patients with differing severity.

Sci China Life Sci 2021 Jun 2. Epub 2021 Jun 2.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID), Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s11427-020-1947-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176871PMC
June 2021

NPC1-regulated dynamic of clathrin-coated pits is essential for viral entry.

Sci China Life Sci 2021 May 27. Epub 2021 May 27.

College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, China.

Viruses utilize cellular lipids and manipulate host lipid metabolism to ensure their replication and spread. Therefore, the identification of lipids and metabolic pathways that are suitable targets for antiviral development is crucial. Using a library of compounds targeting host lipid metabolic factors and testing them for their ability to block pseudorabies virus (PRV) and vesicular stomatitis virus (VSV) infection, we found that U18666A, a specific inhibitor of Niemann-Pick C1 (NPC1), is highly potent in suppressing the entry of diverse viruses including pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NPC1 deficiency markedly attenuates viral growth by decreasing cholesterol abundance in the plasma membrane, thereby inhibiting the dynamics of clathrin-coated pits (CCPs), which are indispensable for clathrin-mediated endocytosis. Significantly, exogenous cholesterol can complement the dynamics of CCPs, leading to efficient viral entry and infectivity. Administration of U18666A improves the survival and pathology of PRV- and influenza A virus-infected mice. Thus, our studies demonstrate a unique mechanism by which NPC1 inhibition achieves broad antiviral activity, indicating a potential new therapeutic strategy against SARS-CoV-2, as well as other emerging viruses.
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http://dx.doi.org/10.1007/s11427-021-1929-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160554PMC
May 2021

High-responsivity broadband photodetection of an ultra-thin InS/CIGS heterojunction on steel.

Opt Lett 2021 May;46(10):2288-2291

${\rm{Cu}}({\rm{In}},{\rm{Ga}}){\rm{S}}{{\rm{e}}_2}$ (CIGS) is a promising light harvesting material for large-area broadband photodetection, but it has been rarely studied up to now. Here an InS/CIGS heterojunction photodiode on steel is shown to be highly broadband photo-sensitive, with a photoresponsivity over 0.8 A/W, an external quantum efficiency over 100%, and a detectivity over 8×10 Jones from 505 to 910nm under a reverse bias of 1 V. Moreover, the CIGS photodiode exhibits an outstanding weak light detection ability (i.e., at light power density of ${{20}}\;\unicode{x00B5} {\rm{W/c}}{{\rm{m}}^2}$), reaching a record responsivity of 2.06 A/W, an impressive EQE of 293%, and a good detectivity of ${2.3} \times {{1}}{{{0}}^{11}}$ Jones at 870 nm under 1 V reverse bias. Importantly, the CIGS photodiode, working as a self-powered photodetector, under 0 V, shows a record detectivity of ${\sim}{3.4} \times {{1}}{{{0}}^{12}}$ Jones with a high responsivity of ${\sim}{0.44}\;{\rm{A/W}}$ and a high EQE of ${\sim}{{63}}\%$, at 870 nm.
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http://dx.doi.org/10.1364/OL.423999DOI Listing
May 2021

Vanillin downregulates NNMT and attenuates NNMT‑related resistance to 5‑fluorouracil via ROS‑induced cell apoptosis in colorectal cancer cells.

Oncol Rep 2021 Jun 28;45(6). Epub 2021 Apr 28.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.

Chemoresistance is the main cause of poor prognosis in colorectal cancer (CRC). Nicotinamide N‑methyltransferase (NNMT) is a metabolic enzyme that is upregulated in various tumor types. It has been reported that NNMT inhibits apoptosis and enhances resistance to 5‑fluorouracil (5‑Fu) via inhibition of the apoptosis signal regulating kinase 1 (ASK1)‑p38 MAPK pathway in CRC cells. A natural product library was screened, and it was found that vanillin, also known as 4‑hydroxy‑3‑methoxybenzaldehyde, a plant secondary metabolite found in several essential plant oils, mainly , , and , may be a promising anticancer compound targeted to NNMT. The aim of the present study was to explore the effect of vanillin on promoting apoptosis and attenuating NNMT‑induced resistance to 5‑Fu in CRC. Lentiviral vectors of short hairpin RNA and small interfering RNA were transfected into HT‑29 cells to construct NNMT‑knockdown HT‑29 cell lines. Vectors containing an open reading frame of NNMT were stably transfected into SW480 cells to induce NNMT overexpression in SW480 cell lines. Vanillin was found to inhibit the mRNA and protein expression levels of NNMT following the inhibition of NNMT activity in HT‑29 cell lines. Vanillin was able to reverse NNMT‑induced increased cell proliferation, decreased cell apoptosis and resistance to 5‑Fu by inhibiting NNMT expression. Furthermore, it increased cell apoptosis by activating the ASK1‑p38 MAPK pathway, which could be inhibited by NNMT. In addition, vanillin increased cell apoptosis by promoting mitochondrial damage and reactive oxygen species. , the combination of vanillin with 5‑Fu yielded a notable synergy in inhibiting tumor growth and inducing apoptosis. Considering that vanillin is an important flavor and aromatic component used in foods worldwide, vanillin is deemed to be a promising anticancer candidate by inhibiting NNMT and may attenuate NNMT‑induced resistance to 5‑Fu in human CRC therapy with few side effects.
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http://dx.doi.org/10.3892/or.2021.8061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082342PMC
June 2021

Correction: Cullin-5 neddylation-mediated NOXA degradation is enhanced by PRDX1 oligomers in colorectal cancer.

Cell Death Dis 2021 Apr 6;12(4):369. Epub 2021 Apr 6.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

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http://dx.doi.org/10.1038/s41419-021-03656-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024314PMC
April 2021

Relapse or Re-Infection, the Situation of Recurrent Tuberculosis in Eastern China.

Front Cell Infect Microbiol 2021 17;11:638990. Epub 2021 Mar 17.

Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, China.

Purpose: Recurrent tuberculosis (TB) is defined by more than one TB episode per patient and is caused by re-infection with a new (Mtb) strain or relapse with the previous strain. Recurrence of TB is one important obstacle for End TB strategy in the world and elucidating the triggers of recurrence is important for the current TB control strategy in China. This study aimed to analyze the sources of recurrent TB by the molecular genotyping method.

Method: A population-based surveillance was undertaking on all culture-positive TB cases in Jiangsu province, China from 2013 to 2019. Phenotypic drug susceptibility test (DST) by proportion method and mycobacterial interspersed repetitive units-variable number of tandem repeat (MIRU-VNTR) were adopted for drug resistance and genotype detection.

Results: A total of 1451 culture-positive TB patients were collected and 30 (2.06%, 30/1451) TB cases had recurrent TB episodes. Except 7 isolates were failed during subculture, 23 paired isolates were assessed. After genotyping by MIRU-VNTR, 12 (52.17%, 12/23) paired recurrence TB were demonstrated as relapse and 11 (47.83%,11/23) paired cases were identified as re-infection. The average interval time for recurrence was 24.04 (95%CI: 19.37-28.71) months, and there was no significant difference between relapse and re-infection. For the relapsed cases, two paired isolates exhibited drug resistance shifting, while four paired isolates revealed inconsistent drug resistance among the re-infection group including two multidrug-resistant tuberculosis (MDR-TB) at the second episode.

Conclusion: Relapse and re-infection contributed equally to the current situation of recurrence TB in Jiangsu, China. Besides, more efficient treatment assessment, specific and vigorous interventions are urgently needed for MDR-TB patients, considering obvious performance among re-infection cases.
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http://dx.doi.org/10.3389/fcimb.2021.638990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010194PMC
July 2021

Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation.

Cell Metab 2021 May 1;33(5):971-987.e6. Epub 2021 Apr 1.

Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address:

Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-β-mediated antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-β production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus infection.
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http://dx.doi.org/10.1016/j.cmet.2021.03.006DOI Listing
May 2021

Cullin-5 neddylation-mediated NOXA degradation is enhanced by PRDX1 oligomers in colorectal cancer.

Cell Death Dis 2021 03 12;12(3):265. Epub 2021 Mar 12.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.

NOXA, a BH3-only proapoptotic protein involved in regulating cell death decisions, is highly expressed but short-lived in colorectal cancer (CRC). Neddylated cullin-5 (CUL5)-mediated ubiquitination and degradation of NOXA is crucial to prevent its overaccumulation and maintain an appropriate action time. However, how this process is manipulated by CRC cells commonly exposed to oxidative stress remain unknown. The peroxiredoxin PRDX1, a conceivable antioxidant overexpressed in CRC tissues, has been shown to inhibit apoptosis and TRAF6 ubiquitin-ligase activity. In this study, we found that PRDX1 inhibits CRC cell apoptosis by downregulating NOXA. Mechanistically, PRDX1 promotes NOXA ubiquitination and degradation, which completely depend on CUL5 neddylation. Further studies have demonstrated that PRDX1 oligomers bind with both the Nedd8-conjugating enzyme UBE2F and CUL5 and that this tricomplex is critical for CUL5 neddylation, since silencing PRDX1 or inhibiting PRDX1 oligomerization greatly dampens CUL5 neddylation and NOXA degradation. An increase in reactive oxygen species (ROS) is not only a hallmark of cancer cells but also the leading driving force for PRDX1 oligomerization. As shown in our study, although ROS play a role in upregulating NOXA mRNA transcription, ROS scavenging in CRC cells by N-acetyl-L-cysteine (NAC) can significantly reduce CUL5 neddylation and extend the NOXA protein half-life. Therefore, in CRC, PRDX1 plays a key role in maintaining intracellular homeostasis under conditions of high metabolic activity by reinforcing UBE2F-CUL5-mediated degradation of NOXA, which is also evidenced in the resistance of CRC cells to etoposide treatment. Based on these findings, targeting PRDX1 could be an effective strategy to overcome the resistance of CRC to DNA damage-inducing chemotherapeutics.
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http://dx.doi.org/10.1038/s41419-021-03557-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954848PMC
March 2021

Hysteresis-free MoS metal semiconductor field-effect transistors with van der Waals Schottky junction.

Nanotechnology 2021 Jan 7;32(13):135201. Epub 2021 Jan 7.

School of Information Science and Engineering, Wuhan University of Science and Technology, Wuhan, 430081, People's Republic of China.

Hysteresis-free and steep subthreshold swing (SS) are essential for low-power reliable electronics. Herein, MoS metal semiconductor field-effect transistors are fabricated with GeSe/MoS van der Waals Schottky junction as a local gate, in which the rectification behavior of the heterojunction offers the modulation of channel carriers. The trap-free gate interface enables the hysteresis-free characteristics of the transistors, and promises an ideal SS of 64 mV/dec at room temperature. All the devices operate with a low threshold voltage less than -1 V with desirable saturation behavior. An OR logic gate is constructed with the dual-gated MoS transistors by varying the back and top gate voltage. The strategy present here is promising for the design of low-power digital electronics based on 2D materials.
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http://dx.doi.org/10.1088/1361-6528/abd2e8DOI Listing
January 2021

Synthesis and Cytotoxic Evaluation of Sanjoseolide and Representative Analogues.

ACS Omega 2020 Dec 14;5(51):33478-33483. Epub 2020 Dec 14.

School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou, Gansu 730070, P. R. China.

The first total synthesis of sanjoseolide (), which was originally obtained from A, was achieved via an efficient route with a longest linear sequence of six steps from the commercially available 2,4-dihydroxyacetophenone in 8.6% overall yield. Meanwhile, a series of sanjoseolide representative analogues were synthesized and assessed for their antiproliferative potency against cancer cells of different origins. Compound inhibited the survival of all tested cancer cell lines in a dose-dependent manner, the IC values of the treatment were about 12.8 μM for human cholangiocarcinoma cell lines RBE and 12.7 μM for human cholangiocarcinoma cell lines HCCC-9810, which was more active than sanjoseolide (). Analysis of the structure-activity relationships revealed that the presence of a trifluoromethyl group may be beneficial in terms of both RBE and HCCC-9810 inhibition.
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http://dx.doi.org/10.1021/acsomega.0c05546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774250PMC
December 2020

The protocol of a prospective, multicenter, randomized, controlled phase III study evaluating different cycles of oxaliplatin combined with S-1 (SOX) as neoadjuvant chemotherapy for patients with locally advanced gastric cancer: RESONANCE-II trial.

BMC Cancer 2021 Jan 5;21(1):20. Epub 2021 Jan 5.

Department of Pancreatic and Gastric Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, No.17 Panjiayuannanli, Chaoyang District, Beijing, 100021, China.

Background: Curing locally advanced gastric cancer through surgery alone is difficult. Adjuvant and neoadjuvant chemotherapy bring potential benefits to more patients with gastric cancer based on several clinical trials. According to phase II studies and guidelines, SOX regimen as neoadjuvant chemotherapy is efficient. However, the optimal duration of neoadjuvant chemotherapy has not been established. In this study, we will evaluate the efficacy and safety of different cycles of SOX as neoadjuvant chemotherapy for patients with locally advanced gastric cancer.

Methods: RESONANCE-II trial is a prospective, multicenter, randomized, controlled phase III study which will enroll 524 patients in total. Eligible patients will be registered, pre-enrolled and receive three cycles of SOX, after which tumor response evaluations will be carried out. Those who show stable disease or progressive disease will be excluded. Patients showing complete response or partial response will be enrolled and assigned into either group A for another three cycles of SOX (six cycles in total) followed by D2 surgery; or group B for D2 surgery (three cycles in total). The primary endpoint is the rate of pathological complete response and the secondary endpoints are R0 resection rate, three-year disease-free survival, five-year overall survival, and safety.

Discussion: This study is the first phase III randomized trial to compare the cycles of neoadjuvant chemotherapy using SOX for resectable locally advanced cancer. Based on a total of six to eight cycles of perioperative chemotherapy usually applied in locally advanced gastric cancer, patients in group A can be considered to have completed all perioperative chemotherapy, the results of which may suggest the feasibility of using chemotherapy only before surgery in gastric cancer.

Trial Registration: Registered prospectively in the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) with registration number ChiCTR1900023293 on May 21st, 2019.
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http://dx.doi.org/10.1186/s12885-020-07764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786891PMC
January 2021

Hysteresis-Free MoSMetal Semiconductor Field-Effect Transistors with van der Waals Schottky Junction.

Nanotechnology 2020 Dec 11. Epub 2020 Dec 11.

School of Physics and Electronics, Key Laboratory for Micro/Nano Optoelectronic Devices of Ministry of Education, Hunan University, Changsha, Hunan, CHINA.

Hysteresis-free and steep subthreshold swing () are essential for low-power reliable electronics. Herein, MoSmetal semiconductor field-effect transistors (MESFETs) are fabricated with GeSe/MoSvan der Waals Schottky junction as a local gate, in which the rectification behavior of the heterojunction offers the modulation of channel carriers. The trap-free gate interface enables the hysteresis-free characteristics of the transistors, and promises an idealof 64 mV/dec at room temperature. All the devices operate with a low threshold voltage less than -1 V with desirable saturation behavior. An OR logic gate is constructed with the dual-gated MoStransistors by varying the back and top gate voltage. The strategy present here is promising for the design of low-power digital electronics based on 2D materials.
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http://dx.doi.org/10.1088/1361-6528/abd2e8DOI Listing
December 2020

TAS-102 has a tumoricidal activity in multiple myeloma.

Am J Cancer Res 2020 1;10(11):3752-3764. Epub 2020 Nov 1.

Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.

TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both and . We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC values in a range from 0.64 to 9.10 μM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716153PMC
November 2020

Iron overload is related to muscle wasting in patients with cachexia of gastric cancer: using quantitative proteome analysis.

Med Oncol 2020 Nov 16;37(12):113. Epub 2020 Nov 16.

Research Institute of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, People's Republic of China.

The incidence of gastric cancer cachexia is high and the clinical management is poor, so the study aimed to clarify the mechanism of muscle wasting to better screen patients with gastric cancer cachexia. Gastric cancer patients undergoing radical gastrectomy were divided into cachexia with sarcopenia (CS, n = 13) and normal (N, n = 10) two groups. The possible mechanism of skeletal muscle reduction was explored through Tandem Mass Tag (TMT) technique, Perls staining, Western blot analysis and measurement of oxidative stress indicators. The preoperative weight, weight loss, body mass index, calorie intake and skeletal muscle index values of the CS group were significantly lower than those of the N group (P < 0.05). We identified 114 differentially expressed proteins (DEP) in the muscles of two groups using TMT analysis. Bioinformatics analysis of DEP revealed that ferritin, iron and oxidative stress may be related to skeletal muscle consumption. Following Perls staining and measurement iron concentration in skeletal muscles, we found that the iron in the muscles of the CS group was significantly increased, and at the same time, western blot analysis showed that the expression of ferritin in the CS group was significantly increased and regulated by hepcidin-ferroportin axis. Finally, the CS group showed increased oxidative stress and weakened antioxidant stress systems in the muscles compared with the N group when oxidative stress indicators were analyzed. In conclusion, iron overload may be related to muscle loss in patients with gastric cancer cachexia. Gastric cancer patients with elevated ferritin are more likely to have muscle wasting.
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http://dx.doi.org/10.1007/s12032-020-01439-wDOI Listing
November 2020

Storm of soluble immune checkpoints associated with disease severity of COVID-19.

Signal Transduct Target Ther 2020 09 7;5(1):192. Epub 2020 Sep 7.

Institute of Infectious Diseases, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.

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http://dx.doi.org/10.1038/s41392-020-00308-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475713PMC
September 2020

PDK1/mTOR Signaling in Myeloid Cells Differentially Regulates the Early and Late Stages of Sepsis.

Mediators Inflamm 2020 25;2020:5437175. Epub 2020 Jul 25.

Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.

The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages.
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http://dx.doi.org/10.1155/2020/5437175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397376PMC
June 2021

miR-204/COX5A axis contributes to invasion and chemotherapy resistance in estrogen receptor-positive breast cancers.

Cancer Lett 2020 11 3;492:185-196. Epub 2020 Aug 3.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China; Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, PR China. Electronic address:

Breast cancer is the most common cancer among women worldwide, with 70% being estrogen receptor-positive (ER+). Although ER-targeted treatment is effective in treating ER + breast cancer, chemoresistance and metastasis still prevail. Outcome-predictable biomarkers can help improve patient prognosis. Through the analysis of the Array Express database, The Cancer Genome Atlas-Breast Cancer datasets, and breast tumor tissue array results, we found that cytochrome c oxidase subunit 5a (COX5A) was related to poor prognosis of ER + breast cancer. Further studies revealed that COX5A was positively associated with metastasis and chemoresistance in ER + breast cancer. In vitro experiments showed that knockdown of COX5A was accompanied by a decrease in ERα expression, cell cycle arrest, and epithelial-mesenchymal transition blockade, resulting in an inhibition of proliferation and invasion. Knockdown of COX5A enhanced the chemosensitivity of breast cancer cells by decreasing adenosine triphosphate and increasing reactive oxygen species levels. We report that miR-204 can target and inhibit the expression of COX5A, thus, reversing the functions of COX5A in ER + breast cancer cells. We found that COX5A may serve as a prognostic biomarker in ER + breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.07.027DOI Listing
November 2020

A retrospective cohort study of isoniazid-resistant tuberculosis treatment outcomes and isoniazid resistance-associated mutations in eastern China from 2013 to 2018.

J Glob Antimicrob Resist 2020 09 30;22:847-853. Epub 2020 Jul 30.

Department of Chronic Communicable Disease, Center for Disease Control and Prevention of Jiangsu Province, Nanjing, Jiangsu, PR China. Electronic address:

Objectives: The current situation of isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) and associated genetic factors is not clear in China.

Methods: A retrospective cohort study was conducted from 2013 to 2018 in Jiangsu Province, China. Phenotypic Hr-TB were identified by drug susceptibility testing on Lowenstein-Jensen medium and using a Mycobacterium Growth Indicator Tube 960 (MGIT 960) system, and mutations in the katG 315 codon and inhA promoter nucleotides -8, -15 and -16 were determined by GenoType MTBDRplus and sequencing. All of the Hr-TB patients enrolled were followed up until June 2019.

Results: A total of 1416 smear-positive sputum samples were collected, of which 57 were excluded due to the presence of nontuberculous mycobacteria. Finally, 63/1359 (4.6%) were determined as Hr-TB. After follow-up, 11 Hr-TB patients (17.5%) showed an unfavourable outcome, of whom 5 (7.9%) relapsed, 4 (6.3%) had treatment failure and 2 (3.2%) died. A total of 52 isolates (82.5%) were detected with either katG 315 or inhA promoter nucleotide -8, -15 or -16 mutations, whereas no canonical mutations were found in 8 isolates (12.7%); 3 isolates failed in mutation detection. TB history was found to be associated with unfavourable outcomes for Hr-TB (odds ratio = 6.13, 95% confidence interval 1.05-35.82; P = 0.04). However, mutations in katG 315 and the inhA promoter region were not found to be associated with Hr-TB unfavourable outcomes (P = 0.15).

Conclusion: Unfavourable outcomes for Hr-TB are serious in eastern China, especially for previously treated patients. Meanwhile, current genetic determination of Hr-TB is inadequate.
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http://dx.doi.org/10.1016/j.jgar.2020.07.012DOI Listing
September 2020

Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2.

J Virol 2020 08 31;94(18). Epub 2020 Aug 31.

Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada

The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models. SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.
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http://dx.doi.org/10.1128/JVI.00940-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459545PMC
August 2020

LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2.

J Virol 2020 08 31;94(18). Epub 2020 Aug 31.

Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA

C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry. Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.
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http://dx.doi.org/10.1128/JVI.00562-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459569PMC
August 2020

Pseudorabies virus encephalitis in humans: a case series study.

J Neurovirol 2020 08 22;26(4):556-564. Epub 2020 Jun 22.

Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.

Pseudorabies virus (PRV) is known to cause severe encephalitis in juvenile pigs and various non-native hosts; recent evidences suggest that PRV might cause encephalitis in humans. In a multicenter cohort study in China, next-generation sequencing of cerebrospinal fluid (CSF) was performed to detect pathogens in all patients with clinically suspected central nervous system infections. This study involved all the patients whose CSF samples were positive for PRV-DNA; their clinical features were evaluated, and species-specific PCR and serological tests were sequentially applied for validation. Among the 472 patients tested from June 1, 2016, to December 1, 2018, six were positive for PRV-DNA, which were partially validated by PCR and serological tests. Additionally, we retrospectively examined another case with similar clinical and neuroimaging appearance and detected the presence of PRV-DNA. These patients had similar clinical manifestations, including a rapid progression of panencephalitis, and similar neuroimaging features of symmetric lesions in the basal ganglia and bilateral hemispheres. Six of the patients were engaged in occupations connected with swine production. PRV infection should be suspected in patients with rapidly progressive panencephalitis and characteristic neuroimaging features, especially with exposure to swine.
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http://dx.doi.org/10.1007/s13365-020-00855-yDOI Listing
August 2020

Partial recovery of disturbed V-J pairing profiles of T-cell receptor in people living with HIV receiving long-term antiretroviral therapy.

Sci China Life Sci 2021 Jan 18;64(1):152-161. Epub 2020 Jun 18.

Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China.

Chronic human immunodeficiency virus (HIV) infection not only causes a gradual loss of CD4 T cells but also leads to a disturbance of the T cell receptor (TCR) repertoire. In people living with HIV (PLWH), monitoring TCR repertoire is challenged by the inconsistency of complementarity determining region 3 (CDR3) and limited cell numbers in clinical samples. Thus, a quantitative method is necessary for monitoring the TCR repertoire in PLWH. We characterized the TCR V-J pairing profile of naïve and memory CD4 T cells in healthy donors, HIV-infected antiretroviral therapy (ART)-naïve patients and long-term (over 5 years) ART-experienced patients by performing TCR sequencing. We developed a V-J index with 18 parameters which were subdivided into five categories (expression coverage, cumulative percentage of the top tenth percentile, diversity, intra-individual similarity and inter-individual similarity). In ART-naïve patients, 14 of the 18 parameters were significantly altered. Long-term ART recovered ten parameters. The four unrecovered parameters were related to inter-individual similarity. Therefore, these findings indicate that long-term ART could only partially recover TCR V-J pairs and introduce newly impacted V-J pairs. Moreover, these results provide new insights into the V-J pairing of the TCR and into the disturbance of TCR repertoire in HIV infection.
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http://dx.doi.org/10.1007/s11427-020-1718-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306449PMC
January 2021

Nicotinamide N-methyltransferase inhibits autophagy induced by oxidative stress through suppressing the AMPK pathway in breast cancer cells.

Cancer Cell Int 2020 24;20:191. Epub 2020 May 24.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016 Zhejiang People's Republic of China.

Background: Nicotinamide N-methyltransferase (NNMT) is highly expressed in several cancers and can regulate cell epigenetic status and various cell metabolism pathways, such as ATP synthesis and cellular stress response. We reported in our previous papers that NNMT overexpression inhibits the apoptosis and enhances the chemotherapy resistance of breast cancer cells. This study aims to investigate the effect of NNMT on autophagy induced by oxidative stress in breast cancer cells, which might provide a novel therapeutic strategy for breast cancer treatment.

Methods: NNMT and LC3B II protein levels in the two cell models (SK-BR-3 and MDA-MB-231) with NNMT overexpression or knockdown were detected by Western blotting and correlated with each other. Changes in cellular viability, intracellular reactive oxygen species (ROS) and ATP levels were assessed after HO treatment. Then, autophagosomes were imaged by transmission electron microscopy, and LC3 puncta were examined by confocal microscopy and flow cytometry. The LC3B II level and AMPK-ULK1 pathway activity were both detected by Western blotting to determine the role of NNMT in the HO-induced autophagy.

Results: NNMT expression was negatively correlated with LC3B II expression in both cell models (SK-BR-3 and MDA-MB-231). Then, NNMT overexpression attenuated the autophagy induced by HO in SK-BR-3 cells, whereas knockdown promoted autophagy induced by HO in MDA-MB-231 cells. Furthermore, mechanistic studies showed that NNMT suppressed the ROS increase, ATP decrease and AMPK-ULK1 pathway activation, resulting in the inhibition of HO-induced autophagy in breast cancer cells.

Conclusions: We conclude that NNMT inhibits the autophagy induced by oxidative stress through the ROS-mediated AMPK-ULK1 pathway in breast cancer cells and may protect breast cancer cells against oxidative stress through autophagy suppression.
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http://dx.doi.org/10.1186/s12935-020-01279-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247246PMC
May 2020
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