Publications by authors named "Bicheng Chen"

132 Publications

Human umbilical cord-derived mesenchymal stem cells improve chronic pancreatitis in rats via the AKT-mTOR-S6K1 signaling pathway.

Bioengineered 2021 Dec;12(1):1986-1996

Department of Hernia and Abdominal Wall Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Chronic pancreatitis (CP) is a progressive inflammatory disease. In clinical treatment, many patients cannot get a timely diagnosis and effective treatment due to the lack of early diagnosis indicators. Mesenchymal stem cells have immunomodulatory and anti-inflammatory effects, and have broad application prospects in treating auto-immune diseases and inflammatory diseases. This study aimed to clarify the mechanisms of human umbilical cord mesenchymal stem cells (HUCMSCs) in the treatment of CP. The rats were randomly divided into four groups, with six rats in each group: control group, CP group, CP + HUCMSCs-treated group I, and CP + HUCMSCs-treated group II. We evaluated the levels of inflammatory factors, fibrosis and apoptosis markers, detected the protein expression levels of AKT-mTOR-S6K1 and assessed histological changes of the pancreas. The results showed that HUCMSCs not only inhibited the secretion of inflammatory cytokines and activation of pancreatic stellate cells but also suppressed the apoptosis of acinar cells. Further investigation revealed that HUCMSCs noticeably suppressed the AKT-mTOR-S6K1 pathway in the pancreatic tissue of DBTC-induced CP. In addition, the therapeutic effect of HUCMSCs injected into the inferior vena cava and left gastric artery in the CP model was also observed, thus providing the basis for the clinical application of intervention measures.
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http://dx.doi.org/10.1080/21655979.2021.1928441DOI Listing
December 2021

Using Population-Based Cancer Registration Data and Period Analysis to Accurately Assess and Predict 5-Year Relative Survival for Lung Cancer Patients in Eastern China.

Front Oncol 2021 11;11:661012. Epub 2021 May 11.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background: The assessment of long-term survival of lung cancer patients based on data from population-based caner registries, using period analysis, was scarce in China. We aimed to accurately assess the long-term survival of lung cancer patients, and to predict the long-term survival in the future, using cancer registry data from Taizhou City, eastern China.

Methods: Four cancer registries with high-quality data were selected. Patients diagnosed with lung cancer during 2004-2018 were included. The long-term survival was evaluated using period analysis, with further stratification by sex, age at diagnosis and region. Additionally, projected 5-year relative survival (RS) of lung cancer patients for 2019-2023 was evaluated, using model-based period analysis.

Results: The 5-year RS of lung cancer patients diagnosed during 2014-2018 was 40.2% (31.5% for men and 56.2% for women). A moderate age gradient was observed for the period estimate, with the estimate decreasing from 50.5 to 26.5% in the age group of 15-44 years and ≥75 years, respectively. The 5-year RS of urban area was higher than that of rural area (52.3% vs. 38.9%). The overall projected 5-year RS of lung cancer patients was 52.7% for 2019-2023, with estimate of 43.0 and 73.2% for men and women, respectively. A moderate age gradient was also observed for the projected estimate. Moreover, estimate reached nearly 50% for rural and urban areas.

Conclusion: Period analysis tended to provide the up-to-date and precise survival estimates for lung cancer patients, which is worth further application, and provides important evidence for prevention and intervention of lung cancer.
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http://dx.doi.org/10.3389/fonc.2021.661012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144707PMC
May 2021

Rapamycin protects against aristolochic acid nephropathy in mice by potentiating mammalian target of rapamycin‑mediated autophagy.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Department of Nephrology, Qilu Hospital, Shandong University, Jinan, Shandong 250015, P.R. China.

Autophagy serves a crucial role in the etiology of kidney diseases, including drug‑induced renal impairment, inherited kidney disease, diabetic nephropathy and aristolochic acid nephropathy (AAN) and is, therefore, a potential target for treatment. We previously demonstrated that rapamycin could attenuate AAN in mice; however, the underlying mechanism remains to be elucidated. Therefore, whether the renal protective effect of rapamycin (an autophagy activator) is related to autophagy in aristolochic acid (AA)‑treated mice was of particular interest. The pathophysiological roles of rapamycin were investigated in AA‑induced nephrotoxicity in mice and the mechanisms of rapamycin action were explored by evaluating the modulation of autophagy in rapamycin‑treated mice and cultured renal tubular epithelial cells. Supplementation with rapamycin reversed AA‑induced kidney injury in mice and improved AA‑induced autophagy damage and . Mechanistically, rapamycin inhibited the renal expression of phosphorylated (p‑)mammalian target of rapamycin (mTOR) and p‑ribosomal S6 protein kinase 1, which in turn activated renal autophagy and decreased apoptosis, probably by removing AA‑elicited damaged mitochondria and misfolded proteins. The findings of the present study demonstrated that rapamycin protects against AA‑induced nephropathy by activating the mTOR‑autophagy axis and suggested that rapamycin may be a promising pharmacological target for the treatment of AAN.
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http://dx.doi.org/10.3892/mmr.2021.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127069PMC
July 2021

Islet Transplantation Reverses Podocyte Injury in Diabetic Nephropathy or Induced by High Glucose via Inhibiting RhoA/ROCK/NF-B Signaling Pathway.

J Diabetes Res 2021 10;2021:9570405. Epub 2021 Mar 10.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.

Objective: Abnormal signaling pathways play a crucial role in the mechanisms of podocyte injury in diabetic nephropathy. They also affect the recovery of podocytes after islet transplantation (IT). However, the specific signaling abnormalities that affect the therapeutic effect of IT on podocytes remains unclear. The purpose of this study was to assess whether the RhoA/ROCK/NF-B signaling pathway is related to podocyte restoration after IT.

Methods: A mouse model of diabetic nephropathy was established using streptozotocin. The mice were then subsequently reared for 4 weeks after islet transplantation to determine the effect of IT. Islet cells, CCG-1423 (RhoA Inhibitor), and fasudil (ROCK inhibitor) were then cocultured with podocytes to assess their protective effects on podocyte injury induced by high glucose (HG). Protein expression levels of RhoA, ROCK1, synaptopodin, IL-6, and MCP-1 in kidney tissues were then measured using immunohistochemistry and Western blotting techniques.

Results: Islet transplantation reduced the expression levels of RhoA/ROCK1 and that of related inflammatory factors such as IL-6 and MCP-1 in the kidney podocytes of diabetic nephropathy. In the same line, islet cells reduced the expression of RhoA, ROCK1, and pp65 in immortalized podocytes under high glucose (35.0 mmol/L glucose) conditions.

Conclusions: Islet transplantation can reverse podocyte injury in diabetes nephropathy by inhibiting the RhoA/ROCK1 signaling pathway. Islet cells have a strong protective effect on podocytes treated with high glucose (35.0 mmol/L glucose). Discovery of signaling pathways affecting podocyte recovery is helpful for individualized efficacy evaluation and targeted therapy of islet transplantation patients.
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http://dx.doi.org/10.1155/2021/9570405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969114PMC
March 2021

Dimethyl Fumarate Induces Metabolic Crisie to Suppress Pancreatic Carcinoma.

Front Pharmacol 2021 22;12:617714. Epub 2021 Feb 22.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC.
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http://dx.doi.org/10.3389/fphar.2021.617714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937954PMC
February 2021

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer.

Cancer Manag Res 2020 31;12:13527-13540. Epub 2020 Dec 31.

Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, People's Republic of China.

Purpose: Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored.

Methods: The Kaplan-Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and therapeutic strategy. In vitro experiments applied VE-822, an effective GC treatment, to assess cell migration and proliferation in gastric mucosa epithelial cells, and real-time PCR was used to measure alterations of autophagy-related gene expression.

Results: High , , , and mRNA levels were associated with good OS, while increased , , , , and mRNA levels related to unfavorable OS in patients with GC. overexpression had different effects on OS due to high levels of heterogeneity. High expression was correlated with good OS in female patients with GC and with bad OS for male patients. Additionally, the increased expression was more likely to get a satisfactory OS in patients who underwent surgery alone but was associated with poor OS for patients treated with 5-FU adjuvant. In addition, elevated expression was related to favorable OS for patients with poorly differentiated type, while for patients with moderate differentiation, it was relevant to poor OS. The in vitro experiments showed that berzosertib could significantly inhibit the migration and proliferation of human gastric mucosa epithelial cells, and further real-time PCR assessment of ATG expressions partially coincided with the bioinformation analysis above.

Conclusion: These results indicate that individual ATGs have unique prognostic significance interpreted using Kaplan-Meier plotter analysis and in vitro experiments, and this may help guide clinical therapeutic strategy and promote OS by individualizing therapy for GC patients.
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http://dx.doi.org/10.2147/CMAR.S278354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783202PMC
December 2020

Periplocin inhibits the growth of pancreatic cancer by inducing apoptosis via AMPK-mTOR signaling.

Cancer Med 2021 01 24;10(1):325-336. Epub 2020 Nov 24.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Periplocin is a monomeric compound that exhibits anti-tumor activities. It is extracted from Cortex Periplocae.

Objective: This study aimed at determining the effect of periplocin treatment on the apoptosis and proliferation of human pancreatic cancer cells, and to elucidate on its mechanisms of action.

Methods: PANC1 and cfpac1 cells were treated with periplocin. Cell proliferation was detected by RTCA, Ki67 immunofluorescence, and a clonogenic assay. The transwell assay was used to examine cell migration and invasion functions. The expression of apoptosis-associated proteins was detected by flow cytometry and western blotting. Total RNA was extracted from the treated and untreated group of PANC1 cells for RNA-seq detection and analysis. Differentially expressed genes were screened for GO biological process and KEGG pathway analysis. Finally, CFPAC1 cells were subcutaneously inoculated into BALB / c nude mice to assess tumor growth.

Results: Periplocin inhibited the proliferation of PANC1 and CFPAC1 cells and induced their apoptosis by activating the AMPK/mTOR pathway and inhibiting p70 S6K. It also attenuated the cell migration, invasion, and inhibited the growth of cfpac1 xenografts in nude mice.

Conclusions: Periplocin inhibits human pancreatic cancer cell proliferation and induces their apoptosis by activating the AMPK / mTOR pathway.
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http://dx.doi.org/10.1002/cam4.3611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826466PMC
January 2021

STRAP as a New Therapeutic Target for Poor Prognosis of Pancreatic Ductal Adenocarcinoma Patients Mainly Caused by Mutation.

Front Oncol 2020 29;10:594224. Epub 2020 Sep 29.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and poor prognosis. , , , and are driver genes of PDAC and 30-75% patients have mutations in at least two of these four genes. Herein, we analyzed the relationship between these genes and prognosis of 762 patients in the absence of coexisting mutations, using data from three independent public datasets. Interestingly, we found that compared with mutations in other driver genes, mutation plays a significant role in leading to poor prognosis of PDAC. Additionally, we found that snoRNA-mediated rRNA maturation was responsible for the progression of cancer in PDAC patients with mutations. Inhibition of STRAP, which regulates the localization of SMN complexes and further affects the assembly of snoRNP, can effectively reduce maturation of rRNA and significantly suppress progression of -mutant or low p53 expression pancreatic cancer cells and . Our study highlighted the actual contribution rate of driver genes to patient prognosis, enriching traditional understanding of the relationship between these genes and PDAC. We also provided a possible mechanism and a new target to combat progression of -mutant PDAC patients.
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http://dx.doi.org/10.3389/fonc.2020.594224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550692PMC
September 2020

Corrigendum to "Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration" [Biomed. Pharmacother. 2020 (128) 110366].

Biomed Pharmacother 2020 Oct 19;130:110631. Epub 2020 Aug 19.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiffiffiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.biopha.2020.110631DOI Listing
October 2020

Upregulation of CENPM facilitates tumor metastasis via the mTOR/p70S6K signaling pathway in pancreatic cancer.

Oncol Rep 2020 Sep 7;44(3):1003-1012. Epub 2020 Jul 7.

Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Pancreatic cancer is a severe disease with high morbidity and mortality. However, the primary molecular mechanisms of pancreatic tumor formation and progression remain unclear. The present study using sequencing technology revealed that the centromere protein M (CENPM) gene was overexpressed in pancreatic cancer tissues. CENPM is one of the components of a complex that plays a central role in kinetochore protein assembly, mitotic progression and chromosome segregation. However, the biological function of CENPM in pancreatic cancer has yet to be determined. Hence, two effective siRNAs were designed to knock down CENPM. Notably, downregulation of CENPM inhibited pancreatic cancer cell proliferation, altered the cell cycle and limited pancreatic cancer cell migration and invasion via the mTOR/p70S6K signaling pathway. This research provides new evidence that CENPM overexpression plays a significant role in the progression of pancreatic cancer. Overall, the present findings indicated that CENPM may be a significant biomarker for predicting the development and progression of pancreatic malignancy.
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http://dx.doi.org/10.3892/or.2020.7673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388243PMC
September 2020

Role of DNA damage in the progress of chronic tubule‑interstitial injury.

Mol Med Rep 2020 Aug 14;22(2):1081-1089. Epub 2020 May 14.

Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Tubulointerstitial fibrosis (TIF) is a common final endpoint of chronic allograft nephropathy. Over the years, several hypotheses have been developed to explain the progression of TIF, including mechanisms such as inflammation, epithelial‑mesenchymal transition, senescence, chronic hypoxia and reactive oxygen species. Furthermore, TIF is reportedly induced by the 'damage‑proliferation‑death' cycle. In the present study, an AA renal fibrosis model was established in vitro to investigate whether the vicious proliferation‑death cycle is a pathophysiological process of TIF following chronic injury to the kidneys. Results from the present study revealed that cell death was associated with the entrance of cells into the cell cycle. Genetic knockdown of p21 was observed to increase cell cycle progression and the proliferative rate of cells, which overall promoted increased rates of cell death. In addition, the activation of the DNA damage response (DDR) signaling pathway was demonstrated to be crucial to the initiation of the vicious cycle of 'proliferation‑death'. Ataxia telangiectasia mutated (ATM) is an important molecule of the DDR and the genetic knockdown of ATM induced apoptosis, increased cell proliferation and promoted cell death. The increase in apoptosis was suggested to be due to the decreased expression levels of p21 observed following the genetic knockdown of ATM. In conclusion, the present study suggested that the crosstalk between the ATM and p21 protein may serve an important role in the regulation of the 'proliferation‑death' cycle in the progress of chronic tubulointerstitial injury.
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http://dx.doi.org/10.3892/mmr.2020.11146DOI Listing
August 2020

Corrigendum to "Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration" [Biomed. Pharmacother. 128 (2020) 110366].

Biomed Pharmacother 2020 Sep 17;129:110394. Epub 2020 Jun 17.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.biopha.2020.110394DOI Listing
September 2020

Baohuoside-1 targeting mTOR inducing apoptsis to inhibit hepatocellular carcinoma proliferation, invasion and migration.

Biomed Pharmacother 2020 Aug 8;128:110366. Epub 2020 Jun 8.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Background: Baohuoside-1 is a flavonoid compound isolated from Epimedium koreanum Nakai. This study tried to systematically explore the potential anti-cancer functions of Baohuoside-1 in Hepatocellular Carcinoma and study related molecular mechanism. Moreover, as a potential candidate anti-cancer agent, Baohuoside-1 has relatively low toxic side effect.

Methods: The anti-cancer function including proliferation, invasion and migration of Baohuoside-1 in liver cancer was systematically assessed via colony formation, transwell assay and migration assay. Moreover, the anti-cancer functions of Baohuoside-1 was confirmed based on the nude mouse transplantation tumor experiment. The potential targeted signaling pathway was tested via flow cytometery and western blot analysis.

Results: In this study, we present the anti-HCC activity of Baohuoside-1 isolated from Epimedium through examing the effect of Baohuoside-1 on two different human liver cancer cell lines (HuH-7 and HepG2). Baohuoside-1 significantly inhibited the proliferation, invasion and migration of two liver cancer cell lines. Furthermore, the anticancer activity of Baohuoside-1 was confirmed via inhibiting liver tumor growth in nude mice in vivo. Additionally, the influence of Baohuoside-1 on liver cancer apoptosis was examined by analyzing the expression of pro/anti-apoptotic proteins (BAX, Bcl-2, caspase-3, and caspase-8). The potential targeting signaling of Baohuoside-1 was determined via testing key members' expression changes of mTOR and JAK2 signaling.

Conclusion: The inhibition of liver cancer by Baohuoside-1 is through targeting mTOR signaling not JAK2 signaling to induce apoptosis. Our study indicates that Baohuoside-1 is a potential candidate drug for therapy against liver cancer.
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http://dx.doi.org/10.1016/j.biopha.2020.110366DOI Listing
August 2020

Adipose‑derived mesenchymal stem cells ameliorate dibutyltin dichloride‑induced chronic pancreatitis by inhibiting the PI3K/AKT/mTOR signaling pathway.

Mol Med Rep 2020 Apr 21;21(4):1833-1840. Epub 2020 Feb 21.

Department of Surgery, Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Adipose‑derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC‑induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase‑3, BAX and Bcl‑2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC‑induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC‑induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future.
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http://dx.doi.org/10.3892/mmr.2020.10995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057804PMC
April 2020

Improved Integrated Whole Proteomic and Phosphoproteomic Profiles of Severe Acute Pancreatitis.

J Proteome Res 2020 06 27;19(6):2471-2482. Epub 2020 Apr 27.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China.

Severe acute pancreatitis (SAP) is caused by complicated biological factors, and revealing its complex pathogenesis by single-target analysis is difficult. Systematic studies have developed slowly because extraction of degradable pancreatic proteins exposed to multiple proteases is challenging. We present integrated whole proteomic and phosphoproteomic profiles of SAP rats based on a modified protein extraction strategy with less protein degradation. Data-dependent acquisition (DDA) and data-independent acquisition (DIA) strategies were applied to select an appropriate method. Total 275 differentially expressed proteins and 757 differentially expressed phosphorylated proteins were identified by DIA-based quantitative proteomics. Several signal transduction pathways, including the AMPK, MAPK, and PI3K-Akt pathways, were enriched in SAP. Up-regulation of phosphorylated proteins involved in the process of TNFA signaling and inflammatory response was also detected in SAP. Our results improve the understanding of SAP development and progression.
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http://dx.doi.org/10.1021/acs.jproteome.0c00229DOI Listing
June 2020

Blockade of the mTOR signaling pathway with rapamycin ameliorates aristolochic acid nephropathy.

Exp Ther Med 2020 Apr 25;19(4):2887-2894. Epub 2020 Feb 25.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Chronic aristolochic acid nephropathy (CAAN) is characterized by widespread apoptosis and interstitial fibrosis, which severely impairs kidney function. mTOR is crucial for cell proliferation and protein synthesis. In the present study, the therapeutic effects of blockade of mTOR activity by rapamycin on aristolochic acid nephropathy were investigated. experiments to determine cell apoptosis and cell cycle alterations caused by aristolochic acid (AA)-induced injury were conducted on three groups of cells: Untreated control, AAI (treated with aristolochic acid I), and AAI + rapamycin (RMS). experiments were conducted in a CAAN mouse model. One group of mice was treated with AAI (the CAAN group), while another group was treated with AAI and rapamycin (the treatment group). Kidney function and pathological changes in these mice were assessed by serum creatinine and urea nitrogen analysis. Hematoxylin and eosin staining of renal tissue was performed to evaluate the treatment effects of rapamycin. Western blotting and immunohistochemical staining were used to explore the mechanisms by which rapamycin inhibited cell proliferation, apoptosis and tissue fibrosis. In the experiments, rapamycin prevented AAI-induced cell apoptosis and G/M checkpoint cell cycle arrest. In the experiments, the treatment group exhibited lower serum creatinine and urea nitrogen, less extensive tubular atrophy and increased amount of glomerulus. Additionally, western blotting and immunohistochemical staining showed that the treatment group exhibited decreased expression levels of fibrosis-, proliferation- and apoptosis-related proteins compared with the CAAN group. The findings suggest that rapamycin can ameliorate kidney injury induced by AAI via blockade of mTOR, and thus could be a therapeutic strategy for patients with CAAN.
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http://dx.doi.org/10.3892/etm.2020.8550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086201PMC
April 2020

KRT17 Functions as a Tumor Promoter and Regulates Proliferation, Migration and Invasion in Pancreatic Cancer via mTOR/S6k1 Pathway.

Cancer Manag Res 2020 19;12:2087-2095. Epub 2020 Mar 19.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People's Republic of China.

Background: Pancreatic cancer (PC) is one of the most well-known malignancies with high mortality, but the underlying mechanism of PC remains unknown. Keratin17 (KRT17) expression has been reported in many malignancies, but its functions in PC are not clear. The aim of our study was to evaluate KRT17 expression and its potential role in PC.

Methods: The online databases GEPIA and THPA were used to identify KRT17 expression in tissues. Quantitative real-time PCR (qRT-PCR) was used to determine KRT17 expression in cell lines. Ki67 and ROS levels were detected by immunofluorescence assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. KRT17 downregulation was induced by the small interfering RNA (siRNA) technique. Proliferation function was evaluated by colony formation assay and RTCA. Migration and invasion were evaluated by transwell migration assay. A Western blot assay was used to detect protein levels.

Results: KRT17 was overexpressed in PC tissues compared to that in normal tissues. The results showed that Ki67 and ROS levels were decreased in pancreatic cancer cells after transfection with siKRT17. After KRT17 downregulation in PC cell lines, cell viability functions, including proliferation, migration and invasion, and mTOR/S6K1 phosphorylation levels were attenuated.

Conclusion: KRT17 knockdown significantly inhibited proliferation, migration and invasion in pancreatic cancer cells.
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http://dx.doi.org/10.2147/CMAR.S243129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090205PMC
March 2020

Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer.

J Cancer 2020 14;11(6):1505-1515. Epub 2020 Jan 14.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-β, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.
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http://dx.doi.org/10.7150/jca.38616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995390PMC
January 2020

Exploring the Mechanism of Skeletal Muscle in a Tacrolimus-Induced Posttransplantation Diabetes Mellitus Model on Gene Expression Profiles.

J Diabetes Res 2020 10;2020:6542346. Epub 2020 Jan 10.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Objective: Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle.

Methods: We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus.

Results: Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin.

Conclusions: This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM.
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http://dx.doi.org/10.1155/2020/6542346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975221PMC
November 2020

Effects of sildenafil on inflammatory injury of the lung in sodium taurocholate-induced severe acute pancreatitis rats.

Int Immunopharmacol 2020 Mar 10;80:106151. Epub 2020 Jan 10.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address:

Background: Inflammatory response and acute lung injury (ALI) occur in sodium taurocholate-induced severe acute pancreatitis (SAP). Because sildenafil has anti-inflammatory, anti-oxidant and immune-modulating effects, we investigated its effect on inflammatory and lung injury in sodium taurocholate-induced SAP-associated ALI rat lung.

Methods: Sodium taurocholate-induced SAP rats received sildenafil (100 mg/kg) or not and were compared to age-matched normal control animals. We evaluated inflammatory response by detecting the expression of inflammatory factors including IL-1β, IL-6 and TNF-α, and detected the level of lung injury through histopathological evaluation. Moreover, we also tested the protein expression of PCNA, P21, Bcl-2 and Bax in the lung.

Results: Sildenafil administration rats had a low level of lung injury and inflammation. In addition, sildenafil significantly increased the expression of proliferation-related markers and decreased the expression of apoptosis-related markers in lung tissue.

Conclusions: Sildenafil administration may attenuate inflammation and lung injury by promoting proliferation and suppressing apoptosis in SAP rats.
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http://dx.doi.org/10.1016/j.intimp.2019.106151DOI Listing
March 2020

Baohuoside I Inhibits the Proliferation of Pancreatic Cancer Cells via mTOR/S6K1-Caspases/Bcl2/Bax Apoptotic Signaling.

Cancer Manag Res 2019 19;11:10609-10621. Epub 2019 Dec 19.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People's Republic of China.

Background: Although the incidence of pancreatic cancer has increased markedly, the 5-year survival rate for this disease is considerably low compared with other types of cancer. Moreover, the mortality rate of pancreatic cancer is similar to its incidence rate. Current therapeutic agents exhibit a lack of specificity for pancreatic cancer. Baohuoside I is traditionally used to treat orgasmic disorder and inflammation. However, its role in pancreatic cancer is unknown.

Objective: To explore the effects of Baohuoside I on pancreatic cancer and to study the potential-related molecular mechanism.

Materials And Methods: In the present study, the antineoplastic effect of Baohuoside I was investigated with regard to pancreatic cancer via colony formation, transwell and migration assay. The energy metabolism changes of pancreatic cancer were tested by flow cytometry analysis and oxidative phosphorylation and glycolysis assay. The target signaling members were analyzed by Western blot.

Results: Baohuoside I inhibited the cell growth of pancreatic cancer cells. In addition, it affected intracellular energy metabolism to induce cancer cell apoptosis via the mTOR/S6K1 and the caspase/Bcl2/Bax signaling pathways.

Conclusion: The present data provide further insight into the development of novel drugs against pancreatic cancer.
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http://dx.doi.org/10.2147/CMAR.S228926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927568PMC
December 2019

DPP4 Inhibitor Attenuates Severe Acute Pancreatitis-Associated Intestinal Inflammation via Nrf2 Signaling.

Oxid Med Cell Longev 2019 15;2019:6181754. Epub 2019 Nov 15.

Department of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.

Severe acute pancreatitis (SAP) is a challenging disease with high morbidity and mortality, often complicated by multiple organ dysfunction syndrome (MODS). The intestine, a major organ involved in MODS, correlates strongly with the evolution of the disease. In this study, we demonstrated that the DPP4 inhibitor, sitagliptin, protects SAP-associated intestinal injury both in vitro and in vivo. These beneficial effects were achieved by suppressing oxidative stress and inflammatory responses. Moreover, in sitagliptin-treated SAP mice, expression of Nrf2 was induced and that of NF-B was reduced, compared to the control SAP mice. In addition, we used Nrf2 mice to test the protective effect of Nrf2 during sitagliptin treatment of SAP; our results indicated that Nrf2 mice had greater pancreatic and intestinal injury than wild-type mice. Taken together, high levels of ROS induced by SAP may be inhibited by sitagliptin, possibly by inactivating the Nrf2-NF-B pathway.
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http://dx.doi.org/10.1155/2019/6181754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885240PMC
April 2020

CircNr1h4 regulates the pathological process of renal injury in salt-sensitive hypertensive mice by targeting miR-155-5p.

J Cell Mol Med 2020 01 28;24(2):1700-1712. Epub 2019 Nov 28.

Department of Clinical Research & Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Circular RNAs are a class of widespread and diverse endogenous RNAs that may regulate gene expression in various diseases, but their regulation and function in hypertensive renal injury remain unclear. In this study, we generated ribosomal-depleted RNA sequencing data from normal mouse kidneys and from injured mouse kidneys induced by deoxycorticosterone acetate-salt hypertension and identified at least 4900 circRNA candidates. A total of 124 of these circRNAs were differentially expressed between the normal and injured kidneys. Furthermore, we characterized one abundant circRNA, termed circNr1h4, which is derived from the Nr1h4 gene and significantly down-regulated in the injured kidneys. RNA sequencing data and qPCR analysis also showed many microRNAs and mRNAs, including miR-155-5p and fatty acid reductase 1 (Far1), were differentially expressed between the normal and injured kidney and related to circNr1h4. In vitro, the silencing of circNr1h4 or overexpression of miR-155-5p significantly decreased Far1 levels and increased reactive oxygen species. Mechanistic investigations indicated that circNr1h4 acts as a competing endogenous RNA for miR-155-5p, leading to regulation of its target gene Far1. Our study provides novel insight into the molecular mechanisms underlying kidney injury in hypertension, which will be required to develop therapeutic strategies of targeting circRNAs for hypertensive kidney injury.
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http://dx.doi.org/10.1111/jcmm.14863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991678PMC
January 2020

Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway.

Oxid Med Cell Longev 2019 6;2019:2197017. Epub 2019 Nov 6.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325015 Zhejiang Province, China.

Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF- treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.
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http://dx.doi.org/10.1155/2019/2197017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875318PMC
April 2020

Effect of ATM on inflammatory response and autophagy in renal tubular epithelial cells in LPS-induced septic AKI.

Exp Ther Med 2019 Dec 21;18(6):4707-4717. Epub 2019 Oct 21.

Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The aim of the present study was to explore the role of ataxia-telangiectasia mutated (ATM) in lipopolysaccharide (LPS)-induced model of septic acute kidney injury (AKI) and the association between ATM, tubular epithelial inflammatory response and autophagy. The renal tubular epithelial cell HK-2 cell line was cultured and passaged, with HK-2 cell injury induced by LPS. The effects of LPS on HK-2 cell morphology, viability, ATM expression and inflammation were observed. Lentiviral vectors encoding ATM shRNA were constructed to knock down ATM expression in HK-2 cells. The efficiency of ATM knockdown in HK-2 cells was detected by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR). HK-2 cells transfected with the ATM shRNA lentivirus were used for subsequent experiments. Following ATM knockdown, corresponding controls were set up, and the effects of ATM on inflammation and autophagy were detected in HK-2 cells using RT-qPCR, western blotting and ELISA. After LPS stimulation, the HK-2 cells were rounded into a slender or fusiform shape with poorly defined outlines. LPS treatment reduced cell viability in a partly dose-dependent manner. LPS increased the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6, with the levels reaching its highest value at 10 µg/ml. IL-6 and IL-1β expression increased with increasing LPS concentration. These findings suggest that LPS reduced HK-2 cell viability whilst increasing the expression of inflammatory factors. Following transfection with ATM shRNA, expression levels of key autophagy indicators microtubule associated protein 1 light chain 3α I/II ratio and beclin-1 in the two ATM shRNA groups were also significantly reduced compared with the NC shRNA group. In summary, downregulation of ATM expression in HK-2 cells reduced LPS-induced inflammation and autophagy in sepsis-induced AKI , suggesting that LPS may induce autophagy in HK-2 cells through the ATM pathway leading to the upregulation of inflammatory factors.
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http://dx.doi.org/10.3892/etm.2019.8115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862447PMC
December 2019

Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis.

Cell Commun Signal 2019 11 12;17(1):145. Epub 2019 Nov 12.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.

Background: Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. However, the role of Notch1 in the formation of myofibroblasts and fibrosis in kidneys following injury remains unknown.

Methods: The activity of Notch1 signalling was evaluated in fibrotic kidneys in CKD patients and in ureteral obstructive models in vivo and in cultured fibroblasts and TECs in vitro. In addition, the crosstalk of Notch1 with TGF-β1/Smad2/3 signalling was also investigated.

Results: Notch1 activity was elevated in fibrotic kidneys of rat models and patients with chronic kidney disease (CKD). Further study revealed that epithelial and interstitial Notch1 activity correlated with an α-SMA-positive myofibroblastic phenotype. In vitro, injury stimulated epithelial Notch1 activation and epithelial-mesenchymal transition (EMT), resulting in matrix deposition in tubular epithelial cells (TECs). Additionally, interstitial Notch1 activation in association with fibroblast-myofibroblast differentiation (FMD) in fibroblasts mediated a myofibroblastic phenotype. These TGF-β1/Smad2/3-dependent phenotypic transitions were abolished by Notch1 knockdown or a specific antagonist, DAPT, and were exacerbated by Notch1 overexpression or an activator Jagged-1-Fc chimaera protein. Interestingly, as a major driving force behind the EMT and FMD, TGF-β1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-β1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis.

Conclusion: These findings suggest that epithelial and interstitial Notch1 activation in kidneys following injury contributes to the myofibroblastic phenotype and fibrosis through the EMT in TECs and to the FMD in fibroblasts by targeting downstream TGF-β1/Smad2/3 signalling.
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http://dx.doi.org/10.1186/s12964-019-0455-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849313PMC
November 2019

Clinical value of combined detection of reactive oxygen species modulator 1 and adenosine deaminase in pleural effusion in the identification of NSCLC associated malignant pleural effusion.

J Clin Lab Anal 2020 Mar 10;34(3):e23091. Epub 2019 Nov 10.

Science and Education Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background: Reactive oxygen species modulator 1 (ROMO1) is recognized to be involved in cell proliferation and is elevated in serum of various cancer patients. However, ROMO1 had little research in distinguishing between malignant pleural effusions (MPEs) and benign pleural effusions (BPEs).

Methods: Malignant pleural effusion samples from patients with non-small-cell lung cancer (NSCLC) and benign pleural effusion (BPE) samples containing tuberculous and inflammatory pleural effusions were collected. The samples were tested for ROMO1, pleural effusion adenosine deaminase (pADA), pleural effusion carbohydrate antigen (pCA125, pCA153, pCA199), pleural effusion ferritin (pFER), and pleural effusion lactate dehydrogenase (pLDH) levels, and the other relevant partial clinical data that were gathered were used to conduct statistical analysis.

Results: The ROMO1, pCA125, pCA199, pCA153, pADA + ROMO1, pCA153 + ROMO1, pCA125 + ROMO1, and pCA199 + ROMO1 levels in MPE were appreciably higher in comparison with BPE group (all P = .000). The concentration of pADA in MPE was markedly lower than BPE (P = .000). When the cutoff = 0.38, the sensitivity of combined detection of ROMO1 + pADA is 98.67% and the specificity is 70.73%, respectively, and the AUC (0.941) is the highest among other parameters.

Conclusion: The combined detection of ROMO1 + ADA in pleural effusion is an effective biomarker for identifying MPE caused by NSCLC.
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http://dx.doi.org/10.1002/jcla.23091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083413PMC
March 2020

STING-Mediated IFI16 Degradation Negatively Controls Type I Interferon Production.

Cell Rep 2019 10;29(5):1249-1260.e4

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; Suzhou Institute of Systems Medicine, Suzhou 215123, China. Electronic address:

γ-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here, we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting the E3 ligase TRIM21. The 1-pyrin region of IFI16 is responsible for the IFI16-STING interaction, and the first three lysines in the N-terminal region of IFI16 are the key sites that lead to STING-mediated IFI16 ubiquitination and degradation. Compared to wild-type IFI16, a higher level of viral DNA triggered IFN-β and antiviral IFN-stimulated gene expression, and thus less HSV-1 infection, was observed in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant that is resistant to degradation. STING-mediated negative feedback regulation of IFI16 restricts IFN-I overproduction during antiviral immunity to avoid autoimmune diseases.
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http://dx.doi.org/10.1016/j.celrep.2019.09.069DOI Listing
October 2019

Islet Transplantation Attenuating Testicular Injury in Type 1 Diabetic Rats Is Associated with Suppression of Oxidative Stress and Inflammation via Nrf-2/HO-1 and NF-B Pathways.

J Diabetes Res 2019 5;2019:8712492. Epub 2019 Sep 5.

Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.

Testicular structural and functional impairment is a serious complication in male diabetes mellitus (DM) patients that leads to impaired fertility in adulthood. In contrast to other endocrine therapies, islet transplantation (IT) can effectively prevent and even reverse diabetic nephropathy and myocardial damage. However, whether IT can alleviate diabetes-induced testicular injury remains unclear. In this study, we sought to investigate the effect of IT on diabetes-induced testicular damage. A diabetic rat model was established by streptozotocin injection. DM, IT, and insulin treatment (INS) groups were compared after 4 weeks of respective treatment. We confirmed that IT could effectively attenuate diabetes-induced testicular damage and recover sperm counts more extensively compared with INS in diabetic rats. In addition, significantly higher levels of superoxide dismutase (SOD) activity and lower contents of malondialdehyde (MDA) were detected in the testes of the IT group versus diabetic rats. Mechanism studies revealed that IT significantly activates the expression of Nrf-2, HO-1, and NQO-1 and inhibits upregulation of the NF-B expression in response to DM, while INS only exhibit slight impact on the protein expression. Therefore, we speculate that IT may prevent the progression of testicular damage by downregulating oxidative stress and inhibiting inflammation via Nrf-2/HO-1 and NF-B pathways.
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http://dx.doi.org/10.1155/2019/8712492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748178PMC
February 2020