Publications by authors named "Lingyun Wu"

218 Publications

The interaction of disulfiram and HS metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth.

Toxicol Appl Pharmacol 2021 Jul 6;426:115642. Epub 2021 Jul 6.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; Department of Biology, Laurentian University, Sudbury, Canada. Electronic address:

Disulfiram (DSF), a sulfur-containing compound, has been used to treat chronic alcoholism and cancer for decades by inactivating aldehyde dehydrogenase (ALDH). Hydrogen sulfide (HS) is a new gasotransmitter and regulates various cellular functions by S-sulfhydrating cysteine in the target proteins. HS exhibits similar properties to DSF in the sensitization of cancer cells. The interaction of DSF and HS on ALDH activity and liver cancer cell survival are not clear. Here it was demonstrated that DSF facilitated HS release from thiol-containing compounds, and DSF and HS were both capable of regulating ALDH through inhibition of gene expression and enzymatic activity. The supplement of HS sensitized human liver cancer cells (HepG2) to DSF-inhibited cell viability. The expression of cystathionine gamma-lyase (a major HS-generating enzyme) was lower but ALDH was higher in mouse liver cancer stem cells (Dt81Hepa1-6) in comparison with their parental cells (Hepa1-6), and HS was able to inhibit liver cancer stem cell adhesion. In conclusion, these data point to the potential of combining DSF and HS for inhibition of cancer cell growth and tumor development by targeting ALDH.
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http://dx.doi.org/10.1016/j.taap.2021.115642DOI Listing
July 2021

U2AF1 mutation promotes tumorigenicity through facilitating autophagy flux mediated by FOXO3a activation in myelodysplastic syndromes.

Cell Death Dis 2021 Jun 28;12(7):655. Epub 2021 Jun 28.

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Mutations in the U2 small nuclear RNA auxiliary factor 1 (U2AF1) gene are the common feature of a major subset in myelodysplastic syndromes (MDS). However, the genetic landscape and molecular pathogenesis of oncogenic U2AF1 mutation in MDS are not totally understood. We performed comprehensive analysis for prognostic significance of U2AF1 mutations in acute myeloid leukemia (AML) cohort based on The Cancer Genome Atlas (TCGA) database. Functional analysis of U2AF1 mutation was performed in vitro. Differentially expressed genes (DEGs) and significantly enriched pathways were identified by RNA sequencing. The forkhead box protein O3a (FOXO3a) was investigated to mediate the function of U2AF1 mutation in cell models using lentivirus. Chromatin immunoprecipitation, immunoblotting analyses, and immunofluorescence assays were also conducted. U2AF1 mutations were associated with poor prognosis in MDS and AML samples, which significantly inhibited cell proliferation and induced cellular apoptosis in cell models. Our data identified that U2AF1-mutant cell lines undergo FOXO3a-dependent apoptosis and NLRP3 inflammasome activation, which induces pyroptotic cell death. Particularly, an increase in the level of FOXO3a promoted the progression of MDS in association with restored autophagy program leading to NLRP3 inflammasome activation in response to U2AF1 mutation. Based on the result that U2AF1 mutation promoted the transcriptional activity of Bim through upregulating FOXO3a with transactivation of cell cycle regulators p21 and p27, FOXO3a, a potentially cancer-associated transcription factor, was identified as the key molecule on which these pathways converge. Overall, our studies provide new insights that U2AF1 mutation functions the crucial roles in mediating MDS disease progression via FOXO3a activation, and demonstrate novel targets of U2AF1 mutations to the pathogenesis of MDS.
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http://dx.doi.org/10.1038/s41419-021-03573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238956PMC
June 2021

Withdrawal Notice: Roles of Aryl-hydrocarbon Receptor in Metabolism and Proliferative Behaviors Of Bone Marrow Mscs: Implications For Targeted Therapy

Curr Top Med Chem 2021 06 11. Epub 2021 Jun 11.

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.

The article has been withdrawn at the request of the authors of the journal Current Topics in Medicinal Chemistry.

Bentham Science apologizes to the readers of the journal for any inconvenience this may cause.

The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php

Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submit-ting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.
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http://dx.doi.org/10.2174/1568026621666210611163043DOI Listing
June 2021

An injectable double-crosslinking iodinated composite hydrogel as a potential radioprotective spacer with durable imaging function.

J Mater Chem B 2021 04 6;9(15):3346-3356. Epub 2021 Apr 6.

College of Materials Science & Engineering, Zhejiang University of Technology, China.

Prostate cancer is one of the leading causes of cancer incidence among males worldwide. Radiotherapy can achieve similar oncological outcomes to those of radical prostatectomy. One concern is, however, radiation damage to the rectum because of the extreme proximity between the two organs. Inserting a biomaterial to separate the prostate and rectum is a promising strategy, and an injectable hydrogel is regarded to be the preferred spacer after screening of various materials. Nevertheless, there exist shortcomings for the currently available injectable hydrogel that cannot fully meet the unique requirements in clinical practice. In this work, a novel injectable hydrogel spacer based on carboxymethyl chitosan (CMC), aldehyde guar gum (AG), and aldehyde iohexol (DHQ) with an imaging function is fabricated. Contrast agent DHQ is chemically attached to CMC-AG network to form a double-crosslinking network to obtain a controlled degradation rate and high strength as well as durable CT imaging function. The hydrogel is injected subcutaneously into rats, where rapid gelation occurs and it serves as a hydrogel spacer. During the month-long in vivo studies, the spacer exhibits remarkable radiation dose attenuation and sustainable imaging function, as well as excellent toxicity profiles. This novel hydrogel shows excellent potential in the protection of critical organs during prostate cancer radiotherapy.
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http://dx.doi.org/10.1039/d0tb02953jDOI Listing
April 2021

Identification of IFN-Induced Transmembrane Protein 1 With Prognostic Value in Pancreatic Cancer Using Network Module-Based Analysis.

Front Oncol 2021 22;11:626883. Epub 2021 Mar 22.

Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Despite improvements reported in diagnosis and treatments in recent decades, pancreatic cancer is still characterized by poor prognosis and low survival rate among solid tumors. Intensive interests have grown in exploring novel predictive biomarkers, aiming to enhance the efficiency in early detection and treatment prognosis. In this study, we identified the differentially expressed genes (DEGs) in pancreatic cancer by analyzing five gene expression profiles and established the functional modules according to the functional interaction (FI) network between the DEGs. A significant upregulation of the selected DEG, interferon (IFN)-induced transmembrane protein 1 (IFITM1), was evaluated in several bioinformatics online tools and verified with immunohistochemistry staining from samples of 90 patients with pancreatic cancer. Prognostic data showed that high expression of IFITM1 associated with poor survival, and multivariate Cox regression analysis showed IFITM1 was one of the independent prognostic factors for overall survival. Meanwhile, significant correlations of the expression of IFITM1 and the infiltration of immune cells were found by TIMER. Furthermore, a higher level of IFITM1 was assessed in pancreatic cancer cell lines compared to normal human pancreatic duct epithelial cells, and silencing IFITM1 in tumor cells remarkedly inhibited cancer tumorigenicity. Collectively, our findings suggested that IFITM1 might have promising utility for pancreatic cancer.
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http://dx.doi.org/10.3389/fonc.2021.626883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044951PMC
March 2021

Evaluation of changes in shoulder balance and prediction of final shoulder imbalance during growing-rod treatment for early-onset scoliosis.

BMC Musculoskelet Disord 2021 Apr 14;22(1):354. Epub 2021 Apr 14.

Department of Orthopedic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Gongti North Rd, No. 8, Beijing, 100020, China.

Background: Obtaining and maintaining final shoulder balance after the entire treatment course is essential for early-onset scoliosis (EOS) patients. The relatively small number of growing-rod (GR) graduates who complete final fusion has resulted in an overall paucity of research on the GR treatment of EOS and a lack of research on the shoulder balance of EOS patients during GR treatment.

Methods: Twenty-four consecutive patients who underwent GR treatment until final fusion were included. Radiographic shoulder balance parameters, including the radiographic shoulder height (RSH), clavicle angle (CA), and T1 tilt angle (T1T), before and after each step of the entire treatment were measured. Shoulder balance changes from GR implantation to the last follow-up after final fusion were depicted and analysed. Demographic data, surgical-related factors, and radiographic parameters were analysed to identify risk factors for final shoulder imbalance. The shoulder balance of patients at different time points was further analysed to explore the potential effect of the series of GR treatment steps on shoulder balance.

Results: The RSH showed substantial improvement after GR implantation (P = 0.036), during the follow-up period after final fusion (P = 0.021) and throughout the entire treatment (P = 0.011). The trend of change in the CA was similar to that of the RSH, and the T1T improved immediately after GR implantation (P = 0.037). Further analysis indicated that patients with shoulder imbalance before final fusion showed significantly improved shoulder balance after fusion (P = 0.045), and their RSH values at early postfusion and the final follow-up did not show statistically significant differences from those in the prefusion shoulder balance group (P > 0.05). Early postfusion shoulder imbalance (odds ratio (OR): 19.500; 95% confidence interval (CI) = 1.777-213.949; P = 0.015) was identified as an independent risk factor for final shoulder imbalance.

Conclusions: Shoulder balance could be improved by GR implantation but often changes during the multistep lengthening process, and the final result is relatively unpredictable. Final fusion could further adjust the prefusion shoulder imbalance. Focusing on the prefusion shoulder balance of GR graduates and providing patients with early shoulder balance after fusion might be necessary.
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http://dx.doi.org/10.1186/s12891-021-04221-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045187PMC
April 2021

Cystathionine gamma-lyase/H S signaling facilitates myogenesis under aging and injury condition.

FASEB J 2021 05;35(5):e21511

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada.

Hydrogen sulfide (H S) can be endogenously produced and belongs to the class of signaling molecules known as gasotransmitters. Cystathionine gamma-lyase (CSE)-derived H S is implicated in the regulation of cell differentiation and the aging process, but the involvements of the CSE/H S system in myogenesis upon aging and injury have not been explored. In this study, we demonstrated that CSE acts as a major H S-generating enzyme in skeletal muscles and is significantly down-regulated in aged skeletal muscles in mice. CSE deficiency exacerbated the age-dependent sarcopenia and cardiotoxin-induced injury/regeneration in mouse skeletal muscle, possibly attributed to inefficient myogenesis. In contrast, supplement of NaHS (an H S donor) induced the expressions of myogenic genes and promoted muscle regeneration in mice. In vitro, incubation of myoblast cells (C2C12) with H S promoted myogenesis, as evidenced by the inhibition of cell cycle progression and migration, altered expressions of myogenic markers, elongation of myoblasts, and formation of multinucleated myotubes. Myogenesis was also found to upregulate CSE expression, while blockage of CSE/H S signaling resulted in a suppression of myogenesis. Mechanically, H S significantly induced the heterodimer formation between MEF2c and MRF4 and promoted the binding of MEF2c/MRF4 to myogenin promoter. MEF2c was S-sulfhydrated at both cysteine 361 and 420 in the C-terminal transactivation domain, and blockage of MEF2c S-sulfhydration abolished the stimulatory role of H S on MEF2c/MRF4 heterodimer formation. These findings support an essential role for H S in maintaining myogenesis, presenting it as a potential candidate for the prevention of age-related sarcopenia and treatment of muscle injury.
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http://dx.doi.org/10.1096/fj.202002675RDOI Listing
May 2021

The expression of microRNA-340 and cyclin D1 and its relationship with the clinicopathological characteristics and prognosis of lung cancer.

Asian J Surg 2021 Mar 10. Epub 2021 Mar 10.

Department of Cardiothoracic Surgery, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China. Electronic address:

Background: To explore the expression of microribonucleic acid-340 (miR-340) and cyclin D1 (CCND1) in lung cancer (LC) tissues and its relationship with the clinicopathological characteristics and prognosis of LC.

Methods: Cancer tissues and paracancerous normal lung tissues of 65 patients with LC admitted to our hospital from January 2014 to March 2015 were included as the LC group, and the paracancerous group, respectively.

Results: The relative expression levels of miR-340 mRNA and miR-340 protein in the LC group were lower than those in the paracancerous group, while the relative expression levels of CCND1 mRNA and CCND1 protein in the LC group were higher than those in the paracancerous group (P < 0.05). Pearson correlation analysis results showed that the mRNA and protein expression of both miR-340 and CCND1 in LC tissues was negatively correlated (r < 0, P < 0.05).The high expression rate (HER) of miR-340 and high expression rate (PER) of CCND1 were related to the tumor size, lymph node metastasis, TNM staging, and degree of differentiation (P < 0.05). The patients with high expression (HE) of miR-340 showed increased 5-year SR compared with the patients with low expression of miR-340, and that of patients positive for CCND1 was lower than that of the patients negative for CCND1 (P < 0.05).

Conclusion: miR-340 was downregulated, whereas CCND1 was upregulated in LC tissues, and the expression levels of the two genes were closely related to the prognosis and clinicopathological characteristics of LC.
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http://dx.doi.org/10.1016/j.asjsur.2021.02.009DOI Listing
March 2021

AHR signaling pathway reshapes the metabolism of AML/MDS cells and potentially leads to cytarabine resistance.

Acta Biochim Biophys Sin (Shanghai) 2021 Mar;53(4):492-500

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Emerging evidence suggests that aryl hydrocarbon receptor (AHR) promotes the initiation, invasion, progression, and metastasis of cancer cells. However, its effects in patients with myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) remain undefined. In this study, we aimed to investigate the effects of AHR activation on malignant cells in patients with MDS/AML. We found that AHR was expressed aberrantly in patients with MDS/AML. Further studies demonstrated that inhibiting AHR decreased the mitochondrial dehydrogenase content and the mitochondrial membrane potential (MMP) in MDS/AML cells. Activating AHR with L-kynurenine (Kyn) increased AHR expression, which was accompanied by an increase in mitochondrial dehydrogenase content and MMP in MDS/AML cells. Moreover, the expression level of mitochondria-associated mitochondrial transcription factor A was increased after activating AHR with L-Kyn when compared with that in the control group but decreased after inhibiting the AHR signal. Activating AHR in MDS/AML cells enhanced the resistance to cytarabine. These findings indicated that activating the AHR signaling pathway reshaped the metabolism in MDS/AML cells, thus contributing to the resistance to cytarabine.
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http://dx.doi.org/10.1093/abbs/gmab017DOI Listing
March 2021

TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways.

Cell Death Dis 2021 01 7;12(1):10. Epub 2021 Jan 7.

Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Zhongshan Road 321, 210008, Nanjing, Jiangsu, People's Republic of China.

Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.
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http://dx.doi.org/10.1038/s41419-020-03278-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790824PMC
January 2021

Gasotransmitter signaling in energy homeostasis and metabolic disorders.

Free Radic Res 2021 Jan 23;55(1):83-105. Epub 2020 Dec 23.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.

Gasotransmitters are small molecules of gases, including nitric oxide (NO), hydrogen sulfide (HS), and carbon monoxide (CO). These three gasotransmitters can be endogenously produced and regulate a wide range of pathophysiological processes by interacting with specific targets upon diffusion in the biological media. By redox and epigenetic regulation of various physiological functions, NO, HS, and CO are critical for the maintenance of intracellular energy homeostasis. Accumulated evidence has shown that these three gasotransmitters control ATP generation, mitochondrial biogenesis, glucose metabolism, insulin sensitivity, lipid metabolism, and thermogenesis, etc. Abnormal generation and metabolism of NO, HS, and/or CO are involved in various abnormal metabolic diseases, including obesity, diabetes, and dyslipidemia. In this review, we summarized the roles of NO, HS, and CO in the regulation of energy homeostasis as well as their involvements in the metabolism of dysfunction-related diseases. Understanding the interaction among these gasotransmitters and their specific molecular targets are very important for therapeutic applications.
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http://dx.doi.org/10.1080/10715762.2020.1862827DOI Listing
January 2021

Comparison of computed tomography- and magnetic resonance imaging-based target delineation for cervical cancer brachytherapy.

J Contemp Brachytherapy 2020 Aug 21;12(4):367-374. Epub 2020 Aug 21.

Department of Radiotherapy, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Purpose: The objective of this study was to compare and assess the accuracy of computed tomography (CT)-based target delineation with that of magnetic resonance imaging (MRI)-based on high-dose-rate brachytherapy (HDR-BT) for patients with cervical cancer.

Material And Methods: Data of 20 patients with locally advanced cervical cancer were collected and evaluated. Dimensions, conformity, and dose parameters of high-risk clinical target volume (CTV) as well as D, D, and D of organs at risk (OARs) based on MRI were compared with those based on CT.

Results: Average age of 20 patients included was 57.8 years. Width, thickness, and volumes of CT-based CTV (CTV-CT) were significantly overestimated compared with those of MRI-based CTV (CTV-MR). Mean values of dice similarity coefficient (DSC), Hausdorff distance (HD), and centroid distance (ΔV) of CTV were 0.82 cm, 0.96 cm, and 0.35 cm, respectively. Dose values of CTV-CT were significantly lower compared with those of CTV-MR. Concerning OARs, geometrical and dosimetric values on CT were comparable to those on MRI.

Conclusions: The delineated ranges of CTV were significantly over-estimated on CT compared with MRI. D and D of CTV-CT were lower than CTV-MR. DSC and ΔV of CTV and CTV were similar to each other; however, there was a difference in terms of HD. CT images regarding pre-BT MR images for delineating were not enough and MRI fusion is still required.
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http://dx.doi.org/10.5114/jcb.2020.98117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690230PMC
August 2020

Hydrogen sulfide guards myoblasts from ferroptosis by inhibiting ALOX12 acetylation.

Cell Signal 2021 02 5;78:109870. Epub 2020 Dec 5.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada. Electronic address:

Recognized as a novel and important gasotransmitter, hydrogen sulfide (HS) is widely present in various tissues and organs. Cystathionine gamma-lyase (CSE)-derived HS has been shown to regulate oxidative stress and lipid metabolism. The aim of the present study is to examine the role of HS in ferroptosis and lipid peroxidation in mouse myoblasts and skeletal muscles. Ferroptosis agonist RSL3 inhibited the expressions of Gpx4 and reduced CSE/HS signaling, which lead to increased oxidative stress, lipid peroxidation, and ferroptotic cell death. In addition, ferroptosis antagonist ferrostatin-1 (Fer-1) up-regulated the expression of CSE, scavenged the generation of reactive oxygen species (ROS) and lipid peroxidation, and improved cell viability. Exogenously applied NaHS was also able to block RSL3-induced ferroptotic cell death. Neither RSL3 nor HS affected cell apoptosis. Furthermore, HS reversed RSL3-induced Drp1 expression and mitochondrial damage, which lead to abnormal lipid metabolism as evidenced by altered expressions of ACSL4, FAS, ACC and CPT1 as well as higher acetyl-CoA contents in both cytoplasm and mitochondria. RSL3 promoted the protein expression and acetylation of ALOX12, a key protein in initiating membrane phospholipid oxidation, while the addition of NaHS attenuated ALOX12 acetylation and protected from membrane lipid peroxidation. Moreover, we observed that CSE deficiency alters the expressions of ferroptosis and lipid peroxidation-related proteins and enhances global protein acetylation in mouse skeletal muscles under aging or injury conditions. These results indicate that downregulation of CSE/HS signaling would contribute to mitochondrial damage, abnormal lipid metabolism, membrane lipid peroxidation, and ferroptotic cell death. CSE/HS system can be a target for preventing ferroptosis in skeletal muscle.
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http://dx.doi.org/10.1016/j.cellsig.2020.109870DOI Listing
February 2021

Interaction among estrogen, IGF-1, and H2S on smooth muscle cell proliferation.

J Endocrinol 2021 01;248(1):17-30

Cardiovascular and Metabolic Research Unit, Laurentian University, Ontario, Canada.

Both estrogen and hydrogen sulfide (H2S) inhibit the proliferation of vascular smooth muscle cells (SMCs) and development of atherosclerosis. In the absence of endogenous H2S as occurred in CSE-knockout (KO) mouse, however, estrogen stimulates the proliferation of vascular SMCs. The underlying mechanisms for this seemingly controversial vascular effect of estrogen are unclear. In the present study, we demonstrated that the stimulatory effect of estrogen on the proliferation of CSE-KO SMCs was suppressed by the inhibitor of insulin-like growth factor-1 receptor (IGF-1R) or knockdown of IGF-1R protein expression. Estrogen downregulated the expression of insulin-like growth factor-1 (IGF-1) and IGF-1R in aortic tissues or aortic SMCs isolated from WT and CSE-KO mice. Furthermore, endogenous H2S downregulated IGF-1R, but upregulated estrogen receptor (ER)-α, in aortic tissues or SMCs. ER-α and IGF-1R were co-located in SMCs and co-immunoprecipitated, which was decreased by H2S. Finally, both endogenous and exogenous H2S induced the S-sulfhydration of IGF-1R, but not ER-α, in WT-SMCs and CSE-KO SMCs, which underlies the decreased formation of IGF-1R/ER-α hybrid in the presence of H2S. Thus, the absence of H2S favors the interaction of estrogen with IGF-1R/ER-α hybrid to stimulate SMCs proliferation. The appreciation of a critical role of H2S in preventing estrogen-induced SMCs proliferation will help better understand the regulation of complex vascular effects of estrogen and sex-related cardiovascular diseases.
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http://dx.doi.org/10.1530/JOE-20-0190DOI Listing
January 2021

Breast Cancer Cell-Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities.

Cancers (Basel) 2020 Oct 8;12(10). Epub 2020 Oct 8.

Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA.

Breast cancer remains the most prevalent cancer in women with limited treatment options for patients suffering from therapy-resistance and metastatic disease. Neutrophils play an important role in breast cancer progression and metastasis. We examined the pro-tumorigenic nature of the breast cancer cell-neutrophil interactions and delineated the differences in neutrophil properties between the chemotherapy-resistant and the parent tumor microenvironment. Our data demonstrated that high neutrophil infiltration is associated with disease aggressiveness and therapy resistance. In the human breast cancer dataset, expression of neutrophil-related signature gene expression was higher in tumors from therapy-resistant patients than therapy-sensitive patients. We observed that breast cancer-derived factors significantly enhanced neutrophil survival, polarization, and pro-inflammatory cytokine expression. Breast cancer cell-derived supernatant treated neutrophils significantly expressed high levels of interleukin-1β (IL-1β), CC-chemokine ligand-2-4 (CCL2, CCL3, CCL4), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase-9 (MMP9), and formed extracellular traps (NETs). Moreover, neutrophils showed increased secretion of MMP9 when cultured with the supernatant of chemotherapy-resistant Cl66-Doxorubicin (Cl66-Dox) and Cl66-Paclitaxel (Cl66-Pac) cells in comparison with the supernatant of Cl66-parent cells. Together, these data suggest an important role of breast cancer cell-neutrophil interactions in regulating pro-tumor characteristics in neutrophils and its modulation by therapy resistance.
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http://dx.doi.org/10.3390/cancers12102884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599756PMC
October 2020

Correction: Calcium sensing receptor protects high glucose-induced energy metabolism disorder via blocking gp78-ubiquitin proteasome pathway.

Cell Death Dis 2020 Sep 21;11(9):784. Epub 2020 Sep 21.

Department of Pathophysiology, Harbin Medical University, Harbin, 150086, China.

Since online publication of this article, the authors noticed that there was an error in Figs. 2 and 4. In Fig. 2c the samples were mislabelled, the correct labelling order is 'Control, HG, HG + NPS R568, HG + Calhex231'. In Fig. 4c, an incorrect image was used to compile the HG + NPS R568 group, meaning the control was accidentally duplicated. The corrected images are provided below. The authors confirm that these errors did not influence the reported data, discussion, or conclusion. The authors apologise for any inconvenience to readers arising from this error.
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http://dx.doi.org/10.1038/s41419-020-02957-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506004PMC
September 2020

Identification of latent core genes and pathways associated with myelodysplastic syndromes based on integrated bioinformatics analysis.

Hematology 2020 Dec;25(1):299-308

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.

Myelodysplastic syndromes (MDS) are relatively common hematological malignancies characterized by dysplastic hematopoiesis in one or more of the lineages of the bone marrow. This study aimed to identify critical pathogenic biomarkers associated with the carcinogenesis and progression of MDS. To explore the candidate genes, the expression profiles of GSE2779, GSE4619, and GSE19429 were downloaded from the Gene Expression Omnibus (GEO) database, which contained CD34+ cells isolated from MDS patients and normal controls. The three microarray datasets were integrated to obtain differentially expressed genes (DEGs) and were deeply analyzed by bioinformatics methods. The construction of protein-protein interaction (PPI) network together with module analysis was performed based on Cytoscape software and the Search Tool for the Retrieval of Interacting Genes (STRING) database. Our study identified 114 DEGs, which were highly enriched in various key pathways, including forkhead box protein O (FoxO) signaling pathway, the primary immunodeficiency, and hematopoietic cell lineage. Twelve core genes, such as FOXO1, PAX5 and CXCR4 were identified with a high degree of connectivity. It is plausible that FoxO signaling pathway plays an important role in MDS, and the dysregulation of FOXO1 was significantly associated with TGFβ, IL2/STAT5, Notch signaling and apoptosis pathways. The current study for the first time identified twelve latent indicators and their downstream targets, which might become significant biomarkers for worse clinical characteristics in MDS.
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http://dx.doi.org/10.1080/16078454.2020.1802917DOI Listing
December 2020

Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer.

Int J Radiat Oncol Biol Phys 2020 12 4;108(5):1368-1379. Epub 2020 Aug 4.

Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Pathology & Pathophysiology of Zhejiang University, School of Medicine, Hangzhou, China. Electronic address:

Purpose: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC.

Methods And Materials: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and β-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo.

Results: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs.

Conclusions: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.ijrobp.2020.07.2322DOI Listing
December 2020

Hydrogen sulfide signaling in regulation of cell behaviors.

Nitric Oxide 2020 10 17;103:9-19. Epub 2020 Jul 17.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada. Electronic address:

Recent advances in the biomedical importance of HS have help us understand various cellular functions and pathophysiological processes from a new aspect. Specially, HS has been demonstrated to play multiple roles in regulating cell behaviors, including cell survival, cell differentiation, cell senescence, cell hypertrophy, cell atrophy, cell metaplasia, and cell death, etc. HS contributes to cell behavior changes via various mechanisms, such as histone modification, DNA methylation, non-coding RNA changes, DNA damage repair, transcription factor activity, and post-translational modification of proteins by S-sulfhydration, etc. In this review, we summarized the recent research progress on HS signaling in control of cell behaviors and discussed the ways of HS regulation of gene expressions. Given the key roles of HS in both health and diseases, a better understanding of the regulation of HS on cell behavior change and the underlying molecular mechanisms will help us to develop novel and more effective strategies for clinical therapy.
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http://dx.doi.org/10.1016/j.niox.2020.07.002DOI Listing
October 2020

CXCR2 signaling promotes secretory cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.

FASEB J 2020 07 26;34(7):9405-9418. Epub 2020 May 26.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies. Desmoplasia and tumor-supporting inflammation are hallmarks of PDAC. The tumor microenvironment contributes significantly to tumor progression and spread. Cancer-associated fibroblasts (CAFs) facilitate therapy resistance and metastasis. Recent reports emphasized the concurrence of multiple subtypes of CAFs with diverse roles, fibrogenic, and secretory. C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor known for its role during inflammation and its adverse role in PDAC. Oncogenic Kras upregulates CXCR2 and its ligands and, thus, contribute to tumor proliferation and immunosuppression. CXCR2 deletion in a PDAC syngeneic mouse model produced increased fibrosis revealing a potential undescribed role of CXCR2 in CAFs. In this study, we demonstrate that the oncogenic Kras-CXCR2 axis regulates the CAFs function in PDAC and contributes to CAFs heterogeneity. We observed that oncogenic Kras and CXCR2 signaling alter CAFs, producing a secretory CAF phenotype with low fibrogenic features; and increased secretion of pro-tumor cytokines and CXCR2 ligands, utilizing the NF-κB activity. Finally, using syngeneic mouse models, we demonstrate that oncogenic Kras is associated with secretory CAFs and that CXCR2 inhibition promotes activation of fibrotic cells (myofibroblasts) and impact tumors in a mutation-dependent manner.
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http://dx.doi.org/10.1096/fj.201902990RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501205PMC
July 2020

HS-stimulated bioenergetics in chicken erythrocytes and the underlying mechanism.

Am J Physiol Regul Integr Comp Physiol 2020 07 20;319(1):R69-R78. Epub 2020 May 20.

Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Ontario, Canada.

The production of HS and its effect on bioenergetics in mammalian cells may be evolutionarily preserved. Erythrocytes of birds, but not those of mammals, have a nucleus and mitochondria. In the present study, we report the endogenous production of HS in chicken erythrocytes, which was mainly catalyzed by 3-mercaptopyruvate sulfur transferase (MST). ATP content of erythrocytes was increased by MST-generated endogenous HS under normoxic, but not hypoxic, conditions. NaHS, a HS salt, increased ATP content under normoxic, but not hypoxic, conditions. ATP contents in the absence or presence of NaHS were eliminated by different inhibitors for mitochondrial electron transport chain in chicken erythrocytes. Succinate and glutamine, but not glucose, increased ATP content. NaHS treatment similarly increased ATP content in the presence of glucose, glutamine, or succinate, respectively. Furthermore, the expression and activity of sulfide:quinone oxidoreductase were enhanced by NaHS. The structural integrity of chicken erythrocytes was largely maintained during 2-wk NaHS treatment in vitro, whereas most of the erythrocytes without NaHS treatment were lysed. In conclusion, HS may regulate cellular bioenergetics as well as cell survival of chicken erythrocytes, in which the functionality of the electron transport chain is involved. HS may have different regulatory roles and mechanisms in bioenergetics of mammalian and bird cells.
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http://dx.doi.org/10.1152/ajpregu.00348.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468790PMC
July 2020

Cyclodextrin-Modified CeO Nanoparticles as a Multifunctional Nanozyme for Combinational Therapy of Psoriasis.

Int J Nanomedicine 2020 15;15:2515-2527. Epub 2020 Apr 15.

College of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, People's Republic of China.

Purpose: Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative strategies eradicating ROS may serve as effective and easy treatment options for psoriasis, while nanozymes with intrinsic antioxidant enzyme-like activity have not been explored for psoriasis treatment. The aim of this study is to fabricate β-cyclodextrins (β-CDs)-modified ceria nanoparticles (β-CDs/CeO NPs) with drug-loaded and multimimic-enzyme activities for combinational psoriasis therapy.

Methods: The β-CDs/CeO NPs were synthesized by a hydrothermal method using unmodified β-CDs as a protecting agent. The structure, size and morphology were analyzed by dynamic light scattering, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. Considering the superoxide dismutase (SOD)- and catalase-mimetic activities, the in vitro antioxidant activity of the β-CDs/CeO2 NPs was investigated. After dithranol (DIT) was loaded, the drug-loading capacity and release profile were determined by UV-visible light spectrophotometer and high-performance liquid chromatography. The anti-psoriatic efficacy was studied in the imiquimod (IMQ)-induced mouse model on the basis of morphological evaluation, psoriasis area and severity index calculation (PASI), and inflammatory cytokine expression.

Results: The average particle size of the blank β-CDs/CeO NPs was 60.89±0.32 nm with a polydispersity index (PDI) of 0.12, whereas that of the DIT-loaded NPs was 79.38±1.06 nm with a PDI of 0.27. TEM results showed the as-prepared NPs formed a uniform quasi-spherical shape with low polydispersity. XPS indicates synthesized NPs have a mixed Ce/Ce valence state. FTIR spectroscopy confirmed the presence of β-CDs and DIT in the NPs. Inhibition of superoxide anion rate by NPs could be reached to 79.4% in the presence of 200 µg/mL, and elimination of HO efficiency reached about 50% in the presence of 40 µg/mL, demonstrating excellent superoxide dismutase- and catalase-mimicking activities, thereby providing remarkable cryoprotection against ROS-mediated damage. Furthermore, β-CDs on the surface endowed the NPs with drug-loading function via host-guest interactions. The entrapment efficiency and drug loading of DIT are 94.7% and 3.48%, respectively. The in vitro drug release curves revealed a suitable release capability of [email protected]β-CDs/CeO NPs under physiological conditions. In IMQ-induced psoriatic model, the [email protected]β-CDs/CeO NPs exhibited excellent therapeutic effect.

Conclusion: This study may pave the way for the application of nanozyme β-CDs/CeO NPs as a powerful tool for psoriasis therapy.
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http://dx.doi.org/10.2147/IJN.S246783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170634PMC
July 2020

Cystathionine gamma-lyase/HS system suppresses hepatic acetyl-CoA accumulation and nonalcoholic fatty liver disease in mice.

Life Sci 2020 Jul 16;252:117661. Epub 2020 Apr 16.

Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada. Electronic address:

Aims: Hydrogen sulfide (HS) as a novel gasotransmitter can be endogenously produced in liver by cystathionine gamma-lyase (CSE). The dysfunctions of CSE/HS system have been linked to various liver diseases. Acetyl-CoA is the key intermediate from the metabolism of lipid. This study examined the roles of HS in hepatic acetyl-CoA and lipid metabolism.

Materials And Methods: Both in vitro cell model and in vivo animal model of lipid accumulation were used in this study. Western blotting and real-time PCR were used for analysis of protein and mRNA expression. Acetyl-CoA was analyzed by a coupled enzyme assay, and lipid accumulation was observed with Oil Red O staining.

Key Findings: Incubation of human liver carcinoma (HepG2) cells with a mixture of free fatty acids (FFAs) or high glucose reduced CSE expression and HS production, promoted intracellular accumulation of acetyl-CoA and lipid. Supply of exogenous NaHS or cysteine reduced acetyl-CoA contents and lipid accumulation, while blockage of CSE activity promoted intracellular lipid accumulation. Furthermore, HS blocked FFAs-induced transcriptions of de novo lipogenesis, inflammation, and fibrosis-related genes. In vivo, knockout of CSE gene stimulated more hepatic acetyl-CoA and lipid accumulation in mice induced by high-fat choline-deficient diet. The expressions of lipogenesis, inflammation, and fibrosis-related genes were significantly higher in liver tissues from CSE knockout mice when compared with wild-type mice.

Significance: CSE/HS system is indispensable for maintaining the homeostasis of acetyl-CoA and lipid accumulation and protecting from the development of inflammation and fibrosis in liver under excessive caloric ingestion.
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http://dx.doi.org/10.1016/j.lfs.2020.117661DOI Listing
July 2020

NPM1 mutation with DNMT3A wild type defines a subgroup of MDS with particularly favourable outcomes after decitabine therapy.

Br J Haematol 2020 06 8;189(5):982-984. Epub 2020 Apr 8.

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

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http://dx.doi.org/10.1111/bjh.16628DOI Listing
June 2020

Neutrophils in the Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1224:1-20

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

Neutrophils are the first responders to inflammation, infection, and injury. As one of the most abundant leukocytes in the immune system, neutrophils play an essential role in cancer progression, through multiple mechanisms, including promoting angiogenesis, immunosuppression, and cancer metastasis. Recent studies demonstrating elevated neutrophil to lymphocyte ratios suggest neutrophil as a potential therapeutic target and biomarker for disease status in cancer. This chapter will discuss the phenotypic and functional changes in the neutrophil in the tumor microenvironment, the underlying mechanism(s) of neutrophil facilitated cancer metastasis, and clinical potential of neutrophils as a prognostic/diagnostic marker and therapeutic target.
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http://dx.doi.org/10.1007/978-3-030-35723-8_1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325741PMC
February 2020

The impact of NBUVB on microbial community profiling in the lesional skin of vitiligo subjects.

Microb Pathog 2020 Mar 7;140:103943. Epub 2020 Jan 7.

Department of Dermatology, Weifang Medical University Hospital, Weifang, Shandong, China. Electronic address:

Background: The impact of NBUVB on the cutaneous microbiota of vitiligo patients remains to be fully elucidated.

Methods: To characterize the cutaneous microbiota in vitiligo patients, cutaneous samples from 60 patients with vitiligo and after NBUVB irradiation were profiled using the Illumina MiSeq platform. Alpha diversity estimations revealed higher microbiota diversity in samples from patients with lesional skin. Beta diversity (Principal Component Analysis (PCA)) analysis showed that the bacterial community structure segregated differently between different groups.

Results: There was a statistically significant increase in the Sobs, ACE, and Chao indices in the NB group compared with NF group, as determined by t-test. The alpha diversity have no significant difference between NF and DB group. At the phylum level, Firmicutes, Proteobacteria and Actinobacteria were the most predominant phyla. Propionibacterium and Pseudomonas were the most predominant genera in each group. In addition, Staphylococcus, Bacillus and Prevotella were enriched in DF group compared to DB group. Propionibacterium was enriched in DB group compared to DF group.

Conclusions: Our studies indicate differences in microbial community dynamics of the lesional and non-lesional sites of vitiligo subjects, with greater diversity and higher association between microbial communities of the unaffected site. And NBUVB irradiation might eliminate these differences.
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http://dx.doi.org/10.1016/j.micpath.2019.103943DOI Listing
March 2020

Golgi Stress Response, Hydrogen Sulfide Metabolism, and Intracellular Calcium Homeostasis.

Antioxid Redox Signal 2020 03 20;32(9):583-601. Epub 2020 Jan 20.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada.

The physiological and pathological importance of hydrogen sulfide (HS) as a novel gasotransmitter has been widely recognized. Cystathionine gamma-lyase (CSE) is one of the major HS-producing enzymes and it regulates diverse functions in connection with intracellular calcium (Ca). The aim of this study is to examine the role of HS in Golgi stress-related cell injury and skeletal muscle disorders. Golgi stressors (brefeldin A [BFA] and monensin) decreased the expression of GM130 and ATP2C1 (two markers of Golgi stress response), induced Golgi apparatus fragmentation, and caused a higher level of oxidative stress and cell apoptosis in mouse myoblast cells. In addition, Golgi stressors upregulated CSE expression and endogenous HS generation, and exogenously applied HS was able to protect but inhibition of CSE/HS system deteriorated Golgi stress response. Activating transcription factor 4 (ATF4) acted as an upstream molecule to increase CSE expression on Golgi stress response. Mechanically, Golgi stressors induced intracellular level of Ca, and chelating cellular Ca markedly attenuated Golgi stress response, indicating the key role of Ca in initiating Golgi stress and cell apoptosis. Further, administration of either angiotensin II or BFA initiated Golgi stress response and induced skeletal muscle atrophy in mice, which was further deteriorated by CSE deficiency but rescued by exogenously applied sodium hydrosulfide (NaHS). The activation of the CSE/HS pathway and the decrease of intracellular Ca are two cellular protective mechanisms against Golgi stress, and the CSE/HS system would be a target for preventing skeletal muscle dysfunctions.
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http://dx.doi.org/10.1089/ars.2019.7824DOI Listing
March 2020

Curcumin Mitigates Neuro-Inflammation by Modulating Microglia Polarization Through Inhibiting TLR4 Axis Signaling Pathway Following Experimental Subarachnoid Hemorrhage.

Front Neurosci 2019 15;13:1223. Epub 2019 Nov 15.

Department of Neurosurgery, Nanjing Drum Tower Hospital, The Affiliated Hospital Nanjing University Medicine School, Nanjing, China.

Subarachnoid hemorrhage (SAH) elicits destruction of neuronal cells and neurological function, which is exacerbated by neuro-inflammation in EBI, and toll-like receptor 4 (TLR4) plays an important role in inflammatory cascade via modulation microglia polarization. Curcumin (Cur), as a natural phytochemical compound, has the potential characteristics on anti-inflammatory and microglia phenotype transformation. In this study, we verified the hypothesis curcumin promotes M2 polarization to inhibiting neuro-inflammation, which through suppressing TLR4 signaling pathway after SAH. In mice and wild type (WT) subjected to prechiasmatic cistern blood injection, Western blotting, brain water content, neurological score, enzyme-linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed to investigate the role of TLR4 on neuro-inflammation response and microglia polarization. Curcumin with three different concentrations (50 mg/kg, 100 mg/kg and 200 mg/kg) were injected intraperitoneally (i.p.) at 15 min after SAH. The levels of TLR4, myeloid differentiation factor 88 (MyD88), nuclear factor- κB (NF-κB), Iba-1, CD86, CD206 and pro/anti-inflammation cytokines were measured by Western blotting and immunofluorescence staining at 24 h after SAH. SAH induction increased the protein levels of TLR4, pro-inflammation cytokines and proportion of M1 phenotype. Curcumin with 100 mg/kg treatment dramatically inhibited the release of pro-inflammatory mediators, and elevated the protein levels of anti-inflammatory cytokines and promoted microglia switch to M2. Meanwhile, curcumin treatment also decreased the expressions of TLR4, Myd88 and NF-κB at 24 h post SAH. TLR4 deficiency ameliorated brain water content, neurological deficit and reduced pro-inflammation cytokines after SAH. Moreover, curcumin treatment in mice further induced M2 polarization, while had no statistic difference on brain water content and neurological score at 24 h post SAH. Our results indicated that curcumin treatment alleviated neuro-inflammation response through promoting microglia phenotype shift toward M2, and which might inhibiting TLR4/MyD88/NF-κB signaling pathway after SAH.
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http://dx.doi.org/10.3389/fnins.2019.01223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872970PMC
November 2019

The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma.

Front Cell Dev Biol 2019 12;7:267. Epub 2019 Nov 12.

Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Several studies have investigated strategies to improve the clinical efficacy of radiotherapy (RT) against hepatocellular carcinoma (HCC), yet the prognosis remains poor. Human adipose tissue-derived mesenchymal stem cells (AT-MSCs), easily accessible and abundant in quantity, have represented as an attractive therapeutic tool for the stem cell-based treatment for cancer diseases. Through direct co-culture and indirect separate culture experiments, we showed that AT-MSCs could enhance inhibitory effect of RT on reducing HCC cell growth, migration and invasion in both and experiments. RNA-sequencing analysis revealed a noticeable interferon-induced transmembrane 1 (IFITM1)-induced tumor gene signature. Gain and loss of mechanistic studies indicated that mechanism was attributed to downregulated expression of signal transducer and activator of transcription 3 (STAT3) and matrix metallopeptidases (MMPs) and upregulated expression of P53 and caspases. Collectively, our findings suggest that AT-MSCs might enhance the therapeutic effects of RT on HCC, providing a rationale for AT-MSCs and RT combination therapy as a new remedy for HCC.
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http://dx.doi.org/10.3389/fcell.2019.00267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861425PMC
November 2019

Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation.

Aging (Albany NY) 2019 11 14;11(21):9626-9642. Epub 2019 Nov 14.

Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.

Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that S100A9 is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype. Exogenous supplemented S100A9 also induced cellular senescence in MSCs and HS-27a cells. Importantly, Toll-like receptor 4 (TLR4) inhibition or knockdown attenuated the cellular senescence induced by S100A9. Furthermore, we showed that S100A9 induces NLRP3 inflammasome formation, and IL-1β secretion; findings in samples from MDS patients further confirmed these thoughts. Moreover, ROS and IL-1β inhibition suppressed the cellular senescence induced by S100A9, whereas NLRP3 overexpression and exogenous IL-1β supplementation induces cellular senescence. Our study demonstrated that S100A9 promotes cellular senescence of bone marrow stromal cells via TLR4, NLRP3 inflammasome formation, and IL-1β secretion for its effects. Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of S100A9 in tumor-environment interactions in bone marrow.
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http://dx.doi.org/10.18632/aging.102409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874461PMC
November 2019