Publications by authors named "Yuntian Shen"

38 Publications

Activation of the ATF6 (Activating Transcription Factor 6) Signaling Pathway in Neurons Improves Outcome After Cardiac Arrest in Mice.

J Am Heart Assoc 2021 Jun 11;10(12):e020216. Epub 2021 Jun 11.

Department of Anesthesiology Center for Perioperative Organ Protection Duke University Medical Center Durham NC.

Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6-KI (short-form ATF6 knock-in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6-KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro-proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum-associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6-KI brain. Accordingly, the CA-induced increase in K48-linked polyubiquitin in the brain was higher in sATF6-KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.
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http://dx.doi.org/10.1161/JAHA.120.020216DOI Listing
June 2021

Comprehensive evaluation of microRNA-10b in digestive system cancers reveals prognostic implication and signaling pathways associated with tumor progression.

J Cancer 2021 13;12(13):4011-4024. Epub 2021 May 13.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Digestive system cancers (DSCs) have been recognized to be linked with high morbidity and mortality. Recent studies have reported that microRNA-10b (miR-10b) is abnormally expressed in DSCs and associated with prognosis. However, the inconclusive results and unknown underlying mechanisms promoted us to perform this study. We systematic searched several databases for eligible studies and conducted quantitative analysis for evidence regarding the associations between miR-10b and survival outcome of DSCs. We also performed a series of bioinformatics analyses to uncover the potential mechanisms. A total of 32 eligible studies with 3392 patients were included. Increased miR-10b expression was linked with unfavorable overall survival (OS) in DSCs (HR=1.72; 95% CI: 1.30-2.27; P <0.001). When stratified by tumor type, the impact of miR-10b overexpression on poor prognosis was observed in colorectal cancer, gastric cancer, hepatocellular carcinoma, and esophageal carcinoma, but not in pancreatic cancer. Subsequently, we predicted the targets of miR-10b and conducted functional enrichment analyses. The results disclosed that miR-10b targets were predominantly enriched in some vital biological terms and pivotal signaling pathways associated with tumor progression including cell cycle, FoxO, proteoglycans, central carbon metabolism, p53, Notch, HIF-1, focal adhesion, AMPK, and pancreatic cancer. Moreover, a protein-protein interaction (PPI) network was also constructed to identify the top ten hub genes and significant modules and demonstrated the underlying interactions among them. Our results indicated that miR-10b could act as a significant biomarker in the prognosis DSCs. However, more research should be performed to test these findings.
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http://dx.doi.org/10.7150/jca.51303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176240PMC
May 2021

Transcriptome sequencing and analysis reveals the molecular mechanism of skeletal muscle atrophy induced by denervation.

Ann Transl Med 2021 Apr;9(8):697

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: The molecular mechanism of denervated muscle atrophy is very complex and has not been elucidated to date. In this study, we aimed to use transcriptome sequencing technology to systematically analyze the molecular mechanism of denervated muscle atrophy in order to eventually develop effective strategies or drugs to prevent muscle atrophy.

Methods: Transcriptome sequencing technology was used to analyze the differentially expressed genes (DEGs) in denervated skeletal muscles. Unsupervised hierarchical clustering of DEGs was performed. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to analyze the DEGs.

Results: Results showed that 2,749 transcripts were up-regulated, and 2,941 transcripts were down-regulated in denervated tibialis anterior (TA) muscles after 14 days of denervation. The up-regulated expressed genes were analyzed through GO and the results demonstrated that biological processes of the up-regulated expressed genes included apoptotic process, cellular response to DNA damage stimulus, aging, and protein ubiquitination; the cellular component of the up-regulated expressed genes included cytoplasm, cytoskeleton, and nucleus; and the molecular function of the up-regulated expressed genes included ubiquitin-protein transferase activity and hydrolase activity. The KEGG pathway of the up-regulated expressed genes included ubiquitin mediated proteolysis, Fc gamma R-mediated phagocytosis, and transforming growth factor-beta (TGF-β) signaling pathway. The biological processes of the down-regulated expressed genes included angiogenesis, tricarboxylic acid cycle, adenosine triphosphate (ATP) biosynthetic process, muscle contraction, gluconeogenesis; the cellular component of the down-regulated expressed genes included mitochondrion, cytoskeleton, and myofibril; and the molecular function of the down-regulated expressed genes included nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase (ubiquinone) activity, proton-transporting ATP synthase activity, ATP binding, electron carrier activity, cytochrome-c oxidase activity, and oxidoreductase activity. The KEGG pathway of the down-regulated expressed genes included oxidative phosphorylation, tricarboxylic acid cycle, glycolysis/gluconeogenesis, and the PI3K-Akt signaling pathway.

Conclusions: A huge number of DEGs were identified in TA muscles after denervation. The up-regulated expressed genes mainly involve in proteolysis, apoptosis, and ageing. The down-regulated expressed genes mainly involve in energy metabolism, angiogenesis, and protein synthesis. This study further enriched the molecular mechanism of denervation-induced muscle atrophy.
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http://dx.doi.org/10.21037/atm-21-1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106053PMC
April 2021

Global alternative splicing landscape of skeletal muscle atrophy induced by hindlimb unloading.

Ann Transl Med 2021 Apr;9(8):643

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: Long-term exposure to microgravity will cause skeletal muscle atrophy, which can cause serious harm to astronauts in space travel. Therefore, it is important to explore skeletal muscle atrophy's molecular mechanism for its prevention and treatment. However, as an important regulatory approach of skeletal muscle physiology, the role of alternative splicing in skeletal muscle atrophy, especially skeletal muscle atrophy caused by disuse, is unclear.

Methods: We established a rat hindlimb unloading model and performed RNA sequencing on soleus muscle, which was seriously atrophied during unloading. Several bioinformatics methods were used to identify alternative splicing events and determine their gene functions.

Results: Many alternative splicing events were found to occur at different time points (12 h, 24 h, 36 h, 3 days, and 7 days) after hindlimb unloading. These differential alternative splicing events mainly occurred in the gene's coding domain sequence region, and 59% of the alternative splicing events caused open reading frameshift. Bioinformatics analysis results showed that genes with different alternative splicing events were enriched in multiple pathways related to muscle atrophy, including the insulin signaling pathway, endocytosis, mitophagy, and ubiquitin-proteasome pathway. Moreover, alternative splicing of several deubiquitinase genes persisted during skeletal muscle atrophy induced by unloading. Additionally, we identified 10 differentially expressed RNA binding proteins during skeletal muscle atrophy induced by unloading, mainly containing Xpo4, Eif4e2, P4ha1, Lrrfip1, Zc3h14, Emg1, Hnrnp h1, Mbnl2, RBfox1, and Mbnl1. Hnrnp h1 and Mbnl2 were significantly downregulated, and RBfox1 and Mbnl1 were significantly upregulated during skeletal muscle atrophy caused by unloading.

Conclusions: To the best of our knowledge, the present study is the first to propose alternative splicing alterations related to disuse-induced muscle atrophy, emphasizing that alternative splicing is a new focus of attention in the occurrence of muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-5388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106077PMC
April 2021

Increasing O-GlcNAcylation is neuroprotective in young and aged brains after ischemic stroke.

Exp Neurol 2021 May 15;339:113646. Epub 2021 Feb 15.

Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. Electronic address:

Spliced X-box binding protein-1 (XBP1s) together with the hexosamine biosynthetic pathway (HBP) and O-GlcNAcylation forms the XBP1s/HBP/O-GlcNAc axis. Our previous studies have provided evidence that activation of this axis is neuroprotective after ischemic stroke and critically, ischemia-induced O-GlcNAcylation is impaired in the aged brain. However, the XBP1s' neuroprotective role and its link to O-GlcNAcylation in stroke, as well as the therapeutic potential of targeting this axis in stroke, have not been well established. Moreover, the mechanisms underlying this age-related impairment of O-GlcNAcylation induction after brain ischemia remain completely unknown. In this study, using transient ischemic stroke models, we first demonstrated that neuron-specific overexpression of Xbp1s improved outcome, and pharmacologically boosting O-GlcNAcylation with thiamet-G reversed worse outcome observed in neuron-specific Xbp1 knockout mice. We further showed that thiamet-G treatment improved long-term functional recovery in both young and aged animals after transient ischemic stroke. Mechanistically, using an analytic approach developed here, we discovered that availability of UDP-GlcNAc was compromised in the aged brain, which may constitute a novel mechanism responsible for the impaired O-GlcNAcylation activation in the aged brain after ischemia. Finally, based on this new mechanistic finding, we evaluated and confirmed the therapeutic effects of glucosamine treatment in young and aged animals using both transient and permanent stroke models. Our data together support that increasing O-GlcNAcylation is a promising strategy in stroke therapy.
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http://dx.doi.org/10.1016/j.expneurol.2021.113646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045434PMC
May 2021

Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy.

Ann Transl Med 2020 Dec;8(24):1681

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: The molecular mechanisms underlying denervated skeletal muscle atrophy with concomitant muscle mass loss have not been fully elucidated. Therefore, this study aimed to attain a deeper understanding of the molecular mechanisms underlying denervated skeletal muscle atrophy as a critical step to developing targeted therapy and retarding the concomitant loss of skeletal muscle mass.

Methods: We employed microarray analysis to reveal the potential molecular mechanisms underlying denervated skeletal muscle atrophy. We used and atrophy models to explore the roles of the interleukin 6 (IL-6), Janus kinase (JAK), and signal transducers and activators of transcription 3 (STAT3) in muscle atrophy.

Results: In this study, microarray analysis of the differentially expressed genes demonstrated that inflammation-related cytokines were markedly triggered and IL-6/JAK/STAT3 signaling pathway was strongly activated during denervated skeletal muscle atrophy. The high level of IL-6 enhanced C2C12 myotube atrophy through the activation of JAK/STAT3, while inhibiting JAK/STAT3 pathway by ruxolitinib (a JAK1/2 inhibitor) or C188-9 (a STAT3 inhibitor) significantly attenuated C2C12 myotube atrophy induced by IL-6. Pharmacological blocking of IL-6 by tocilizumab (antibody against IL-6 receptor) and pharmacological/genetic inhibition of JAK/STAT3 pathway by ruxolitinib/C188-9 (JAK/STAT3 inhibitor) and STAT3 short hairpin RNA (shRNA) lentivirus in tibialis anterior muscles could suppress muscle atrophy and inhibit mitophagy, and was accompanied by the decreased expression of atrophic genes ( and ) and autophagy-related genes (, , , , and ).

Conclusions: Taken together, the results suggest that IL-6/JAK/STAT3 pathway may be a principal mediator in denervated skeletal muscle atrophy, meaning targeted therapy against IL-6/JAK/STAT3 pathway might have potential as a therapeutic strategy for prevention of skeletal muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-7269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812230PMC
December 2020

RNA sequencing (RNA-seq) analysis of gene expression provides new insights into hindlimb unloading-induced skeletal muscle atrophy.

Ann Transl Med 2020 Dec;8(23):1595

Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, China.

Background: Weightlessness-induced skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, has potentially damaged consequences. However, there is still an insufficient effective strategy to treat skeletal muscle atrophy. Therefore, exploring the molecular mechanisms regulating skeletal muscle atrophy and effective protection is necessary.

Methods: RNA sequencing (RNA-seq) analysis was used to detect differentially expressed genes (DEGs) in the soleus muscle at 12, 24, 36 hours, three days, and seven days after hindlimb unloading in rats. Pearson correlation heatmaps and principal component analysis (PCA) were applied to analyze DEGs' expression profiles. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for cluster analysis of DEGs. Ingenuity pathway analysis (IPA) was used to analyze specific biological processes further.

Results: At different time points (12, 24, 36 hours, three days, seven days) after hindlimb unloading, the expression levels of 712, 1,109, 1,433, 1,162, and 1,182 genes in rat soleus muscle were upregulated, respectively, whereas the expression levels of 1,186, 1,324, 1,632, 1,446, and 1,596 genes were downregulated, respectively. PCA revealed that rat soleus muscle showed three different transcriptional phases within seven days after hindlimb unloading. KEGG and GO annotation indicated that the first transcriptional phase primarily involved the activation of stress responses, including oxidative stress, and the inhibition of cell proliferation and angiogenesis; the second transcriptional phase primarily involved the activation of proteolytic systems and, to a certain degree, inflammatory responses; and the third transcriptional phase primarily involved extensive activation of the proteolytic system, significant inhibition of energy metabolism, and activation of the aging process and slow-to-fast muscle conversion.

Conclusions: Different physiological processes in rat skeletal muscles were activated sequentially after unloading. From these activated biological processes, the three transcriptional phases after skeletal muscle unloading can be successively defined as the stress response phase, the atrophic initiation phase, and the atrophic phase. Our study not only helps in the understanding of the molecular mechanisms underlying weightlessness-induced muscle atrophy but may also provide an important time window for the treatment and prevention of weightlessness-induced muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-7400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791259PMC
December 2020

Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling.

Ann Transl Med 2020 Nov;8(22):1524

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Background: Our prior studies have shown that inflammation may play an important triggering role during the process of denervated muscle atrophy. The nonsteroidal anti-inflammatory drug aspirin exhibits the effect of anti-inflammatory factors. This study will investigate the protective effect of aspirin on denervated muscle atrophy and the underlying mechanism.

Methods: Mouse models of denervated muscle atrophy were established. The protective effect of aspirin (20 mg/kg/d, i.p.) on denervated muscle atrophy was analyzed using the wet weight ratio of tibialis anterior (TA) muscle and muscle fiber cross-sectional area (CSA). The levels of inflammatory factors were detected using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) and Signal transducer and activator of transcription 3 (STAT3) signaling pathway and the muscle fiber type related proteins in TA muscle after denervation were analyzed by western blot assay.

Results: Intraperitoneal injection of aspirin (20 mg/kg/d) effectively alleviated denervation-induced muscle atrophy. This mainly manifested as follows: The wet weight ratio of TA muscle and muscle fiber CSA of mice treated with aspirin were significantly greater compared with mice treated with normal saline. The level of myosin heavy chain (MHC) increased, and the levels of muscle specific E3 ubiquitin ligase Muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were decreased. Mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy related proteins PINK1, BNIP3, LC3B and Atg7 in mice treated with aspirin compared with mice treated with saline. In addition, aspirin treatment inhibited the slow-to-fast twitch muscle fiber conversion, which were related with triggering the expression of Sirt1 and PGC-1α. Moreover, aspirin reduced the levels of inflammatory factors interleukin-6, interleukin-1β and tumor necrosis factor-α and decreased the activation of STAT3 signaling pathway.

Conclusions: This is the first study to find that aspirin can alleviate denervation-induced muscle atrophy and inhibit the type I-to-type II muscle fiber conversion and mitophagy possibly through regulating the STAT3 inflammatory signaling pathway and Sirt1/PGC-1α signal axis. This study expands our knowledge regarding the pharmacological function of aspirin and provides a novel strategy for prevention and treatment of denervated muscle atrophy.
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http://dx.doi.org/10.21037/atm-20-5460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729378PMC
November 2020

Small ubiquitin-like modifier 2 (SUMO2) is critical for memory processes in mice.

FASEB J 2020 11 10;34(11):14750-14767. Epub 2020 Sep 10.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Small ubiquitin-like modifier (SUMO1-3) conjugation (SUMOylation), a posttranslational modification, modulates almost all major cellular processes. Mounting evidence indicates that SUMOylation plays a crucial role in maintaining and regulating neural function, and importantly its dysfunction is implicated in cognitive impairment in humans. We have previously shown that simultaneously silencing SUMO1-3 expression in neurons negatively affects cognitive function. However, the roles of the individual SUMOs in modulating cognition and the mechanisms that link SUMOylation to cognitive processes remain unknown. To address these questions, in this study, we have focused on SUMO2 and generated a new conditional Sumo2 knockout mouse line. We found that conditional deletion of Sumo2 predominantly in forebrain neurons resulted in marked impairments in various cognitive tests, including episodic and fear memory. Our data further suggest that these abnormalities are attributable neither to constitutive changes in gene expression nor to alterations in neuronal morphology, but they involve impairment in dynamic SUMOylation processes associated with synaptic plasticity. Finally, we provide evidence that dysfunction on hippocampal-based cognitive tasks was associated with a significant deficit in the maintenance of hippocampal long-term potentiation in Sumo2 knockout mice. Collectively, these data demonstrate that protein conjugation by SUMO2 is critically involved in cognitive processes.
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http://dx.doi.org/10.1096/fj.202000850RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606628PMC
November 2020

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation.

Front Physiol 2020 12;11:988. Epub 2020 Aug 12.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis the ubiquitin-proteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases-muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed triggering expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors-interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)-in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.
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http://dx.doi.org/10.3389/fphys.2020.00988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435639PMC
August 2020

Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.

J Cereb Blood Flow Metab 2021 May 12;41(5):1091-1102. Epub 2020 Aug 12.

Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.
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http://dx.doi.org/10.1177/0271678X20948612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054717PMC
May 2021

PERK (Protein Kinase RNA-Like ER Kinase) Branch of the Unfolded Protein Response Confers Neuroprotection in Ischemic Stroke by Suppressing Protein Synthesis.

Stroke 2020 05 26;51(5):1570-1577. Epub 2020 Mar 26.

From the Department of Anesthesiology, Center for Perioperative Organ Protection, Duke University Medical Center, Durham, NC.

Background and Purpose- Ischemic stroke impairs endoplasmic reticulum (ER) function, causes ER stress, and activates the unfolded protein response. The unfolded protein response consists of 3 branches controlled by ER stress sensor proteins, which include PERK (protein kinase RNA-like ER kinase). Activated PERK phosphorylates eIF2α (eukaryotic initiation factor 2 alpha), resulting in inhibition of global protein synthesis. Here, we aimed to clarify the role of the PERK unfolded protein response branch in stroke. Methods- Neuron-specific and tamoxifen-inducible PERK conditional knockout (cKO) mice were generated by cross-breeding Camk2a-CreERT2 with mice. Transient middle cerebral artery occlusion was used to induce stroke. Short- and long-term stroke outcomes were evaluated. Protein synthesis in the brain was assessed using a surface-sensing-of-translation approach. Results- After tamoxifen-induced deletion of in forebrain neurons was confirmed in PERK-cKO mice, PERK-cKO and control mice were subjected to transient middle cerebral artery occlusion and 3 days or 3 weeks recovery. PERK-cKO mice had larger infarcts and worse neurological outcomes compared with control mice, suggesting that PERK-induced eIF2α phosphorylation and subsequent suppression of translation protects neurons from ischemic stress. Indeed, better stroke outcomes were observed in PERK-cKO mice that received postischemic treatment with salubrinal, which can restore the ischemia-induced increase in phosphorylated eIF2α in these mice. Finally, our data showed that post-treatment with salubrinal improved functional recovery after stroke. Conclusions- Here, we presented the first evidence that postischemic suppression of translation induced by PERK activation promotes recovery of neurological function after stroke. This confirms and further extends our previous observations that recovery of ER function impaired by ischemic stress critically contributes to stroke outcome. Therefore, future research should include strategies to improve stroke outcome by targeting unfolded protein response branches to restore protein homeostasis in neurons.
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http://dx.doi.org/10.1161/STROKEAHA.120.029071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188566PMC
May 2020

Identification of miR-210 and combination biomarkers as useful agents in early screening non-small cell lung cancer.

Gene 2020 Mar 9;729:144225. Epub 2019 Dec 9.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China; Institute of Radiotherapy & Oncology, Soochow University, Suzhou, China. Electronic address:

Background: Recently, extensive researches have explored the potential biomarker roles of microRNA-210 (miR-210) in non-small cell lung cancer (NSCLC). Inconsistent results, however, have prevented its widespread use in diagnosis. In the present study, we aimed to clarify the biomarker roles of miR-210 in NSCLC through a comprehensive meta-analysis and an integrative bioinformatics analysis.

Methods: Relevant studies were searched from several literature databases and included for qualitative synthesis based on the bivariate random-effects meta-analysis model. At the same time, we combined several bioinformatics analysis methods for exploring the potential mechanism of miR-210 involved in NSCLC.

Results: Overall, miR-210 yieled the area under curve (AUC) of 0.80 (95%CI: 0.76-0.83) with sensitivity of 0.66 (0.59-0.73) and specificity of 0.79 (0.74-0.84) for being applied to discriminate NSCLC cases from normal individuals. Besides, the combination biomarkers based on miR-210 had a higher diagnostic value accuracy than individual miR-210, with the sensitivity of 0.76 (0.72-0.79), specificity of 0.88 (0.86-0.90) and AUC of 0.91 (0.88-0.93). Through bioinformatics analysis including gene ontology, pathway enrichment, protein-protein interaction networks construction and analysis, crucial genes, pathways, modules and functional terms were identified, which were proved highly involved in the initiation and development of NSCLC.

Conclusions: In summary, the current study suggests that miR-210 may function as a potential biomarker in NSCLC detection. Particularly, combination biomarkers may be more comprehensive indicators than single miR-210. However, the clinical diagnostic utilization and additional exploration still remain to be further tested and verified through more future studies.
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http://dx.doi.org/10.1016/j.gene.2019.144225DOI Listing
March 2020

Achyranthes bidentata polypeptide k suppresses neuroinflammation in BV2 microglia through Nrf2-dependent mechanism.

Ann Transl Med 2019 Oct;7(20):575

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.

Background: Activated microglia play a critical role in regulating neuroinflammatory responses in central nervous system. Previous studies have shown that Achyranthes bidentata polypeptide k's (ABPPk's) neuroprotective effects are partly due to its anti-inflammatory effect, but the mechanism remains unknown. This study is aimed to investigate the anti-inflammatory effect of ABPPk on lipopolysaccharide (LPS)-activated neuroinflammation in BV2 microglia.

Methods: We pretreated BV2 microglia with different concentrations of ABPPk (0.04-5 µg/mL) for 30 minutes, and then stimulated microglia with LPS for 24 hours. Pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO) and prostaglandin E (PGE) production were measured by enzyme-linked immunosorbent assay (ELISA) kits. Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylated nuclear factor kappa B (NF-κB), heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression levels were detected by western blot. Glutathione (GSH) level was measured by GSH-Glo™ Glutathione assay. Immunofluorescent staining was used to detect the nuclear translocation of NF-κB and Nrf2. BV2 microglia transfected with Nrf2 siRNA were used to investigate the effect of Nrf2 on the anti-inflammatory activity of ABPPk.

Results: ABPPk (0.2-5 µg/mL) reduced the iNOS mediated NO and COX-2 mediated PGE production significantly in LPS-activated BV2 microglia. ABPPk (1 and 5 µg/mL) also suppressed the production of TNF-α and IL-6 significantly. NF-κB is phosphorylated and translocated into nuclear in LPS-activated BV2 microglia, but ABPPk is shown to inhibit the phosphorylation and translocation of NF-κB in a concentration-dependent way. ABPPk increased the protein expression levels of HO-1 and Nrf2, as well as the GSH content in BV2 microglia. Immunofluorescent staining showed that ABPPk also promoted nuclear translocation of Nrf2. After knocking down Nrf2 in BV2 cells with siRNA interference, ABPPk's inhibitory effect on pro-inflammatory mediators also disappeared.

Conclusions: The present study suggests that ABPPk inhibits neuroinflammation in BV2 microglia through Nrf2-dependent mechanism. This provides some strong evidence for the potential of this neuroprotective natural compound to treat neurodegenerative diseases such as ischemic stroke and Parkinson's disease.
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http://dx.doi.org/10.21037/atm.2019.09.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861762PMC
October 2019

Microarray Analysis of Gene Expression Provides New Insights Into Denervation-Induced Skeletal Muscle Atrophy.

Front Physiol 2019 11;10:1298. Epub 2019 Oct 11.

Key Laboratory of Neuroregeneration of Jiangsu, Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Denervation induces skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, with potentially devastating outcomes even an increased mortality. Currently, however, there remains a paucity of effective strategies to treat skeletal muscle atrophy. Therefore, it is required to understand the molecular mechanisms of skeletal muscle atrophy and formulate new treatment strategies. In this study, we investigated the transcriptional profile of denervated skeletal muscle after peripheral nerve injury in rats. The cDNA microarray analysis showed that a huge number of genes in tibialis anterior (TA) muscles were differentially expressed at different times after sciatic nerve transection. Notably, the 24 h of denervation might be a critical time point for triggering TA muscle atrophy. According to the data from self-organizing map (SOM), Pearson correlation heatmap, principal component analysis (PCA), and hierarchical clustering analysis, three nodal transitions in gene expression profile of the denervated TA muscle might partition the period of 0.25 h-28 days post nerve injury into four distinct transcriptional phases. Moreover, the four transcriptional phases were designated as "oxidative stress stage", "inflammation stage", "atrophy stage" and "atrophic fibrosis stage", respectively, which was concluded from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses at each transcriptional phase. Importantly, the differentially expressed genes at 24 h post sciatic nerve transection seemed to be mainly involved in inflammation, which might be a critical process in denervation-induced muscle atrophy. Overall, our study would contribute to the understanding of molecular aspects of denervation-induced muscle atrophy, and may also provide a new insight into the time window for targeted therapy.
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http://dx.doi.org/10.3389/fphys.2019.01298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798177PMC
October 2019

Identification of microRNA-181 as a promising biomarker for predicting the poor survival in colorectal cancer.

Cancer Med 2019 10 25;8(13):5995-6009. Epub 2019 Aug 25.

Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Background: A series of studies have investigated the vital role of microRNA-181 (miR-181) in the initiation and development of colorectal cancer (CRC), and demonstrated that it might be associated with the prognosis of CRC. However, inconsistent findings have hindered its clinical application.

Methods: A comprehensive meta-analysis and an integrative bioinformatics analysis were carried out for concluding current available evidence, clarifying the preliminary prognostic value and unfolding the underlying biological function of miR-181 in CRC patients.

Results: The findings revealed that elevated expression levels of miR-181 were associated with significantly poorer overall survival rates (HR = 1.75, 95% CI: 1.26-2.43, P < .05). Meanwhile, the target genes of miR-181 were identified and enriched into several important gene ontology (GO) categories and signaling pathways including miRNAs in cancer, pathways in cancer, proteoglycans in cancer, colorectal cancer, FoxO signaling pathway, PI3K-Akt signaling pathway, VEGF signaling pathway, HIF-1 signaling pathway, mTOR signaling pathway, and cAMP signaling pathway, which were confirmed highly involved in the initiation and progression of CRC. In addition, the protein-protein interaction (PPI) networks were set up by miR-181 targets to screen hub nodes and significant modules, which were also considerably associated with the molecular pathogenesis of CRC.

Conclusions: The present study demonstrated that miR-181 could be a promising biomarker with predictive value for prognosis for CRC patients. However, future studies comprising large cohorts from multicenter are warranted to further investigate the biomarker value of miR-181.
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http://dx.doi.org/10.1002/cam4.2520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792490PMC
October 2019

Integrated analyses of microRNA-29 family and the related combination biomarkers demonstrate their widespread influence on risk, recurrence, metastasis and survival outcome in colorectal cancer.

Cancer Cell Int 2019 15;19:181. Epub 2019 Jul 15.

1Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, Jiangsu 215004 China.

Background: Emerging evidence has revealed miR-29 family as promising biomarkers for colorectal cancer (CRC), but their biomarker potential and molecular mechanisms remain poorly understood.

Methods: We performed a comprehensive meta-analysis to evaluate the biomarker performance of individual miR-29 and the related miRNA combination biomarkers. Meanwhile, we conducted an integrative bioinformatics analysis to unfold the underlying biological function of miR-29 and their relationship with CRC.

Results: Using miR-29 expression to diagnose CRC produced 0.82 area under the curve, 70% sensitivity and 81% specificity while the combination biomarkers based on miR-29 enhanced the diagnostic power with an AUC of 0.86, a sensitivity of 78% and a specificity of 91%. For the prognosis evaluation, patients with higher expression of miR-29 had better survival outcome (pooled HR 0.78; 95% CI 0.56-1.07). In addition, miR-29 has also been identified as potential biomarker for predicting recurrence and metastasis in CRC. Then the genes regulated by the miR-29 family were retrieved and found closely associated with the molecular pathogenesis of CRC according to the gene ontology and pathway analysis. Furthermore, hub nodes and significant modules were identified from the protein-protein interaction network constructed with miR-29 family targets, which were also confirmed highly involved in the establishment and development of CRC.

Conclusions: Current evidences suggest miR-29 family may become promising biomarkers for risk, recurrence, metastasis and survival outcome of CRC. Meanwhile our data highlight the potential clinical use of miRNA combination biomarkers. Nevertheless, further prospective studies are warranted before the application of the useful biomarkers in the clinical.
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http://dx.doi.org/10.1186/s12935-019-0907-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633652PMC
July 2019

Identification of microRNA-92a and the related combination biomarkers as promising substrates in predicting risk, recurrence and poor survival of colorectal cancer.

J Cancer 2019 2;10(14):3154-3171. Epub 2019 Jun 2.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.

: Previous studies demonstrated that microRNA-92a (miR-92a) may serve as a novel promising biomarker in colorectal cancer (CRC) patients. However, a comprehensive analysis of the contribution of miR-92a in CRC is lacking. We aimed to systematically summarize the diagnostic and prognostic values of miR-92a in CRC. : The diagnostic and prognostic roles of individual miR-92a and the combination biomarkers based on miR-92a were evaluated through comprehensive meta-analyses. Meanwhile, the function and potential mechanisms of miR-92a were assessed by an integrative bioinformatics analysis. : According to the results, we found that miR-92a yielded a pooled area under ROC curve (AUC) of 0.82 (sensitivity: 76%, specificity: 75%) in discriminating CRC from controls. Notably, the combination biomarkers based on miR-92a increased the diagnostic performance, yielding an AUC of 0.91, with a sensitivity of 83% and a specificity of 87%. For the prognostic meta-analysis, patients with higher expression of miR-92a had significant shorter overall survival (pooled HR: 2.30; 95% CI: 1.03-5.12). In addition, the regulated genes of miR-92a were retrieved and enriched through gene ontology and pathway analysis, indicating their correlations with the initiation and progression of CRC. Furthermore, protein-protein interaction network was set up with miR-92a targets and screened for hub nodes and significant modules, which were confirmed strongly involved in the occurrence and development of CRC again. : Current evidences suggest miR-92a is a promising biomarker for early detection and prognosis of CRC while miRNA combination biomarkers may be considered as the right way for clinical practice. However, more prospective studies are required to highlight the theoretical strengths.
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http://dx.doi.org/10.7150/jca.30306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603388PMC
June 2019

Identification of potential genes and pathways for response prediction of neoadjuvant chemoradiotherapy in patients with rectal cancer by systemic biological analysis.

Oncol Lett 2019 Jan 18;17(1):492-501. Epub 2018 Oct 18.

Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.

Currently, neoadjuvant chemoradiotherapy (CRT) followed by radical surgery is the standard of care for locally advanced rectal cancer. However, to the best of our knowledge, there are no effective biomarkers for predicting patients who may benefit from neoadjuvant treatment. The aim of the current study was to screen potential crucial genes and pathways associated with the response to CRT in rectal cancer, and provide valid biological information to assist further investigation of CRT optimization. In the current study, differentially expressed (DE) genes were identified from the tumor samples of responders and non-responders to neoadjuvant CRT in the GSE35452 gene expression profile. Seven hub genes and one significant module were identified from the protein-protein interaction (PPI) network. Functional enrichment analysis of all the DE genes and the hub genes, retrieved from PPI network analysis, revealed their associations with CRT response. Genes were identified that may be used to discriminate patients who would or would not clinically benefit from neoadjuvant CRT. Several important pathways enriched by the DE genes, hub genes and selected module were identified, and revealed to be closely associated with radiation response, including excision repair, homologous recombination, Ras signaling pathway, the forkhead box O signaling pathway, focal adhesion and the Wnt signaling pathway. In conclusion, the current study demonstrated that the identified gene signatures and pathways may be used as molecular biomarkers for predicting CRT response. Furthermore, combinations of these biomarkers may be helpful for optimizing CRT treatment and promoting understanding of the molecular basis of response differences; this needs to be confirmed by further experiments.
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http://dx.doi.org/10.3892/ol.2018.9598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313202PMC
January 2019

Achyranthes bidentata polypeptide k improves long-term neurological outcomes through reducing downstream microvascular thrombosis in experimental ischemic stroke.

Brain Res 2019 03 8;1706:166-176. Epub 2018 Nov 8.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. Electronic address:

Achyranthes bidentata Bl. (A. bidentata) occupies an important position in traditional Chinese medicine owing to the property of promoting the circulation of blood and removing stasis. Achyranthes bidentata polypeptide k (ABPPk) is one of the active components isolated from A. bidentata. We previously demonstrated that ABPPk has potent neuroprotective effects against neuronal apoptosis both in vitro and in vivo, but the roles and mechanisms of ABPPk on long-term functional recovery after ischemic stroke remain unknown. In the current study, we investigated the neuroprotective effects of ABPPk on filament transient middle cerebral artery occlusion (tMCAO) rats and found that ABPPk reduced the infarct volume and maintained the neuronal integrity in the ischemic penumbra. Moreover, we found that ABPPk might reduce the formation of downstream microthrombus through preventing ischemic-induced oxidative damage of brain endothelial cells and activation of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), and NF-κB. ABPPk also inhibited polymorphonuclear leukocytes (PMNs) infiltration and matrix metalloproteinase-2/-9 (MMP-2/-9) activation in the ischemic penumbra. Morris water maze, foot fault test, and modified neurological severity score were assessed for a period of 6 weeks following tMCAO. ABPPk improved long-term recognition abilities and neurological outcomes after stroke compared with saline-treated rats. Taken together, these results suggested that ABPPk is beneficial to the improvement of long-term outcomes after transient cerebral ischemia injury and can be used as a potential neuroprotective agent.
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http://dx.doi.org/10.1016/j.brainres.2018.11.010DOI Listing
March 2019

Aging Is Associated With Impaired Activation of Protein Homeostasis-Related Pathways After Cardiac Arrest in Mice.

J Am Heart Assoc 2018 09;7(17):e009634

1 Center for Perioperative Organ Protection Department of Anesthesiology Duke University Medical Center Durham NC.

Background The mechanisms underlying worse outcome at advanced age after cardiac arrest ( CA ) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA , we investigated the effects of age on proteostasis-related prosurvival pathways activated after CA . Methods and Results Young (2-3 months old) and aged (21-22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation ( CPR ). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA / CPR -related changes in small ubiquitin-like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet-G was used to increase O-linked β-N-acetylglucosamine modification. After CA / CPR , aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin-like modifier conjugation, ubiquitination, unfolded protein response, and O-linked β-N-acetylglucosamine modification were activated after CA / CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O-linked β-N-acetylglucosamine modification after CA improved outcome. Conclusions Results suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA / CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging-related impairment of proteostasis-related pathways after CA / CPR may represent a promising therapeutic strategy.
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http://dx.doi.org/10.1161/JAHA.118.009634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201440PMC
September 2018

17β-Estradiol Enhances Schwann Cell Differentiation via the ERβ-ERK1/2 Signaling Pathway and Promotes Remyelination in Injured Sciatic Nerves.

Front Pharmacol 2018 9;9:1026. Epub 2018 Oct 9.

Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.

Remyelination is critical for nerve regeneration. However, the molecular mechanism involved in remyelination is poorly understood. To explore the roles of 17β-estradiol (E2) for myelination in the peripheral nervous system, we used a co-culture model of rat dorsal root ganglion (DRG) explants and Schwann cells (SCs) and a regeneration model of the crushed sciatic nerves in ovariectomized (OVX) and non-ovariectomized (non-OVX) rats for and analysis. E2 promoted myelination by facilitating the differentiation of SCs , which could be inhibited by the estrogen receptors (ER) antagonist ICI182780, ERβ antagonist PHTPP, or ERK1/2 antagonist PD98059. This suggests that E2 accelerates SC differentiation via the ERβ-ERK1/2 signaling. Furthermore, E2 promotes remyelination in crushed sciatic nerves of both OVX and non-OVX rats. Interestingly, E2 also significantly increased the expression of the lysosome membrane proteins LAMP1 and myelin protein P0 in the regenerating nerves. Moreover, P0 has higher degree of colocalization with LAMP1 in the regenerating nerves. Taking together, our results suggest that E2 enhances Schwann cell differentiation and further myelination via the ERβ-ERK1/2 signaling and that E2 increases the expression of myelin proteins and lysosomes in SCs to promotes remyelination in regenerating sciatic nerves.
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http://dx.doi.org/10.3389/fphar.2018.01026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189327PMC
October 2018

Comprehensive and integrative analysis identifies microRNA-106 as a novel non-invasive biomarker for detection of gastric cancer.

J Transl Med 2018 05 15;16(1):127. Epub 2018 May 15.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China.

Background: Recently, accumulating evidences have revealed that microRNA-106 (miR-106) may serve as a non-invasive and cost-effective biomarker in gastric cancer (GC) detection. However, inconsistent results have prevented its application to clinical practice.

Methods: As a result of this, a comprehensive meta-analysis was conducted to evaluate the diagnostic performance of miR-106 alone and miR-106-related combination markers for GC detection. Meanwhile, an integrative bioinformatics analysis was performed to explore the function of miR-106 at the systems biology level.

Results: The results in our work showed that sensitivity of 0.71 (95% CI 0.65-0.76) and specificity of 0.82 (0.72-0.88), with the under area AUC (area under the curve) value of 0.80 (0.76-0.83) for miR-106 alone. Prospectively, miR-106-related combination markers improved the combined sensitivity, specificity and AUC, describing the discriminatory ability of 0.78 (0.65-0.87), 0.83 (0.77-0.89) and 0.88 (0.85-0.90) in the present analysis. Furthermore, targets of miR-106 were obtained and enriched by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealing their associations with the occurrence and development of GC. Hub genes and significant modules were identified from the protein-protein interaction networks constructed by miR-106 targets and found closely associated with the initiation and progression of GC again.

Conclusions: Our comprehensive and integrative analysis revealed that miR-106 may be suitable as a diagnostic biomarker for GC while microRNA combination biomarkers may provide a new alternative for clinical application. However, it is necessary to conduct large-scale population-based studies and biological experiments to further investigate the diagnostic value of miR-106.
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http://dx.doi.org/10.1186/s12967-018-1510-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952699PMC
May 2018

Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.

Lab Invest 2018 06 22;98(6):799-813. Epub 2018 Feb 22.

Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.
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http://dx.doi.org/10.1038/s41374-018-0035-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397426PMC
June 2018

Identification of genomic expression differences between right-sided and left-sided colon cancer based on bioinformatics analysis.

Onco Targets Ther 2018 31;11:609-618. Epub 2018 Jan 31.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou.

Introduction: More and more findings have demonstrated that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are distinct clinical and biological entities and suggest that they should be treated as different diseases. However, the reasons why RCC and LCC harbor different clinical and biological features remain unclear.

Materials And Methods: To identify the genomic expression differences between RCC and LCC and uncover the mechanisms underlying these differences, we chose the gene expression profiles of GSE14333 from the Gene Expression Omnibus (GEO) database as an object of study. Then, a systematic and integrative bioinformatics analysis was performed to research the possible mechanism of the differentially expressed (DE) genes from the Gene Expression Omnibus dataset including gene ontology (GO) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. Totally, we extracted 3,793 DE genes from samples of colon cancer including 1,961 genes upregulated in RCC and 1,832 genes upregulated in LCC from the selected dataset.

Results: The results of GO and pathway enrichment analysis indicated that RCC and LCC could predispose to different pathways regulated by different genes. Based on the PPI network, , , , , , , , , , and were identified as the key hub genes. Also, significant modules were screened from the PPI network.

Conclusion: In conclusion, the present study indicated that the identified genes and pathways may promote new insights into the underlying molecular mechanisms contributing to the difference between RCC and LCC and might be used as specific therapeutic targets and prognostic markers for the personalized treatment of RCC and LCC.
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http://dx.doi.org/10.2147/OTT.S154207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797455PMC
January 2018

SUMOylation in brain ischemia: Patterns, targets, and translational implications.

J Cereb Blood Flow Metab 2018 01 17;38(1):5-16. Epub 2017 Nov 17.

3 Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA.

Post-translational protein modification by small ubiquitin-like modifier (SUMO) regulates a myriad of homeostatic and stress responses. The SUMOylation pathway has been extensively studied in brain ischemia. Convincing evidence is now at hand to support the notion that a major increase in levels of SUMOylated proteins is capable of inducing tolerance to ischemic stress. Therefore, the SUMOylation pathway has emerged as a promising therapeutic target for neuroprotection in the face of brain ischemia. Despite this, it is prudent to acknowledge that there are many key questions still to be addressed in brain ischemia related to SUMOylation. Accordingly, herein, we provide a critical review of literature within the field to summarize current knowledge and in so doing highlight pertinent translational implications of the SUMOylation pathway in brain ischemia.
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http://dx.doi.org/10.1177/0271678X17742260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757445PMC
January 2018

PPP1CC is associated with astrocyte and microglia proliferation after traumatic spinal cord injury in rats.

Pathol Res Pract 2017 Nov 28;213(11):1355-1364. Epub 2017 Sep 28.

Department of Osteology, People Hospital of Nantong, Nantong, Jiangsu 226001, China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College, Nantong University, Nantong, Jiangsu 226001, China. Electronic address:

Reactive astrogliosis and microgliosis after spinal cord injury (SCI) contribute to glial scar formation that impedes axonal regeneration. The mechanisms underlying reactive astrocyte and microglia proliferation upon injury remain partially understood. Protein phosphatase 1, catalytic subunit, gamma isozyme (PPP1CC) participates in cell proliferation, differentiation and apoptosis. However, the expression and functions of PPP1CC following SCI are still unknown. In this study, an acute spinal cord contusion injury model in adult rats was established to investigate the potential role of PPP1CC during the pathological process of SCI. The palpable expression increase of PPP1CC after SCI was found by western blot and immunohistochemistry staining. Double immunofluorescence staining showed that PPP1CC expression mainly increased in astrocytes and microglia, as well as PPP1CC and proliferating cell nuclear antigen (PCNA) co-localized in astrocytes and microglia. Furthermore, PCNA expression also elevated after SCI in a similar manner as PPP1CC. In vitro, PPP1CC and PCNA expression in primary rat spinal cord astrocytes and microglia changed in a similar concentration- and time-dependent manner according to LPS treatment. In addition, PPP1CC knockdown in astrocytes and microglia resulted in the decrease of PCNA expression and the number of Brdu positive cells after LPS stimulation, showing that PPP1CC promoted astrocyte and microglia proliferation after inflammation. In a word, PPP1CC might be associated with astrocyte and microglia proliferation after SCI, implying that PPP1CC is a potential molecular target for the therapy of SCI.
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http://dx.doi.org/10.1016/j.prp.2017.09.020DOI Listing
November 2017

Screening candidate microRNA-mRNA regulatory pairs for predicting the response to chemoradiotherapy in rectal cancer by a bioinformatics approach.

Sci Rep 2017 09 12;7(1):11312. Epub 2017 Sep 12.

Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Extensive efforts have been undertaken in search of biomarkers for predicting the chemoradiotherapy response in rectal cancer. However, most attention on treatment efficiency prediction in carcinoma is addicted to single or limited molecules. Network biomarkers are considered to outperform single molecules in predictive power. In this study, candidate microRNAs (miRNAs) were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were obtained from four experimentally confirmed interactions and three computationally predicted databases. Functional enrichment analysis of all the targets revealed their associations with chemoradiotherapy response, indicating they could be promising biomarkers. Two lists of key target mRNAs of the candidate miRNAs were retrieved from protein-protein interaction (PPI) network and mRNA expression profiles, respectively. Pathway analysis and literature validation revealed that the mRNA lists were highly related to the ionizing radiation. The above miRNAs along with the key miRNA targets provide potential miRNA-mRNA regulatory pairs as network biomarkers in which all the network components may be used for predicting the chemoradiotherapy response. These results demonstrated that the network biomarkers could provide a useful model for predicting the chemoradiotherapy response and help in further understanding the molecular basis of response differences, which should be prioritized for further study.
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http://dx.doi.org/10.1038/s41598-017-11840-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595906PMC
September 2017

Therapeutic benefits of combined treatment with tissue plasminogen activator and 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside in an animal model of ischemic stroke.

Neuroscience 2016 07 7;327:44-52. Epub 2016 Apr 7.

Jiangsu Key Laboratory of Neuroregeneration, Collaborative Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, JS 226001, China. Electronic address:

Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke, but tPA therapy is limited by a short therapeutic window and some adverse side effects. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, a salidroside analog (code-named SalA-4g), has shown potent neuroprotective effects. In this study, a rat model of embolic middle cerebral artery occlusion (MCAO) was used to mimic ischemic stroke. The embolic MCAO rats were intravenously (iv) injected with tPA alone, SalA-4g alone, or a combination of tPA and SalA-4g. Compared to treatment with tPA alone at 4h post MCAO, combined treatment with tPA at 4h post MCAO and SalA-4g starting at 4h post MCAO and continuing for 3days at an interval of 24h significantly reduced neurological deficits and infarct volume, and significantly inhibited the intracerebral bleeding, edema formation, neuronal loss, and cellular apoptosis in the ischemic brain. Our results suggested that additive neuroprotective actions of SalA-4g contributed to widening the therapeutic window of tPA therapy and ameliorating its side effects in treating MCAO rats. The therapeutic benefits of combined treatment with tPA and SalA-4g for ischemic stroke might be associated with its effects on cerebral glucose metabolism.
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http://dx.doi.org/10.1016/j.neuroscience.2016.04.006DOI Listing
July 2016

Involvement of Fra-1 in Retinal Ganglion Cell Apoptosis in Rat Light-Induced Retina Damage Model.

Cell Mol Neurobiol 2017 Jan 22;37(1):83-92. Epub 2016 Mar 22.

Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.

Cell cycle re-entry, in which Fra-1 (transcription factor FOS-related antigen 1) plays an important role, is a key process in neuronal apoptosis. However, the expression and function of Fra-1 in retinal ganglion cell (RGC) apoptosis are unknown. To investigate whether Fra-1 was involved in RGC apoptosis, we performed a light-induced retinal damage model in adult rats. Western blot revealed that up-regulation of Fra-1 expression appeared in retina after light exposure (LE). Immunostaining indicated that increased Fra-1 was mainly expressed in RGCs in retinal ganglion cell layer (GCL) after LE. Co-localization of Fra-1 with active caspase-3 or TUNEL-positive cells in GCL after LE was also detected. In addition, Fra-1 expression increased in parallel with cyclin D1 and phosphorylated mitogen-activated protein kinase p38 (p-p38) expression in retina after LE. Furthermore, Fra-1, cyclin D1, and active caspase-3 protein expression decreased by intravitreal injection of SB203580, a highly selective inhibitor of p38 MAP kinase (p38 MAPK). All these results suggested that Fra-1 may be associated with RGC apoptosis after LE regulated by p38 MAPK through cell cycle re-entry mechanism.
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http://dx.doi.org/10.1007/s10571-016-0346-3DOI Listing
January 2017