Publications by authors named "Chuanfu Li"

158 Publications

The degeneration changes of basal forebrain are associated with prospective memory impairment in patients with Wilson's disease.

Brain Behav 2021 Jun 14. Epub 2021 Jun 14.

School of Medical Information Engineering, Anhui University of Chinese Medicine, Hefei, Anhui, China.

Introduction: Degeneration changes of the basal forebrain (BF) are suggested to play an important role in cognitive impairment and memory loss in patients with Alzheimer's disease and Parkinson's disease. However, little is known about if and how the structure and function of BF are abnormal in Wilson's disease (WD).

Methods: Here, we employed the structural and resting-state functional magnetic resonance imaging (fMRI) data from 19 WD individuals and 24 healthy controls (HC). Voxel-based morphometry (VBM) and functional connectivity analysis were applied to investigate the structural and functional degeneration changes of BF in WD. Moreover, the linear regression analyses were performed in the patient group to depict the correlations between the aberrant gray volume and functional connectivity of the BF and clinical performances, such as the prospective memory (PM) and mini-mental state examination (MMSE).

Results: VBM analysis showed that compared with HC, the volume of overlapping cell groups of BF termed CH1-3 and CH4 was significantly reduced in WD. Additionally, the decreased functional connectivity of the CH4 was distributed in the bilateral temporal-parietal junction (TPJ), right thalamus, orbitofrontal gyrus (ORB), and left middle cingulate cortex (MCC). The performances of the time-based prospective memory (TBPM) and event-based prospective memory (EBPM) were related to reduced functional connectivity between CH4 and right ORB. Besides, the functional connectivity of left TPJ was also significantly correlated with EBPM in WD.

Conclusion: These findings indicated that the degenerative changes of BF may affect PM through the innervation brain function and may help to understand the neural mechanisms underlying cognitive impairment in WD.
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http://dx.doi.org/10.1002/brb3.2239DOI Listing
June 2021

Structural and Functional Changes Are Related to Cognitive Status in Wilson's Disease.

Front Hum Neurosci 2021 25;15:610947. Epub 2021 Feb 25.

Medical Imaging Center, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.

Patients with Wilson's disease (WD) suffer from prospective memory (PM) impairment, and some of patients develop cognitive impairment. However, very little is known about how brain structure and function changes effect PM in WD. Here, we employed multimodal neuroimaging data acquired from 22 WD patients and 26 healthy controls (HC) who underwent three-dimensional T1-weighted, diffusion tensor imaging (DTI), and resting state functional magnetic resonance imaging (RS-fMRI). We investigated gray matter (GM) volumes with voxel-based morphometry, DTI metrics using the fiber tractography method, and RS-fMRI using the seed-based functional connectivity method. Compared with HC, WD patients showed GM volume reductions in the basal ganglia (BG) and occipital fusiform gyrus, as well as volume increase in the visual association cortex. Moreover, whiter matter (WM) tracks of WD were widely impaired in association and limbic fibers. WM tracks in association fibers are significant related to PM in WD patients. Relative to HC, WD patients showed that the visual association cortex functionally connects to the thalamus and hippocampus, which is associated with global cognitive function in patients with WD. Together, these findings suggested that PM impairment in WD may be modulated by aberrant WM in association fibers, and that GM volume changes in the association cortex has no direct effect on cognitive status, but indirectly affect global cognitive function by its aberrant functional connectivity (FC) in patients with WD. Our findings may provide a new window to further study how WD develops into cognitive impairment, and deepen our understanding of the cognitive status and neuropathology of WD.
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http://dx.doi.org/10.3389/fnhum.2021.610947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947794PMC
February 2021

Hsa_circ_0107593 Suppresses the Progression of Cervical Cancer Sponging hsa-miR-20a-5p/93-5p/106b-5p.

Front Oncol 2020 15;10:590627. Epub 2021 Jan 15.

Reproductive Medical Center, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.

Circular RNAs (circRNAs) are a new class of single-stranded RNAs that form a continuous loop with crucial role in regulation of gene expression. Because their circular conformation conforms numerous properties, circRNAs have been investigated recently to demonstrate their important role in the development and progression of various cancers. However, the function of circRNAs and their regulatory outcomes in cervical cancer (CC) have rarely been explored. In this study, the role and molecular mechanism of hsa_circ_0107593 in cervical cancer are demonstrated. Quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of hsa_circ_0107593 and three miRNAs (hsa-miR-20a-5p, 93-5p, and 106b-5p) in paired CC tissues (tumor tissue adjacent normal cervical tissue), CC cell lines, and human normal cervical epithelial immortalized cell line. A series of functional experiments were conducted to assess the function of hsa_circ_0107593 in CC development. The Receiver Operating Characteristic (ROC) curve was plotted to estimate the diagnostic value of hsa_circ_0107593 in CC. The dual-luciferase reporter assay was used to explore the interaction between hsa_circ_0107593 and hsa-miR-20a-5p/93-5p/106b-5p. Bioinformatic analysis was conducted to predict the target mRNAs, pathways, and functional enrichment. The results revealed that hsa_circ_0107593 has low expression in CC tissues and CC cell lines. Moreover, negative correlations of hsa_circ_0107593 expression were found against tumor diameter, FIGO stage, and myometrial invasion. Also, hsa_circ_0107593 impedes CC cell proliferation, migration, and invasion. Based on ROC curve analysis, hsa_circ_0107593 could serve as a diagnostic biomarker. Its low expression may indicate increased patient's risk to developing cervical cancer. Mechanistically, hsa_circ_0107593 serves as a sponge of hsa-miR-20a-5p, hsa-miR-93-5p, and hsa-miR-106b-5p. Collectively, our study implies that hsa_circ_0107593 has tumor-suppressing activity in CC by physically binding with hsa-miR-20a-5p, hsa-miR-93-5p, and hsa-miR-106b-5p.
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http://dx.doi.org/10.3389/fonc.2020.590627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874083PMC
January 2021

Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation GPR81-Mediated Signaling.

Front Immunol 2020 6;11:587913. Epub 2020 Oct 6.

Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

Recent evidence from cancer research indicates that lactate exerts a suppressive effect on innate immune responses in cancer. This study investigated the mechanisms by which lactate suppresses macrophage pro-inflammatory responses. Macrophages [Raw 264.7 and bone marrow derived macrophages (BMDMs)] were treated with LPS in the presence or absence of lactate. Pro-inflammatory cytokines, NF-κB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-α and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-κB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-κB activation and TNFα production. Importantly, lactate suppressed YAP activation and nuclear translocation is mediated by GPR81 dependent AMKP and LATS activation which phosphorylates YAP, resulting in YAP inactivation. Finally, we demonstrated that LPS stimulation induces an interaction between YAP and NF-κB subunit p65, while lactate decreases the interaction of YAP and NF-κB, thus suppressing LPS induced pro-inflammatory cytokine production. Our study demonstrates that lactate exerts a previously unknown role in the suppression of macrophage pro-inflammatory cytokine production GPR81 mediated YAP inactivation, resulting in disruption of YAP and NF-κB interaction and nuclear translocation in macrophages.
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http://dx.doi.org/10.3389/fimmu.2020.587913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573489PMC
July 2021

Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Department of Surgery and.

Angiogenesis is essential for cardiac functional recovery after myocardial infarction (MI). HSPA12B is predominately expressed in endothelial cells and required for angiogenesis. Yes-associated protein (YAP) plays an important role in tumor angiogenesis. This study investigated the cooperative role of HSPA12B and YAP in angiogenesis after MI. Silencing of either HSPA12B or YAP impaired hypoxia-promoted endothelial cell proliferation and angiogenesis. Deficiency of HSPA12B suppressed YAP expression and nuclear translocation after hypoxia. Knockdown of YAP attenuated hypoxia-stimulated HSPA12B nuclear translocation and abrogated HSPA12B-promoted endothelial cell angiogenesis. Mechanistically, hypoxia induced an interaction between endothelial HSPA12B and YAP. ChIP assay showed that HSPA12B is a target gene of YAP/transcriptional enhanced associated domain 4 (TEAD4) and a coactivator in YAP-associated angiogenesis. In vivo studies using the MI model showed that endothelial cell-specific deficiency of HSPA12B (eHspa12b-/-) or YAP (eYap-/-) impaired angiogenesis and exacerbated cardiac dysfunction compared with WT mice. MI increased YAP expression and nuclear translocation in WT hearts but not eHspa12b-/- hearts. HSPA12B expression and nuclear translocation were upregulated in WT MI hearts but not eYap-/- MI myocardium. Our data demonstrate that endothelial HSPA12B is a target and coactivator for YAP/TEAD4 and cooperates with YAP to regulate endothelial angiogenesis after MI.
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http://dx.doi.org/10.1172/jci.insight.139640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526558PMC
September 2020

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma.

Theranostics 2020 9;10(19):8573-8590. Epub 2020 Jul 9.

Department of Anesthesiology, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.

Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.
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http://dx.doi.org/10.7150/thno.44321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392002PMC
May 2021

Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macrophage Inflammatory Responses in Polymicrobial Sepsis.

Front Immunol 2020 7;11:825. Epub 2020 May 7.

Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

Endothelial cell dysfunction contributes to sepsis induced initiate immune response and the infiltration of immune cells into organs, resulting in organ injury. Heat shock protein A12B (HSPA12B) is predominantly expressed in endothelial cells. The present study investigated whether endothelial HSPA12B could regulate macrophage pro-inflammatory response during sepsis. Wild type (WT) and endothelial cell-specific HSPA12B deficient (HSPA12B) mice were subjected to CLP sepsis. Mortality and cardiac function were monitored. Higher mortality, worsened cardiac dysfunction, and greater infiltrated macrophages in the myocardium and spleen were observed in HSPA12B septic mice compared with the WT septic mice. The serum levels of TNF-α and IL-1β were higher and the levels of IL-10 were lower in HSPA12B septic mice than in WT septic mice. Importantly, endothelial exosomes contain HSPA12B which can be uptaken by macrophages. Interestingly, endothelial exosomal HSPA12B significantly increases IL-10 levels and decreases TNF-α and IL-1β production in LPS-stimulated macrophages. Mechanistic studies show that endothelial exosomal HSPA12B downregulates NF-κB activation and nuclear translocation in LPS stimulated macrophages. These data suggest that endothelial HSPA12B plays a novel role in the regulation of macrophage pro-inflammatory response via exosomes during sepsis and that sepsis induced cardiomyopathy and mortality are associated with endothelial cell deficiency of HSPA12B.
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http://dx.doi.org/10.3389/fimmu.2020.00825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221167PMC
March 2021

Endothelial HSPA12B Exerts Protection Against Sepsis-Induced Severe Cardiomyopathy via Suppression of Adhesion Molecule Expression by miR-126.

Front Immunol 2020 29;11:566. Epub 2020 Apr 29.

Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells (ECs) and has been reported to protect against cardiac dysfunction from endotoxemia or myocardial infarction. This study investigated the mechanisms by which endothelial HSPA12B protects polymicrobial sepsis-induced cardiomyopathy. Wild-type (WT) and endothelial HSPA12B knockout (HSPA12B) mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP). Cecal ligation and puncture sepsis accelerated mortality and caused severe cardiac dysfunction in HSPA12B mice compared with WT septic mice. The levels of adhesion molecules and the infiltrated immune cells in the myocardium of HSPA12B septic mice were markedly greater than in WT septic mice. The levels of microRNA-126 (miR-126), which targets adhesion molecules, in serum exosomes from HSPA12B septic mice were significantly lower than in WT septic mice. Transfection of ECs with adenovirus expressing HSPA12B significantly increased miR-126 levels. Increased miR-126 levels in ECs prevented LPS-stimulated expression of adhesion molecules. delivery of miR-126 carried by exosomes into the myocardium of HSPA12B mice significantly attenuated CLP sepsis increased levels of adhesion molecules, and improved CLP sepsis-induced cardiac dysfunction. The data suggest that HSPA12B protects against sepsis-induced severe cardiomyopathy via regulating miR-126 expression which targets adhesion molecules, thus decreasing the accumulation of immune cells in the myocardium.
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http://dx.doi.org/10.3389/fimmu.2020.00566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201039PMC
March 2021

HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression.

Cell Death Differ 2020 09 24;27(9):2651-2667. Epub 2020 Apr 24.

Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A (HSPA12A) is a novel member of the HSP70 family. Here, we report that LPS increased HSPA12A nuclear translocation in hepatocytes, while knockout of HSPA12A (Hspa12a) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMD (markers of pyroptosis) were greater in livers of Hspa12a mice compared with its wild type controls. Loss- and gain-of-function studies showed that HSPA12A deficiency promoted, whereas HSPA12A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMD generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by HSPA12A deficiency, whereas AOAH overexpression reversed the HSPA12A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that HSPA12A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed HSPA12A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte HSPA12A represents a viable strategy for the management of liver injury in sepsis patients.
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http://dx.doi.org/10.1038/s41418-020-0536-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429872PMC
September 2020

Neural and Psychological Predictors of Cognitive Enhancement and Impairment from Neurostimulation.

Adv Sci (Weinh) 2020 Feb 21;7(4):1902863. Epub 2020 Jan 21.

Hefei National Laboratory for Physical Sciences at the Microscale, and School of Life Sciences University of Science and Technology of China Hefei Anhui 230027 China.

Modulating the temporoparietal junction (TPJ), especially the right counterpart, shows promises in enhancing social cognitive ability. However, it is ambiguous whether the functional lateralization of TPJ determines people's responsiveness to brain stimulation. Here, this issue is investigated with an individual difference approach. Forty-five participants attended three sessions of transcranial direct current stimulation (tDCS) experiments and one neuroimaging session. The results support the symmetric mechanism of left and right TPJ stimulation. First, the left and right TPJ stimulation effect are comparable in the group-level analysis. Second, the individual-level analysis reveals that a less right-lateralized TPJ is associated with a higher level of responsiveness. Participants could be classified into positive responders showing cognitive enhancement and negative responders showing cognitive impairment due to stimulation. The positive responders show weaker connectivity between bilateral TPJ and the medial prefrontal cortex, which mediates the prediction of offline responsiveness by the lateralization and the social-related trait. These findings call for a better characterization and predictive models for whom tDCS should be used for, and highlight the necessity and feasibility of prestimulation screening.
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http://dx.doi.org/10.1002/advs.201902863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029648PMC
February 2020

A deep-learning-based approach for adenoid hypertrophy diagnosis.

Med Phys 2020 Jun 10;47(5):2171-2181. Epub 2020 Mar 10.

Center for Biomedical Imaging, University of Science and Technology of China, 230026, Hefei, Anhui, China.

Purpose: Adenoid hypertrophy is a pathological hyperplasia of adenoids and may cause snoring, apnea, and impede breathing during sleep. In clinical practice, radiologists diagnose the severity of adenoid hypertrophy by measuring the ratio of adenoid width (A) to nasopharyngeal width (N) according to the lateral cephalogram, which indicates the locations of four keypoints. The entire diagnostic process is tedious and time-consuming due to the acquisition of A and N. Thus, there is an urgent need to develop computer-aided diagnostic tools for adenoid hypertrophy.

Methods: In this paper, we first propose the use of deep learning to solve the problem of adenoid hypertrophy classification. Deep learning driven by big data has developed greatly in the image processing field. However, obtaining a large amount of training data is hard, making the application of deep learning to medical images more difficult. This paper proposes a keypoint localization method to incorporate more prior information to improve the performance of the model under limited data. Furthermore, we design a novel regularized term called VerticalLoss to capture the vertical relationship between keypoints to provide prior information to strengthen the network performance.

Results: To evaluate the performance of our proposed method, we conducted experiments with a clinical dataset from the First Affiliated Hospital of Anhui Medical University consisting of a total of 688 patients. As our results show, we obtained a classification accuracy of 95.6%, a macro F1-score of 0.957, and an average AN ratio error of 0.026. Furthermore, we obtained a macro F1-score of 0.89, a classification accuracy of 94%, and an average AN ratio error of 0.027 while using only half of the data for training.

Conclusions: The study shows that our proposed method can achieve satisfactory results in the task of adenoid hypertrophy classification. Our approach incorporates more prior information, which is especially important in the field of medical imaging, where it is difficult to obtain large amounts of training data.
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http://dx.doi.org/10.1002/mp.14063DOI Listing
June 2020

Triad3A attenuates pathological cardiac hypertrophy involving the augmentation of ubiquitination-mediated degradation of TLR4 and TLR9.

Basic Res Cardiol 2020 02 1;115(2):19. Epub 2020 Feb 1.

Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center For Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, China.

Activation of TLRs mediated the NF-κB signaling pathway plays an important pathophysiological role in cardiac hypertrophy. Triad3A, a ubiquitin E3 ligase, has been reported to negatively regulate NF-κB activation pathway via promoting ubiquitination and degradation of TLR4 and TLR9 in innate immune cells. The role of Triad3A in cardiac hypertrophic development remains unknown. The present study investigated whether there is a link between Triad3A and TLR4 and TLR9 in pressure overload induced cardiac hypertrophy. We observed that Triad3A levels were markedly reduced following transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, stimulation of neonatal rat cardiac myocytes (NRCMs) with angiotensin-II (Ang II) significantly decreased Triad3A expression. To determine the role of Triad3A in TAC-induced cardiac hypertrophy, we transduced the myocardium with adenovirus expressing Triad3A followed by induction of TAC. We observed that increased expression of Triad3A significantly attenuated cardiac hypertrophy and improved cardiac function. To investigate the mechanisms by which Triad3A attenuated cardiac hypertrophy, we examined the Triad3A E3 ubiquitination on TLR4 and TLR9. We found that Triad3A promoted TLR4 and TLR9 degradation through ubiquitination. Triad3A mediated TLR4 and TLR9 degradation resulted in suppression of NF-κB activation. Our data suggest that Triad3A plays a protective role in the development of cardiac hypertrophy, at least through catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, thus negatively regulating NF-κB activation.
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http://dx.doi.org/10.1007/s00395-020-0779-1DOI Listing
February 2020

Longitudinal Changes in Functional Connectivity of the Caudate Is Associated With Recovery From Bell's Palsy.

Front Aging Neurosci 2019 7;11:295. Epub 2019 Nov 7.

Department of Medical Information Engineering, Anhui University of Chinese Medicine, Hefei, China.

Several studies have demonstrated through resting-state functional magnetic resonance imaging (fMRI) that functional connectivity changes are important in the recovery from Bell's palsy (BP); however, these studies have only focused on the cortico-cortical connectivity. It is unclear how corticostriatal connectivity relates to the recovery process of patients with BP. In the present study, we evaluated the relationship between longitudinal changes of caudate-based functional connectivity and longitudinal changes of facial performance in patients with intractable BP. Twenty-one patients with intractable BP underwent resting-state fMRI as well as facial behavioral assessments prior to treatment (PT) and at the middle stage of treatment (MT); and 21 age- and sex-matched healthy controls (HC) were recruited and received the same protocol. The caudate was divided into dorsal and ventral sub-regions and separate functional connectivity was calculated. Compared with HC, patients with intractable BP at the PT stage showed decreased functional connectivity of both the dorsal and ventral caudate mainly distributed in the somatosensory network, including the bilateral precentral gyrus (MI), left postcentral gyrus, media frontal gyrus, and superior temporal gyrus (STG). Alternatively, patients in the MT stage showed decreased functional connectivity primarily distributed in the executive network and somatosensory network, including the bilateral cingulate cortex (CC), left anterior cingulate cortex (LACC), inferior prefrontal gyrus (IFG), MI, STG, and paracentral lobe. The longitudinal changes in functional connectivity of both the dorsal and ventral caudate were mainly observed in the executive network, including the right ACC, left CC, and IFG. Functional connectivity changes in the right ACC and left IFG were significantly correlated with changes in facial behavioral performance. These findings indicated that corticostriatal connectivity changes are associated with recovery from BP.
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http://dx.doi.org/10.3389/fnagi.2019.00295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853889PMC
November 2019

Magnetism and hybrid improper ferroelectricity in LaMO/YMO superlattices.

Phys Chem Chem Phys 2019 Sep;21(36):20132-20136

School of Science, Nantong University, Nantong, 226007, China.

Using first-principles calculations, we investigate the structural, electronic, and magnetic properties of perovskite LaMO3/YMO3 superlattices (M = Cr, Mn, Co and Ni). It is found that ferroelectricity can emerge in LaMO3/YMO3 superlattices (M = Cr, Mn, Co), allowing them to be promising multiferroic candidates, while no ferroelectricity is found in the LaNiO3/YNiO3 superlattice. The electronic structure calculations indicate that the LaCrO3/YCrO3, LaMnO3/YMnO3, and LaCoO3/YCoO3 superlattices are insulators, and their magnetic ground states exhibit G-type antiferromagnetic (AFM), A-type AFM, and G-type AFM order, respectively, while the LaNiO3/YNiO3 superlattice is however a half-metallic ferromagnet. The electronic structure and magnetic ground state are discussed, based on the projected density of states data and Heisenberg model, respectively, and the magnetic phase transition temperature is evaluated based on mean-field theory. In the meantime, the spontaneous ferroelectric polarization of the LaMO3/YMO3 superlattices (M = Cr, Mn, Co) is determined respectively using the Born effective charge model and Berry phase method, and their hybrid improper ferroelectric character is predicted, with the net polarization mainly from the different displacements of the LaO layers and YO layers along the b-axis. It is suggested that alternative multiferroic materials can be obtained by properly designing superlattices that consist of two non-polar magnetic materials but exhibit tunable magnetic ground states and transition temperature and hybrid improper ferroelectricity.
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http://dx.doi.org/10.1039/c9cp03675jDOI Listing
September 2019

Peli1 induction impairs cardiac microvascular endothelium through Hsp90 dissociation from IRE1α.

Biochim Biophys Acta Mol Basis Dis 2019 10 29;1865(10):2606-2617. Epub 2019 Jun 29.

Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China. Electronic address:

Ameliorating cardiac microvascular injury is the most effective means to mitigate diabetes-induced cardiovascular complications. Inositol-requiring 1α (IRE1α), a sensor of endoplasmic reticulum stress, is activated by Toll like receptors (TLRs), and then promotes cardiac microvascular injury. Peli1 is a master regulator of TLRs and activates IRE1α. This study aims to investigate whether Peli1 in endothelial cells promotes diabetes-induced cardiac microvascular injury through activating IRE1α. Here we found that Peli1 was markedly up-regulated in cardiac endothelial cells of both diabetic mice and in AGEs-treated cardiac microvascular endothelial cells (CMECs). Peli1 deficiency in endothelial cells significantly alleviated diabetes-induced cardiac microvascular permeability, promoted microvascular regeneration, and suppressed apoptosis, accompanied by the attenuation of adverse cardiac remodeling. Furthermore, Peli1 deletion in CMECs ameliorated AGEs-induced damages in vitro. We identified heat shock protein 90 (Hsp90) as a potential binding partner for Peli1, and the Ring domain of Peli1 directly bound with Hsp90 to enhance IRE1α phosphorylation. Our study suggests that blocking Peli1 in endothelial cells may protect against diabetes-induced cardiac microvascular injury by restraining ER stress.
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http://dx.doi.org/10.1016/j.bbadis.2019.06.017DOI Listing
October 2019

Loss of monocyte metabolic plasticity in endotoxin tolerance: A model for understanding sepsis-induced immune paralysis?

J Leukoc Biol 2019 07 14;106(1):7-9. Epub 2019 May 14.

Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, 37614, USA.

Discussion on implications of the immune paralysis that occurs in many sepsis patients.
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http://dx.doi.org/10.1002/JLB.4CE0319-100RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597287PMC
July 2019

Aberrant Coupling Between Resting-State Cerebral Blood Flow and Functional Connectivity in Wilson's Disease.

Front Neural Circuits 2019 18;13:25. Epub 2019 Apr 18.

Laboratory of Digital Medical Imaging, Medical Imaging Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.

Both abnormalities of resting-state cerebral blood flow (CBF) and functional connectivity in Wilson's disease (WD) have been identified by several studies. Whether the coupling of CBF and functional connectivity is imbalanced in WD remains largely unknown. To assess this possibility, 27 patients with WD and 27 sex- and age-matched healthy controls were recruited to acquire functional MRI and arterial spin labeling imaging data. Functional connectivity strength (FCS) and CBF were calculated based on standard gray mask. Compared to healthy controls, the CBF-FCS correlations of patients with WD were significantly decreased in the basal ganglia and the cerebellum and slightly increased in the prefrontal cortex and thalamus. In contrast, decreased CBF of patients with WD occurred predominately in subcortical and cognitive- and emotion-related brain regions, including the basal ganglia, thalamus, insular, and inferior prefrontal cortex, whereas increased CBF occurred primarily in the temporal cortex. The FCS decrease in WD patients was predominately in the basal ganglia and thalamus, and the increase was primarily in the prefrontal cortex. These findings suggest that aberrant neurovascular coupling in the brain may be a possible neuropathological mechanism underlying WD.
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http://dx.doi.org/10.3389/fncir.2019.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482267PMC
January 2020

HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ.

Cell Death Differ 2019 Nov 11;26(11):2253-2267. Epub 2019 Feb 11.

Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, 210029, Nanjing, China.

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a) in mice attenuated high-fat diet (HFD)-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia compared to their wild type (WT) littermates. Increased insulin sensitivity was observed in Hspa12a mice compared to WT mice. The HFD-induced upregulation of PPARγ and its target adipogenic genes in white adipose tissues (WAT) of Hspa12a mice were also attenuated. Loss- and gain-of-function studies revealed that the differentiation of primary adipocyte precursors, as well as the expression of PPARγ and target adipogenic genes during the differentiation, was suppressed by HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A expression was downregulated by PPARγ inhibition but upregulated by PPARγ activation in primary adipocytes. A direct binding of PPARγ to the PPAR response element in the Hspa12a promoter region was confirmed by chromatin immunoprecipitation assay, and this binding was increased after differentiation of primary adipocytes. These findings indicate that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans.
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http://dx.doi.org/10.1038/s41418-019-0300-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888823PMC
November 2019

HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization.

Diabetes 2019 02 19;68(2):361-376. Epub 2018 Nov 19.

Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease worldwide. Macrophage-mediated inflammation plays a critical role in NASH pathogenesis; however, optimum therapies for macrophage activation and NASH remain elusive. HSPA12A encodes a novel member of the HSP70 family. Here, we report that NASH patients showed increased hepatic HSPA12A expression and serum HSPA12A contents. Intriguingly, knockout of HSPA12A ( ) in mice attenuated high-fat diet (HFD)-induced hepatic steatosis and injury. HFD-induced macrophage polarization toward an M1 phenotype and inflammatory responses in the liver of mice were also attenuated. Loss- and gain-of-function studies revealed that the de novo lipogenesis in hepatocytes was regulated by the paracrine effects of macrophage HSPA12A rather than by hepatocyte HSPA12A. In-depth molecular analysis revealed that HSPA12A interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and increased its nuclear translocation, thereby promoting M1 polarization and secretion of proinflammatory M1 cytokines; this led, ultimately, to hepatocyte steatosis via paracrine effects. Taken together, these findings show that HSPA12A acts as a novel regulator of M1 macrophage polarization and NASH pathogenesis by increasing nuclear PKM2. Strategies that inhibit macrophage HSPA12A might be a potential therapeutic intervention for NASH.
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http://dx.doi.org/10.2337/db18-0035DOI Listing
February 2019

Cardiomyocyte-specific deficiency of HSPB1 worsens cardiac dysfunction by activating NFκB-mediated leucocyte recruitment after myocardial infarction.

Cardiovasc Res 2019 01;115(1):154-167

Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Guangzhou Rd. 300, Nanjing, China.

Aims: Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI.

Methods And Results: To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI.

Conclusion: These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.
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http://dx.doi.org/10.1093/cvr/cvy163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657285PMC
January 2019

[Effects on the regional homogeneity of resting-state brain function in the healthy subjects of gastric distention treated with acupuncture at the front- and back- points of the stomach, Weishu (BL 21) and Zhongwan (CV 12)].

Zhongguo Zhen Jiu 2018 Apr;38(4):379-86

Graduate School of Anhui University of CM, Hefei 230012, China.

Objective: To observe the regional homogeneity (ReHo) of resting-state brain function in the healthy subjects of gastric distention treated with acupuncture at the back- and front- points of the stomach, Weishu (BL 21) and Zhongwan (CV 12) and the correlation with gastric motility so as to explore the mechanism on the central integration of the front- and back- points of the stomach.

Methods: The crossover test design was adopted. Twenty-four healthy subjects were assigned to a Weishu group, a Zhongwan group and a combined-point group separately, 8 cases in each one in each of the three times. Totally, 24 subjects were included in each group. Under the water load condition, the subjects received acupuncture at Weishu (BL 21), Zhongwan (CV 12) and the combined Weishu (BL 21) and Zhongwan (CV 12). Before and after each acupuncture, the resting-state brain functional magnetic resonance imaging (fMRI) scan and electrogastrogram (EGG) test were applied. The ReHo value was calculated in the collected fMRI imaging data. The changes in ReHo values were analyzed and compared before and after acupuncture in each group, as well as among the groups. The gastric motility was analyzed before and after acupuncture. Additionally, the correlative analysis was conducted between the gastric motility and ReHo changes before and after acupuncture.

Results: (1) After acupuncture, EGG amplitudes in the subjects of each group were lower remarkably as compared with those before acupuncture (all <0.01). The EGG frequencies were not different significantly as compared with those before acupuncture (all >0.05). The EGG amplitudes in the Weishu group and the Zhongwan group were higher than those in the combined-point group (both <0.05). (2) As compared with the conditions before acupuncture, acupuncture at the combined front- and the back- points as well as Weishu (BL 21) and Zhongwan (CV 12) separately all induced the changes in the brain ReHo. Acupuncture at the combined front- and the back- points significantly increased Reho values in the right inferior temporal gyrus, the left thalamus, the precuneus and the posterior cingulate gyrus (all <0.05) and remarkably reduced the ReHo values in the the middle temporal gyrus of the right temporal pole, sulcus calcarinus and precuneus (all <0.05). Compared with the single point groups, acupuncture at the combined front- and the back- points induced the increase of ReHo value in the posterior cingulate gyrus and the decrease of ReHo in the temporal pole (all <0.05). (3) The correlative analysis showed that the changes in the ReHo values in the posterior cingulate gyrus, the thalamus and the precuneus were positively correlated to the changes of the gastric motility amplitudes. The changes in the ReHo values in the temporal pole was negatively correlated to the changes of the gastric motility amplitudes.

Conclusion: Acupuncture at the combined back- and front- points of the stomach, as well as acupuncture at single Weishu (BL 21) and Zhongwan (CV 12) induce the ReHo changes in the different brain regions. Acupuncture at the combined back- and front- points of the stomach may induce the ReHo changes in some new brain regions as compared with the acupuncture at the single point. The thalamus, the posterior cingulate gyrus and the precuneus may be the the important integrated brain regions for acupuncture at the back- and the front- points in regulating the gastric motility. The effects of acupuncture at the back- and the front- points for the regulation of the gastric motility are closely related to the thalamus, the limbic system and the default network of the brain regions.
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http://dx.doi.org/10.13703/j.0255-2930.2018.04.010DOI Listing
April 2018

Heat shock protein A12A encodes a novel prosurvival pathway during ischaemic stroke.

Biochim Biophys Acta Mol Basis Dis 2018 May 10;1864(5 Pt A):1862-1872. Epub 2018 Mar 10.

Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. Electronic address:

Heat shock protein A12A (HSPA12A) is a newly discovered member of the Hsp70 family. The biological characteristics and functional roles of HSPA12A are poorly understood. This study investigated the effects of HSPA12A on ischaemic stroke in mice. Ischaemic stroke was induced by left middle cerebral artery occlusion for 1 h followed by blood reperfusion. We observed that HSPA12A was highly expressed in brain neurons, and neuronal HSPA12A expression was downregulated by ischaemic stroke and stroke-associated risk factors (aging, obesity and hyperglycaemia). To investigate the functional requirement of HSPA12A in protecting ischaemic brain injury, HSPA12A knockout mice (Hspa12a) were generated. Hspa12a mice exhibited an enlarged infarct volume and aggravated neurological deficits compared to their wild-type (WT) littermates after stroke. These aggravations in Hspa12a mice were accompanied by more apoptosis and severer hippocampal morphological abnormalities in ischaemic hemispheres. Long-term examination revealed impaired motor function recovery and neurogenesis in stroke-affected Hspa12a mice compared to stroke-affected WT controls. Significant reduced activation of GSK-3β/mTOR/p70S6K signalling was also observed in ischaemic hemispheres of Hspa12a mice compared to WT controls. Administration with lithium (non-selective GSK-3β inhibitor) activated GSK-3β/mTOR/p70S6K signalling in stroke-affected Hspa12a mice. Notably, lithium administration attenuated the HSPA12A deficiency-induced aggravation in infarct size, neurological deficits and neuronal death in Hspa12a mice after stroke. Altogether, the findings suggest that HSPA12A expression encodes a critical novel prosurvival pathway during ischaemic stroke. We identified HSPA12A as a novel neuroprotective target for stroke patients.
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http://dx.doi.org/10.1016/j.bbadis.2018.03.006DOI Listing
May 2018

HSPA12B promotes functional recovery after ischaemic stroke through an eNOS-dependent mechanism.

J Cell Mol Med 2018 04 7;22(4):2252-2262. Epub 2018 Feb 7.

Departments of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.

Stroke is the leading cause of disability worldwide. HSPA12B, a heat-shock protein recently identified expression specifically in endothelial cells, is able to promote angiogenesis. Here, we have investigated its effects on functional recovery at chronic phase of ischaemic stroke. Ischaemic stroke was induced by 60 min. of middle cerebral artery occlusion in transgenic mice with overexpression of HSPA12B (HSPA12B Tg) and wild-type littermates (WT). HSPA12B Tg mice demonstrated a significant higher survival rate than WT mice within 28 days post-stroke. Significant improved neurological functions, increased spontaneous locomotor activity and decreased anxiety were detected inHSPA12B Tg mice compared with WT controls within 21 days post-stroke. Stroke-induced hippocampal degeneration was attenuated in HSPA12B Tg mice examined at day 28 post-stroke. Interestingly, HSPA12B Tg mice showed enhanced peri-infarct angiogenesis (examined 28 days post-stroke) and hippocampal neurogenesis (examined 7 days post-stroke), respectively, compared to WT mice. The stroke-induced eNOS phosphorylation and TGF-β1 expression were augmented in HSPA12B Tg mice. However, administration with eNOS inhibitor L-NAME diminished the HSPA12B-induced protection in neurological functional recovery and mice survival post-stroke. The data suggest that HSPA12B promoted functional recovery and survival after stroke in an eNOS-dependent mechanism. Targeting HSPA12B expression may have a therapeutic potential for the stroke-evoked functional disability and mortality.
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http://dx.doi.org/10.1111/jcmm.13507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867065PMC
April 2018

TLR3 Mediates Repair and Regeneration of Damaged Neonatal Heart through Glycolysis Dependent YAP1 Regulated miR-152 Expression.

Cell Death Differ 2018 05 22;25(5):966-982. Epub 2018 Jan 22.

Departments of Surgery, East Tennessee State University, Johnson City, TN, USA.

The present study investigated whether TLR3 is required for neonatal heart repair and regeneration following myocardial infarction (MI). TLR3 deficient neonatal mice exhibited impaired cardiac functional recovery and a larger infarct size, while wild type neonatal mice showed cardiac functional recovery and small infarct size after MI. The data suggest that TLR3 is essential for the regeneration and repair of damaged neonatal myocardium. In vitro treatment of neonatal cardiomyocytes with a TLR3 ligand, Poly (I:C), significantly enhances glycolytic metabolism, YAP1 activation and proliferation of cardiomyocytes which were prevented by a glycolysis inhibitor, 2-deoxyglucose (2-DG). Administration of 2-DG to neonatal mice abolished cardiac functional recovery and YAP activation after MI, suggesting that TLR3-mediated regeneration and repair of the damaged neonatal myocardium is through glycolytic-dependent YAP1 activation. Inhibition of YAP1 activation abolished Poly (I:C) induced proliferation of neonatal cardiomyocytes. Interestingly, activation of YAP1 increases the expression of miR-152 which represses the expression of cell cycle inhibitory proteins, P27kip1 and DNMT1, leading to cardiomyocyte proliferation. We conclude that TLR3 is required for neonatal heart regeneration and repair after MI. The mechanisms involve glycolytic-dependent YAP1 activation, resulting in miR-152 expression which targets DNMT1/p27kip1.
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http://dx.doi.org/10.1038/s41418-017-0036-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943401PMC
May 2018

The positive effects of Xueshuan Xinmai tablets on brain functional connectivity in acute ischemic stroke: a placebo controlled randomized trial.

Sci Rep 2017 11 10;7(1):15244. Epub 2017 Nov 10.

State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, P.R. China.

Through a placebo controlled randomized study, the purpose of this report was to investigate the effects of Xueshuan Xinmai tablets (XXMT) on neurologic deficits, quality of life and brain functional connectivity in acute ischemic stroke patients and to explore the mechanism of action of XXMT. In total, 44 acute ischemic stroke patients were randomly divided to the XXMT treatment group (n = 22) or the placebo group (n = 22) in a 2-week trial. Before and after the treatment, the neurological assessment and functional magnetic resonance imaging examinations were carried out. Compared to the placebo group, the scores of the National Institutes of Health Stroke Scale (NIHSS) and Stroke-Specific Quality of Life Scale (SSQOL) significantly improved in the treatment group. In addition, XXMT-treated patients demonstrated significantly enhanced functional connectivity within the default mode, frontal-parietal, and motor control networks. Furthermore, the changed connectivity in the left precuneus was positively correlated to the improvement of NIHSS and SSQOL scores. The present study indicated that XXMT treatment significantly improved the neurologic deficit and quality of life of acute ischemic stroke patients and that the therapeutic effect may be based on the modulation of XXMT on the functional connectivity of brain networks.
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http://dx.doi.org/10.1038/s41598-017-15456-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681502PMC
November 2017

The Research of Clinical Decision Support System Based on Three-Layer Knowledge Base Model.

J Healthc Eng 2017 27;2017:6535286. Epub 2017 Jul 27.

Medical Imaging Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei 230031, China.

In many clinical decision support systems, a two-layer knowledge base model (disease-symptom) of rule reasoning is used. This model often does not express knowledge very well since it simply infers disease from the presence of certain symptoms. In this study, we propose a three-layer knowledge base model (disease-symptom-property) to utilize more useful information in inference. The system iteratively calculates the probability of patients who may suffer from diseases based on a multisymptom naive Bayes algorithm, in which the specificity of these disease symptoms is weighted by the estimation of the degree of contribution to diagnose the disease. It significantly reduces the dependencies between attributes to apply the naive Bayes algorithm more properly. Then, the online learning process for parameter optimization of the inference engine was completed. At last, our decision support system utilizing the three-layer model was formally evaluated by two experienced doctors. By comparisons between prediction results and clinical results, our system can provide effective clinical recommendations to doctors. Moreover, we found that the three-layer model can improve the accuracy of predictions compared with the two-layer model. In light of some of the limitations of this study, we also identify and discuss several areas that need continued improvement.
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http://dx.doi.org/10.1155/2017/6535286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551511PMC
July 2019

Study on Lesion Assessment of Cerebello-Thalamo-Cortical Network in Wilson's Disease with Diffusion Tensor Imaging.

Neural Plast 2017 11;2017:7323121. Epub 2017 Jul 11.

The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.

Wilson's disease (WD) is a genetic disorder of copper metabolism with pathological copper accumulation in the brain and any other tissues. This article aimed to assess lesions in cerebello-thalamo-cortical network with an advanced technique of diffusion tensor imaging (DTI) in WD. 35 WD patients and 30 age- and sex-matched healthy volunteers were recruited to accept diffusion-weighted images with 15 gradient vectors and conventional magnetic resonance imaging (MRI). The DTI parameters, including fractional anisotropy (FA) and mean diffusion (MD), were calculated by diffusion kurtosis estimator software. After registration, patient groups with FA mappings and MD mappings and normal groups were compared with 3dttest and receiver-operating characteristic (ROC) curve analysis, corrected with FDR simulations ( = 0.001, = 0.05, cluster size = 326). We found that the degree of FA increased in the bilateral head of the caudate nucleus (HCN), lenticular nucleus (LN), ventral thalamus, substantia nigra (SN), red nucleus (RN), right dentate nucleus (DN), and decreased in the mediodorsal thalamus and extensive white matter. The value of MD increased in HCN, LN, SN, RN, and extensive white matter. The technique of DTI provides higher sensitivity and specificity than conventional MRI to detect Wilson's disease. Besides, lesions in the basal ganglia, thalamus, and cerebellum might disconnect the basal ganglia-thalamo-cortical circuits or dentato-rubro-thalamic (DRT) track and disrupt cerebello-thalamo-cortical network finally, which may cause clinical extrapyramidal symptoms.
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http://dx.doi.org/10.1155/2017/7323121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525080PMC
May 2018

Lactate and Immunosuppression in Sepsis.

Shock 2018 02;49(2):120-125

Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.

Serum lactate levels are traditionally interpreted as a marker of tissue hypoxia and often used clinically as an indicator of severity and outcome of sepsis/septic shock. Interestingly, recent studies involving the effects of tumor-derived lactate suggest that lactate itself may have an immunosuppressive effect in its local environment. This finding adds to the recent advances in immunometabolism that shed light on the importance of metabolism and metabolic intermediates in the regulation of innate immune and inflammatory responses in sepsis. In this article, we summarize recent studies, showing that the activation of immune cells requires aerobic glycolytic metabolism and that lactate produced by aerobic glycolysis may play an immunosuppressive role in sepsis.
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http://dx.doi.org/10.1097/SHK.0000000000000958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757670PMC
February 2018

Decreased Mean Platelet Volume is Associated with Cervical Cancer Development

Asian Pac J Cancer Prev 2017 07 27;18(7):1769-1772. Epub 2017 Jul 27.

Department of Gynaecology and Obstetrics, First Affiliated Hospital of Chinese PLA General Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China.

Background: Cervical cancer is the most common gynecological malignant disorder worldwide. Activated platelets play a key role in cancer development and progression. Mean platelet volume (MPV) is an early indicator of platelet activation. The aim of the present study was to evaluate MPV levels in patients with cervical cancer. Materials and methods: A total of 181 patients with cervical cancer and 181 controls between January 2015 and June 2015 were included in the study. Patient characteristics and hematologic test data at initial diagnosis were collected and odds ratios (ORs) and 95% confidence intervals (CIs) for risk of cervical cancer were calculated using multivariate logistic regression analyses across MPV quartiles. Results: MPV levels were decreased in patients with cervical cancer compared with control subjects. A significant correlation between MPV and FIGO stage was found. Moreover, after adjusting for other risk factors, the ORs (95%CIs) for cervical cancer according to MPV quartiles were 4.450 (1.975-10.026), 2.505 (1.206-5.202), 0.573 (0.261-1.259), and 1.000, respectively. Conclusions: MPV was found to be independently associated with the presence of cervical cancer. Our results suggest that MPV could be potential diagnostic screening tool.
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http://dx.doi.org/10.22034/APJCP.2017.18.7.1769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648377PMC
July 2017

Enhanced Glycolytic Metabolism Contributes to Cardiac Dysfunction in Polymicrobial Sepsis.

J Infect Dis 2017 05;215(9):1396-1406

Departments of Surgery.

Background: Cardiac dysfunction is present in >40% of sepsis patients and is associated with mortality rates of up to 70%. Recent evidence suggests that glycolytic metabolism plays a critical role in host defense and inflammation. Activation of Toll-like receptors on immune cells can enhance glycolytic metabolism. This study investigated whether modulation of glycolysis by inhibition of hexokinase will be beneficial to septic cardiomyopathy.

Methods: Male C57B6/J mice were treated with a hexokinase inhibitor (2-deoxy-d-glucose [2-DG], 0.25-2 g/kg, n = 6-8) before cecal ligation and puncture (CLP) induced sepsis. Untreated septic mice served as control. Sham surgically operated mice treated with or without the 2-DG inhibitor served as sham controls. Cardiac function was assessed 6 hours after CLP sepsis by echocardiography. Serum was harvested for measurement of inflammatory cytokines and lactate.

Results: Sepsis-induced cardiac dysfunction was significantly attenuated by administration of 2-DG. Ejection fraction and fractional shortening in 2-DG-treated septic mice were significantly (P < .05) greater than in untreated CLP mice. 2-DG administration also significantly improved survival outcome, reduced kidney and liver injury, attenuated sepsis-increased serum levels of tumor necrosis factor α and interleukin 1β as well as lactate, and enhanced the expression of Sirt1 and Sirt3 in the myocardium, which play an important role in mitochondrial function and metabolism. In addition, 2-DG administration suppresses sepsis-increased expression of apoptotic inducers Bak and Bax as well as JNK phosphorylation in the myocardium.

Conclusions: Glycolytic metabolism plays an important role in mediating sepsis-induced septic cardiomyopathy. The mechanisms may involve regulation of inflammatory response and apoptotic signaling.
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http://dx.doi.org/10.1093/infdis/jix138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451607PMC
May 2017
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