Publications by authors named "Hong-Gang Wang"

222 Publications

Circ_0134944 inhibits osteogenesis through miR-127-5p/PDX1/SPHK1 pathway.

Regen Ther 2021 Dec 29;18:391-400. Epub 2021 Sep 29.

Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, PR China.

Introduction: Osteoporosis, a common skeletal disorder mainly affecting postmenopausal women, is characterized by the imbalance between osteogenesis and osteoclastogenesis. Circ_0134944 has been recently found to be upregulated in postmenopausal osteoporosis (PMOP) patients. However, its role in osteogenesis remains unknown. Here we aimed to explore the role of circ_0134944 in osteogenesis and reveal the underlying mechanism.

Methods: qRT-PCR was used to determine the expression of circ_0134944, miR-127-5p, PDX1 and SPHK1 in the blood mononuclear cells (BMCs) of PMOP patients. Bone marrow mesenchymal stem cells (BMSCs) were used as the cellular model. Western blotting and qRT-PCR were used to determine the expression of osteogenesis-related genes (Runx2, OPN, OCN). ALP and Alizarin Red S staining were performed to evaluate osteogenic differentiation. The interactions between circ_0134944 and miR-127-5p, miR-127-5p and PDX1, PDX1 and SPHK1 were determined by dual-luciferase reporter and ChIP assay.

Results: Circ_0134944, PDX1 and SPHK1 were upregulated while miR-127-5p was downregulated in PMOP patients. Enhanced expression of circ_0134944 suppressed osteogenesis, which was then reversed by miR-127-5p overexpression. The binding between circ_0134944 and miR-127-5p, PDX1 and miR-127-5p were confirmed by dual-luciferase reporter assay. Moreover, PDX1 was enriched in the promoter region of SPHK1, and SPHK1 overexpression prevented the promotion of osteogenesis induced by miR-127-5p overexpression.

Conclusions: Taken together, these results demonstrate that circ_0134944 inhibit osteogenesis via miR-127-5p/PDX1/SPHK1 axis. Thus, the present study offered evidence that circ_0134944/miR-127-5p/PDX1/SPHK1 axis could be a potential therapeutic target for PMOP.
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http://dx.doi.org/10.1016/j.reth.2021.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531758PMC
December 2021

PIGN spatiotemporally regulates the spindle assembly checkpoint proteins in leukemia transformation and progression.

Sci Rep 2021 Sep 24;11(1):19022. Epub 2021 Sep 24.

Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.

Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) has been linked to the suppression of chromosomal instability. The spindle assembly checkpoint complex is responsible for proper chromosome segregation during mitosis to prevent chromosomal instability. In this study, the novel role of PIGN as a regulator of the spindle assembly checkpoint was unveiled in leukemic patient cells and cell lines. Transient downregulation or ablation of PIGN resulted in impaired mitotic checkpoint activation due to the dysregulated expression of spindle assembly checkpoint-related proteins including MAD1, MAD2, BUBR1, and MPS1. Moreover, ectopic overexpression of PIGN restored the expression of MAD2. PIGN regulated the spindle assembly checkpoint by forming a complex with the spindle assembly checkpoint proteins MAD1, MAD2, and the mitotic kinase MPS1. Thus, PIGN could play a vital role in the spindle assembly checkpoint to suppress chromosomal instability associated with leukemic transformation and progression.
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http://dx.doi.org/10.1038/s41598-021-98218-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463542PMC
September 2021

TPEN attenuates amyloid-β-induced neuronal damage with changes in the electrophysiological properties of voltage-gated sodium and potassium channels.

Mol Brain 2021 08 12;14(1):124. Epub 2021 Aug 12.

College of Life Sciences, Nankai University, Tianjin, 300071, People's Republic of China.

To understand the role of intracellular zinc ion (Zn) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N', N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn-specific chelator, could attenuate Aβ-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ-induced neuronal death, reversed the Aβ-induced increase in intracellular Zn concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aβ, relieved the Aβ-induced decrease in the peak amplitude of transient outward K currents (I) and outward-delayed rectifier K currents (I) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of I shifted toward the hyperpolarization direction caused by Aβ. These results suggest that Aβ-induced neuronal damage correlated with Zn dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K channels. Moreover, Zn-specific chelator-TPEN attenuated Aβ-induced neuronal damage by recovering the intracellular Zn concentration.
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http://dx.doi.org/10.1186/s13041-021-00837-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359616PMC
August 2021

NMR resonance assignments of human Atg3 in aqueous solution and bicelles.

Biomol NMR Assign 2021 10 22;15(2):421-425. Epub 2021 Jul 22.

Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.

Human Atg3 (hAtg3) is an E2-like enzyme that catalyzes the conjugation of LC3 family proteins to phosphatidylethanolamine (PE) lipids in the autophagosomal membrane during autophagy. The reaction product, LC3-PE, acts as a marker for autophagic cargo and is required for the effective construction of functional autophagosomes. However, the structural and molecular basis of this conjugation reaction remains elusive, at least in part, because of the absence of lipid bilayers in structural studies conducted to date. Here, we report a sequential resonance assignment for an hAtg3 construct both in aqueous solution and in bicelles. hAtg3 has 314 residues, and our construct lacks the unstructured region from residues 90 to 190. Our results demonstrate a structural rearrangement of hAtg3 N-terminus when it interacts with membranes.
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http://dx.doi.org/10.1007/s12104-021-10040-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484069PMC
October 2021

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

Genet Med 2021 10 23;23(10):1922-1932. Epub 2021 Jun 23.

Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Purpose: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.

Methods: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.

Results: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.

Conclusion: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
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http://dx.doi.org/10.1038/s41436-021-01232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488020PMC
October 2021

Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors.

JCI Insight 2021 Aug 9;6(15). Epub 2021 Aug 9.

Cardiovascular Research Institute.

SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel's distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function, and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.
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http://dx.doi.org/10.1172/jci.insight.150698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410058PMC
August 2021

Fecal microbiota transplantation ameliorates experimental colitis gut microbiota and T-cell modulation.

World J Gastroenterol 2021 Jun;27(21):2834-2849

Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.

Background: Emerging evidence has demonstrated that fecal microbiota transplantation (FMT) has a promising therapeutic effect on mice with experimental colitis and patients with ulcerative colitis (UC), although the mechanism of FMT is unclear.

Aim: To evaluate the protective effect of FMT on UC and clarify its potential dependence on the gut microbiota, through association analysis of gut microbiota with colon transcriptome in mice.

Methods: Dextran sodium sulfate (DSS)-induced experimental colitis was established and fecal microbiota was transplanted by gavage. Severity of colon inflammation was measured by body weight, disease activity index, colon length and histological score. Gut microbiota alteration was analyzed through 16S ribosomal ribonucleic acid sequencing. The differentially expressed genes (DEGs) in the colon were obtained by transcriptome sequencing. The activation status of colonic T lymphocytes in the lamina propria was evaluated by flow cytometry.

Results: Compared with the DSS group, the weight loss, colon length shortening and inflammation were significantly alleviated in the FMT group. The scores of disease activity index and colon histology decreased obviously after FMT. FMT restored the balance of gut microbiota, especially by upregulating the relative abundance of and downregulating the relative abundance of and . In the transcriptomic analysis, 128 DEGs intersected after DSS treatment and FMT. Functional annotation analysis suggested that these DEGs were mainly involved in T-lymphocyte activation. In the DSS group, there was an increase in colonic T helper CD4 and T cytotoxic CD8 cells by flow cytometry. FMT selectively downregulated the ratio of colonic CD4 and CD8 T cells to maintain intestinal homeostasis. Furthermore, was significantly related to inflammation-related genes including , and .

Conclusion: FMT ameliorated DSS-induced colitis in mice regulating the gut microbiota and T-cell modulation.
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http://dx.doi.org/10.3748/wjg.v27.i21.2834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173381PMC
June 2021

Data-Driven Math Model of FLT3-ITD Acute Myeloid Leukemia Reveals Potential Therapeutic Targets.

J Pers Med 2021 Mar 11;11(3). Epub 2021 Mar 11.

Department of Physics, Pennsylvania State University, University Park, PA 16802, USA.

-mutant acute myeloid leukemia (AML) is an aggressive form of leukemia with poor prognosis. Treatment with inhibitors frequently produces a clinical response, but the disease nevertheless often recurs. Recent studies have revealed system-wide gene expression changes in -mutant AML cell lines in response to drug treatment. Here we sought a systems-level understanding of how these cells mediate these drug-induced changes. Using RNAseq data from AML cells with an internal tandem duplication mutation (-ITD) under six drug treatment conditions including quizartinib and dexamethasone, we identified seven distinct gene programs representing diverse biological processes involved in AML drug-induced changes. Based on the literature knowledge about genes from these modules, along with public gene regulatory network databases, we constructed a network of -ITD AML. Applying the BooleaBayes algorithm to this network and the RNAseq data, we created a probabilistic, data-driven dynamical model of acquired resistance to these drugs. Analysis of this model reveals several interventions that may disrupt targeted parts of the system-wide drug response. We anticipate co-targeting these points may result in synergistic treatments that can overcome resistance and prevent eventual recurrence.
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http://dx.doi.org/10.3390/jpm11030193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998618PMC
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Itaconate aggravates experimental colitis.

Clin Res Hepatol Gastroenterol 2021 03 8;45(2):101629. Epub 2021 Feb 8.

Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Electronic address:

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http://dx.doi.org/10.1016/j.clinre.2021.101629DOI Listing
March 2021

Effective immune-inflammation index for ulcerative colitis and activity assessments.

World J Clin Cases 2021 Jan;9(2):334-343

Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.

Background: The inverse association between systemic immune-inflammation index (SII) and overall survival in tumors has been studied.

Aim: To evaluate the hematological indexes for assessing the activity of ulcerative colitis (UC).

Methods: In this case-control study, 172 UC patients and healthy participants were included. Comparisons were made among groups of white blood cells, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, SII, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The relationship with hematological inflammation was verified by Spearman correlation analyses. The efficiency of SII, NLR, and PLR for distinguishing between UC and severe disease status was assessed by the receiver operator curve and logistic regression analyses.

Results: The values of SII, NLR, and PLR were higher in UC patients than in controls ( < 0.001) and were positively correlated with the Mayo endoscopic score, extent, Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The cut-off NLR value of 562.22 predicted UC with a sensitivity of 79.65% and a specificity of 76.16%. Logistic regression analysis revealed that patients with SII and NLR levels above the median had a significantly higher risk of UC ( < 0.05). Risk factors independently associated with DUBLIN ≥ 3 included SII ≥ 1776.80 [odds ratio (OR) = 11.53, = 0.027] and NLR value of 2.67-4.23 (OR = 2.96, = 0.047) on multivariate analysis. Compared with the first quartile, SII ≥ 1776.80 was an independent predictor of UCEIS ≥ 5 (OR = 18.46, = 0.012).

Conclusion: SII has a certain value in confirming UC and identifying its activity.
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http://dx.doi.org/10.12998/wjcc.v9.i2.334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812895PMC
January 2021

An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy.

Nat Commun 2021 01 14;12(1):374. Epub 2021 Jan 14.

Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.

During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3-PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR. Collectively, our results demonstrate that the N-terminal conserved region of hAtg3 works in concert with its geometry-selective AH to promote LC3-PE conjugation only on the target membrane, and substantiate the concept that highly curved membranes drive spatial regulation of the autophagosome biogenesis during autophagy.
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http://dx.doi.org/10.1038/s41467-020-20607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809043PMC
January 2021

Identification of regulators of poly-ADP-ribose polymerase inhibitor response through complementary CRISPR knockout and activation screens.

Nat Commun 2020 11 30;11(1):6118. Epub 2020 Nov 30.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.

Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells.
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http://dx.doi.org/10.1038/s41467-020-19961-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704667PMC
November 2020

Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia.

J Hematol Oncol 2020 11 19;13(1):155. Epub 2020 Nov 19.

Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.

Acute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.
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http://dx.doi.org/10.1186/s13045-020-00992-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678146PMC
November 2020

Chemotherapy-Induced Upregulation of Small Extracellular Vesicle-Associated PTX3 Accelerates Breast Cancer Metastasis.

Cancer Res 2021 01 28;81(2):452-463. Epub 2020 Oct 28.

Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.

Although neoadjuvant chemotherapy is a standard component of breast cancer treatment, recent evidence suggests that chemotherapeutic drugs can promote metastasis through poorly defined mechanisms. Here we utilize xenograft mouse models of triple-negative breast cancer to explore the importance of chemotherapy-induced tumor-derived small extracellular vesicles (sEV) in metastasis. Doxorubicin (DXR) enhanced tumor cell sEV secretion to accelerate pulmonary metastasis by priming the premetastatic niche. Proteomic analysis and CRISPR/Cas9 gene editing identified the inflammatory glycoprotein PTX3 enriched in DXR-elicited sEV as a critical regulator of chemotherapy-induced metastasis. Both genetic inhibition of sEV secretion from primary tumors and pharmacologic inhibition of sEV uptake in secondary organs suppressed metastasis following chemotherapy. Taken together, this research uncovers a mechanism of chemotherapy-mediated metastasis by which drug-induced upregulation of sEV secretion and PTX3 protein cargo primes the premetastatic niche and suggests that inhibition of either sEV uptake in secondary organs or secretion from primary tumor cells may be promising therapeutic strategies to suppress metastasis. SIGNIFICANCE: These findings show that chemotherapy-induced small extracellular vesicles accelerate breast cancer metastasis, and targeted inhibition of tumor-derived vesicles may be a promising therapeutic strategy to improve the efficacy of chemotherapy treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855036PMC
January 2021

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.

Nat Commun 2020 10 27;11(1):5424. Epub 2020 Oct 27.

Division of Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.
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http://dx.doi.org/10.1038/s41467-020-19193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591536PMC
October 2020

Awareness and attitude of fecal microbiota transplantation through transendoscopic enteral tubing among inflammatory bowel disease patients.

World J Clin Cases 2020 Sep;8(17):3786-3796

Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China.

Background: Transendoscopic enteral tubing (TET) has been used in China as a novel delivery route for fecal microbiota transplantation (FMT) into the whole colon with a high degree of patient satisfaction among adults.

Aim: To explore the recognition and attitudes of FMT through TET in patients with inflammatory bowel disease (IBD).

Methods: An anonymous questionnaire, evaluating their awareness and attitudes toward FMT and TET was distributed among IBD patients in two provinces of Eastern and Southwestern China. Question formats included single-choice questions, multiple-choice questions and sorting questions. Patients who had not undergone FMT were mainly investigated for their cognition and acceptance of FMT and TET. Patients who had experience of FMT, the way they underwent FMT and acceptance of TET were the main interest. Then all the patients were asked whether they would recommend FMT and TET. This study also analyzed the preference of FMT delivery in IBD patients and the patient-related factors associated with it.

Results: A total of 620 eligible questionnaires were included in the analysis. The survey showed that 44.6% (228/511) of patients did not know that FMT is a therapeutic option in IBD, and 80.6% (412/511) of them did not know the concept of TET. More than half (63.2%, 323/511) of the participants stated that they would agree to undergo FMT through TET. Of the patients who underwent FMT TET [62.4% (68/109)], the majority [95.6% (65/68)] of them were satisfied with TET. Patients who had undergone FMT and TET were more likely to recommend FMT than patients who had not (94.5% 86.3%, = 0.018 and 98.5% 87.8%, = 0.017). Patients' choice for the delivery way of FMT would be affected by the type of disease and whether the patient had the experience of FMT. When compared to patients without experience of FMT, Crohn's disease and ulcerative colitis patients who had experience of FMT preferred mid-gut TET ( < 0.001) and colonic TET ( < 0.001), respectively.

Conclusion: Patients' experience of FMT through TET lead them to maintain a positive attitude towards FMT. The present findings highlighted the significance of patient education on FMT and TET.
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http://dx.doi.org/10.12998/wjcc.v8.i17.3786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479546PMC
September 2020

Fecal microbiota transplantation therapy for Parkinson's disease: A preliminary study.

Medicine (Baltimore) 2020 Aug;99(35):e22035

Department of Gastroenterology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China.

Imbalances in the gut microbiota mediate the progression of neurodegenerative diseases such as Parkinson's disease (PD). Fecal microbiota transplantation (FMT) is currently being explored as a potential therapy for PD. The objective of this study was to assess the efficacy and safety of FMT on PD. Fifteen PD patients were included, 10 of them received FMT via colonoscopy (colonic FMT group) and 5 received FMT via nasal-jejunal tube (nasointestinal FMT group). The score of PSQI, HAMD, HAMA, PDQ-39, NMSQ and UPDRS-III significantly decreased after FMT treatment (all P < .05). Colonic FMT group showed significant improvement and longer maintenance of efficacy compared with nasointestinal FMT (P = .002). Two patients achieved self-satisfying outcomes that last for more than 24 months. However, nasointestinal FMT group had no significant therapeutic effect, although UPDRS-III score slightly reduced. There were no patients were satisfied with nasointestinal FMT for more than 3 months. Among 15 PD patients, there were 5 cases had adverse events (AEs), including diarrhea (2 cases), abdominal pain (2 cases) and flatulence (1 case). These AEs were mild and self-limiting. We conclude that FMT can relieve the motor and non-motor symptoms with acceptable safety in PD. Compared with nasointestinal FMT, colonic FMT seems better and preferable.
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http://dx.doi.org/10.1097/MD.0000000000022035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458210PMC
August 2020

Genistein inhibits amyloid peptide 25-35-induced neuronal death by modulating estrogen receptors, choline acetyltransferase and glutamate receptors.

Arch Biochem Biophys 2020 10 25;693:108561. Epub 2020 Aug 25.

Department of Zoology and Developmental Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. Electronic address:

Purpose: To explore genistein, the most active component of soy isoflavones, on viability, expression of estrogen receptor (ER) subtypes, choline acetyltransferase (ChAT), and glutamate receptor subunits in amyloid peptide 25-35-induced hippocampal neurons, providing valuable data and basic information for neuroprotective effect of genistein in Aβ-induced neuronal injury.

Methods: We established an in vitro model of Alzheimer's disease by exposing primary hippocampal neurons of newborn rats to amyloid peptide 25-35 (20 μM) for 24 h and observing the effects of genistein (10 μM, 3 h) on viability, expression of ER subtypes, ChAT, NMDA receptor subunit NR2B and AMPA receptor subunit GluR2 in Aβ-induced hippocampal neurons.

Results: We found that amyloid peptide 25-35 exposure reduced the viability of hippocampal neurons. Meanwhile, amyloid peptide 25-35 exposure decreased the expression of ER subtypes, ChAT and GluR2, and increased the expression of NR2B. Genistein at least partially reversed the effects of amyloid peptide 25-35 in hippocampal neurons.

Conclusion: Genistein could increase the expression of ChAT as a consequence of activating estrogen receptor subtypes, modulating the expression of NR2B and GluR2, and thereby ameliorating the status of hippocampal neurons and exerting neuroprotective effects against amyloid peptide 25-35. Our data suggest that genistein might represent a potential cell-targeted therapy which could be a promising approach to treating AD.
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http://dx.doi.org/10.1016/j.abb.2020.108561DOI Listing
October 2020

Targeting the ESCRT-III component CHMP2A for noncanonical Caspase-8 activation on autophagosomal membranes.

Cell Death Differ 2021 02 17;28(2):657-670. Epub 2020 Aug 17.

Department of Pediatrics, Penn State College of Medicine, Hershey, PA, 17033, USA.

Autophagosomal membranes can serve as activation platforms for intracellular death-inducing signaling complexes (iDISCs) to initiate Caspase-8-dependent apoptosis. In this study, we explore the impact of ESCRT-III-dependent phagophore closure on iDISC assemblies and cell death in osteosarcoma and neuroblastoma cells. Inhibition of phagophore closure by conditional depletion of CHMP2A, an ESCRT-III component, stabilizes iDISCs on immature autophagosomal membranes and induces Caspase-8-dependent cell death. Importantly, suppression of the iDISC formation via deletion of ATG7, an E1 enzyme for ubiquitin-like autophagy-related proteins, blocks Caspase-8 activation and cell death following CHMP2A depletion. Although DR5 expression and TRAIL-induced apoptosis are enhanced in CHMP2A-depleted cells, the canonical extrinsic pathway of apoptosis is not responsible for the initiation of cell death by CHMP2A depletion. Furthermore, the loss of CHMP2A impairs neuroblastoma tumor growth associated with decreased autophagy and increased apoptosis in vivo. Together, these findings indicate that inhibition of the ESCRT-III-dependent autophagosome sealing process triggers noncanonical Caspase-8 activation and apoptosis, which may open new avenues for therapeutic targeting of autophagy in cancer.
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http://dx.doi.org/10.1038/s41418-020-00610-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862398PMC
February 2021

Computational Identification of Gene Networks as a Biomarker of Neuroblastoma Risk.

Cancers (Basel) 2020 Jul 28;12(8). Epub 2020 Jul 28.

Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033, USA.

Neuroblastoma is a common cancer in children, affected by a number of genes that interact with each other through intricate but coordinated networks. Traditional approaches can only reconstruct a single regulatory network that is topologically not informative enough to explain the complexity of neuroblastoma risk. We implemented and modified an advanced model for recovering informative, omnidirectional, dynamic, and personalized networks (idopNetworks) from static gene expression data for neuroblastoma risk. We analyzed 3439 immune genes of neuroblastoma for 217 high-risk patients and 30 low-risk patients by which to reconstruct large patient-specific idopNetworks. By converting these networks into risk-specific representations, we found that the shift in patients from a low to high risk or from a high to low risk might be due to the reciprocal change of hub regulators. By altering the directions of regulation exerted by these hubs, it may be possible to reduce a high risk to a low risk. Results from a holistic, systems-oriented paradigm through idopNetworks can potentially enable oncologists to experimentally identify the biomarkers of neuroblastoma and other cancers.
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http://dx.doi.org/10.3390/cancers12082086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465094PMC
July 2020

Expression of R345W-Fibulin-3 Induces Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells.

Front Cell Dev Biol 2020 19;8:469. Epub 2020 Jun 19.

Department of Ophthalmology, Penn State Hershey College of Medicine, Hershey, PA, United States.

Purpose: To investigate the role of protein misfolding in retinal pigment epithelial (RPE) cell dysfunction, the effects of R345W-Fibulin-3 expression on RPE cell phenotype were studied.

Methods: Primary RPE cells were cultured to confluence on Transwells and infected with lentivirus constructs to express wild-type (WT)- or R345W-Fibulin-3. Barrier function was assessed by evaluating zonula occludens-1 (ZO-1) distribution and trans-epithelial electrical resistance (TER). Polarized secretion of vascular endothelial growth factor (VEGF), was measured by Enzyme-linked immunosorbent assay (ELISA). Differentiation status was assessed by qPCR of genes known to be preferentially expressed in terminally differentiated RPE cells, and conversion to an epithelial-mesenchymal transition (EMT) phenotype was assessed by a migration assay.

Results: Compared to RPE cells expressing WT-Fibulin-3, ZO-1 distribution was disrupted and TER values were significantly lower in RPE cells expressing R345W-Fibulin-3. In cells expressing mutant Fibulin-3, VEGF secretion was attenuated basally but not in the apical direction, whereas Fibulin-3 secretion was reduced in both the apical and basal directions. Retinal pigment epithelial signature genes were downregulated and multiple genes associated with EMT were upregulated in the mutant group. Migration assays revealed a faster recovery rate in ARPE-19 cells overexpressing R345W-Fibulin-3 compared to WT.

Conclusions: The results suggest that expression of R345W-Fibulin-3 promotes EMT in RPE cells.
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http://dx.doi.org/10.3389/fcell.2020.00469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317295PMC
June 2020

Expression Patterns of Immune Genes Reveal Heterogeneous Subtypes of High-Risk Neuroblastoma.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.

High risk neuroblastoma (HR-NB) remains difficult to treat, and its overall survival (OS) is still below 50%. Although HR-NB is a heterogeneous disease, HR-NB patients are currently treated in a similar fashion. Through unsupervised biclustering, we further stratified HR-NB patients into two reproducible and clinically distinct subtypes, including an ultra-high risk neuroblastoma (UHR-NB) and high risk neuroblastoma (HR-NB). The UHR-NB subtype consistently had the worst OS in multiple independent cohorts ( P < 0 . 008 ). Out of 283 neuroblastoma-specific immune genes that were used for stratification, 39 of them were differentiated in UHR-NB, including four upregulated and 35 downregulated, as compared to HR-NB. The four UHR-NB upregulated genes (ADAM22, GAL, KLHL13 and TWIST1) were all upregulated in MYCN amplified neuroblastoma in 5 additional cohorts. TWIST1 and ADAM22 were also positively correlated with cancer stage, while GAL was an independent OS predictor in addition to MYCN and age. Furthermore, we identified 26 commonly upregulated and 311 downregulated genes in UHR-NB from all 4723 immune-related genes. While 43 KEGG pathways with molecular functions were enriched in the downregulated immune-related genes, only the P53 signaling pathway was enriched in the upregulated ones, which suggested that UHR-NB was a TP53 related subtype with reduced immune activities.
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http://dx.doi.org/10.3390/cancers12071739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408437PMC
June 2020

Clinical Characteristics and Blood Test Results in COVID-19 Patients.

Ann Clin Lab Sci 2020 May;50(3):299-307

Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, China

Objective: An outbreak of pneumonia named COVID-19 caused by a novel coronavirus in Wuhan is rapidly spreading worldwide. The objective of the present study was to clarify further the clinical characteristics and blood parameters in COVID-19 patients.

Materials And Methods: Twenty-three suspected patients and 64 patients with laboratory-confirmed SARS-Cov-2 infection were admitted to a designated hospital. Epidemiological, clinical, laboratory, and treatment data were collected and analyzed.

Results: Of the 64 patients studied, 47 (73.4%) had been exposed to a confirmed source of COVID-19 transmission. On admission, the most common symptoms were fever (75%) and cough (76.6%). Twenty-eight (43.8%) COVID-19 patients showed leukopenia, 10 (15.6%) showed lymphopenia, 47 (73.4%) and 41 (64.1%) had elevated high-sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR), respectively, and 30 (46.9%) had increased fibrinogen concentration. After the treatment, the counts of white blood cells and platelets, and the level of prealbumin increased significantly, while aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and hsCRP decreased. COVID-19 patients with the hospital stay longer than 12 days had higher body mass index (BMI) and increased levels of AST, LDH, fibrinogen, hsCRP, and ESR.

Conclusions: Results of blood tests have potential clinical value in COVID-19 patients.
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May 2020

A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission.

Nat Struct Mol Biol 2020 06 18;27(6):570-580. Epub 2020 May 18.

Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.

The ESCRT complexes drive membrane scission in HIV-1 release, autophagosome closure, multivesicular body biogenesis, cytokinesis, and other cell processes. ESCRT-I is the most upstream complex and bridges the system to HIV-1 Gag in virus release. The crystal structure of the headpiece of human ESCRT-I comprising TSG101-VPS28-VPS37B-MVB12A was determined, revealing an ESCRT-I helical assembly with a 12-molecule repeat. Electron microscopy confirmed that ESCRT-I subcomplexes form helical filaments in solution. Mutation of VPS28 helical interface residues blocks filament formation in vitro and autophagosome closure and HIV-1 release in human cells. Coarse-grained (CG) simulations of ESCRT assembly at HIV-1 budding sites suggest that formation of a 12-membered ring of ESCRT-I molecules is a geometry-dependent checkpoint during late stages of Gag assembly and HIV-1 budding and templates ESCRT-III assembly for membrane scission. These data show that ESCRT-I is not merely a bridging adaptor; it has an essential scaffolding and mechanical role in its own right.
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http://dx.doi.org/10.1038/s41594-020-0426-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339825PMC
June 2020

Excessive anxiety in IBD patients is unnecessary for COVID-19.

Clin Res Hepatol Gastroenterol 2020 10 12;44(5):e121-e122. Epub 2020 May 12.

Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China. Electronic address:

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http://dx.doi.org/10.1016/j.clinre.2020.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214333PMC
October 2020

Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia.

Blood 2020 08;136(9):1067-1079

Department of Pediatrics.

FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor-dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.
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http://dx.doi.org/10.1182/blood.2019003124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453151PMC
August 2020

Efficacy of Serum Total Bilirubin in Predicting the Severity of Ulcerative Colitis: A Cross-Sectional Study.

Ann Clin Lab Sci 2020 Mar;50(2):228-232

Department of Gastroenterology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu Province, China

Objective: Several serum parameters can be used to assess ulcerative colitis (UC) disease activity. However, the value of these parameters for predicting UC severity has not been studied in depth. Therefore, we sought to investigate the value of serum total bilirubin (TB) as a predictor of UC severity.

Materials And Methods: This cross-sectional study included 448 UC patients and 308 healthy participants. Data regarding the serum levels of TB, hemoglobin (Hb), albumin (Alb), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were collected. UC severity was evaluated according to the Truelove and Witts criteria. Wilcoxon rank sum tests were used to compare data between groups, while Spearman correlation analyses between TB and the levels of Hb, Alb, ESR and CRP were performed. Logistic regression analyses were used to determine the odds ratios (ORs) for severe UC in UC patients.

Results: UC patients had lower Hb, Alb, and TB levels than healthy participants (<0.001). The Hb, Alb, and TB levels were lower in severe UC patients than in mild-to-moderate UC patients (<0.001). TB was positively correlated with Hb and Alb, but negatively correlated with ESR and CRP (<0.05). Logistic regression analysis revealed that the ORs for severe UC were 2.35 and 2.04 at TB concentrations of ≤8.00 μmol/L and 8.01-10.90 μmol/L, respectively (<0.05).

Conclusions: Serum TB level is an effective predictor of the severity of UC.
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March 2020

An Indole Alkaloid Extracted from Inhibits Colonic Motility of Rats .

Gastroenterol Res Pract 2020 3;2020:8610653. Epub 2020 Apr 3.

Department of Gastroenterology, Taizhou Municipal Hospital, Taizhou, Zhejiang, China 318000.

Evodiamine (Evo) is an indole alkaloid extracted from the traditional Chinese medicinal herb . Evo may regulate gastrointestinal motility, but the evidence is insufficient, and the mechanisms remain unknown. The aim of this study was to investigate the effect of Evo on colonic motility of rats and the underlying mechanisms . Rat colonic muscle was exposed to Evo (10 and 100 M) followed by immunohistochemistry of cholecystokinin receptor 1 (CCK1R). Muscle contractions were studied in an organ bath system to determine whether CCK1R, nitric oxide (NO), and enteric neurons are involved in the relaxant effect of Evo. Whole-cell patch-clamp was used to detect L-type calcium currents ( ) in isolated colonic smooth muscle cells (SMCs). CCK1R was observed in SMCs, intermuscular neurons, and mucosa of rat colon. Evo could inhibit spontaneous muscle contractions; NO synthase, inhibitor L-NAME CCK1R antagonist, could partly block this effect, while the enteric neurons may not play a major role. Evo inhibited the peak in colonic SMCs at a membrane potential of 0 mV. The current-voltage (I-V) relationship of L-type calcium channels was modified by Evo, while the peak of the I-V curve remained at 0 mV. Furthermore, Evo inhibited the activation of L-type calcium channels and decreased the peak . The relaxant effect of Evo on colonic muscle is associated with the inhibition of L-type calcium channels. The enteric neurons, NO, and CCK1R may be partly related to the inhibitory effect of Evo on colonic motility. This study provides the first evidence that evodiamine can regulate colonic motility in rats by mediating calcium homeostasis in smooth muscle cells. These data form a theoretical basis for the clinical application of evodiamine for treatment of gastrointestinal motility diseases.
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http://dx.doi.org/10.1155/2020/8610653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157783PMC
April 2020
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