Publications by authors named "Rengong Zhuo"

12 Publications

  • Page 1 of 1

Steroid Receptor Coactivator-3 Is Required for Inhibition of the Intestinal Muscularis Inflammatory Response of Postoperative Ileus in Mice.

Inflammation 2021 Jun 4;44(3):1145-1159. Epub 2021 Jan 4.

Department of Gastrointestinal Surgery, Ward 3 Areas of Cancer Center, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, 361003, China.

Inflammation theory has suggested that the pathogenesis of postoperative ileus (POI) involves the steroid receptor coactivator-3 (SRC-3). Therefore, we investigated the role of SRC-3 in the muscles of the small intestine using a mouse POI model. Here, we reported that intestinal manipulation (IM) significantly reduced the extent of phenol red migration in the entire gastrointestinal tract, and the calculated geometric center (GC) value in wild-type (WT) mice at 24 h after surgery was higher than that in the knockout (KO) mice and in the sham-operated control group. The expression of SRC-3 was upregulated in the mouse intestinal muscularis at 24 h after surgical manipulation, and the mRNA and protein levels of inflammatory cytokines were upregulated compared with those in the control group. At 24 h after IM, the number of neutrophils in the experimental group was significantly higher than that in the control group; in the IM group, the number of neutrophils in the SRC-3 mice was markedly higher than that in the WT mice. At 24 h after IM, the myeloperoxidase (MPO) activity in the experimental group was significantly higher than that in the control group. In the IM group, the MPO activity of the SRC-3 mice was markedly higher than that of the WT mice. In summary, proinflammatory cytokines, the number of neutrophils, and the MPO activity were significantly increased in the muscularis of the jejunum and ileum of KO mice after IM compared with those of the WT mice, indicating that SRC-3 might play a protective role in POI.
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http://dx.doi.org/10.1007/s10753-020-01409-4DOI Listing
June 2021

Suppression of PTTG1 inhibits cell angiogenesis, migration and invasion in glioma cells.

Med Oncol 2020 Jul 28;37(8):73. Epub 2020 Jul 28.

School of Medicine, Xiamen University, Xiang'an District, Xiamen, 361102, China.

Pituitary tumor-transforming gene 1 (PTTG1) has been identified as an oncogene and is overexpressed in many tumor types. However, the role of PTTG1 in glioblastoma (GBM) has not been well characterized, especially in relation to angiogenesis, migration, and invasion. In the present study, our results showed that the expression of PTTG1 was significantly higher in patients with GBM. Bioinformatic analysis showed that angiogenesis and the cell migration-related process were increased in patients with high PTTG1 expression levels; meanwhile, PTTG1 was positively correlated with marker genes of angiogenesis, migration and the evasion of apoptosis. In vitro assays showed that PTTG1 knockdown dramatically suppressed angiogenesis, migration and invasion, and increased the apoptosis of GBM cells. Moreover, our results also showed that silencing PTTG1 suppressed the activity of the TGF-β/PI3K-AKT-mTOR pathway, which induced tumor deterioration in multiple organs. Overall, our findings indicate that PTTG1 is a glioma malignant factor that promotes angiogenesis, migration, invasion, and the evasion of apoptosis, and these roles may be related to the TGF-β/PI3K-AKT-mTOR pathway. Thus, the targeted inhibition of PTTG1 might be a novel therapeutic strategy and a potential diagnostic biomarker for GBM-targeted therapies.
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http://dx.doi.org/10.1007/s12032-020-01398-2DOI Listing
July 2020

Oleoylethanolamide Increases Glycogen Synthesis and Inhibits Hepatic Gluconeogenesis via the LKB1/AMPK Pathway in Type 2 Diabetic Model.

J Pharmacol Exp Ther 2020 04 5;373(1):81-91. Epub 2020 Feb 5.

Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China (T.R., A.M., R.Z., H.Z., L.P., X.J., L.Y.) and Department of Cardiology, Fujian Medical University Union Hospital, Fujian Institute of Coronary Artery Disease, Fujian Heart Medical Center, Fuzhou, China (E.Y.)

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor (PPAR) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPAR-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPAR was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor -independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways.
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http://dx.doi.org/10.1124/jpet.119.262675DOI Listing
April 2020

Oleoylethanolamide stabilizes atherosclerotic plaque through regulating macrophage polarization via AMPK-PPARα pathway.

Biochem Biophys Res Commun 2020 04 25;524(2):308-316. Epub 2020 Jan 25.

Xiamen University Affiliated Zhongshan Hospital, Xiamen, China. Electronic address:

Background: Atherosclerotic plaque rupture is the major trigger of acute cardiovascular risk events, and manipulation of M1/M2 macrophage homeostasis is an effective strategy for regulating atherosclerotic plaque stability. This study was aimed to illuminate the effects of oleoylethanolamide (OEA) on macrophage polarization and plaque stability.

Methods: Macrophages derived from THP-1 were treated with OEA followed by LPS/IFN-γ, and the markers of M1, M2 macrophages were monitored by western blot, real-time PCR and immunofluorescence staining. The effect of OEA on macrophage polarization in the arch of aortic arteries was tested by immunofluorescence staining and western blot, and the plaque stability was completed by Masson's trichrome and hematoxylin and eosin (HE) in apolipoprotein E (ApoE) mice.

Results: OEA treatment enhanced the expression of two classic M2 macrophage markers, macrophage mannose receptor (CD206) and transforming growth factor (TGF-β), while the expression of iNOS (M1 macrophages) was decreased in THP-1-derived macrophages. Blocking of PPARα using siRNA and inhibition of AMP-activated protein kinase (AMPK) by its inhibitor compound C attenuated the OEA-induced expression of M2 macrophage markers. In addition, OEA significantly suppressed M1, promoted M2 macrophage polarization, increased collagen content and decreased necrotic core size in atherosclerotic plaques in ApoE mice, which were linked with the expression of PPARα.

Conclusions: OEA improved atherosclerotic plaque stability through regulating macrophage polarization via AMPK-PPARα pathway.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.103DOI Listing
April 2020

Chronic oleoylethanolamide treatment attenuates diabetes-induced mice encephalopathy by triggering peroxisome proliferator-activated receptor alpha in the hippocampus.

Neurochem Int 2019 10 9;129:104501. Epub 2019 Jul 9.

Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China. Electronic address:

Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPARα mice using Morris water maze (MWM) test. Neuron staining, dementia markers and neuroplasticity in the hippocampus were assessed to evaluate the neuropathological changes. The results showed that chronic OEA treatment significantly lowered hyperglycemia, recovered cognitive performance, reduced dementia markers, and inhibited hippocampal neuron loss and neuroplasticity impairments in diabetic mice. In contrast, the changes in MWM performance and neuron loss were not observed in PPARα knockout mice via OEA administration. These results indicated that OEA may provide a potential alternative therapeutic for DE by activating PPARα signaling.
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http://dx.doi.org/10.1016/j.neuint.2019.104501DOI Listing
October 2019

Author Correction: Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model.

Nat Commun 2019 Jul 2;10(1):2923. Epub 2019 Jul 2.

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.

The original version of this Article omitted the following from the end of the Acknowledgements: 'X.C. also received funding from the Shenzhen Basic Research Program JCYJ20170818140904167.' This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-10950-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606585PMC
July 2019

Moringa oleifera seed extract protects against brain damage in both the acute and delayed stages of ischemic stroke.

Exp Gerontol 2019 07 27;122:99-108. Epub 2019 Apr 27.

Xiamen Key Laboratory of Chiral Drugs, School of Medicine, Xiamen University, Xiamen, China. Electronic address:

The extract of Moringa oleifera (M. oleifera) seeds exerts various pharmacological effects. Our previous study demonstrated that M. oleifera seed extract (MSE) alleviates scopolamine-induced learning and memory impairment in mice. In the present study, we investigate the neuropharmacological properties of 70% ethanolic MSE in the acute and delayed stages of ischemic stroke. MSE may be effective for the prevention and/or treatment of acute ischemic stroke. The most effective dose was 500 mg/kg, and the therapeutic window seemed to be within 4 h after reperfusion. Additionally, we found that MSE treatment improved animal survival, reversed spatial cognitive impairment and promoted hippocampal neurogenesis and neuroplasticity as well as the cholinergic neurotransmission system during the recovery stages of ischemic stroke. Our findings verified that MSE has neuroprotective effects in both the acute and chronic stages of ischemic stroke. The relevant mechanism of protection may occur by promoting hippocampal neurogenesis and synaptic plasticity as well as improving cholinergic function. These findings suggest that M. oleifera seed extract may be a promising neuroprotective agent for the treatment of ischemic stroke.
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http://dx.doi.org/10.1016/j.exger.2019.04.014DOI Listing
July 2019

Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model.

Nat Commun 2019 03 25;10(1):1365. Epub 2019 Mar 25.

Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, China.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
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http://dx.doi.org/10.1038/s41467-019-09118-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433910PMC
March 2019

Immunomodulatory effect of oleoylethanolamide in dendritic cells via TRPV1/AMPK activation.

J Cell Physiol 2019 08 20;234(10):18392-18407. Epub 2019 Mar 20.

Medical College, Xiamen University, Xiamen, China.

Oleoylethanolamide (OEA) is an endogenous lipid mediator involved in the control of feeding, body weight, and energy metabolism. However, whether OEA modulates maturation of dendritic cells (DCs) has never been addressed. Hence, we evaluated the effect of OEA on DCs maturation in bone marrow-derived DCs (BMDCs) in four aspects: (a) Cell surface markers were determined using flow cytometric analysis; (b) cell mobile ability was testified with the transwell assay; (c) stimulation of T cells proliferation was performed in a coculture system; and (d) cytokine production was measured using polymerase chain reaction (PCR). The result showed that, in mature BMDCs induced by lipopolysaccharides (LPS), the OEA treatment decreased expressions of cell surface markers, reduced cell migration, diminished the proliferation of cocultured T cells, and regulated cytokine production of BMDCs, indicating the modulatory effect of OEA on DCs maturation. Furthermore, to explore the underlying mechanism of the immunomodulatory effect of OEA, we used antagonists of transient receptor potential vanilloid-1 (TRPV1) and AMP-activated protein kinase (AMPK), determined the protein expressions of TRPV1/AMPK and Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) using western blot, and measured the intracellular calcium concentration using calcium imaging. The result illustrated that OEA downregulated TLR4/NF-κB, the classical pathway leading to DCs maturation induced by LPS, through the activation of TRPV1 and AMPK. Collectively, the present study suggests that OEA suppresses DCs maturation through the activation of TRPV1/AMPK. These findings increase our understanding of this endogenous lipid OEA.
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http://dx.doi.org/10.1002/jcp.28474DOI Listing
August 2019

Oleoylethanolamide inhibits glial activation via moudulating PPARα and promotes motor function recovery after brain ischemia.

Pharmacol Res 2019 03 17;141:530-540. Epub 2019 Jan 17.

Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen, 361102, PR China; Key Laboratory of Chiral Drugs, Xiamen, 361102, PR China. Electronic address:

Glial activation and scar formation impede the neurological function recovery after cerebral ischemia. Oleoylethanolamide (OEA), a bioactive lipid mediator, shows neuroprotection against acute brain ischemia, however, its long-term effect, especially on glial scar formation, has not been characterized. In this research, we investigate the effect of OEA on glial activation and scar formation after cerebral ischemia in vitro and in vivo experiments. Glial scar formation in vitro model was induced by transforming growth factor β1 (TGF-β1) in C6 glial cell culture, and experiment model in vivo was induced by middle cerebral artery occlusion (MCAO) in mice. The protein expressions of the markers of glial activation (S100β, GFAP, or pSmads) and glial scar (neurocan) were detected by Western blot and/or immunofluorescence staining; To evaluate the role of PPARɑ in the effect of OEA on glial activation, the PPARɑ antagonist GW6471 was used. Behavior tests were used to assay the effect of OEA on motor function recovery 14 days after brain ischemia in mice. Our results show that OEA (10-50 μM) concentration-dependently inhibited the upregulation of S100β, GFAP, pSmads and neurocan induced by TGF-β1 in C6 glial cells. At the same time, OEA promoted the protein expression and nuclear transportation of PPARɑ in glial cells. PPARα antagonist GW6471 abolished the effect of OEA on glial activation. In addition, we found that delay administration of OEA inhibited the astrocyte activation and promoted the recovery of motor function after brain ischemia in mice. These results indicate that OEA may be developed into a new candidate for attenuating astrocytic scar formation and improving motor function after ischemic stroke.
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http://dx.doi.org/10.1016/j.phrs.2019.01.027DOI Listing
March 2019

P7, a novel antagonist of corticotropin releasing factor receptor type 1 (CRFR1) screened from phage display library.

Biochem Biophys Res Commun 2015 Jul 18;463(3):200-4. Epub 2015 May 18.

State Key Laboratory of Toxicology and Medical Countermeasures, Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, PR China. Electronic address:

The corticotropin releasing factor (CRF) plays a central role in regulating the activities of hypothalamic-pituitary-adrenal (HPA) axis in the presence of a variety of stressful stimuli via binding to its type 1 receptors (CRFR1). Despite that many peptidic or non-peptidic antagonists of CRFR1 have been developed to serve as therapeutic tools to CRF-related pathologies, none of them have been utilized clinically. Targeting the extracellular domain 1 (EC1) of CRFR1, the CRF-binding site, represents a new strategy to inhibit the function of the receptor. However, no such agents have been identified up to now. Herein, by using an 87-amino acid fragment corresponding to the EC1 region as the bait, we screened the binding polypeptides from a phage display (Ph.D.-12) peptide library. After 3-round biopanning, positive clones were selected and the polypeptides carried by them were identified. 5 polypeptides were found to bind with the target specifically. Among them, the P7 exhibited the highest affinity. By evaluating the cAMP accumulation in the CRFR1 or CRFR2-expressing HEK293 cells, we demonstrated that P7 blocking the function of CRFR1, but not CRFR2. In addition, we also found that P7 and CRF act on CRFR1 competitively. Taken together, we reveal that P7, a novel polypeptide identified from phage display library, inhibits the function of CRFR1 effectively and specifically by binding at its EC1 domain. The new polypeptide might provide a promising agent for diagnostic or therapeutic utilities in CRF-related disorders.
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http://dx.doi.org/10.1016/j.bbrc.2015.05.021DOI Listing
July 2015

A novel muscarinic antagonist R2HBJJ inhibits non-small cell lung cancer cell growth and arrests the cell cycle in G0/G1.

PLoS One 2012 28;7(12):e53170. Epub 2012 Dec 28.

Beijing Institute of Pharmacology and Toxicology, Beijing, China.

Lung cancers express the cholinergic autocrine loop, which facilitates the progression of cancer cells. The antagonists of mAChRs have been demonstrated to depress the growth of small cell lung cancers (SCLCs). In this study we intended to investigate the growth inhibitory effect of R2HBJJ, a novel muscarinic antagonist, on non-small cell lung cancer (NSCLC) cells and the possible mechanisms. The competitive binding assay revealed that R2HBJJ had a high affinity to M3 and M1 AChRs. R2HBJJ presented a strong anticholinergic activity on carbachol-induced contraction of guinea-pig trachea. R2HBJJ markedly suppressed the growth of NSCLC cells, such as H1299, H460 and H157. In H1299 cells, both R2HBJJ and its leading compound R2-PHC displayed significant anti-proliferative activity as M3 receptor antagonist darifenacin. Exogenous replenish of ACh could attenuate R2HBJJ-induced growth inhibition. Silencing M3 receptor or ChAT by specific-siRNAs resulted in a growth inhibition of 55.5% and 37.9% on H1299 cells 96 h post transfection, respectively. Further studies revealed that treatment with R2HBJJ arrested the cell cycle in G0/G1 by down-regulation of cyclin D1-CDK4/6-Rb. Therefore, the current study reveals that NSCLC cells express an autocrine and paracrine cholinergic system which stimulates the growth of NSCLC cells. R2HBJJ, as a novel mAChRs antagonist, can block the local cholinergic loop by antagonizing predominantly M3 receptors and inhibit NSCLC cell growth, which suggest that M3 receptor antagonist might be a potential chemotherapeutic regimen for NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053170PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532118PMC
July 2013