Publications by authors named "Ai-Ling Li"

73 Publications

Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice.

J Transl Med 2021 May 24;19(1):220. Epub 2021 May 24.

Center for Translational NeuroImaging, Northeastern University, Boston, MA, USA.

Background: The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.

Methods: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.

Results: CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex.

Conclusion: The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.
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http://dx.doi.org/10.1186/s12967-021-02891-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142641PMC
May 2021

Hsa Circ 001839 Promoted Inflammation in Renal Ischemia-Reperfusion Injury Through NLRP3 by miR-432-3p.

Nephron 2021 May 11:1-13. Epub 2021 May 11.

College of Sports, Southwest Medical University, Luzhou, China.

Background: In recent years, increasing discovery of the extremely important regulatory effects of circular RNAs on biological development, angiogenesis, tumor genesis, and development, as well as stem cell proliferation and differentiation has provided new opportunities for investigating regulation mechanism in angiogenesis.

Objectives: This study explored the expression of circ 001839 in renal ischemia-reperfusion injury (RI-RI) rats and whether its upstream microRNA-432-3p (miR-432-3p) affects inflammation in both RI-RI rats and NRK52E cells.

Methods: Rat model of RI-RI was made, and circ 001839 was identified by the gene-chip analysis in RI-RI rats. Expression of circ 001839 and miR-432-3p was measured by reverse transcription-quantitative polymerase chain reaction, protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon (IFN)-γ, IL-6, and IL-18 in rat serum and cell supernatant was determined by ELISA, and the expression of NOD-like receptor 3 (NLRP3) and other gap-associated proteins in NRK52E cells was evaluated by Western blot analysis. Next, to verify the regulatory relationship between circ 001839 and miR-432-3p, 2 luciferase reporters were constructed.

Results: Circ 001839 expression of RI-RI rats and NRK52E cells was significantly upregulated, compared with the control group. Circ 001839 overexpression significantly increased inflammation through promoting TNF-α, IFN-γ, and IL-6 expression levels in NRK52E cells. Overexpression of miR-432-3p significantly promoted inflammation in NRK52E cells via induction of NLRP3. Moreover, miR-432-3p decreased the effects of circ 001839-induced inflammation in NRK52E cells.

Conclusions: These findings suggested that circ 001839 promoted inflammation in RI-RI through NLRP3 by miR-432-3p.
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http://dx.doi.org/10.1159/000515279DOI Listing
May 2021

G3BP1 Inhibition Alleviates Intracellular Nucleic Acid-Induced Autoimmune Responses.

J Immunol 2021 May 3;206(10):2453-2467. Epub 2021 May 3.

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China

The detection of intracellular nucleic acids is a fundamental mechanism of host defense against infections. The dysregulated nucleic acid sensing, however, is a major cause for a number of autoimmune diseases. In this study, we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for both intracellular DNA- and RNA-induced immune responses. We found that in both human and mouse cells, the deletion of G3BP1 led to the dampened cGAS activation by DNA and the insufficient binding of RNA by RIG-I. We further found that resveratrol (RSVL), a natural compound found in grape skin, suppressed both intracellular DNA- and RNA-induced type I IFN production through inhibiting G3BP1. Importantly, using experimental mouse models for Aicardi-Goutières syndrome, an autoimmune disorder found in humans, we demonstrated that RSVL effectively alleviated intracellular nucleic acid-stimulated autoimmune responses. Thus, our study demonstrated a broader role of G3BP1 in sensing different kinds of intracellular nucleic acids and presented RSVL as a potential treatment for autoimmune conditions caused by dysregulated nucleic acid sensing.
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http://dx.doi.org/10.4049/jimmunol.2001111DOI Listing
May 2021

GCG inhibits SARS-CoV-2 replication by disrupting the liquid phase condensation of its nucleocapsid protein.

Nat Commun 2021 04 9;12(1):2114. Epub 2021 Apr 9.

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing, 100850, China.

Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid-liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, N exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.
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http://dx.doi.org/10.1038/s41467-021-22297-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035206PMC
April 2021

LPA signaling acts as a cell-extrinsic mechanism to initiate cilia disassembly and promote neurogenesis.

Nat Commun 2021 01 28;12(1):662. Epub 2021 Jan 28.

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.

Dynamic assembly and disassembly of primary cilia controls embryonic development and tissue homeostasis. Dysregulation of ciliogenesis causes human developmental diseases termed ciliopathies. Cell-intrinsic regulatory mechanisms of cilia disassembly have been well-studied. The extracellular cues controlling cilia disassembly remain elusive, however. Here, we show that lysophosphatidic acid (LPA), a multifunctional bioactive phospholipid, acts as a physiological extracellular factor to initiate cilia disassembly and promote neurogenesis. Through systematic analysis of serum components, we identify a small molecular-LPA as the major driver of cilia disassembly. Genetic inactivation and pharmacological inhibition of LPA receptor 1 (LPAR1) abrogate cilia disassembly triggered by serum. The LPA-LPAR-G-protein pathway promotes the transcription and phosphorylation of cilia disassembly factors-Aurora A, through activating the transcription coactivators YAP/TAZ and calcium/CaM pathway, respectively. Deletion of Lpar1 in mice causes abnormally elongated cilia and decreased proliferation in neural progenitor cells, thereby resulting in defective neurogenesis. Collectively, our findings establish LPA as a physiological initiator of cilia disassembly and suggest targeting the metabolism of LPA and the LPA pathway as potential therapies for diseases with dysfunctional ciliogenesis.
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http://dx.doi.org/10.1038/s41467-021-20986-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843646PMC
January 2021

CEP55 promotes cilia disassembly through stabilizing Aurora A kinase.

J Cell Biol 2021 Feb;220(2)

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.

Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55-/- mice display clinical manifestations of Meckel-Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55-/- mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel-Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.
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http://dx.doi.org/10.1083/jcb.202003149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829976PMC
February 2021

[Diagnostic Application of Invasive Cardiopulmonary Exercise Test in Patients with Unexplained Dyspnea].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Jan;52(1):142-148

Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.

Objective: To explore the clinical diagnostic application of invasive cardiopulmonary exercise test (iCPET) in patients with unexplained dyspnea.

Methods: A retrospective analysis was conducted, covering patients with a chief complaint of exertional dyspnea between May 5, 2017 and October 1, 2020. Right cardiac catheterization examination was performed on patients whose cause had not been identified through routine examination, and further iCPET was performed on patients if no clear etiology was identified through right cardiac catheterization. According to the results and the diagnostic criteria of iCPET, patients showing no obvious abnormalities in the right cardiac catheterization examination were divided into four subgroups: exercise-induced pulmonary arterial hypertension (eiPAH), exercise-induced heart failure with preserved ejection fraction (eiHFpEF), preload failure, and oxidative myopathy. By comparing the lab test, echocardiography, right heart catheter and iCPET peak exercise data of the subgroups, the disease distribution and exercise hemodynamic characteristics of patients with unexplained dyspnea examined by iCPET were described.

Results: Of the 1 046 patients with exertional dyspnea, 771 were diagnosed with routine examination, while among the remaining 275 patients, 131 (47.6%) were diagnosed with right cardiac catheterization and 144 (52.4%) showed no clear etiology after routine examination and right cardiac catheterization. Of these 144 patients, 49 (34.0%) received iCPET with a median exercise time of 375 s. A total of 47 patients completed the examination, with a male-to-female ratio of 0.27∶1 and an average age of (47.9±14.4) years old. Among the 47 patients, 76.6% (36/47) aged between 20 and 59 and 78.7% (36/47) lived in urban areas. The preload failure group ( =27) showed low right atrium pressure at peak exercise intensity. The eiHFpEF group ( =9) showed high wedge pressure of pulmonary capillaries at peak of exercise intensity. The eiPAH group ( =8) showed high average pulmonary artery pressure at peak exercise intensity. The oxidative myopathy group ( =3) was characterized by impairment of tissue uptake and/or utilization of oxygen during exercise. According to the comparison among the three subgroups of the preload failure, eiHFpEF and eiPAH, the eiPAH group had the highest blood K level in routine examination, while the preload failure group had the lowest blood K level ( =0.014). The iCPET of the three subgroups showed statistically significant ( =0.001) difference in right atrial pressure increase during exercise. Among the three, the eiHFpEF group had the highest increase and the preload failure group had the lowest increase.  In unexplained dyspnea patients showing no abnormal results in right cardiac catheterization examination, the main cause was preload failure, which manifested as low right atrial pressure at peak exercise intensity. The study showed that iCPET was of important value for dyspnea cases when the cause of the condition was not revealed with right cardiac catheterization.
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http://dx.doi.org/10.12182/20210160205DOI Listing
January 2021

Naturally-derived diterpenoid sphaeropsidin C as an activator of Nrf2/ARE pathway and its potential capability of relieving intracellular oxidative stress in human lung epithelial cells.

Biomed Pharmacother 2020 Jan 19;121:109669. Epub 2019 Nov 19.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan 250012, PR China. Electronic address:

Oxidative stress is closely associated to the onset and progression of many human diseases. Activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway using naturally-derived molecules is an efficient strategy for alleviating the intracellular oxidative insults, and thus blocking the pathogenesis of oxidative stress-induced diseases. In the present study, a naturally-derived isopimarane-type diterpenoid sphaeropsidin C (SC) was identified to be an activator of Nrf2/ARE signaling pathway. Our data indicated that SC was able to stimulate Nrf2-mediated defensive system through promoting Nrf2 translocation, inhibiting Nrf2 ubiquitination, and enhancing Nrf2 stability in normal human lung epithelial Beas-2B cells. Furthermore, SC-induced Nrf2 activation required the involvement of protein kinases, exemplified by protein kinase C (PKC), protein kinase R-like endoplasmic reticulum kinase (PERK), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). It alleviated sodium arsenite [As(III)]-induced intracellular oxidative stress in an Nrf2-dependent manner. These results suggested that SC displayed potential application for the prevention and therapy against oxidative stress-induced diseases. Moreover, isopimarane-type diterpenoid represents a promising skeleton for developing Nrf2 activators.
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http://dx.doi.org/10.1016/j.biopha.2019.109669DOI Listing
January 2020

CYP3A4 and microRNA-122 are involved in the apoptosis of HepG2 cells induced by ILs 1-decyl-3-methylimidazolium bromide.

J Biochem Mol Toxicol 2020 Jan 8;34(1):e22419. Epub 2019 Nov 8.

School of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan, China.

Ionic liquids (ILs) as green alternatives for volatile organic solvents are increasingly used in commercial applications. It is necessary to explore the cytotoxic mechanism of ILs to reduce the risk to human health. For this purpose, cell viability, apoptosis, cytochrome P450 3A4 (CYP3A4), glucose transporter type 2 (GLUT2), and microRNA-122 (miR-122) gene expression in HepG2 cells was evaluated after IL exposure. The results showed that ILs reduced the viability of HepG2 cells through apoptotic cell death. Moreover, ILs markedly upregulated the transcription and protein levels of CYP3A4, but did not affect the expression of GLUT2 in either messenger RNA level or protein level. Finally, ILs increased the expression of miR-122 and inhibition of miR-122 with miR-122 inhibitor blocked ILs-induced apoptosis in HepG2 cells. This finding may contribute to an increased understanding of the in vitro molecular toxicity mechanism of ILs to further understand IL-related human health risks.
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http://dx.doi.org/10.1002/jbt.22419DOI Listing
January 2020

Rab7 regulates primary cilia disassembly through cilia excision.

J Cell Biol 2019 12 16;218(12):4030-4041. Epub 2019 Oct 16.

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China

The primary cilium is a sensory organelle that protrudes from the cell surface. Primary cilia undergo dynamic transitions between assembly and disassembly to exert their function in cell signaling. In this study, we identify the small GTPase Rab7 as a novel regulator of cilia disassembly. Depletion of Rab7 potently induced spontaneous ciliogenesis in proliferating cells and promoted cilia elongation during quiescence. Moreover, Rab7 performs an essential role in cilia disassembly; knockdown of Rab7 blocked serum-induced ciliary resorption, and active Rab7 was required for this process. Further, we demonstrate that Rab7 depletion significantly suppresses cilia tip excision, referred to as cilia ectocytosis, which has been identified as required for cilia disassembly. Mechanically, the failure of F-actin polymerization at the site of excision of cilia tips caused suppression of cilia ectocytosis on Rab7 depletion. Overall, our results suggest a novel function for Rab7 in regulating cilia ectocytosis and cilia disassembly via control of intraciliary F-actin polymerization.
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http://dx.doi.org/10.1083/jcb.201811136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891077PMC
December 2019

MAVS O-GlcNAcylation Is Essential for Host Antiviral Immunity against Lethal RNA Viruses.

Cell Rep 2019 08;28(9):2386-2396.e5

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

It is known that lethal viruses profoundly manipulate host metabolism, but how the metabolism alternation affects the immediate host antiviral immunity remains elusive. Here, we report that the O-GlcNAcylation of mitochondrial antiviral-signaling protein (MAVS), a key mediator of interferon signaling, is a critical regulation to activate the host innate immunity against RNA viruses. We show that O-GlcNAcylation depletion in myeloid cells renders the host more susceptible to virus infection both in vitro and in vivo. Mechanistically, we demonstrate that MAVS O-GlcNAcylation is required for virus-induced MAVS K63-linked ubiquitination, thereby facilitating IRF3 activation and IFNβ production. We further demonstrate that D-glucosamine, a commonly used dietary supplement, effectively protects mice against a range of lethal RNA viruses, including human influenza virus. Our study highlights a critical role of O-GlcNAcylation in regulating host antiviral immunity and validates D-glucosamine as a potential therapeutic for virus infections.
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http://dx.doi.org/10.1016/j.celrep.2019.07.085DOI Listing
August 2019

Botrysphin D attenuates arsenic-induced oxidative stress in human lung epithelial cells via activating Nrf2/ARE signaling pathways.

Biochem Biophys Res Commun 2019 10 21;518(3):526-532. Epub 2019 Aug 21.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, People's Republic of China. Electronic address:

Oxidative stress is one of the main pathogenesis for many human diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays a key role in regulating intracellular antioxidant responses, and thus activation of Nrf2/ARE signaling pathway is a potential chemopreventive or therapeutic strategy to treat diseases caused by oxidative damage. In the present study, we have found that treatment of Beas-2B cells with botrysphins D (BD) attenuated sodium arsenite [As (III)]-induced cell death and apoptosis. Meanwhile, BD was able to upregulate protein levels of Nrf2 and its downstream genes NQO1 and γ-GCS through inducing Nrf2 nuclear translocation, enhancing protein stability, and inhibiting ubiquitination. It was also found that BD-induced activation of the Nrf2/ARE pathway was regulated by PI3K, MEK1/2, PKC, and PERK kinases. Collectively, BD is a novel activator of Nrf2/ARE pathway, and is verified to be a potential preventive agent against oxidative stress-induced damage in human lung tissues.
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http://dx.doi.org/10.1016/j.bbrc.2019.08.074DOI Listing
October 2019

Novel diterpenoid-type activators of the Keap1/Nrf2/ARE signaling pathway and their regulation of redox homeostasis.

Free Radic Biol Med 2019 09 2;141:21-33. Epub 2019 Jun 2.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, No. 44 Wenhua Xi Road, Jinan, 250012, People's Republic of China. Electronic address:

Oxidative stress is involved in the onset and progression of many human diseases. Activators of the Keap1/Nrf2/ARE pathway effectively inhibit the progression of oxidative stress-induced diseases. Herein, a small library of diterpenoids was established by means of phytochemical isolation, and chemical modification on naturally occurring molecules. The diterpenoids were subjected to a NAD(P)H: quinone reductase (QR) assay to evaluate its potential inhibition against oxidative stress. Sixteen diterpenoids were found to be novel potential activators of Nrf2-mediated defensive response. Of which, an isopimarane-type diterpenoid, sphaeropsidin A (SA), was identified as a potent activator of the Keap1/Nrf2/ARE pathway, and displayed approximately 5-folds potency than that of sulforaphane (SF). SA activated Nrf2 and its downstream cytoprotective genes through enhancing the stabilization of Nrf2 in a process involving PI3K, PKC, and PERK, as well as potentially interrupting Nrf2-Keap1 protein-protein interaction. In addition, SA conferred protection against sodium arsenite [As(III)]- and cigarette smoke extract (CSE)-induced redox imbalance and cytotoxicity in human lung epithelial cells, as wells as inhibited metronidazole (MTZ)-induced oxidative insult in Tg (krt4: NTR-hKikGR) transgenic zebrafish and lipopolysaccharide (LPS)-induced oxidative damage in wild-type AB zebrafish. These results imply that SA is a lead compound for therapeutic agent against oxidative stress-induced diseases, and diterpenoid is a good resource for discovering drug candidates and leads of antioxidant therapy.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.06.001DOI Listing
September 2019

AMPK-mediated activation of MCU stimulates mitochondrial Ca entry to promote mitotic progression.

Nat Cell Biol 2019 04 11;21(4):476-486. Epub 2019 Mar 11.

State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, China.

The capacity of cells to alter bioenergetics in response to the demands of various biological processes is essential for normal physiology. The coordination of energy sensing and production with highly energy-demanding cellular processes, such as cell division, is poorly understood. Here, we show that a cell cycle-dependent mitochondrial Ca transient connects energy sensing to mitochondrial activity for mitotic progression. The mitochondrial Ca uniporter (MCU) mediates a rapid mitochondrial Ca transient during mitosis. Inhibition of mitochondrial Ca transients via MCU depletion causes spindle checkpoint-dependent mitotic delay. Cellular ATP levels drop during early mitosis, and the mitochondrial Ca transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). Our results establish a critical role for AMPK- and MCU-dependent mitochondrial Ca signalling in mitosis and reveal a mechanism of mitochondrial metabolic adaptation to acute cellular energy stress.
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http://dx.doi.org/10.1038/s41556-019-0296-3DOI Listing
April 2019

Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity.

Cell 2019 03 21;176(6):1447-1460.e14. Epub 2019 Feb 21.

State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China. Electronic address:

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
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http://dx.doi.org/10.1016/j.cell.2019.01.016DOI Listing
March 2019

Lignan and flavonoid support the prevention of cinnamon against oxidative stress related diseases.

Phytomedicine 2019 Feb 5;53:143-153. Epub 2018 Sep 5.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China. Electronic address:

Background: Oxidative stress contributes to the pathogenesis of many human diseases. Cinnamon is a worldwide used spice, dietary supplement and traditional medicine, and is used for the therapy of oxidative stress related diseases. A well-established concept is that the functions of cinnamon preventing oxidative stress-induced diseases are attributed to the occurrence of cinnamaldehyde and its analogues.

Hypothesis: In our continuous searching of natural molecules with antioxidant capacity, we have found that cinnamaldehyde and its analogues in cinnamon are weak inhibitors of oxidative stress, and thus we speculate that there are novel and/or potent molecules inhibiting oxidative stress in cinnamon.

Study Design And Methods: A systemic phytochemical investigation of cinnamon using column chromatography was performed to identify the chemical constituents of cinnamon, and then their capacity of inhibiting oxidative stress and action of mechanism targeting Nrf2 pathway were investigated using diverse bioassay, including NAD(P)H: quinone reductase (QR) assay, immunoblot analysis, luciferase reporter gene assay, immunofluorescence and flow cytometry.

Results: Cinnamon improved the intracellular antioxidant capacity. A systemic phytochemical investigation of cinnamon gave the isolation of twenty-two chemical ingredients. The purified constituents were tested for their potential inhibitory effects against oxidative stress. Besides cinnamaldehyde analogues, a lignan pinoresinol (PRO) and a flavonol (-)-(2R,3R)-5,7-dimethoxy-3', 4'-methylenedioxy-flavan-3-ol (MFO) were firstly identified to be inhibitors of oxidative stress. Further study indicated that PRO and MFO activated Nrf2-mediated antioxidant response, and protected human lung epithelial cells against sodium arsenite [As(III)]-induced oxidative insults.

Conclusion: The lignan PRO and the flavonoid MFO are two novel Nrf2 activators protecting tissues against oxidative insults, and these two constituents support the application of cinnamon as an agent against oxidative stress related diseases.
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http://dx.doi.org/10.1016/j.phymed.2018.09.022DOI Listing
February 2019

Microtubule asters anchored by FSD1 control axoneme assembly and ciliogenesis.

Nat Commun 2018 12 11;9(1):5277. Epub 2018 Dec 11.

State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, 100850, China.

Defective ciliogenesis causes human developmental diseases termed ciliopathies. Microtubule (MT) asters originating from centrosomes in mitosis ensure the fidelity of cell division by positioning the spindle apparatus. However, the function of microtubule asters in interphase remains largely unknown. Here, we reveal an essential role of MT asters in transition zone (TZ) assembly during ciliogenesis. We demonstrate that the centrosome protein FSD1, whose biological function is largely unknown, anchors MT asters to interphase centrosomes by binding to microtubules. FSD1 knockdown causes defective ciliogenesis and affects embryonic development in vertebrates. We further show that disruption of MT aster anchorage by depleting FSD1 or other known anchoring proteins delocalizes the TZ assembly factor Cep290 from centriolar satellites, and causes TZ assembly defects. Thus, our study establishes FSD1 as a MT aster anchorage protein and reveals an important function of MT asters anchored by FSD1 in TZ assembly during ciliogenesis.
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http://dx.doi.org/10.1038/s41467-018-07664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290075PMC
December 2018

G3BP1 promotes DNA binding and activation of cGAS.

Nat Immunol 2019 01 3;20(1):18-28. Epub 2018 Dec 3.

State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, China.

Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1-cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA-induced autoinflammatory responses in an Aicardi-Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.
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http://dx.doi.org/10.1038/s41590-018-0262-4DOI Listing
January 2019

Cannabinoid CB2 Agonist AM1710 Differentially Suppresses Distinct Pathological Pain States and Attenuates Morphine Tolerance and Withdrawal.

Mol Pharmacol 2019 02 30;95(2):155-168. Epub 2018 Nov 30.

Department of Psychological and Brain Sciences (A.-L.L., X.L., A.S.D., A.C.T., L.M.C., K.M., A.G.H.), Program in Neuroscience (A.C.T., L.M.C., K.M., A.G.H.), Genome, Cell and Developmental Biology Program (A.C.T., A.G.H.), and Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana; and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (Y.L., S.P.N., A.M.)

AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 remains incompletely characterized. It is not known whether AM1710 behaves as a broad-spectrum analgesic and/or suppresses the development of opioid tolerance and physical dependence. In vitro, AM1710 inhibited forskolin-stimulated cAMP production and produced enduring activation of extracellular signal-regulated kinases 1/2 phosphorylation in human embryonic kidney (HEK) cells stably expressing mCB2. Only modest species differences in the signaling profile of AM1710 were observed between HEK cells stably expressing mCB2 and hCB2. In vivo, AM1710 produced a sustained inhibition of paclitaxel-induced allodynia in mice. In paclitaxel-treated mice, a history of AM1710 treatment (5 mg/kg per day × 12 day, i.p.) delayed the development of antinociceptive tolerance to morphine and attenuated morphine-induced physical dependence. AM1710 (10 mg/kg, i.p.) did not precipitate CB1 receptor-mediated withdrawal in mice rendered tolerant to Δ-tetrahydrocannabinol, suggesting that AM1710 is not a functional CB1 antagonist in vivo. Furthermore, AM1710 (1, 3, 10 mg/kg, i.p.) did not suppress established mechanical allodynia induced by complete Freund's adjuvant (CFA) or by partial sciatic nerve ligation (PSNL). Similarly, prophylactic and chronic dosing with AM1710 (10 mg/kg, i.p.) did not produce antiallodynic efficacy in the CFA model. By contrast, gabapentin suppressed allodynia in both CFA and PSNL models. Our results indicate that AM1710 is not a broad-spectrum analgesic agent in mice and suggest the need to identify signaling pathways underlying CB2 therapeutic efficacy to identify appropriate indications for clinical translation.
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http://dx.doi.org/10.1124/mol.118.113233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324648PMC
February 2019

A model of pain behaviors in freely moving rats generated by controllable electrical stimulation of the peripheral nerve.

J Neurosci Methods 2019 01 10;311:13-16. Epub 2018 Oct 10.

Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA. Electronic address:

Background: Neuropathic pain patients have described experiencing unprovoked, intermittent pain attacks with shooting, stabbing, and burning qualities. Rodent models used in previous literature usually only involve acute exposure, and/or are unable to manipulate the stimulation intensity in vivo by the experimenter during an experiment.

New Method: This paper describes a method to induce controllable pain behaviors in rodents using a wireless portable electronic device that can be manipulated within the course of an experiment. A stimulating electrode was implanted at the L5 spinal nerve location in Sprague-Dawley rats and our custom-built wireless stimulating device was attached to deliver variable stimulation in freely moving animals (50 Hz, 0.5 V; 100 Hz, 1 V).

Results: Implantation itself did not induce hypersensitivity as measured by the mechanical paw withdrawal threshold test. Observation of pain behaviors (paw elevation and licking) indicated that high stimulation intensity yielded a significant increase in pain behaviors. Even further, high intensity stimulation resulted in a behavioral "wind-up" of pain behaviors that persisted into the resting period when no stimulation was applied.

Comparison With Existing Methods And Conclusions: This method can be used to study pain behaviors in a controllable way in freely moving rodents in comparison to existing models that are acute and/or are unable to manipulate the stimulation intensity in vivo.
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http://dx.doi.org/10.1016/j.jneumeth.2018.10.009DOI Listing
January 2019

( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

J Med Chem 2018 10 21;61(19):8639-8657. Epub 2018 Sep 21.

Center for Drug Discovery and Department of Pharmaceutical Sciences , Northeastern University , Boston , Massachusetts 02115 , United States.

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( K of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC = 0.6 ± 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00611DOI Listing
October 2018

Homoeriodictyol protects human endothelial cells against oxidative insults through activation of Nrf2 and inhibition of mitochondrial dysfunction.

Vascul Pharmacol 2018 10 11;109:72-82. Epub 2018 Jun 11.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China. Electronic address:

Excess intracellular reactive oxygen species (ROS) production is a significant causative factor of many diseases, exemplified by vascular diseases. Mitochondria are a major source of endogenous ROS, which simultaneously induce mitochondrial dysfunction. Nuclear factor-erythroid 2-related factor 2 (Nrf2) represents an important intracellular defense system that protects cells against oxidative insults caused by ROS. Therefore, molecules with the capacities of inducing Nrf2, and preventing mitochondrial dysfunction can inhibit cell apoptosis, and thus are potential drug candidates for the therapy of ROS-mediated vascular diseases. Homoeriodictyol (HE), previously isolated from Viscum articulatum Burm, has been found to be an Nrf2 inducer. In the present study, we investigated its protection on ROS-induced endothelial cell injury using a HO-induced human umbilical vein EA.hy926 cell oxidative insult model. Our results indicated that HE activated Nrf2 signaling pathway and protected cells against HO-induced cell damage. HE alleviated HO-induced loss of mitochondrial membrane potential (MMP), blocked the releases of cytochrome C and apoptosis inducing factor (AIF) from mitochondria, and thus inhibited mitochondria-mediated cell apoptosis. Furthermore, HE inhibited HO-induced changes of apoptosis-related proteins, such as Bcl-2, Bcl-xL, caspases -3, -9 and PARP. Further study demonstrated that the protection of HE against HO-induced endothelial cell damage was Nrf2-dependent. Collectively, our observations suggest that HE is capable of counteracting oxidative insults in endothelial cells, and has a potential to be a therapeutic agent against ROS-mediated vascular diseases.
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http://dx.doi.org/10.1016/j.vph.2018.06.007DOI Listing
October 2018

Catecholic Isoquinolines from Portulaca oleracea and Their Anti-inflammatory and β-Adrenergic Receptor Agonist Activity.

J Nat Prod 2018 04 8;81(4):768-777. Epub 2018 Mar 8.

Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , Jinan , Shandong 250012 , People's Republic of China.

Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC = 18.0-497.7 μM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC = 82.4 μM), with EC values of 18.0, 18.1, 35.4, 36.3, and 58.7 μM, respectively. Additionally, at 100 μM, compounds 1-12 showed different degrees of β-adrenergic receptor (β-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed β-AR as detected by a calcium assay. The EC values of 2 and 10 were 5.1 μM and 87.9 nM, respectively.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00762DOI Listing
April 2018

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer.

BMC Cancer 2018 03 6;18(1):259. Epub 2018 Mar 6.

State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing, 100850, China.

Background: Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application.

Methods: A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort.

Results: A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P <  0.001) and SCC patients (27 months vs. not reached, HR 9.97; P <  0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P = 0.018).

Conclusions: Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.
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http://dx.doi.org/10.1186/s12885-018-4104-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840771PMC
March 2018

Changes in intraocular pressure and central corneal thickness during pregnancy: a systematic review and Meta-analysis.

Int J Ophthalmol 2017 18;10(10):1573-1579. Epub 2017 Oct 18.

Department of Ophthalmology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China.

Aim: To conduct a Meta-analysis for investigating the variations in intraocular pressure (IOP) and central corneal thickness (CCT) during normal pregnancy.

Methods: We searched for clinical trials published up to November 2015 without language or region restrictions in PubMed, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, Ovid, EBSCO, Elsevier, the Chinese Biomedicine Database, WanFang, CNKI, CQVIP and Google Scholar. Studies of the ocular changes observed in pregnant women were selected. The main outcomes were assessed by changes in IOP and CCT.

Results: Fifteen studies were included. In subgroup analyses, IOP was significantly decreased during the second MD=-1.53, 95%CI (-2.19, -0.87); <0.00001, and third MD=-2.91, 95%CI (-3.74, -2.08); <0.00001 trimesters of pregnancy. CCT was increased during the second MD=10.12, 95%CI (2.01, 18.22); =0.01, trimester of pregnancy; moreover, during the third trimester of pregnancy, the CCT displayed an increasing trend, but the difference was not significant MD=5.98, 95%CI (-1.11, 13.07); =0.1.

Conclusion: A decrease in IOP is accompanied by an increase in CCT in the second and third trimesters of a normal pregnancy in women.
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http://dx.doi.org/10.18240/ijo.2017.10.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638980PMC
October 2017

NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation.

Mol Cell 2017 Oct 21;68(1):185-197.e6. Epub 2017 Sep 21.

State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China; Collaborative Innovation Center for Biotherapy, China. Electronic address:

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.
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http://dx.doi.org/10.1016/j.molcel.2017.08.017DOI Listing
October 2017

Identification of novel Nrf2 activators from Cinnamomum chartophyllum H.W. Li and their potential application of preventing oxidative insults in human lung epithelial cells.

Redox Biol 2018 04 14;14:154-163. Epub 2017 Sep 14.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China. Electronic address:

Human lung tissue, directly exposed to the environmental oxidants and toxicants, is apt to be harmed to bring about acute or chronic oxidative insults. The nuclear factor erythroid 2-related factor 2 (Nrf2) represents a central cellular defense mechanism, and is a target for developing agents against oxidative insult-induced human lung diseases. Our previous study found that the EtOH extract of Cinnamomum chartophyllum protected human bronchial epithelial cells against oxidative insults via Nrf2 activation. In this study, a systemic phytochemical investigation of the aerial parts of C. chartophyllum led to the isolation of thirty chemical constituents, which were further evaluated for their Nrf2 inducing potential using NAD(P)H: quinone reductase (QR) assay. Among these purified constituents, a sesquiterpenoid bearing α, β-unsaturated ketone group, 3S-(+)-9-oxonerolidol (NLD), and a diphenyl sharing phenolic groups, 3, 3', 4, 4'-tetrahydroxydiphenyl (THD) significantly activated Nrf2 and its downstream genes, NAD(P)H quinone oxidoreductase 1 (NQO-1), and γ-glutamyl cysteine synthetase (γ-GCS), and enhanced the nuclear translocation and stabilization of Nrf2 in human lung epithelial cells. Importantly, NLD and THD had no toxicities under the Nrf2 inducing doses. THD also demonstrated a potential of interrupting Nrf2-Keap1 protein-protein interaction (PPI). Furthermore, NLD and THD protected human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. Taken together, we conclude that NLD and THD are two novel Nrf2 activators with potential application of preventing acute and chronic oxidative insults in human lung tissue.
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http://dx.doi.org/10.1016/j.redox.2017.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608562PMC
April 2018

Extrapolating meaning from local field potential recordings.

J Integr Neurosci 2017 ;16(1):107-126

Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, Indiana, 47405, USA.

Local field potentials (LFP) reflect the spatially weighted low-frequency activity nearest to a recording electrode. LFP recording is a window to a wide range of cellular activities and has gained increasing attention over recent years. We here review major conceptual issues related to LFP with the goal of creating a resource for non-experts considering implementing LFP into their research. We discuss the cellular activity that constitutes the local field potential; recording techniques, including recommendations and limitations; approaches to analysis of LFP data (with focus on power-banded analyses); and finally we discuss reports of the successful use of LFP in clinical applications.
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http://dx.doi.org/10.3233/JIN-170011DOI Listing
May 2018

Physalis alkekengi L. var. franchetii (Mast.) Makino: An ethnomedical, phytochemical and pharmacological review.

J Ethnopharmacol 2018 Jan 31;210:260-274. Epub 2017 Aug 31.

Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China. Electronic address:

Ethnopharmacological Relevance: The calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino (Physalis Calyx seu Fructus), have been widely used in traditional and indigenous Chinese medicines for the therapy of cough, excessive phlegm, pharyngitis, sore throat, dysuria, pemphigus, eczema, and jaundice with a long history.

Aim Of The Review: The present review aims to achieve a comprehensive and up-to-date investigation in ethnomedical uses, phytochemistry, pharmacology, and toxicity of P. alkekengi var. franchetii, particularly its calyxes and fruits. Through analysis of these findings, evidences supporting their applications in ethnomedicines are illustrated. Possible perspectives and opportunities for the future research are analyzed to highlight the gaps in our knowledge that deserves further investigation.

Material And Methods: Information on P. alkekengi var. franchetii was collected via electronic search of major scientific databases (e.g. Web of Science, SciFinder, Google Scholar, Pubmed, Elsevier, SpringerLink, Wiley online and China Knowledge Resource Integrated) for publications on this medicinal plant. Information was also obtained from local classic herbal literature on ethnopharmacology.

Results: About 124 chemical ingredients have been characterized from different parts of this plant. Steroids (particularly physalins) and flavonoids are the major characteristic and bioactive constituents. The crude extracts and the isolated compounds have demonstrated various in vitro and in vivo pharmacological functions, such as anti-inflammation, inhibition of tumor cell proliferation, antimicrobial activity, diuretic effect, anti-diabetes, anti-asthma, immunomodulation, and anti-oxidation.

Conclusions: P. alkekengi var. franchetii is an important medicinal plant for the ethnomedical therapy of microbial infection, inflammation, and respiratory diseases (e.g. cough, excessive phlegm, pharyngitis). Phytochemical and pharmacological investigations of this plant definitely increased in the past half century. The chemical profiles, including ingredients and structures, have been adequately verified. Modern pharmacological studies supported its uses in the traditional and folk medicines, however, the molecular mechanisms of purified compounds remained unclear and were worth of further exploration. Therefore, the researchers should be paid more attention to a better utilization of this plant.
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http://dx.doi.org/10.1016/j.jep.2017.08.022DOI Listing
January 2018

Cannabinoid CB Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB Mechanism that is Independent of CB Receptors in Mice.

J Pharmacol Exp Ther 2017 08 7;362(2):296-305. Epub 2017 Jun 7.

Department of Psychological and Brain Sciences (A-L L, L.M.C., K.M., A.G.H.), Program in Neuroscience (L.M.C., K.M., A.G.H.), Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana

GW405833, widely accepted as a cannabinoid receptor 2 (CB) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB and CB knockout (KO) mice, their respective wild-type (WT) mice, and both CB and CB antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CBKO mice and absent in CBKO mice. Furthermore, the antiallodynic efficacy of GW405833 (30 mg/kg i.p.) was completely blocked by the CB antagonist rimonabant (10 mg/kg i.p.) but not by the CB antagonist SR144528 (10 mg/kg i.p.). Thus, the antinociceptive properties of GW405833 are dependent on CB receptors. GW405833 (30 mg/kg i.p.) was also inactive in a tetrad of tests measuring cardinal signs of CB activation. Additionally, unlike rimonabant (10 mg/kg i.p.), GW405833 (10 mg/kg, i.p.) did not act as a CB antagonist in vivo to precipitate withdrawal in mice treated chronically with Δ-tetrahydrocannabinol. The present results suggest that the antiallodynic efficacy of GW405833 is CB-dependent but does not seem to involve engagement of the CB receptor's orthosteric site.
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http://dx.doi.org/10.1124/jpet.117.241901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502377PMC
August 2017