Publications by authors named "Yunman Li"

97 Publications

10-O-(N N-Dimethylaminoethyl)-Ginkgolide B Methane-Sulfonate (XQ-1H) Ameliorates Cerebral Ischemia Via Suppressing Neuronal Apoptosis.

J Stroke Cerebrovasc Dis 2021 Sep 14;30(9):105987. Epub 2021 Jul 14.

State Key Laboratory of Natural Medicines, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Objectives: The 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1H) is an effective novel drug for the treatment of ischemic cerebrovascular disease derived from Ginkgolide B, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, whether XQ-1H exerts neuroprotective effect via regulating neuronal apoptosis and the underlying mechanism remain to be elucidated.

Materials And Methods: This study was aimed to investigate the neuroprotective effect of XQ-1H in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and the oxygen glucose deprivation/reoxygenation (OGD/R) induced neuronal apoptosis on pheochromocytoma (PC-12) cells.

Results: The results showed that administration of XQ-1H at different dosage (7.8, 15.6, 31.2 mg/kg) reduced the brain infarct and edema, attenuated the neuro-behavioral dysfunction, and improved cell morphology in brain tissue after MCAO/R in rats. Moreover, incubation with XQ-1H (1 µM, 3 µM, 10 µM, 50 µM, 100 µM) could increase the cell viability, and showed no toxic effect to PC-12 cells. XQ-1H at following 1 µM, 10 µM, 100 µM decreased the lactate dehydrogenase (LDH) activity and suppressed the cell apoptosis in PC-12 cells exposed to OGD/R. In addition, XQ-1H treatment could significantly inhibit caspase-3 activation both in vivo and in vitro, reciprocally modulate the expression of apoptosis related proteins, bcl-2, and bax via activating PI3K/Akt signaling pathway. For mechanism verification, LY294002, the inhibitor of PI3K/Akt pathway was introduced the expressions of bcl-2 and phosphorylated Akt were down-regulated, the expression of bax was up-regulated, indicating that XQ-1H could alleviate the cell apoptosis through activating the PI3K/Akt pathway.

Conclusions: Our findings demonstrated that XQ-1H treatment could provide a neuroprotective effect against ischemic stroke induced by cerebral ischemia/reperfusion injury in vivo and in vitro through regulating neuronal survival and inhibiting apoptosis. The findings of the study confirmed that XQ-1H could be develop as a potential drug for treatment of cerebral ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105987DOI Listing
September 2021

Pyroptosis in stroke-new insights into disease mechanisms and therapeutic strategies.

J Physiol Biochem 2021 May 4. Epub 2021 May 4.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.

Stroke is a common disease with high mortality and disability worldwide. Different forms of cell deaths, including apoptosis and necrosis, occur in ischemic or hemorrhagic brain tissue, among which pyroptosis, a newly discovered inflammation-related programmed cell death, is generally divided into two main pathways, the canonical inflammasome pathway and the non-canonical inflammasome pathway. Caspase-mediated pyroptosis requires the assembly of inflammasomes such as NLRP3, which leads to the release of inflammatory cytokines IL-1β and IL-18 through the pores formed in the plasma membrane by GSDMD followed by neuroinflammation. Recently, pyroptosis and its relationship with inflammation have attracted more and more attention in the study of cerebral ischemia or hemorrhage. In addition, many inhibitors of pyroptosis targeting caspase, NLRP3, and the upstream pathway have been found to reduce brain tissue damage after stroke. In this review, we mainly introduce the pathology of stroke, the molecular mechanism, and process of pyroptosis, as well as the pivotal roles of pyroptosis in stroke, in order to provide new insights for the treatment of stroke.
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http://dx.doi.org/10.1007/s13105-021-00817-wDOI Listing
May 2021

XQ-1H promotes cerebral angiogenesis via activating PI3K/Akt/GSK3β/β-catenin/VEGF signal in mice exposed to cerebral ischemic injury.

Life Sci 2021 May 17;272:119234. Epub 2021 Feb 17.

State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Stroke still ranks as a most lethal disease worldwide. Angiogenesis during the chronic phase of ischemic stroke can alleviate ischemic injury and attenuate neurological deficit. XQ-1H is a new compound derived from the structure modification of ginkgolide B, which exerts anti-inflammation and neuroprotection against cerebral ischemic injury during the acute or subacute phase. However, whether XQ-1H facilitates angiogenesis and neural functional recovery during the chronic phase remains unclear. This research was designed to explore whether XQ-1H promotes angiogenesis after ischemic stroke and to preliminarily elucidate the mechanism. In vitro, XQ-1H was found to facilitate proliferation, migration and tube formation in bEnd.3 cells. In vivo, XQ-1H raised the CD31 positive microvessel number and increased focal cerebral blood flow in mice exposed to cerebral ischemic injury, and improved the neurological function. Mechanism studies revealed that XQ-1H exerted angiogenesis promoting effect via the PI3K/Akt/GSK3β/β-catenin/VEGF signal pathway, which was reversed by LY294002 (the specific inhibitor of PI3K/Akt). In conclusion, XQ-1H exerts angiogenetic effect both in vivo and in vitro, which is a potential agent against ischemic stroke during chronic phase.
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http://dx.doi.org/10.1016/j.lfs.2021.119234DOI Listing
May 2021

Pretreatment of Indobufen and Aspirin and their Combinations with Clopidogrel or Ticagrelor Alleviates Inflammasome Mediated Pyroptosis Via Inhibiting NF-κB/NLRP3 Pathway in Ischemic Stroke.

J Neuroimmune Pharmacol 2021 Jan 29. Epub 2021 Jan 29.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.

Increasing studies showed that several anti-platelet drugs turned out to be a promising strategy for inflammatory response. In this study, we investigated the protective efficiency of pretreatment of indobufen or aspirin combined with clopidogrel or ticagrelor (IACT) on cerebral ischemic injury via NF-κB/NLRP3 pathway. Ischemia/reperfusion (I/R) injury was simulated in vivo by middle cerebral artery occlusion/reperfusion (MCAO/R) model, and rats were pretreated with indobufen and aspirin and their combinations with clopidogrel or ticagrelor respectively. The platelet aggregation, cerebral infarct size, water content, neurological impairment and LDH release were measured. The relative expression of inflammasome mediated pyroptosis was determined by ELISA, RT-PCR, Tunel, Immunofluorescence and Western blotting as appropriate. In vitro, I/R injury was simulated in PC12 cells using oxygen glucose deprivation/reperfusion (OGD/R) and Lipopolysaccharide (LPS) to induce pyroptosis. The effect of combinations were significantly greater than MCAO/R group on decreasing the platelet aggregation, infarct size, brain edema, LDH release and neurologic impairment. LPS aggravated I/R-induced PC12 cell injury, which was significantly suppressed by pretreatment of IACT and Bay11-7082. Mechanistically, IACT alleviated transcriptionally encoded IL-1β, IL-18 and NLRP3 via inhibiting nuclear transportation of NF-κB. Importantly, at protein level, NLRP3, Caspase-1, IL-18, IL-1β and GSDMD were significantly decreased in combination groups both in vivo and vitro. IACT reduce inflammasome mediated pyroptosis in MCAO/R rats and OGD/R PC12 cells through inhibiting NF-κB/NLRP3 signaling pathway, which suggests that drug combination is a protective strategy with clinical potential against I/R-induced injury. Graphical abstract.
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http://dx.doi.org/10.1007/s11481-020-09978-9DOI Listing
January 2021

Targeting pyroptosis to regulate ischemic stroke injury: Molecular mechanisms and preclinical evidences.

Brain Res Bull 2020 12 14;165:146-160. Epub 2020 Oct 14.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Stroke is one of the leading causes of death worldwide with limited therapies. After ischemic stroke occurs, a robust sterile inflammatory response happens and lasts for days and determines neurological prognosis. Pyroptosis is an inflammatory programmed cell death characterized by cleavage of pore-forming proteins gasdermins as a result of activating caspases and inflammasomes. It has morphological characteristics of rapid plasma-membrane rupture and release of proinflammatory intracellular contents as well as cytokines. Recent researches implicate pyroptosis involvement in the pathogenesis of ischemic stroke and inhibition of pyroptosis attenuates ischemic brain injury. In this review, we discussed molecular mechanisms of pyroptosis, evidences for pyroptosis involvement in different kinds of the central nervous system cells, as well as potential inhibitors for intervention of pyroptosis. Based on the review, we hypothesize the feasibility of therapeutic strategies targeting pyroptosis in the context of ischemic stroke.
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http://dx.doi.org/10.1016/j.brainresbull.2020.10.009DOI Listing
December 2020

Long Non-coding RNAs (lncRNAs), A New Target in Stroke.

Cell Mol Neurobiol 2020 Aug 31. Epub 2020 Aug 31.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.

Stroke has become the most disabling and the second most fatal disease in the world. It has been a top priority to reveal the pathophysiology of stroke at cellular and molecular levels. A large number of long non-coding RNAs (lncRNAs) are identified to be abnormally expressed after stroke. Here, we summarize 35 lncRNAs associated with stroke, and clarify their functions on the prognosis through signal transduction and predictive values as biomarkers. Changes in the expression of these lncRNAs mediate a wide range of pathological processes in stroke, including apoptosis, inflammation, angiogenesis, and autophagy. Based on the exploration of the functions and mechanisms of lncRNAs in stroke, more timely, accurate predictions and more effective, safer treatments for stroke could be developed.
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http://dx.doi.org/10.1007/s10571-020-00954-8DOI Listing
August 2020

The role of Th17 cells in psoriasis.

Immunol Res 2020 10 22;68(5):296-309. Epub 2020 Aug 22.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, Jiangsu, 210009, People's Republic of China.

T helper 17 (Th17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases, like psoriasis, multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). However, the role of Th17 cells in psoriasis has not been clarified completely. Th17-derived proinflammatory cytokines including IL-17A, IL-17F, IL-21, IL-22, and IL-26 have a critical role in the pathogenesis of these disorders. In this review, we introduced the signaling and transcriptional regulation of Th17 cells. And then, we demonstrate the immunopathology role of Th17 cells and functions of the related cytokines in the psoriasis to get a better understanding of the inflammatory mechanisms mediated by Th17 cells in this disease.
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http://dx.doi.org/10.1007/s12026-020-09149-1DOI Listing
October 2020

Protective Mechanism and Treatment of Neurogenesis in Cerebral Ischemia.

Neurochem Res 2020 Oct 13;45(10):2258-2277. Epub 2020 Aug 13.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.

Stroke is the fifth leading cause of death worldwide and is a main cause of disability in adults. Neither currently marketed drugs nor commonly used treatments can promote nerve repair and neurogenesis after stroke, and the repair of neurons damaged by ischemia has become a research focus. This article reviews several possible mechanisms of stroke and neurogenesis and introduces novel neurogenic agents (fibroblast growth factors, brain-derived neurotrophic factor, purine nucleosides, resveratrol, S-nitrosoglutathione, osteopontin, etc.) as well as other treatments that have shown neuroprotective or neurogenesis-promoting effects.
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http://dx.doi.org/10.1007/s11064-020-03092-1DOI Listing
October 2020

JLX001 attenuates blood-brain barrier dysfunction in MCAO/R rats via activating the Wnt/β-catenin signaling pathway.

Life Sci 2020 Nov 5;260:118221. Epub 2020 Aug 5.

State key laboratory of Nature Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

JLX001, a new dihydrochloride of Cyclovirobuxine D (CVB-D), has bioactivities against ischemia injury. The blood-brain barrier (BBB) disruption is involved in the pathogeneses of ischemic stroke. This study was designed to explore the effect and potential mechanism of JLX001 on the BBB after ischemic stroke. Rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to mimic cerebral ischemia in vivo. In vitro, rat primary brain microvascular endothelial cells (PBMECs) were cultured and exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). Posttreatment of JLX001 for 15 days after MCAO/R improved the behavior, learning and memory ability. Pretreatment of JLX001 for 3 days significantly attenuated infarct volume, lessened brain edema, mitigated BBB disruption and decreased the neurological deficit score in MCAO/R rats. Moreover, JLX001 increased cell viability and reduced sodium fluorescein leakage after OGD/R injury. In addition, JLX001 increased the expressions of Claudin-5 and Occludin, decreased the expression of MMP-9 both in vivo and in vitro. Moreover, immunofluorescence staining and western immunoblotting results showed that JLX001 increased the expressions of tight junction proteins via activating Wnt/β-catenin signal pathway in vivo and in vitro, which may be associated with the activation of PI3K/Akt signaling. Besides, XAV939 (an inhibitor of the Wnt/β-catenin pathway) proved the connection of JLX001 and Wnt/β-catenin pathway. These results suggest that JLX001 alleviates BBB disruption after MCAO/R and OGD/R possibly by alleviating MMP-9 and activating the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2020.118221DOI Listing
November 2020

Effect of Wnt signaling pathway on neurogenesis after cerebral ischemia and its therapeutic potential.

Brain Res Bull 2020 11 5;164:1-13. Epub 2020 Aug 5.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Neurogenesis process in the chronic phase of ischemic stroke has become the focus of research on stroke treatment recently, mainly through the activation of related pathways to increase the differentiation of neural stem cells (NSCs) in the brain sub-ventricular zone (SVZ) and subgranular zone (SGZ) of hippocampal dentate gyrus (DG) areas into neurons, promoting neurogenesis. While there is still debate about the longevity of active adult neurogenesis in humans, the SVZ and SGZ have the capacity to upregulate neurogenesis in response to cerebral ischemia, which opens discussion about potential treatment strategies to harness this neuronal regenerative response. Wnt signaling pathway is one of the most important approaches potentially targeting on neurogenesis after cerebral ischemia, appropriate activation of which in NSCs may help to improve the sequelae of cerebral ischemia. Various therapeutic approaches are explored on preclinical stage to target endogenous neurogenesis induced by Wnt signaling after stroke onset. This article describes the composition of Wnt signaling pathway and the process of neurogenesis after cerebral ischemia, and emphatically introduces the recent studies on the mechanisms of this pathway for post-stroke neurogenesis and the therapeutic possibility of activating the pathway to improve neurogenesis after stroke.
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http://dx.doi.org/10.1016/j.brainresbull.2020.07.005DOI Listing
November 2020

XQ-1H attenuates ischemic injury in PC12 cells via Wnt/β-catenin signaling though inhibition of apoptosis and promotion of proliferation.

Cell Biol Int 2020 Nov 14;44(11):2363-2369. Epub 2020 Aug 14.

Department of Physiology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) is a new derivative of ginkgolide B and has previously been proven to exert neuroprotective effects on ischemic injury. However, it is not clear whether XQ-1H affects the cell survival and proliferation in oxygen-glucose deprivation/reoxygenation (OGD/R) damaged PC12 cells. Our results showed that OGD/R improved cell viability after 24 hr of posttreatment with XQ-1H (10 or 5 μM), inhibiting cell injury and apoptosis by upregulating the expression of brain-derived neurotrophic factor, nerve growth factor, and antiapoptotic B-cell lymphoma-extra large, while reducing proapoptotic cleaved caspase-3 protein. By introducing the Wnt/β-catenin signaling inhibitor XAV-939 and 5-bromo-2'-deoxyuridine staining, it was proved that XQ-1H promoted the proliferation of PC12 cells in a Wnt-signal-dependent manner via inhibiting the activation of glycogen synthase kinase-3β after phosphatidylinositol 3-kinase/protein kinase B signal activation, thereby activating Wnt1, β-catenin, and the expression of downstream neurogenic differentiation 1 and cyclin D1, which was comparable to Wnt/β-catenin signaling agonist 4,6-disubstituted pyrrolopyrimidine. We conclude that XQ-1H, after OGD/R damage to PC12 cells, may limit cell apoptosis in a Wnt/β-catenin signal-dependent manner, promoting cell proliferation and survival.
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http://dx.doi.org/10.1002/cbin.11438DOI Listing
November 2020

Ma xing shi gan decoction eliminates PM2.5-induced lung injury by reducing pulmonary cell apoptosis through Akt/mTOR/p70S6K pathway in rats.

Biosci Rep 2020 07;40(7)

State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.

The present study was designed to investigate the anti-apoptosis effect of Ma xing shi gan decoction (MXD) on PM2.5-induced lung injury via protein kinase B (Akt)/mTOR/p70S6K pathway. A UPLC-MS/MS system was introduced for component analysis of MXD. Rats were instilled with PM2.5 solution suspension intratracheally to induce acute lung injury. The rats were then orally administered with MXD (16, 8, and 4 g/kg) once a day for 7 consecutive days. The therapeutic effects of MXD were evaluated by Hematoxylin and Eosin (HE) staining. The apoptotic cell death was analyzed by terminal-deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay. The alterations in cytochrome c (Cytc) and cleaved-caspase-3 (C-caspase-3) were measured by immunohistochemistry (IHC). The expressions of Bax, B-cell lymphoma 2 (Bcl-2), p-Akt, p-mTOR and p-p70S6K were detected by Western blot. In vitro, PM2.5 exposure model was introduced in A549 cell, followed by incubation with MXD-medicated serum. Hoechst staining was used to determine apoptotic rate. The levels of Bax, Bcl-2, p-Akt, p-mTOR and p-p70S6K were detected by Western blot. Our results in vivo indicated that treatment with MXD decreased histopathological changes score, TUNEL-positive cells rate, expressions of Cytc and C-caspase-3. The in vitro results revealed that incubation with MXD-mediated serum decreased apoptotic rate. Both results in vivo and in vitro demonstrated that MXD inhibited pro-apoptotic protein Bax and promoted anti-apoptotic protein Bcl-2 expression. Likewise, MXD activated Akt/mTOR/p70S6K signal pathway, which was also confirmed by Western immunoblotting. In conclusion, MXD attenuates lung injury and the underlying mechanisms may relate to regulating the apoptosis via Akt/mTOR/p70S6K signaling pathway activation.
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http://dx.doi.org/10.1042/BSR20193738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350893PMC
July 2020

Research progress of mechanisms for tight junction damage on blood-brain barrier inflammation.

Arch Physiol Biochem 2020 Jul 1:1-12. Epub 2020 Jul 1.

State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.

Inflammation in the central nervous system (CNS) contributes to disease pathologies by disrupting the integrity of the blood-brain barrier (BBB). Tight junctions (TJ) are a key component of the BBB. Following hypoxic-ischaemic or mechanical injury to the brain, inflammatory mediators are released such as cytokines, chemokines, and growth factors. Simultaneously, matrix metalloproteinases (MMPs) are released which can degrade TJ proteins. Subsequently, the function and morphology of the BBB are disrupted, which allows immune cells an opportunity to enter into the brain parenchyma. This review summarises the information on the role of TJ protein families in the BBB and provides a comprehensive summary of the mechanisms whereby inflammation breaks down the BBB by increasing degradation of TJ proteins.
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http://dx.doi.org/10.1080/13813455.2020.1784952DOI Listing
July 2020

Total glucosides of paeony (TGP) alleviates constipation and intestinal inflammation in mice induced by Sjögren's syndrome.

J Ethnopharmacol 2020 Oct 7;260:113056. Epub 2020 Jun 7.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address:

Ethnopharmacological Relevance: Sjögren's syndrome (SS) is an autoimmune disease and can cause gastrointestinal disorders such as constipation and intestinal inflammation. As a kind of medicinal material, Paeonia lactiflora Pall has a variety of pharmacological effects, and it is also an indispensable component in many pharmaceutical preparations, which has been widely concerned by the medical and pharmaceutical circles. Total glucosides of paeony (TGP) is a mixture of biologically active compounds extracted from the root of Paeonia lactiflora Pall and has therapeutic effects on a variety of autoimmune diseases.

Aim Of The Study: To investigate the therapeutic effect of TGP on constipation and intestinal inflammation in mice modeled by SS, and to provide a basis for clinical research.

Materials And Methods: The SS model was set up by submandibular gland (SMG) immune induction method and then treated with TGP for 24 weeks. The fecal characteristics were observed and the fecal number and moisture content were measured. Colonic pathology was observed by H&E staining. The levels of serum P substance (SP), vasoactive intestinal peptide (VIP), interleukin (IL)-1β, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, nitric oxide (NO), and nitric oxide synthase (NOS) were determined by enzyme linked immunosorbent assay (ELISA) and microplate method, respectively. Reverse transcription polymerase chain reaction (RT-PCR) was employed to analyze the mRNA expression of c-kit and stem cell factor (SCF) in colon.

Results: Compared with the model group, the dry and rough condition of the feces was improved, and the fecal gloss, number and moisture content significantly increased after the administration of TGP capsules. Meanwhile, TGP treatment improved colonic pathological damage, inhibited the serum concentrations of NO, NOS, IL-1β, TNF-α, NF-κB and SP, increased serum VIP concentration, and up-regulated mRNA expression of SCF and c-kit in colon.

Conclusions: TGP could obviously attenuate SS-mediated constipation and intestinal inflammation in mice by acting on some intestinal motility related factors and inflammatory factors.
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http://dx.doi.org/10.1016/j.jep.2020.113056DOI Listing
October 2020

Total glucosides of paeony (TGP) alleviates Sjogren's syndrome through inhibiting inflammatory responses in mice.

Phytomedicine 2020 Jun 6;71:153203. Epub 2020 Mar 6.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Background: Sjogren's syndrome (SS) is an inflammatory autoimmune disease whose etiology is complicated. Total glucosides of paeony (TGP) has a variety of pharmacological effects.

Purpose: To evaluate the therapeutic effects of TGP on SS in mice and anti-inflammatory mechanism.

Study Design: SS animal model was developed from C57BL/6J mice through immunological induction (SS mice) and NOD/ShiltJNju (NOD) mice. Inflammatory cytokines and other related indicators were measured.

Methods: TGP (720, 360, 180 mg/kg) was intragastrically administered for 6 or 16 weeks for SS mice and NOD mice, respectively. Average food and water intake, average body weight, saliva flow, submandibular gland (SMG) and spleen index, and SMG pathology were measured. ELISA was used to evaluate serum inflammatory cytokines in SS mice and autoantigens in NOD mice. Real-time PCR, Western blot and Luminex liquid suspension chip assay were applied to analyze SMG inflammatory cytokines mRNA and protein expression of NOD mice.

Results: Compared with SS mice, TGP treatment improved SMG pathological damage. TGP (720 mg/kg) treatment increased saliva flow, and reduced organ indexes and serum IL-6 and IFN-γ concentration. TGP (360 mg/kg) treatment decreased serum IFN-γ concentration. TGP (180 mg/kg) treatment for 6 weeks decreased average body weight. Compared with NOD mice, TGP treatment increased saliva flow from 9 to 15 weeks, decreased body weight, and alleviated pathological damage of SMG after 2 and 16 weeks. After 2 weeks of administration, TGP treatment inhibited serum concentration of SSB/La, SSA/Ro and α-fodrin, decreased TNF-α, IL-1β and IFN-γ in SMG, and down-regulated protein expressions of BAFF and IL-17A and mRNA expressions of BAFF, TNF-α, IL-17A, CXCL9 and CXCL13 in SMG. After 8 weeks of administration, TGP treatment decreased the concentration of α-fodrin in serum, TNF-α and IL-6 in SMG, and down-regulated mRNA expressions of IL-17A, TNF-α, CXCL9, CXCL13 and BAFF and protein expressions of IL-17A and BAFF in SMG. After 16 weeks of administration, TGP treatment reduced serum SSA/Ro, SSB/La and α-fodrin concentration, and decreased BAFF protein expression and TNF-α, CXCL9, CXCL13, IL-17A, and BAFF mRNA expressions.

Conclusion: TGP has a certain therapeutic effect on SS mice and NOD mice through inhibiting inflammatory responses.
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http://dx.doi.org/10.1016/j.phymed.2020.153203DOI Listing
June 2020

The role of P2Y12 receptor inhibition in ischemic stroke on microglia, platelets and vascular smooth muscle cells.

J Thromb Thrombolysis 2020 Nov;50(4):874-885

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.

P2Y12 receptors on platelets have long been the main target of antiplatelet drugs. However, a growing number of studies have revealed that P2Y12 receptor activation on microglia and vascular smooth muscle cells (VSMCs) also aggravates ischemic stroke injury. The proliferation and migration of VSMCs in the vascular wall have important influence on the early lesion of atherosclerosis, which may lead to the origin of cerebral ischemic attack of atherosclerosis. Blockage of cellular P2Y12 receptors could inhibit microglial activation, block formation of platelet-leukocyte aggregates, reduce proinflammatory cytokine levels and suppress migration and proliferation of VSMCs, implying that apart from anti-thrombotic effect, P2Y12 inhibitors have additional neuroprotective, anti-inflammatory and anti-atherosclerotic therapeutic benefits against ischemic stroke. In this review, we will summarize recent advances in studies on P2Y12 receptors and emphatically introduce their significance in microglia, platelets and VSMCs after ischemic stroke, discussing how to exert the beneficial effects of P2Y12 inhibition.
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http://dx.doi.org/10.1007/s11239-020-02098-4DOI Listing
November 2020

Pharmacokinetics and pharmacodynamics analysis of XQ-1H and its combination therapy with clopidogrel on cerebral ischemic reperfusion injury in rats.

J Pharm Biomed Anal 2020 Feb 6;179:112975. Epub 2019 Nov 6.

State Key Laboratory of Natural Medicines, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Ischemic stroke is the main cause of disability and mortality worldwide. 10-O-(N N-dimethylaminoethyl)-ginkgolide B methane-sulfonate (XQ-1 H) is a novel drug based on the remedial approach for ischemic stroke. Clopidogrel, a widely used anti-platelet drug, is often co-prescribed in the clinic. In this study, we established an UPLC-MS/MS spectrometry method for the determination of XQ-1H and investigated the pharmacokinetic effect of clopidogrel on XQ-1H in rats subjected to middle cerebral artery occlusion (MCAO). Meanwhile, the anti-apoptotic and neuroprotective effects of XQ-1H and its combination with clopidogrel were also studied. The results revealed that XQ-1H and its combination with clopidogrel abridged brain infarct volume, cerebral edema and alleviated neurological dysfunction caused by cerebral ischemic reperfusion injury. Further study demonstrated that XQ-1H combined with clopidogrel lessened TUNEL positive cells, up-regulated bcl-2 expression notably and down-regulated bax expression as compared to both XQ-1H and clopidogrel individually. In addition, a rapid, sensitive UPLC-MS/MS method was developed to quantify the concentration of XQ-1H in MCAO/R rats. Our pharmacokinetic results showed that clopidogrel significantly increased the exposure of XQ-1H, increased the peak plasma concentration (C), area under the curve (AUC) and slowed elimination of XQ-1H in the co-administered group. Besides, for further exploring which CYP450 isoforms are involved in the XQ-1H metabolism, XQ-1H was incubated in human liver microsomes (HLMs) system with or without P450 isoform-selective inhibitors. Our results revealed that clopidogrel altered pharmacokinetics of XQ-1H potentially and subsequently enhanced the pharmacological effect of XQ-1H. Moreover, XQ-1H could be applied as an efficacious neuroprotective agent for ischemic stroke because of its considerable effect on averting neuronal apoptosis.
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http://dx.doi.org/10.1016/j.jpba.2019.112975DOI Listing
February 2020

Ginkgo diterpene lactones inhibit cerebral ischemia/reperfusion induced inflammatory response in astrocytes via TLR4/NF-κB pathway in rats.

J Ethnopharmacol 2020 Mar 31;249:112365. Epub 2019 Oct 31.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

Ethnopharmacological Relevance: Ginkgo biloba L. (Ginkgoaceae) is a traditional Chinese medicine known to treating stroke and other cardio-cerebrovascular diseases for thousands of years in China. Ginkgo diterpene lactones (GDL) attracted much attention because of their neuroprotective properties.

Aim Of The Study: To uncover the effects of GDL, which consist of ginkgolide A (GA), ginkgolide B (GB), and ginkgolide K (GK), on ischemic stroke, as well as the underlying molecular mechanisms.

Materials And Methods: We used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models mimicking the process of ischemia/reperfusion in vivo and in vitro, respectively. Anticoagulant effects of GDL were investigated on platelet activating factor (PAF), arachidonic acid (AA) and adenosine diphosphate (ADP)-induced platelet aggregation both in vivo and in vitro. We also evaluated the effects of GDL on lipopolysaccharide (LPS)-induced inflammatory response in primary cultured rats' astrocytes. Infarct size, neurological deficit score, and brain edema were measured at 72 h after MCAO. Immunohistochemistry was utilized to analyze neurons necrosis and astrocytes activation. Expression of pro-inflammatory cytokines, including tumor necrotic factor-α (TNF-α) and interleukin-1β (IL-1β) were detected using enzyme-linked immunosorbent assay (ELISA) and real time PCR. The levels of toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB) were assessed by real time PCR or Western blot.

Results: Compared with MCAO/R rats, GDL significantly reduced infarct size and brain edema, improved neurological deficit score. Meanwhile, GDL suppressed platelet aggregation, astrocytes activation, pro-inflammatory cytokines releasing, TLR4 mRNA expression and transfer of NF-κB from cytoplasm to nucleus. Furthermore, GDL alleviated OGD/R injury and LPS-induced inflammatory response in primary astrocytes, characterized by promoting cell viability, decreasing lactate dehydrogenase (LDH) activity, and inhibiting IL-1β and TNF-α releasing.

Conclusions: In summary, GDL attenuate cerebral ischemic injury, inhibit platelet aggregation and astrocytes activation. The anti-inflammatory activity might be associated with the downregulation of TLR4/NF-κB signal pathway. Our present findings provide an innovative insight into the novel treatment of GDL in ischemic stroke therapy.
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http://dx.doi.org/10.1016/j.jep.2019.112365DOI Listing
March 2020

Levo-corydalmine Attenuates Vincristine-Induced Neuropathic Pain in Mice by Upregulating the Nrf2/HO-1/CO Pathway to Inhibit Connexin 43 Expression.

Neurotherapeutics 2020 01;17(1):340-355

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Mailbox 207, Tongjiaxiang 24, Nanjing, 210009, Jiangsu, People's Republic of China.

Antimicrotubulin chemotherapeutic agents, including plant-derived vincaalkaloids such as vincristine, can cause peripheral neuropathic pain. Exogenously activated heme oxygenase 1 (HO-1) is a potential therapy for chemotherapy-induced neuroinflammation. In this study, we investigated a role for Nrf2/HO-1/CO in mediating vincristine-induced neuroinflammation by inhibiting connexin 43 (Cx43) production in the spinal cord following the intrathecal application of the HO-1 inducer protoporphyrin IX cobalt chloride (CoPP) or inhibitor protoporphyrin IX zinc (ZnPP), and we analyzed the underlying mechanisms by which levo-corydalmine (l-CDL, a tetrahydroprotoberberine) attenuates vincristine-induced pain. Treatment with levo-corydalmine or oxycodone hydrochloride (a semisynthetic opioid analgesic, used as a positive control) attenuated vincristine-induced persistent pain hypersensitivity and degeneration of the sciatic nerve. In addition, the increased prevalence of atypical mitochondria induced by vincristine was ameliorated by l-CDL in both A-fibers and C-fibers. Next, we evaluated whether nuclear factor E2-related factor 2 (Nrf2), an upstream activator of HO-1, directly bound to the HO-1 promoter sequence and degraded heme to produce carbon monoxide (CO) following stimulation with vincristine. Notably, l-CDL dose-dependently increased HO-1/CO expression by activating Nrf2 to inhibit Cx43 expression in both the spinal cord and in cultured astrocytes stimulated with TNF-α, corresponding to decreased Cx43-mediated hemichannel. Furthermore, l-CDL had no effect on Cx43 following the silencing of the HO-1 gene. Taken together, our findings reveal a novel mechanism by which Nrf2/HO-1/CO mediates Cx43 expression in vincristine-induced neuropathic pain. In addition, the present findings suggest that l-CDL likely protects against nerve damage and attenuates vincristine-induced neuroinflammation by upregulating Nrf2/HO-1/CO to inhibit Cx43 expression.
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http://dx.doi.org/10.1007/s13311-019-00784-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007458PMC
January 2020

XQ-1H alleviates cerebral ischemia in mice through inhibition of apoptosis and promotion of neurogenesis in a Wnt/β-catenin signaling dependent way.

Life Sci 2019 Oct 6;235:116844. Epub 2019 Sep 6.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Aims: 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a new derivative of ginkgolide B, has drawn great attention for its potent bioactivities against ischemia-induced injury. The purpose of this study was to further investigate the effect of XQ-1H against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO/R) injuries in mice.

Main Methods: Treatment of XQ-1H (78 or 39 mg/kg, i.g., bid) 2 h after MCAO improved motor skills and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes and the activation of a pro-apoptotic protein Cleaved-Caspase-3, which in turn induced anti-apoptotic Bcl-xL. Through introducing Wnt/β-catenin signaling inhibitor XAV-939, XQ-1H was proven to intensively promoted neurogenesis in the peri-infarct cortex, subventricular area (SVZ) and the dentate gyrus (DG) subgranular area (SGZ) in a Wnt signal dependent way by compromising the activation of GSK3β, which in turn upregulated Wnt1, β-catenin, Neuro D1 and Cyclin D1, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).

Key Findings: We conclude that XQ-1H preserved the motor functions, limited apoptosis, and concomitantly promoted neurogenesis-related protein expression by Wnt signaling-dependently compromising GSK3β/Caspase-3 activity and enhancing the expression of Wnt1/β-catenin/Neuro D1/Cyclin D1 and Bcl-xL.

Significance: This research may benefit the development of stroke therapeutics targeting neurogenesis through Wnt upregulation by XQ-1H.
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http://dx.doi.org/10.1016/j.lfs.2019.116844DOI Listing
October 2019

The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy.

Curr Drug Targets 2020 ;21(3):288-301

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, China.

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system.

Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour.

Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.
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http://dx.doi.org/10.2174/1389450120666190906153652DOI Listing
February 2021

Protective effects of Clematichinenoside AR against inflammation and cytotoxicity induced by human tumor necrosis factor-α.

Int Immunopharmacol 2019 Oct 10;75:105563. Epub 2019 Aug 10.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, # 24 TongJiaXiang, Nanjing 210009, PR China. Electronic address:

Clematichinenoside AR (AR), a major active ingredient extracted from traditional Chinese herb Clematis chinensis Osbeck, has been demonstrated to possess anti-inflammatory and immune-modulatory activities in the treatment of experimental rheumatoid arthritis (RA). The therapeutic potential of AR was supposed to be closely correlated to its ability against tumor necrosis factor-α (TNF-α). Therefore, we aimed to explore the protective effects of Clematichinenoside AR against inflammation and cytotoxicity induced by human TNF-α. AR treatment significantly decreased IL-6 and IL-8 secretion, and attenuated MMP-1 production in human RA-derived fibroblast-like synoviocyte MH7A cells stimulated by recombinant human TNF-α (rhTNF-α). AR might antagonize rhTNF-α-induced responses in MH7A cells through inhibiting p38 and ERK MAPKs signal activation. In TNF-α-sensitive murine fibroblast L929 cells, AR treatment attenuated the proliferation inhibition ratio induced by rhTNF-α/ActD and antagonized rhTNF-α-induced cytotoxicity. The cellular and nuclear morphological alterations in apoptotic characteristics induced by rhTNF-α/ActD in L929 cells were observed to be attenuated by the pretreatment with AR under a phase-contrast and fluorescence microscopy, respectively. The Annexin V-FITC/PI double-staining assay was performed to confirm that AR pretreatment obviously decreased the cell death. The antagonistic effects of AR against rhTNF-α-induced cytotoxicity might be potentially attributed to the degeneration of reactive oxygen species and the increasing of mitochondrial membrane potential, along with the suppression of durative phosphorylation of c-Jun N-terminal kinase (JNK). Collectively, our results indicated that AR antagonizes the inflammatory and cytotoxic activities induced by human TNF-α effectively in vitro, which provided further evidence for a novel mechanism underlying AR for treating RA correlating with excessive TNF-α production.
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http://dx.doi.org/10.1016/j.intimp.2019.04.010DOI Listing
October 2019

Clematichinenoside Facilitates Recovery of Neurological and Motor Function in Rats after Cerebral Ischemic Injury through Inhibiting Notch/NF-κB Pathway.

J Stroke Cerebrovasc Dis 2019 Nov 6;28(11):104288. Epub 2019 Aug 6.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China. Electronic address:

Purpose: The present study was to observe the therapeutic efficiency of Clematichinenoside (AR) on cerebral ischemic injury in rats, especially on neurological and motor function recovery and to explore the underlying mechanism.

Methods: Following middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, rats were treated orally with 32, 16, and 8 mg/kg AR respectively for 14 days during which cerebral injury was evaluated and proinflammatory factors tumor necrosis factor-α and interleukin-6 as well as neurotrophic factors brain-derived neurotrophic factor and Neurotrophin-3 levels were determined with ELISA kits. Immunohistochemical analysis on number of neurons and reactive astrocytes in the hippocampus was to demonstrate the effect of AR on neuronal survival. Motor, learning, and memory recovery were assessed by Morris water maze, passive avoidance experiment, and rotatory rod test. Neuroprotection and anti-inflammation-related Notch and nuclear factor-κB (NF-κB) signaling pathways were analyzed by PCR and Western blot techniques on mammalian achaete-scute homologs1, Notch-1, intracellular Notch receptor domain, Jagged-1, transcription factor hairy, enhancer of split1 (Hes1), as well as the nuclear import of NF-κB in hippocampus.

Results: AR administration reduced cerebral injury in rats exposed to MCAO/R and after treatment of AR for 14 days, proinflammatory reaction was inhibited, with neuronal survival rate raised and motor function recovery facilitated. PCR and WB analysis of Notch/NF-κB signaling pathway revealed the inhibitory effect of AR on pathway related components.

Conclusions: AR is beneficial to recovery of neurological and motor function in rats after cerebral ischemic injury via inhibiting Notch/NF-κB pathway.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.07.004DOI Listing
November 2019

Total glucosides of paeony attenuates animal psoriasis induced inflammatory response through inhibiting STAT1 and STAT3 phosphorylation.

J Ethnopharmacol 2019 Oct 26;243:112121. Epub 2019 Jul 26.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address:

Ethnopharmacological Relevance: Psoriasis is an immune system meditated disease, especially T cells. It disturbed many people around the world and hard to therapy. Paeonia lactiflora Pall has been used as a medicine in china for thousands of years. Recent studies found that the main component of Paeonia lactiflora Pall can alleviates the immune response in many diseases. In this study, we researched the effects and possible mechanisms of total glucosides of paeony (TGP) on animal psoriasis.

Aim Of The Study: To study the therapeutic effects and mechanisms of TGP in 5% propranolol cream-induced psoriasis in guinea pigs and Imiquimod (IMQ) cream-induced psoriasis in mice.

Materials And Methods: The effect of TGP was evaluated using a psoriasis-like model of guinea pigs and mice. Ear thickness was accessed, and pathology injury was observed by H&E staining. The levels of serum IL-1β, IL-6, IL-12, IL-17, IL-23, TNF-α, and IFN-γ, skin IL-17A, IL-22 and orphan nuclear receptor (RORγt) mRNA expression, proliferating cell nuclear antigen (PCNA), total or phosphorylated signal transducers and activators of transcription (STAT1, STAT3) were determined by enzyme linked immunosorbent assays (ELISAs), real time PCR, immunohistochemical staining, and western blotting, respectively.

Results: Compared with model group, TGP treatment decreased the ear thickness, improved pathology of psoriasis, alleviated IMQ-induced keratinocyte proliferation, reduced the inflammatory cytokine, and downregulated IL-17A, IL-22, and RORγt mRNA in mice. Further study indicated that TGP inhibited STAT1 and STAT3 phosphorylation in lesion skins of psoriasis-like mice.

Conclusions: TGP alleviates the symptoms of psoriasis-like guinea pigs and mice, and the possible mechanism may relate to inhibit T helper 17 (TH17) cell differentiation and keratinocytes proliferation by inhibiting STAT1 and STAT3 phosphorylation.
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http://dx.doi.org/10.1016/j.jep.2019.112121DOI Listing
October 2019

JLX001 Modulated the Inflammatory Reaction and Oxidative Stress in pMCAO Rats via Inhibiting the TLR2/4-NF-κB Signaling Pathway.

Neurochem Res 2019 Aug 15;44(8):1924-1938. Epub 2019 Jun 15.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24, Tongjia Alley, Gulou District, Nanjing, 210009, Jiangsu, China.

Inflammatory reactions and oxidative stress play critical roles in cerebral ischemic injuries. Microglia are activated after ischemic injury. Activated microglia produce neurotoxic proinflammatory factors and reactive oxygen species (ROS), which have been demonstrated closely related TLR2/4-NF-κB signal pathways. This study was to evaluate the effect of JLX001 against ischemic injury and investigate the mechanisms. The permanent middle cerebral artery occlusion (pMCAO) model was employed in rats. The neurobehavioral score, brain infarction rate, brain water content, pathological changes, immunohistochemical staining, biochemical index (T-AOC, SOD, and MDA), proinflammatory factors (IL-1β, TNF-α, and NO), expression of TLR2/4 and nuclear translocation of NF-κB p65 were determined. To explore probable underlying mechanism of the neuroprotective effect of JLX001, BV-2 cells were exposed to in oxygen-glucose deprivation (OGD) for 4 h to mimic ischemic injury in vitro. The result showed that JLX001 significantly decreased neurological deficit score, infarct size, and brain edema, attenuated pathological changes, inhibited the activation of microglia, improved the process of oxidative stress, reduced the release of proinflammatory cytokines and downregulated TLR2/4-NF-κB signal pathway. Moreover, OGD reduced BV2 cell viability, induced oxidative damage, increased the release of proinflammatory factors and activated TLR2/4-NF-κB signal pathway, which was significantly reversed by the intervention of JLX001. This study demonstrates that JLX001 is effective in protecting the brain from ischemic injury, which may be mediated by regulating oxidative stress, inflammation and inhibiting TLR2/4-NFκB signal pathway.
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http://dx.doi.org/10.1007/s11064-019-02826-0DOI Listing
August 2019

The Function of RAS Mutation in Cancer and Advances in its Drug Research.

Curr Pharm Des 2019 ;25(10):1105-1114

State Key Laboratory of Natural Medicines, Department of Physiology, China Phar maceutical University, Nanjing 210009, China.

RAS (H-ras, K-ras, and N-ras), as the second largest mutated gene driver in various human cancers, has long been a vital research target for cancer. Its function is to transform the extracellular environment into a cascade of intracellular signal transduction. RAS mutant protein regulates tumor cell proliferation, apoptosis, metabolism and angiogenesis through downstream MAPK, PI3K and other signaling pathways. In KRAS or other RAS-driven cancers, current treatments include direct inhibitors and upstream/downstream signaling pathway inhibitors. However, the research on these inhibitors has been largely restricted due to their escape inhibition and off-target toxicity. In this paper, we started with the role of normal and mutant RAS genes in cancer, elucidated the relevant RAS regulating pathways, and highlighted the important research advancements in RAS inhibitor research. We concluded that for the crosstalk between RAS pathways, the effect of single regulation may be limited, and the multi-target drug combined compensation mechanism is becoming a research hotspot.
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http://dx.doi.org/10.2174/1381612825666190506122228DOI Listing
February 2020

Berberine Facilitates Angiogenesis Against Ischemic Stroke Through Modulating Microglial Polarization via AMPK Signaling.

Cell Mol Neurobiol 2019 Aug 24;39(6):751-768. Epub 2019 Apr 24.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.

Evidence suggests that microglia/macrophages can change their phenotype to M1 or M2 and participate in tissue damage or repair. Berberine (BBR) has shown promise in experimental stroke models, but its effects on microglial polarization and long-term recovery after stroke are elusive. Here, we investigated the effects of BBR on angiogenesis and microglial polarization through AMPK signaling after stroke. In the present study, C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO), intragastrically administrated with BBR at 50 mg/kg/day. Neo-angiogenesis was observed by Ga-NODAGA-RGD micro-PET/CT and immunohistochemistry. Immunofluorescent staining further exhibited an increase of M2 microglia and a reduction of M1 microglia at 14 days after stroke. In vitro studies, the lipopolysaccharide (LPS)-induced BV2 microglial cells were used to confirm the AMPK activation effect of BBR. RT-PCR, Flow cytometry, and ELISA all demonstrated that BBR could inhibit M1 polarization and promote M2 polarization. Furthermore, treatment of human umbilical vein endothelial cells (HUVEC) with conditioned media collected from BBR-treated BV2 cells promoted angiogenesis. All effects stated above were reversed by AMPK inhibitor (Compound C) and AMPK siRNA. In conclusion, BBR treatment improves functional recovery and promotes angiogenesis following tMCAO via AMPK-dependent microglial M2 polarization.
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http://dx.doi.org/10.1007/s10571-019-00675-7DOI Listing
August 2019

The progress of neuronal autophagy in cerebral ischemia stroke: Mechanisms, roles and research methods.

J Neurol Sci 2019 May 16;400:72-82. Epub 2019 Mar 16.

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

There is increasing evidence indicating that autophagy may be a new target in the treatment of ischemic stroke. Moderate autophagy can clear damaged organelles, thereby protecting cells against various injuries. However, long-term excessive autophagy brings redundant degradation of cell contents, leading to cell death and eventually serious damage to tissues and organs. A number of different animal models of ischemic brain injury shows that autophagy is activated and involved in the regulation of neuronal death during ischemic brain injury. This article summarizes the role of autophagy, its underlying regulators and mechanisms in ischemic neuronal injury. We briefly introduce the relationship between apoptosis and autophagy and give a summary of research methods and modulators of autophagy.
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http://dx.doi.org/10.1016/j.jns.2019.03.015DOI Listing
May 2019

Significance and Mechanisms of P-glycoprotein in Central Nervous System Diseases.

Curr Drug Targets 2019 ;20(11):1141-1155

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

P-glycoprotein (P-gp) is a member of ATP-Binding Cassette (ABC) transporter family. Because of its characteristic luminal surface location, high transport potency and structural specificity, Pgp is regarded as a selective gatekeeper of the Blood Brain Barrier (BBB) to prevent the entry of toxins or unwanted substances into the brain. In recent years, increasing evidence has shown that P-gp is involved in the immune inflammatory response in the Central Nervous System (CNS) disorders by regulating microglia activation, and mediating immune cell migration. Furthermore, Glucocorticoid Receptor (GR) may play a crucial role in P-gp-mediated microglia activation and immune cell migration via GR-mediated mRNA decay. In this article, we will review P-gp structure, distribution, function, regulatory mechanisms, inhibitors and effects of P-gp in the pathogenesis of several CNS diseases and will discuss the role of P-gp in microglia activation, immune cell migration and the relationship with cytokine secretion.
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http://dx.doi.org/10.2174/1389450120666190308144448DOI Listing
August 2020

Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia.

Neurochem Int 2019 05 19;125:99-110. Epub 2019 Feb 19.

State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China. Electronic address:

CCR2 could recruit immune cells migrating into brain after ischemic stroke. It is unclear whether and why Propagermanium (PG, a CCR2 inhibitor) is able to protect against ischemic injury. Middle cerebral artery occlusion (MCAO) and reperfusion injury in C57BL/6 J male mice were performed in vivo to mimic ischemic stroke. Cultured BV2 microglia exposed to oxygen and glucose deprivation (OGD)/reoxygenation injury, LPS or IL-4 incubation were served in vitro. TTC staining, neurological score, brain water content, and MRI scan were performed to evaluate stroke outcome. Real time PCR, ELISA, and immunofluorescence were used to estimate inflammatory cytokines expression and releasing. Western blot was utilized to detect pSTAT1/STAT1 expression. Compared with MCAO mice, PG treatment significantly reduced infarction size and brain edema, improved neurological behavior at 72 h after MCAO. For inflammatory response, PG treatment inhibited inflammatory cytokines releasing, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and IL-23. Further studies indicated that PG treatment downregulated mRNA expression of pro-inflammatory iNOS and CD86, and inhibited CD16 expressed in microglia. In vitro, PG incubation inhibited BV2 polarized to pro-inflammatory phenotype through STAT1 downregulation, while had no obvious effect on anti-inflammatory phenotype. Our observations suggest that CCR2 inhibitor PG downregulated pro-inflammatory microglia polarization for decreasing pro-inflammatory microglia phenotype marker, and thereafter inhibited inflammatory responses after MCAO in a STAT1-dependent manner.
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http://dx.doi.org/10.1016/j.neuint.2019.02.010DOI Listing
May 2019
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