Hansen Chen

All Publications

• Comprehensive immune modulation mechanisms of Angong Niuhuang Wan in ischemic stroke: Insights from mass cytometry analysis. CNS neuroscience & therapeutics Yao, Y., Ni, W., Feng, L., Meng, J., Tan, X., Chen, H., Shen, J., Zhao, H. 2024; 30 (7): e14849

  Abstract

  BACKGROUND: Angong Niuhuang Wan (AGNHW, ), is a classical medicinal formula in Traditional Chinese Medicine (TCM) that has been appreciated for its neuroprotective properties in ischemic cerebral injuries, yet its intricate mechanisms remain only partially elucidated.AIMS: This study leverages advanced Mass cytometry (CyTOF) to analyze AGNHW's multifaceted immunomodulation effects in-depth, emphasizing previously underexplored areas.RESULTS: AGNHW mitigated monocyte-derived macrophages (MoDM) infiltration in the brain, distinguishing its effects on those from microglia. While the vehicle group exhibited elevated inflammatory markers like CD4, CD8a, and CD44 in ischemic brains, the AGNHW-treated group attenuated their expressions, indicating AGNHW's potential to temper the post-ischemic inflammatory response. Systemically, AGNHW modulated fundamental immune cell dynamics, notably augmenting CD8+ T cells, B cells, monocytes, and neutrophil counts in the peripheral blood under post-stroke conditions. Intracellularly, AGNHW exhibited its targeted modulation of the signaling pathways, revealing a remarked inhibition of key markers like IkappaBalpha, indicating potential suppression of inflammatory responses in ischemic brain injuries.CONCLUSION: This study offers a comprehensive portrait of AGNHW's immunomodulation effects on ischemic stroke, illuminating its dual sites of action-both cerebral and systemic-and its nuanced modulation of cellular and molecular dynamics.

  View details for DOI 10.1111/cns.14849

  View details for PubMedID 39075660

• Hypochlorous acid derived from microglial myeloperoxidase could mediate high-mobility group box 1 release from neurons to amplify brain damage in cerebral ischemia-reperfusion injury JOURNAL OF NEUROINFLAMMATION Chen, S., Pan, J., Gong, Z., Wu, M., Zhang, X., Chen, H., Yang, D., Qi, S., Peng, Y., Shen, J. 2024; 21 (1): 70

  Abstract

  Myeloperoxidase (MPO) plays critical role in the pathology of cerebral ischemia-reperfusion (I/R) injury via producing hypochlorous acid (HOCl) and inducing oxidative modification of proteins. High-mobility group box 1 (HMGB1) oxidation, particularly disulfide HMGB1 formation, facilitates the secretion and release of HMGB1 and activates neuroinflammation, aggravating cerebral I/R injury. However, the cellular sources of MPO/HOCl in ischemic brain injury are unclear yet. Whether HOCl could promote HMGB1 secretion and release remains unknown. In the present study, we investigated the roles of microglia-derived MPO/HOCl in mediating HMGB1 translocation and secretion, and aggravating the brain damage and blood-brain barrier (BBB) disruption in cerebral I/R injury. In vitro, under the co-culture conditions with microglia BV cells but not the single culture conditions, oxygen-glucose deprivation/reoxygenation (OGD/R) significantly increased MPO/HOCl expression in PC12 cells. After the cells were exposed to OGD/R, MPO-containing exosomes derived from BV2 cells were released and transferred to PC12 cells, increasing MPO/HOCl in the PC12 cells. The HOCl promoted disulfide HMGB1 translocation and secretion and aggravated OGD/R-induced apoptosis. In vivo, SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus different periods of reperfusion. Increased MPO/HOCl production was observed at the reperfusion stage, accomplished with enlarged infarct volume, aggravated BBB disruption and neurological dysfunctions. Treatment of MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH) and HOCl scavenger taurine reversed those changes. HOCl was colocalized with cytoplasm transferred HMGB1, which was blocked by taurine in rat I/R-injured brain. We finally performed a clinical investigation and found that plasma HOCl concentration was positively correlated with infarct volume and neurological deficit scores in ischemic stroke patients. Taken together, we conclude that ischemia/hypoxia could activate microglia to release MPO-containing exosomes that transfer MPO to adjacent cells for HOCl production; Subsequently, the production of HOCl could mediate the translocation and secretion of disulfide HMGB1 that aggravates cerebral I/R injury. Furthermore, plasma HOCl level could be a novel biomarker for indexing brain damage in ischemic stroke patients.

  View details for DOI 10.1186/s12974-023-02991-8

  View details for Web of Science ID 001188911800001

  View details for PubMedID 38515139

  View details for PubMedCentralID PMC10958922

• Natural Products for the Potential Use of Neuroprotective and Neurorestorative Effects in Stroke. Pharmaceuticals (Basel, Switzerland) Chen, H., Liu, Q. 2023; 16 (11)

  Abstract

  Stroke is the second leading cause of death and the third leading cause of disability worldwide, with limited treatment options [...].

  View details for DOI 10.3390/ph16111516

  View details for PubMedID 38004382

• Editorial: Natural products in the treatment of neurological diseases: identification of novel active compounds and therapeutic targets. Frontiers in pharmacology Zhao, J., Wang, D., Cui, W., Chen, H. 2023; 14: 1294625

  View details for DOI 10.3389/fphar.2023.1294625

  View details for PubMedID 37808185

  View details for PubMedCentralID PMC10556858

• Editorial: Advances in integrative medicine for neurodegenerative diseases: from basic research to clinical practice. Frontiers in neurology Liu, S., Zheng, G., Chen, H., Li, G., Guo, X. 2023; 14: 1197641

  View details for DOI 10.3389/fneur.2023.1197641

  View details for PubMedID 37260607

  View details for PubMedCentralID PMC10227565

• Rapid Complement Activation Induced By Acute Hyperglycemia Worsens Ischemic Stroke Outcome Chen, H., Chiang, T., Kim, A., Tomlinson, S., Bliss, T., Cheng, M. Y., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for DOI 10.1161/str.54.suppl_1.WP225

  View details for Web of Science ID 000992453800802

• Angong Niuhuang Wan reduces hemorrhagic transformation and mortality in ischemic stroke rats with delayed thrombolysis: involvement of peroxynitrite-mediated MMP-9 activation. Chinese medicine Chen, H., Luo, Y., Tsoi, B., Gu, B., Qi, S., Shen, J. 2022; 17 (1): 51

  Abstract

  BACKGROUND: Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood-brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation.METHODS: We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague-Dawley rats were subjected to 5h of middle cerebral artery occlusion (MCAO) followed by 19h of reperfusion plus t-PA infusion (10mg/kg) at 5h of cerebral ischemia. AGNHW (257mg/kg) was given orally at 2h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood-brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5h of oxygen and glucose deprivation (OGD) plus 5h of reoxygenation with t-PA treatment (20g/ml).RESULTS: AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains.CONCLUSION: AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation.

  View details for DOI 10.1186/s13020-022-00595-7

  View details for PubMedID 35477576

• Optogenetic Stimulation Effects On Cortico-thalamic Circuit Plasticity After Stroke Chiang, T., Vahdat, S., Pendharkar, A., Harvey, S., Uchino, H., Cao, Z., Kim, A., Choy, M., Chen, H., Lee, H., Cheng, M. Y., Lee, J., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1161/str.53.suppl_1.TMP117

  View details for Web of Science ID 000788100600285

• Editorial: Blood-Brain Barrier Dysregulation and Recovery Following Brain Ischemia: Cellular Constituents, Molecular Mechanisms, and Therapeutic Strategies Enabling Successful Brain Remodeling. Frontiers in cellular neuroscience Chen, H., Cao, Z., Gu, Y., Hermann, D. M. 2022; 16: 968425

  View details for DOI 10.3389/fncel.2022.968425

  View details for PubMedID 35875354

• Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free radical biology & medicine Wen, Y., Chen, H., Zhang, L., Wu, M., Zhang, F., Yang, D., Shen, J., Chen, J. 2021

  Abstract

  Reactive oxygen species (ROS)/reactive nitrogen species (RNS)-mediated ferroptosis becomes a novel effective target for anti-cancer treatment. In the present study, we tested the hypothesis that 18-beta-glycyrrhetinic acid (GA), an active compound from medicinal herbal Licorice, could induce the production of ROS/RNS, increase lipid peroxidation and trigger ferroptosis in MDA-MB-231 triple negative breast cancer cells. To confirm the GA's anti-cancer effects, we detected cell viability, apoptosis and ferroptosis in the MDA-MB-231 cells. To explore the effects of GA on inducing ferroptosis, we measured ROS/RNS production, lipid peroxidation, ferrous ion, glutathione (GSH), System Xc-, GPX4, glutathione peroxidases (GPX), NADPH oxidase and iNOS in the MDA-MB-231 cells. The major discoveries are included as below: (1) GA treatment selectively decreased cell viability and induced ferroptosis companied with the increased lipid peroxidation and ferrous ion in the MDA-MB-231 triple negative breast cancer cells. Iron chelator deferoxamine mesylate (DFO) and ferroptosis inhibitor Ferrostatin-1 abolished the effects of GA. (2) GA treatment up-regulated the expression and activity of NADPH oxidase and iNOS, and increased ROS/RNS productions (O2-, OH, NO and ONOO-) in the MDA-MB-231 cells; (3) GA down-regulated the expression of SLC7A11 of System Xc-, decreased glutathione (GSH) level and inhibited GPX activity. Taken together, GA could promote the productions of ROS and RNS via activating NADPH oxidases and iNOS, and decreasing GSH and GPX activity, subsequently aggravating lipid peroxidation and triggering ferroptosis in triple-negative breast cancer cells.

  View details for DOI 10.1016/j.freeradbiomed.2021.07.019

  View details for PubMedID 34271106

• Ischemic Postconditioning Protects Against Hemorrhagic Transformation Induced by Hyperglycemia in Ischemic Stroke Chen Hansen, Cheng, M. Y., Bliss, T., Zhao Heng, Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P781

  View details for Web of Science ID 000670883500890

• Promotion of Momordica Charantia polysaccharides on neural stem cell proliferation by increasing SIRT1 activity after cerebral ischemia/reperfusion in rats. Brain research bulletin Ma, J., Fan, H., Cai, H., Hu, Z., Zhou, X., Li, F., Chen, H., Shen, J., Qi, S. 2021

  Abstract

  The deacetylase SIRT1 has been reported to play a critical role in regulating neurogenesis, which may be an adaptive processes contributing to recovery after stroke. Our previous work showed that the antioxidant capacity of Momordica charantia polysaccharides (MCPs) could protect against cerebral ischemia/reperfusion (I/R) after stroke. However, whether the protective effect of MCPs on I/R injury is related to NSCs proliferation remains unclear. In the present study, we designed in vivo and in vitro experiments to elucidate the underlying mechanisms by which MCPs promote endogenous NSCs proliferation during cerebral I/R. In vivo results showed that MCPs rescued the memory and learning abilities of rats after I/R damage and enhanced NSCs proliferation in the rat subventricular zone (SVZ) and subgrannular zone (SGZ) during I/R. In vitro experiments demonstrated that MCPs could stimulate the proliferation of C17.2 cells under oxygen-glucose deprivation (OGD) conditions. Further studies revealed that the proliferation-promoting mechanism of MCPs relied on increasing the activity of SIRT1, decreasing the level of deacetylation of beta-catenin in the cytoplasm, and then triggering the translocation of beta-catenin into the nucleus. These data provide experimental evidence that the up-regulation of SIRT1 activity by MCP led to an increased cytoplasmic deacetylation of beta-catenin, which promoted translocation of beta-catenin to the nucleus to participate in the signaling pathway involved in NSCs proliferation. The present study reveals that MCPs function as a therapeutic drug to promote stroke recovery by increasing the activity of SIRT1, decreasing the level of acetylated beta-catenin, promoting the nuclear translocation of beta-catenin and thereby increasing endogenous NSC proliferation.

  View details for DOI 10.1016/j.brainresbull.2021.02.016

  View details for PubMedID 33647420

• Peroxynitrite activates NLRP3 inflammasome and contributes to hemorrhagic transformation and poor outcome in ischemic stroke with hyperglycemia. Free radical biology & medicine Chen, H., Guan, B., Chen, S., Yang, D., Shen, J. 2021; 165: 171-183

  Abstract

  This study aims to test the hypothesis that peroxynitrite-mediated inflammasome activation could be a crucial player in the blood-brain barrier (BBB) disruption, hemorrhagic transformation (HT) and poor outcome in ischemic stroke with hyperglycemia. We used an experimental rat stroke model subjected to 90 min of middle cerebral artery occlusion plus 24 h or 7 days of reperfusion with or without acute hyperglycemia. We detected the production of peroxynitrite, the expression of NADPH oxidase, iNOS, MMPs and NLRP3 inflammasome in the ischemic brains, and evaluated infarct volume, brain edema, HT, neurological deficit score and survival rates. Our results show that: (1) Hyperglycemia increased the expression of NADPH oxidase subunits p47phox and p67phox, and iNOS, and the production of peroxynitrite. (2) Hyperglycemia increased infarct volume, aggravated the BBB hyperpermeability, induced brain edema and HT, and worsened neurological outcomes. These brain damages and poor outcome were reversed by the treatments of FeTmPyP (a representative peroxynitrite decomposition catalyst, PDC), peroxynitrite scavenger uric acid, and iNOS inhibitor 1400W. Furthermore, the activations of MMPs and NLRP3 inflammasome including pro/active-caspase-1 and IL-1β were inhibited both PDC and 1400W, indicating the roles of peroxynitrite in the inductions of MMPs and NLRP3 inflammasome in the ischemic brains under hyperglycemia. (3) NLRP3 inflammasome inhibitor MCC950, caspase-1 inhibitor VX-765 and IL-1β inhibitor diacerein attenuated brain edema, minimized hemorrhagic transformation and improved neurological outcome, demonstrating the roles of NLRP3 inflammasome in the hyperglycemia-mediated HT and poor outcome in the ischemic stroke rats with acute hyperglycemia. In conclusion, peroxynitrite could mediate activations of MMPs and NLRP3 inflammasome, aggravate the BBB damage and HT, and induce poor outcome in ischemic stroke with hyperglycemia. Therefore, targeting peroxynitrite-mediated NLRP3 inflammasome could be a promising strategy for ischemic stroke with hyperglycemia.

  View details for DOI 10.1016/j.freeradbiomed.2021.01.030

  View details for PubMedID 33515754

• Brain-wide neural dynamics of poststroke recovery induced by optogenetic stimulation. Science advances Vahdat, S., Pendharkar, A. V., Chiang, T., Harvey, S., Uchino, H., Cao, Z., Kim, A., Choy, M., Chen, H., Lee, H. J., Cheng, M. Y., Lee, J. H., Steinberg, G. K. 2021; 7 (33)

  Abstract

  Poststroke optogenetic stimulations can promote functional recovery. However, the circuit mechanisms underlying recovery remain unclear. Elucidating key neural circuits involved in recovery will be invaluable for translating neuromodulation strategies after stroke. Here, we used optogenetic functional magnetic resonance imaging to map brain-wide neural circuit dynamics after stroke in mice treated with and without optogenetic excitatory neuronal stimulations in the ipsilesional primary motor cortex (iM1). We identified key sensorimotor circuits affected by stroke. iM1 stimulation treatment restored activation of the ipsilesional corticothalamic and corticocortical circuits, and the extent of activation was correlated with functional recovery. Furthermore, stimulated mice exhibited higher expression of axonal growth-associated protein 43 in the ipsilesional thalamus and showed increased Synaptophysin+/channelrhodopsin+ presynaptic axonal terminals in the corticothalamic circuit. Selective stimulation of the corticothalamic circuit was sufficient to improve functional recovery. Together, these findings suggest early involvement of corticothalamic circuit as an important mediator of poststroke recovery.

  View details for DOI 10.1126/sciadv.abd9465

  View details for PubMedID 34380610

• Rehmapicroside ameliorates cerebral ischemia-reperfusion injury via attenuating peroxynitrite-mediated mitophagy activation. Free radical biology & medicine Zhang, Y., He, Y., Wu, M., Chen, H., Zhang, L., Yang, D., Wang, Q., Shen, J. 2020; 160: 526-539

  Abstract

  Peroxynitrite (ONOO-)-mediated mitophagy activation represents a vital pathogenic mechanism in ischemic stroke. Our previous study suggests that ONOO- mediates Drp1 recruitment to the damaged mitochondria for excessive mitophagy, aggravating cerebral ischemia/reperfusion injury and the ONOO--mediated mitophagy activation could be a crucial therapeutic target for improving outcome of ischemic stroke. In the present study, we tested the neuroprotective effects of rehmapicroside, a natural compound from a medicinal plant, on inhibiting ONOO--mediated mitophagy activation, attenuating infarct size and improving neurological functions by using the in vitro cultured PC12 cells exposed to oxygen glucose deprivation with reoxygenation (OGD/RO) condition and the in vivo rat model of middle cerebral artery occlusion (MCAO) for 2 h of transient cerebral ischemia plus 22 h of reperfusion. The major discoveries include following aspects: (1) Rehmapicroside reacted with ONOO- directly to scavenge ONOO-; (2) Rehmapicroside decreased O2- and ONOO-, up-regulated Bcl-2 but down-regulated Bax, Caspase-3 and cleaved Caspase-3, and down-regulated PINK1, Parkin, p62 and the ratio of LC3-II to LC3-I in the OGD/RO-treated PC12 cells; (3) Rehmapicroside suppressed 3-nitrotyrosine formation, Drp1 nitration as well as NADPH oxidases and iNOS expression in the ischemia-reperfused rat brains; (4) Rehmapicroside prevented the translocations of PINK1, Parkin and Drp1 into the mitochondria for mitophagy activation in the ischemia-reperfused rat brains; (5) Rehmapicroside ameliorated infarct sizes and improved neurological deficit scores in the rats with transient MCAO cerebral ischemia. Taken together, rehmapicroside could be a potential drug candidate against cerebral ischemia-reperfusion injury, and its neuroprotective mechanisms could be attributed to inhibiting the ONOO--mediated mitophagy activation.

  View details for DOI 10.1016/j.freeradbiomed.2020.06.034

  View details for PubMedID 32784031

• Proteomics-Guided Study on Buyang Huanwu Decoction for Its Neuroprotective and Neurogenic Mechanisms for Transient Ischemic Stroke: Involvements of EGFR/PI3K/Akt/Bad/14-3-3 and Jak2/Stat3/Cyclin D1 Signaling Cascades MOLECULAR NEUROBIOLOGY Chen, X., Chen, H., He, Y., Fu, S., Liu, H., Wang, Q., Shen, J. 2020

  Abstract

  Buyang Huanwu Decoction (BHD), a classic traditional Chinese medicine (TCM) formula, has been used for recovering neurological dysfunctions and treating post-stroke disability in China for 200 years. In the present study, we investigated the effects of BHD on inhibiting neuronal apoptosis, promoting proliferation and differentiation of neural stem cells (NSCs) and neurite formation and enhancing learning and memory functional recovery in an experimental rat ischemic stroke model. BHD significantly reduced infarct volume and decreased cell apoptosis in the ischemic brain. BHD enhanced neuronal cell viability in vitro. BHD dose-dependently promoted the proliferation of NSCs in ischemic rat brains in vivo. Moreover, BHD promoted neuronal and astrocyte differentiation in primary cultured NSCs in vitro. Water maze test revealed that BHD promoted the recovery of learning function but not memory functions in the transient ischemic rats. We then investigated the changes of the cellular signaling molecules by using two-dimension (2D) gel electrophoresis and focused on the PI3K/Akt/Bad and Jak2/Stat3/cyclin D1signaling pathway to uncover its underlying mechanisms for its neuroprotective and neurogenetic effects. BHD significantly upregulated the expression of p-PI3K, p-Akt, and p-Bad as well as the expression of p-Jak, p-Stat3, and cyclin D1 in vitro and in vivo. In addition, BHD upregulated Hes1 and downregulated cav-1 in vitro and in vivo. Taken together, these results suggest that BHD has neuroprotective effects and neurogenesis-promoting effects via activating PI3K/Akt/Bad and Jak2/Stat3/Cyclin D1 signaling pathways. Graphical Abstract Buyang Huanwu Decoction (BHD) activates the PI3K-AKT-BAD pathway in the ischemic brain for neuroprotection. BHD also activates JAK2/STAT3/Cyclin D1 signaling cascades for promoting neurogenesis in the hippocampus of post-ischemic brains. Moreover, BHD inhibits the expression of caveolin-1 and increases the expression of HES1 for promoting neuronal differentiation. The neuroprotective and neurogenesis-promoting effects in the hippocampus of post-ischemic brains promote learning ability.

  View details for DOI 10.1007/s12035-020-02016-y

  View details for Web of Science ID 000551397100001

  View details for PubMedID 32700252

• A Highly Selective and Sensitive Chemiluminescent Probe for Real-Time Monitoring of Hydrogen Peroxide in Cells and Animals. Angewandte Chemie (International ed. in English) Yang, D., Ye, S., Hananya, N., Green, O., Chen, H., Zhao, A. Q., Shen, J., Shabat, D. 2020

  Abstract

  Selective and sensitive molecular probes for hydrogen peroxide (H 2 O 2 ), which plays diverse roles in oxidative stress and redox signalling, are urgently needed to investigate the physiological and pathological effects of H 2 O 2 . A lack of reliable tools for in vivo imaging has hampered the development of H 2 O 2 mediated therapeutics. By combining a specific tandem Payne/Dakin reaction with a chemiluminescent scaffold, H 2 O 2 -CL-510 was developed as a highly selective and sensitive probe for detection of H 2 O 2 both in vitro and in vivo . A rapid 430-fold enhancement of chemiluminescence was triggered directly by H 2 O 2 without any laser excitation. Arsenic trioxide induced oxidative damage in leukemia was successfully detected. In particular, cerebral ischemia-reperfusion injury induced H 2 O 2 fluxes were visualized in rat brains using H 2 O 2 -CL-510 , providing a new chemical tool for real-time monitoring of H 2 O 2 dynamics in living animals.

  View details for DOI 10.1002/anie.202005429

  View details for PubMedID 32472602

• Targeting Myeloperoxidase (MPO) Mediated Oxidative Stress and Inflammation for Reducing Brain Ischemia Injury: Potential Application of Natural Compounds FRONTIERS IN PHYSIOLOGY Chen, S., Chen, H., Du, Q., Shen, J. 2020; 11: 433

  Abstract

  Oxidative stress and inflammation are two critical pathological processes of cerebral ischemia-reperfusion injury. Myeloperoxidase (MPO) is a critical inflammatory enzyme and therapeutic target triggering both oxidative stress and neuroinflammation in the pathological process of cerebral ischemia-reperfusion injury. MPO is presented in infiltrated neutrophils, activated microglial cells, neurons, and astrocytes in the ischemic brain. Activation of MPO can catalyze the reaction of chloride and H2O2 to produce HOCl. MPO also mediates oxidative stress by promoting the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), modulating the polarization and inflammation-related signaling pathways in microglia and neutrophils. MPO can be a therapeutic target for attenuating oxidative damage and neuroinflammation in ischemic stroke. Targeting MPO with inhibitors or gene deficiency significantly reduced brain infarction and improved neurological outcomes. This article discusses the important roles of MPO in mediating oxidative stress and neuroinflammation during cerebral ischemia-reperfusion injury and reviews the current understanding of the underlying mechanisms. Furthermore, we summarize the active compounds from medicinal herbs with potential as MPO inhibitors for anti-oxidative stress and anti-inflammation to attenuate cerebral ischemia-reperfusion injury, and as adjunct therapeutic agents for extending the window of thrombolytic treatment. We highlight that targeting MPO could be a promising strategy for alleviating ischemic brain injury, which merits further translational study.

  View details for DOI 10.3389/fphys.2020.00433

  View details for Web of Science ID 000538441200001

  View details for PubMedID 32508671

  View details for PubMedCentralID PMC7248223

• Ischemic postconditioning for stroke treatment: current experimental advances and future directions. Conditioning medicine Chen, H., Shen, J., Zhao, H. 2020; 3 (2): 104-115

  Abstract

  Ischemic postconditioning (IPostC) protects against brain injury induced by stroke and is a potential strategy for ischemic stroke treatment. Understanding its underlying mechanisms and potential hurdles is essential for clinical translation. In this review article, we will summarize the current advances in IPostC for stroke treatment and the underlying protective mechanisms. Strong evidence suggests that IPostC reduces brain infarct size, attenuates blood-brain barrier (BBB) damage and brain edema, and improves neurological outcomes. IPostC also promotes neurogenesis and angiogenesis at the recovery phase of ischemic stroke. The protective mechanisms involve its effects on anti-oxidative stress, anti-inflammation, and anti-apoptosis. In addition, it regulates neurotransmitter receptors, ion channels, heat shock proteins (HSP) 40/70, as well as growth factors such as BDNF and VEGF. Furthermore, IPostC modulates several cell signaling pathways, including the PI3K/Akt, MAPK, NF-κB, and the Gluk2/PSD95/MLK3/MKK7/JNK3 pathways. We also discuss the potential hurdles for IPostC's clinical translation, including insufficient IPostC algorithm studies, such as therapeutic time windows and ischemia-reperfusion periods and cycles, as well as its long-term protection. In addition, future studies should address confounding factors such as age, sex, and pre-existing conditions such as hypertension and hyperglycemia before stroke onset. At last, the combination of IPostC with other treatments, such as tissue plasminogen activator (t-PA), merits further exploration.

  View details for PubMedID 34396060

  View details for PubMedCentralID PMC8360401

• Potential Natural Compounds for Preventing 2019-nCoV Infection Chen, H., Du, Q. www.preprints.org. 2020
• Therapeutic Targets of Oxidative/Nitrosative Stress and Neuroinflammation in Ischemic Stroke: Applications for Natural Product Efficacy with Omics and Systemic Biology. Pharmacological research Chen, H. n., He, Y. n., Chen, S. n., Qi, S. n., Shen, J. n. 2020: 104877

  Abstract

  Oxidative/nitrosative stress and neuroinflammation are critical pathological processes in cerebral ischemia-reperfusion injury, and their intimate interactions mediate neuronal damage, blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) during ischemic stroke. We review current progress towards understanding the interactions of oxidative/nitrosative stress and inflammatory responses in ischemic brain injury. The interactions between reactive oxygen species (ROS)/reactive nitrogen species (RNS) and innate immune receptors such as TLR2/4, NOD-like receptor, RAGE, and scavenger receptors are crucial pathological mechanisms that amplify brain damage during cerebral ischemic brain injury. Furthermore, we review the current progress of omics and systematic biology approaches for studying complex network regulations related to oxidative/nitrosative stress and inflammation in the pathology of ischemic stroke. Targeting oxidative/nitrosative stress and neuroinflammation could be a promising therapeutic strategy for ischemic stroke treatment. We then review recent advances in discovering compounds from medicinal herbs with the bioactivities of simultaneously regulating oxidative/nitrosative stress and pro-inflammatory molecules for minimizing ischemic brain injury. These compounds include sesamin, baicalin, salvianolic acid A, 6-paradol, silymarin, apocynin, 3H-1,2-Dithiole-3-thione, (-)-epicatechin, rutin, Dl-3-N-butylphthalide, and naringin. We finally summarize recent developments of the omics and systematic biology approaches for exploring the molecular mechanisms and active compounds of Traditional Chinese Medicine (TCM) formulae with the properties of antioxidant and anti-inflammation for neuroprotection. The comprehensive omics and systematic biology approaches provide powerful tools for exploring therapeutic principles of TCM formulae and developing precision medicine for stroke treatment.

  View details for DOI 10.1016/j.phrs.2020.104877

  View details for PubMedID 32407958

• Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling. Translational stroke research Chen, H., Guan, B., Wang, B., Pu, H., Bai, X., Chen, X., Liu, J., Li, C., Qiu, J., Yang, D., Liu, K., Wang, Q., Qi, S., Shen, J. 2019

  Abstract

  Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.

  View details for DOI 10.1007/s12975-019-00772-1

  View details for PubMedID 31872339

• Astragaloside VI Promotes Neural Stem Cell Proliferation and Enhances Neurological Function Recovery in Transient Cerebral Ischemic Injuryvia Activating EGFR/MAPK Signaling Cascades MOLECULAR NEUROBIOLOGY Chen, X., Wu, H., Chen, H., Wang, Q., Xie, X., Shen, J. 2019; 56 (4): 3053–67

  Abstract

  Radix Astragali (AR) is a commonly used medicinal herb for post-stroke disability in Traditional Chinese Medicine but its active compounds for promoting neurogenic effects are largely unknown. In the present study, we tested the hypothesis that Astragaloside VI could be a promising active compound from AR for adult neurogenesis and brain repair via targeting epidermal growth factor (EGF)-mediated MAPK signaling pathway in post-stroke treatment. By using cultured neural stem cells (NSCs) and experimental stroke rat model, we investigated the effects of Astragaloside VI on inducing NSCs proliferation and self-renewal in vitro, and enhancing neurogenesis for the recovery of the neurological functions in post-ischemic brains in vivo. For animal experiments, rats were undergone 1.5 h middle cerebral artery occlusion (MCAO) plus 7 days reperfusion. Astragaloside VI (2 μg/kg) was daily administrated by intravenous injection (i.v.) for 7 days. Astragaloside VI treatment promoted neurogenesis and astrogenic formation in dentate gyrus zone, subventricular zone, and cortex of the transient ischemic rat brains in vivo. Astragaloside VI treatment enhanced NSCs self-renewal and proliferation in the cultured NSCs in vitro without affecting NSCs differentiation. Western blot analysis showed that Astragaloside VI up-regulated the expression of nestin, p-EGFR and p-MAPK, and increased neurosphere sizes, whose effects were abolished by the co-treatment of EGF receptor inhibitor gefitinib and ERK inhibitor PD98059. Behavior tests revealed that Astragaloside VI promoted the spatial learning and memory and improved the impaired motor function in transient cerebral ischemic rats. Taken together, Astragaloside VI could effectively activate EGFR/MAPK signaling cascades, promote NSCs proliferation and neurogenesis in transient cerebral ischemic brains, and improve the repair of neurological functions in post-ischemic stroke rats. Astragaloside VI could be a new therapeutic drug candidate for post-stroke treatment.

  View details for DOI 10.1007/s12035-018-1294-3

  View details for Web of Science ID 000465498200059

  View details for PubMedID 30088176

• Kinesin-1 Regulates Extrasynaptic Targeting of NMDARs and Neuronal Vulnerability Toward Excitotoxicity ISCIENCE Lin, R., Duan, Z., Sun, H., Fung, M., Chen, H., Wang, J., Lau, C., Yang, D., Liu, Y., Ni, Y., Wang, Z., Cui, J., Wu, W., Yung, W., Chan, Y., Lo, A. Y., Xia, J., Shen, J., Huang, J. 2019; 13: 82-+

  Abstract

  N-methyl-D-aspartate (NMDA) receptor (NMDAR) is highly compartmentalized in neurons, and its dysfunction has been implicated in various neuropsychiatric and neurodegenerative disorders. Recent failure to exploit NMDAR antagonization as a potential therapeutic target has driven the need to identify molecular mechanisms that regulate NMDAR compartmentalization. Here, we report that the reduction of Kif5b, the heavy chain of kinesin-1, protected neurons against NMDA-induced excitotoxicity and ischemia-provoked neurodegeneration. Direct binding of kinesin-1 to the GluN2B cytoplasmic tails regulated the levels of NMDAR at extrasynaptic sites and the subsequent influx of calcium mediated by extrasynaptic NMDAR by regulating the insertion of NMDARs into neuronal surface. Transient increase of Kif5b restored the surface levels of NMDAR and the decreased neuronal susceptibility to NMDA-induced excitotoxicity. The expression of Kif5b was repressed in cerebral ischemia preconditioning. Our findings reveal that kinesin-1 regulates extrasynaptic NMDAR targeting and signaling, and the reduction of kinesin-1 could be exploited to defer neurodegeneration.

  View details for DOI 10.1016/j.isci.2019.02.009

  View details for Web of Science ID 000462829500008

  View details for PubMedID 30826728

  View details for PubMedCentralID PMC6402234

• Active compounds and molecular targets of Chinese herbal medicine for neurogenesis in stroke treatment: Implication for cross talk between Traditional Chinese Medicine and Biomedical Sciences World Journal of Traditional Chinese Medicine Chen, X., Chen, H., Shen, J. 2019

  View details for DOI 10.4103/wjtcm.wjtcm_14_19

• Potential molecular targets of peroxynitrite in mediating blood-brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment FREE RADICAL RESEARCH Chen, H., Chen, X., Luo, Y., Shen, J. 2018; 52 (11-12): 1220–39

  Abstract

  Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood-brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia-reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), are important players in cerebral ischaemia-reperfusion injury. In particular, ONOO- and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3β. Herein, we review current progress about the roles of ONOO- in mediating those signalling pathways and their impacts on the t-PA-induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO- as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke.

  View details for DOI 10.1080/10715762.2018.1521519

  View details for Web of Science ID 000457432500004

  View details for PubMedID 30468092

• Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO--MMP-9 Pathway TRANSLATIONAL STROKE RESEARCH Chen, H., Guan, B., Chen, X., Chen, X., Li, C., Qiu, J., Yang, D., Liu, K., Qi, S., Shen, J. 2018; 9 (5): 515–29

  Abstract

  Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

  View details for DOI 10.1007/s12975-017-0598-3

  View details for Web of Science ID 000444426000009

  View details for PubMedID 29275501

• Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery ACTA PHARMACOLOGICA SINICA Chen, H., Chen, X., Li, W., Shen, J. 2018; 39 (5): 669–82

  Abstract

  Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.

  View details for DOI 10.1038/aps.2018.27

  View details for Web of Science ID 000431513300003

  View details for PubMedID 29595191

  View details for PubMedCentralID PMC5943912

• Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1 alpha and Wnt/beta-catenin signaling pathway FREE RADICAL BIOLOGY AND MEDICINE Chen, X., Zhou, B., Yan, T., Wu, H., Feng, J., Chen, H., Gao, C., Peng, T., Yang, D., Shen, J. 2018; 117: 158–67

  Abstract

  Hypoxic/ischemic stimulation could mediate growth and differentiation of neural stem/progenitor cells (NSCs) into mature neurons but its underlying mechanisms are largely unclear. Peroxynitrite formation is considered as a crucial pathological process contributing to cerebral ischemia-reperfusion injury. In the present study, we tested the hypothesis that peroxynitrite at low concentration could function as redox signaling to promote the growth of NSCs under hypoxic/ischemic conditions. Increased NSCs proliferation was accompanied by peroxynitrite production in the rat brains with 1 h of ischemia plus 7 days of reperfusion in vivo. Cell sorting experiments revealed that endogenous peroxynitrite level affected the capacity of proliferation and self-renewal in NSCs in vitro. Hypoxia stimulated peroxynitrite production and promoted NSCs self-renewal, proliferation and neuronal differentiation whereas treatments of peroxynitrite decomposition catalysts (PDCs, FeTMPyP and FeTPPS) blocked the changes in NSCs self-renewal, proliferation and neuronal differentiation. Exogenous peroxynitrite treatment revealed similar effects to promote NSCs proliferation, self-renewal and neuronal differentiation. Furthermore, the neurogenesis-promoting effects of peroxynitrite were partly through activating HIF-1α correlated with enhanced Wnt/β-catenin signaling pathway. In conclusion, peroxynitrite could be a cellular redox signaling for promoting NSCs proliferation, self-renewal and neuronal differentiation and peroxynitrite production could contribute to neurogenesis in ischemic/hypoxic NSCs.

  View details for DOI 10.1016/j.freeradbiomed.2018.02.011

  View details for Web of Science ID 000427420600016

  View details for PubMedID 29427793

• One-Compound-Multi-Target: Combination Prospect of Natural Compounds with Thrombolytic Therapy in Acute Ischemic Stroke CURRENT NEUROPHARMACOLOGY Chen, H., Qi, S., Shen, J. 2017; 15 (1): 134–56

  Abstract

  Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seem not to be satisfied, and a multitarget strategy is warranted to resolve such complex disease. Recently, large amount of efforts have been made to explore the active compounds from herbal supplements to treat ischemic stroke. Some natural compounds revealed both neuro- and bloodbrain- barrier (BBB)-protective effects by concurrently targeting multiple cellular signaling pathways in cerebral ischemia-reperfusion injury. Thus, those compounds are potential to be one-drug-multi-target agents as combined therapy with t-PA for ischemic stroke. In this review article, we summarize current progress about molecular targets involving in t-PA-mediated HT and neurotoxicity in ischemic brain injury. Based on these targets, we select 23 promising compounds from currently available literature with the bioactivities simultaneously targeting several important molecular targets. We propose that those compounds merit further investigation as combined therapy with t-PA. Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important issues to be addressed in the future for the development of natural compound as an adjunct therapy.

  View details for DOI 10.2174/1570159X14666160620102055

  View details for Web of Science ID 000391855800015

  View details for PubMedID 27334020

  View details for PubMedCentralID PMC5327453

• Baicalin Reduces Hemorrhagic Transformation of Rat Ischemic Stroke with Delayed T-PA Treatment Chen, H., Shen, J. ELSEVIER SCIENCE INC. 2016: S159

  View details for DOI 10.1016/j.freeradbiomed.2016.10.417

  View details for Web of Science ID 000444355800377

• Glycyrrhizin Could Inhibit HMGB1-MMP-9 Signaling and Prevent Hemorrhagic Transformation in Ischemic Stroke with Delayed T-PA Treatment Shen, J., Chen, H. ELSEVIER SCIENCE INC. 2016: S167

  View details for DOI 10.1016/j.freeradbiomed.2016.10.440

  View details for Web of Science ID 000444355800400

• Caveolin-1 Is Critical for Lymphocyte Trafficking into Central Nervous System during Experimental Autoimmune Encephalomyelitis JOURNAL OF NEUROSCIENCE Wu, H., Deng, R., Chen, X., Wong, W., Chen, H., Gao, L., Nie, Y., Wu, W., Shen, J. 2016; 36 (19): 5193–99

  Abstract

  Multiple sclerosis (MS) is a progressive autoimmune disease of the CNS with its underlying mechanisms not fully understood. In the present study, we tested the hypothesis that caveolin-1, a major membrane scaffolding protein, plays a critical role in the pathogenesis of experimental autoimmune encephalomyelitis, a laboratory murine model of MS. We found increased expression of caveolin-1 in serum and spinal cord tissues in association with disease incidence and severity in wild-type mice with active encephalomyelitis. After immunization, Cav-1 knock-out mice showed remarkable disease resistance with decreased incidence and clinical symptoms. Furthermore, Cav-1 knock-out mice had alleviated encephalitogenic T cells trafficking into the CNS with decreased expressions of adhesion molecules ICAM-1 and VCAM-1 within the lesions. In agreement with in vivo studies, in vitro knockdown of caveolin-1 compromised the upregulation of ICAM-1 in endothelial cells, leading to the amelioration of the transendothelial migration of pathogenic TH1 and TH17 cells. Together, those results indicate that caveolin-1 serves as an active modulator of CNS-directed lymphocyte trafficking and could be a therapeutic target for neuroinflammatory diseases, such as multiple sclerosis.The hallmark feature of neuroinflammatory diseases is the massive infiltrations of encephalitogenic leukocytes into the CNS parenchyma, a process that remains largely unclear. Our study demonstrates the critical contribution of caveolin-1 to encephalomyelitis pathogenesis and CNS-directed lymphocyte trafficking by modulation of adhesion molecules ICAM-1 and VCAM-1, highlighting the pathological involvement of caveolin-1 in neuroinflammatory diseases.

  View details for DOI 10.1523/JNEUROSCI.3734-15.2016

  View details for Web of Science ID 000378279500003

  View details for PubMedID 27170118

  View details for PubMedCentralID PMC6601805

• Targeting ONOO-/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment Integrative Medicine International Chen, H., Guan, B., Shen, J. 2016

  View details for DOI 10.1159/000442468

• Peroxynitrite Decomposition Catalyst Reduces Delayed Thrombolysis-induced Hemorrhagic Transformation in Ischemia-reperfused Rat Brains CNS NEUROSCIENCE & THERAPEUTICS Chen, H., Chen, X., Feng, J., Liu, K., Qi, S., Shen, J. 2015; 21 (7): 585–90

  Abstract

  Hemorrhagic transformation (HT) is a major complication of delayed tissue plasminogen activator (t-PA) treatment in ischemic stroke. We aimed to explore whether peroxynitrite decomposition catalyst (PDC) could prevent such complication.Male Sprague-Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) with t-PA (10 mg/kg) or t-PA plus FeTMPyP (3 mg/kg, a representative PDC) at MCAO for 2 or 5 h and reperfusion for 22 or 19 h, respectively. HT was assessed with hemoglobin assay. Neurological deficit was evaluated with Modified Neurological Severity Score (mNSS). Peroxynitrite formation was examined by detecting 3-nitrotyrosine (3-NT) formation. The expression and activity of MMP-9/MMP-2 were assessed by Western blotting and gelatin zymography.t-PA treatment at 2 h of MCAO did not induce HT but attenuated neurological deficit, whereas treatment at 5 h significantly induced HT and worsened the neurological outcome. Such complications were prevented by FeTMPyP cotreatment. Early t-PA treatment inhibited 3-NT and MMP-9/MMP-2 expression, whereas delayed treatment induced 3-NT and MMP-9/MMP-2 expression and activity. FeTMPyP cotreatment downregulated 3-NT and inhibited MMP-9/MMP-2 in both time points.Peroxynitrite decomposition catalyst could prevent hemorrhagic transformation and improve neurological outcome ischemic rat brains with delayed t-PA treatment via inhibiting peroxynitrite-mediated MMP activation.

  View details for DOI 10.1111/cns.12406

  View details for Web of Science ID 000356704000007

  View details for PubMedID 25996167

  View details for PubMedCentralID PMC6495263

• Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway NEUROPHARMACOLOGY Gong, J., Sun, F., Li, Y., Zhou, X., Duan, Z., Duan, F., Zhao, L., Chen, H., Qi, S., Shen, J. 2015; 91: 123–34

  Abstract

  Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury.

  View details for DOI 10.1016/j.neuropharm.2014.11.020

  View details for Web of Science ID 000350926100015

  View details for PubMedID 25510970

• Pros and cons of current approaches for detecting peroxynitrite and their applications Biomedical Journal Chen, X., Chen, H., Deng, R., Shen, J. 2014; 37

  View details for DOI 10.4103/2319-4170.134084

• Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury ACTA PHARMACOLOGICA SINICA Chen, X., Chen, H., Xu, M., Shen, J. 2013; 34 (1): 67–77

  Abstract

  Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.

  View details for DOI 10.1038/aps.2012.82

  View details for Web of Science ID 000314191000012

  View details for PubMedID 22842734

  View details for PubMedCentralID PMC4086503