Publications by authors named "Wugang Hou"

33 Publications

An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke.

Sci Transl Med 2021 06;13(597)

Translational Research Institute of Brain and Brain-Like Intelligence and Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, Tongji University School of Medicine, Shanghai 200434, China.

Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly increased in cortical neurons after stroke. We synthesized a small peptide, Trans-trans-activating (Tat)-cold-inducible RNA binding protein (Tat-CIRP), which perturbed the function of MD2 and strongly protected neurons against excitotoxic injury in vitro. In addition, systemic administration of Tat-CIRP or genetic deletion of MD2 induced robust neuroprotection against ischemic and hemorrhagic stroke in mice. Tat-CIRP reduced the brain infarct volume and preserved neurological function in rhesus monkeys 30 days after ischemic stroke. Tat-CIRP efficiently crossed the blood-brain barrier and showed a wide therapeutic index for stroke because no toxicity was detected when high doses were administered to the mice. Furthermore, we demonstrated that MD2 elicited neuronal apoptosis and necroptosis via a TLR4-independent, Sam68-related cascade. In summary, Tat-CIRP provides robust neuroprotection against stroke in rodents and gyrencephalic nonhuman primates. Further efforts should be made to translate these findings to treat both ischemic and hemorrhagic stroke in patients.
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http://dx.doi.org/10.1126/scitranslmed.abb6716DOI Listing
June 2021

Rosmarinic acid protects rats against post-stroke depression after transient focal cerebral ischemic injury through enhancing antioxidant response.

Brain Res 2021 04 4;1757:147336. Epub 2021 Feb 4.

Department of Anesthesiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address:

Rosmarinic acid (RA), a natural polyphenol, possesses potent antioxidant and anti-inflammatory activities. To evaluate the ability of RA to cure ischemic stroke and post-stroke depression (PSD), rats were treated with various doses of RA after cerebral ischemia. Neurological deficits and infarct volume of the brain were measured. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) were examined at different time points. In addition, a forced swimming test and sucrose preference test were performed to detect the anti-depressive effects of RA. Our results revealed RA administration significantly alleviated neurological deficits and reduced infarct volumes. RA attenuated the decrease of SOD, CAT activities and GSH levels in the ischemic penumbra of the brain. Most importantly, RA treatment alleviated the depression behaviors. Increased expression of Nrf2 was also induced by RA, while down regulation Nrf2 by Nrf2-short-hairpin RNA sequences reversed the increasing activity of SOD and CAT induced by RA, as well as the protection against PSD. The present study indicates that RA exerts a potent neuroprotective effect against stroke and PSD, which could be a promising therapeutic intervention for stroke.
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http://dx.doi.org/10.1016/j.brainres.2021.147336DOI Listing
April 2021

Microglia: A Potential Therapeutic Target for Sepsis-Associated Encephalopathy and Sepsis-Associated Chronic Pain.

Front Pharmacol 2020 27;11:600421. Epub 2020 Nov 27.

Department of Anaesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Neurological dysfunction, one of the severe manifestations of sepsis in patients, is closely related to increased mortality and long-term complications in intensive care units, including sepsis-associated encephalopathy (SAE) and chronic pain. The underlying mechanisms of these sepsis-induced neurological dysfunctions are elusive. However, it has been well established that microglia, the dominant resident immune cell in the central nervous system, play essential roles in the initiation and development of SAE and chronic pain. Microglia can be activated by inflammatory mediators, adjacent cells and neurotransmitters in the acute phase of sepsis and then induce neuronal dysfunction in the brain. With the spotlight focused on the relationship between microglia and sepsis, a deeper understanding of microglia in SAE and chronic pain can be achieved. More importantly, clarifying the mechanisms of sepsis-associated signaling pathways in microglia would shed new light on treatment strategies for SAE and chronic pain.
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http://dx.doi.org/10.3389/fphar.2020.600421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729164PMC
November 2020

Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses.

Mol Neurobiol 2021 Mar 21;58(3):1052-1061. Epub 2020 Oct 21.

Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, China.

Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide. Neuroinflammation involving microglia and astrocyte activation has been demonstrated to play critical role in the secondary injury induced by TBI. A1 astrocytes, which are induced by activated microglia, can directly kill neurons by secreting neurotoxic complement C3. Estrogen has been proved to possess neuroprotective effects, but the effect and underlying mechanism of estrogen on TBI-induced neuroinflammatory injury remain largely unclear. In this study, we constructed an adult male mouse model of TBI and immediately after injury treated the mice with 17β-estradiol (E2) (100 μg/kg, once every day via intraperitoneal injection) for 3 days. We found that E2 treatment significantly alleviated TBI-induced neurological deficits, neuronal injuries, and brain edema and significantly inhibited Iba1 and GFAP expression, which are markers of microglia and astrocyte activation, respectively. E2 treatment also significantly inhibited TLR4 and NF-κB protein expression, and significantly reduced the expression of the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, E2 treatment significantly decreased the number of complement C3d/GFAP-positive cells and complement C3d protein expression. Taking these results together, we concluded that E2 treatment dramatically alleviates TBI neuroinflammatory injury by inhibiting TLR4/NF-κB pathway-mediated microglia and astrocyte activation and neuroinflammation and reducing A1-phenotype neurotoxic astrocyte activation. Our findings indicate that E2 treatment may be a potential therapy strategy for TBI-induced neuroinflammation injury.
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http://dx.doi.org/10.1007/s12035-020-02171-2DOI Listing
March 2021

Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte.

J Neuroinflammation 2020 Sep 11;17(1):270. Epub 2020 Sep 11.

Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.

Background: Ischemic stroke is the second leading cause of death globally. The narrow time window for administering effective thrombolytic therapy motivates the search for alternative prevention strategies. Microglia and astrocyte activation-mediated inflammation play a pivotal role in ischemic stroke injury. Cottonseed oil (CSO) has been shown to exert anti-inflammatory effects against peripheral tissue injury, although CSO is mostly used as a solvent for lipid-soluble drugs. However, the role of CSO in neuroprotection against stroke has not been previously reported.

Methods: We treated adult male rats with CSO (1.3 ml/kg, subcutaneous injection, once every other day for 3 weeks) and then constructed a middle cerebral artery occlusion (MCAO) model followed by 24 h of reperfusion. Then, we measured the neurological scores, infarction volume, neuronal injury, and brain edema; we also measured the levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), degree of microglial and astrocytic activation, protein expression levels of Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), C3d and S100A10, and the presence of A1 type astrocytes and A2 type astrocytes.

Results: We found that CSO treatment significantly improved the neurological deficit, reduced infarction volume, and alleviated neuronal injuries, blood-brain barrier (BBB) disruption, and brain edema. Additionally, CSO treatment significantly reduced microglial and astrocytic activation, inhibited TLR4 and NF-κB protein expression, and reduced the release of IL-1β, IL-6, and TNF-α. Finally, CSO treatment significantly decreased the number of C3d/glial fibrillary acidic protein (GFAP)-positive cells and C3d protein expression, and increased the number of S100A10/GFAP-positive cells and S100A10 protein expression.

Conclusion: Our results first found that CSO treatment alleviated ischemic stroke injury by reducing microglial and astrocytic activation and inflammation, which was related to the inhibition of TLR4/NF-κB pathway and the reduction of A1 phenotype neurotoxic astrocyte activation, suggesting that CSO could be a new strategy in the prevention of ischemic stroke.
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http://dx.doi.org/10.1186/s12974-020-01946-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488511PMC
September 2020

Astroglial N-myc downstream-regulated gene 2 protects the brain from cerebral edema induced by stroke.

Glia 2021 02 11;69(2):281-295. Epub 2020 Jul 11.

Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Air Force Military Medical University, Xi'an, China.

Brain edema is a grave complication of brain ischemia and is the main cause of herniation and death. Although astrocytic swelling is the main contributor to cytotoxic edema, the molecular mechanism involved in this process remains elusive. N-myc downstream-regulated gene 2 (NDRG2), a well-studied tumor suppressor gene, is mainly expressed in astrocytes in mammalian brains. Here, we found that NDRG2 deficiency leads to worsened cerebral edema, imbalanced Na transfer, and astrocyte swelling after ischemia. We also found that NDRG2 deletion in astrocytes dramatically changed the expression and distribution of aquaporin-4 and Na -K -ATPase β1, which are strongly associated with cell polarity, in the ischemic brain. Brain edema and astrocyte swelling were significantly alleviated by rescuing the expression of astrocytic Na -K -ATPase β1 in NDRG2-knockout mouse brains. In addition, the upregulation of astrocytic NDRG2 by lentiviral constructs notably attenuated brain edema, astrocytic swelling, and blood-brain barrier destruction. Our results indicate a particular role of NDRG2 in maintaining astrocytic polarization to facilitate Na and water transfer balance and to protect the brain from ischemic edema. These findings provide insight into NDRG2 as a therapeutic target in cerebral edema.
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http://dx.doi.org/10.1002/glia.23888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754347PMC
February 2021

Loss of Estrogen Efficacy Against Hippocampus Damage in Long-Term OVX Mice Is Related to the Reduction of Hippocampus Local Estrogen Production and Estrogen Receptor Degradation.

Mol Neurobiol 2020 Aug 15;57(8):3540-3551. Epub 2020 Jun 15.

Department of Anaesthesiology, The Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, China.

Postmenopausal women experience a higher risk for neurodegenerative diseases, including cognitive impairment and ischemic stroke. Many preclinical studies have indicated that estrogen replacement therapy (ERT) may provide protective effects against these neurological diseases. However, the results of Women's Health Initiative (WHI) studies have led to the proposal of "critical period hypothesis," which states that there is a precise window of opportunity for administering beneficial hormone therapy following menopause. However, the underlying molecular mechanisms require further characterization. Here, we explored the effects of ERT on cognition decline and global cerebral ischemia (GCI)-induced hippocampal neuronal damage in mice that had experienced both short-term (ovariectomized (OVX) 1 week) and long-term (OVX 10 weeks) estrogen deprivation. We also further explored the concentration of 17β-estradiol (E2) in the circulation and hippocampus and the expression of aromatase and estrogen receptors (ERα, ERα-Ser118, and ERβ). We found that the neuroprotective effectiveness of ERT against hippocampus damage exhibited in OVX1w mice was totally absent in OVX10w mice. Interestingly, the concentration of hippocampal E2 was irreversibly reduced in OVX10w mice, which was related to the decrease of aromatase expression in the hippocampus. In addition, long-term estrogen deprivation (LTED) led to a decrease in estrogen receptor proteins in the hippocampus. Thus, we concluded that the loss of ERT neuroprotection against hippocampus injury in LTED mice was related to the reduction in hippocampus E2 production and estrogen receptor degradation. These results provide several intervention targets to restore the effectiveness of ERT neuroprotection in elderly post-menopausal women.
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http://dx.doi.org/10.1007/s12035-020-01960-zDOI Listing
August 2020

JUND-dependent up-regulation of HMOX1 is associated with cisplatin resistance in muscle-invasive bladder cancer.

J Biochem 2020 Jul;168(1):73-82

Department of Urology, 73rd Group Army Hospital, PLA Army, No. 94 Wenyuan Road, Xia'men 361000, China.

The standard-of-care for metastatic muscle-invasive bladder cancer (MIBC) is platinum-based chemotherapy regimens. Acquired resistance that occurs frequently through unidentified mechanisms, however, remains the major obstacle for implementing therapeutic effectiveness. Here, using data mining and analysis on clinical samples, we show that expression of JUND, a core component of activator protein-1 family, was significantly induced in cisplatin (CDDP)-resistant MIBC. Accumulation of nuclear JUND was associated with low post-chemotherapy survival in MIBC patients. In both genetically engineered cell models and murine xenograft models, we provided evidence that bladder cancer (BC) cells with excessive JUND expression were less responsive to CDDP treatment. This CDDP resistance was further demonstrated to be mediated, at least in part, by transactivation of HMOX1 [the gene encoding heme oxygenase-1 (HO-1)], one of the most important antioxidant signalling pathways of cell adaptation to stress. One mutation within the HMOX1 promoter successfully abolished oxidative stress-enhanced and JUND-driven HMOX1 promoter activation, suggesting that this unique site synergized for maximal HO-1 induction in CDDP-challenged BC cells. Overall, our data highlight an indispensible role of JUND, both as a target as a modifier of the oxidative stress signalling, in conferring an adaptive response during the pathogenesis of CDDP resistance in MIBC.
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http://dx.doi.org/10.1093/jb/mvaa027DOI Listing
July 2020

The Critical Period for Neuroprotection by Estrogen Replacement Therapy and the Potential Underlying Mechanisms.

Curr Neuropharmacol 2020 ;18(6):485-500

Anesthesia and Operation Center, The First Medical Center to Chinese PLA General Hospital, Beijing 100853, China.

17β-Estradiol (estradiol or E2) is a steroid hormone that has been broadly applied as a neuroprotective therapy for a variety of neurodegenerative and cerebrovascular disorders such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. Several laboratory and clinical studies have reported that Estrogen Replacement Therapy (ERT) had no effect against these diseases in elderly postmenopausal women, and at worst, increased their risk of onset and mortality. This review focuses on the growing body of data from in vitro and animal models characterizing the potential underlying mechanisms and signaling pathways that govern successful neuroprotection by ERT, including the roles of E2 receptors in mediating neuroprotection, E2 genomic regulation of apoptosis- related pathways, membrane-bound receptor-mediated non-genomic signaling pathways, and the antioxidant mechanisms of E2. Also discussed is the current evidence for a critical period of effective treatment with estrogen following natural or surgical menopause and the outcomes of E2 administration within an advantageous time period. The known mechanisms governing the duration of the critical period include depletion of E2 receptors, the switch to a ketogenic metabolic profile by neuronal mitochondria, and a decrease in acetylcholine that accompanies E2 deficiency. Also the major clinical trials and observational studies concerning postmenopausal Hormone Therapy (HT) are summarized to compare their outcomes with respect to neurological disease and discuss their relevance to the critical period hypothesis. Finally, potential controversies and future directions for this field are discussed throughout the review.
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http://dx.doi.org/10.2174/1570159X18666200123165652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457406PMC
March 2021

N-myc downstream-regulated gene 2 deficiency aggravates memory impairment in Alzheimer's disease.

Behav Brain Res 2020 02 25;379:112384. Epub 2019 Nov 25.

Center for Brain Science & Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address:

Alzheimer's disease (AD) is a chronic degenerative disease of the central nervous system and the most common dementia type in elderly people. N-myc downstream-regulated gene 2 (NDRG2), a cell stress response gene, is primarily expressed in astrocytes in mammalian brains. The hippocampal protein levels of NDRG2 in AD patients were significantly higher than those in healthy peers. However, whether the increase in NDRG2 is involved in the development of AD or is an endogenous protective response initiated by stress remains unknown. Here, we investigated the roles of NDRG2 in the development of memory impairment in AD using mouse models established by amyloid β injection or crossing of APP/PS1 mice. We found that NDRG2 deficiency worsened the memory impairment in AD mice. In addition, NDRG2 deletion induced downregulation of the proteasome functional subunit PSMB6 in AD mice. These findings suggest that NDRG2 is an endogenous neuroprotectant that participates in the pathological course of waste-clearing impairment and memory damage in AD. NDRG2 may be a therapeutic target for the intervention of AD memory degradation.
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http://dx.doi.org/10.1016/j.bbr.2019.112384DOI Listing
February 2020

Selective activation of estrogen receptor β alleviates cerebral ischemia neuroinflammatory injury.

Brain Res 2020 01 29;1726:146536. Epub 2019 Oct 29.

Anesthesia and Operation Center, The First Medical Center to Chinese PLA General Hospital, Beijing 100853, China. Electronic address:

The stroke incidence in menopausal women was abruptly increased combining with much worse stoke outcomes. Estrogen replacement therapy has the potential to become a new neuroprotective strategy against stroke. But the adverse oncogenic events extremely limited its clinical application. As estrogen receptor (ER) β is seldom expressed in the female reproductive organs, selective activation of ERβ is a promising alternative therapy. However, the role and mechanism of ERβ in stroke neuroprotection remain largely unknown. In this study, we investigated the effects of activating ERβ on microglia and astrocyte activation and NF-κB mediated neuroinflammatory injury induced by middle cerebral artery occlusion and reperfusion (MCAO-R) or oxygen and glucose deprivation and reperfusion (OGD-R). We found that 8 mg/kg DPN (ERβ-specific agonist) replacement therapy (3 weeks) to the ovariectomized (OVX) mice significantly reduced ischemia injury and alleviated microglia and astrocyte activation, and markedly inhibited the expression of NF-κB and proinflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, pretreatment (72 h) with 10 nM DPN to the cell line of microglia (N9) or astrocyte (MA1800) significantly increased the cell viability and decreased the cell apoptosis and damage after OGD-R injury, and significantly inhibited the expression of NF-κB and proinflammatory cytokines. These results concluded that DPN replacement treatment alleviated the cerebral ischemia-reperfusion injury via inhibiting the activation of microglia and astrocyte and NF-κB mediated neruoinflammation. As ERβ agonist have only minor effects in classic estrogen target tissues, we propose that selective activating ERβ is a promising therapy to suppress stroke neuroinflammatory injury in menopausal women.
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http://dx.doi.org/10.1016/j.brainres.2019.146536DOI Listing
January 2020

N-myc downstream-regulated gene 2 controls astrocyte morphology via Rho-GTPase signaling.

J Cell Physiol 2019 11 19;234(11):20847-20858. Epub 2019 Apr 19.

Anesthesia and Operation Center, The First Medical Center to Chinese PLA General Hospital, Beijing, China.

Astrocyte undergoes morphology changes that are closely associated with the signaling communications at synapses. N-myc downstream-regulated gene 2 (NDRG2) is specifically expressed in astrocytes and is associated with several important astrocyte functions, but its potential role(s) relating to astrocyte morphological changes remain unknown. Here, primary astrocytes were prepared from neonatal Ndrg2 and Ndrg2 pups, and the drug Y27632 was used to induce stellation. We then used a variety of methods to measure the levels of NDRG2, α-Actinin4, and glial fibrillary acidic protein (GFAP), and the activity of RhoA, Rac1, and Cdc42 in Y27632-treated astrocytes as well as in Ndrg2 , Ndrg2 , or Ndrg2  + lentivirus (restore NDRG2 expression) astrocytes. We also conducted live-imaging and proteomics studies of the cultured astrocytes. We found that induction of astrocytes stellation (characterized by cytoplasmic retraction and process outgrowth) resulted in increased NDRG2 protein expression and Rac1 activity and in reduced α-Actinin4 protein expression and RhoA activity. Ndrg2 deletion induced astrocyte flattening, whereas the restoration of NDRG2 expression induced stellation. Ndrg2 deletion also significantly increased α-Actinin4 protein expression and RhoA activity yet reduced GFAP protein expression and Rac1 activity, and these trends were reversed by restoration of NDRG2 expression. Collectively, our results showed that Ndrg2 deletion promoted cell proliferation, interrupted stellation capability, and extensively altered the protein expression profiles of proteins that function in Rho-GTPase signaling. These findings suggest that NDRG2 functions to regulate astrocytes morphology via altering the accumulation of the Rho-GTPase signaling pathway components, thereby supporting that NDRG2 should be understood as a regulator of synaptic plasticity and thus neuronal communications.
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http://dx.doi.org/10.1002/jcp.28689DOI Listing
November 2019

The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation.

J Neuroinflammation 2018 Jul 12;15(1):206. Epub 2018 Jul 12.

Department of Anaesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.

Background: The steroid hormone estrogen (17-β-estradiol, E2) provides neuroprotection against cerebral ischemic injury by activating estrogen receptors. The novel estrogen receptor G protein-coupled receptor 30 (GPR30) is highly expressed in the brain and provides acute neuroprotection against stroke. However, the underlying mechanisms remain unclear.

Methods: In this study, ovariectomized female mice were subjected to middle cerebral artery occlusion (MCAO), and E2, G1, and ICI182780 were administered immediately upon reperfusion. The infarction volume, neurological scores, and neuronal injuries were examined. Primary microglial cells were subjected to oxygen-glucose deprivation (OGD), and the drugs were administered immediately upon reintroduction. The pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in penumbra and microglia were assessed by ELISA. The cell viability and lactose dehydrogenase (LDH) release of neurons co-cultured with microglia were analyzed using cell counting kit-8 (CCK8) and LDH release assays. Microglial activation as well as GPR30, Iba1, and Toll-like receptor 4 (TLR4) protein expression and TLR4 mRNA expression were detected. Additionally, NF-κB activity was detected in lipopolysaccharide (LPS)-activated microglia after the activation of GPR30.

Results: GPR30 was highly expressed in microglia and significantly increased after ischemic injury. The activation of GPR30 significantly reduced the infarction volume, improved the neurological deficit, and alleviated neuronal injuries. Moreover, GPR30 activation significantly reduced the release of TNF-α, IL-1β, and IL-6 from ischemic penumbra and microglia subjected to OGD and alleviated neuronal injury as assessed using the CCK8 and LDH assays. Finally, the activation of GPR30 relieved microglial activation, reduced Iba1 and TLR4 protein expression and TLR4 mRNA levels, and inhibited NF-κB activity.

Conclusions: Microglial GPR30 exerts acute neuroprotective effects by inhibiting TLR4-mediated microglial inflammation, which indicates that GPR30 may be a potential target for the treatment of ischemic stroke.
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http://dx.doi.org/10.1186/s12974-018-1246-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043971PMC
July 2018

Liver X receptor β in the hippocampus: A potential novel target for the treatment of major depressive disorder?

Neuropharmacology 2018 06 11;135:514-528. Epub 2018 Apr 11.

Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen 361101, China; Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Liver X receptors (LXRs), including LXRα and LXRβ isoforms, have been implicated in multiple physiological functions including promoting neurogenesis, improving synaptic plasticity, preventing neurodegeneration, inhibiting inflammation as well as regulating cholesterol metabolism. However, a potential role of LXRs in the treatment of major depressive disorder (MDD) has never been investigated previously. Our present results demonstrated that levels of hippocampal LXRβ but not LXRα were down-regulated in rats exposed to chronic unpredictable stress (CUS) and were negatively correlated with the severity of CUS-induced depressive-like behaviors. Furthermore, rats with LXRβ knockdown by short hairpin RNA (shRNA) in hippocampus displayed depressive-like behaviors and impaired hippocampal neurogenesis similar to those observed after CUS exposure. Conversely, LXRs activation by GW3965 (GW), a synthetic dual agonist for both LXRα and LXRβ isoforms, could improve depression-like behaviors and reverse the impaired hippocampal neurogenesis in rats exposed to CUS. LXRβ knockdown by shRNA completely abrogated the antidepressant and hippocampal neurogenesis-promoting effects of GW, suggesting that LXRβ isoform mediated the antidepressant and hippocampal neurogenesis-promoting effects of the LXRα/β dual agonist. However, ablation of hippocampal neurogenesis with x-irradiation only partly but not completely abolished the antidepressant effects of GW in the behavioral tests, implying that the antidepressant effects mediated by LXRβ isoform are likely through both neurogenesis-dependent and -independent pathways. Thus, our findings suggest that LXRβ activation may represent a potential novel target for the treatment of MDD and also provide a novel insight into the underlying mechanisms of MDD.
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http://dx.doi.org/10.1016/j.neuropharm.2018.04.014DOI Listing
June 2018

Kelch-like ECH-associated Protein 1-dependent Nuclear Factor-E2-related Factor 2 Activation in Relation to Antioxidation Induced by Sevoflurane Preconditioning.

Anesthesiology 2017 Mar;126(3):507-521

From the Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China (M.C., L.T., B.D., W.H., L.S., H.D.); and Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing, China (L.T.).

Background: The authors have reported that antioxidative effects play a crucial role in the volatile anesthetic-induced neuroprotection. Accumulated evidence shows that endogenous antioxidation could be up-regulated by nuclear factor-E2-related factor 2 through multiple pathways. However, whether nuclear factor-E2-related factor 2 activation is modulated by sevoflurane preconditioning and, if so, what is the signaling cascade underlying upstream of this activation are still unknown.

Methods: Sevoflurane preconditioning in mice was performed with sevoflurane (2.5%) 1 h per day for five consecutive days. Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. Expression of nuclear factor-E2-related factor 2, kelch-like ECH-associated protein 1, manganese superoxide dismutase, thioredoxin-1, and nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 was detected (n = 6). The antioxidant activities and oxidative product expression were also examined. To determine the role of kelch-like ECH-associated protein 1 inhibition-dependent nuclear factor-E2-related factor 2 activation in sevoflurane preconditioning-induced neuroprotection, the kelch-like ECH-associated protein 1-nuclear factor-E2-related factor 2 signal was modulated by nuclear factor-E2-related factor 2 knockout, kelch-like ECH-associated protein 1 overexpression lentivirus, and kelch-like ECH-associated protein 1 deficiency small interfering RNA (n = 8). The infarct volume, neurologic scores, and cellular apoptosis were assessed.

Results: Sevoflurane preconditioning elicited neuroprotection and increased nuclear factor-E2-related factor 2 nuclear translocation, which in turn up-regulated endogenous antioxidation and reduced oxidative injury. Sevoflurane preconditioning reduced kelch-like ECH-associated protein 1 expression. Nuclear factor-E2-related factor 2 ablation abolished neuroprotection and reversed sevoflurane preconditioning by mediating the up-regulation of antioxidants. Kelch-like ECH-associated protein 1 overexpression reversed nuclear factor-E2-related factor 2 up-regulation and abolished the neuroprotection induced by sevoflurane preconditioning. Kelch-like ECH-associated protein 1 small interfering RNA administration improved nuclear factor-E2-related factor 2 expression and the outcome of mice subjected to ischemia/reperfusion injury.

Conclusions: Kelch-like ECH-associated protein 1 down-regulation-dependent nuclear factor-E2-related factor 2 activation underlies the ability of sevoflurane preconditioning to activate the endogenous antioxidant response, which elicits its neuroprotection.
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http://dx.doi.org/10.1097/ALN.0000000000001485DOI Listing
March 2017

Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor β.

Sci Rep 2016 Feb 19;6:21467. Epub 2016 Feb 19.

Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.

The incidence of ischemic stroke is significantly increased in postmenopausal women. However, the neuroprotective effects of estrogen replacement therapy (ERT) against stroke remain controversial, and the role of astrocytes in ERT has rarely been explored. In this study, we investigated the effects of estrogen and selective estrogen receptor (ER) agonists on astrocytes activation and neuronal apoptosis in mice under conditions of cell culture oxygen and glucose deprivation and reperfusion (OGD-R), and global cerebral ischemia (GCI). We demonstrated that hippocampal astrocytes primarily express ERβ. In astrocytes, 2.5-20 nM 17β-estradiol (E2) or 10 nM DPN (ERβ agonist) not 10 nM PPT (ERα agonist), significantly increased GFAP expression. And 10 nM E2, DPN or E2+MPP (ERα antagonist), but not PPT or E2+PHTPP (ERβ antagonist), significantly reduced neuronal apoptosis following the subjection of astrocyte and neuronal cocultures to OGD-R. We also found that either 50 μg/kg E2 or 8 mg/kg DPN replacement (3 weeks) significantly increased GFAP expression and reduced GCI-induced neuronal apoptosis in hippocampal CA1 region of ovariectomized mice. These results indicate that estrogen-induced neuroprotection against ischemia-reperfusion injury involves activation of astrocytes via ERβ. Thus, the discovery and design of astrocyte-selective ERβ modulators may offer a new strategy for ERT of ischemic stroke.
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http://dx.doi.org/10.1038/srep21467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759820PMC
February 2016

Cardiac Output and Cerebral Blood Flow: The Integrated Regulation of Brain Perfusion in Adult Humans.

Anesthesiology 2015 Nov;123(5):1198-208

From the Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California (L.M., A.W.G.); Department of Anesthesiology, The Fourth Military Medical University Xijing Hospital, Xi'an, Shaanxi Province, China (W.H.); Department of Anesthesia and Perioperative Medicine, University of Western Ontario, London, Ontario, Canada (J.C.); and Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (R.H.).

Cerebral blood flow (CBF) is rigorously regulated by various powerful mechanisms to safeguard the match between cerebral metabolic demand and supply. The question of how a change in cardiac output (CO) affects CBF is fundamental, because CBF is dependent on constantly receiving a significant proportion of CO. The authors reviewed the studies that investigated the association between CO and CBF in healthy volunteers and patients with chronic heart failure. The overall evidence shows that an alteration in CO, either acutely or chronically, leads to a change in CBF that is independent of other CBF-regulating parameters including blood pressure and carbon dioxide. However, studies on the association between CO and CBF in patients with varying neurologic, medical, and surgical conditions were confounded by methodologic limitations. Given that CBF regulation is multifactorial but the various processes must exert their effects on the cerebral circulation simultaneously, the authors propose a conceptual framework that integrates the various CBF-regulating processes at the level of cerebral arteries/arterioles while still maintaining autoregulation. The clinical implications pertinent to the effect of CO on CBF are discussed. Outcome research relating to the management of CO and CBF in high-risk patients or during high-risk surgeries is needed.
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http://dx.doi.org/10.1097/ALN.0000000000000872DOI Listing
November 2015

DDR1 may play a key role in destruction of the blood-brain barrier after cerebral ischemia-reperfusion.

Neurosci Res 2015 Jul 25;96:14-9. Epub 2015 Jan 25.

Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Discoidin domain receptor 1 (DDR1) has been shown to mediate matrix metalloproteinase-9 (MMP-9) secretions and degrade all extracellular matrix compounds in mammalian tumor cells. We hypothesized that DDR1 expression will be elevated and the blood-brain barrier (BBB) will be damaged after focal cerebral ischemia in rats. Inhibiting DDR1 expression can alleviate BBB disruption and cerebral ischemic damage via down-regulation of MMP-9 expression and activity. To test our hypothesis, we injected specific DDR1 siRNA into ipsilateral ischemic lateral ventricles in a focal ischemic model. Our results showed that phospho-DDR1 expression increased after ischemia/reperfusion (I/R) injury (p < 0.01). Inactivation of DDR1 by specific siRNA caused a decrease in phospho-DDR1 and MMP-9 expression in the ischemic cortex, reduced stroke-induced infarct volume, and alleviated BBB disruption in rat brain following I/R injury (p < 0.01). Our results suggested that DDR1-siRNA attenuates phospho-DDR1 and MMP-9 upregulation, which was followed by a reduction in infarction and BBB disruption in the ischemic brain after I/R injury. DDR1 may represent a molecular target for the prevention of BBB disruption after cerebral I/R injury.
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http://dx.doi.org/10.1016/j.neures.2015.01.004DOI Listing
July 2015

Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.

Int J Biol Sci 2014 8;10(4):457-65. Epub 2014 Apr 8.

1. Department of Anesthesiology, Xijing Hospital, Forth Military Medical University, Xi'an, China;

Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.
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http://dx.doi.org/10.7150/ijbs.7562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979998PMC
January 2015

N-myc downstream-regulated gene 2 expression is associated with glucose transport and correlated with prognosis in breast carcinoma.

Breast Cancer Res 2014 Mar 18;16(2):R27. Epub 2014 Mar 18.

Introduction: N-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism. We investigated whether NDRG2 is involved in any glucose-dependent energy metabolism, as well as the nature of its correlation with breast carcinoma.

Methods: The correlations between NDRG2 expression and glucose transporter 1 (GLUT1) expression in clinical breast carcinoma tissues were analysed. The effects of NDRG2 on glucose uptake were assessed in breast cancer cells and xenograft tumours. The consequences of NDRG2-induced regulation of GLUT1 at the transcription and translation levels and the interaction between NDRG2 and GLUT1 were examined.

Results: Data derived from clinical breast carcinoma specimens revealed that (1) patients with high NDRG2 expression had better disease-free survival and overall survival than those with low NDRG2 expression and (2) NDRG2 expression was negatively correlated with GLUT1 expression in these breast carcinoma tissues. NDRG2 inhibited glucose uptake by promoting GLUT1 protein degradation without affecting GLUT1 transcription in both breast cancer cells and xenograft tumours. In addition, NDRG2 protein interacted and partly colocalised with GLUT1 protein in cell cytoplasm areas.

Conclusions: The results of our study support the notion that NDRG2 plays an important role in tumour glucose metabolism, in which GLUT1 is a likely candidate contributor to glucose uptake suppression and tumour growth. Targeting the actions of NDRG2 in cell glucose-dependent energy delivery may provide an attractive strategy for therapeutic intervention in human breast carcinoma.
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http://dx.doi.org/10.1186/bcr3628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053222PMC
March 2014

Rosmarinic acid ameliorates PTSD-like symptoms in a rat model and promotes cell proliferation in the hippocampus.

Prog Neuropsychopharmacol Biol Psychiatry 2014 Jun 11;51:16-22. Epub 2014 Jan 11.

Department of Psychosomatic Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Rosmarinic acid (RA) is an important component of Chinese herbal medicine treatments and has been demonstrated to exert therapeutic effects in mood disorders. The present study was designed to assess the effects of RA on post-traumatic stress disorder (PTSD)-like symptoms, hippocampal cell proliferation and phosphorylation extracellular regulated protein kinases (pERK1/2) expression. We found that administration of RA (10mg/kg) alleviated PTSD-like symptoms in rats exposed to an enhanced single prolonged stress (ESPS) paradigm and restored hippocampal proliferation and pERK1/2 expression. Interestingly, the effects of RA were inhibited by the blockage of the ERK signaling. These data support the use of RA for treating PTSD and indicate that the ERK1/2 signaling cascade may play a critical role in the therapeutic efficacy of RA in treating such conditions.
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http://dx.doi.org/10.1016/j.pnpbp.2014.01.002DOI Listing
June 2014

Retrograde ductal administration of the adenovirus-mediated NDRG2 gene leads to improved sialaden hypofunction in estrogen-deficient rats.

Mol Ther 2014 May 17;22(5):908-18. Epub 2013 Dec 17.

Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.

One of the most common oral manifestations of menopause is xerostomia. Oral dryness can profoundly affect quality of life and interfere with basic daily functions, such as chewing, deglutition, and speaking. Although the feeling of oral dryness can be ameliorated after estrogen supplementation, the side effects of estrogen greatly restrict its application. We previously found that N-myc downstream-regulated gene 2 (NDRG2) is involved in estrogen-mediated ion and fluid transport in a cell-based model. In the present study, we used an ovariectomized rat model to mimic xerostomia in menopausal women and constructed two adenovirus vectors bearing NDRG2 to validate their therapeutic potential. Ovariectomized rats exhibited severe sialaden hypofunction, including decreased saliva secretion and ion reabsorption as well as increased water intake. Immunohistochemistry revealed that the expression of NDRG2 and Na(+) reabsorption-related Na(+)/K(+)-ATPase and epithelial sodium channels (EnaC) decreased in ovariectomized rat salivary glands. We further showed that the localized delivery of NDRG2 improved the dysfunction of Na(+) and Cl(-) reabsorption. In addition, the saliva flow rate and water drinking recovered to normal. This study elucidates the mechanism of estrogen deficiency-mediated xerostomia or sialaden hypofunction and provides a promising strategy for therapeutic intervention.
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http://dx.doi.org/10.1038/mt.2013.286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015234PMC
May 2014

Involvement of a chromatin modifier in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell injury: probably an indirect action via the regulation of NFκB/FasL circuitry.

Biochem Biophys Res Commun 2013 Nov 8;440(4):749-55. Epub 2013 Oct 8.

Department of Urology, 174th Hospital of PLA, Fujian 361001, China.

The Fas/FasL signaling pathway, controlled by nuclear factor-κB (NFκB) at the transcriptional level, is critical for triggering germ cell apoptosis in response to mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cell (SC) injury, but the exact regulation mechanism remain unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), a component of the Mi-2/nucleosome remodeling and deacetylase complex, was upregulated in SCs during the early recovery after MEHP exposure. This expression change was in line with the dynamic changes in germ cell apoptosis in response to MEHP treatment. Furthermore, a knockdown of MTA1 by RNAi in SCs was found to impair the MEHP-induced early activation of NFκB pathway and abolish the recruitment of NFκB onto FasL promoter, which consequently diminished the MEHP-triggered FasL induction. Considering that Fas/FasL is a well characterized apoptosis initiating signaling during SCs injury, our results point to a potential "switch on" effect of MTA1, which may govern the activation of NFκB/FasL cascade in MEHP-insulted SCs. Overall, the MTA1/NFκB/FasL circuit may serve as an important defensive/repairing mechanism to help to control the germ cell quality after SCs injury.
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http://dx.doi.org/10.1016/j.bbrc.2013.09.135DOI Listing
November 2013

NDRG2 is a novel p53-associated regulator of apoptosis in C6-originated astrocytes exposed to oxygen-glucose deprivation.

PLoS One 2013 22;8(2):e57130. Epub 2013 Feb 22.

Department of Anesthesiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.

N-myc downstream-regulated gene 2 (NDRG2) has been documented to be a pro-differentiative and anti-proliferative gene in cancer research. Our previous study found a significant NDRG2 up-regulation in reactive astrocytes of penumbra after transient focal cerebral ischemia, which was parallel to the enhancement of TUNEL-positive signals. However, it is still uncertain whether NDRG2 participates in cellular apoptosis induced by ischemia-reperfusion injury in brain. In this study, we investigated the role of NDRG2 in cellular apoptosis induced by oxygen-glucose deprivation (OGD) in IL-6-differentiated C6 glioma cells. The results showed that NDRG2 was up-regulated and translocated from the cytoplasm to the nucleus after OGD exposure. NDRG2 over-expression exhibited an anti-proliferative effect and increased the Bax/Bcl-2 ratio after OGD exposure, while NDRG2 silencing promoted the cellular proliferation and attenuated the up-regulation of Bax/Bcl-2 ratio. The pro-apoptotic effect of p53 was verified by the results in which p53 silencing greatly reduced the percentage of OGD-induced apoptotic cells. p53 silencing also reduced the OGD-induced NDRG2 up-regulation. However, over-expression of p53 did not further improve the NDRG2 up-regulation. In conclusion, NDRG2 is a p53-associated regulator of apoptosis in C6-originated astrocytes after OGD exposure. These findings bring insight to the roles of NDRG2 in ischemic-hypoxic injury and provide potential targets for future clinical therapies on stroke.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057130PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579777PMC
September 2013

Expression of Rap1 during germ cell development in the rat and its functional implications in 2-methoxyacetic acid-induced spermatocyte apoptosis.

Urology 2013 Mar 3;81(3):696.e1-8. Epub 2013 Jan 3.

Institute of Clinical Laboratory Medicine, Nanjing Jinling Hospital, Nanjing University Clinical School of Medical College, Nanjing, China.

Objective: To investigate the expression pattern of Ras-related protein 1 (Rap1) during testicular development and to clarify whether its expression is developmentally regulated and whether this expression is involved in the process of germ cell apoptosis.

Materials And Methods: The expression pattern of Rap1 in the adult rat testicle was compared with that in the developing rat testicle using immunoblotting and immunohistochemical analyses. After the adult rats were treated with methoxyacetic acid (MAA), which selectively depletes primary spermatocytes, we correlated Rap1 expression with apoptotic dynamics using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), double immunofluorescent staining, and coimmunoprecipitation assays.

Results: During testicular development, Rap1 was expressed in the nucleus of gonocytes and in the Golgi apparatus of spermatocytes. The expression pattern of Rap1 during spermatogenesis was also shown to be stage specific. After 12 hours of MAA treatment, we found that Rap1 was translocated into the nucleus of some spermatocytes and the overlapping rate of Rap1 and NF-κB was much greater than that of Rap1 and TUNEL staining. In addition, Rap1 protein could be co-immunoprecipitated with NF-κB protein.

Conclusion: In cooperation with NF-κB, Rap1 might be involved in the early stage of the apoptotic process occurring in the MAA-treated rat testicle. Additional characterization of this small guanosine triphosphatase in the apoptotic dynamics should provide information on the early diagnosis of MAA-induced male infertility.
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http://dx.doi.org/10.1016/j.urology.2012.11.005DOI Listing
March 2013

Effects of PEMF on microcirculation and angiogenesis in a model of acute hindlimb ischemia in diabetic rats.

Bioelectromagnetics 2013 Apr 5;34(3):180-8. Epub 2012 Sep 5.

Department of Internal Medicine, 92th Hospital, Nanping, China.

Hindlimb ischemia is a major complication of diabetic patients due to poor neovascularization. Therapy with pulsed electromagnetic fields (PEMF) can promote angiogenesis in ischemic lesions. However, the efficacy and therapeutic mechanisms of PEMF in diabetes-related hindlimb ischemia are unclear. Sprague-Dawley rats were injected with streptozocin to induce diabetes, and 10 weeks later diabetic rats were subjected to surgical induction of acute hindlimb ischemia. The rats were randomized and treated with PEMF, and the blood perfusion of individual rats was determined longitudinally by laser Doppler perfusion imaging (LDPI). The neovascular density was examined using immunofluorescent analysis of CD31 expression and alkaline phosphatase (AP) staining. The levels of VEGF, VEGFR, FGF-2, and FGFR1 expression, and ERK 1/2 and P38 phosphorylation in the muscles were characterized using enzyme-linked immunosorbent assay (ELISA) and Western blot assays. The values of LDPI in the PEMF-treated rats at 14 and 28 days post surgery were significantly greater than those in the controls, accompanied by significantly elevated levels of anti-CD31 and AP staining. The relative levels of FGF-2 and FGFR1, but not VEGF and VEGFR expression, and ERK1/2, but not P38 phosphorylation, in the muscles of the PEMF-treated rats were significantly higher than those in the controls. Our data indicated that PEMF enhanced acute hindlimb ischemia-related perfusion and angiogenesis, associated with up-regulating FGF-2 expression and activating the ERK1/2 pathway in diabetic rats. Therefore, PEMF may be valuable for the treatment of diabetic patients with ischemic injury.
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http://dx.doi.org/10.1002/bem.21755DOI Listing
April 2013

Microarray profiling of HepG2 cells ectopically expressing NDRG2.

Gene 2012 Jul 25;503(1):48-55. Epub 2012 Apr 25.

Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, People's Republic of China.

Previous studies have demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor that is downregulated in many human cancers and when overexpressed, can inhibit tumor growth and metastasis. However, its molecular function, its modulatory targets, and signaling pathways associated with it remain unclear. Here, in an effort to identify the genes modulated by NDRG2 expression, a microarray study was conducted to detect the expression profile of HepG2 cells overexpressing NDRG2 or LacZ. Gene Ontology (GO) biological process analysis revealed that genes related to G protein signaling pathway were upregulated. Five of them were selected and verified by real-time PCR. Gene sets related to M phase of cell cycle were downregulated. This was in agreement with cell cycle analysis. Signaling pathway analysis demonstrated apparent augmented hematopoietic cell lineage pathway and cell adhesion, but reduced glycosylphosphatidylinositol (GPI)-anchor biosynthesis, protein degradation and SNARE interactions. Furthermore, through motif analysis and experimental validation, we found that the p38 phosphorylation can be increased by NDRG2. Our research provides the molecular basis for understanding the role of NDRG2 in tumor cells and raises interesting questions about its mechanisms and potential use in cancer therapy.
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http://dx.doi.org/10.1016/j.gene.2012.04.044DOI Listing
July 2012

Hypoxia-induced deacetylation is required for tetraploid differentiation in response to testicular ischemia-reperfusion (IR) injury.

J Androl 2012 Nov-Dec;33(6):1379-86. Epub 2012 May 3.

Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China.

Accumulated understanding of epigenetic modifications during ischemia-reperfusion (IR) injury suggests that additional targeted approaches and novel mechanisms that have not been explored in the reproductive system underlie the pathogenesis. Here we show, with a standard murine model of testicular IR, ischemia-induced histone deacetylase (HDAC) activity in the testis with concomitant reduction in histone acetyl transferase activity in vivo. Pretreatment with chemical HDAC inhibitors significantly induced apoptosis in tetraploid pachytene spermatocytes during ischemic insult and thereafter resulted in attenuated meiotic differentiation. We also identified the distinct HDACs involved in primary spermatocytes upon hypoxic stress. In vitro, elevated expression of HDAC2 was physiologically associated with p53, a master regulator believed to be a guardian of genome integrity during spermatogenesis. p53-mediated apoptosis was inhibited by deacetylation of p53 in differentiating pachytene spermatocytes in response to ischemic stress. Overall, the current data suggest that hypoxia-induced deacetylation may operate as an indispensible defensive mechanism for meiotic differentiation during the ischemic period of IR testis, thus pointing to a novel therapeutic target for future medical intervention.
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http://dx.doi.org/10.2164/jandrol.112.016584DOI Listing
October 2014

N-myc downstream-regulated gene 2, a novel estrogen-targeted gene, is involved in the regulation of Na+/K+-ATPase.

J Biol Chem 2011 Sep 19;286(37):32289-99. Epub 2011 Jul 19.

Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.

Na(+)/K(+)-ATPase, a plasma membrane protein abundantly expressed in epithelial tissues, has been identified and linked to numerous biological events, including ion transport and reabsorption. In Na(+)/K(+)-ATPase, the β-subunit plays a fundamental role in the structural integrity and functional maturation of holoenzyme. Estrogens are important circulating hormones that can regulate Na(+)/K(+)-ATPase abundance and activity; however, the specific molecules participating in this process are largely unknown. Here, we characterize that N-myc downstream-regulated gene 2 (NDRG2) is an estrogen up-regulated gene. 17β-Estradiol binds with estrogen receptor β but not estrogen receptor α to up-regulate NDRG2 expression via transcriptional activation. We also find that NDRG2 interacts with the β1-subunit of Na(+)/K(+)-ATPase and stabilizes the β1-subunit by inhibiting its ubiquitination and degradation. NDRG2-induced prolongation of the β1-subunit protein half-life is accompanied by a similar increase in Na(+)/K(+)-ATPase-mediated Na(+) transport and Na(+) current in epithelial cells. In addition, NDRG2 silencing largely attenuates the accumulation of β1-subunit regulated by 17β-estradiol. Our results demonstrate that estrogen/NDRG2/Na(+)/K(+)-ATPase β1 pathway is important in promoting Na(+)/K(+)-ATPase activity and suggest this novel pathway might have substantial roles in ion transport, fluid balance, and homeostasis.
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http://dx.doi.org/10.1074/jbc.M111.247825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173200PMC
September 2011

Evaluation of global DNA hypomethylation in human prostate cancer and prostatic intraepithelial neoplasm tissues by immunohistochemistry.

Urol Oncol 2013 Jul 25;31(5):628-34. Epub 2011 Jun 25.

Department of Urology, Xijing Hospital, Fourth Military Medical University, State Key Laboratory of Cancer Biology, Shaanxi, 710032, China.

Objective: To identify the differences of 5-methylcytosine (5-MC) level between primary prostate cancer tissues (PCTs), prostate cancer-adjacent benign tissues (PCABTs), low-grade prostatic intraepithelial neoplasia (LGPIN), and high-grade prostatic intraepithelial neoplasia (HGPIN), and further analysis the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis.

Materials And Methods: Immunohistochemistry method with a 5-MC monoclonal antibody was used to identify the 5-methylcytosine (5-MC) levels in PCTs, PCABTs, LGPIN, and HGPIN specimens in the present study. Statistical analysis with SPSS software (SPSS Inc., Chicago, IL) was used to compare differences of 5-MC levels in the four groups and evaluate the 5-MC alterations in prostate cancer with pathologic grade and clinical prognosis.

Results: We found that 38 of 48 (79.1%) patients studied showed a decrease in 5-MC staining of PCTs compared with PCABTs. The difference in the methylation levels for the PCTs and the PCABTs was highly statistically significant (P < 0.001). Spearman correlation showed there was no statistically significant association between the average score of 5-MC staining and Gleason score sum. Kaplan-Meier survival analysis showed that patient group with no or weak 5-MC staining compared with group with moderate and strong 5-MC staining was associated with better survival of patients, although there was no statistically significant difference between the 2 groups in predicating prognosis (P = 0.385). The average scores of 5-MC staining for LGPIN, HGPIN, PCABTs, and PCTs groups were 6.91, 1.58, 6.63, and 3.10, respectively. The methylation level of HGPIN group, as well as that of PCTs group, was significantly lower than those of LGPIN (P < 0.001; P < 0.001) and PCABTs groups (P < 0.001; P < 0.001), respectively, with the 5-MC levels of PCABTS group similar to that of LGPIN group (P = 0.476). 5-MC levels of HGPIN group was lower than that PCTs group (P = 0.004).

Conclusions: We found that global DNA methylation was low in most prostate cancer compared with benign regions from the same patient's sections. None of the DNA hypomethylation changes in primary cancers were associated with pathologic grade and clinical prognosis. In addition, immunohistochemistry showed that the global methylation was lower in HGPIN compared with LGPIN and methylcytosine staining in HGPIN was lower than that of PCTs. The results suggest that global DNA hypomethylation might play an important role in the process of prostate cancer initiation rather than progression.
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http://dx.doi.org/10.1016/j.urolonc.2011.05.009DOI Listing
July 2013
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