Jie Lv

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

Adenosine is a key endogenous signaling molecule that regulates immune responses. A2B adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A2BAR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A2BAR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A2BAR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A2BAR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cβ–protein kinase C and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL-6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.

Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis

Cysteinyl leukotrienes (CysLTs) are potent proinflammatory mediators and are considered to play a key role in inflammatory diseases such as asthma. Antagonists targeting the receptor of CysLTs (CysLT1) are currently used as antiasthmatic drugs. CysLTs have also been implicated in other inflammatory reactions. In this study, we report that in experimental autoimmune encephalomyelitis animals, CysLT1 is upregulated in immune tissue and the spinal cord, and CysLT levels in the blood and cerebrospinal fluid are also higher than in normal mice. Two clinically used antiasthma drugs, montelukast and zafirlukast, both targeting CysLT1, effectively block the CNS infiltration of inflammatory cells and thus reduce the incidence, peak severity, and cumulative clinical scores. Further study indicated that CysLT1 signaling does not affect the differentiation of pathogenic T helper cells. It might affect the pathogenesis of experimental autoimmune encephalomyelitis by increasing the secretion of IL-17 from myelin oligodendrocyte glycoprotein-specific T cells, increasing the permeability of the blood–brain barrier and inducing chemotaxis of T cells. These effects can be blocked by CysLT1 antagonists. Our findings indicate that the antiasthmatic drugs against CysLT1 can also be used to treat multiple sclerosis.

The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis

Background: Dysregulation of T cell survival and apoptosis is the common cause of autoimmune diseases including multiple sclerosis (MS). Results: Valproic acid (VPA) treatment restores the dysregulated apoptosis of T cells and reduces the symptoms of EAE. Conclusion: In addition to the antiepileptic activity, VPA also regulates T cell homeostasis. Significance: As an orally available drug, VPA might be used to treat autoimmune diseases, such as MS. Maintaining a constant number and ratio of immune cells is one critical aspect of the tight regulation of immune homeostasis. Breakdown of this balance will lead to autoimmune diseases such as multiple sclerosis (MS). The antiepileptic drug valproic acid (VPA) was reported to regulate the growth, survival, and differentiation of many cells. However, its function in T cell homeostasis and MS treatment remains unknown. In this study, VPA was found to reduce spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis, a mouse model of MS. Further study indicated that VPA induces apoptosis in activated T cells and maintains the immune homeostasis. This effect was found to be mainly mediated by the caspase-8/caspase-3 pathway. Interestingly, this phenomenon was also confirmed in T cells from normal human subjects and MS patients. Considering the long history of clinical use and our new findings, we believe VPA might be a safe and effective therapy for autoimmune diseases, such as multiple sclerosis.

Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination

Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.

Activation of A 1 and A 2a Adenosine Receptors Promotes Neural Progenitor Cell Proliferation

Neural progenitor cells (NPCs) play a key role not only in the maintenance of the adult central nervous system (CNS) but also in the ability to recover from injury and disease. In this study, we established a 96-well-based screening system to screen small molecules modulating the proliferation of NPCs. A compound library composed of 1280 compounds was screened. We found that the A1 adenosine receptor agonist cyclopentyladenosine (CPA) and the A2a adenosine receptor agonist CGS-21680 increased proliferation of NPCs. The A1 adenosine receptor agonist-induced cell proliferation was attenuated by A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPA). Accordingly, the A2a adenosine receptor agonist-induced cell proliferation was attenuated by A2a adenosine receptor antagonist SCH-58261. Further study indicated that CPA and CGS-21680 treatment induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and CPA-induced or CGS-21680-induced cell proliferation was inhibited by ERK and Akt inhibitors. These results suggested that the activation of A1 and A2a adenosine receptor stimulated the proliferation of NPCs via the ERK and Akt signaling pathways.

Investigation on dynamic equalisation performance of lithium battery pack management

Lithium batteries must be connected in series to achieve large capacity and high-power output. Battery management system (BMS), which is designed to protect battery pack from damage and increase battery life, is important in electrical power system. The present equalisation techniques have many disadvantages: The passive balancing wastes energy and generates heat, while active balancing is complex. This study proposes an intelligent BMS with dynamic equalisation (DBMS) which contains active and passive balancing circuit independently per cell. Experimental results indicate that DBMS can reduce the inconsistency among cells. Moreover, the DBMS can assist battery stack to store and release more energy. Besides, the battery stack with DBMS gives an energy efficiency of 96.5% which is 7.7% higher than that without balancing. In addition, the battery stack with DBMS can reduce the maximum state of charge difference of cells from 10.415% to 4.51% after three charge-discharge cycles. What is more, the DBMS is simple and can decrease the auxiliary power level and the system heat. Such a DBMS will help us to provide a high-performance battery pack.

Development of supervising system for battery energy storage system based on the two-level architecture

The real-time monitoring of status parameters, such as cell voltage and state of charge (SOC), is an important guarantee of the safety operation of the battery energy storage system (BESS). And the two-level architecture of hardware system which includes several battery management units (BMU) and the central management unit (CMU) is designed with the communication protocol and data conversion algorithm for achieving the data acquisition and communication. Moreover, an enhanced SOC method involving the resting time and the terminal voltage is researched and programmed in the software system. The battery supervising system is verified by lots of experiments that it could satisfy the monitoring demand of BESS and has improved the accuracy of SOC estimation effectively.

Research on the capacity of hybrid energy storage system and its control method in rail transit traction grid

The hybrid energy storage system (HESS) composed of super capacitors and batteries is proposed in this paper for the power supply system of rail transmit to prevent the overtension of grid voltage caused by the braking energy. According to the power fluctuations and allocation principle, the capacity and control method of HESS are designed to achieve the voltage stabilization of the traction grid as well as the proportion optimization between super capacitors and batteries. The simulation results show that HESS could restrain the voltage within the safety operating range and effectively reduce the redundant capacity and cost of the system.