Glia-based biomarkers and their functional role in the CNS.

Jha, Mithilesh Kumar,Suk, Kyoungho Future Drugs Ltd 2013 Expert review of proteomics Vol.10 No.1

<P>Glial cells, a close partner to neurons, are able to communicate with each other and with neurons through secreted proteins and other molecules. Secreted proteins in the extracellular environment probably play a direct role in the control and regulation of numerous biological and disease processes in the nervous system. Provision of precise diagnosis and prognosis to patients with a neurological disorder is problematic. Glial activation is a hallmark of every type of injury to the nervous system. In these circumstances, it is the glial biomarker whose development and implementation can be the most suitable approach to assessment of neuroinflammation and neurotoxicity. Here, the importance of glial secreted proteins as diagnostic/prognostic biomarkers and their functional contribution to regulation of neuroinflammation are reviewed. Evidence for the use of glia-based biomarkers for improvement of diagnostic and prognostic accuracy is also summarized and recommendations for future glia-based biomarker research are provided.</P>

Functional dissection of astrocyte-secreted proteins: Implications in brain health and diseases

Jha, Mithilesh Kumar,Kim, Jong-Heon,Song, Gyun Jee,Lee, Won-Ha,Lee, In-Kyu,Lee, Ho-Won,An, Seong Soo A.,Kim, SangYun,Suk, Kyoungho Elsevier 2018 Progress in neurobiology Vol.162 No.-

<P><B>Abstract</B></P> <P>Astrocytes, which are homeostatic cells of the central nervous system (CNS), display remarkable heterogeneity in their morphology and function. Besides their physical and metabolic support to neurons, astrocytes modulate the blood-brain barrier, regulate CNS synaptogenesis, guide axon pathfinding, maintain brain homeostasis, affect neuronal development and plasticity, and contribute to diverse neuropathologies via secreted proteins. The identification of astrocytic proteome and secretome profiles has provided new insights into the maintenance of neuronal health and survival, the pathogenesis of brain injury, and neurodegeneration. Recent advances in proteomics research have provided an excellent catalog of astrocyte-secreted proteins. This review categorizes astrocyte-secreted proteins and discusses evidence that astrocytes play a crucial role in neuronal activity and brain function. An in-depth understanding of astrocyte-secreted proteins and their pathways is pivotal for the development of novel strategies for restoring brain homeostasis, limiting brain injury/inflammation, counteracting neurodegeneration, and obtaining functional recovery.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Astrocytes are important regulators of brain functions, and crucial functions are executed via astrocyte-secreted proteins. </LI> <LI> Astrocyte-secreted proteins play key roles in physiological processes and execute both detrimental and beneficial actions in CNS disorders. </LI> <LI> Understanding the many functions of astrocyte-secreted proteins under specific spatiotemporal conditions may lead to major advancements in astrocyte biology. </LI> <LI> Functional dissection of astrocyte-secreted proteins can facilitate the development of novel diagnostic and therapeutic strategies for neurological disorders. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Pyruvate Dehydrogenase Kinase as a Potential Therapeutic Target for Malignant Gliomas

( Mithilesh Kumar Jha ),( Kyoungho Suk ) 대한뇌종양학회·대한신경종양학회·대한소아뇌종양학회 2013 Brain Tumor Research and Treatment Vol.1 No.2

Metabolic aberrations in the form of altered flux through key metabolic pathways are the major hallmarks of several life-threatening malignancies including malignant gliomas. These adaptations play an important role in the enhancement of the survival and proliferation of gliomas at the expense of the surrounding normal/healthy tissues. Recent studies in the field of neurooncology have directly targeted the altered metabolic pathways of malignant tumor cells for the development of anti-cancer drugs. Aerobic glycolysis due to elevated production of lactate from pyruvate regardless of oxygen availability is a common metabolic alteration in most malignancies. Aerobic glycolysis offers survival advantages in addition to generating substrates such as fatty acids, amino acids and nucleotides required for the rapid proliferation of cells. This review outlines the role of pyruvate dehydrogenase kinase (PDK) in gliomas as an inhibitor of pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate. An in-depth investigation on the key metabolic enzyme PDK may provide a novel therapeutic approach for the treatment of malignant gliomas.

Acute Phase Protein Lipocalin-2 Is Associated with Formalin-induced Nociception and Pathological Pain

Mithilesh Kumar Jha,Sangmin Jeon,Myungwon Jin,이원하,석경호 대한면역학회 2013 Immune Network Vol.13 No.6

Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/ biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.

Glia as a Link between Neuroinflammation and Neuropathic Pain

Mithilesh Kumar Jha,전상민,석경호 대한면역학회 2012 Immune Network Vol.12 No.2

Contemporary studies illustrate that peripheral injuries activate glial components of the peripheral and central cellular circuitry. The subsequent release of glial stressors or activating signals contributes to neuropathic pain and neuroinflammation. Recent studies document the importance of glia in the development and persistence of neuropathic pain and neuroinflammation as a connecting link, thereby focusing attention on the glial pathology as the general underlying factor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a key process in nervous system disorders involving the release of strong pro-inflammatory cytokines, which can trigger worsening of multiple disease states. This review will briefly discuss the recent findings that have shed light on the molecular and cellular mechanisms of glia as a connecting link between neuropathic pain and neuroinflammation.

Innate immune proteins as biomarkers for CNS injury: critical evaluation (WO2013119673 A1)

Jha, Mithilesh Kumar,Lee, Ho-Won,Kim, SangYun,Suk, Kyoungho Informa UK, Ltd. 2015 Expert opinion on therapeutic patents Vol.25 No.2

<P><B><I>Introduction:</I></B> Injuries to the CNS represent a major global health problem. CNS injuries cause the elevation of many proteins, including innate immune proteins in biological fluids, such as the cerebrospinal fluid (CSF). These innate immune proteins can be considered as biomarkers to predict the severity of CNS injury in patients.</P><P><B><I>Areas covered:</I></B> This invention describes a method for the diagnosis/prognosis, treatment or rehabilitation efforts, and monitoring of post-treatment responses after CNS injuries in a patient, based on the detection and quantification of the expression levels of protein components of inflammasomes in the CSF. This study evaluates the elevated levels of inflammasome proteins such as NLRP1 (NAcht leucine-rich-repeat protein 1), ASC and caspase-1 in biological samples as important biomarkers that can assess the extent of neuroinflammation and reflect the magnitude of inflammation-induced damage following CNS injury.</P><P><B><I>Expert opinion:</I></B> Although inflammasome proteins may be of great clinical significance in the near future, a more detailed analysis of inflammasome proteins needs to be taken into account for the prognosis and treatment of diverse CNS conditions. Moreover, the potential inflammasome biomarker candidates have to be validated in a large number of patients for an extended period post-injury to further support clinical relevance.</P>

Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis

Jha, Mithilesh Kumar,Song, Gyun Jee,Lee, Maan Gee,Jeoung, Nam Ho,Go, Younghoon,Harris, Robert A.,Park, Dong Ho,Kook, Hyun,Lee, In-Kyu,Suk, Kyoungho Society for Neuroscience 2015 The Journal of neuroscience Vol.35 No.42

<P>Pyruvate dehydrogenase kinases (PDK1–4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of <I>Pdk2</I> and/or <I>Pdk4</I> in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, <I>Pdk2/4</I> deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. <I>In vitro</I> studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain.</P><P><B>SIGNIFICANCE STATEMENT</B> The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis.</P>

Metabolic Control of Glia-Mediated Neuroinflammation

Kumar Jha, Mithilesh,Ho Park, Dong,Kook, Hyun,Lee, In-Kyu,Lee, Won-Ha,Suk, Kyoungho Bentham Science 2016 Current Alzheimer research Vol.13 No.4

<P>The central nervous system (CNS) shows dynamic immune and inflammatory responses to a variety of insults having crucial implications for reactive gliosis. Glial cells in the CNS serve not only as the source, but also as targets of proinflammatory mediators. Undoubtedly, these cells efficiently work towards the disposal of tissue debris and promotion of wound healing as well as tissue repair. However, these non-neuronal glial cells synthesize and release numerous inflammatory mediators, which can be detrimental to neurons, axons, myelin, and the glia themselves. While an acute insult is typically transient and unlikely to be detrimental to neuronal survival, chronic neuroinflammation is a long-standing and often self-perpetuating response, which persists even long after the initial injury or insult. It can serve as a point of origin for diverse neurological disorders including Alzheimer's disease. Accumulating evidence demonstrates the contribution of metabolic dysfunction and mitochondrial failure to the pathogenesis of neuroinflammatory and neurodegenerative diseases. Neurodegenerative conditions are also characterized by increased oxidative and endoplasmic reticulum stresses and autophagy defects. Furthermore, neuroinflammatory conditions are accompanied by an alteration in glial energy metabolism. Here, we comprehensively review the metabolic hallmarks of glia-mediated neuroinflammation and how the glial metabolic shift orchestrates the neuroinflammatory response and pathophysiology of diverse neurological disorders.</P>

Acute Phase Protein Lipocalin-2 Is Associated with Formalin-induced Nociception and Pathological Pain

Jha, Mithilesh Kumar,Jeon, Sangmin,Jin, Myungwon,Lee, Won-Ha,Suk, Kyoungho The Korean Association of Immunobiologists 2013 Immune Network Vol.13 No.6

Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.

Glia as a Link between Neuroinflammation and Neuropathic Pain

Jha, Mithilesh Kumar,Jeon, Sang-Min,Suk, Kyoung-Ho The Korean Association of Immunobiologists 2012 Immune Network Vol.12 No.2

Contemporary studies illustrate that peripheral injuries activate glial components of the peripheral and central cellular circuitry. The subsequent release of glial stressors or activating signals contributes to neuropathic pain and neuroinflammation. Recent studies document the importance of glia in the development and persistence of neuropathic pain and neuroinflammation as a connecting link, thereby focusing attention on the glial pathology as the general underlying factor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a key process in nervous system disorders involving the release of strong pro-inflammatory cytokines, which can trigger worsening of multiple disease states. This review will briefly discuss the recent findings that have shed light on the molecular and cellular mechanisms of glia as a connecting link between neuropathic pain and neuroinflammation.