High-mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been reevaluated to be a prototypical damage-associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen-associated molecular pattern (PAMP), completes the body's alarmin system against disturbances in homeostasis. HMGB1 can be released into the extracellular matrix (ECM) by either granulocytes or necrotic cells to serve as a chemotaxis/cytokine during infection, endotoxemia, hypoxia, ischemia-reperfusion events, and cancer. Different isoforms of HMGB1 present with distinctive physiological functions in ECM-fully-reduced HMGB1 (all thiol) acts as the initial damage signal to recruit circulating myeloid cells, disulfide HMGB1 behaves as a cytokine to activate macrophages and neutrophils, and both signals are turned off when HMGB1 is terminally oxidized into the final sulfonate form. Targeting HMGB1 constitutes a favorable therapeutic strategy for inflammation and inflammatory diseases. Antagonists such as ethyl pyruvate inhibit HMGB1 by interfering with its cytoplasmic exportation, while others such as glycyrrhizin directly bind to HMGB1 and render it unavailable for its receptors. The fact that a mixture of different HMGB1 isoforms is present in the ECM poses a challenge in pinpointing the exact role of an individual antagonist. A more discriminative probe for HMGB1 may be necessary to advance our knowledge of HMGB1, HMGB1 antagonists, and inflammatory-related diseases.

HMGB1 as a therapeutic target in disease.

Anti-HMGB1 monoclonal antibody therapy for a wide range of CNS and PNS diseases.

Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti-epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high-mobility group box protein 1 (HMGB1), a DNA-binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1-targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14663

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Natural products as a potential modulator of microglial polarization in neurodegenerative diseases.

Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

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High Mobility Group Box-1 and Blood-Brain Barrier Disruption.

The inflammatory mediator high-mobility group box 1 (HMGB1) plays a critical role in the pathogenesis of human multiple sclerosis (MS) and mouse experimental autoimmune encephalomyelitis (EAE). Glycyrrhizin (GL), a glycoconjugated triterpene extracted from licorice root, has the ability to inhibit the functions of HMGB1; however, GL's function against EAE has not been thoroughly characterized to date. To determine the benefit of GL as a modulator of neuroinflammation, we used an in vivo study to examine GL's effect on EAE along with primary cultured cortical neurons to study the GL effect on HMGB1 release. Treatment of EAE mice with GL from onset to the peak stage of disease resulted in marked attenuation of EAE severity, reduced inflammatory cell infiltration and demyelination, decreased tumor necrosis factor-alpha (TNF-α), IFN-γ, IL-17A, IL-6, and transforming growth factor-beta 1, and increased IL-4 both in serum and spinal cord homogenate. Moreover, HMGB1 levels in different body fluids were reduced, accompanied by a decrease in neuronal damage, activated astrocytes and microglia, as well as HMGB1-positive astrocytes and microglia. GL significantly reversed HMGB1 release into the medium induced by TNF-α stimulation in primary cultured cortical neurons. Taken together, the results indicate that GL has a strong neuroprotective effect on EAE mice by reducing HMGB1 expression and release and thus can be used to treat central nervous system inflammatory diseases, such as MS.

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Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release.

Despite remarkable advances in our understanding of brain functions, the neural substrates and correlates of consciousness remain unclear [1]. It has been argued that classical physics is intrinsically incapable of explaining the holistic aspects of consciousness, especially its hard problem: phenomenal consciousness (P-consciousness) [2]. Several theorists have therefore proposed quantum mind theories of consciousness such as the Orch-OR (Orchestrated objective reduction) theory [3]; they offer descriptions of P-consciousness and interpretations of access consciousness (A-consciousness) based on quantum mechanics or quantum models. Recent experimental findings have suggested that biophotonic activity and transmission in neural circuits may be involved in the higher brain functions associated with consciousness and may play an important role in the generation of the quantum mind [4–6]; however, the underlying mechanisms are far from being understood. Although there are disagreements regarding the categorization of consciousness, it has been widely accepted that in human beings it can be divided into sub-consciousness, unconsciousness, and consciousness, and animals may also have similar states [7]. Many studies have shown that neurotransmitters and their receptors in the brain have close relationships with altered states of consciousness. Acetylcholine (ACh) plays an important role in the enhancement of alertness, in sustaining attention, and in learning and memory. Dopamine (DA) contributes to the action-selection process and plays roles in the decisionmaking and reward systems. The effects of norepinephrine (NE) manifest as alertness, arousal, and readiness for action. 5-Hydroxytryptamine (5-HT) regulates mood, appetite, and sleep, as well as some cognitive functions, including learning and memory. In addition, theoretical analyses have proposed that 5-HT plays a possible quantum role in consciousness [8]. Therefore, it is interesting to investigate whether the biophotonic activity and transmission mediated by neurotransmitters are related to the origin of consciousness and its different states. We have previously demonstrated that a long-lasting application of 50 mmol/L glutamate to a mouse brain slice leads to a gradual and significant increase in biophotonic activity and achieves the maximal effect within *90 min (initiation period) and then presents a stable state for up to several hours (maintenance period) [4]. Here, we found that the mean intensity of biophotonic activity in the early maintenance period (91–150 min) (Fig. S1A, B) not only showed a relatively stable level for a period of days but Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12264-018-0215-9) contains supplementary material, which is available to authorized users.

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Biophotonic Activity and Transmission Mediated by Mutual Actions of Neurotransmitters are Involved in the Origin and Altered States of Consciousness.

Glutamate is the most abundant excitatory neurotransmitter in the brain, and it plays an essential and important role in neural functions. Current studies have shown that glutamate can induce neural biophotonic activity and transmission, which may involve the mechanism of photon quantum brain; however, it is unclear whether such a mechanism follows the principle of quantum mechanics. Here we show that the action of glutamate on its receptors leads to a decrease in its quantum energy levels, and glutamate then partially or completely loses its function to further induce the biophotonic activity in mouse brain slices. The reduced quantum energy levels of glutamate can be restored by direct-current electrical discharges and the use of energy transfer of chloroplast photosynthesis; hence, the quantum energy recovered glutamate can again induce significant biophotonic activity. Furthermore, the changes in quantum energy levels of glutamate are related to the exchange and transfer of electron energy on its active hydrogen atom. These findings suggest that the glutamate-induced neural biophotonic signals may be involved in the transfer of the quantum energy levels of glutamate, which implies a quantum mechanism of neurotransmitter action.

/pdf/quantum-energy-levels-of-glutamate-modulate-neural-1sspmg2yu7.pdf

Quantum energy levels of glutamate modulate neural biophotonic signals.

Glutamate is the most abundant excitatory neurotransmitter in the brain, and it plays an essential and important role in neural functions. Hypofunction of the glutamatergic pathway and the changes in the glutamate-glutamine cycle function are important neuropathological mechanisms of severe mental disorders including schizophrenia and depression. Current studies have shown that glutamate can induce neural biophotonic activity and transmission, which may involve the mechanism of photon quantum brain; however, it is unclear whether such a mechanism follows the principle of quantum mechanics. Here we show that the action of glutamate on its receptors leads to a decrease in its quantum energy levels, and glutamate then partially or completely loses its function to further induce the biophotonic activity in mouse brain slices. The reduced quantum energy levels of glutamate can be restored by direct-current electrical discharges and the use of energy transfer of chloroplast photosynthesis; hence, the quantum energy recovered glutamate can again induce significant biophotonic activity. Furthermore, the changes in quantum energy levels of glutamate are related to the exchange and transfer of electron energy on its active hydrogen atom. These findings suggest that the glutamate-induced neural biophotonic signals may be involved in the transfer of the quantum energy levels of glutamate, which implies a quantum mechanism of neurotransmitter action. The process of glutamate recycling that is related to the synergism of neurons and glial cells and certain key enzymes may be necessary for the recovery of quantum energy levels of glutamate after completion of the neural signal transmission. These findings may also provide a new idea to develop quantum drugs.

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Quantum energy levels of glutamate modulate neural biophotonic signals

The invention provides an application of a generic technology for electric stimulation to increase biomolecular and quantum energy. As a result of difference between an atom and electrons outside of the atom in a biomolecule in quantum level, a ultra-weak biophoton imaging system (UBIS) is applied to detecting. For the biomolecules subjected to direct current or alternating current electric stimulation, electric spark electric stimulation, electromagnetic stimulation of different strength and frequencies or electric stimulation by employing an electron gun which emits electrons, the quantum level of the biomolecule can be improved and radiation of biomolecule-induced biophotons of a brain slice can be obviously enhanced. Experiments detect and verify that the application of a generic technology for electric stimulation to increase biomolecular quantum energy has the characteristics of being simple to operate, reliable, high in efficiency, good in expandability, rich in function and thelike, can be applied to quantum energy increase of various biomolecules, and has application value in life medical research, novel drug research, preparation development, natural and conventional drug modification, quantum biomedical prevention and treatment, chemical industry, agricultural production, functional food and environmental protection and the like.

Zhengrong Han

Papers

Glycyrrhizin Protects Mice Against Experimental Autoimmune Encephalomyelitis by Inhibiting High-Mobility Group Box 1 (HMGB1) Expression and Neuronal HMGB1 Release.

Biophotonic Activity and Transmission Mediated by Mutual Actions of Neurotransmitters are Involved in the Origin and Altered States of Consciousness.

Quantum energy levels of glutamate modulate neural biophotonic signals.

Quantum energy levels of glutamate modulate neural biophotonic signals

Application of generic technology for electric stimulation to increase biomolecular quantum energy