Electrical Control in Neurons by the Ketogenic Diet

The ketogenic diet is used as a diet treatment for drug-resistant epilepsy, but there are no antiepileptic drugs based on the ketogenic diet. The ketogenic diet changes energy metabolites (ketone bodies, glucose and lactate) in the brain, which consequently changes electrical activities in neurons and ultimately suppresses seizures in epileptic patients. In order to elucidate the antiseizure effects of the ketogenic diet, it is important to clarify the mechanism by which these metabolic changes are converted to electrical changes in neurons. In this review, we summarize electrophysiological studies focusing on electrical control in neurons by the ketogenic diet. Recent studies have identified electrical regulators driven by the ketogenic diet: ion channels (ATP-sensitive K+ channels and voltage-dependent Ca2+ channels), synaptic receptors (AMPA-type glutamate receptors and adenosine A1 receptors), neurotransmitter transporters (vesicular glutamate transporters), and others (BCL-2-associated agonist of cell death and lactate dehydrogenase). Thus, the ketogenic diet presumably elicits neuronal inhibition via the combined actions of these molecules. From the viewpoint of drug development, these molecules are valuable as targets for the development of new antiepileptic drugs. Drug therapy to mimic the ketogenic diet may be feasible in the future, through the combination of multiple antiepileptic drugs targeting these molecules

Trials for Health Promotion by Indoor Environment Modifications

Two attempts to address health issues by indoor environment modifications are introduced. One approach involves enhancement of natural killer cell activity by negatively charged particle dominant indoor air conditions (NCPDIAC) resulting from extra-porous charcoal paint and application of an electric voltage on the wall surface to adsorb positively charged small particles (approx. 20 nm in diameter). This apparatus creates relatively continuous NCPDIAC. The other approach involves prevention of pollen allergy symptoms by a cloth containing specific ore powder (CCSNOP). With the former approach, we engaged in short-term (2.5 hour), middle-term (2 W night stay), and long-term (3 M) stays under NCPDIAC and found that IL-2 levels increased under short-term stays and that natural killer cell activity was enhanced in middle- and long-term stay experiments. Implementation of this strategy may partially prevent the occurrence of cancers and viral-mediated diseases. With the latter approach, a 1-hour stay within a CCSNOP room resulted in improvement of symptoms in patients with pollen allergies in addition to a reduction in bad moods caused by any remaining symptoms. In both cases, longer-term experiments should be performed in an effort to confirm and delineate the biological effects of these indoor environment modifications on human health problems

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

Fibrous and particulate environmental substances such as asbestos fibers and silica particles cause not only lung fibrosis but also various health disturbances. Asbestos induce malignant tumors such as pleural mesothelioma and lung cancer. Silicosis patients exposed to silica particles show complications of various autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis/nephritis. The causative alteration of immune cells exposed to these environmental substances may form baseline modification of human immune system not only localized pulmonary lesions, alteration of alveolar macrophages, and others but also general immune system and changes of function in effector, regulatory, and cytotoxic T cells and natural killer cells. In this review, both (localized and generalized) immune alterations caused by environmental fibrous and particulate substances are summarized and reported

Alteration of Various Lymphocytes by Particulate and Fibrous Substances

Various occupational and environmental substances alter the cellular and molecular function of the human lymphoid system. For example, silicosis patients who have been chronically exposed to silica particles often complicate with autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. From our investigations, silica particles affect CD4+ responder T cells and regulatory T cells (Tregs), which results in the disruption of autoimmunity. Asbestos fibers are a type of mineral silicate, and patients exposed to asbestos fibers revealed cancers such as mesothelioma and lung cancer. In these cases, asbestos fibers may reduce antitumor immunity. Our results investigating the effect of asbestos on cytotoxic T lymphocyte, natural killer (NK) cells, CD4+ cells, and Tregs revealed a reduction in antitumor immunity. To date, the effects of silica and asbestos on Th17 cells and antigen-presenting cells such as dendritic cells and macrophages remain unclear. Based on these findings, it will be possible to generate earlier detection methods to identify the occurrence of immune alterations in silicosis as well as the appearance of a decreased antitumor immunity in asbestos-exposed populations. Additionally, research efforts should also be directed at discovering and identifying physiological substances from foods, plants, and other sources that can restore the immune status in people exposed to particulate and fibrous substances

Biological Effects of Negatively Charged Particle-Dominant Indoor Air Conditions

To identify health-promoting indoor air conditions, we developed negatively charged particle-dominant indoor air conditions (NCPDIAC). Experiments assessing the biological effects of NCPDIAC comprised (1) 2.5-h stays in NCPDIAC or control rooms, (2) 2-week nightly stays in control followed by NCPDIAC rooms, (3) 3-month OFF to ON and ON to OFF trials in individual living homes equipped with NPCDIAC in their sleeping or living rooms, and (4) in vitro assays comparing the immune effects between negatively charged particle-dominant and control cell culture incubators. The most significant difference examined between NCPDIAC and control rooms in the 2.5-h stays was an increase in interleukin (IL)-2 with occupancy of the NCPDIAC room. For the 2-week nightly stay experiments, natural killer (NK) cell activity increased with occupancy of the NCPDIAC room. The 3-month OFF to ON trial showed an increase in NK cell activity, while the ON to OFF trial yielded a decrease in NK cell activity. Additionally, the in vitro assays also showed an increase in NK cell activity. The use of NCPDIAC resulted in increased NK cell activity, which has the effect of enhancing immune surveillance for the occurrence of cancer and improving symptoms associated with viral infections

Cytotoxicity Caused by Asbestos Fibers and Acquisition of Resistance by Continuous Exposure in Human T Cells

The cytotoxic effects of asbestos fibers on human T cells and the acquisition of resistance against asbestos-induced apoptosis have been studied. These analyses are based on the establishment of a continuous and relatively low-dose exposure model of human immune cells exposed to asbestos that resembles actual exposure in the human body. The MT-2 T cell line was selected as the candidate for the investigations. A transient and high-dose exposure to chrysotile resulted in apoptosis with production of reactive oxygen species (ROS) and activation of the mitochondrial apoptotic pathway. However, sublines continuously exposed to low dose of asbestos exhibited resistance to asbestos-induced apoptosis. The mechanism of resistance acquisition involved excess production of IL-10, activation of STAT3, and enhanced expression of Bcl-2 located downstream of STAT3. These changes were also found in a subline continuously exposed to crocidolite. Furthermore, sublines showed a marked decrease in the expression of forkhead box O1 (FoxO1) transcription factor. FoxO1 is known to regulate apoptosis and various other cellular processes. Regarding apoptosis, sublines continuously exposed to asbestos showed reduction of FoxP1-driven proapoptotic genes. This pathway is also considered one of the mechanisms that result in resistance to asbestos-induced apoptosis in sublines. These sublines also exhibited several characteristics suggesting reduction of antitumor immunity

Enhanced expression of nicotinamide nucleotide transhydrogenase (NNT) and its role in a human T cell line continuously exposed to asbestos

The effects of asbestos fibers on human immune cells have not been well documented. We have developed a continuously exposed cell line model using the human T-lymphotropic virus 1 (HTLV-1)-immortalized human T cell line MT-2. Sublines continuously exposed to chrysotile (CH) or crocidolite (CR) showed acquired resistance to asbestos-induced apoptosis following transient and high-dose re-exposure with fibers. These sublines in addition to other immune cells such as natural killer cells or cytotoxic T lymphocytes exposed to asbestos showed a reduction in anti-tumor immunity. In this study, the expression of genes and molecules related to antioxidative stress was examined. Furthermore, complexes related to oxidative phosphorylation were investigated since the production of reactive oxygen species (ROS) is important when considering the effects of asbestos in carcinogenesis and the mechanisms involved in resistance to asbestos-induced apoptosis. In sublines continuously exposed to CH or CR, the expression of thioredoxin decreased. Interestingly, nicotinamide nucleotide transhydrogenase (NNT) expression was markedly enhanced. Thus, knockdown of NNT was then performed. Although the knockdown clones did not show any changes in proliferation or occurrence of apoptosis, these clones showed recovery of ROS production with returning NADPH/NADP+ ratio that increased with decreased production of ROS in continuously exposed sublines. These results indicated that NNT is a key factor in preventing ROS-induced cytotoxicity in T cells continuously exposed to asbestos. Considering that these sublines showed a reduction in anti-tumor immunity, modification of NNT may contribute to recovery of the anti-tumor effects in asbestos-exposed T cells

Autoantibodies in Silicosis Patients: Silica-Induced Dysregulation of Autoimmunity

Silica particles cause silicosis (SIL) and represent one of the most typical environmental and occupational substances that induce autoimmune disorders among the exposed population. Anti-nuclear antibody (ANA), anti-Sjögren’s-syndrome-related antigen A (SS-A), anti-centromere protein B (CENP)-B, and anti-scleroderma (Scl)-70 autoantibodies were examined in SIL and compared with those in healthy volunteers (HV) and patients with systemic sclerosis (SSc). Individuals with SIL were prone to autoimmune diseases and some autoantibodies seemed to be important as an estimation of this condition. Anti-Fas autoantibody found in SIL was functionally capable of inducing apoptosis in Fas-expressing cells, and this may cause a decrease of regulatory T cells (Tregs) expressing Fas in SIL. Moreover, responder T cells (Tresps) in SIL seemed to be activated chronically and protected from Fas-mediated apoptosis. Thus, an imbalance of Tresps (dominant) and Tregs (less) occurred in SIL. All of these causes of SIL are ready to further develop autoimmune diseases

Skewing T helper cells exposed to asbestos fibers toward reduction of tumor immunity or activation of autoimmunity

Asbestos fibers cause malignant tumors such as lung cancer and malignant mesothelioma. Furthermore, with carcinogenic activity, they alter the human immune system. Our previous findings indicated that immune cells exposed to asbestos revealed cellular and molecular alterations that resulted in a reduction in anti-tumor immunity. Focusing on regulatory T cells (Tregs), we found enhanced function and proliferating activity resulting from asbestos exposure using an in vitro cell line model. Additionally, surface C-X-C motif chemokine receptor 3 (CXCR3) levels in T helper (Th) cells as well as the capacity to produce interferon γ were reduced, which lead to decreased anti-tumor immunity. However, our recent findings showed that IL-17 production in the intracellular CXCR3-rich fraction in Th cells was enhanced by asbestos exposure. Regarding alterations of autoimmunity, some investigators have reported the detection of autoantibodies against endothelial cells and mesothelial cells in an asbestosexposed mouse model and suggested that these autoantibodies contribute to the formation of pulmonary fibrosis. However, the precise mechanisms by which asbestos affects the human immune system and causes cancers and the production of certain autoantibodies to create pathophysiological conditions found in asbestos-exposed patients remains to be elucidated