Si-based agent alleviated small bowel ischemia-reperfusion injury through antioxidant effects.

The progression of small bowel ischemia-reperfusion (IR) injury causes cells in the intestinal tract to undergo necrosis, necessitating surgical resection, which may result in loss of intestinal function. Therefore, developing therapeutic agents that can prevent IR injury at early stages and suppress its progression is imperative. As IR injury may be closely related to oxidative stress, antioxidants can be effective therapeutic agents. Our silicon (Si)-based agent, an antioxidant, generated a large amount of hydrogen in the intestinal tract for a prolonged period after oral administration. As it has been effective for ulcerative colitis, renal failure, and IR injury during skin flap transplantation, it could be effective for small intestinal IR injury. Herein, we investigated the efficacy of an Si-based agent in a mouse model of small intestinal IR injury. The Si-based agent suppressed the apoptosis of small intestinal epithelial cells by reducing the oxidative stress induced by IR injury. In addition, the thickness of the mucosal layer in the small intestine of the Si-based agent-administered group was significantly higher than that in the untreated group, revealing that Si-based agent is effective against small intestinal IR injuries. In the future, Si-based agents may improve the success rate of small intestine transplantation.

LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.

Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.

Histochemical analysis of the biphasic properties of formalin pain-induced behavior.

The formalin test has been established as a method for evaluating mouse models of pain. Although there have been numerous reports of formalin-pain-induced behavior, few reports of a detailed histochemical analysis of the central nervous system focus on behavioral biphasic properties. To investigate the alternation of spinal neuronal activity with formalin-induced pain, we performed immunofluorescent staining with c-Fos antibodies as neuronal activity markers using acute pain model mice induced by 2% formalin stimulation. As a result, phase-specific expression patterns were observed. In the spinal dorsal horn region, there were many neural activities in the deep region (layers V-VII) in the behavioral first phase and those in the surface region (layers I-III) in the behavioral second phase. Furthermore, we conducted comparative studies using low concentrations (0.25%) of formalin and capsaicin, which did not show distinct behavioral biphasic properties. Neural activity was observed only in the spinal dorsal horn surface region for both stimuli. Our study suggested that the histochemical biphasic nature of formalin-induced pain was attributable to the activity of the deep region of the spinal cord. In the future, treatment strategies focusing on the deep region neuron will lead to the development of effective treatments for allodynia and intractable chronic pain.

Early life stress impairs brain and mental development during childhood increasing the risk of developing psychiatric disorders.

In recent years, it has become known that stress in childhood, called early life stress (ELS), affects the mental health of children, adolescents, and adults. Child maltreatment (CM) is an inappropriate form of childcare that interferes with children's normal brain and mind development. Previous studies have reported that CM severely affects brain development and function. For example, ELS causes brain vulnerability and increases the risk of developing psychiatric disorders. In addition, it is known that the different types and timing of abuse have different effects on the brain. Epidemiological and clinical studies are being conducted to understand the mechanism underlying abuse on a child's mental health and appropriate brain development; however, they are not fully understood. Therefore, studies using animal models, as well as humans, have been conducted to better understand the effects of CM. In this review, we discuss the effects of comparing previous findings on different types of CM in human and animal models. However, it should be noted that there are differences between animal models and humans such as genetic polymorphism and susceptibility to stress. Our review provides the latest insights into the negative effects of CM on children's development and on psychiatric disorders in adulthood.

Diverse Possibilities of Si-Based Agent, a Unique New Antioxidant.

Antioxidant therapy is an effective approach for treating diseases in which oxidative stress is involved in the onset of symptoms. This approach aims to rapidly replenish the antioxidant substances in the body when they are depleted due to excess oxidative stress. Importantly, a supplemented antioxidant must specifically eliminate harmful reactive oxygen species (ROS) without reacting with physiologically beneficial ROS, which are important to the body. In this regard, typically used antioxidant therapies can be effective, but may cause adverse effects due to their lack of specificity. We believe that Si-based agents are epoch-making drugs that can overcome these problems associated with current antioxidative therapy. These agents alleviate the symptoms of oxidative-stress-associated diseases by generating large amounts of the antioxidant hydrogen in the body. Moreover, Si-based agents are expected to be highly effective therapeutic drug candidates because they have anti-inflammatory, anti-apoptotic, and antioxidant effects. In this review, we discuss Si-based agents and their potential future applications in antioxidant therapy. There have been several reports of hydrogen generation from silicon nanoparticles, but unfortunately, none have been approved as pharmaceutical agents. Therefore, we believe that our research into medical applications using Si-based agents is a breakthrough in this research field. The knowledge obtained thus far from animal models of pathology may greatly contribute to the improvement of existing treatment methods and the development of new treatment methods. We hope that this review will further revitalize the research field of antioxidants and lead to the commercialization of Si-based agents.

Effect of the new silicon-based agent on the symptoms of interstitial pneumonitis.

Interstitial pneumonia (IP) is a collective term for diseases whose main lesion is fibrosis of the pulmonary interstitium, and the prognosis associated with acute exacerbation of these conditions is often poor. Therapeutic agents are limited to steroids, immunosuppressants, and antifibrotic drugs, which and have many side effects; therefore, the development of new therapeutic agents is required. Because oxidative stress contributes to lung fibrosis in IP, optimal antioxidants may be effective for the treatment of IP. Silicon (Si)-based agents, when administered orally, can continuously generate a large amount of antioxidant hydrogen in the intestinal tract. In this study, we investigated the effect of our Si-based agent on methotrexate-induced IP, using the IP mouse models. Pathological analysis revealed that interstitial hypertrophy was more significantly alleviated in the Si-based agent-treated group than in the untreated group (decreased by about 22%; P < 0.01). Moreover, additional morphological analysis demonstrated that infiltration of immune cells and fibrosis in the lungs were significantly inhibited by treatment with the Si-based agent. Furthermore, Si-based agent reduced oxidative stress associated with IP by increasing blood antioxidant activity. (increased by about 43%; P < 0.001). Taken together, these results suggest that Si-based agents can be effective therapeutic agents for IP.

Neuroinflammation and Oxidative Stress in the Pathogenesis of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) characterized by impairments in social communication, repetitive behaviors, restricted interests, and hyperesthesia/hypesthesia caused by genetic and/or environmental factors. In recent years, inflammation and oxidative stress have been implicated in the pathogenesis of ASD. In this review, we discuss the inflammation and oxidative stress in the pathophysiology of ASD, particularly focusing on maternal immune activation (MIA). MIA is a one of the common environmental risk factors for the onset of ASD during pregnancy. It induces an immune reaction in the pregnant mother's body, resulting in further inflammation and oxidative stress in the placenta and fetal brain. These negative factors cause neurodevelopmental impairments in the developing fetal brain and subsequently cause behavioral symptoms in the offspring. In addition, we also discuss the effects of anti-inflammatory drugs and antioxidants in basic studies on animals and clinical studies of ASD. Our review provides the latest findings and new insights into the involvements of inflammation and oxidative stress in the pathogenesis of ASD.

Prenatal Sex Hormone Exposure Is Associated with the Development of Autism Spectrum Disorder.

Sexual differentiation is a major developmental process. Sex differences resulting from sexual differentiation have attracted the attention of researchers. Unraveling what contributes to and underlies sex differences will provide valuable insights into the development of neurodevelopmental disorders that exhibit sex biases. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual's social interaction and communication abilities, and its male preponderance has been consistently reported in clinical studies. The etiology of male preponderance remains unclear, but progress has been made in studying prenatal sex hormone exposure. The present review examined studies that focused on the association between prenatal testosterone exposure and ASD development, as well as sex-specific behaviors in individuals with ASD. This review also included studies on maternal immune activation-induced developmental abnormalities that also showed striking sex differences in offspring and discussed its possible interacting roles in ASD so as to present a potential approach for future studies on sex biases in ASD.

Localization and potential role of prostate microbiota.

Introduction: We aimed to clarify the presence and localization of the prostate microbiota and examine its association with benign prostate enlargement (BPE). Methods: The microbiota of prostate tissues and catheterized urine from 15 patients were analyzed by 16S metagenomic analysis and compared to show that the prostate microbiota was not a contaminant of the urinary microbiota. Fluorescence in situ hybridization (FISH) and in situ hybridization (ISH) using the specific probe for eubacteria was performed on prostate tissue to show the localization of bacteria in the prostate. The BPE group was defined as prostate volume ≥30 mL, and the non-BPE group as prostate volume <30 mL. The microbiota of the two groups were compared to clarify the association between prostate microbiota and BPE. Results: Faith's phylogenetic diversity index of prostate tissue was significantly higher than that of urine (42.3±3.8 vs 25.5±5.6, P=0.01). Principal coordinate analysis showed a significant difference between the microbiota of prostate tissue and catheterized urine (P<0.01). FISH and ISH showed the presence of bacteria in the prostatic duct. Comparison of prostate microbiota between the BPE and non-BPE groups showed that the Chao1 index of the BPE group was significantly lower than that of the latter [142 (50-316) vs 169 (97-665), P=0.047] and the abundance of Burkholderia was significantly higher in the BPE group than in the latter. Conclusions: We demonstrated that the prostate microbiota was located in the prostatic duct and reduced diversity of prostate microbiota was associated with BPE, suggesting that prostate microbiota plays a role in BPE.

Prenatal methamphetamine exposure causes dysfunction in glucose metabolism and low birthweight.

Methamphetamine (METH) is a psychostimulant drug that induces addiction. Previous epidemiological studies have demonstrated that maternal METH abuse during pregnancy causes low birthweight (LBW) in the offspring. As a source of essential nutrients, in particular glucose, the placenta plays a key role in fetal development. LBW leads to health problems such as obesity, diabetes, and neurodevelopmental disorders (NDDs). However, the detailed mechanism underlying offspring's LBW and health hazards caused by METH are not fully understood. Therefore, we investigated the effects of prenatal METH exposure on LBW and fetal-placental relationship by focusing on metabolism. We found dysfunction of insulin production in the pancreas of fetuses exposed to METH. We also found a reduction of the glycogen cells (GCs) storing glycogens in the junctional zone of placenta, all of which suggest abnormal glucose metabolism affects the fetal development. These results suggest that dysfunction in fetal glucose metabolism may cause LBW and future health hazards. Our findings provide novel insights into the cause of LBW via the fetal-placental crosstalk.

Therapeutic strategy for facial paralysis based on the combined application of Si-based agent and methylcobalamin.

Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Intractable facial paralysis has a poor prognosis, and new treatments are required. Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Reactive oxygen species can inhibit peripheral nerve regeneration after injury. Therefore, the administration of an appropriate antioxidant can promote nerve regeneration. Silicon (Si)-based agents can react with water to generate antioxidant hydrogen. Oral administration of Si-based agents can effectively alleviate symptoms of disease models associated with oxidative stress. Thus, we orally administered a Si-based agent to a facial paralysis model mice to investigate whether promotion of nerve regeneration occurred. The combined administration of methylcobalamin (MeCbl) with the Si-based agent was also investigated. The Si-based agent improved the clinical score evaluation of facial paralysis. Electroneuronography and immunostaining showed that the Si-based agent promoted myelination and recovery of facial nerve function. Furthermore, in the drug-administered group, oxidative stress associated with facial nerve injury was reduced more than that in the non-administered group. The clinical score evaluation, neuroregeneration effect, and reduction of oxidative stress were improved in the combination group compared to the single administration group. The Si-based agent could rapidly improve the disappearance of facial expressions by promoting myelin sheath formation and alleviating oxidative stress. Combination therapy with a Si-based agent and MeCbl should improve the prognosis and treatment of intractable facial paralysis.

The development of a novel antioxidant-based antiemetic drug to improve quality of life during anticancer therapy.

Anticancer agents can effectively treat several types of cancers but are often limited in clinical settings due to various adverse effects. In particular, nausea and vomiting are serious side effects that markedly reduce the patients' quality of life. Accordingly, the development of novel antiemetic drugs that lack side effects is crucial, given that most conventional antiemetic drugs are known to possess side effects. In addition, reactive oxygen species generated by anticancer agents are involved in nausea and vomiting; hence, appropriate antioxidants might also be effective toward nausea and vomiting. Silicon (Si)-based agents can abundantly generate antioxidant hydrogen in the intestine. Therefore, we assessed whether Si-based agents could be effective against nausea associated with anticancer agents in cisplatin-injected mice. We observed numerous neurons expressing c-Fos protein, a neuronal activity marker, in the nausea-associated regions of the dorsal medulla (area postrema, nuclei of the solitary tract, and dorsal vagal nuclei) 24 h after cisplatin injection. Conversely, mice fed a diet containing 2.5% Si-based agents showed a reduction in c-Fos-positive neurons. These findings revealed that the Si-based agent alleviated cisplatin-induced nausea. Si-based agents demonstrate potent antioxidant effects by producing hydrogen, which has no known side effects and will be a safer antiemetic agent and greatly help improve the quality of life of patients undergoing anticancer drug treatment.

SR 57227A, a serotonin type-3 receptor agonist, as a candidate analgesic agent targeting nociplastic pain.

Pain is influenced by various factors, such as fear, anxiety, and memory. We previously reported that pain-like behaviors in mice can be induced by environmental cues in which a pain stimulus was previously presented, and that pain was reduced using fentanyl (an opioid). Although opioid analgesics are currently used to treat persistent pain, their inappropriate use causes a significant number of deaths in the United States. Thus, alternative medicines to opioids are needed. Here, we reported that SR 57227A, a serotonin type-3 receptor agonist, significantly reduced pain-like behaviors. The number of c-Fos positive cells increased by environmental cues in PFC was decreased by SR 57227A. Moreover, SR 57227A reduced pain-like behaviors of the formalin test, and restored reductions in paw withdrawal thresholds by acidic saline intramuscular injection and sciatic nerve ligation. Unlike opioids, SR 57227A induced no preference behaviors as measured by the conditioned place preference test. These data suggested that SR 57227A is an effective alternative pain reliever to opioids that targets chronic pain.

Genomic Strategies for Understanding the Pathophysiology of Autism Spectrum Disorder.

Recent breakthroughs in sequencing technology and technological developments have made it easier to analyze the entire human genome than ever before. In addition to disease-specific genetic mutations and chromosomal aberrations, epigenetic alterations in individuals can also be analyzed using genomics. Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) caused by genetic and/or environmental factors. More than a thousand genes associated with ASD have been identified which are known to be involved in brain development. However, it is difficult to decode the roles of ASD-associated genes without in vitro and in vivo validations, particularly in the process of brain development. In this review, we discuss genomic strategies for understanding the pathological mechanisms underlying ASD. For this purpose, we discuss ASD-associated genes and their functions, as well as analytical strategies and their strengths and weaknesses in cellular and animal models from a basic research perspective.

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Measurement of intraluminal pH changes in the gastrointestinal tract of mice with gastrointestinal diseases.

As a fundamental and essential property, gastrointestinal (GI) tract pH reflects its condition and changes in several GI diseases such as inflammatory bowel disease (IBD), gastritis, etc. As a result, accurately measuring the GI pH is crucial for treatment, diagnosis, and prevention of GI diseases and contributes to developing GI disease models for basic studies. However, among pH measuring studies with animal models, there is no reliable method that can reflect the value and changing trends of GI pH in actual patients. In the current study, we developed a fast, simple method with pH indicator paper to measure the GI pH changes with GI content in normal mice and mice with colitis or hepatitis. Results demonstrated that normal mice's mean GI pH values were between 6.0 and 8.0, which was consistent with previous reports. Furthermore, the GI pH of colitis and hepatitis model mice showed the same pattern of lower values in the intestine and higher values in the stomach compared with normal mice. Our simple and timesaving method can accurately measure the dramatic changes in the GI pH of mice with GI diseases and is suitable for measuring the pH of sticky liquids with limited volume. Given all the merits listed above, this method is helpful for further research.

A new therapy against ulcerative colitis via the intestine and brain using the Si-based agent.

Ulcerative colitis (UC) is a non-specific inflammatory bowel disease that causes ulcers and erosions in the colonic mucosa and becomes chronic with cycles of amelioration and exacerbation. Because its exact etiology remains largely unclear, and the primary therapy is limited to symptomatic treatment, the development of new therapeutic agent for UC is highly desired. Because one of the disease pathogenesis is involvement of oxidative stress, it is likely that an appropriate antioxidant will be an effective therapeutic agent for UC. Our silicon (Si)-based agent, when ingested, allowed for stable and persistent generation of massive amounts of hydrogen in the gastrointestinal tract. We demonstrated the Si-based agent alleviated the mental symptom as well as the gastrointestinal symptoms, inflammation, and oxidation associated with dextran sodium sulfate-induced UC model through Hydrogen and antioxidant sulfur compounds. As the Si-based agent was effective in treating UC in the brain and large intestine of mice, it was considered to be capable of suppressing exacerbations and sustaining remission of UC.

Social Communication of Maternal Immune Activation-Affected Offspring Is Improved by Si-Based Hydrogen-Producing Agent.

Maternal immune activation (MIA) is triggered by infection or autoimmune predisposition during pregnancy, and cytokines produced by MIA are transmitted through the placenta to the fetal brain, implicating at the onset risks and vulnerability for developmental and psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia. To address these kinds of problem in child health, we have developed a silicon (Si)-based hydrogen-producing antioxidant (Si-based agent) that continuously and effectively produces hydrogen in the body. Medical hydrogen is known to have antioxidative, anti-inflammatory, and antiapoptotic effects, therefore we applied our Si-based agent as a potential therapeutic agent to MIA. Using a MIA mouse model, we found that the Si-based agent improved the social communication of MIA offspring mice. We also found that the Si-based agent suppressed the expressions of inflammation-associated genes Ifna1 and Il-6 in the mouse brain. These results demonstrate that the Si-based agent is an effective prophylactic agent against MIA during pregnancy, suggesting that our Si-based agent may be a preventative or therapeutic agent for ASD and other disease risks in child health suppressing MIA damage.

IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine.

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.