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.

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.

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.

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.

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.

Laparoscopic total gastrectomy performed for juvenile polyposis of the stomach: A case report.

INTRODUCTION AND IMPORTANCE: Juvenile polyposis of the stomach (JPST) is a very rare disease and has been reported to have malignant potential. Total gastrectomy has been recommended as a standard treatment. Recently, the usefulness of laparoscopic surgery for this disease has been reported; however, in laparoscopic surgery, maintaining the surgical space is difficult because of the distended and thickened stomach wall that polyposis causes. CASE PRESENTATION: A 64-year-old woman was admitted to our hospital because she became malnourished due to loss of appetite. She had no family history of gastrointestinal polyposis and was diagnosed with gastric polyposis and polyp-related anemia eight years previously. She received endoscopic submucosal dissection of early gastric cancer twice in another hospital. Thereafter, the patient received an annual upper gastrointestinal endoscopy and took iron supplements for anemia due to occasional bleeding from polyps. However, the number of polyps increased over time. Enhanced computed tomography showed gastric wall thickening and multiple gastric polyps. She was diagnosed as having JPST and underwent laparoscopic total gastrectomy. She was discharged on postoperative Day 10. CLINICAL DISCUSSION: In the present case, similar to previous cases, standard laparoscopic surgery could be performed although the patient had excessive distention and congestion of the stomach. This report suggests that laparoscopic surgery is a safe and feasible option for patients with JPST and is preferable because of better cosmetic effects, especially for young female patients. CONCLUSION: We successfully performed laparoscopic surgery to treat a rare case of JPST.

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.

Sepsis-Associated Encephalopathy: A Mini-Review of Inflammation in the Brain and Body.

Sepsis is defined as a life-threatening multi-organ dysfunction triggered by an uncontrolled host response to infectious disease. Systemic inflammation elicited by sepsis can cause acute cerebral dysfunction, characterized by delirium, coma, and cognitive dysfunction, known as septic encephalopathy. Recent evidence has reported the underlying mechanisms of sepsis. However, the reasons for the development of inflammation and degeneration in some brain regions and the persistence of neuroinflammation remain unclear. This mini-review describes the pathophysiology of region-specific inflammation after sepsis-associated encephalopathy (SAE), clinical features, and future prospects for SAE treatment. The hippocampus is highly susceptible to inflammation, and studies that perform treatments with antibodies to cytokine receptors, such as interleukin-1ß, are in progress. Future development of clinically applicable therapies is expected.

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.

Hydrogen-generating Si-based agent protects against skin flap ischemia-reperfusion injury in rats.

Hydrogen is effective against ischemia-reperfusion (I/R) injury in skin flaps. However, the difficulty of continuously administering a sufficient amount of hydrogen using conventional methods has been an issue in the clinical application of hydrogen-based therapy. An Si-based agent administered orally was previously shown to continuously generate a large amount of hydrogen in the intestinal environment. In this study, we assessed the effect of the Si-based agent on the inhibition of I/R injury in skin flaps using a rat model. In the I/R groups, the vascular pedicle of the abdominal skin flap was occluded for three hours followed by reperfusion. In the I/R + Si group, the Si-based agent was administered perioperatively. After reperfusion, flap survival rate, blood flow, oxidative stress markers, inflammatory markers/findings, and degree of apoptosis were evaluated. Flap survival rate was significantly higher, and histological inflammation, apoptotic cells, oxidative stress markers, and levels of inflammatory cytokine mRNA and protein expression were significantly lower, in the I/R + Si group compared to the I/R group. The Si-based agent suppressed oxidative stress, apoptosis, and inflammatory reactions resulting from I/R injury, thereby contributing to improvements in skin flap survival.

Pain-like behavior in mice can be induced by the environmental context in which the pain stimulus was previously given.

It has been known for decades that classical conditioning influences pain perception. However, the precise mechanism of pain modified by conditioning remains unclear, partly because of the lack of dedicated behavioral tests. In the present study, we aimed to develop a new method to detect conditioned pain using mice that were injected with formalin as an unconditioned nociceptive stimulus into the hind paw repetitively under a neutral environment. On the test day, the mice exhibited a pain-like behavior without the application of a pain stimulus in the environment. These results demonstrate that a conditioned nociceptive response can be induced by exposure alone to the environmental context in which the pain was previously experienced. The conditioned nociceptive response was sustained for at least 2 weeks. Furthermore, the conditioned nociceptive response was reduced by fentanyl but not by ibuprofen, pregabalin or fluvoxamine. This method may be useful for studying the mechanisms of irritable chronic pain and for the development of novel therapeutic strategies.

Si-Based Hydrogen-Producing Nanoagent Protects Fetuses From Miscarriage Caused by Mother-to-Child Transmission.

Mother-to-child transmission of viruses and bacteria increases the risk of miscarriage and various diseases in children. Such transmissions can result in infections and diseases in infants or the induction of an inflammatory immune response through the placenta. Recently, we developed a silicon (Si)-based hydrogen-producing nanoagent (Si-based agent) that continuously and effectively produces hydrogen in the body. Since medical hydrogen has antioxidative, anti-inflammatory, antiallergic, and antiapoptotic effects, we investigated the effects of our Si-based agent on mother-to-child transmission, with a focus on the rate of miscarriage. In pregnant mice fed a diet containing the Si-based agent, lipopolysaccharide (LPS)-induced miscarriage due to mother-to-child transmission was reduced and inflammation and neutrophil infiltration in the placenta were suppressed. We also found that the Si-based agent suppressed IL-6 expression in the placenta and induced the expression of antioxidant and antiapoptotic genes, such as Hmox1 and Ptgs2. The observed anti-inflammatory effects of the Si-based agent suggest that it may be an effective preventative or therapeutic drug for miscarriage or threatened miscarriage during pregnancy by suppressing maternal inflammation caused by bacterial and viral infections.

Diagnosis and treatment of gastric hamartomatous inverted polyp (GHIP) using a modified combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (modified CLEAN-NET): a case report.

BACKGROUND: Gastric hamartomatous inverted polyp (GHIP) is a pathological condition where enlarged gastric glands with cystic dilatation grow in the submucosa. It is difficult to excise the tissue due to its location. In addition, even if the tissue is taken correctly, making an accurate diagnosis is difficult due to foveolar epithelium in the tissue, which can be misdiagnosed as gastric mucosal epithelium. Thus, an accurate diagnosis of GHIP is rarely established from a biopsy alone preoperatively. We here report a case of GHIP with a central dimple, which was diagnosed and treated using a modified combination of laparoscopic and endoscopic approaches to neoplasia with a non-exposure technique (modified CLEAN-NET). CASE PRESENTATION: A 60-year-old man with a submucosal tumor (SMT) in the stomach was referred to our hospital by a primary care doctor. On examination, a gastrointestinal stromal tumor was suspected. Modified CLEAN-NET was performed for diagnostic and therapeutic purposes. The histopathological examination of the resected specimen showed an enlarged gland duct in the submucosal layer. This finding, along with immunostaining results, led to the diagnosis of GHIP. The postoperative course was uneventful without any symptoms. CONCLUSIONS: GHIP should be considered among the differential diagnoses of SMT of the stomach. Modified CLEAN-NET may be beneficial in the removal of SMTs such as GHIP with a central dimple because it can avoid stomach deformation of the stomach and tumor dissemination.