Cytoprotective effects of Hangekobokuto against corticosterone-induced cell death in HT22 cells.

The hypothalamic-pituitary-adrenal (HPA) system plays an important role in stress response. Chronic stress is thought to induce neuronal damage and contribute to the pathogenesis of psychiatric disorders by causing dysfunction of the HPA system and promoting the production and release of glucocorticoids, including corticosterone and cortisol. Several clinical studies have demonstrated the efficacy of herbal medicines in treating psychiatric disorders; however, their effects on corticosterone-induced neuronal cell death remain unclear. Here, we used HT22 cells to evaluate the neuroprotective potential of herbal medicines used in neuropsychiatry against corticosterone-induced hippocampal neuronal cell death. Cell death was assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction and Live/Dead assays. Hangekobokuto, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan were supplied in the form of water-extracted dried powders. Exposure of HT22 cells to ≥ 100 µM corticosterone decreased MTT values. Exposure to 500 µM corticosterone alone reduced MTT values to 18%, while exposure to 10 µM Mifepristone (RU486)-a glucocorticoid receptor antagonist-restored values to 36%. Corticosterone-induced cell death was partially suppressed by treatment with RU486. At 100 µg/mL, Hangekobokuto significantly suppressed the decrease in MTT values (15-32%) and increase in the percentage of ethidium homodimer-1-positive dead cells caused by corticosterone exposure (78-36%), indicating an inhibitory effect on cell death. By contrast, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan did not affect corticosterone-induced cell death. Therefore, our results suggest that Hangekobokuto may ameliorate the onset and progression of psychiatric disorders by suppressing neurological disorders associated with increased levels of glucocorticoids.

Decline in Liver Mitochondria Metabolic Function Is Restored by Hochuekkito Through Sirtuin 1 in Aged Mice With Malnutrition.

Malnutrition impairs basic daily activities and leads to physical frailty, which is aggravated in the elderly compared with young adults. It is also well-known that the elderly are more vulnerable to metabolic stress. Therefore, in this study, using a food restricted (FR) mouse, we aimed to evaluate the effect of aging on locomotor activity and liver metabolic function. Further, we also investigated the involvement of hepatic mitochondria in liver metabolic function during aging, as well as the therapeutic benefit of the traditional Japanese medicine, hochuekkito (HET). Our findings indicated that following food restriction provided as 30% of ad libitum intake for 5 days, the locomotor activity was lower in 23-26-month-old (aged) mice than in 9-week-old (young) mice. Further, compared with young mice, aged mice exhibited significant decreases in the levels of metabolites related to the urea cycle, mitochondrial function, and anti-oxidative stress. The livers of the aged mice also showed a greater decrease in mitochondrial DNA copy number than young mice. Furthermore, the gene expression levels of sirtuin 1 (SIRT1) and mitochondrial biogenesis-related regulators were attenuated in aged mice. However, these changes were partially restored by HET treatment, which also improved locomotor activity, and combined treatment with alanine resulted in more significant effects in this regard. Therefore, our findings suggested that the decrease in locomotor activity in aged FR mice was associated with a decline in the metabolic function of hepatic mitochondria via decreased SIRT1 expression, which was restored by HET treatment. This implies that enhancing the metabolic function of liver mitochondria can contribute to alleviating energy deficiency in the elderly.

Ghrelin Enhancer, the Latest Evidence of Rikkunshito.

Rikkunshito is a Japanese herbal medicine (Kampo) that has been attracting attention and researched by many researchers not only in Japan but also worldwide. There are 214 rikkunshito articles that can be searched on PubMed by August 2021. The reason why rikkunshito has attracted so much attention is due to an epoch-making report (Gastroenterology, 2008) discovered that rikkunshito promotes the secretion of the orexigenic peptide ghrelin. Since then, many researchers have discovered that rikkunshito has a direct effect on the ghrelin receptor, GHS-R1a, and an effect of enhancing the ghrelin signal to the brain. Additionally, a lot of evidence that rikkunshito is expected to be effective for various gastrointestinal diseases have also been demonstrated. Numerous basic and clinical studies have suggested that rikkunshito affects (i) various discomforts caused by anticancer drugs, gastroesophageal reflux disease, functional dyspepsia, (ii) various stress-induced anorexia, (iii) hypophagia in the elderly, and (iv) healthy lifespan. In this review, as one who discovered the ghrelin enhancer effect of rikkunshito, we will review the research of rikkunshito so far and report on the latest research results.

Clinical utility of thoracoscopy in elderly tuberculous pleurisy patients under local anesthesia.

INTRODUCTION: Diagnosing tuberculous pleurisy is important in Japan because it currently has a moderate tuberculosis prevalence. However, physicians often have difficulty making a diagnosis. It was reported that thoracoscopy under local anesthesia is useful for the diagnosis of tuberculous pleurisy, but there are no reports focusing on elderly patients. METHODS: In this study, the usefulness of thoracoscopy under local anesthesia was evaluated in elderly patients. Among 170 patients who underwent thoracoscopy under local anesthesia at our hospital during 11 years from January 2008 to December 2018, those aged 75 years or older (n = 75) were investigated retrospectively. RESULTS: A total of 55 patients underwent thoracoscopy under local anesthesia for detailed examination of pleural effusion of unknown cause. Of these, 18 were diagnosed as tuberculous pleurisy. The median age was 82 years (range: 75-92 years). The diagnosis of tuberculous pleurisy was made in 11 patients in whom Mycobacterium tuberculosis was detected and in four patients whose pathological findings indicated epithelioid granuloma accompanied by caseous necrosis. Clinical diagnosis was made in the remaining three patients based on thoracoscopic findings of the pleural cavity and a high level of adenosine deaminase in pleural fluid. No serious complications attributable to the examination were observed in any patient. CONCLUSIONS: Thoracoscopy under local anesthesia was useful for the diagnosis of tuberculous pleurisy in elderly patients, with useful information being also obtained for the treatment of tuberculosis.

Dopamine D2 receptor supersensitivity in the hypothalamus of olfactory bulbectomized mice.

Olfactory bulbectomy (OBX) in rodents induces neurochemical and behavioral changes similar to those observed in individuals with depressive disorders. Our previous study suggested that OBX alters dopaminergic function in the striatum of mice; however, the effects on dopaminergic function in the hypothalamus is unknown. Therefore, in this study we examined dopaminergic system changes in the hypothalamus after OBX. Mice were administrated either the nonselective dopamine (DA) agonist apomorphine or the selective D2 agonist quinelorane, or pretreated with the selective D1 antagonist SCH23390 in combination with the selective D2 antagonist sulpiride or D3 antagonist SB277011A. Body temperature, which is regulated by the hypothalamic dopaminergic system, was monitored to evaluate changes in the dopaminergic system of the hypothalamus. DA D2 receptor (D2DR), tyrosine hydroxylase (TH), and phosphorylated (p)- DA- and cAMP-regulated phosphoprotein-32 (DARPP-32) levels in the hypothalamus were evaluated by western blotting. OBX mice exhibited significantly enhanced apomorphine-induced or quinelorane-induced hypothermia. The apomorphine-induced hypothermic response was reversed by the administration of sulpiride, but not SCH23390 or SB277011A. Moreover, TH and p-DARPP-32 levels were reduced and D2DR increased in the hypothalamus of OBX mice. These findings revealed that the OBX mice display enhanced DA receptor responsiveness associated with the hypothalamus, which may relate to some of the behavioral and neurochemical alterations reported in this animal model. Identification of changes in the hypothalamic dopaminergic system of OBX mice may provide useful information for the development of novel antidepressant treatments.

[A Nutritional Supplement with a High Blend Ratio of ω-3 Fatty Acids(Prosure®) Reduces Severe Oral Mucositis and Body Weight Loss for Head and Neck Cancer Patients Treated with Chemoradiotherapy].

BACKGROUND: Oral mucositis and body weight loss are the most critical conditions known to lead to the discontinuation of chemoradiotherapy for head and neck cancer. We investigated the effect of a nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)on body weight loss, oral mucositis, and the completion rate of chemoradiotherapy in patients with oropharyngeal and hypopharyngeal cancer. PATIENTS AND METHODS: The study group comprised patients with oropharyngeal and hypopharyngeal cancer who were treated with concomitant cisplatin and 70 Gy of radiotherapy. These patients received 2 packs of Prosure®per day during chemoradiotherapy. RESULTS: A total of 17 patients were included in this study. The reduction in body weight was significantly improved compared with that in the historical control group that did not receive Prosure®(7.3% vs 10.3%, p<0.01), and the rate of Grade 3-4 oral mucositis was significantly reduced for the patient groups that received Prosure®(CTCAE v3.0 GradeB3; 24% vs 58%, p<0.05). The completion rate of chemoradiotherapy was not significantly different between both groups(77% vs 60%, NS). CONCLUSIONS: A nutritional supplement with a high blend ratio of w-3 fatty acids(Prosure®)had effects on oral mucositis and body weight loss in head and neck cancer patients treated with chemoradiotherapy.

Yokukansan, a traditional Japanese herbal medicine, enhances the anxiolytic effect of fluvoxamine and reduces cortical 5-HT2A receptor expression in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia. AIM OF THE STUDY: To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice. MATERIALS AND METHODS: The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT1A and 5-HT2A receptor in the mouse brain regions were quantified by western blot analysis. RESULTS: A single administration of fluvoxamine (5-20 mg/kg, i.p.) before the test session dose-dependently and significantly suppressed freezing behavior in mice. In the combination study, a sub-effective dose of fluvoxamine (5 mg/kg, i.p.) significantly suppressed freezing behavior in mice that had been repeatedly pretreated with yokukansan (0.3 and 1 g/kg, p.o.) once a day for 6 days after the conditioning session. Western blot analysis revealed that the expression level of 5-HT2A receptor was specifically decreased in the prefrontal cortex of mice that had been administered yokukansan and fluvoxamine. Furthermore, microinjection of the 5-HT2A receptor antagonist ketanserin (5 nmol/mouse) into the prefrontal cortex significantly suppressed freezing behavior. CONCLUSION: The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT2A receptor-mediated signaling in the prefrontal cortex. Therefore, combination therapy with fluvoxamine and yokukansan may be beneficial for the treatment of anxiety disorders.

Psychological stress in aged female mice causes acute hypophagia independent of central serotonin 2C receptor activation.

Sex differences exist in the activation of the hypothalamic-pituitary-adrenal axis following exposure to stress, and the stress response is further affected by aging. This study was conducted to elucidate the mechanism of hypophagia in aged female mice exposed to stress. Immediately after a stress load, aged female mice exhibited acute hypophagia and a rise in plasma corticosterone levels. The administration of a serotonin 2C receptor (5-HT2CR) antagonist suppressed plasma corticosterone but did not affect the reduction in food intake. In contrast, an endogenous ghrelin enhancer, rikkunshito (RKT), significantly inhibited the reduction in food intake. An increase in peripheral acylated ghrelin levels during fasting, which occurs in young mice, was not observed in aged female mice. Moreover, in these mice, significantly increased levels of ghrelin and gastric preproghrelin mRNA expression were observed in the fed status. Moreover, plasma ghrelin levels were elevated by RKT and not by the 5-HT2CR antagonist. In female mice, the hypothalamic non-edited (INI) and partially edited mRNA 5-HT2CR isoforms (VNV, VNI, VSV or VSI) decreased with age, while in male mice, the editing isoform was unchanged by aging or stress. Estrogen receptor α (ERα)-positive cell counts in the arcuate nucleus of young male mice exposed to stress and control aged male mice were increased compared with those in young control mice. In aged male mice exposed to stress, the number of ERα-expressing cells in the paraventricular nucleus were significantly increased compared with those in aged control mice; in female mice, there was no increase in the number of ERα-positive cells. Hypophagia in aged female mice exposed to stress may be independent of 5-HT2CR activation. It seems likely that the mechanisms may be caused by sex dependent, differential regulation in 5-HT2CR mRNA expression, peripheral acylated ghrelin secretion and/or hypothalamic ERα expression.

Inhibitory effect of yokukansan on the decrease in the hippocampal excitatory amino acid transporter EAAT2 in stress-maladaptive mice.

Chronic stress is widely recognized as a risk factor for the development of major depression and anxiety disorders. Recently, we reported that yokukansan (YKS), a traditional Japanese herbal medicine, alleviated emotional abnormality in stress-maladaptive mice. The aim of the present study was to examine the effect of YKS on the expression of excitatory amino acid transporter (EAAT) 1-4 in the prefrontal cortex and hippocampus in stress-maladaptive mice. Mice were chronically exposed to inadaptable stress, i.e. repeated restraint stress for 240 min/day for 14 days. After the final exposure to stress, brains of mice were rapidly removed and the hippocampus and prefrontal cortex were dissected. Expressions of EAAT1-4 and glial fibrillary acidic protein (GFAP), a marker of astrocytes, in the brain tissues were analyzed by western blotting. Western blot analysis revealed that the expression level of EAAT2 was specifically decreased in the hippocampus of stress-maladaptive mice while there were no changes in the level of GFAP, and this change was inhibited by chronic treatment with YKS. In contrast, no changes were observed in the levels of EAAT1, EAAT3 or EAAT4 in stress-maladaptive mice. These results suggest that YKS may protect against the decrease in hippocampal EAAT2 expression induced by stress maladaptation, and this may contribute, at least in part, to the improvement of emotional abnormality.

Therapeutic effects of human amnion-derived mesenchymal stem cell transplantation and conditioned medium enema in rats with trinitrobenzene sulfonic acid-induced colitis.

Cell therapy with mesenchymal stem cells (MSCs) is expected to provide a new strategy for the treatment of inflammatory bowel disease (IBD). Large amounts of MSCs can be obtained from human amnion. Therefore, we investigated the effect of transplantation of human amnion-derived MSCs (hAMSCs) or enema of conditioned medium (CM) from hAMSCs into rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. In the first experiment, 10-week-old male Sprague-Dawley rats were intravenously injected with hAMSCs (1 × 106 cells) 3 h after rectal administration of TNBS (45 mg/kg). In the second experiment, rats with TNBS-induced colitis received CM by enema into the colon for 3 days. Colitis was investigated by endoscopy, histology, immunohistochemistry, and by measuring mRNA expression of inflammatory mediators. Administration of hAMSCs or CM enema significantly improved the endoscopic score. In addition, these two interventions resulted in significantly decreased infiltration of neutrophils and monocytes/macrophages and decreased expression levels of TNF-α, CXCL1, and CCL2. In conclusion, transplantation of hAMSCs and CM enema provided significant improvement in rats with TNBS-induced colitis. CM from hAMSCs and hAMSCs may be new strategies for the treatment of IBD.

Yokukansan enhances the proliferation of B65 neuroblastoma.

Yokukansan, a traditional Japanese herbal medicine, has been considered to be a novel alternative treatment for several neurological diseases such as neurodegenerative disorders, as well as neurosis, insomnia, and behavioral and psychological symptoms in Alzheimer's disease. Moreover, it has been shown that yokukansan has antidepressant-like and pain-relieving effects in animal models. Recently, several studies have shown that yokukansan has a neuroprotective effect. In this study, we focused on whether or no yokukansan influences cell proliferation related to cell-cycle progression by using B65 neuroblastoma cells derived from monoaminergic neurons. Under treatment with yokukansan, the proliferation rate of B65 neuroblastoma cells significantly increased in a dose-dependent manner. In particular, a proliferative effect was observed after treatment with yokukansan for 48 h and 72 h. Moreover, among seven medicinal herbs that comprise yokukansan, both Bupleuri Radix and Glycyrrhize Radix also enhanced the proliferation of B65 neuroblastoma cells. We assessed the effect of yokukansan on p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in B65 neuroblastoma cells, and found that yokukansan increased p44/42 MAPK phosphorylation after treatment for 48 h. In contrast, neither Bupleuri Radix nor Glycyrrhize Radix altered the level of p44/42 MAPK phosphorylation, although they did increase cell proliferation. Our findings suggest that yokukansan has a cell-proliferative due to both Bupleuri Radix and Glycyrrhize Radix, and this is unrelated to the p44/42 MAPK signaling cascade.

Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells.

Zanthoxylum fruit, obtained from the Japanese pepper plant (Zanthoxylum piperitum De Candolle), and its extract (Zanthoxylum fruit extract, ZFE) have multiple physiological activities (e.g., antiviral activity). However, the potential anticancer activity of ZFE has not been fully examined. In this study, we investigated the ability of ZFE to induce autophagic cell death (ACD). ZFE caused remarkable autophagy-like cytoplasmic vacuolization, inhibited cell proliferation, and ultimately induced cell death in the human cancer cell lines DLD-1, HepG2, and Caco-2, but not in A549, MCF-7, or WiDr cells. ZFE increased the level of LC3-II protein, a marker of autophagy. Knockdown of ATG5 using siRNA inhibited ZFE-induced cytoplasmic vacuolization and cell death. Moreover, in cancer cells that could be induced to undergo cell death by ZFE, the extract increased the phosphorylation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 attenuated both vacuolization and cell death. Based on morphology and expression of marker proteins, ZFE-induced cell death was neither apoptosis nor necrosis. Normal intestinal cells were not affected by ZFE. Taken together, our findings show that ZFE induces JNK-dependent ACD, which appears to be the main mechanism underlying its anticancer activity, suggesting a promising starting point for anticancer drug development.

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia.

Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities.

Influence of Aging and Gender Differences on Feeding Behavior and Ghrelin-Related Factors during Social Isolation in Mice.

Psychological stress due to social isolation is known to cause abnormal feeding behaviors, but the influences of gender and aging on subchronic stress-induced changes in feeding behaviors are unknown. Thus, we examined the changes in body weight, food intake, and orexigenic ghrelin-related factors during 2 weeks of isolation stress in young and aged mice. Food intake increased significantly in young mice in the isolation group compared with the group-housed control throughout the experimental period. This isolation-induced increase in food intake was not observed in aged mice. In young mice, there were no significant differences in body weight between the isolated group and group-housed control up to 2 weeks. However, aged male mice exhibited significant weight loss at 2 weeks and a similar tendency was observed in aged female mice. Young male mice, but not female mice, had significantly increased (2.2-fold) plasma acylated ghrelin levels after 1 week of isolation compared with the group-housed control. A significant but lower increase (1.3-fold) was also observed in aged male mice. Hypothalamic preproghrelin gene expression decreased significantly with isolation in young male mice, whereas it increased significantly in female mice. The expression levels of NPY and AGRP in the hypothalamus, which are transmitted by elevated peripheral ghrelin signals, increased significantly in isolated young male mice, whereas the AGRP expression levels decreased significantly in young female mice. Isolation caused no significant differences in the expression levels of these genes in aged mice. In isolation, young female mice exhibited markedly increased dark- and light-phase locomotor activities compared with male mice, whereas male and female aged mice exhibited no obvious increases in activity immediately after the dark phase started. We conclude that the gender-specific homeostatic regulatory mechanisms required to maintain body weight operated during subchronic psychological stress in young mice but not in aged mice.

A New Strategy Using Rikkunshito to Treat Anorexia and Gastrointestinal Dysfunction.

Because the clinical condition of gastrointestinal dysfunction, including functional dyspepsia, involves tangled combinations of pathologies, there are some cases of insufficient curative efficacy. Thus, traditional herbal medicines (Kampo medicines) uniquely developed in Japan are thought to contribute to medical treatment for upper gastrointestinal symptoms. Rikkunshito is a Kampo medicine often used to treat dyspeptic symptoms. Over the past few years, several studies have investigated the efficacy of rikkunshito for dysmotility, for example, upper abdominal complaints, in animals and humans. Rikkunshito ameliorated the decrease in gastric motility and anorexia in cisplatin-treated rats, stress-loaded mice, and selective serotonin reuptake inhibitor-treated rats by enhancing plasma ghrelin levels via serotonin2B/2C receptor antagonism. In addition, rikkunshito ameliorated the decrease in food intake in aged mice and stress-loaded decreased gastric motility via enhanced ghrelin receptor signaling. Several clinical studies revealed that rikkunshito was effective in ameliorating upper gastrointestinal symptoms, including dyspepsia, epigastric pain, and postprandial fullness. In this review, we discuss these studies and propose additional evidence-based research that may promote the clinical use of Kampo medicines, particularly rikkunshito, for treating anorexia and gastrointestinal dysfunction.

Hangeshashinto improves the completion rate of chemoradiotherapy and the nutritional status in patients with head and neck cancer.

PURPOSE: Severe oral and pharyngeal mucositis is one of the most critical toxicities known to lead to the discontinuation of chemoradiotherapy (CRT) for head and neck cancer (HNC). Hangeshashinto (TJ-14) is a Kampo medicine that relieves chemotherapy-induced oral mucositis. We investigated the effect of TJ-14 on mucositis, nutritional status, and the completion rate of CRT. METHODS: The study group comprised patients with advanced HNC who were treated with concomitant weekly cisplatin and 70 Gy of radiotherapy. The primary endpoint was the completion rate of chemotherapy, and the secondary endpoints were the grade of mucositis and the nutritional status. RESULTS: A total of 57 patients were included in this study. The completion rate of CRT among patients who were treated with TJ-14 was 91.4%. There was a significant difference in the completion rate of CRT between the groups treated with and without TJ-14 (p = 0.0452). The reduction in body weight was significantly improved from 10.89 to 5.89% with TJ-14 administration (p = 0.003), and the reduction in serum albumin was also significantly decreased from 17.37 to 8.73%. (p = 0.024). CONCLUSION: This therapy allowed a high completion rate of CRT as well as significant benefits in terms of nutritional status. We plan to carry out a further large-scale study of TJ-14.

Herbal medicines for the treatment of cancer chemotherapy-induced side effects.

Accumulating evidence suggests that Japanese herbal medicines, called Kampo, have beneficial effects on cancer chemotherapy-induced side effects. Rikkunshito ameliorates cisplatin-induced anorexia through an antagonistic effect on the 5-HT receptors and by increasing the serum ghrelin levels. Hangeshashinto improves irinotecan-induced diarrhea and chemotherapy-induced mucositis by inhibiting the activity of ß-glucuronidase as well as the synthesis of prostaglandin E2. Goshajinkigan prevents oxaliplatin-induced neurotoxicity, possibly through suppressing functional alterations of the transient receptor potential channels. In this review, we will summarize the currently available literature regarding the clinical efficacy and potential mechanisms of Kampo medicines in the treatment of cancer chemotherapy-induced side effects.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BACKGROUND: The incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. METHODS: Two hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. RESULTS: There were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. CONCLUSIONS: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals). TRIAL REGISTRATION: (UMIN000005880).

Neuroprotective effect of yokukansan against cytotoxicity induced by corticosterone on mouse hippocampal neurons.

Yokukansan, a traditional Japanese herbal medicine, has been used for the management of neurodegenerative disorders and for the treatment of neurosis, insomnia, and behavioral and psychological symptoms of dementia. Recently, several studies have shown that yokukansan has a neuroprotective effect. The aim of this study was to examine the neuroprotective effect of yokukansan on hippocampal neurons from embryonic mouse brain against the effects of corticosterone, which is considered to be a stress hormone and to be cytotoxic toward neurons. The cell survival rates were measured by the WST-8 assay and LDH assay. Twenty-four hours after treatment with corticosterone, cell numbers were significantly decreased compared with the control or treatment with vehicle in a dose-dependent manner. When cells were treated with 30 µM corticosterone, the decrease in the number of cells was significantly recovered by treatment with yokukansan (100-1,000 µg/ml) in a dose-dependent manner. However, yokukansan did not suppress the decrease in cell numbers that was induced by treatment with 100 µM corticosterone. In the LDH assay, treatment with yokukansan at a high concentration (500-1,000 µg/ml) suppressed the LDH concentration induced by treatment with both 30 µM and 100 µM corticosterone compared to treatment with corticosterone alone, respectively. These results suggest that yokukansan protects against the cytotoxic effect of a low concentration of corticosterone on hippocampal neurons.

Pumpkin Seed Oil Extracted From Cucurbita maxima Improves Urinary Disorder in Human Overactive Bladder.

The pumpkin seed oil obtained from Cucurbita pepo has been shown to be useful for the treatment of nocturia in patients with urinal disorders in several western countries. In this study, we evaluated the effect of the pumpkin seed oil from Cucurbita maxima on urinary dysfunction in human overactive bladder (OAB). Forty-five subjects were enrolled in this study. An extract of pumpkin seed oil from C. maxima (10 g of oil/day) was orally administrated for 12 weeks. After 6 and 12 weeks, urinary function was evaluated using Overactive Bladder Symptom Score (OABSS). Pumpkin seed oil from C. maxima significantly reduced the degree of OABSS in the subjects. The results from our study suggest that pumpkin seed oil extracts from C. maxima as well as from C. pepo are effective for urinary disorders such as OAB in humans.